IP Library › Granted Patent US 11,919,913
Granted Patent B2
US 11,919,913 · App. 17/320,158 · Granted Mar 5, 2024

4-phenylpiperidines, their preparation and use

Inventors: Konstantin Petrukhin (New Windsor, NY); Christopher Cioffi (Troy, NY); Graham Johnson (Sanbornton, NH); Nicoleta Dobri (New York, NY); Emily Freeman (Voorheesville, NY); Ping Chen (Slingerlands, NY); Michael Conlon (Schenectady, NY); Lei Zhu (Glenmont, NY)
Assignee: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
C07D498/04A61K31/437A61K31/4375A61K31/454A61K31/4545A61K31/497A61K31/501A61K31/5025A61K31/506A61P27/02C07D401/06C07D405/14C07D409/06C07D471/04C07D487/04C07D491/052C07D495/04
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Quick Facts
Patent No.
US 11,919,913
App. No.
17/320,158
Granted
Mar 5, 2024
Kind
B2
Abstract

The present invention provides a compound having the structure: wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl; R 4 is H, OH, or halogen; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro substituted indole; and the pyrazole, when substituted, is substituted with other than trifluoromethyl, or a pharmaceutically acceptable salt thereof.

Claims (96)

1. A compound having the structure:

R 1 , R 2 , R 3 , and R 4 , are each independently H, halogen, CF 3 or C 1 -C 4 alkyl, and R 5 is halogen, CF 3 or C 1 -C 4 alkyl;

R 6 is H, OH, or halogen;

B has the structure:

wherein

n is an integer from 0-2;

Z 2 is S, O, or N—R 7 ,

wherein R 7 is H, C 1 -C 10 alkyl, or oxetane;

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently C(R 9 ) 2 , N—R 10 , O, N, SO 2 , or C═O,

wherein

R 9 is H or C 1 -C 10 alkyl;

R 10 is H, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 10 alkyl)-CF 3 , (C 1 -C 10 alkyl)-OCH 3 , (C 1 -C 10 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 10 alkyl)-CF 3 , SO 2 —(C 1 -C 10 alkyl)-OCH 3 , SO 2 —(C 1 -C 10 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 10 alkyl)-CF 3 , C(O)—(C 1 -C 10 alkyl)-OCH 3 , C(O)—(C 1 -C 10 alkyl)-halogen, C(O)—NH—(C 1 -C 10 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 10 alkyl)-C(O)OH, C(O)—NH 2 or oxetane;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein B has the structure

wherein

n is an integer from 0-1;

Z 2 is S, O, or N—R 7 ,

wherein R 7 is H, C 1 -C 10 alkyl, or oxetane;

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently C(R 9 ) 2 , N—R 10 , O, N, SO 2 , or C═O,

wherein

R 9 is H or C 1 -C 10 alkyl;

R 10 is H, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 10 alkyl)-CF 3 , (C 1 -C 10 alkyl)-OCH 3 , (C 1 -C 10 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 10 alkyl)-CF 3 , SO 2 —(C 1 -C 10 alkyl)-OCH 3 , SO 2 —(C 1 -C 10 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 10 alkyl)-CF 3 , C(O)—(C 1 -C 10 alkyl)-OCH 3 , C(O)—(C 1 -C 10 alkyl)-halogen, C(O)—NH—(C 1 -C 10 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 10 alkyl)-C(O)OH, C(O)—NH 2 or oxetane.

3. The compound of claim 2 , wherein B has the structure:

wherein

n is 0;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 and Y 3 are each CH 2 or C(CH 3 ) 2 ; and

Y 2 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O) OH, C(O)—NH 2 or oxetane.

4. The compound of claim 2 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 2 , and Y 4 are each CH 2 or C(CH 3 ) 2 ; and

Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-O C H 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O) OH, C(O)—NH 2 or oxetane.

5. The compound of claim 2 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 3 , and Y 4 are each CH 2 or C(CH 3 ) 2 ; and

Y 2 is Or SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O) OH, C(O)—NH 2 or oxetane.

6. The compound of claim 1 , wherein B has the structure:

wherein

n is 2;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 3 , and each occurrence of Y 4 are each CH 2 or C(CH 3 ) 2 ; and

Y 2 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O) OH, C(O)—NH 2 or oxetane.

7. The compound of claim 1 , wherein B has the structure:

8. The compound of claim 7 ,

wherein R 10 is C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 , C(O)—CH(CH 3 ) 2 , C(O)—CH 2 CH(CH 3 ) 2 , C(O)-t-Bu, C(O) CH 2 OCH 3 r C(O) CH 2 CF 3 , C(O)—CH 2 Cl, C(O)—CH 2 F, C(O)—CH 2 CH 2 OCH 3 , C(O)—CH 2 CH 2 CF 3 , C(O)—CH 2 CH 2 Cl, C(O)—CH 2 CH 2 F,

9. The compound of claim 2 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 and Y 4 are each CH 2 ; and

Y 2 is C═O and Y 3 is N—R 10 , or Y 3 is C═O and Y 2 is N—R 10 ,

wherein

R 10 is H, or C 1 -C 4 alkyl.

10. The compound of claim 1 wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O)OH, C(O)—NH 2 or oxetane.

11. The compound of claim 10 , wherein B has the structure:

12. The compound of claim 11 ,

wherein R 10 is C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 , C(O)—CH(CH 3 ) 2 , C(O)—CH 2 CH(CH 3 ) 2 , C(O)-t-Bu, C(O) CH 2 OCH 3 , C(O) CH 2 CF 3 , C(O)—CH 2 Cl, C(O)—CH 2 F, C(O)—CH 2 CH 2 OCH 3 , C(O)—CH 2 CH 2 CF 3 , C(O)—CH 2 CH 2 C 1 , C(O)—CH 2 CH 2 F,

13. A compound having the structure:

R 1 , R 2 , R 3 , and R 4 , are each independently H, halogen, CF 3 or C 1 -C 4 alkyl, and R 5 is halogen, CF 3 or C 1 -C 4 alkyl;

R 6 is H, OH, or halogen;

B has the structure:

wherein

R 7 is H, C 1 -C 4 alkyl, or oxetane; and

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N, wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN, or CF 3 .

14. The compound of claim 1 ,

wherein

R 1 , R 2 , R 3 , and R 4 , are each H, t-Bu, Cl, F, or CF 3 ; and

R 6 is H, OH, or F.

15. The compound of claim 1 having the structure:

16. The compound of claim 1 having the structure:

17. The compound of claim 13 having the structure:

18. The compound of claim 1 , wherein

R 5 is CF 3 ; and

R 1 , R 2 , R 3 , R 4 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl.

19. The compound of claim 1 ,

wherein

R 5 is CF 3 ; and

R 2 , R 2 , R 3 , R 4 are each independently H or halogen.

Assignments (3)
CONFIRMATORY LICENSE Recorded Dec 5, 2023
From: COLUMBIA UNIV NEW YORK MORNINGSIDE
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065775/0117 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2021
From: PETRUKHIN, KONSTANTIN; JOHNSON, GRAHAM; DOBRI, NICOLETA
To: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
Reel/Frame 056261/0742 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2021
From: CIOFFI, CHRISTOPHER; FREEMAN, EMILY; CHEN, PING; CONLON, MICHAEL; ZHU, LEI
To: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
Reel/Frame 056261/0825 →
Continuity (4)
Division 16151019 · Oct 3, 2018
Division 14775532
Provisional Application 61785187 · Mar 14, 2013
Related Publication 20210363155A1 · Nov 25, 2021