US2010297035A1PendingUtilityA1
Thiazole Amides, Imidazole Amides and Related Analogues
Est. expirySep 26, 2025(expired)· nominal 20-yr term from priority
A61P 3/04A61P 25/00C07D 403/06C07D 231/14C07D 417/14A61P 1/08C07D 233/64C07D 417/04C07D 417/06C07D 401/06C07D 277/30C07D 417/12C07D 471/04C07D 451/04C07D 233/90C07D 277/28
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Claims
Abstract
Thiazole amides, imidazole amides and related analogues of the Formula: are provided, in which variables are as described herein. Such compounds may be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) and other disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is: (a) C 1 -C 8 alkyl, C 2 -C 8 alkenyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 1 , R 3 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 3 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 4 is hydrogen or taken together with R 1 , R 2 or R 3 to form an optionally substituted 4- to 8-membered heterocycloalkyl;
n is 1, 2 or 3;
X is CH 2 or C═O;
Y is:
A is CR 5 , N, NR 6 or S; and B is CR 5 , N, NR 6 , O or S; such that at least one of A and B is not CR 5 ;
D and E are independently CR 5 or N;
G is NR 6 , O or S;
Each R 5 is hydrogen, halogen, cyano or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Each R 6 is hydrogen or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Ar is phenyl, naphthyl, biphenyl or a 5- to 13-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
such that Y is not
if R 1 is C 1 -C 6 alkyl and Ar is optionally substituted phenyl;
and if Y is
then at least one of R 2 and R 3 forms a ring.
2 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2 or 3;
X is CH 2 or C═O;
R 1 is: (a) C 1 -C 8 alkyl, C 2 -C 8 alkenyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 1 , R 3 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 3 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 4 is hydrogen or taken together with R 1 , R 2 or R 3 to form an optionally substituted 4- to 8-membered heterocycloalkyl;
A is CR 5 , N, NR 6 or S; and B is CR 5 , N, NR 6 , O or S; such that at least one of A and B is not CR 5 and A is not N if B is O;
Each R 5 is hydrogen, halogen, cyano or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Each R 6 is hydrogen or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Ar is phenyl, naphthyl, biphenyl or a 5- to 13-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, and mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
3 . A compound or salt according to claim 2 , wherein B is N, NR 6 , O or S.
4 . A compound or salt according to claim 2 , wherein A is N, NR 6 or S.
5 . A compound or salt according to claim 4 , wherein A is N or NR 6 .
6 . A compound or salt according to claim 5 , wherein B is N, NR 6 , O or S.
7 . A compound or salt according to claim 2 , wherein the compound has the formula:
8 . A compound or salt according to claim 2 , wherein the compound has the formula:
9 . A compound or salt according to any one of claims 1 - 8 , wherein X is CO.
10 . A compound or salt according to any one of claims 1 - 8 , wherein X is CH 2 .
11 . A compound or salt according to any one of claims 1 - 10 , wherein R 3 is hydrogen or C 1 -C 8 alkyl.
12 . A compound or salt according to any one of claims 1 - 11 , wherein the compound has the formula:
13 . A compound or salt according to any one of claims 1 - 11 , wherein the compound has the formula:
14 . A compound or salt according to claim 13 , wherein the compound has the formula:
15 . A compound or salt according to any one of claims 1 - 11 , wherein the compound has the formula:
16 . A compound or salt according to any one of claims 1 - 15 , wherein Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with form 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, C 2 -C 4 alkanoyloxy and mono- and di-(C 1 -C 4 alkyl)amino.
17 . A compound or salt according to any one of claims 1 - 15 , wherein Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.
18 . A compound or salt according to any one of claim 1 - 11 or 13 - 15 , wherein R 1 is C 1 -C 6 alkyl and R 4 is hydrogen.
19 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2 or 3;
X is CH 2 or C═O;
R 1 is: (a) C 1 -C 8 alkyl, C 2 -C 8 alkenyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 1 , R 3 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 3 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 4 is hydrogen or taken together with R 1 , R 2 or R 3 to form an optionally substituted 4- to 8-membered heterocycloalkyl;
A is CR 5 , N or NR 6 ; and B is CR 5 , N, NR 6 , O or S; such that at least one of A and B is not CR 5 ;
Each R 5 is hydrogen, halogen, cyano or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Each R 6 is hydrogen or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Ar is phenyl, naphthyl, biphenyl or a 5- to 13-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, and mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
20 . A compound or salt according to claim 19 , wherein X is CO.
21 . A compound or salt according to claim 19 , wherein X is CH 2 .
22 . A compound or salt according to any one of claims 19 - 21 , wherein R 3 is hydrogen or C 1 -C 8 alkyl.
23 . A compound or salt according to any one of claims 19 - 22 , wherein the ring designated:
24 . A compound or salt according to any one of claims 19 - 23 , wherein the compound has the formula:
25 . A compound or salt according to any one of claims 19 - 23 , wherein the compound has the formula:
26 . A compound or salt according to claim 25 , wherein the compound has the formula:
27 . A compound or salt according to claim 25 , wherein the compound has the formula:
28 . A compound or salt according to any one of claims 19 - 27 , wherein Ar is phenyl, pyridyl, naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with form 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, C 2 -C 4 alkanoyloxy and mono- and di-(C 1 -C 4 alkyl)amino.
29 . A compound or salt according to any one of claims 19 - 27 , wherein Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.
30 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2 or 3;
X is CH 2 or C═O;
R 1 is: (a) C 1 -C 8 alkyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 2 is C 1 -C 8 alkyl or taken together with R 1 , R 3 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 3 is hydrogen, C 1 -C 8 alkyl or taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 4 is hydrogen or taken together with R 1 , R 2 or R 3 to form an optionally substituted 4- to 8-membered heterocycloalkyl;
Such that at least one of R 2 and R 3 forms a ring;
D and E are independently CR 5 or N;
Each R 5 is hydrogen, halogen, cyano or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Ar is phenyl, naphthyl, biphenyl or a 5- to 13-membered heteroaryl, each of which is optionally substituted with from 0 to 4 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, and mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
31 . A compound or salt according to claim 30 , wherein D and E are independently CR 5 .
32 . A compound or salt according to claim 31 , wherein D and E are each CH.
33 . A compound or salt according to claim 30 , wherein D or E is N.
34 . A compound or salt according to any one of claims 30 - 33 , wherein X is CO.
35 . A compound or salt according to any one of claims 30 - 33 , wherein X is CH 2 .
36 . A compound or salt according to any one of claims 30 - 35 , wherein R 3 is hydrogen or C 1 -C 8 alkyl.
37 . A compound or salt according to any one of claims 30 - 36 , wherein the compound has the formula:
38 . A compound or salt according to any one of claims 30 - 35 , wherein the compound has the formula:
39 . A compound or salt according to claim 38 , wherein the compound has the formula:
40 . A compound or salt according to claim 38 , wherein the compound has the formula:
41 . A compound or salt according to any one of claims 30 - 35 , wherein the compound has the formula:
42 . A compound or salt according to any one of claims 30 - 41 , wherein Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with form 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, C 2 -C 4 alkanoyloxy and mono- and di-(C 1 -C 4 alkyl)amino.
43 . A compound or salt according to any one of claims 30 - 41 , wherein Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.
44 . A compound or salt according to any one of claims 30 - 36 and 38 - 43 , wherein R 1 is C 1 -C 6 alkyl and R 4 is hydrogen.
45 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2 or 3;
X is CH 2 or C═O;
R 1 is: (a) C 1 -C 8 alkyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 2 is C 1 -C 8 alkyl or taken together with R 1 , R 3 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 3 is hydrogen, C 1 -C 8 alkyl or taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 4 is hydrogen or taken together with R 1 , R 2 or R 3 to form an optionally substituted 4- to 8-membered heterocycloalkyl;
G is NR 6 , O or S;
Each R 6 is hydrogen or C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Ar is phenyl, naphthyl, biphenyl or a 5- to 13-membered heteroaryl, each of which is optionally substituted with from 0 to 4 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, and mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
46 . A compound or salt according to claim 45 , wherein G is O or S.
47 . A compound or salt according to claim 45 , wherein G is NR 6 .
48 . A compound or salt according to any one of claims 45 - 47 , wherein X is CO.
49 . A compound or salt according to any one of claims 45 - 47 , wherein X is CH 2 .
50 . A compound or salt according to any one of claims 45 - 49 , wherein R 3 is hydrogen or C 1 -C 8 alkyl.
51 . A compound or salt according to any one of claims 45 - 50 , wherein the compound has the formula:
52 . A compound or salt according to any one of claims 45 - 50 , wherein the compound has the formula:
53 . A compound or salt according to claim 52 , wherein the compound has the formula:
54 . A compound or salt according to claim 52 , wherein the compound has the formula:
55 . A compound or salt according to claim 45 , wherein the compound has the formula:
56 . A compound or salt according to any one of claims 45 - 55 , wherein Ar is phenyl, pyridyl, naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with form 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, C 2 -C 4 alkanoyloxy and mono- and di-(C 1 -C 4 alkyl)amino.
57 . A compound or salt according to any one of claims 45 - 55 , wherein Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.
58 . A compound or salt according to any one of claim 45 - 50 or 51 - 57 , wherein R 1 is C 1 -C 6 alkyl and R 4 is hydrogen.
59 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2 or 3;
X is CH 2 or C═O;
R 1 is: (a) C 1 -C 8 alkyl, C 2 -C 8 alkenyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 1 , R 3 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 3 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl or taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from R A ;
R 4 is hydrogen or taken together with R 1 , R 2 or R 3 to form an optionally substituted 4- to 8-membered heterocycloalkyl;
R 7 represents 0, 1 or 2 substituents independently chosen from hydrogen, halogen, cyano and C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Each R 8 independently represents 0, 1 or 2 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether and C 1 -C 8 alkoxy, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, and mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
60 . A compound or salt according to claim 59 , wherein X is CO.
61 . A compound or salt according to claim 59 , wherein X is CH 2 .
62 . A compound or salt according to any one of claims 59 - 61 , wherein each R 8 represents 0 or 1 substituent independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.
63 . A compound or salt according to any one of claims 59 - 62 , wherein R 3 is hydrogen or C 1 -C 8 alkyl.
64 . A compound or salt according to any one of claims 59 - 63 , wherein the compound satisfies the formula:
65 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X is CH 2 , CHOH or C═O;
R 1 is: (a) C 1 -C 8 alkyl or (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ; or (b) taken together with R 2 or R 4 to form a 4- to 8-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from oxo and R A ;
R 7 represents 0, 1 or 2 substituents independently chosen from hydrogen, halogen, cyano and C 1 -C 8 alkyl that is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano and C 1 -C 4 alkoxy;
Ar is naphthyl or a 9- or 10-membered heteroaryl, each of which is optionally substituted with from 0 to 4 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, and 5- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R A is independently chosen at each occurrence from:
(a) hydroxy, halogen, amino, cyano, nitro, oxo, —COOH, aminosulfonyl and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkanoyl, C 3 -C 8 alkanone, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkoxycarbonyl, C 2 -C 8 alkanoyloxy, C 2 -C 8 alkanoylamino, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, mono- and di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- and di-(C 1 -C 6 alkyl)aminosulfonyl, C 1 -C 6 alkylsulfonylamino, and mono- and di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
66 . A compound or salt according to claim 65 , wherein X is CHOH or CO.
67 . A compound or salt according to claim 65 , wherein X is CH 2 .
68 . A compound or salt according to any one of claims 65 - 67 , wherein the compound satisfies the formula:
wherein each R 8 independently represents 0, 1 or 2 substituents independently chosen from:
(a) hydroxy, halogen, amino, cyano, nitro, —COOH and aminocarbonyl; and
(b) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkyl ether and C 1 -C 8 alkoxy, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
69 . A compound or salt according to claim 68 , wherein each R 8 represents 0 or 1 substituent independently chosen from halogen, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy.
70 . A compound or salt according to any one of claims 1 - 69 , wherein the compound has a K i value of 1 micromolar or less, as determined using an assay for H3 receptor GTP binding.
71 . A compound or salt according to claim 70 , wherein the compound has a K i value of 100 nanomolar or less, as determined using an assay for H3 receptor GTP binding.
72 . A pharmaceutical composition, comprising at least one compound or salt according to any one of claims 1 - 69 in combination with a physiologically acceptable carrier or excipient.
73 . A pharmaceutical composition according to claim 72 wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
74 . A method for treating a condition responsive to H3 receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of a compound or salt according to any one of claims 1 - 69 , and thereby alleviating the condition in the patient.
75 . A method according to claim 74 , wherein the compound exhibits H3 receptor antagonist activity.
76 . A method according to claim 74 , wherein the condition is attention deficit disorder, attention deficit hyperactivity disorder, schizophrenia, a cognitive disorder, epilepsy, migraine, narcolepsy, allergic rhinitis, vertigo, motion sickness, a memory disorder, or Parkinson's disease.
77 . A method according to claim 74 , wherein the condition is obesity, an eating disorder or diabetes.
78 . A method according to claim 74 , wherein the patient is a human.
79 . A compound or salt according to any one of claims 1 - 69 , wherein the compound or salt is radiolabeled.
80 . A method for determining the presence or absence of H3 receptor in a sample, comprising the steps of:
(a) contacting a sample with a compound or salt according to any one of claims 1 - 69 , under conditions that permit binding of the compound to H3 receptor; and (b) detecting a level of the compound bound to H3 receptor, and therefrom determining the presence or absence of H3 receptor in the sample.
81 . A method according to claim 80 , wherein the compound is radiolabeled, and wherein the step of detection comprises the steps of:
(i) separating unbound compound from bound compound; and (ii) detecting the presence or absence of bound compound in the sample.
82 . A packaged pharmaceutical preparation, comprising:
(a) a pharmaceutical composition according to claim 72 in a container; and (b) instructions for using the composition to treat a condition responsive to H3 receptor modulation in a patient.
83 . A packaged pharmaceutical preparation according to claim 82 , wherein the condition is attention deficit disorder, attention deficit hyperactivity disorder, schizophrenia, a cognitive disorder, epilepsy, migraine, narcolepsy, allergic rhinitis, vertigo, motion sickness, a memory disorder, or Parkinson's disease.
84 . A packaged pharmaceutical preparation according to claim 82 , wherein the condition is obesity, an eating disorder or diabetes.
85 . The use of a compound or salt according to any one of claims 1 - 69 for the manufacture of a medicament for the treatment of a condition responsive to H3 receptor modulation.
86 . A use according to claim 85 , wherein the condition is attention deficit disorder, attention deficit hyperactivity disorder, schizophrenia, a cognitive disorder, epilepsy, migraine, narcolepsy, allergic rhinitis, vertigo, motion sickness, a memory disorder, or Parkinson's disease.
87 . A use according to claim 85 , wherein the condition is obesity, an eating disorder or diabetes.Join the waitlist — get patent alerts
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