Pyrazole compounds as modulators of FSHR and uses thereof
The present invention relates to pyrazole compounds, and pharmaceutically acceptable compositions thereof, useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR).
1. A compound of formula I-c,
or a pharmaceutically acceptable salt thereof, wherein:
Z is N;
each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
R 1 is —OR,
R 2 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R 3 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted;
R 5 is C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
R 6 is hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
or R 5 and R 6 , together with the atom to which each is attached, form a 3-8 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-8 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
and
p is 0 or 1.
2. The compound of claim 1 , wherein R 1 is —OR, and R is C 1-6 aliphatic.
3. The compound of claim 1 , wherein R 2 is hydrogen, Br, CN,
4. The compound of claim 3 , wherein R 2 is
5. The compound of claim 3 , wherein R 2 is
6. The compound of claim 1 , wherein R 3 is
7. The compound of claim 1 , wherein R 5 is methyl, t-butyl, —CD 3 ,
8. The compound of claim 7 , wherein R 5 is t-butyl, and R 6 is an optionally substituted C 1-6 aliphatic.
9. The compound of claim 1 , wherein Z is N and the ring formed by Z, R 5 and R 6 is
10. The compound of claim 9 , wherein Z is N and the ring formed by Z, R 5 and R 6 is
11. The compound of claim 1 , wherein R 6 is hydrogen, methyl, t-butyl, or —CD 3 .
12. The compound of claim 1 , of formula I-f:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein R 2 is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted; and R 3 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
14. The compound of claim 1 , of formula I-h:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein R 1 is —OR and R is C 1-6 aliphatic; and R 2 is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted.
16. The compound of claim 1 , selected from Table 1:
TABLE 1
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
17. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
18. A method for treating a FSHR-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 .
19. A method for treating fertility disorders in a subject, comprising the step of administering to said subject a compound of claim 1 or a physiologically acceptable salt thereof.