Substituted pyridines that are JNK inhibitors
View Patent ↗Disclosed are compounds of the formula (I) wherein X is N or CH, and Y is N or CR 5 . Also disclosed are methods of treating JNK and ERK mediated diseases using the compounds of formula 1.0.
1. A compound of the formula:
or pharmaceutically acceptable salts or esters thereof, wherein
X is N;
Y is CR 5 wherein R 5 is H;
R 1A is H;
R 2A is H;
R 3 is —C(O)NR 8 R 9 ;
R 4 is —C(O)NR 6 R 7 ;
R 6 is H;
R 7 is alkyl;
R 8 is H;
R 9 is selected from the group consisting of:
(1) heteroarylalkyl-, and
(2) substituted heteroarylalkyl wherein said substituted heteroarylalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of:
(a) —NH 2 ,
(b) —NH(C 1 to C 6 )alkyl,
(c) —N((C 1 to C 6 )alkyl) 2 wherein each alkyl is independently selected,
(d) alkyl,
(e) halo,
(f) aryl,
(g) substituted aryl wherein said substituted aryl is substituted with 1 to 3 substituents independently selected from the group consisting of: (i) —SO 2 R 20 , (ii) —OR 21 , (iii) -halo, (iv) —CN, (v) —CF 3 , (vi) aminoalkyl-, (vii) —S(O)R 26 , and (viii) alkyl,
(h) heterocycloalkyl,
(i) heteroaryl,
(j) substituted aryl substituted with 1 to 3 substituents independently selected from the group consisting of: alkyl, —CF 3 , F, Cl, and Br,
(k) substituted heteroaryl, substituted with 1 to 3 substituents selected from the group consisting of: (i) alkyl, (ii) halo, (iii) CN, (iv) NH 2 , (v) —NH(C 1 -C 6 alkyl), (vi) —N(C 1 -C 6 alkyl) 2 wherein each alkyl is independently selected, (vii) —CF 3 , (viii) substituted aryl wherein said substituted aryl is substituted with 1 to 3 substitutents independently selected from the group consisting of: —S(O) 2 R 42 and —CN, and (ix) —C(O)NR 44 R 46 ,
(l) alkylamino-,
(m) heterocycloalkyl-alkyl-amino-,
(n) alkylaminoalkylamino-,
(o) —NHC(O)OR 30 , and
(p) —NHC(O)NR 32 R 34 ;
R 20 is selected from the group consisting of: (1) alkyl, (2) dialkylamino (wherein each alkyl is independently selected), (3) —NH 2 , (4) alkylamino, (5) heterocycloalkyl, and (6) substituted heterocycloalkyl wherein said substituted heterocycloalkyl is substituted with 1 to 2 substitutents independently selected from the group consisting of: —C(O)OR 40 ;
R 21 is alkyl;
R 26 is alkyl;
R 30 is alkyl;
Each R 32 and R 34 is independently selected from the group consisting of: H, alkyl, aryl, aryl substituted with a —OH group, and heteroaryl;
R 40 is alkyl; and
Each R 44 and R 46 is independently selected from the group consisting of: H and alkyl.
2. The compound of claim 1 wherein R 4 is —C(O)NH(i-propyl).
3. The compound of claim 1 wherein R 9 is heteroarylalkyl.
4. The compound of claim 1 wherein R 9 is heteroarylalkyl and said heteroarylalkyl is pyrazolyl-(C 1 to C 6 )alkyl-.
5. The compound of claim 1 wherein R 9 is substituted heteroarylalkyl.
6. The compound of claim 1 wherein R 9 is substituted heteroarylalkyl and said substituted heteroarylalkyl is substituted pyrazolylalkyl-.
7. The compound of claim 1 wherein R 9 is substituted heteroarylalkyl and said substituted heteroarylalkyl is selected from the group consisting of: phenyl-pyrazolyl-CH 2 —, N-methylpyrazolyl-CH 2 —, N-isopropylpyrazolyl-CH 2 —, N-(m-methylphenyl)-pyrazolyl-CH 2 —, N-(p-methylphenyl)-pyrazolyl-CH 2 —, N-(m-Cl-p-F-phenyl)-pyrazolyl-CH 2 —, N-(m-Cl-phenyl)-pyrazolyl-CH 2 —, N-(m-CN-phenyl)-pyrazolyl-CH 2 —, N-(p-CN-phenyl)-pyrazolyl-CH 2 —, N-(m-SO 2 CH 3 -phenyl)-pyrazolyl-CH 2 —, N-(p-SO 2 CH 3 -phenyl)-pyrazolyl-CH 2 —, N-(m,m-di-Cl-phenyl)pyrazolyl-CH 2 —, N-(m-F-phenyl)-pyrazolyl-CH 2 —, N-(m-CF 3 -phenyl)-pyrazolyl-CH 2 —, N-(quinolinyl)-pyrazolyl-CH 2 —, N-(pyrimidinyl)-pyrazolyl-CH 2 —, N-(methylquinolinyl)-pyrazolyl-CH 2 —, N-(m-CF 3 -p-F-phenyl)pyrazolyl-CH 2 —, N-(quinoxalinyl)-pyrazolyl-CH 2 —, N-(p-(CH 3 )SO-phenyl)-pyrazolyl-CH 2 —, N-(m-Br-m-CN-phenyl)-pyrazolyl-CH 2 —, N-(o-Cl-phenyl)pyrazolyl-CH 2 —, N-(o-CN-phenyl)-pyrazolyl-CH 2 —, N-(pyrimidinyl)-pyrazolyl-CH 2 —, N—(CNpyridyl)-pyrazolyl-CH 2 —, N-(m-F-m-CN-phenyl)-pyrazolyl-CH 2 —, N-(thiazolyl)-pyrazolyl-CH 2 —, N-(aminothiazolo[4,5-b]pyridinyl)-pyrazolyl-CH 2 —, N-(imidazo[1,2-a]pyridinyl)-pyrazolyl-CH 2 —, N-(imidazo[1,2-a]pyrimidinyl)-pyrazolyl-CH 2 —, N-(quinazolinyl)-pyrazolyl-CH 2 —, N-(3H-imidazo[4,5-b]pyridinyl)-pyrazolyl-CH 2 —, N-([1,5]-naphthyridinyl)-pyrazolyl-CH 2 —, N-(1-isopropyl-2-methyl-1H-benzoimidazolyl)-pyrazolyl-CH 2 —, N-(1,2-dimethyl-1H-benzoimidazolyl)-pyrazolyl-CH 2 —, N-(1-methyl-2-CF 3 -1H-benzoimidazolyl)-pyrazolyl-CH 2 —, N-(1-methyl-2-isopropyl-1H-benzoimidazolyl)-pyrazolyl-CH 2 —, N-(1-methyl-2-pyridin-3-yl-1H-benzoimidazolyl)-pyrazolyl-CH 2 —, N—(H 2 NSO 2 phenyl)-pyrazolyl-CH 2 —, N—(CH 3 NHSO 2 phenyl)-pyrazolyl-CH 2 —, N-(piperazinylSO 2 phenyl)-pyrazolyl-CH 2 —, N-(p-(CH 3 ) 2 NSO 2 )-m-Cl-phenyl)-pyrazolyl-CH 2 —
8. The compound of claim 1 wherein R 9 is a substituted heteroarylalkyl and said substituted heteroarylalkyl is substituted pyrazolyl-CH 2 —.
9. The compound of claim 1 wherein R 9 is substituted heteroarylalkyl and said substituted heteroarylalkyl is N-(methylquinolinyl)-pyrazolyl-CH 2 —.
10. The compound of claim 1 wherein R 3 is selected from the group consisting of:
11. The compound of claim 1 wherein R 3 is selected from the group consisting of:
12. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable carrier.
13. A compound selected from the group consisting of:
Compound
102
103
105
116
117
119
127
128
129
130
131
132
133
134
135
136
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
210
213
216
219
222
228
233
234
235
236
241
244
245
246
247
248
309
and
310
14. The compound of claim 13 selected from the group consisting of:
Compound
134
137
142
149
152
222
228
233
246
and
248
15. A compound selected from the group consisting of:
Compound
5
7
8
13
14
47
53
64
65
71
85
86
87
92
93
99
100
101
102
103
104
105
106
107
108
113
114
115
116
117
118
119
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
171
174
175
176
177
178
179
180
181
182
183
184
185
186
200
201
202
203
205
206
207
210
213
216
219
222
228
233
234
235
238
241
244
245
246
247
248
254
255
256
257
258
309
and
310
16. The compound of claim 15 selected from the group consisting of:
Compound
144
149
151
222
228
233
241
246
and
248
17. The compound of claim 16 wherein said compound is compound 144:
18. The compound of claim 16 wherein said compound is compound 149:
19. The compound of claim 16 wherein said compound is compound 151:
20. The compound of claim 16 wherein said compound is compound 222:
21. The compound of claim 16 wherein said compound is compound 228:
22. The compound of claim 16 wherein said compound is compound 233:
23. The compound of claim 16 wherein said compound is compound 241:
24. The compound of claim 16 wherein said compound is compound 246:
25. The compound of claim 16 wherein said compound is compound 248: