IP Library › Granted Patent US 12,209,180
Granted Patent B2
US 12,209,180 · App. 17/295,420 · Granted Jan 28, 2025

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

Inventors: Jesper A. Gromada (Concord, MA); Viktoria Gusarova (Pleasantville, NY); Amy Han (Hockessin, DE); Sokol Haxhinasto (Brookfield, CT); Andrew J. Murphy (Croton-on-Hudson, NY); William Olson (Yorktown Heights, NY); Matthew Sleeman (Yorktown Heights, NY)
Assignee: REGENERON PHARMACEUTICALS, INC.
C08L5/16A61K47/6803A61K47/6849A61K47/6883A61K47/6889C07D249/16
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Quick Facts
Patent No.
US 12,209,180
App. No.
17/295,420
Granted
Jan 28, 2025
Kind
B2
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.

Claims (128)

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

or

a pharmaceutically acceptable salts or solvates thereof.

25. The compound of claim 15 , wherein the compound is

or

a pharmaceutically acceptable salt or solvate thereof.

26. The compound of claim 22 , wherein the compound is

or

a pharmaceutically acceptable salt or solvate thereof.

27. A linker-payload comprising the compound of claim 1 bonded to a linker.

28. The linker-payload of claim 27 having a Formulae LPa, LPb, LPc, or LPd

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

L is a linker;

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 , —N(H)R 4 —, —N(H)—, —N(R 5 ) 2 , or —N(R 5 ) 2 —;

R 2 is —N(H)R 4 , —N(H)R 4 —, or —N(H)—;

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, substituted acyl, or -alkylene-;

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 alkylene, 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.

29. An antibody-drug-conjugate comprising the compound of claim 1 bonded to an antibody, or an antigen binding fragment thereof.

30. A compound of Formula A, B, C, or D

or a pharmaceutically acceptable salt, or stereoisomeric form thereof, wherein

L is a linker;

BA is an antibody or antigen binding fragment thereof;

k ranges from about one to about thirty;

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 , —N(H)R 4 —, —N(H)—, —N(R 5 ) 2 , or —N(R 5 ) 2 —;

R 2 is —N(H)R 4 , —N(H)R 4 —, or —N(H);

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, substituted acyl, or —alkylene-;

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 alkylene, 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.

31. The compound of claim 30 , wherein 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, or —alkylene-.

32. The compound of claim 30 , having the Formulae A′, B′, C′, or D′

wherein SP 1 and SP 2 , when present, are spacer groups;

each AA is an amino acid residue; and

p1 is an integer from one to ten.

33. The compound of claim 32 , wherein the compound is selected from the group consisting of

34. The compound of claim 30 , of the Formula (A″)

or

a pharmaceutically acceptable salt, or stereoisomeric form thereof, or a regioisomer thereof, wherein

each SP 1 , SP 2 , and SP 3 is a spacer group, where SP 3 is linked to one AA of (AA) p1 ;

each AA is an amino acid residue;

p1 is an integer from one to ten; and

EG is an enhancement agent.

35. The compound of claim 34 , wherein

the SP 1 spacer is

 wherein

RG′ is a reactive group residue following reaction of a reactive group RG with a binding agent;

is a bond, direct or indirect, to the binding agent; and

b is an integer from one to four;

the (AA) p1 -SP 2 — is —NH-lysine-valine-alanine-, —NH-lysine-valine-citrulline-, or —NH-lysine-valine-citrulline-PABC-;

the SP 3 spacer is

 wherein

RG′ is a reactive group residue following reaction of a reactive group RG with an enhancement agent EG;

is a bond to the enhancement agent; and

is a bond to (AA) p1 .

36. The compound of claim 34 , wherein the compound is selected from the group consisting of

37. The compound of claim 30 , wherein k ranges from about 0.5 to about five.

38. The compound of claim 30 , wherein BA is an antibody, or antigen binding fragment thereof, that binds HER2, PRLR, or MSR1.

39. The compound of claim 30 , wherein BA is an antibody or antigen-binding fragment thereof, and conjugation is through at least one Q295 residue.

40. The compound of claim 30 , wherein BA is an antibody or antigen-binding fragment thereof, and conjugation is through two Q295 residues.

41. The compound of claim 30 , wherein BA is a N297Q antibody or antigen-binding fragment thereof.

42. The compound of claim 30 , wherein BA is a N297Q antibody or antigen-binding fragment thereof, and conjugation is through at least one Q295 and at least one Q297 residue.

43. The compound of claim 30 , wherein BA is a N297Q antibody or antigen-binding fragment thereof, and conjugation is through two Q295 residues and two Q297 residues.

44. A pharmaceutical composition comprising the compound of claim 30 and a pharmaceutically acceptable excipient, carrier, or diluent.

45. A method for the treatment of dyslipidemia, a metabolic disease, inflammation, or a neurodegenerative disease in a subject comprising the administration to the subject of an effective treatment amount of the compound of claim 30 .

Assignments (2)
CORRECTIVE ASSIGNMENT TO CORRECT THE THIRD AND FOURTH INVENTOR'S FIRST NAME PREVIOUSLY RECORDED AT REEL: 056319 FRAME: 0423. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT . Recorded Jun 1, 2021
From: GROMADA, JESPER; GUSAROVA, VIKTORIA; HAN, AMY; HAXHINASTO, SOKOL; SLEEMAN, MATTHEW; MURPHY, ANDREW J.; WILLIAM, OLSON
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 057321/0257 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 21, 2021
From: GROMADA, JESPER; GUSAROVA, VIKTORIA; HAN, ANY; HAXHINASTO, SAKOL; SLEEMAN, MATTHEW; MURPHY, ANDREW J.; OLSON, WILLIAM
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 056319/0423 →
Continuity (2)
Provisional Application 62769946 · Nov 20, 2018
Related Publication 20220080052A1 · Mar 17, 2022
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