US2021253592A1PendingUtilityA1
Selective estrogen receptor degraders and uses thereof
Est. expiryFeb 5, 2036(~9.6 yrs left)· nominal 20-yr term from priority
C07D 491/048C07D 471/04A61P 35/00C07D 495/04C07D 471/14A61K 31/473A61K 31/4365A61K 31/437C07D 495/14A61K 31/4745A61P 5/32A61K 31/436A61K 31/4375C07D 491/147A61K 31/4355
69
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Claims
Abstract
The present disclosure provides compounds of Formula (I) and Formula (II). The compounds described herein may be useful in treating proliferative diseases (e.g., cancer). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
A is —CR A ═ or —N═, as valency permits;
W is —NH—, —O—, or —S—;
a is 1, 2, or 3;
n is 1, 2, 3, or 4;
each instance of R 1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, —OR A , or —CN;
R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl;
R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR A , or —N(R B ) 2 ;
R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR A or —N(R B ) 2 ;
R 5 is hydrogen, halogen, substituted or unsubstituted alkyl;
R 6 is hydrogen, halogen, substituted or unsubstituted alkyl;
R 7 is hydrogen, halogen, substituted or unsubstituted alkyl, —OR A or —N(R B ) 2 ;
R 7 is hydrogen or substituted or unsubstituted alkyl, or oxygen protecting group; and
R B is hydrogen or substituted or unsubstituted alkyl, nitrogen protecting group, or optionally two R B are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.
2 . The compound of claim 1 , wherein the compound is of the formula (IA):
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, wherein A is —CH═ or —N═.
4 . The compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, wherein W is —NH—, —O—, or —S—.
5 . The compound of any one of claims 1 - 4 , or a pharmaceutically acceptable salt thereof, wherein a is 1.
6 . The compound of any one of claims 1 - 5 , or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4.
7 . The compound of any one of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is hydrogen.
8 . The compound of any one of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is halogen, which is fluorine or chlorine.
9 . The compound of any one of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is —OR A , in which R A is hydrogen or substituted or unsubstituted C 1-6 alkyl.
10 . The compound of any one of claims 1 - 6 or 9 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is —OMe, —CF 3 , or —CN.
11 . The compound of any one of claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted or unsubstituted C 1-6 alkyl.
12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl or —CF 3 .
13 . The compound of any one of claims 1 - 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is fluorine.
14 . The compound of any one of claims 1 - 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted or unsubstituted C 1-6 alkyl.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.
16 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt thereof, wherein R 4 is fluorine.
17 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted or unsubstituted C 1-6 alkyl.
18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
19 . The compound of any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, wherein R 5 is chlorine.
20 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt thereof, wherein R 6 is chlorine.
21 . The compound of any one of claims 1 - 20 , or a pharmaceutically acceptable salt thereof, wherein R 7 is substituted or unsubstituted C 1-6 alkyl.
22 . The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —CH 2 R a , in which R a is halogen.
23 . The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —CH 2 F.
24 . The compound of any one of claims 1 - 23 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
25 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
A is —CR A ═ or —N═, as valency permits;
W is —NH—, —O—, or —S—;
a is 1, 2, or 3;
each instance of R 1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, —OR A , or —CN;
R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl;
R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR A or —N(R B ) 2 ;
R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR A or —N(R B ) 2 , or R 3 and R 4 are taken together with the intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;
R 8 is hydrogen, halogen, or methyl;
R A1 is substituted or unsubstituted alkyl, chlorine, or fluorine;
R A2 is substituted or unsubstituted alkyl, chlorine, or fluorine, wherein: (i) either R A1 or R A2 is chlorine; or (ii) one of R A1 and R A2 is fluorine, and the other one of R A1 and R A2 is selected from the group consisting of substituted or unsubstituted alkyl, chlorine, and fluorine;
R A is hydrogen or substituted or unsubstituted alkyl, or oxygen protecting group; and
R B is hydrogen or substituted or unsubstituted alkyl, nitrogen protecting group, or optionally two R B are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.
26 . The compound of claim 25 , wherein the compound is of the Formula (IIA):
or a pharmaceutically acceptable salt thereof.
27 . The compound of any one of claims 25 or 26 , or a pharmaceutically acceptable salt thereof, wherein A is —CH═ or —N═.
28 . The compound of any one of claims 25 - 27 , or a pharmaceutically acceptable salt thereof, wherein W is —NH—, —O—, or —S—.
29 . The compound of any one of claims 25 - 28 , or a pharmaceutically acceptable salt thereof, wherein a is 1.
30 . The compound of any one of claims 25 - 29 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is hydrogen.
31 . The compound of any one of claims 25 - 29 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is halogen, which is fluorine or chlorine.
32 . The compound of any one of claims 25 - 29 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is —OR A , in which R A is hydrogen or substituted or unsubstituted C 1-6 alkyl.
33 . The compound of any one of claims 25 - 29 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 1 is —OH, —OMe, or substituted or unsubstituted C 1-6 alkyl.
34 . The compound of any one of claims 25 - 33 , or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted or unsubstituted C 1-6 alkyl.
35 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl, ethyl, or —CF 3 .
36 . The compound of any one of claims 25 - 35 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 3 , R 4 , R 8 , is independently selected from the group consisting of hydrogen, fluorine, and substituted or unsubstituted C 1 -C 6 alkyl.
37 . The compound of any one of claims 25 - 36 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together with the intervening atom(s) to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl.
38 . The compound of claim 37 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together with the intervening atom(s) to form substituted or unsubstituted cyclopropyl.
39 . The compound of any one of claims 25 - 38 , or a pharmaceutically acceptable salt thereof, wherein at least one of R A1 and R A2 is chlorine.
40 . The compound of claim 39 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
41 . The compound of any one of claims 25 - 38 , or a pharmaceutically acceptable salt thereof, wherein R A1 is fluorine, and R A2 is substituted or unsubstituted C 1 -C 6 alkyl or chlorine.
42 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein R A1 is fluorine and R A2 is methyl.
43 . The compound of any one of claims 25 - 38 , or a pharmaceutically acceptable salt thereof, wherein R A1 is fluorine and R A2 is fluorine.
44 . The compound of any one of claims 25 - 39 , or a pharmaceutically acceptable salt thereof, wherein R A1 is chlorine and R A2 is chlorine.
45 . The compound of claim 42 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
46 . The compound of any one of claims 25 - 45 , or a pharmaceutically acceptable salt thereof, wherein when both R A1 and R A2 are fluorine, the compound further satisfies at least one of the following conditions:
W is O or S; at least one of R 1 is not hydrogen; R 2 is not hydrogen or methyl; A is —N═; R 3 and R 4 are taken together with the intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; or at least two of R 3 , R 4 , and R 8 are each independently halogen.
47 . The corn und of claim 46 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
48 . A pharmaceutical composition comprising a compound of any one of claims 1 - 47 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
49 . A method of treating a proliferative disease, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 48 .
50 . The method of claim 49 , wherein the proliferative disease is cancer.
51 . The method of claim 50 , wherein the cancer is breast cancer or a gynecological disease or cancer.
52 . The method of claim 51 , wherein the cancer is ER+ breast cancer or gynecological disease or cancer associated with ER.
53 . A kit for use in treating a proliferative disease, comprising:
a compound of any one of claims 1 - 47 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48 ; and instructions for using the compound or pharmaceutical composition.Cited by (0)
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