IP Library › Granted Patent US 10,221,135

Granted Patent B2

US 10,221,135 · App. 15/903,150 · Granted Mar 5, 2019

1,4-substituted piperidine derivatives

Inventors: Nadine C. Becknell (Coatesville, PA); Reddeppa Reddy Dandu (Downingtown, PA); Bruce D. Dorsey (Ambler, PA); Dimitar B. Gotchev (Hatboro, PA); Robert L. Hudkins (Chester Springs, PA); Linda Weinberg (King of Prussia, PA); Craig A. Zificsak (Downingtown, PA); Allison L. Zulli (Wayne, PA)

Assignee: 89BIO LTD

C07D211/44 C07D211/54 C07D211/58 C07D401/04 C07D401/12 C07D401/14 C07D405/06 C07D405/12 C07D405/14 C07D409/12 C07D409/14 C07D413/14 C07D417/12 C07D417/14 C07D471/02 C07D471/04 C07D471/08 C07D491/048 C07D495/02 C07D495/04

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Quick Facts

Patent No.: US 10,221,135
App. No.: 15/903,150
Granted: Mar 5, 2019
Kind: B2

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Abstract

Described herein are 1,4-substituted piperidine compounds according to Formula I that have demonstrated activity as fatty acid synthase inhibitors. Also described herein are pharmaceutical compositions containing the described 1,4-substituted piperidine compounds, and methods of treating diseases mediated by fatty acid synthase, by administering one or more of the compounds or pharmaceutical formulations described herein. Also described herein are methods of synthesizing the compounds described, including the described 1,4-substituted piperidine compounds and synthetic intermediates useful in those syntheses.

Claims (258)

1. A pharmaceutical composition comprising at least one compound according to Formula V(a):

or a pharmaceutically acceptable salt thereof, wherein:

R 1b is selected from —NR 7 R 8 and —N(OR 8 )R 7 ;

R 4 is selected from —H, —(C 1 -C 6 ) alkyl, —OH, —O(C 1 -C 6 ) alkyl, halogen, and —CN;

X is selected from —O— and —S—;

R 5 is selected from —H, —C 1 -C 7 hydrocarbyl, —C 3 -C 6 heterocyclyl; halogen, —(C 1 -C 3 ) haloalkyl, —OR 7a , —CN, —NR 7a R 8a , —O(CH 2 ) n NR 7a R 8a , —O(CH 2 ) n OR 8a , —NR 8a (CH 2 ) n NR 7a R 8a , —NR 8a (CH 2 ) n OR 8a , —C(═O)NR 7a R 8a , —C(═O)OR 7a , 5-6 membered heteroaryl and substituted 5-6 membered heteroaryl;

n is an integer selected from 1, 2, 3, and 4;

R 7 is selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —C(═O)R 8 , and —(C 1 -C 6 ) heteroalkyl;

R 8 is selected from —H, and —(C 1 -C 6 ) alkyl, wherein R 7 can optionally be structurally connected to R 8 to form a 5 to 7 membered heterocyclyl ring;

R 7a is selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —C(═O)R 8 , and —(C 1 -C 6 ) heteroalkyl;

R 8a is selected from —H, and —(C 1 -C 6 ) alkyl, wherein R 7a can optionally be structurally connected to R 8a to form a 5 to 7 membered heterocyclyl ring;

Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 are independently selected from N and C—R 12 , provided that 1, 2 or 3 of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 are N, and the remainder of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 are C—R 12 ;

each R 12 is independently selected from —H, halogen, —(C 1 -C 6 ) alkyl, —(C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, —OH, —O(C 1 -C 6 ) alkyl, —O(CH 2 ) p -(5-6 membered heterocyclyl), —O(CH 2 ) p —O(C 1 -C 6 ) alkyl, —NH 2 , —CN, —NH(C 1 -C 6 ) alkyl, —N(C 1 -C 6 alkyl) 2 , —NH(CH 2 ) p —O(C 1 -C 6 ) alkyl, —NH(CH 2 ) p —N(C 1 -C 6 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 ) alkyl, and —C(═O)N(C 1 -C 6 alkyl) 2 ; and

p is an integer selected independently from 1, 2, 3, and 4;

and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1 , wherein X is —O—.

3. The pharmaceutical composition according to claim 1 , wherein R 5 is selected from —H, —(C 1 -C 7 ) hydrocarbyl, and halogen.

4. The pharmaceutical composition according to claim 1 , wherein one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 is N, and the remainder of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 are C—R 12 .

5. The pharmaceutical composition according to claim 4 , wherein one of Q 2 and Q 6 is N; the other of Q 2 and Q 6 is C—R 12 ; and Q 1 , Q 3 , Q 4 , Q 5 and Q 7 are C—R 12 .

6. The pharmaceutical composition according to claim 1 , wherein the compound according to Formula V(a) is selected from:

isoxazolidin-2-yl-[4-(4-quinolin-3-yl-phenoxy)-piperidin-1-yl]-methanone;

[4-(4-isoquinolin-3-yl-phenoxy)-piperidin-1-yl]-isoxazolidin-2-yl-methanone; isoxazolidin-2-yl-{4-[4-(8-methylquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;

{4-[4-(4-chloroquinolin-3-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;

{4-[4-(8-chloroquinolin-7-yl)-phenoxy]-piperidin-1-yl}-isoxazolidin-2-yl-methanone;

isoxazolidin-2-yl-{4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;

isoxazolidin-2-yl-{4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidin-1-yl}-methanone;

isoxazolidin-2-yl-{4-[4-(7-methylquinolin-3-yl)-phenoxy]-piperidin-1-yl}-methanone;

isoxazolidin-2-yl-[4-(4-quinoxalin-2-yl-phenoxy)-piperidin-1-yl]-methanone;

4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acid methoxyamide;

4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acid methoxymethylamide;

4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acid ethylamide;

4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acid methylamide;

4-[4-(8-methoxyquinolin-7-yl)-phenoxy]-piperidine-1-carboxylic acid ethylamide;

4-[4-(4-methylquinolin-3-yl)-phenoxy]-piperidine-1-carboxylic acid hydroxyamide;

N-ethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N,N-dimethyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-methoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-isopropyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-ethoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-pyrrolidin-1-yl-methanone;

N-methyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;

4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(1-piperidyl)methanone;

[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-morpholinomethanone;

N-methoxy-4-[4-(8-methoxy-7-quinolyl)phenoxy]piperidine-1-carboxamide;

3-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-oxazolidin-2-one;

1-[4-(4-quinolin-3-yl-phenoxy)-piperidine-1-carbonyl]-pyrrolidin-2-one;

N-ethyl-4-[4-(2-hydroxy-8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-pyrrolidin-1-ylethyl)piperidine-1-carboxamide; 4-[4-(8-methyl-7-quinolyl)phenoxy]-N-(2-morpholinoethyl)piperidine-1-carboxamide;

(4-isopropylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone; (4-methylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;

[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(4-morpholino-1-piperidyl)methanone; (4-ethylpiperazin-1-yl)-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;

N-(cyclopropylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-isobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-(2-methoxyethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-isopropoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-isobutoxy-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

N-(2-dimethylaminoethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide; N-[2-(1H-imidazol-4-yl)ethyl]-4-[4-(8-methyl-7-quinolyl)phenoxy],piperidine-1-carboxamide;

4-[4-(8-methyl-7-quinolyl)phenoxy]-N-tetrahydropyran-4-yl-piperidine-1-carboxamide; N-cyclobutyl-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carbohydroxamic acid;

[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]-(oxazinan-2-yl)methanone;

N-(cyclobutylmethyl)-4-[4-(8-methyl-7-quinolyl)phenoxy]piperidine-1-carboxamide; azepan-1-yl-[4-[4-(8-methyl-7-quinolyl)phenoxy]-1-piperidyl]methanone;

4-[4-(8-methyl-7-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;

N-ethyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;

N-isobutyl-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;

N-(cyclopropylmethyl)-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide; N-isopropoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(1-methyl-6-isoquinolyl)phenoxy]-N-propoxypiperidine-1-carboxamide;

4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carbohydroxamic acid;

N-ethoxy-4-[4-(1-methyl-6-isoquinolyl)phenoxy]piperidine-1-carboxamide;

N-ethoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;

N-isopropoxy-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propoxy-piperidine-1-carboxamide;

N-isobutyl-4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carboxamide;

4-[4-(4-methyl-3-quinolyl)phenoxy]-N-propyl-piperidine-1-carboxamide;

4-[4-(4-methyl-3-quinolyl)phenoxy]-N-methylsulfanyl-piperidine-1-carboxamide;

4-[4-(4-methyl-3-quinolyl)phenoxy]-N-ethylsulfanyl-piperidine-1-carboxamide,

1-[4-[4-(4-methyl-3-quinolyl)phenoxy]piperidine-1-carbonyl]pyrrolidin-2-one;

or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 , further comprising an antipsychotic agent.

8. The pharmaceutical composition according to claim 7 , wherein the antipsychotic agent is clozapine, risperidone, aripiprazole, olanzapine, quetiapine or ziprasidone or a combination thereof.

9. The pharmaceutical composition according to claim 1 , wherein the compound of formula (Va) is

or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 1 , wherein the compound of formula (Va) is

or a pharmaceutically acceptable salt thereof.

11. A method of treating a subject suffering from a disorder mediated by fatty acid synthase, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 1 .

12. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

13. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

14. A method of treating a subject suffering from a disorder mediated by fatty acid synthase, comprising administering to the subject a therapeutically effective amount of a compound according to Formula V(a):

or a pharmaceutically acceptable salt thereof, wherein:

R 1b is selected from —NR 7 R 8 and —N(OR 8 )R 7 ;

R 4 is selected from —H, —(C 1 -C 6 ) alkyl, —OH, —O(C 1 -C 6 ) alkyl, halogen, and —CN;

X is selected from —O— and —S—;

n is an integer selected from 1, 2, 3, and 4;

R 7 is selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —C(═O)R 8 , and —(C 1 -C 6 ) heteroalkyl;

R 8 is selected from —H, and —(C 1 -C 6 ) alkyl, wherein R 7 can optionally be structurally connected to R 8 to form a 5 to 7 membered heterocyclyl ring;

R 7a is selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —C(═O)R 8 , and —(C 1 -C 6 ) heteroalkyl;

R 8a is selected from —H, and —(C 1 -C 6 ) alkyl, wherein R 7a can optionally be structurally connected to R 8a to form a 5 to 7 membered heterocyclyl ring;

p is an integer selected independently from 1, 2, 3, and 4.

15. The method according to claim 14 , wherein X is —O—.

16. The method according to claim 14 , wherein R 5 is selected from —H, —(C 1 -C 7 ) hydrocarbyl, and halogen.

17. The method according to claim 14 , wherein one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 is N, and the remainder of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 are C—R 12 .

18. The method according to claim 17 , wherein one of Q 2 and Q 6 is N; the other of Q 2 and Q 6 is C—R 12 ; and Q 1 , Q 3 , Q 4 , Q 5 and Q 7 are C—R 12 .

19. The method according to claim 14 , wherein the compound according to Formula V(a) is selected from: