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 a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C5-C10 monocyclic or bicyclic aryl;
B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C 6 -C 10 monocyclic or bicyclic aryl;
wherein
at least one R 6 is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;
R 1 and R 2 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, NO 2 , COC 1 -C 6 alkyl, CO—C 6 -C 10 aryl; CO(5- to 10-membered heteroaryl); CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC 2 -C 6 alkynyl, NHCOOCC 1 -C 6 alkyl, NH—(C═NR 13 )NR 11 R 12 , CONR 8 R 9 , SF 5 , SC 1 -C 6 alkyl, S(O 2 )C 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl,
wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 and, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC 2 -C 6 alkynyl;
wherein each C 1 -C 6 alkyl substituent and each C 1 -C 6 alkoxy substituent of the R 1 or R 2 C 3 -C 7 cycloalkyl or of the R 1 or R 2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR 8 R 9 , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, and OC 1 -C 6 alkyl;
or at least one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C 4 -C 8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally substituted with hydroxy, halo, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ;
R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, NO 2 , COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , CONR 8 R 9 , SF 5 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and a C 2 -C 6 alkenyl,
wherein R 6 and R 7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 and, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC 2 -C 6 alkynyl, C 6 -C 10 aryloxy, and S(O 2 )C 1 -C 6 alkyl; and wherein the C 1 -C 6 alkyl or C 1 -C 6 alkoxy that R 6 or R 7 is substituted with is optionally substituted with one or more hydroxyl, C 6 -C 10 aryl or NR 8 R 9 , or wherein R 6 or R 7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
wherein the 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, and OC 1 -C 6 alkyl;
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 CVCs carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , CH 2 NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 and, and CONR 8 R 9 ;
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 selected from hydrogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and
wherein the C 1 -C 2 alkylene group is optionally substituted by oxo; and
R 14 is hydrogen, C 1 -C 6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C 6 -C 10 monocyclic or bicyclic aryl, wherein each C 1 -C 6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R 6 ,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein A is a 5- to 6-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .
3. The compound of claim 1 , wherein A is any one of:
furanyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ;
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 2 R 2 ;
thiazolyl 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 .
4. The compound of claim 1 , wherein m=1 and n=0;
and wherein A is any one of:
5. The compound of claim 1 , wherein m=1 and n=1;
and wherein A is any one of:
6. The compound of claim 1 , wherein m=2 and n=1;
and wherein A is any one of:
7. The compound of claim 1 , wherein each of R 1 and R 2 , when present, is I independently selected from the group consisting of C 3 -C 6 alkyl optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkoxy, or NR 8 R 9 ; C 3 -C 7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or NR 8 R 9 wherein the C 1 -C 6 salkoxy or C 1 -C 6 alkyl is further optionally substituted with one to three hydroxy, halo, NR 8 R 9 , or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkyl, or NR 8 R 9 wherein the C 1 -C 6 alkoxy or C 1 -C 6 alkyl is further optionally substituted with one to three hydroxy, halo, NR 8 R 9 , or oxo; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; halo; CN; CO—C 1 -C 6 alkyl; CO—C 6 -C 10 aryl; CO(5- to 10-membered heteroaryl); CO 2 C 1 -C 6 alkyl; CO 2 C 3 -C 8 cycloalkyl; OCOC 1 -C 6 alkyl; OCOC 6 -C 10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C 6 -C 10 aryl; 5- to 10-membered heteroaryl; NH 2 ; NHC 1 -C 6 alkyl; N(C 1 -C 6 alkyl) 2 ; CONR 8 R 9 ; SF 5 ; S(O 2 )NR 11 R 12 ; S(O)C 1 -C 6 alkyl; and S(O 2 )C 1 -C 6 alkyl.
8. 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-hydroxy ethyl; 2-hydroxy ethyl; 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 .
9. The compound of claim 7 , 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-hydroxy ethyl; 2-hydroxy ethyl; 1-hydroxyl-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 .
10. 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 .
11. The compound of claim 10 , wherein B is any one of:
12. The compound of claim 1 , wherein R 3 is hydrogen.
13. A compound selected from the group consisting of the compounds below:
Compound
Structure
101′
101
102
103′
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
163
164
165
166
167
168
169
170
171
172
172a
172b
173
173a
173b
174
175
176
176a
176b
177
177a
177b
178
178a
178b
179
179a
179b
180
180a
180b
181
181a
181b
182
182a
182b
183
183a
183b
184
185
185a
185b
186
186a
186b
187
187a
187b
188
188a
188b
189
189a
189b
190
190a
190b
191
192
192a
192b
193
193a
193b
105a
105b
106a
106b
107a
107b
108a
108b
109a
109b
110a
110b
112a
112b
116a
116b
120a
120b
121a
121b
122a
122b
125a
125b
129a
129b
130a
130b
131a
131b
134a
134b
135a
135b
136a
136b
143a
143b
144a
144b
145a
145b
148a
148b
149a
149b
151a′
151b′
151a
151b
152a
152b
153a
153b
154a
154b
157a
157b
158a
158b
161a
161b
165a
165b
167a
167b
168a
168b
170a
170b
171a
171b
174a
174b
191a
191b
195
195a
195ba
195bb
196
197
198
200
202
202a
202b
205
205a
205b
206
206a
206b
207
207a
207b
208
209
211
212
212a
212b
213
216
220
220a
220b
221
223a
223b
225a
225b
270
113a
113b
137a
137b
138a
138b
139a
139b
159a
159ba
159ab
195e
207bb
207aa
207c
303
303a
303b
306
307
308
308a
308b
309
310
311
312
313
314
315
315b
315a
316
316b
317
317ab
317aa
317bb
317ba
318
318a
318b
319
319ab
319ba
319aa
319bb
320
320a
320b
321
321b
321a
322
323
323ab
323aa
323bb
323ba
324
325
325a
325b
326
326b
326a
327
328b
328a
329
329a
329b
330
330a
330b
331
332
332a
332b
333
333a
333b
334
334ba
334bb
334aa
334ab
334b
334a
335
335b
335a
336
336a
336b
337
337b
338
338a
339
339a
340
340a
340b
341
341b
342
343
343a
343b
344
345
346
347
348
349
350
351
352
352b
352a
353
354
354a
354b
355
356
357
357a
357b
358
359
359a
360ba
360bb
361b
363b
363a
364a
364b
365a
365b
366a
366b
367a
367b
369a
369b
371b
372b
373b
375
375a
375b
376
376a
376b
377
378
379
379a
379b
380
380a
380b
380c
380d
382
382a
382b
383
383a
383b
384a
384b
387a
387b
and pharmaceutically acceptable salts thereof.
14. The compound according to claim 1 , wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (S) stereochemistry.
15. The compound according to claim 1 , wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (R) stereochemistry.
16. A pharmaceutical composition comprising a compound or salt as claimed in claim 1 and one or more pharmaceutically acceptable excipients.
17. A method of treating a subject in need thereof having a disease, disorder or condition in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease disorder or condition, comprising administering to the subject an effective amount of a compound according to claim 1 .
18. The method according to claim 17 , wherein the disease, disorder or condition is a metabolic disorder, selected from the group consisting of Type 2 diabetes, atherosclerosis, obesity and gout;
a disease of the central nervous system, selected from the group consisting of Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis and Parkinson's disease;
lung disease, selected from the group consisting of asthma, COPE) and pulmonary idiopathic fibrosis;
liver disease, selected from the group consisting of NASH syndrome, viral hepatitis and cirrhosis;
pancreatic disease, selected from the group consisting of acute pancreatitis and chronic pancreatitis;
kidney disease, selected from the group consisting of acute kidney injury and chronic kidney injury;
intestinal disease, selected from the group consisting of Crohn's disease and Ulcerative Colitis;
skin disease, that is psoriasis;
musculoskeletal disease, that is scleroderma;
a vessel disorder, that is giant cell arteritis;
a disorder of the bones, selected from the group consisting of osteoarthritis, osteoporosis and osteopetrosis disorders;
eye disease, selected from the group consisting of glaucoma, macular degeneration, and a disease caused by viral infection, optionally wherein the diseases caused by viral infection is HIV or AIDS;
an autoimmune disease, selected from the group consisting of Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis cancer, and aging, optionally wherein the disorder or condition that is cancer is selected from the group consisting of: myelodysplastic syndromes (MDS); non-small ceil lung cancer; acute lymphoblastic leukemia (ALL); Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML); chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis.
19. The method according to claim 17 , further comprising administering a therapeutically effective amount of an anti-TNFα agent to the subject; optionally wherein:
the NLRP3 antagonist is administered to the subject prior to administration of the anti-TNFα agent to the subject; or
wherein the anti-TNFα agent is administered to the subject prior to the administration of the NLRP3 antagonist to the subject; or
wherein the NLRP3 antagonist and the anti-TNFα agent are administered to the subject at substantially the same time.