Compounds and compositions for treating conditions associated with NLRP activity
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured. The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
1. A compound of Formula AA
wherein
m=0, 1, or 2;
n=0, 1, or 2;
o=1 or 2;
p=0, 1, 2, or 3;
wherein
A is:
thiophenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
phenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
thiazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
oxazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
pyridyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
pyrazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
B is phenyl, pyridyl, or pyrimidinyl;
wherein
at least one R 6 is ortho to the bond connecting the B ring to the C(R 4 R 5 ) group of Formula AA;
R 1 and R 2 are each independently selected from C 1 -C 6 alkyl, halo, CN, COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, C 6 -C 10 aryl, S(O)C 1 -C 6 alkyl, 5- to 10-membered heteroaryl, and 3- to 7-membered heterocycloalkyl,
wherein the C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and oxo;
R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CN, NO 2 COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CONR 8 R 9 , and 3- to 7-membered heterocycloalkyl,
wherein the C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo, or at least one pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C 5 -C 8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo;
each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;
R 10 is C 1 -C 6 alkyl;
each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, (C═NR 13 )NR 11 R 12 , S(O 2 )C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , COR 13 , CO 2 R 13 and CONR 11 R 12 ; wherein the C 1 -C 6 alkyl is optionally substituted with one or more hydroxy, halo, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;
R 13 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl;
each of R 11 and R 12 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;
R 3 is hydrogen,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein A is any one of:
thiophenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
oxazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2R 2 ;
thiazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2R 2 ; or
phenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2R 2 .
3. The compound of claim 1 , wherein m=1 and n=0; optionally wherein the substituted ring A is any one of:
4. The compound of claim 1 , wherein m=1 and n=1; optionally wherein the substituted ring A is any one of:
5. The compound of claim 1 , wherein m=2 and n=1; optionally wherein the substituted ring A is any one of:
6. The compound of claim 1 , wherein R 1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH 3 ; COCH 2 CH 3 ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .
7. The compound of claim 1 , wherein R 2 is selected from the group consisting of fluoro; chloro; cyano; methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH 3 ; COPh; 2-methoxy-2-propyl; (dimethylamino)methyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .
8. The compound of claim 1 , wherein B is phenyl substituted with 1 or 2 R 6 and optionally substituted with 1, 2, or 3 R 7 ; optionally wherein the substituted ring B is any one of
9. The compound of claim 1 , wherein B is pyridyl; o=1 or 2; and p=0, 1, or 2; optionally wherein the substituted ring B is
10. The compound of claim 1 , wherein each of R 4 and R 5 is hydrogen.
11. The compound, selected from the group consisting of the compounds below:
Compound
Structure
101
101a
101b
102
103
104
104a
104b
105
106
106a
106b
107
107a
107b
108
109
110
110a
110b
111
112
112a
112b
113
114
114a
114b
115
116
116a
116b
117
117a
117b
118
119
120
121
122
123
123a
123b
124
125
126
126a
126b
127
128
129
129a
129b
130
130a
130b
131
131a
131b
132
132a
132b
133
133a
133b
134
135
136
137
138
138a
138b
139
139a
139b
140
140a
140b
141
141a
141b
142
143
144
144a
144b
145
145a
145b
146
147
147a
147b
148
148a
148b
149a
149b
150
150a
150b
151
152
152a
152b
153
154
155
158
159
160
161
162
163
164
165
168
169
170
171
172
173
176
177
178
180
181
182
183
184
185
186
189
190
191
192
194
195
196
197
197a
197b
198
198a
198b
Compound
Structure
104a
104b
106a
106b
107a
107b
110a
110b
126a
126b
130a
130b
146
147
148
149a
149b
150
151
152
152a
152b
110a′
110b′
201
201b
201a
202
202a
203
203b
204
204b
204a
205
206
207
208
209
210
210b
211
213
213a
213b
215
216
216a
216b
217
217a
218
218a
219
220
220a
221
221a
221b
222
224
225
225a
226
226a
226b
227
227a
227b
228
228a
228b
229
229a
229b
230
231
232
233
234
234a
234b
236
236a
236b
237
238
238a
238b
239
239a
239b
241
242
242a
242b
243
243a
243b
244ba
245
247
248
249
249a
249b
250
251
251a
251b
252
253
254
255
256
256a
256b
257
258
258a
258b
261a
261b
262b
263
263a
263b
264
264a
and a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (S) stereochemistry, or (R) stereochemistry.
13. A pharmaceutical composition comprising a compound or salt as claimed in claim 1 and one or more pharmaceutically acceptable excipients.