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, —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 0;
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,
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 thereof.
2. The compound of claim 1 , wherein at least one of:
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 C1-C4 alkyl;
R 4 is iso-propyl or tert-butyl;
R 5 is H, an optionally substituted C1-6alkyl, hydroxylaklyl, or alkylamino substituted lower alkyl;
R 6 is 4-methylthiazol-5-yl, oxazol-5-yl, or 4-methyloxazole-5-yl.
3. The compound of claim 1 , wherein R 6 is 4-methylthiazol-5-yl.
4. The compound of claim 1 , wherein R 6 is chloro or —CN.
5. The compound of claim 1 , wherein when R6 is 4-methylthiazol-5-yl, the methyl group can be substituted with lower alkyl or hydroxyl groups.
6. The compound of claim 1 , wherein at least one of:
R 1 is OH;
R 2 is OH;
R 3 is an optionally substituted methyl or an optionally substituted ethyl;
R 4 is tert-butyl;
R 5 is methyl, ethyl, CH 2 F, or CH 2 NHCH 3 ; or
a combination thereof.
7. The compound of claim 1 , wherein R 3 is methyl.
8. The compound of claim 1 , wherein R 5 is H or a methyl.
9. The compound of claim 1 , wherein q is 1 or more.
10. The compound of claim 9 , wherein each -(A)-is selected independently from the group consisting of a bond, 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 4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 0-6 R L1 and/or R L2 groups, aryl optionally substituted with 0-6 R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moiety which can be further substituted with 0-4 R L5 groups,
wherein R L1 , R L2 , R L3 , R L4 , and R L5 are, each independently, H, halo, 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 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , 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 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(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 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 .
11. The compound of claim 1 , wherein L is selected from the group consisting of:
12. The compound of claim 1 , wherein L is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units.
13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;
(2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide;
(2S,4R)-4-hydroxy-1-[(2S)-2-[1-(4-{[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;
(2S,4R)-4-hydroxy-1-[(2S)-2-[1-(4-{[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide;
(2S,4R)-4-hydroxy-1-[(2S)-2-(1-{4-[(5-hydroxy-3-methyl-2-phenyl-1H-indol-1-yl)methyl]phenyl}-1,4,7,10-tetraoxadodecan-12-amido)-3,3-dimethylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;
(2S,4R)-1-[(2S)-2-{2-[2-({1-[2-(4-{[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl]piperidin-4-yl}oxy)ethoxy]acetamido}-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;
(2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;
(2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-bromophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;
(2S,4R)-4-hydroxy-1-[(2S)-2-{2-[2-({1-[2-(4-{[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl]piperidin-4-yl}oxy)ethoxy]acetamido}-3,3-dimethylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide; and
a pharmaceutically acceptable salt thereof.
14. 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.
15. (The composition of claim 14 , further comprising at least one additional bioactive or therapeutic agent.
16. W The composition of claim 15 , wherein the additional bioactive or therapeutic agent is an anti-neoplastic agent.
17. The composition of claim 16 , wherein the anti-neoplastic agent is selected from: an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone, a hormonal analogue, a signal transduction pathway inhibitor, a non-receptor tyrosine angiogenesis inhibitor, an immunotherapeutic agent, a proapoptotic agent, and a cell cycle signaling inhibitor.
18. A method of treating an estrogen receptor-mediated disease or disorder in a subject comprising the steps of providing a subject in need thereof, and administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the estrogen receptor-mediated disease or disorder is a cancer selected from the group consisting of breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer, and the compound is effective for treating or ameliorating at least one symptom of an estrogen receptor-mediated disease or disorder.
19. A method of making the compound of claim 1
the method comprising:
covalently linking the
to a chemical linker (L); and
covalently linking L to a compound of structure:
wherein 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.
20. The composition of claim 17 , wherein:
the anti-microtubule agent is a diterpenoid or vinca alkaloid;
the alkylating agent is a nitrogen mustard, oxazaphosphorine, alkylsulfonate, nitrosourea, or triazene;
the antibiotic agent is anthracyclin, actinomycin and bleomycin;
the topoisomerase II inhibitor is epipodophyllotoxin; antimetabolite, purine analogue, pyrimidine analogue, or anti-folate compound; or
the topoisomerase I inhibitor is camptothecin.