ZA200604543B - Heterocyclic anti-migraine agents - Google Patents

Heterocyclic anti-migraine agents Download PDF

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Publication number
ZA200604543B
ZA200604543B ZA200604543A ZA200604543A ZA200604543B ZA 200604543 B ZA200604543 B ZA 200604543B ZA 200604543 A ZA200604543 A ZA 200604543A ZA 200604543 A ZA200604543 A ZA 200604543A ZA 200604543 B ZA200604543 B ZA 200604543B
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South Africa
Prior art keywords
methyl
indazol
piperidine
dihydroquinazolin
ethyl
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ZA200604543A
Inventor
Luo Guanglin
Andrew P Degnan
John E Macor
Prasad V Chaturvedula
Chen Ling
Gene M Dubowchik
George O Tora
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Bristol Myers Squibb Co
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Description

HETEROCYCLIC ANTI-MIGRAINE AGENTS
FIELD OF THE INVENTION
The present invention relates to novel small molecule antagonists of calcitonin gene-related peptide receptors (“CGRP-receptor”), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.
BACKGROUND OF THE INVENTION
Calcitonin gene-related peptide (CGRP) is a naturally occurring 37- amino-acid peptide first identified in 1982 (Amara, S. G. et al, Science 1982, 298, 240-244). Two forms of the peptide are expressed (®<CGRP and BCGRP) which differ by one and three amino acids in rats and humans, respectively. The peptide is widely distributed in both the peripheral (PNS) and central nervous system (CNS), principally localized in sensory afferent and central neurons, and displays a number of biological effects, including vasodilation.
When released from the cell, CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological action predominantly by activation of intracellular adenylate cyclase (Poyner, D. R. et al, Br J Pharmacol 1992, 105, 441-7; Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8.). Two classes of CGRP receptors, CGRP, and CGRP, have been proposed based on the antagonist properties of the peptide fragment CGRP(8-37) and the ability of linear analogues of CGRP to activate CGRP; receptors (Juaneda, C. et al. TiPS 2000, 21, 432-438). However, there is lack of molecular evidence for the CGRP, receptor (Brain, S. D. et al, TiPS 2002, 23, 51-53). The CGRP, receptor has three components: (i) a 7 transmembrane calcitonin receptor-like receptor (CRLR); (ii) the single transmembrane receptor activity modifying protein type one (RAMPL); and (iii) the intracellular receptor component protein (RCP) (Evans B. N. et al., J
Biol Chem. 2000, 275, 31438-43). RAMP is required for transport of CRLR to the plasma membrane and for ligand binding to the CGRP-receptor (McLatchie,
L. M. et al, Nature 1998, 393, 333-339). RCP is required for signal transduction (Evans B. N. et al., J Biol Chem. 2000, 275, 31438-43). There are known species- specific differences in binding of small molecule antagonists to the CGRP- receptor with typically greater affinity seen for antagonism of the human receptor than for other species (Brain, S. D. et al, TiPS 2002, 23, 51-53). The amino acid sequence of RAMP1 determines the species selectivity, in particular, the amino acid residue Trp74 is responsible for the phenotype of the human receptor (Mallee et al. J Biol Chem 2002, 277, 14294-8).
Inhibitors at the receptor level to CGRP are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, menopausal flushing, and asthma. CGRP receptor activation has been implicated in the pathogenesis of migraine headache (Edvinsson L. CNS
Drugs 2001;15(10):745-53; Williamson, D. J. Microsc. Res. Tech. 2001, 53, 167- 178.; Grant, A. D. Brit. J. Pharmacol. 2002, 135, 356-362.). Serum levels of
CGRP are elevated during migraine (Goadsby PJ, et al. Ann Neurol 1990;28:183- 7) and treatment with anti-migraine drugs returns CGRP levels to normal coincident with alleviation of headache (Gallai V. et al. Cephalalgia 1995;15: 384-90). Migraineurs exhibit elevated basal CGRP levels compared to controls (Ashina M, et al., Pain. 2000;86(1-2):133-8.2000). Intravenous CGRP infusion produces lasting headache in migraineurs (Lassen LH, et al. Cephalalgia. 2002
Feb;22(1):54-61). Preclinical studies in dog and rat report that systemic CGRP blockade with the peptide antagonist CGRP(8-37) does not alter resting systemic hemodynamics nor regional blood flow (Shen, Y-T. et al, J Pharmacol Exp Ther 2001, 298, 551-8). Thus, CGRP-receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular liabilities of active vasoconstriction associated with non-selective 5-HT p/p agonists, ‘triptans’ (e.g., sumatriptan). See Olesen, et al., New England Journal of Medicine, 2004, 350 (11), 1104-1110.
A number of non-peptidic, small molecule CGRP-receptor antagonists have been recently reported. WO 97/09046 and equivalents disclose inter alia quinine and quinidine related compounds which are ligands, in particular antagonists, of CGRP-receptor. WO 98/09630 and WO 98/56779 and equivalents disclose inter alia variously substituted, nitrobenzamide compounds as CGRP-receptor antagonists. WO 01/32649, WO 01/49676, and WO 01/32648 and equivalents disclose inter alia a series of 4-oxobutanamides and related cyclopropane derivatives as CGRP-receptor antagonists. WO 00/18764, WO 08/11128 and WO 00/55154 and equivalents disclose inter alia benzimidazolinyl piperidines as antagonists to CGRP-receptor. Unrelated to CGRP, a series of somatostatin antagonists have been disclosed in WO 99/52875 and WO 01/25228 and equivalents. See also US 6,344,449, US 6,313,097, US 6,521,609, US 6,552,043, US 20030181462, US20030191068 and WO 03/076432 and related applications. Yet other CGRP-receptor antagonist and related applications include US20030139417A1, US20030181462, US20030191068A1,
US20030212057A1, US20030236282A1, US20040014679A1,
US20040076587A1, US20040132716A1, US20040192729A1,
W02004082602A2, WO2004082605A2, W0O2004082678A1,
WO02004083187A1, W02004092168A1, W0O2004092166A2 and
WO02004091514A2. A great need for the development of novel CGRP-receptor antagonists effective for the treatment of neurogenic inflammation, migraine and other disorders exists.
SUMMARY OF THE INVENTION
Thus according to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I)
Q
~ AA , 4 or pharmaceutically acceptable salts or solvates thereof wherein
Vis a S-membered ring selected from the group consisting of imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, isoxazolyl, oxadiazolyl, triazolyl, thiadiazolyl and tetrazolyl; or . a 6-membered ring selected from the group consisting of pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl and tetrazinyl; or a fused bicyclic ring system selected from the group consisting of indolyl, isoindolyl, indazolyl, benzimidazolyl, benzythiazolyl, triazolopyridinyl,imidazopyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and benzfuranyl; wherein V is optionally substituted with one to three of the same or different substituents selected from the group consisting of
C\4alkyl, C)salkoxy, C,shydroxyalkyl, C(O)OC:.3alkyl,
C alkylcarbonyl, carboxy, C;4alkylcarboxy, trifluoromethyl, halo, cyano, amino, amido, nitro, carbamoyl, ureido,
C,.salkylamino, C; 4dialkylamino, C;..dialkylaminoC,.,alkyl, sulphonamide and sulphonyl; and
V optionally contains 1 or 2 carbonyls; provided that if t is 1, then V is optionally substituted with one of the ubstitutents selected from the group consisting of halo,
C,4alkyl, Cy _salkylidine, salkylidine,C;4alkoxy, Cishydroxyalkyl,
C,.salkylcarbonyl, trifluoromethyl, halo and cyano; and
V optionally contains 1 or 2 carbonyls; (V"), wherein tis O or 1; and
V'is selected from the group consisting of Cs cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, : pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and wherein
V' is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, Cyalkyl, C)shaloalkyl,
Cialkoxy, hydroxy, amino, Cs.scycloalkyl,
C,alkylamino, C,4dialkylamino, (C1.3alkyl)g.oureido, C(O)OC;.3alkyl, carboxy, amido, nitro, phenyl and benzyl; and wherein
V' optionally contains 1 or 2 carbonyls; and
V and V' are optionally interrupted by C,_salkylene, O, -(CH2)0.2C(0)-(CH3)o.2-; or -N-Cj4alkyl, said C,_jalkylene being optionally interrupted by or having attached thereto
O,NorS;
U is CHa, O, or NH;
Qis (S*)R% $Y is C alkylene or C;.salkylidene and sis O or 1;
R*is R* or R* wherein
R*is y) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of 0, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings; (ii) a4 to 6 membered heterocycle containing one to : three of the same or different heteroatoms selected from the group consisting of O, N and §, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; (iii) Cs.cycloalkyl; (iv) carbazolyl, fluorenyl, phenyl, -O-phenyl, -O-
C,.4alklylene-phenyl, or napthyl; or (v) Cisalkyl, Cp7alkenyl, -C(O)R*, CHC(O)O-R?,
CH(CH;)C(0)O-R* ,-C(0)O-R* or Cy.salkynyl; and wherein R is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-
C,.3alkylenephenyl, -C;.3alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C,.alkyl, C|.3mono-bi- tri-haloalkyl, C,.3mono-bi-tri-haloalkyloxy, (Ci. salkyl), ;amine, -OR®, -C(O)R”, -C(0)O-R?, -O-
C(OR®, -N®R*)2, -CONR),
NR)CO)R?)2, -NR*ICONR),
NR*)C(O)OR*, -O-C(O)N(R*),,
NR*)SO;R?, -SO:N(R*)2and -SOR’;
WQ 2005/056550 PCT/US2004/040721
R¥is H or -C, salkyl;
R*®is R* but is not said phenyl or said substituted phenyl; provided that if V and V' together form substitued or unsubstituted imidazol-2-y! or a substituted or unsubstituted fused bicyclic system containing imidazol-2-yl, then R? is R*";
D is O, NCN or NSO,C.salkyl;
Ais C,Nor CH; m and n are independently 0, 1 or 2; provided that if m and n are 0, then A is not N; if mis 2, then n is not 2; or if n is 2, then m is not 2;
Eis N,CH or C; pisQorl; if pis 1, then G, J and E together form A* or A”
A is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of
O, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle;
AY is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle;
wherein A* and AY are optionally substituted with
C,4alkyl, Ci4alkoxy, Cy.shaloalkyl, cyano,
Cs.rcycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or if p is O such that G and J are each attached to A, then A is C, and : G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein GJA is
Afor A.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein m is 1 and n isl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 1.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein pis 1 and E is N.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein pis 1 and E is C.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 1 and E is CH.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 1 and G, J and A form a A”.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 1 and G, J and A form a A” and wherein A*is a fused heterocycle with two fused rings each having 6 members.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 1 and G, J and A form a A” and wherein A* is 3,4- dihydro-1H-quinazolin-2-one.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 1 and G, J and A form a AX and wherein A* is 3,4- dihydro-1H-quinazolin-2-one optionally halogenated.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is I and G, J and A form a A* and wherein A” is 8- fluoro-2-ox0-1,2-dihydroquinazolin-3(4H)-yl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 0.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 0 and G, J and A form a A™.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 0 and G, J and A form a A* and wherein A*is a fused heterocycle with two fused rings each having 6 members and where said fused heterocycle forms a spirocyclic ring system containing A.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein p is 0 and G, J and A form a A* and wherein A*is a fused heterocycle with two fused rings each having 6 members, wherein one of said 6-membered rings, Which contains A, further contains a nitrogen and an oxygen which are interrupted by a carbonyl said oxygen attached to A and wherein said fused heterocycle forms a spirocyclic ring system containing A.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein is s is 1and S” is methylene.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein is s is 1, S*is methylene and R3is R®.
According to a another emobdiment of the first aspect of the present : invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein is s is 1, S? is methylene and R® is R* wherein R¥is a heterocycle having two fused rings, one of said fused rings having six members and being attached to SY and the other of said rings having 5 members and containing two nitrogens.
According to a another emobdiment of the first aspect of the present “invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein is s is 1, SY is methylene and R® is R** wherein R*is 7- methyl-1H-indazol-5-yl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein is s is 1, Sis methylene and R? is R* wherein R*is 7- ethyl-3-methyl-1H-indazol-5-yl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein D is O and U is O.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein D is O and U is CHa.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein D is O and U is NH.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein t is 0.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein t is 1.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein t is 1 and V' is selected from the group consisting of Cs. scycloalkyl, phenyl, tetrahydrofuranyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino and dioxolanyl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein t is 1 and V' is selected from the group consisting of phenyl, pyridyl and piperidinyl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof wherein t is 1 and V' is selected from the group consisting of phenyl, pyridyl and piperidinyl and V' is substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C,4alkyl,
C,shaloalkyl, C;4alkoxy, hydroxy, amino, Cs.icycloalkyl, C,4alkylamino,
C,«dialkylamino, (C,.salkyl)o.ureido, C(O)OC,.salkyl, carboxy, amido, nitro, phenyl and benzyl.
According to a another emobdiment of the first aspect of the present invention are compounds of Formula (I) or pharmaceutically acceptable salts or

Claims (1)

  1. What is claimed is:
    1. A compound of Formula (I) Q D AA u N A— oO 4 or a pharmaceutically acceptable salt or solvate thereof wherein Vis a S-membered ring selected from the group consisting of imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, isoxazolyl, oxadiazolyl, triazolyl, thiadiazolyl and tetrazolyl; or a 6-membered ring selected from the group consisting of pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl and tetrazinyl; or a fused bicyclic ring system selected from the group consisting of indolyl, isoindolyl, indazolyl, benzimidazolyl, benzythiazolyl, triazolopyridinyl, imidazopyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and benzfuranyl; wherein V is optionally substituted with one to three of the same or different substituents selected from the group consisting of
    C).salkyl, Cy 4alkoxy, C 1 shydroxyalkyl, C(0)OC:.3alkyl, Calkylcarbonyl, carboxy, Ci4alkylcarboxy, trifluoromethyl, halo, cyano, amino, amido, nitro, carbamoyl, ureido, Ci4alkylamino, C,4dialkylamino, C).4dialkylaminoC;.zalkyl, sulphonamide and sulphonyl; and V optionally contains 1 or 2 carbonyls; provided that if tis 1, then V is optionally substituted with one of the substitutents selected from the group consisting of halo,
    Ci4alkyl, C;.salkylidine, salkylidine,C, 4alkoxy, C,shydroxyalkyl, C4alkylcarbonyl, trifluoromethyl, halo and cyano; and V optionally contains 1 or 2 carbonyls; (V'), wherein tis O or 1; and V' is selected from the group consisting of C,.qcycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and wherein V' is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, Cy4alkyl, C\4haloalkyl, C, alkoxy, hydroxy, amino, C.;cycloalkyl, C1alkylamino, C,4dialkylamino,
    (C1.3alkyl).oureido, C(O)OC; salkyl, carboxy, amido, nitro, phenyl and benzyl; and wherein V' optionally contains 1 or 2 carbonyls; and V and V' are optionally interrupted by Ci.;alkylene, oO, -(CH2)0.2C(0)-(CHz)o-2= or -N-Cy.salkyl, said C,.salkylene being optionally interrupted by or having attached thereto O,NorS; U is CHa, O, or NH; Qis (SMR; wherein S? is C;.salkylene or C,.salkylidene and s isOor1l; R*isR® orR® wherein
    R*is 1) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon : atom of said carbonyl is a member of said fused rings; (ii) a4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; . (ili) Cs.ocycloalkyl; (iv) carbazolyl, fluorenyl, phenyl, -O-phenyl, -O- C,alklylene-phenyl, or napthyl; or ) Cisalkyl, Czalkenyl, -C(O)R?, CHC(O)O-R?, CH(CH;3)C(0)O-R*,-C(0)O-R* or Cyqalkynyl; and wherein R* is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-
    C,.salkylenephenyl, -C,.3alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, Cyalkyl, C,.3mono-bi- tri-haloalkyl, C;.3mono-bi-tri-haloalkyloxy, (Ci. jalkyl),.;amine, -OR?,-C(O)R?, -C(0)O-R*, -O-C(O)R”, NR). C(ONR®)2, NR*)CO)R* 2. - NR*ICONR®),, -NR*)C(O)OR*, -O-
    C(ONR®),, -NR*)SO:R?,
    -SO,N(R*),and -SOR*; R¥'is H or -C; alkyl; Ris R* but is not said phenyl or said substituted phenyl;
    provided that if V and V' together form substitued or unsubstituted imidazol-2-yl or a substituted or unsubstituted fused bicyclic system containing imidazol-2-yl, then R® is R®;
    D is O, NCN or NSO,C;.salkyl; Ais C,N or CH; : m and n are independently 0, 1 or 2; provided that if m and n are 0, then A is not N; if m is 2, then n is not 2; or if n is 2, then m is not 2; EisN,CHorC; pisOorl; if pis 1, then G, J and E together form Aor A A* is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle . containing one to four of the same or different heteroatoms selected from the group consisting of O, Nand S; and ) optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle; A’ is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl! is a member of said 4 to 6 membered heterocycle; wherein A*and A’ are optionally substituted with Csalkyl, C; alkoxy, Ci.shaloalkyl, cyano,
    Cs.cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazoliny), imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, : pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or if p is 0 such that G and J are each attached to A, then A is C, and G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein GJA is Ator A’.
    2. A compound according to claim 1 wherein mis 1 and nisl.
    3. A compound according to claim 1 wherein pis 1. i 4, A compound according to claim 1 wherein pis 1 and Eis N.
    5. A compound according to claim 1 wherein pis 1and Eis C.
    6. A compound according to claim 1 wherein p is 1 and E is CH.
    7. A compound according to claim 1 wherein pis 1 and G, J and A form a A%
    8. A compound according to claim 1 wherein p is 1 and G, J and A form a A* and wherein A” is a fused heterocycle with two fused rings each having 6 members. Oo A compound according to claim 1 wherein p is 1 and G, J and A form a A” and wherein A* is 3,4-dihydro-1H-quinazolin-2-one.
    10. A compound according to claim 1 wherein p is1 and G, J and A form a A* and wherein A* is 3,4-dihydro-1H-quinazolin-2-one optionally halogenated.
    11. A compound according to claim 1 wherein p is 1 and G,J and A form a A* and wherein A’ is 8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl.
    12. A compound according to claim 1 wherein p is 0.
    13. A compound according to claim 1 wherein p is 0 and G, J and A form a
    A*.
    14. A compound according to claim 1 wherein p is0and G,J and A form a A* and wherein A*is a fused heterocycle with two fused rings each having 6 members and where said fused heterocycle forms a spirocyclic ring system containing A.
    15. A compound according to claim 1 wherein p is 0 and G, J and A form a A* and wherein Ais a fused heterocycle with two fused rings each having 6 members, wherein one of said 6-membered rings, which contains A, further contains a nitrogen and an oxygen which are interrupted by a carbonyl said oxygen attached to A and wherein said fused heterocycle forms a spirocyclic ring system containing A.
    16. A compound according to claim 1 wherein s is land S’ is methylene.
    17. A compound according to claim 1 wherein is s is 1, SY is methylene and Ris R®.
    18. A compound according to claim 1 wherein is s is 1, SY is methylene and R%is R* wherein R* is a heterocycle having two fused rings, one of said fused rings having six members and being attached to SY and the other of said rings having 5 members and containing two nitrogens.
    19. A compound according to claim 1 wherein is s is 1, S” is methylene and R3is R% wherein R* is 7-methyl-1H-indazol-5-yl.
    20. A compound according to claim 1 wherein is s is 1, $7 is methylene and R3is R* wherein R* is 7-ethyl-3-methyl-1H-indazol-5-yl.
    21. A compound according to claim 1 wherein D isO and Uis O.
    22. A compound according to claim 1 wherein D is O and U is CHa.
    23. A compound according to claim 1 wherein D is O and U is NH.
    24. A compound according to claim 1 wherein t is 0.
    25. A compound according to claim 1 wherein tis 1.
    26. A compound according to claim 1 wherein tis 1 and V' is selected from the group consisting of Cs.scycloalkyl, phenyl, tetrahydrofuranyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
    pyranyl, pyridyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino and dioxolanyl.
    27. A compound according to claim 1 wherein tis 1 and V' is selected from the group consisting of phenyl, pyridyl and piperidinyl.
    28. A compound according to claim 1 wherein tis 1 and V' is selected from the group consisting of phenyl, pyridyl and piperidinyl and V' is substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C1 4alkyl, C, shaloalkyl, C;4alkoxy, hydroxy, amino, Cs.scycloalkyl, C4alkylamino, C;4dialkylamino, (C1-3alkyl)ooureido, C(O)OC:salkyl, carboxy, amido, nitro, phenyl and benzyl.
    29. A compound according to claim 1 wherein t is 1 and V' is selected from the group consisting of phenyl, pyridyl and piperidinyl and V'is substituted with 1 or 2 of the same or different substituents selected from the group consisting of C;_«dialkylamino, C(0)OC,.3alkyl, carboxy, amido, nitro and phenyl.
    30. A compound according to claim 1 wherein V is said 5-membered ning.
    31. A compound according to claim 1 wherein V is said 6-membered ring.
    32. A compound according to claim 1 wherein V is said fused bicyclic ring system.
    33. A compound according to claim 1 wherein V is furanyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidine, quinolinyl, Cj alkylcarbonyl, carboxy, indazolyl, triazolopyridinyl or imidazopyridinyl.
    34. A compound according to claim 1 wherein V contains a carbonyl.
    35. A compound according to claim 1 wherein V is furanyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidine, quinolinyl, C,.salkylcarbonyl, carboxy, indazolyl or [1,2,4]Triazolo[4,3-a]pyridin-3-yl or H- ‘Imidazo[1,5-a]pyridin-3-yl).
    36. A compound according to claim 1 wherein V and V' are interrupted by methylene, ethylene and -(CH2)p2C(O)-(CH2)o-2--
    37. A compound according to claim 1 wherein V and V' are interrupted by methylene, ethylene and -(CH3)0.2C(0)-(CHy)o.2- wherein said interrupting substituents are unsubstituted.
    38. A compound according to claim 1 wherein s is 1, S? is methylene and Ris R* wherein R*is an optionally C)_salkyl-substituted indazolyl; U is CHa, O, or NH; Dis O; A is CH; m and n are each 1; Eis N; pis 1; and G, J and E together form A”, wherein A’is an optionally halogenated dihydroquinazolinone.
    39. A compound according to claim 1 wherein V is furanyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidine, quinolinyl, C,.salkylcarbonyl, carboxy, indazolyl, triazolopyridinyl or imidazopyridinyl; tisOorl;
    V' is selected from the group consisting of phenyl, pyridyl and piperidinyl and V' is substituted with 1 or 2 of the same or different substituents selected from the group consisting of C,4dialkylamino, C(0)OC;.3alkyl, carboxy, amido, nitro and phenyl; wherein V and V' are interrupted by methylene, ethylene and - (CH2)0.2C(0)-(CHz)o.o- wherein said interrupting substituents are unsubstituted; sis 1, S? is methylene and R?is R* wherein R*is an optionally C;salkyl-substituted indazolyl; U is CH,, O, or NH; Dis O; Ais CH; m and n are each 1; Eis N; pis 1; and G, J and E together form A*, wherein A” is an optionally halogenated dihydroquinazolinone.
    40. (®)-3-{ 1-{4-(7-Methyl-1H-indazol-5-yl)-3-pyridin-2-yl-butyryl]-piperidin- 4-yl}-3,4-dihydro-1H-quinazolin-2-one; (+)-3-{1-[3-(3-Benzyl-[1 2,4]oxadiazol-5-yl)-4-(7-methyl-1H-indazol-5-yl)- butyryl]-piperidin-4-yl}-3,4-dihydro-1 H-quinazolin-2-one; *)-3-{ 1-[4-(7-Methyl-1H-indazol-5-yl)-3-(3-piperidin-1 -ylmethyl- [1,2,4]oxadiazol-5-yl)-butyryl]-piperidin-4-yl }-3.4-dihydro-1H-quinazolin-2-one; (2)-3-{1-[4-(7-Methyl-1 H-indazol-5-yl)-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)- butyryl]-piperidin-4-yl }-3,4-dihydro-1H-quinazolin-2-one; (%)-3-{ 1-[4-(7-Methyl-1H-indazol-5-yl)-3-(3-methyl-[1 .2,4Joxadiazol-5-yl)- butyryl]-piperidin-4-yl }-3,4-dihydro-1H-quinazolin-2-one; (£)-3-{ 1-[4-(7-Methyl-1H-indazol-5-yl)-3-(3-pyridin-4-ylmethyl- [1 2,4]oxadiazol-5-yl)-butyryl]-piperidin-4-yl }-3,4-dihydro-1H-quinazolin-2-one;
    (x)-3-{1-[3-(3 -Dimethylaminomethyl-[1,2,4)oxadiazol-5-yl)-4-(7 -methyl-1H- indazol-5-yl)-butyryl]-piperidin-4-yl }-3,4-dihydro-1H-quinazolin-2-one; (£)-3-{1-[3-(3-Benzyl-[1 ,2,4]Joxadiazol-5-y1)-4-(7-methyl-1 H-indazol-5-yl)- butyryl]- 4,4"-piperidinyl }-1 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine;
    (2)-3-{ 1-[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-4-(7-methyl- 1H-indazol-5-yl)- butyryl]- 4,4'-piperidinyl }-1 + 2_dihydro-2'-oxospiro-[4H-3',1-benzoxazine; (£)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1- (3-benzyl-[1,2,4]0xadiazol-5-yl)-2-(7-methyl-1H-indazol-5-yD)-ethyl]-amide;
    (£)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-
    (7-methyl-1H-indazol-5-yl)-1 -(3-methyl-[1 ,2,4Joxadiazol-5-yl)-ethyl]-amide; - (x)-4-(2-Oxo0-1 .4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2- (7-methyl-1H-indazol-5-y1)-1 -(3-pyridin-4-ylmethyl-{1 ,2,4]oxadiazol-5-yl)- ethyl]-amide; ()-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-
    (3-dimethylaminomethyl-[1 2 4loxadiazol-5-yl)-2-(7-methyl-1H-indazol-5-yl)-
    ethyl]-amide; (4)-4-(2-Oxo-1 4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2- (7-ethyl-3-methyl-1H-indazol-5-yl)-1-(1H-tetrazol-5-yl)-ethyl]-amide; (#)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1-carboxylic acid [2-
    (7-ethy)-3-methyl-1H-indazol-5-yl)-1-(phenethyl-1H-tetrazol-5-yl)-ethyl]-amide;
    (4)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2- (7-ethyl-3-methyl-1H-indazol-5-yl)-1-(2-phenethyl-2H-tetrazol-5-yl)-ethyl]- amide;
    (+)-4-(2-Oxo-1 4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-
    (7-ethyl-3-methyl-1 H-indazol-5-yl)-1-(1-methyl- 1H-tetrazol-5-yl)-ethyl]-amide;
    (#)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1- (1-benzyl-1H-tetrazol-5-yl)-2-(7 -ethyl-3-methyl-1H-indazol-5 -yl)-ethyl]-amide; (+)-4-(2-Ox0-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2- (7-ethyl-3-methyl-1H-indazol-5-yl)-1-pyridin-4-yl methyl-1H-tetrazol-5-yl)-
    ethyl]-amide;
    (1)-4-(2-Ox0-1 4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2- (7-ethyl-3-methyl-1H-indazol-5-y1)-1-(2-oxo-2Phenethyl-2H-tetrazol-5-yl)- ethyl]-amide;
    (1)-4-(2-Oxo-1 4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylicacid [2-(7-
    ethyl-3-methyl- 1H-indazol-5-y1)-1-{1-(2-ox0-2-phenyl-ethyl)- 1H-tetrazol-5-y1)- ethyl}-amide;
    : (4)-3-(1-(3-(4-Ethylpyridin-2-y1)-4-(7-methyl- 1H-indazol-5- ylbutanoyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one; (+)-8-Fluoro-3-(1-(4-(7-methyl-1H-indazol-5-y})-3-(pyridin-2-
    ylbutanoylpiperidin-4-yl)-3 4-dihydroquinazolin-2(1H)-one; (#)-3-(1-(4-(7-Methyi-1 H-indazol-5-yl)-3-(pyridin-2-yl)butanoyl)piperidin-4- yhquinolin-2(1H)-one; ()-3-(1-(4-(7-Methyl-1H-indazol-5-y1)-3-(3-methylpyridin-2- yl)butanoyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one;
    ()-3-(1-(4-(7-Methyl-1H-indazol-5-y})-3-(5-methylpyridin-2- y)butanoyl)piperidin-4-yl)-3,4-dihydroguinazolin-2(1H)-one; (2)-3-(1-(3-(5-(Hydroxymethyl)pyridin-2-y!)-4-(7-methyl-1H-indazol-5- yl)butanoyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one;
    (1)-6-(1 -(7-Methyl- 1H-indazol-5-yl)-4-0x0-4-(4-(2-0xo- 1,2-dihydroquinazolin-
    3(4H)-yl)piperidin-1-yl)butan-2-yDnicotinaldehyde; (£)3-(1-(4-(7-Methyl-1H-indazol-5-yl)-3-(5-(piperidin-1-ylmethyl)pyridin-2- yl)butanoyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one; ()-N-(1-(6-Bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-ylethyl)-4-(2-0xo- 1 ,2-dihydroquinazolin-3(4H)-yl)piperidine-1 carboxamide;
    (#)-N-(2-(7-Methyl-1 H-indazol-5-y1)-1 -(pyridin-2-yl)ethyl)-4-(2-oxo0- 1,2- dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide; (£)-N-(2-(7-Methyl-1H-indazol-5-yl)-1-(4-nitropyridin-2-yl)ethyl)-4-(2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide; (@)-N-(1-(4-Fluoropyridin-2-yl)-2-(7-methyl- 1H-indazol-5-yl)ethyl)-4-(2-oxo-
    1 2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide;
    (£)-N-(2-(7-Methyl-1H-indazol-5-yl)-1 -(quinolin-2-yl)ethyl)-4-(2-oxo-1 2- dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide; ()-4-(8-Fluoro-2-ox0-1,2-dihydroquinazolin-3(4H)-yl)-N-(2-(7-methyl-1 H- indazol-5-y1)-1-(quinolin-2-yl)ethyl)piperidine- 1-carboxamide;
    N-(1-(Isoquinolin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1 -carboxamide; (£)-N-(2-(7-Methyl-1H-indazol-5-y1)-1 -(6-phenylpyridin-2-yhethyl)-4- (2-oxo-
    1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide;
    (2)-N-(2-(7-Methyl-1H-indazol-5-y})- 1-(6-methylpyridin-2-yl)ethy})-4-(2-oxo0- 1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide;
    H)-1 -(6-Bromopyridin-2-yl)-2-(7-methyl-1 H-indazol-5-yl)ethyl-4-(8-fluoro-2-
    oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate;
    (#)-1 -(6-Bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl-4-(2-0xo- 1,2-
    dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxylate;
    (#1 -(6-tert-Butoxypyridin-2-y1)-2-(7 -methyl-1H-indazol-5 -yl)ethyl-4-(2-ox0-- 1,2-dihydroquinazolin-3(4H)-yl)piperidine-1 carboxylate;
    (+)-2-(7-Methyl- 1H-indazol-5-yl)-1 -(6-0x0-1,6-dihydropyridin-2-ylethyl 4-(2- oxo-1,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxylate; @)- 1-(6-Isobutylpyridin-2-yl)-2-(7-methyl-1H-indazol-5-ylethyl 4-(8-fluoro-2-
    oxo-1 2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate; ®)-1 -(6-(3,5-Difluorobenzyl)pyridin-2-y1)-2-(7-methyl-1H-indazol-5-yl)ethyl 4- (8-fluoro-2-oxo-1 2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate;
    #*)-1 -(6-Cyanopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yDethyl 4-(8-fluoro-2- oxo-1 2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate;
    (B)-1 -(4-(Hydroxymethyl)pyridin-2-yl)-2-(7-methyl-1H-indazol-5-yDethyl 4-(2- oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxylate; ()-1-(4-Formylpyridin-2-yl)-2-(7-methyl-1H-indazol-5-yDethyl 4-(2-0x0-1,2- dihydroguinazolin-3(4H)-yl)piperidine-1-carboxylate;
    (3)-2-(2-(7-Methyl-1 H-indazol-5-yl)-1-(4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-
    yl)piperidine-1 -carbonyloxy)ethyl)isonicotinic acid;
    (£)-2-(7-Methyl-1H-indazol-5-yl)-1 -(4-(piperidine-1 -carbonyl)pyridin-2-yl)ethyl 4-(2-o0x0-1 ,2-dihydroquinazolin-3(4H)-yl)piperidi ne-1-carboxylate; N-(1-(isoquinolin-3-y1)-2-(7-methyl- 1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxamide;
    S 4-(8-fluoro-2-oxo-1 ,2-dihydroquinazolin-3(4H)-y1)-N-(1 -(isoquinolin-3-yl)-2-(7- methyl-1H-indazol-5-yl)ethyl)piperidine- 1-carboxamide;
    1-(Isoquinolin-3-y1)-2-(7-methyl- 1H-indazol-5-y})ethyl 4-(8-fluoro-2-oxo-1,2- dihydroquinazolin-3 (4H)-y))piperidine-1-carboxylate; 1-(Isoquinolin-3-y1)-2-(7-methyl-1H. -indazol-5-yl)ethyl 4-(2-oxo-1,2-
    dihydroquinazolin-3(4H)-yl)piperidine-1 carboxylate; 2-(7-methyl-1H-indazol-5-y})-1 ~(pyridin-2-yl)ethyl 4-(2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxylate; 2-(7-methyl-1H-indazol-5-yl)-1 (pyridin-2-yDethy} 4-(8-fluoro-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxylate;
    1-(Furan-2-yl)-2-(7-methyl-1 H-indazol-5-yl)ethyl 4-(2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxylate; 2-(7-Methyl-1H-indazol-5-y})-1 ~(pyridin-4-ylethyl 4-(2-oxo-1 2- dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxylate; 2-(7-Methyl-1H-indazol-5-yl)-1 -(pyridin-3-ylethyl 4-(2-oxo-1 ,2-
    dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxylate; 2-(7-Methyl-1H-indazol-5-yl)-1 ~(pyridin-3-yDethyl 4-(8-fluoro-2-oxo- 1,2- dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxylate;
    1-(Furan-2-yl)-2-(7-methyl-1H-indazol-5 -ylethyl 4-(8-fluoro-2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxylate;
    2-(7-Methyl-1H-indazol-5-yl)-1 -(quinolin-2-yl)ethyl 4-(2-oxo- 1,2- dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxylate;
    1-(4,6-Dimethylpyrimidin-2-y1)-2-(7 -methyl-1H-indazol-5-yl)ethyl 4-(2-oxo- 1,2- dihydroquinolin-3-yl)piperidine-1 -carboxylate; 1-(4,6-Dimethylpyrimidin-2-yl)-2-(7-methyl-1 H-indazol-5-yl)ethyl 4-(8-fluoro-2-
    oxo-1,2-dihydroquinazolin-3 (4H)-y))piperidine-1-carboxylate;
    1 -(Benzofuran-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(2-0x0-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxylate; (2)-N-(1-(1H-Imidazol-2-y1)-2-(7-methyl-1H-indazol-5 -yl)ethyl)-4-(2-oxo-1,2- dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxamide;
    (2)-N-(1-(1-Methyl-1 H-imidazol-2-yl)-2-(7-methyl-1 H-indazol-5-yl)ethyl)-4-(2- oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine- I-carboxamide; (2)-N-(1-(1-Benzyl-1 H-imidazol-2-yl)-2-(7 -methyl-1H-indazol-5 -yl)ethyl)-4-(2- oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (£)-N-(1-(1-(3-Fluorobenzyl)- 1H-imidazol-2-yl)-2-(7-methyl- 1H-indazol-5-
    ylethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine-1 -carboxamide; : (£)-N-(1-(1-(3,5-Difluorobenzyl)-1 H-imidazol-2-y1)-2-(7-methyl-1 H-indazol-5- yDethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (+)-N-(2-(7-Methyl-1H-indazol-5-y1)-1-(1 -phenethyl-1 H-imidazol-2-yl)ethyl)-4- (2-oxo-1,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxamide;
    (£)-N-(1-(1-(2-Fluorobenzyl)-1 H-imidazol-2-y1)-2-(7-methyl-1H-indazol-5- yDethyl)-4-(2-0x0-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (2)-N-(1-(1-(4-Fluorobenzyl)-1 H-imidazol-2-yl)-2-(7-methyl-1 H-indazol-5- yl)ethyl)-4-(2-0x0-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (£)-N-(2-(7-Methyl-1H-indazol-5-yl)-1-(1 -(pyridin-4-ylmethyl)-1H-imidazol-2-
    yl)ethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (£)-N-(1-(1-(3-Cyanobenzyl)-1 H-imidazol-2-yl)-2-(7-methyl-1 H-indazol-5- yl)ethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidi ne-1-carboxamide;
    (2)-N-(1-(1-(4-tert-Butylbenzy!l)- 1H-imidazol-2-yl)-2-(7-methyl- 1H-indazol-5- yl)ethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide;
    (£)-3-((2-(2-(7-Methyl-1 H-indazol-5-yl)-1-(4-(2-oxo-1 ,2-dihydroquinazolin- 3(4H)-yl)piperidine-1 -carboxamido)ethyl)-1H-imidazol-1 -yl)methyl)benzoic acid;
    (2)-N-(1-(1-(3-Carbamoylbenzyl)-1 H-imidazol-2-yl)-2-(7-methyl-1H-indazol-5- yl)ethyl)-(2-ox0-1 ,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxamide;
    (R)-1-(1-(3,5-difluorobenzyl)- 1H-imidazol-2-yl)-2-(7-methyl-1 H-indazol-5- yDethyl 4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1 -carboxylate;
    (2)-N-(2-(7-Methyl-1H-indazol-5-yl)-1-(1 -(2-nitrophenyl)-1H-imidazol-2- yl)ethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yDpi peridine-1-carboxamide; (R)-1-(1-(3,5-difluorobenzyl)-1 H-imidazol-2-yl)-2-(7-methyl- 1H-indazol-5- yhethyl 4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1 -carboxylate;
    S (2)-N-(2-(7-Methyl-1H-indazol-5-y1)-1 -(1-(2-nitrophenyl)-1H-imidazol-2- yhethyl)-4-(2-0xo-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (2)-4-(8-Fluoro-2-oxo-1 ,2-dihydroquinazolin-3 [4H]-yl)-N-(2{7-methyl-1H- indazol-5-yl}-1-{ 1H-tetrazol-5-yl }ethyl)piperidin-1 -carboxamide;
    (+)-4-(8-Fluoro-2-oxo-1 ,2-dihydroquinazolin-3 (4H)-y1)-N-(2-[7-methyl-1 H-
    indazol-5-yll-1-[1 -(piperidin-4-ylmethyl)-1 H-tetrazol-5-yl]ethyl)piperidin-1- carboxamide;
    (+)-4-(8-Fluoro-2-oxo-1 ,2-dihydroquinazolin-3(4H)-yl)-N-(2- [7-methyl-1H- indazol-5-yl]-1-[2-(piperidin4-ylmethyl)-1 H-tetrazol-5-ylJethyl)piperidin-1- carboxamide;
    (&)-N-(1-([1,2,4]Triazolo[4,3-a]pyridin-3 -yl)-2-(7-methyl-1 H-indazol-5-yl)ethyl)- 4-(8-fluoro-2-oxo-1 ,2-dihydroguinazolin-3(4H)-yl)piperidine-1 -carboxamide; (2)-N-(2-(7-Methyl-1 H-indazol-5-yl)-1-(1-neopentyl-1 H-tetrazol-5-yl)ethyl)-4- (2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (R)-N-(1-(H-Imidazo[1,5-a)pyridin-3-y1)-2-(7 -methyl- 1H-indazol-5-yl)ethyl)-4-
    (2-0x0-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide; (#)-N-(1-(4-Bromo-1 H-imidazol-2-y1)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2- oxo-1,2-dibydroquinazolin-3(4H)-yl)piperidine-1 -carboxamide; (x)-N-(1-(4,5-Dibromo-1 H-imidazol-2-y1)-2-(7-methyl-1 H-indazol-5-yl)ethyl)-4- (2-oxo0-1,2-dihydroquinazolin-3 (4H)-yb)piperidine-1-carboxamide;
    (#)-N-(1-(1-(3,5-Difluorobenzyl)-5-bromo- 1H-imidazol-2-yl)-2-(7-methyl-2H- indazol-5-yl)ethyl)-4-(2-ox0-1 ,2-dihydroquinazolin-3(4H)-yl)piperidine- 1- carboxamide;
    (2)-N-(1-(1-(3 -Fluorobenzyl)-4-methyl-1 H-imidazol-2-yl)-2-(7-methyl-1H- indazol-5-yl)ethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)-yD)piperidine- 1- carboxamide;
    (+)-N-(1-(4-Methyl- 1H-imidazol-2-yl)-2-(7-methyl- 1H-indazol-5-yl)ethyl)-4-(2- oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine- 1-carboxamide; (£)-N-(2-(7-Methyl-1H-indazol-5-yl)-1-(1 -(pyridin-3-ylmethyl)-1 H-imidazol-2- yhethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3 (4H)-yl)piperidine-1 carboxamide;
    S (x)-N-(2-(7-Methyl-1H-indazol-5-y1)-1-(1 -(pyridin-2-ylmethyl)-1 H-imidazol-2- yhethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3 (4H)-yl)piperidine-1 -carboxamide; ()-N-(1-(1 ~((2-Chloro-6-methylpyridin-4-yhmethyl)- 1H-imidazol-2-y1)-2-(7- methyl- 1H-indazol-5-yl)ethyl)4-(2-oxo-1 ,2-dihydroquinazolin-3(4H)- yl)piperidine- 1-carboxamide;
    : 10 (4£)-N-(2-(7-Methyl- 1H-indazo!-5-y})-1-(1-((2-methylpyridin-4-yhmethyl)- 1H- imidazol-2-yl)ethyl)-4-(2-oxo-1 ,2-dihydroquinazolin-3 (4H)-yD)piperidine-1- carboxamide; 3-(1-(3-(1-(4-tert-Butylbenzyl)- 1H-imidazol-2-yl)-4-(7-methyl-3a,7 a-dihydro- 1H-indazol-5-yl)butanoyl)piperidin-4-y1)-3 ,4-dihydroquinazolin-2(1H)-one;
    3-(1-(3-(1-(4-tert-Butylbenzyl)- 1H-imidazol-2-yl)-4-(7-methyl-3a,7 a-dihydro- 1H-indazol-5-yl)butanoyl)piperidin-4-y1)-8-fluoro-3 ,4-dihydroquinazolin-2(1H)- one; 3-(1-(4-(7-Methyl-3a,7a-dihydro-1 H-indazol-5-yl)-3-(1-(pyridin-4-ylmethyl)-1 H- imidazol-2-yl)butanoyl)piperidin-4-yl)-3 ,A-dihydroquinazolin-2(1H)-one;
    3-(1-(3-(1 H-Benzo{d]imidazol-2-yl)-4-(7 -methyl-3a,7a-dihydro-1 H-indazol-5- yl)butanoyl)piperidin-4-yl)-3 ,A-dihydroquinazolin-2(1H)-one; 3-(1-(3-(1-Ethyl-1 H-benzo[d}imidazol-2-yl)-4-(7-methyl-3 a,7a-dihydro-1H- indazol-5-yl)butanoyl)piperidin-4-yl)-3 ,4-dihydroquinazolin-2(1H)-one; (R)-1-(3-(4-Fluorophenyl)-1 2,4-0xadiazol-5-y1)-2-(7-methyl- 1H-indazol-5-
    ylethyl 4-(2-oxo0-1 ,2-dihydroquinolin-3-yl)piperidine- 1-carboxylate; (R)-2-(7-Methyl-1H-indazol-5-yD)-1 -(3-(pyridin-4-yl)-1 ,2,4-oxadiazol-5-yl)ethyl 4-(2-0xo-1,2-dihydroquinazolin-3(4H)- yl)piperidine-1-carboxylate; (R)-2-(7-Methyl-1H-indazol-5-y1)-1-(3 ~(pyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)ethyl 4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine- 1-carboxylate; or
    (R)-1-(3-(Ethoxycarbonyl)-1 2,4-oxadiazol-5-yl)-2-(7-methyl- 1H-indazol-5- yl)ethyl 4-(2-oxo-1 2-dihydroquinolin-3-yl)piperidine-1 -carboxylate;
    PCT/US2004/040721 or a pharmaceutically acceptable salt or solvate thereof.
    4]. A compound selected from the group consisting of Examples 1-103 having an IC50 of less than 10 nM.
    42. A pharmaceutical composition comprising a compound according to claim 1.
    43. Use of a compound according to claim 1 in the manufacture of a medicament for treating migraine in a patient in need thereof.
    44. A compound according to any one of claims 1 to 41, substantially as herein : described with reference to and as illustrated in any of the examples. 45, A composition according to claim 42, substantially as herein described with reference to and as illustrated in any of the examples.
    46. Use according to claim 43, substantially as herein described with reference to and as illustrated in any of the examples. - 226 - AMENDED SHEET
ZA200604543A 2003-12-05 2006-06-02 Heterocyclic anti-migraine agents ZA200604543B (en)

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