IP Library › Granted Patent US 11,795,162

Granted Patent B2

US 11,795,162 · App. 16/639,807 · Granted Oct 24, 2023

Modulators of the estrogen-related receptor

Inventors: Thomas Burris (Columbia, IL); John K. Walker (St. Louis, MO); Carissa S. Hampton (Litchfield, IL); Keith McCormick Haynes (St. Louis, MO); Kristine Griffett (St. Louis, MO); Cyrielle Billon (St. Louis, MO); Sadichha Sitaula (St. Louis, MO)

Assignee: Saint Louis University

C07D413/04 C07D209/42 C07D231/14 C07D277/56 C07D277/82 C07D307/68 C07D333/38 C07D401/04 C07D409/04 C07D409/12 C07D417/04 C07F5/027

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Quick Facts

Patent No.: US 11,795,162
App. No.: 16/639,807
Granted: Oct 24, 2023
Kind: B2

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Abstract

In one aspect, the present disclosure describes new estrogen receptor-related orphan receptor (EER) inverse agonist compounds. Also described are pharmaceutical formulations, methods of synthesis and uses thereof.

Claims (104)

1. A compound of the formula:

X 1 -Y 1 -L-A-R 1 (I)

wherein:

X 1 is aryl (C≤12) or a substituted version of this group; or -arenediyl (C≤12) -R 2 or a substituted version thereof, wherein:

R 2 is -B(OR′)(OR″), —NR 3 R 4 , —C(O)OR 5 , —C(O)NR 6 R 7 ; wherein:

R 3 , R 4 , R 6 , and R 7 are each independently hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤12) , or a substituted version of any of these groups, or a monovalent amino protecting group; or R 3 and R 4 or R 6 and R 7 are taken together and are a divalent amino protecting group;

R′ and R″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; and

R 5 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

R 2 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤18) , heteroaryl (C≤18) , heterocycloalkyl (C≤12) , aralkyl (C≤18) , heteroaralkyl (C≤18) , alkoxy (C≤12) , cycloalkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , or a substituted version of any of these eleven groups;

Y 1 is thiophene or substituted thiophene;

L is —C(O)—;

A is -NR 8 —, wherein:

R 8 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;

R 1 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤18) , heteroaryl (C≤18) , aralkyl (C≤18) , or a substituted version of any of these groups; or aryl (C≤12) or substituted aryl (C≤12) , wherein two hydrogen atoms have been replaced with —NR a C(O)NR b —;

wherein:

R a and R b are each independently hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; or

R 1 is -arenediyl (C≤12) -R 9 , -heteroarenediyl (C≤12) -R 9 , or a substituted version thereof, wherein:

R 9 is -B(OR′″)(OR″″), -NR 10 R 11 , —C(O)OR 12 , —C(O)NR 13 R 14 ; wherein:

R 10 , R 11 , R 13 , and R 14 are each independently hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , acyl (C≤12) , or a substituted version of any of these groups, or a monovalent amino protecting group; or R 10 and R 11 or R 13 and R 14 are taken together and are a divalent amino protecting group;

R′″ and R″″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; and

R 12 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

R 9 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤18) , heterocycloalkyl (C≤12) , aralkyl (C≤18) , heteroaralkyl (C≤18) , alkoxy (C≤12) , cycloalkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , or a substituted version of any of these eleven groups;

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula:

X 1 -Y 1 -L-A-R 1 (I)

wherein:

X 1 is aryl (C≤12) or a substituted version of this group; or -arenediyl (C≤12) -R 2 or a substituted version thereof, wherein:

R 2 is -B(OR′)(OR″), —NR 3 R 4 , —C(O)OR 5 , —C(O)NR 6 R 7 , —C(O)R 15 , —SO 2 R 16 ; wherein:

R′ and R″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; and

R 5 , R 15 , and R 16 are each independently alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

Y 1 is thiophene or substituted thiophene;

L is —C(O)—;

A is -NR 8 —, wherein:

R 8 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;

R a and R b are each independently hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; or

R 1 is -arenediyl (C≤12) -R 9 , -heteroarenediyl (C≤12) -R 9 , or a substituted version thereof, wherein:

R 9 is -B(OR′″)(OR″″), -NR 10 R 11 , —C(O)OR 12 , —C(O)NR 13 R 14 ; wherein:

R′″ and R″″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; and

R 12 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

R 9 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤18) , heteroaryl (C≤18) , heterocycloalkyl (C≤12) , aralkyl (C≤18) , heteroaralkyl (C≤18) , alkoxy (C≤12) , cycloalkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , or a substituted version of any of these eleven groups;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 further defined as:

X 1 -Y 1 -C(O)-A-R 1 (I)

wherein:

X 1 is aryl (C≤12) or a substituted version of this group; or -arenediyl (C≤12) -R 2 or a substituted version thereof, wherein:

R 2 is -B(OR′)(OR″), —NR 3 R 4 , —C(O)OR 5 , —C(O)NR 6 R 7 ; wherein:

R′ and R″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl(c≤12), or a substituted version of any of these groups; and

R 5 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

Y 1 is thiophene or substituted thiophene;

A is -NR 8 —, wherein:

R 8 is hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) ;

R a and R b are each independently hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; or

R 1 is -arenediyl (C≤12) -R 9 , -heteroarenediyl (C≤12) -R 9 , or a substituted version thereof, wherein:

R 9 is -B(OR′″)(OR″″), -NR 10 R 11 , —C(O)OR 12 , —C(O)NR 13 R 14 ; wherein:

R′″ and R″″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; and

R 12 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 further defined as:

X 1 -Y 1 -C(O)-A-R 1 (I)

wherein:

X 1 is aryl (C≤12) or a substituted version of this group; or -arenediyl (C≤12) -R 2 or a substituted version thereof, wherein:

R 2 is -B(OR′)(OR″), —NR 3 R 4 , —C(O)OR 5 , —C(O)NR 6 R 7 ; wherein:

R′ and R″ are hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; and

R 5 is alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups; or

Y 1 is thiophene or substituted thiophene;

A is -NR 8 —, wherein:

R 8 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;

R 1 is aryl (C≤18) , heteroaryl (C≤18) , aralkyl (C≤18) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 further defined as:

X 1 -Y 1 -C(O)-A-R 1 (I)

wherein:

X 1 is aryl (C≤12) or a substituted version of this group;

Y 1 is thiophene or substituted thiophene;

A is -NR 8 —, wherein:

R 8 is hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) ;

R 1 is aryl (C≤18) , heteroaryl (C≤18) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein Y 1 is thiophene.

7. The compound of claim 1 , wherein X 1 is aryl (C≤12) or substituted aryl (C≤12) .

8. The compound of claim 7 , wherein X 1 is aryl (C≤12) .

9. The compound of claim 7 , wherein X 1 is substituted aryl (C≤12) .

10. The compound of claim 1 , wherein X 1 is -arenediyl (C≤12) -R 2 .

11. The compound of claim 1 , wherein R 1 is aryl (C≤12) or substituted aryl (C≤12) .

12. The compound of claim 1 , wherein R 1 is heteroaryl (C≤12) or substituted heteroaryl (C≤12) .

13. The compound of claim 1 , wherein R 1 is -arenediyl (C≤12) -R 9 .

14. The compound of claim 1 further defined as:

15. A pharmaceutical composition comprising:

(A) a compound of claim 1 ; and

(B) an excipient.

16. A method of treating obesity, diabetes, non-alcoholic fatty liver disease, muscular dystrophy, or a neurological disease or disorder, wherein the neurological disorder is selected from dementia, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's Disease in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound or composition of claim 1 .

17. The method of claim 16 , wherein the disease or disorder is obesity, diabetes, or non-alcoholic fatty liver disease.

18. The method of claim 16 , wherein the disease or disorder is a muscular dystrophy or a neurological disease or disorder, wherein the neurological disorder is selected from dementia, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's disease.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 19, 2020

From: BURRIS, THOMAS; WALKER, JOHN K.; HAMPTON, CARISSA S.; HAYNES, KEITH MCCORMICK; GRIFFETT, KRISTINE; BILLON, CYRIELLE; SITAULA, SADICHHA

To: SAINT LOUIS UNIVERSITY

Reel/Frame 051864/0969 →

Continuity (2)

Provisional Application 62547555 · Aug 18, 2017

Related Publication 20200247792A1 · Aug 6, 2020