Indole derivatives as estrogen receptor degraders
The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.
1. A compound of formula (I):
wherein:
R 1 is H or a halogen;
R 2 is —OH or —OC 1-3 alkyl; and
R 3 is H or an optionally substituted lower alkyl,
or a salt thereof.
2. The compound of claim 1 , wherein:
R 1 is H, F, Br, or Cl;
R 2 is OH or OCH 3 ;
R 3 is H or an optionally substituted C1-C4 alkyl; or
a combination thereof.
3. The compound of claim 2 , wherein R 1 is H, F, or Cl.
4. The compound of claim 2 , wherein R 2 is OH.
5. The compound of claim 2 , wherein when R 3 is methyl.
6. The compound of claim 1 , wherein:
R 1 is halogen;
R 2 is OH;
R 3 is an optionally substituted methyl or an optionally substituted ethyl; or
a combination thereof.
7. The compound of claim 1 , wherein R 3 is methyl.
8. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, diluent, or excipient.
9. A method of making a bifunctional molecule having the chemical structure
the method comprising:
covalently linking the
to a chemical linker (L); and
covalently linking L to a compound of structure:
wherein
R 1 is H, OH, —OC 1-3 alkyl, or a halogen;
R 2 is —OH or —OC 1-3 alkyl;
R 3 is H or an optionally substituted lower alkyl;
L is one or more covalently connected structural units of -(A) q -, wherein A is a chemical moiety, and q is an integer greater than or equal to 1;
R 4 is a straight chain or branched C 1-6 alkyl, or C 3-6 cycloalkyl;
R 5 is H or an optionally substituted lower alkyl; and
R 6 is 4-methylthiazol-5-yl, oxazol-5-yl, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, halogen, or cyano group, or a pharmaceutically acceptable salt.
10. The method of claim 9 , wherein:
R 1 is H, OH, F, Br, Cl, or OCH 3 ;
R 2 is OH or OCH 3 ;
R 3 is H or an optionally substituted C 1-4 alkyl; or
a combination thereof.
11. The method of claim 10 , wherein R 1 is H, OH, F, or Cl.
12. The method of claim 10 , wherein R 2 is OH.
13. The method of claim 10 , wherein R 3 is methyl.
14. The method of claim 9 , wherein:
R 1 is OH or halogen;
R 2 is OH;
R 3 is an optionally substituted methyl or an optionally substituted ethyl; or
a combination thereof.
15. The method of claim 14 , wherein:
R 1 is OH or halogen;
R 2 is OH;
R 3 is an optionally substituted methyl or an optionally substituted ethyl; or
a combination thereof.
16. The method of claim 9 , wherein R 3 is methyl.
17. The method of claim 9 , wherein:
each A is independently selected from CR L1 R L2 , O, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 1-6 R L1 and/or R L2 groups, aryl optionally substituted with 1-6 R L1 and/or R L2 groups, and heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, wherein R L1 or R L2 , each independently can be linked to other A groups to form a cycloalkyl or heterocyclyl moiety that can be further substituted with 1-4 R L5 groups; and
each R L1 , R L2 , R L3 , R L4 and R L5 is independently selected from H, halogen, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 3-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl) 2 , N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 .
18. The method of claim 9 , wherein the L is selected from:
19. The method of claim 9 , wherein the L has a structure selected from:
wherein:
each m, n, o, p, q, and r of the L is independently selected from 0, 1, 2, 3, 4, 5, and 6, when the number is zero, there is no N—O or O—O bond;
R of L is H, methyl, or ethyl;
X of L is H or F.