US2017119786A1PendingUtilityA1
Heterocyclic modulators of lipid synthesis
Est. expiryMar 8, 2031(~4.7 yrs left)· nominal 20-yr term from priority
A61K 31/451A61K 31/501A61K 31/55C07D 401/14C07D 491/10C07D 405/10A61K 31/453A61K 31/496A61K 31/454A61K 31/4525C07D 491/052C07D 401/04C07D 487/04C07D 413/14A61K 31/5377A61K 31/437C07D 491/048C07D 401/06C07D 401/12C07D 491/107C07D 513/04A61K 31/506C07D 405/12C07D 413/10C07D 405/14C07D 401/10A61K 31/4545C07D 471/04C07D 405/04A61K 31/444A61K 31/435
62
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Claims
Abstract
Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders, such as non-alcoholic steatohepatitis (NASH).
Claims
exact text as granted — not AI-modified1 . A method of treating fatty liver disease in a subject in need thereof, the method comprising administering to the subject a fatty acid synthase inhibitor having a formula of:
(a) Formula (IX)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl, wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl; or
(b) Formula (X):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH or halogen;
L 3 is C(R 60 ) 2 , O or NR 50 ;
each R 60 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 , wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
each R 50 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 501 ) 2 , C 1 -C 4 straight or branched alkyl, wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
n is 1, 2 or 3;
m is 1 or 2;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl, wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, C 1 -C 2 alkyl;
each R 26 is independently —OH, —CN, halogen, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 1 -C 4 alkyl), or —C(O)—N(R 501 ) 2 , wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
s is 0, 1 or 2;
each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and
wherein two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 ; or
(c) Formula (VI-J)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 35 is —C(O)—R 351 , —C(O)—NHR 351 , —C(O)—O—R 351 or S(O) 2 R 351 ; and
R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or
(d) Formula (XII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
each R 241 is independently H or C 1 -C 2 alkyl; and
R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl; or
(e) Formula (XIII)
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1;
each u is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl; or
(f) Formula (XIV):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl) t -N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O t -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl; or
(g) Formula (XV):
or pharmaceutically acceptable salts thereof, wherein:
L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R 50 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;
n is 1, 2, or 3;
m is 1 or 2 with the proviso that n+m≧3;
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and
R 22 is H, halogen, or C 1 -C 2 alkyl; or
(h) Formula (XVI):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
each of R 24 and R 25 is independently H, C 1 -C 4 alkyl, or halogen; or
(i) Formula (XVII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
R 241 is H or C 1 -C 2 alkyl; or
(j) Formula (XVIII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or
(k) Formula (XIX):
or pharmaceutically acceptable salts thereof, wherein:
each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;
each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);
each R 27 is independently H or C 1 -C 4 alkyl or both R 27 are C 1 -C 4 alkyl and join to form a 3- to 6-membered ring together with the N to which they are attached and wherein the ring optionally includes one oxygen atom as one of the members of the ring;
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and
R 22 is H, halogen or C 1 -C 2 alkyl; or
(l) Formula (XX):
or a pharmaceutically acceptable salt thereof, wherein:
L-Ar is
Ar is
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogen;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl;
R 24 is —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O—(C 3 -C 5 cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R 24 is optionally substituted with one or more hydroxyl or halogen; and
R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen; or
(m) Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl).
2 . The method of claim 1 , wherein the fatty liver disease is selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
3 . (canceled)
4 . The method of claim 1 , wherein the fatty acid synthase inhibitor has a Formula (IX), (X), (XII), (XIV), (XV), or (XX).
5 - 10 . (canceled)
11 . The method of claim 1 , wherein the fatty acid synthase inhibitor is selected from:
12 . The method of claim 1 , wherein the fatty acid synthase inhibitor is selected from:
13 . A method of treating a disease or condition selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, liver cirrhosis, liver fibrosis, and liver cancer, in a subject in need thereof, the method comprising administering to the subject a fatty acid synthase inhibitor having a formula of:
(a) Formula (IX)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl, wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl; or
(b) Formula (X):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH or halogen;
L 3 is C(R 60 ) 2 , O or NR 50 ;
each R 60 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 , wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
each R 50 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 501 ) 2 , C 1 -C 4 straight or branched alkyl, wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
n is 1, 2 or 3;
m is 1 or 2;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl, wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, C 1 -C 2 alkyl;
each R 26 is independently —OH, —CN, halogen, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 1 -C 4 alkyl), or —C(O)—N(R 501 ) 2 , wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
s is 0, 1 or 2;
each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and
wherein two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 ; or
(c) Formula (VI-J)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 35 is —C(O)—R 351 , —C(O)—NHR 351 , —C(O)—O—R 351 or S(O) 2 R 351 ; and
R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or
(d) Formula (XII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
each R 241 is independently H or C 1 -C 2 alkyl; and
R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl; or
(e) Formula (XIII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1;
each u is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl; or
(f) Formula (XIV):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl) t -N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O t -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl; or
(g) Formula (XV):
or pharmaceutically acceptable salts thereof, wherein:
L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R 50 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;
n is 1, 2, or 3;
m is 1 or 2 with the proviso that n+m≧3;
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and
R 22 is H, halogen, or C 1 -C 2 alkyl; or
(h) Formula (XVI):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
each of R 24 and R 25 is independently H, C 1 -C 4 alkyl, or halogen; or
(i) Formula (XVII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
R 241 is H or C 1 -C 2 alkyl; or
(j) Formula (XVIII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or
(k) Formula (XIX):
or pharmaceutically acceptable salts thereof, wherein:
each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;
each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);
each R 27 is independently H or C 1 -C 4 alkyl or both R 27 are C 1 -C 4 alkyl and join to form a 3- to 6-membered ring together with the N to which they are attached and wherein the ring optionally includes one oxygen atom as one of the members of the ring;
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl) when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and
R 22 is H, halogen or C 1 -C 2 alkyl; or
(l) Formula (XX):
or a pharmaceutically acceptable salt thereof, wherein:
L-Ar is
Ar is
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogen;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl;
R 24 is —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O—(C 3 -C 5 cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R 24 is optionally substituted with one or more hydroxyl or halogen; and
R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen; or
(m) Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl).
14 - 18 . (canceled)
19 . A method of treating a disease or condition in which interleukin 1 beta (IL1β) levels are elevated, or a disease or condition in which regulatory t cells (T reg ) are reduced or suppressed, or a disease or condition in which t-helper (T h ) cell levels are elevated in a subject in need thereof, the method comprising administering to the subject a fatty acid synthase inhibitor having a formula of:
(a) Formula (IX)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl, wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl; or
(b) Formula (X):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH or halogen;
L 3 is C(R 60 ) 2 , O or NR 50 ;
each R 60 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 , wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
each R 50 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 501 ) 2 , C 1 -C 4 straight or branched alkyl, wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
n is 1, 2 or 3;
m is 1 or 2;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl, wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, C 1 -C 2 alkyl;
each R 26 is independently —OH, —CN, halogen, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 1 -C 4 alkyl), or —C(O)—N(R 501 ) 2 , wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
s is 0, 1 or 2;
each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and
wherein two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 ; or
(c) Formula (VI-J)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 35 is —C(O)—R 351 , —C(O)—NHR 351 , —C(O)—O—R 351 or S(O) 2 R 351 ; and
R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or
(d) Formula (XII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
each R 241 is independently H or C 1 -C 2 alkyl; and
R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl; or
(e) Formula (XIII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1;
each u is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl; or
(f) Formula (XIV):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl) t -N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O t -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
each t is independently 0 or 1; and
each R 241 is independently H or C 1 -C 2 alkyl; or
(g) Formula (XV):
or pharmaceutically acceptable salts thereof, wherein:
L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R 50 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;
n is 1, 2, or 3;
m is 1 or 2 with the proviso that n+m≧3;
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and
R 22 is H, halogen, or C 1 -C 2 alkyl; or
(h) Formula (XVI):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
each of R 24 and R 25 is independently H, C 1 -C 4 alkyl, or halogen; or
(i) Formula (XVII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl; and
R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, alkyl)-N(R 241 ) 2 , alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
t is 0 or 1;
u is 0 or 1;
with the proviso that when u is 1, t is 1; and
R 241 is H or C 1 -C 2 alkyl; or
(j) Formula (XVIII):
or pharmaceutically acceptable salts thereof, wherein:
L-Ar is
Ar is
with the proviso that when L-Ar is
Ar is not
L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or
(k) Formula (XIX):
or pharmaceutically acceptable salts thereof, wherein:
each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;
each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);
each R 27 is independently H or C 1 -C 4 alkyl or both R 27 are C 1 -C 4 alkyl and join to form a 3- to 6-membered ring together with the N to which they are attached and wherein the ring optionally includes one oxygen atom as one of the members of the ring;
Ar is
Het is a 5- to 6-membered heteroaryl;
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 11 is H or —CH 3 ;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and
R 22 is H, halogen or C 1 -C 2 alkyl; or
(l) Formula (XX):
or a pharmaceutically acceptable salt thereof, wherein:
L-Ar is
Ar is
R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogen;
each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
R 3 is H or F;
R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
R 22 is H, halogen or C 1 -C 2 alkyl;
R 24 is —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O—(C 3 -C 5 cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R 24 is optionally substituted with one or more hydroxyl or halogen; and
R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen; or
(m) Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
R 22 is H, halogen, or C 1 -C 2 alkyl; and
R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl).
20 - 21 . (canceled)
22 . The method of claim 13 , wherein the fatty acid synthase inhibitor has a Formula (IX), (X), (XII), (XIV), (XV), or (XX).
23 . The method of claim 19 , wherein the fatty acid synthase inhibitor has a Formula (IX), (X), (XII), (XIV), (XV), or (XX).
24 - 28 . (canceled)
29 . The method of claim 13 , wherein the fatty acid synthase inhibitor is selected from:
30 . The method of claim 13 , wherein the fatty acid synthase inhibitor is selected from:
31 . The method of claim 19 , wherein the disease or condition in which interleukin 1 beta (IB1β) levels are elevated is selected from Familial Mediterranean fever (FMF), Pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), Cryopyrin-associated periodic syndromes (CAPS), Hyper IgD syndrome (HIDS), Adult and juvenile Still disease, Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS), Blau syndrome; Sweet syndrome, Deficiency in IL-1 receptor antagonist (DIRA), Recurrent idiopathic pericarditis, Macrophage activation syndrome (MAS), Urticarial vasculitis, Antisynthetase syndrome, Relapsing chondritis, Behçet disease, Erdheim-Chester syndrome (histiocytosis), Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO), Rheumatoid arthritis, Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), Urate crystal arthritis (gout), Type 2 diabetes, Smoldering multiple myeloma, Postmyocardial infarction heart failure, Osteoarthritis, Transfusion-related acute lung injury, Ventilator-induced lung injury, Pulmonary fibrosis including Idiopathic, Chronic obstructive pulmonary disease and Asthma.
32 . The method of claim 19 , wherein the disease or condition in which regulatory t cells (T reg ) are reduced or suppressed is selected from Psoriasis, Rheumatoid arthritis, Multiple sclerosis, Ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis and transplant rejection.
33 . The method of claim 19 , wherein the elevated t-helper cell is T h 1, T h 2, T h 9, or. T h 17.
34 . The method of claim 33 , wherein the elevated t-helper cell is T 17 .
35 . The method of claim 19 , wherein T reg cells are suppressed.
36 . The method of claim 19 , wherein the fatty acid synthase inhibitor is selected from:
37 . The method of claim 19 , wherein the fatty acid synthase inhibitor is selected from:
38 . The method of claim 19 , wherein the disease or condition in which t-helper (T h ) cell levels are elevated is selected from Psoriasis, Rheumatoid arthritis, Multiple sclerosis, Ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis and transplant rejection.Cited by (0)
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