# US 10,865,202 B2 · Indole derivatives as estrogen receptor degraders

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- Number: US 10,865,202 B2
- Document ID: US10865202B2
- Status: Granted
- Kind: B2
- Application number: 16/376,225
- Filed: 2019-04-05
- Published: 2019-08-01
- Granted: 2020-12-15
- Earliest claimed: 2016-09-15
- Assignees: Arvinas Operations, Inc.
- Applicants: Arvinas Operations, Inc.
- Inventors: Andrew P. Crew; Yimin Qian; Hanqing Dong; Jing Wang
- Web page: https://patentgrep.com/patent/US10865202B2

## CPC

- C07D 417/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- C07K 5/06052: {Val-amino acid}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

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.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 is H, —OH, —OC1-3alkyl, or a halogen;
R2 is —OH or —OC1-3alkyl;
R3 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;
R4 is a straight chain or branched C1-6alkyl, or C3-6 cycloalkyl;
R5 is H, or an optionally substituted lower alkyl,
R6 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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein at least one of:
R1 is H, OH, F, Br, Cl, or OCH3;
R2 is OH or OCH3;
R3 is H or an optionally substituted C1-C4 alkyl;
R4 is iso-propyl or tert-butyl;
R5 is H, an optionally substituted C1-6alkyl, hydroxylaklyl, or alkylamino substituted lower alkyl;
R6 is 4-methylthiazol-5-yl, oxazol-5-yl, or 4-methyloxazole-5-yl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R6 is 4-methylthiazol-5-yl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R6 is chloro or —CN.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

The compound of claim 1, wherein at least one of:
R1 is OH;
R2 is OH;
R3 is an optionally substituted methyl or an optionally substituted ethyl;
R4 is tert-butyl;
R5 is methyl, ethyl, CH2F, or CH2NHCH3; or
a combination thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is methyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R5 is H or a methyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein q is 1 or more.

### Claim 10 (depends on 9)

The compound of claim 9, wherein each -(A)-is selected independently from the group consisting of a bond, CRL1RL2, O, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NR4, CO, CRL1═CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═NCN)NRL4, NRL3C(═NCN), NRL3C(═CNO2)NRL4, C3-11 cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C3-11heterocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups, where RL1 or RL2, each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moiety which can be further substituted with 0-4 RL5 groups,
wherein RL1, RL2, RL3, RL4, and RL5 are, each independently, H, halo, C1-8alkyl, OC1-8alkyl, SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(O)(OC1-8alkyl)(C1-8alkyl), P(O)(OC1-8alkyl)2, CC—C1-8alkyl, CCH, CH═CH(C1-8alkyl), C(C1-8alkyl)═CH(C1-8alkyl), C(C1-8alkyl)═C(C1-8 alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8 alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8 alkyl)CONH(C1-8alkyl), N(C1-8 alkyl)CON(C1-8 alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl) SO2N(C1-8alkyl)2, NHSO2NH(C1-8alkyl), NHSO2N(C1-8alkyl)2, NH SO2NH2.

### Claim 11 (depends on 1)

The compound of claim 1, wherein L is selected from the group consisting of:

### Claim 12 (depends on 1)

The compound of claim 1, wherein L is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units.

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 14)

(The composition of claim 14, further comprising at least one additional bioactive or therapeutic agent.

### Claim 16 (depends on 15)

W The composition of claim 15, wherein the additional bioactive or therapeutic agent is an anti-neoplastic agent.

### Claim 17 (depends on 16)

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.

### Claim 18 (depends on 1)

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.

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 17)

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.