1,4-substituted piperidine derivatives

Patent metadata

Field	Value
Publication number	US-9902696-B2
Application number	US-201615185710-A
Country	US
Kind code	B2
Filing date	Jun 17, 2016
Priority date	Jun 18, 2015
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

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.

First claim

What is claimed is:

1. A compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A is selected from —C(═O)— and —SO 2 —;
R 1 is selected from —H, —(C 1 -C 10 ) hydrocarbyl, substituted —(C 1 -C 10 ) hydrocarbyl, 3-7 membered heterocyclyl, substituted 3-7 membered heterocyclyl, —(C 6 -C 10 ) aryl, substituted —(C 6 -C 10 ) aryl, 5-6 membered heteroaryl, substituted 5-6 membered heteroaryl, —NR 7 R 8 , —OR 7 , —SR 7 , —N(OR 8 )R 7 , —N(SR 8 )R 7 and —C(═O)—(C 1 -C 6 ) alkyl;
a and b are independently selected from 0 and 1;
each R 2 is independently selected from —H and —(C 1 -C 4 ) alkyl;
each R 3 is independently selected from —H and —(C 1 -C 4 ) alkyl
R 4 is selected from —H, —(C 1 -C 6 ) alkyl, ═O, —OH, —O(C 1 -C 6 ) alkyl, halogen, and —CN; wherein one of the R 3 groups can optionally be structurally connected to one of the R 2 groups to form an alkylene bridge to produce a bicyclic ring; or
one of the R 3 groups can optionally be structurally connected to the R 1 group to form a 5 to 7 membered heterocyclyl ring fused to the 1-2 face of the piperidine ring; or
one of the R 3 groups can optionally be structurally connected to the R 4 group to form a 5-7 membered carbocyclic or heterocyclic ring fused to the 2-3 face of the piperidine ring;
indicates that the designated bond is a carbon-carbon single bond or a carbon-carbon double bond;
X is selected from —O—, —S—, —SO—, —SO 2 —, —NH— and —NR 9 —;
W 1 , W 2 and W 3 are independently selected from N, CH, and C—R 10 ; provided that W 2 and W 3 are not both N;
R 5 is selected from —H, —C 1 -C 7 hydrocarbyl, —C 3 -C 6 heterocyclyl; halogen, —(C 1 -C 3 ) haloalkyl, —O—(C 1 -C 7 ) hydrocarbyl, —O— substituted —(C 1 -C 7 ) hydrocarbyl, —O—C(═O)R 8 , —O—(C 1 -C 6 ) heteroalky, —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, substituted 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, and substituted 8-10 membered bicyclic heteroaryl;
n is an integer selected from 1, 2, 3, and 4;
R 6 is selected from:

wherein, when R 6 is (i), 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 ;
when R 6 is (ii), Q 1a , Q 2a , Q 3a , Q 4a , Q 5a , Q 6a and Q 7a are independently selected from N and C—R 12 , provided that 1, 2 or 3 of Q 1a , Q 2a , Q 3a , Q 4a , Q 5a , Q 6a and Q 7a are N, and the remainder of Q 1a , Q 2a , Q 3a , Q 4a , Q 5a , Q 6a and Q 7a are C—R 12 ;
when R 6 is (iii), Q 8 is selected from O, S, and N—R 12n , Q 9 , Q 10 and Q 11 are independently selected from N and C—R 12 , provided that 1 or 2 of Q 9 , Q 10 and Q 11 are N, and the remainder of Q 9 , Q 10 and Q 11 are C—R 12 ;
when R 6 is (iv), Q 8a is selected from O, S, and N—R 12n , Q 9a , Q 10a and Q 11a are independently selected from N and C—R 12 , provided that 1 or 2 of Q 9a , Q 10a and Q 11a are N, and the remainder of Q 9a , Q 10a and Q 11a are C—R 12 ;
when R 6 is (v), Q 12 , Q 13 and Q 14 are independently selected from N and C—R 12 ; and
when R 6 is (vi), Q 12a , Q 13a and Q 14a are independently selected from N and C—R 12 ;
when R 6 is (vii), Q 15 is selected from N—R 12n and C—R 12 and Q 16 is selected from N and C—R 12 ; provided that Q 15 and Q 16 are not both C—R 12 ;
wherein the non-bridgehead ring carbon ring atoms in (i), (ii), (iii), (iv), (v), (vi) and (vii) are substituted or unsubstituted;
and wherein 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 ) r -(5-6 membered heterocyclyl), —O(CH 2 ) r —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 ) r —O(C 1 -C 6 ) alkyl, —NH(CH 2 ) r —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 ; wherein r is an integer selected independently from 1, 2, 3, and 4; and
each R 12n is independently selected from —H, —(C 1 -C 7 ) hydrocarbyl and substituted —(C 1 -C 7 ) hydrocarbyl;
R 7 is selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —C(═O)R 8 , —(C 1 -C 6 ) heteroalkyl, 5-6 membered aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl;
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;
R 9 is selected from —(C 1 -C 7 ) hydrocarbyl, wherein R 9 can optionally be structurally connected to R 4 to form a 5 to 7 membered heterocyclyl ring;
each R 10 is independently selected from —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, halogen, —C(═O)(C 1 -C 7 ) hydrocarbyl, —C(═O)NH 2 , —C(═O)NH(C 1 -C 7 ) hydrocarbyl, —C(═O)N((C 1 -C 7 )hydrocarbyl) 2 , —O(C 1 -C 7 ) hydrocarbyl, substituted —O(C 1 -C 7 ) hydrocarbyl, —(C 3 -C 6 ) heterocyclyl, substituted —(C 3 -C 6 )heterocyclyl —CN, —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —NH(CH 2 ) m —R 11 , —N(C 1 -C 6 alkyl)(CH 2 ) m —R 11 , —O—(CH 2 ) m —R 11 , and —(C 1 -C 6 ) heteroalkyl;
m is an integer independently selected from 1, 2, 3, and 4; and
R 11 is selected from —O(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —(C 3 -C 6 )heterocyclyl and substituted —(C 3 -C 6 ) heterocyclyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is:

wherein 1 or 2 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 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is:

wherein one or two of Q 2 , Q 4 and Q 6 is N, and the remainder of Q 2 , Q 4 and Q 6 are C—R 12 , and q is an integer selected from 0, 1, 2 and 3.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W 1 , W 2 and W 3 are CH.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from —(C 1 -C 10 ) hydrocarbyl, —SR 7 —NR 7 R 8 , and —N(OR 8 )R 7 .

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —H or halogen.

8. A compound according to Formula V(a):

or a pharmaceutically acceptable salt thereo

Assignees

• Cephalon Inc

Inventors

• Becknell Nadine C
• Dandu Reddeppa Reddy
• Dorsey Bruce D
• Gotchev Dimitar B
• Hudkins Robert L
• Weinberg Linda
• Zificsak Craig A
• Zulli Allison L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title