Spiropiperidine derivatives
Described herein are spiropiperidine compounds according to Formula I that have demonstrated activity as fatty acid synthase inhibitors. Also described herein are pharmaceutical compositions containing the described spiropiperidine 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 spiropiperidine compounds and synthetic intermediates that are useful in those syntheses.
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 —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, 3-7 membered heterocyclyl, —NR 7 R 8 , —SR 7 , —NR 7 (OR 8 ) and —NR 7 (SR 8 );
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 each R 4 is independently selected from —H, —(C 1 -C 6 ) alkyl, —OH, —O(C 1 -C 6 ) alkyl, halogen, —CN, or the two geminal R 4 groups may together form a carbonyl group;
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;
X is selected from —O(CH 2 ) q (CR 9 R 9a ) p1 —, —S(CH 2 ) q (CR 9 R 9a ) p2 —, —(CH 2 ) q (CR 9 R 9a ) p3 — and —CH═CH—;
p1 is an integer selected from 0 and 1;
p2 is an integer selected from 0 and 1;
p3 is an integer selected from 1 and 2;
q is an integer selected from 0 and 1;
R 5 is selected from —H, —C 1 -C 7 hydrocarbyl, halogen, —(C 1 -C 3 ) haloalkyl, —OR 7a , —CN,
NR 7a R 8a , —(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; wherein n is an integer selected from 2, 3 and 4;
R 6 is selected from naphthyl, substituted naphthyl, 9-10 membered bicyclic heteroaryl and substituted 9-10 membered bicyclic heteroaryl;
R 7 is selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —C(═O)R 8b , —(C 1 -C 6 ) heteroalkyl, 6 membered aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, wherein R 8b is selected from —H and —(C 1 -C 6 ) alkyl;
R 8 is selected from —H, 3-7 membered heterocyclyl, 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 8b and —(C 1 -C 6 ) heteroalkyl, wherein R 8b is selected from —H and —(C 1 -C 6 ) alkyl;
R 8b 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;
each R 9 is independently selected from —H, —OH, —(C 1 -C 7 ) hydrocarbyl, —O(C 1 -C 7 ) hydrocarbyl, and halogen; and
each R 9a is —H.
2. A compound according to claim 1 , wherein R 6 is selected from 9-10 membered bicyclic heteroaryl, and substituted 9-10 membered bicyclic heteroaryl.
3. A compound according to claim 2 , wherein 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 10 , provided that 0, 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 10 ;
when R 6 is (ii), Q 8 is selected from O, S, and N—R 10m and Q 9 , Q 10 and Q 11 are independently selected from N and C—R 10 ;
when R 6 is (iii), Q 8a is selected from O, S, and N-R 10n , Q 9a , Q 10a and Q 11a are independently selected from N and C—R 10 ;
when R 6 is (iv), Q 8b is selected from O, S, and N—R 10n ; and Q 9b and Q 10b are independently selected from N and C—R 10 ; and
when R 6 is (v), Q 8c is selected from O, S, and N—R 10n ; and Q 9c and Q 10c are independently selected from N and C—R 10 ; wherein
and wherein each R 10 is independently selected from —H, halogen, —(C 1 -C 6 ) alkyl, —(C 3 -C 6 ) cycloalkyl, —(C 1 -C 3 ) haloalkyl, —O(C 1 -C 3 ) haloalkyl, -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, —O(CH 2 ) r —NH(C 1 -C 6 alkyl) 2 , —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 10n is independently selected from —H, —(C 1 -C 7 ) hydrocarbyl, substituted —(C 1 -C 7 ) hydrocarbyl, —CO 2 (C 1 -C 7 ) hydrocarbyl, —C(═O)(C 1 -C 7 ) hydrocarbyl and substituted —C(═O)(C 1 -C 7 ) hydrocarbyl.
4. The compound according to claim 3 , wherein R 6 is:
wherein 1 or 2 of Q1, Q2, Q3, Q4, Q5, 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 10 .
5. The compound according to claim 3 , 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 10 , and z is an integer selected from 0, 1, 2 and 3.
6. The compound according to claim 1 , wherein X is selected from —O—, —OCH 2 —, —O-(CH 2 ) 2 —, —S—, —S-(CH 2 ) 2 —, —(CH 2 )—, —(CH 2 ) 2 —, and —(CH 2 ) 3 .
7. The compound according to claim 6 , wherein X is —(CH 2 ) 2 —.
8. The compound according to claim 1 , wherein R 1 is selected from —NR 7 R 8 and —N(OR 8 )R 7 .
9. The compound according to claim 1 , wherein a and b are 1.
10. The compound according to claim 1 , wherein each R 2 , R 3 , and R 4 is H.
11. The compound according to claim 1 , selected from: [6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-methanone; [6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; [6-(1-cyclopropyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]methanone; [6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-propan-1-one; [6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-cyclo-propyl-methanone; [6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(8-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(8-methyl-3-quinolyl)spiro-[chromane-2,4′-piperidine]-1′-yl]methanone; [6-(8-methyl-3-quinolyl)spiro-[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; cyclopropyl-[6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]methanone; [6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(8-methyl-6-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one;
cyclopropyl-[6-(8-methyl-6-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]methanone; 1-[6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; [6-(8-methyl-6-quinolyl)spiro]chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; cyclo-propyl-[6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-methanone; [6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]methanone; 1-[6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2, 4′-piperidine]-1′-yl]methanone; [6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; 2-methyl-1-]6-(7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-methanone; 1-[6-(3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; 2-methyl-1-[6-(3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; 1-[6-(1,5-naphthyridin-3-yl)spiro[4H-1,3-benzo-dioxine-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(1,5-naphthyridin-3-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]methanone; cyclopropyl-[6-(3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]methanone; cyclobutyl-[6-(3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]methanone; 1-[4-hydroxy-6-(3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]propan-1-one; 1-[6-(3-quinolyl)spiro[chromene-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(3-quinolyl)spiro[chromene-2,4′-piperidine]-1′-yl]methanone; cyclobutyl-[6-(3-quinolyl)spiro[chromene-2,4′-piperidine]-1′-yl]methanone; cyclopropyl-[4-hydroxy-6-(3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]methanone; 1-[6-(3-quinolyl)spiro[chromane-2, 4′-piperidine]-1′-yl]propan-1-one; [6-(3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; cyclopropyl-[6-(8-methoxy-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]methanone; [6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzo-dioxine-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 6-(4-methyl-3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(4-methyl-3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; 1-[6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; cyclopropyl-[6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]methanone; 1-[6-(8-methoxy-7-quinolyl)-spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; [6-(8-methoxy-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; 1-[6-(8-chloro-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]propan-1-one; [6-(8-chloro-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-cyclopropyl-methanone; [6-(8-chloro-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-[(2R)-tetrahydrofuran-2-yl]methanone; [2-[6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]-2-oxo-ethyl]-acetate; 2-hydroxy-1-[6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-ethanone, 2-hydroxy-1-[6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-yl]ethanone; 6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; [2-[6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-2-oxo-ethyl] acetate; 6-(8-chloro-7-quinolyl)-N-tetrahydropyran-2-yloxy-spiro[chromane-2, 4′-piperidine]-1′-carboxamide; 6-(8-chloro-7-quinolyl)-N-ethyl-spiro[chromane-2,4′-piperidine]-1′-carboxamide; 1-[6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-yl]-2-hydroxy-ethanone; 6-(8-chloro-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(8-chloro-7-quinolyl)-N-ethoxy-spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(8-chloro-7-quinolyl)-N-methoxy-spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(benzofuran-5-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; benzothiazol-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1-methylindol-5-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1H-indol-5-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 7-(8-methyl-7-quinolyl)spiro[4,5-dihydro-1,3-benzodioxepine-2,4′-piperidine]-1′-carboxamide; N-ethyl-7-(8-methyl-7-quinolyl)spiro[4,5-dihydro-1,3-benzodioxepine-2,4′-piperidine]-1′-carboxamide; N-ethoxy-7-(8-methyl-7-quinolyl)spiro[4,5-dihydro-1,3-benzodioxepine-2,4′-piperidine]-1′-carboxamide; N-methoxy-7-(8-methyl-7-quinolyl)spiro[4,5-dihydro-1,3-benzodioxepine-2,4′-piperidine]-1′-carboxamide; 6-(1-methylbenzimidazol-5-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1-methylbenzimidazol-5-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(1,3-benzothiazol-5-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-thieno[2,3-b]pyridin-5-ylspiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-1,3-benzoxazol-5-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1,3-benzoxazol-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-thieno[2,3-b]pyridin-5-ylspiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(1,8-naphthyridin-3-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; tert-butyl 3-(1′-carbamoylspiro-[chromane-2,4′-piperidine]-6-yl)indole-1-carboxylate; 6-(1H-indol-3-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1H-indol-3-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-isobutyl-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropyl-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(8-methyl-7-quinolyl)-N-propyl-spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-(cyclopropylmethyl)-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(8-methyl-7-quinolyl)-N-propoxy-spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isobutoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropyl-6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropyl-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-isopropyl-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)-spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carbohydroxamic acid; N-ethyl-6-(7-methyl-pyrazolo[1,5-a]pyridin-6-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carbox-amide; 6-(7-methylpyrazolo[pyridin-6-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(8-chloro-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(4-methyl-3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(4-methyl-3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(8-chloro-7-quinolyl)-N-methoxy-spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(8-chloro-7-quinolyl)-N-ethoxy-spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(8-chloro-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carbohydroxamic acid; N-ethoxy-6-(4-methyl-3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(4-methyl-3-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(5-methylimidazo[1,2-a]pyridin-6-yl)spiro[chromane-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(3-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(3-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(3-isoquinolyl)-N-tetrahydropyran-2-yloxy-spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(3-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(3-isoquinolyl)-N-tetrahydropyran-2-yloxy-spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(3-soquinolyl)-N-methoxy-spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(3-isoquinolyl)-N-methoxy-spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(3-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(3 soquinolyl)spiro-[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(3-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carbohydroxamic acid; 5-(8-methyl-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-methoxy-5-(8-methyl-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethoxy-5-(8-methyl-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 5-(8-methyl-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carbohydroxamic acid; N-ethyl-5-(8-methyl-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-methoxy-5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethoxy-5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethyl-5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carbohydroxamic acid; 5-(8-methoxy-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethyl-5-(8-methoxy-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 5-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethyl-5-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-methoxy-5-(8-methoxy-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethoxy-5-(8-methoxy-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 5-(8-methoxy-7-quinolyl)-N-tetrahydropyran-2-yloxy-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-ethoxy-5-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; N-methoxy-5-(7-methylpyrazolo[1,5-a]pyridin-6-yl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 5-(7-methylpyrazolo[1,5-a]pyridin-6-yl)-N-tetrahydropyran-2-yloxy-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide; 6-(8-methyl-2-oxo-1H-quinolin-7-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 5-(8-methoxy-7-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(8-methoxy-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(5-chloroimidazo[1,2-a]pyridin-6-yl)-N-isobutylic-spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isobutyl-6-(1-methyl-6-isoquinolyl)-spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1-methyl-6-isoquinolyl)-N-propoxy-spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1-methyl-6-isoquinolyl)-N-propyl-spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carbo-hydroxamic acid; 6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carbo-hydroxamic acid; N-methoxy-6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-isopropoxy-6-(4-methyl-3-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(1-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carbohydroxamic acid; 6-(3-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(3-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(3-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(3-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carbohydroxamic acid; N-methoxy-6-(3-methyl-6-isoquinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 6-(3-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(3-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethyl-6-(3-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(3-methyl-6-soquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-methoxy-6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-ethoxy-6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(8-methyl-7-quinolyl)-4-oxo-Spiro[chromane-2,4′-piperidine]-1′-carboxamide; 4-hydroxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 4-fluoro-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 7-Fluoro-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 7-Fluoro-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(Benzofuran-2-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(1H-Indol-2-yl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 8-Fluoro-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 8-Fluoro-N-methoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 5-Fluoro-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′ carboxamide; 5-Methyl-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 5-methyl-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 8-Fluoro-N-methoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 5-Fluoro-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 7-Methyl-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-methoxy-7-methyl-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; N-Methoxy-7-methyl-6-(1-methyl-6-isoquinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 8-Methoxy-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 8-Methoxy-6-(8-methyl-7-quinolyl)spiro[4H-1,3-benzodioxine-2,4′-piperidine]-1′-carboxamide; 8-chloro-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 8-Chloro-N-methoxy-6-(8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; 6-(4-Hydroxy-8-methyl-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide; and pharmaceutically acceptable salts of such compounds.
12. A pharmaceutical composition comprising at least one compound according to claim 1 , and at least one pharmaceutically acceptable excipient.
13. 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 claim 1 .
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 pharmaceutical composition according to claim 12 .
15. A method of treating a subject who is suffering from weight gain associated with drug therapy with an antipsychotic agent, said method comprising administering a compound according to claim 1 .
16. The method of claim 15 , wherein the antipsychotic agent is selected from clozapine, risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, and combinations thereof.