US2008015183A1PendingUtilityA1
Substituted quinazolin-4-ylamine analogues
Est. expiryJan 17, 2022(expired)· nominal 20-yr term from priority
Inventors:Rajagopal BakthavatchalamCharles A. BlumHarry BrielmannTimothy CaldwellStéphane De LombaertKevin HodgettsXiaozhang ZhengJames KrauseUri HerzbergTaeyoung Yoon
A61P 39/02A61P 43/00A61P 9/14A61P 9/10A61P 3/10A61P 31/18A61P 29/00A61P 29/02A61P 35/00A61P 31/22A61P 25/28A61P 25/04A61P 25/02A61P 25/06A61P 3/04A61P 1/04C07D 215/42C07D 417/14C07D 413/14A61P 11/08C07D 471/04A61P 21/02A61P 11/16A61P 11/00A61P 21/00A61P 11/14C07D 401/12C07D 401/04C07D 419/14C07D 215/44C07D 237/34A61P 17/04A61P 1/02A61P 1/14A61P 17/02A61P 15/00A61P 11/06C07D 401/14C07D 239/94C07D 405/14
60
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Claims
Abstract
Substituted quinazolin-4-ylamine analogues are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkanone, C 2 -C 8 alkenyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 2 is a 5- to 7-membered aromatic heterocycle, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
Ar 1 is a 5- to 10-membered aromatic carbocycle or heterocycle, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m -1-S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ; and
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl).
2 . A compound according to claim 1 , wherein V is N.
3 . A compound according to claim 1 , wherein X is N.
4 .- 5 . (canceled)
6 . A compound according to claim 1 , wherein W, Y and Z are each independently N or CH.
7 . A compound according to 6 , wherein W and Y are each CH and Z is N, or wherein W and Z are each CH and Y is N.
8 . A compound according to claim 1 , wherein Ar 2 is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and thiadiazolyl, each of which is unsubstituted or substituted with 1 or 2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 2 -C 8 alkyl ether, C 1 -C 6 alkanoyl, amino, mono- and di-(C 1 -C 6 alkyl)amino.
9 . A compound according to claim 1 , wherein Ar 2 is pyridyl, isoxazolyl, thiadiazolyl or pyrazolyl, each of which is unsubstituted or substituted with halogen, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl.
10 . A compound according to claim 1 , wherein Ar 1 is phenyl or pyridyl, optionally substituted with halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy or haloC 1 -C 6 alkoxy.
11 . A compound according to claim 1 , wherein U is CR 2 , and R 2 is:
(i) hydrogen or halogen; or (ii) C 1 -C 6 alkyl, —(CH 2 ) n NH 2 , —(CH 2 ) n NH(C 1 -C 8 alkyl), —(CH 2 ) n N(C 1 -C 8 alkyl) 2 , —(CH 2 ) n (5- to 8-membered heterocycloalkyl), or —(CH 2 ) n OH, each of which is unsubstituted or substituted with from 1 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl.
12 .- 13 . (canceled)
14 . A compound according to claim 13 , wherein Ar 1 and Ar 2 are each pyridyl, substituted with 1 substituent independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy.
15 . (canceled)
16 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkanone, C 2 -C 8 alkenyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 1 and Ar 2 are independently chosen from phenyl and 5- and 6-membered aromatic heterocycles, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m -1-S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ;
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl); and
R 7 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, mono- or di(C 1 -C 8 alkyl)amino or a 3- to 10-membered heterocycle, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkyl ether, haloC 1 -C 8 alkyl and haloC 1 -C 8 alkoxy.
17 . A compound according to claim 16 , wherein V is N.
18 . A compound according to claim 16 , wherein X is N.
19 .- 20 . (canceled)
21 . A compound according to claim 16 , wherein W, Y and Z are each independently N or CH.
22 . A compound according to 21 , wherein W and Y are each CH and Z is N, or wherein W and Z are each CH and Y is N.
23 . A compound according to claim 16 , wherein Ar 2 is phenyl or pyridyl, each of which is optionally substituted with 1 or 2 substituents selected from halogen, cyano, C 1 -C 6 alkyl and haloC 1 -C 6 alkyl.
24 . A compound according to claim 16 , wherein Ar 2 is phenyl, optionally substituted with halogen, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl.
25 . A compound according to claim 16 , wherein Ar 1 is phenyl or pyridyl, optionally substituted with halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy or haloC 1 -C 6 alkoxy.
26 . A compound according to claim 16 , wherein U is CR 2 and R 2 is
(i) hydrogen or halogen; or (ii) C 1 -C 6 alkyl, —(CH 2 ) n NH 2 , —(CH 2 ) n NH(C 1 -C 8 alkyl), —(CH 2 ) n N(C 1 -C 8 alkyl) 2 , —(CH 2 ) n (5- to 8-membered heterocycloalkyl) or —(CH 2 ) n OH, each of which is unsubstituted or substituted with from 1 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkyl and haloC 1 -C 6 alkyl.
27 .- 28 . (canceled)
29 . A compound according to claim 16 , wherein R 7 comprises a nitrogen atom directly bonded to the SO 2 .
30 . A compound according to claim 29 , wherein R 7 is amino, mono- or di(C 1 -C 6 alkyl)amino, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, each of which is unsubstituted or substituted with from 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl and haloC 1 -C 6 alkyl.
31 . A compound according to claim 16 , wherein R 7 is C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, optionally substituted with from 1 to 5 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl ether, haloC 1 -C 6 alkyl and haloC 1 -C 6 alkoxy.
32 .- 33 . (canceled)
34 . A compound of the formula:
Wherein:
V, X, W, Y and Z are selected from the following combinations:
V
X
W
Y
Z
N
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
N
CH
CH
CH
N
CH
CH
N
CH
CH
N
CH
N
CH
CH
N
CH
N
CH
N
CH
CH
CH
N
CH
N
CH
CH
N
CH
N
CH
CH
N
N
CH
N
CH
CH
CH
N
N
CH
CH
CH
N
N
CH
CH
N
CH
N
CH
N
CH
N
N
CH
N
N
N
N
CH
N
CH
N
N
CH
N
N
CH
CH
N
N
CH
N
CH
N
N
N
N
CH
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 6 alkyl)amino;
Ar 1 and Ar 2 are independently selected from phenyl and 5- to 7-membered aromatic heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m —, —S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ;
R 3 and R 4 are:
(i) each independently selected from:
(a) hydrogen;
(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 3 -C 8 alkanone, C 2 -C 8 alkanoyl, C 2 -C 8 alkyl ether, C 6 -C 10 arylC 0 -C 8 alkyl, 5- to 10-membered heterocycleC 0 -C 8 alkyl and —(SO 2 )C 1 -C 8 alkyl, each of which is optionally substituted with from 1 to 9 substituents independently selected from R b ; and
(c) groups that are joined to an R 5 or R 6 to form a 4- to 10-membered heterocyclic group that is unsubstituted or substituted with from 1 to 6 substituents independently selected from R b ; or
(ii) joined to form, with the N to which they are bound, a 4- to 10-membered heterocyclic group that is unsubstituted or substituted with from 1 to 6 substituents independently selected from R b , C 1 -C 8 alkanoyl, 4- to 7-membered heterocycloalkylC 0 -C 4 alkyl, and mono- and di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl;
R 5 and R 6 are, independently at each occurrence:
(i) each independently selected from:
(a) hydrogen or hydroxy;
(b) C 1 -C 8 alkyl, unsubstituted or substituted with 1 or 2 substituents independently selected from R b ; and
(c) groups that are joined to R 3 or R 4 to form a 4- to 10-membered heterocyclic group that is unsubstituted or substituted with from 1 to 6 substituents independently selected from R b ;
(ii) taken together to form a keto group; or
(iii) joined to form a 3- to 7-membered carbocyclic or heterocyclic ring, unsubstituted or substituted with from 1 to 4 substituents selected from R b ;
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl); and
n is 1, 2 or 3.
35 .- 36 . (canceled)
37 . A compound or salt according to claim 34 , wherein Y is N and W and Z are CH.
38 . A compound or salt according to claim 34 , wherein Z is N and W and Y are CH.
39 . A compound or salt according to claim 34 , wherein W, Y and Z are each CH.
40 . A compound or salt according to claim 34 , wherein Ar 1 and Ar 2 are independently selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted with 0, 1 or 2 substituents.
41 . A compound or salt according to claim 40 , wherein:
(i) Ar 1 is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 or 2 substituents selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkoxy; and (ii) Ar 2 is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, cyano, amino, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, —(SO 2 )R 2 , —NR x S(O) m —, and —N(S(O m ) 2 ; wherein m is 1 or 2, R x is hydrogen or C 1 -C 6 alkyl, and R 2 is C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, amino, mono- or di-(C 1 -C 6 alkyl)amino or a 5- to 10-membered, N-linked heterocyclic group, each of which R 2 is optionally substituted with R b .
42 . A compound or salt according to claim 41 , wherein:
(i) Ar 1 is pyridyl, unsubstituted or substituted with halogen, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl; and (ii) Ar 2 is phenyl or pyridyl, each of which is unsubstituted or substituted with halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 2 -C 4 alkyl ether, C 1 -C 4 alkanoyl or —(SO 2 )R a , wherein R a is C 1 -C 4 alkyl or haloC 1 -C 4 alkyl.
43 . A compound or salt according to claim 42 , wherein:
(i) Ar 1 is pyridin-2-yl, 3-methyl-pyridin-2-yl, 3-trifluoromethyl-pyridin-2-yl or 3-halo-pyridin-2-yl; and (ii) Ar 2 is phenyl, 2-pyridyl or 3-pyridyl, each of which is substituted at the 4-position with trifluoromethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, t-butyl, trifluoromethyl or 2,2,2-trifluoro-1-methyl-ethyl.
44 . A compound or salt according to claim 34 , wherein R 3 and R 4 are each independently:
(i) hydrogen; or (ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, phenylC 0 -C 4 alkyl, indanylC 0 -C 4 alkyl, 5- to 6-membered heteroarylC 0 -C 4 alkyl, or 4- to 7-membered heterocycloalkylC 0 -C 4 alkyl, each of which is unsubstituted or substituted with from 1 to 4 substituents independently selected from hydroxy, halogen, amino, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkoxy.
45 . A compound or salt according to claim 44 , wherein R 3 and R 4 are each independently:
(i) hydrogen; or (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, 5- to 7-membered heterocycloC 0 -C 4 alkyl, C 2 -C 6 alkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from hydroxy, halogen and C 1 -C 4 alkyl.
46 . A compound or salt according to claim 44 , wherein one of R 3 and R 4 is pyridylC 0 -C 4 alkyl, pyrimidylC 0 -C 4 alkyl, imidazolylC 0 -C 4 alkyl or tetrazolylc 0 -C 4 alkyl, each of which is substituted with 0, 1 or 2 substituents.
47 . A compound or salt according to claim 34 , wherein R 3 and R 4 are joined to form a 5 to 10-membered heterocyclic group that is substituted with from 0 to 4 substituents.
48 . A compound or salt according to claim 47 , wherein the heterocyclic group is substituted with at least one substituent selected from hydroxy, halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy, C 1 -C 4 alkanoyl, and aminocarbonyl.
49 . A compound or salt according to claim 47 , wherein the heterocyclic group comprises an aromatic ring.
50 . (canceled)
51 . A compound or salt according to claim 47 , wherein the heterocyclic group is a 5- to 10-membered heterocycloalkyl, substituted with from 0 to 4 substituents.
52 .- 54 . (canceled)
55 . A compound or salt according to claim 34 , wherein each R 5 and R 6 is independently selected from hydrogen and C 1 -C 6 alkyl.
56 . (canceled)
57 . A compound or salt according to claim 34 , wherein n is 1.
58 .- 60 . (canceled)
61 . A compound or salt according to claim 1 wherein the compound has an IC 50 value of 100 nanomolar or less in a capsaicin receptor calcium mobilization assay.
62 . A compound or salt according to claim 16 wherein the compound has an IC 50 value of 100 nanomolar or less in a capsaicin receptor calcium mobilization assay.
63 . A compound or salt according to claim 34 , wherein the compound has an IC 50 value of 100 nanomolar or less in a capsaicin receptor calcium mobilization assay.
64 .- 69 . (canceled)
70 . A pharmaceutical composition, comprising at least one compound or salt according to claim 1 in combination with a physiologically acceptable carrier or excipient.
71 . A pharmaceutical composition, comprising at least one compound or salt according to claim 16 in combination with a physiologically acceptable carrier or excipient.
72 . A pharmaceutical composition, comprising at least one compound or salt according to claim 34 in combination with a physiologically acceptable carrier or excipient.
73 . A pharmaceutical composition according to claim 70 wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
74 . A pharmaceutical composition according to claim 71 wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
75 . A pharmaceutical composition according to claim 72 wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
76 . A method for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell expressing a capsaicin receptor with at least one compound or salt of the formula:
wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, N(R z ), S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 arylC 0 -C 8 alkyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 1 and Ar 2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m -1-S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ; and
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
and thereby reducing calcium conductance of the capsaicin receptor.
77 . A method according to claim 76 , wherein the compound is a compound according to claim 1 .
78 . A method according to claim 76 , wherein the compound is a compound according to claim 16 .
79 . A method according to claim 76 , wherein the compound is a compound according to claim 34 .
80 . A method according to claim 76 , wherein the cell is a neuronal cell that is contacted in vivo in an animal.
81 . A method according to claim 80 , wherein during contact the compound is present within a body fluid of the animal.
82 . A method according to claim 81 , wherein the compound is present in the blood of the animal at a concentration of 100 nanomolar or less.
83 . A method according to claim 80 , wherein the animal is a human.
84 . A method according to claim 80 , wherein the compound is administered orally.
85 .- 93 . (canceled)
94 . A method according to claim 89 , wherein the compound is present in the blood of the patient at a concentration of 100 nanomolar or less.
95 . A method for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a capsaicin receptor modulatory amount of at least one compound or salt of the formula:
wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, N(R z ), S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 arylC 0 -C 8 alkyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 1 and Ar 2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m -1-S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ; and
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
and thereby alleviating the condition in the patient.
96 . A method according to claim 95 , wherein the compound is a compound according to claim 1 .
97 . A method according to claim 95 , wherein the compound is a compound according to claim 16 .
98 . A method according to claim 95 , wherein the compound is a compound according to claim 34 .
99 . A method according to claim 95 , wherein the patient is suffering from (i) exposure to capsaicin, (ii) burn or irritation due to exposure to heat, (iii) burns or irritation due to exposure to light, (iv) burn, bronchoconstriction or irritation due to exposure to tear gas, air pollutants or pepper spray, or (v) burn or irritation due to exposure to acid.
100 . A method according to claim 95 , wherein the compound is present in the blood of the animal at a concentration of 100 nanomolar or less.
101 . A method according to claim 95 , wherein the condition is treating asthma or chronic obstructive pulmonary disease.
102 . A method for treating pain in a patient, comprising administering to a patient suffering from pain a capsaicin receptor modulatory amount of at least one compound or salt of the formula:
wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, N(R z ), S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 arylC 0 -C 8 alkyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 1 and Ar 2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m —, —S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ; and
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
and thereby alleviating pain in the patient.
103 . A method according to claim 102 , wherein the compound is a compound according claim 1 .
104 . A method according to claim 102 , wherein the compound is a compound according to claim 16 .
105 . A method according to claim 102 , wherein the compound is a compound according to claim 34 .
106 . A method according to claim 102 , wherein the compound is present in the blood of the animal at a concentration of 100 nanomolar or less.
107 . A method according to claim 102 , wherein the patient is suffering from neuropathic pain.
108 . A method according to claim 102 , wherein the pain is associated with a condition selected from: postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, toothache, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal cord injury-related pain, surgery-related pain, musculoskeletal pain, back pain, headache, migraine, angina, labor, hemorrhoids, dyspepsia, Charcot's pains, intestinal gas, menstruation, cancer, venom exposure, irritable bowel syndrome, inflammatory bowel disease, and/or trauma.
109 . A method according to claim 102 , wherein the patient is a human.
110 . A method for treating itch in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt of the formula:
wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, N(R z ), S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 arylC 0 -C 8 alkyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 1 and Ar 2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m -1-S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ; and
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
and thereby alleviating itch in the patient.
111 . A method according to claim 110 , wherein the compound is a compound according to claim 1 .
112 . A method according to claim 110 , wherein the compound is a compound according to claim 16 .
113 . A method according to claim 110 , wherein the compound is a compound according to claim 34 .
114 . A method for treating cough or hiccup in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt of the formula:
wherein:
U, V, X, W, Y and Z are selected from the following combinations:
U
V
X
W
Y
Z
CR 2
N
CH
CH
CH
CH
CR 2
CH
N
CH
CH
CH
N
CH
N
CH
CH
CH
CR 2
N
CH
CH
N
CH
CR 2
CH
N
CH
N
CH
N
CH
N
CH
N
CH
CR 2
N
CH
CH
CH
N
CR 2
CH
N
CH
CH
N
N
CH
N
CH
CH
N
CR 2
N
CH
N
CH
CH
CR 2
CH
N
N
CH
CH
N
CH
N
N
CH
CH
CR 2
N
CH
N
CH
N
CR 2
CH
N
N
CH
N
CR 2
N
N
N
CH
N
N
CH
N
N
CH
N
CR 2
N
CH
CH
N
N
CR 2
CH
N
CH
N
N
CR 2
N
N
CH
N
N
N
CH
N
CH
N
N;
R 1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, C 1 -C 8 alkoxy, haloC 1 -C 8 alkoxy and mono- and di-(C 1 -C 8 alkyl)amino;
R 2 is:
(i) hydrogen, halogen or cyano;
(ii) C 2 -C 8 alkanoyl or C 3 -C 8 alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(iii) a group of the formula —R c -M-A-R y , wherein:
R c is C 0 -C 3 alkyl;
M is a bond, N(R z ), S, SO 2 , (C═O) p N(R z ), N(R z )(C═O) p , SO 2 N(R z ), or N(R z )SO 2 , wherein p is 0 or 1;
A is a bond or C 1 -C 8 alkyl, optionally substituted with from 1 to 3 substituents independently selected from R d ; and
R y and R z , if present, are:
(a) independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 arylC 0 -C 8 alkyl, a 4- to 10-membered carbocycle, or joined to R c to form a 4- to 10-membered carbocycle, wherein each R y and R z is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ; or
(b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from R d ;
wherein R d is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylthio, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
Ar 1 and Ar 2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LR a ;
L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) m —, —NR x —, —C(═O)NHR x —, —NHR x C(═O)—, —NR x S(O) m -1-S(O) m NR x — and —N[S(O) m R x ]S(O) m —; wherein m is independently selected at each occurrence from 0, 1 and 2; and R x is independently selected at each occurrence from hydrogen and C 1 -C 8 alkyl;
R a is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C 1 -C 8 alkyl)amino and (3- to 10-membered heterocycle)C 1 -C 6 alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from R b ; and
R b is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, phenyl, phenyl(C 1 -C 8 alkyl), mono- and di-(C 1 -C 6 alkyl)amino, (SO 2 )C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle) (C 1 -C 8 alkyl);
and thereby alleviating cough or hiccup in the patient.
115 . A method according to claim 114 , wherein the compound is a compound according to claim 1 .
116 . A method according to claim 114 , wherein the compound is a compound according to claim 16 .
117 . A method according to claim 114 , wherein the compound is a compound according to claim 34 .
118 .- 133 . (canceled)
134 . A compound or salt according to claim 51 , wherein the heterocyclic group is substituted with from 1 to 4 substituents independently selected from methyl and ethyl.
135 . A compound or salt according to claim 1 , wherein the compound is selected from the group consisting of:
(4-trifluoromethyl-phenyl)-[6-(2-trifluoromethyl-phenyl)-phthalazin-1-yl]amine; (4-tert-Butyl-phenyl)-(6-pyridin-2-yl-phthalazin-1-yl)-amine; (4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinolin-4-yl]-amine; (4-tert-butyl-phenyl)-[6-(2-trifluoromethyl-phenyl)-isoquinolin-1-yl]-amine; (4-trifluoromethyl-phenyl)-[6-(2-trifluoromethyl-phenyl)-isoquinolin-1-yl]amine; and (4-tert-butyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-amine.Join the waitlist — get patent alerts
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