Bruton's tyrosine kinase inhibitors
The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.
1. A method for treating cancer, the method comprising:
administering to a human subject an effective amount of a compound having the formula:
or a pharmaceutically acceptable salt thereof;
wherein:
X 1 is —O—, —CR 5 R 6 — or —NR 7 —;
X 2 is ═CR 8 — or ═N—;
p is 0-5;
y is 0, 1, or 2;
z is 0, 1, or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0;
each R 1 is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or
two R 1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
two R 1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by —NR—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, or —S—, or
two R 1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or
two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R 2 , R 3 , R 5 , R 6 , and R 8 is independently R, halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, or —OC(O)N(R) 2 ; or
R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole, pyrazole, imidazole, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R 4 and R 7 is independently R, —CN, —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
Ring A 1 is an optionally substituted phenylene ring;
Ring A 2 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L is a covalent bond or an optionally substituted, bivalent C 1-7 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are independently replaced by -Cy-, —CR 2 —, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—, wherein at least one methylene unit of L is replaced by —N(R)—; and
each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
2. The method of claim 1 , wherein the cancer is leukemia or lymphoma.
3. The method of claim 1 , wherein L is —NH—C(O)—NH—, —NH—C(O)—, —NH—, or —NHSO 2 —.
4. The method of claim 3 , wherein L is —NH—C(O)—NH—or —NH—.
5. The method of claim 1 , wherein L is:
wherein s and t are independently 0, 1, or 2, and the sum of s and t is 0-4.
6. The method of claim 1 , wherein the compound is of formula I-a-i, or I-a-ii:
7. The method of claim 1 , wherein the compound is of formula I-b-i, or I-b-ii:
8. The method of claim 1 , wherein the compound is of formula IV-a:
9. The method of claim 1 , wherein the compound is of formula IV-b:
10. The method of claim 1 , wherein Ring A 2 is optionally substituted phenyl.
11. The method of claim 10 , wherein substituents on Ring A 2 are selected from R, halogen, —CN, —CF 3 , —OH, —OR, —NH 2 , —N(R) 2 , —COOH, —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , and —S(O) 2 N(R) 2 .
12. The method of claim 1 , wherein Ring A 2 is of the formula:
wherein R h is F, Cl, Br, or I.
13. The method of claim 10 , wherein the carbons on Ring A 2 that are ortho to the carbon attached to —L— are each independently substituted with R, halogen, —CN, —CF 3 , —OH, —OR, —NH 2 , —N(R) 2 , or —COOH.
14. The method of claim 10 , wherein a carbon on Ring A 2 that is ortho to the carbon attached to —L— is substituted with an optionally substituted 1-pyrrolidine moiety.
15. The method of claim 1 , wherein Ring A 2 is:
16. The method of claim 15 , wherein Ring A 2 is:
17. The method of claim 1 , wherein the compound is of formula VIII:
18. The method of claim 1 , wherein the compound is selected from
2
16
3
18
4
19
5
22
23
29
25
30
26
32
27
33
28
34
35
40
36
41
37
42
39
44
45
50
46
51
47
52
48
53
43
54
49
61
55
62
56
63
57
64
59
66
60
74
88
75
89
85
90
86
91
87
94
96
102
98
103
99
104
100
105
101
126
121
129
122
123
130
124
131
125
133
134
145
135
146
138
147
140
148
144
149
150
155
151
156
152
157
153
158
154
159
160
165
161
166
162
167
163
168
164
169
170
175
171
176
172
177
173
178
174
179
180
185
181
186
182
187
183
188
184
189
190
195
191
196
192
197
193
198
194
199
200
206
201
207
202
208
203
209
204
210
211
216
212
217
213
218
214
219
215
269
or a pharmaceutically acceptable salt thereof.