US 7,544,803 B2
Vanilloid receptor ligands and their use in treatments
Christopher Hulme, Indianapolis, Ind. (US); Mghele Vellah Ncube, Simi Valley, Calif. (US); Mark H. Norman, Thousand Oaks, Calif. (US); Vassil I. Ognyanov, Thousand Oaks, Calif. (US); Liping H. Pettus, Thousand Oaks, Calif. (US); Xianghong Wang, Moorpark, Calif. (US); and Jiawang Zhu, Thousand Oaks, Calif. (US)
Assigned to Amgen Inc., Thousand Oaks, Calif. (US)
Filed on Jan. 21, 2005, as Appl. No. 11/41,173.
Claims priority of provisional application 60/538772, filed on Jan. 23, 2004.
Prior Publication US 2005/0165049 A1, Jul. 28, 2005
Int. Cl. C07D 215/38 (2006.01)
U.S. Cl. 546—159  [546/153; 546/157] 4 Claims
 
1. A compound having the formula,

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt, wherein,
P is selected from phenyl, heteroaryl or heterocyclyl;
R1 and R2 are independently selected from halo, alkyl, alkoxy, cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO2, —OH, ═O, —OCF3, —CF3, NR4R5, —S(O)mR6, —S(O)2NR4R5, —OS(O)2R6, —OS(O)2CF3, —O(CH2)nNR4R5, —C(O)CF3, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar, —C(O)(CH2)nOR6, C(O)(CH2)nNR4R5, —C(O)alkoxy, —C(O)NR4R5, —(CH2)nC(O)alkoxy, (CH2)nOC(O)R6, —O(CH2)nOR6, —(CH2)nOR6, —(CH2)nC(O)NR4R5, —(CH2)nN(R4)C(O)R6, —(CH2)nS(O)2NR4R5, (CH2)nN(R4)S(O)2R6, -ZAr, —(CH2)nS(O)2R6, —(OCH2)nS(O)2R6, N(R4)S(O)2R6, —N(R4)C(O)R6, —(CH2)nN(R4)S(O)2R6, —(CH2)nN(R4)C(O)R6 or —(CH2)nC(O)alkyl;
R3 is selected from alkyl, alkoxy, —CF3, halo, —O(CH2)nOR6, —O(CH2)nNR4R5, phenyl, cyclohexyl, benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl; wherein said alkyl, alkoxy, phenyl, cyclohexyl, benzo[1,3]dioxolyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl, triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl, oxediazolyl, isothiazolyl, isoxazolyl and thiadiazolyl groups may be optionally substituted by one or more groups, which may be the same or different, selected from R2;
R4 and R5 may be the same or different and represent —H or alkyl or R4 and R5 together with the nitrogen atom to which they are attached form a hetero cyclic ring;
R6 is —H, alkyl or aryl;
R7 is —H, alkyl or aryl;
R8 is selected from H, alkyl, hydroxyalkyl, cycloalkyl, aralkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, -—(O)mR6, —C(O)CF3, —C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar, —C(O)(CH2)nOR6, —C(O)(CH2)nNR4R5, C(O)alkoxy, —C(O)NR4R5, —(CH2)nC(O)alkoxy, —(CH2)nOC(O)R6, —(CH2)nOR6, —(CH2)nNR4R5, —(CH2)nC(O)NR4R5, —(CH2)nN(R4)C(O)R6, —(CH2)nS(O)2NR4R5, —(CH2)nN(R4)S(O)2R6, —(CH2)nS(O)2R6, —(CH2)nN(R4)S(O)2R6, —(CH2)nN(R4)C(O)R6 or —(CH2)nC(O)alkyl; or where X is NR8 and Y is C(R9)2, R8 may combine with R1 to form a benzoquinuclidine group;
R9 is H or R1;
Ar is aryl or heteroaryl, each of which may be optionally substituted by R2;
Z is a bond, S, NR7 or CH2;
m is 0, 1 or 2;
n is an integer value from 1 to 6;
q and r are independently selected from 0, 1, 2 or 3; and
s is 0, 1, 2 or 3;
with the proviso that said compound of formula (I) is not a compound selected from:
N-{3-[(N,N-Dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;
N-{3-[(N,N-Dimethylamino)methyl]-1-formyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;
N-{1-Acetyl-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;
N-{3-[(N,N-Dimethylamino)methyl]-1-methylsulfonyl-1,2,3,4-tetrahydro-7-quinolinyl}-4-biphenylcarboxamide;
5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3 carboxamide;
5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide;
5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide; and
5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.