Bis-octahydrophenanthrene carboxamide derivatives and protein conjugates thereof for use as LXR agonists

Patent metadata

Field	Value
Publication number	US-12209180-B2
Application number	US-201917295420-A
Country	US
Kind code	B2
Filing date	Nov 19, 2019
Priority date	Nov 20, 2018
Publication date	Jan 28, 2025
Grant date	Jan 28, 2025

Abstract

Provided herein are compounds or payloads, linker-payloads, antibody-drug conjugates, and compositions, and methods for the treatment of diseases and disorders associated with the liver X receptor, including bis-octahydrophenanthrene carboxamides and protein (e.g., antibody) drug conjugates thereof.

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein
each of Q 1 and Q 2 is independently —CH 2 —, —C(O)—, —C(H)(OH)—, —C(OH) 2 —, —SO 2 —, —SO—, —PO(OR 3 )—, —PO(NR 3 NR 4 )—, —NR 3 —, or —N═;
W is —CH 2 —, —N(H)—, or —O—;
R 1 is —N(H)R 4 or —N(R 5 ) 2 ;
R 2 is —N(H)R 4 ;
each R 4 is, independently in each instance, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety comprising aliphatic polyesters, alkyl, substituted alkyl, acyl, or substituted acyl;
R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and when substituted includes at least one-OH and —CH 2 OH, or at least one primary or secondary nitrogen;
each R 6 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, —CN, O-glucose, O-amino acid residue, or O-PEG n1 , wherein each n is an integer from zero to fourteen, and each n1 is an integer from one to twelve; and
each R 3 is independently hydrogen, alkyl, or aryl.

2. The compound of claim 1 according to Formula I

or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein
each of Q 1 and Q 2 is independently —CH 2 —, —C(O)—, —C(H)(OH)—, —C(OH) 2 —, —SO 2 —, —SO—, —PO(OR 3 )—, —PO(NR 3 NR 4 )—, —NR 3 —, or —N═;
W is —CH 2 —, —N(H)—, or —O—;
R 1 is —N(H)R 4 or —N(R 5 ) 2 ;
R 2 is —N(H)R 4 ;
each R 4 is, independently in each instance, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety comprising aliphatic polyesters, or alkyl;
R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and when substituted includes at least one-OH and —CH 2 OH, or at least one primary or secondary nitrogen;
each R 6 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, —CN, O-glucose, O-amino acid residue, or O-PEG n1 , wherein each n is an integer from zero to fourteen, and each n1 is an integer from one to twelve; and

each R 3 is independently hydrogen, alkyl, or aryl.

3. The compound of claim 1 according to Formula I

or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein each of Q 1 and Q 2 is independently —CH 2 —, —C(O)—, —C(H)(OH)—, or —C(OH) 2 —;
W is —CH 2 , —N(H)—, or —O—;
R 1 is —N(H)R 4 or —N(R 5 ) 2 ;
R 2 is —N(H)R 4 ;
each R 4 is, independently in each instance, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety comprising aliphatic polyesters, or alkyl;
R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and when substituted includes at least one-OH and —CH 2 OH, or at least one primary or secondary nitrogen; and
each R 6 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, —CN, O-glucose, O-amino acid residue, or O-PEG n1 , wherein each n is an integer from zero to fourteen, and each n1 is an integer from one to twelve.

4. The compound of claim 3 according to Formula II

or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof.

5. The compound of claim 1 wherein Q 1 is —CH 2 — and Q 2 is —C(O)—.

6. The compound of claim 1 wherein Q 1 is —C(H)(OH)— and Q 2 is —C(O)—.

7. The compound of claim 1 wherein Q 1 is —C(O)— and Q 2 is —C(O)—.

8. The compound of claim 1 wherein Q 1 is —C(O)— and Q 2 is —CH 2 —.

9. The compound of claim 1 wherein Q 1 is —C(O)— and Q 2 is —C(H)(OH)—.

10. The compound of claim 1 wherein W is —CH 2 —.

11. The compound of claim 1 wherein W is —O—.

12. The compound of claim 1 wherein W is —NH—.

13. The compound of claim 1 according to Formula III

or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof.

14. The compound of claim 1 wherein R 1 is —N(H)R 4 .

15. The compound of claim 1 wherein R 1 is —N(R 5 ) 2 .

16. The compound of claim 14 , wherein R 1 is —NH 2 ; and
each R 4 is, independently in each instance, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety comprising aliphatic polyesters, or alkyl.

17. The compound of claim 16 , wherein each R 4 is, independently in each instance, an amino acid residue; and
the amino acid residue is selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, arginine, histidine, lysine, aspartic acid, and glutamic acid.

18. The compound of claim 17 selected from the group consisting of

a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 16 , wherein each R 4 is, independently in each instance, a peptide residue, wherein the peptide residue comprises an amino acid selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, arginine, histidine, lysine, aspartic acid, and glutamic acid, and the residues thereof.

20. The compound of claim 19 wherein the compound is

or
a pharmaceutically acceptable salt or solvate thereof.

21. The compound of claim 14 , wherein the compound is

or
a pharmaceutically acceptable salt or solvate thereof.

22. The compound of claim 1 , wherein R 1 and R 2 are —N(H)R 4 .

23. The compound of claim 22 , wherein each R 4 is, independently in each instance, an amino acid residue; wherein
the amino acid is selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, arginine, histidine, lysine, aspartic acid, and glutamic acid, and the residues thereof.

24. The compound of claim 23 , where the compound is selected from the group consisting of

Assignees

• Regeneron Pharma

Inventors

• Gromada Jesper A
• Gusarova Viktoria
• Han Amy
• Haxhinasto Sokol
• Murphy Andrew J
• Olson William
• Sleeman Matthew

Classifications

• C07D225/08

  condensed with two six-membered rings · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• C07C2603/22

  containing only six-membered rings · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07D249/16

  condensed with carbocyclic rings or ring systems · CPC title