AU2003297694A1 - Calcitonin gene related peptide receptor antagonists - Google Patents

Calcitonin gene related peptide receptor antagonists Download PDF

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AU2003297694A1
AU2003297694A1 AU2003297694A AU2003297694A AU2003297694A1 AU 2003297694 A1 AU2003297694 A1 AU 2003297694A1 AU 2003297694 A AU2003297694 A AU 2003297694A AU 2003297694 A AU2003297694 A AU 2003297694A AU 2003297694 A1 AU2003297694 A1 AU 2003297694A1
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oxo
dihydro
piperidine
methyl
ethyl
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AU2003297694A
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Ling Chen
Rita Civiello
Andrew P. Degnan
Gene M. Dubowchik
Xiaojun Han
Xiang Jun J. Jiang
Guanglin Luo
John E. Macor
George Tora
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Description

WO 2005/065779 PCT/US2003/038799 1 CALCITONIN GENE RELATED PEPTIDE RECEPTOR ANTAGONISTS Field of the Invention The present invention relates to novel small molecule antagonists of 5 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 10 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 15 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 (aCGRP and pCGRP) 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), 20 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 JPharmacol 1992, 105, 441-7; 25 Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8.). Two classes of CGRP receptors, CGRP 1 and CGRP 2 , 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 2 receptors (Juaneda, C. et al. TiPS 2000, 21, 432-438). However, there is lack of molecular evidence for the CGRP 2 receptor (Brain, S. D. et al, TiPS 30 2002, 23, 51-53). The CGRPI receptor has three components: (i) a 7 transmembrane calcitonin receptor-like receptor (CRLR); (ii) the single transmembrane receptor activity modifying protein type one (RAMP 1); and (iii) the intracellular receptor component protein (RCP) (Evans B. N. et al., JBiol Chem. 2000, 275, 31438-43).
WO 2005/065779 PCT/US2003/038799 2 RAMP I 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., JBiol Chem. 2000, 275, 31438-43). There are known species-specific differences in binding of small 5 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 RAMPI determines the species selectivity, in particular, the amino acid residue Trp74 is responsible for the phenotype of the human receptor (Mallee et al. JBiol Chem 2002, 277, 14294-8). 10 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 15 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 20 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 25 antagonist CGRP(8-37) does not alter resting systemic hemodynamics nor regional blood flow (Shen, Y-T. et al, JPharmacol 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 HT1B/lD agonists, 'triptans' (e.g., sumatriptan). 30 There are various in vivo migraine models known in the literature (see De Vries, P. et al, Eur JPharmacol 1999, 375, 61-74). Some electrically stimulate the trigeminal ganglion and measure dilation of the intracranial vessels which they innervate (e.g., Williamson et al. Cephalalgia 1997 17:518-24). Since facial arteries WO 2005/065779 PCT/US2003/038799 3 are also innervated by the trigeminal nerve, other models study changes in facial blood flow induced by electrical trigeminal activation (e.g., Escott et al. Brain Res 1995 669:93). Alternatively, other peripheral nerves (e.g., saphenous) and vascular beds (e.g., abdominal blood flow) are also studied (e.g., Escott et al. Br JPharmacol 5 1993 110, 772-6;). All models have been shown to be blocked by pretreatment with the peptide antagonist CGPR(8-37) a peptide fragment that is absent the Is seven residues, or by a small molecule CGRP-receptor antagonist. In some instances, exogenous CGRP has been used as a stimulus. However, these models are all invasive terminal procedures, and none have shown the clinically important abortive 10 effect of reversing an established increase in artery dilation or increased blood flow using post-treatment of a CGRP-receptor antagonist. Williamson et al. Cephalalgia 1997 17:518-24, and Williamson et al. Cephalalgia. 1997 17:525-31: used inter alia i.v. CGRP as a stimulus to increase intracranial dural artery diameter in sodium pentobarb anesthetized rats employing a terminal 'intravital' procedure that involved 15 drilling to thin the skull and the creation of a closed cranial window to visualize dural arteries. The effect was blocked by pretreatment with i.v. CGRP(8-37). Escott et al. Brain Res 1995 669:93; inter alia drilled into the rat skull and used brain electrodes to electrically stimulate the trigeminal ganglion and measured laser Doppler facial blood flow in a terminal procedure in sodium pentobarb anesthetized rats involving 20 neuromuscular blockade, tracheal intubation and artificial ventilation. The effect was blocked by pretreatment with CGRP(8-37). Escott et al. Br JPharmacol 1993 110, 772-6; inter alia used intradermal (i.d.) CGRP as the stimulus to increase blood flow in rat abdominal skin of sodium pentobarb anesthetized animals outfitted with cannulated jugular veins for anesthetic and drug delivery. The effect was blocked by 25 pretreatment with i.v. CGRP(8-37). Chu et al. Neurosci Lett 2001 310, 169-72 used inter alia i.d. CGRP as the stimulus in rats and measured laser Doppler changes in blood flow in the skin of the back in a terminal method using sodium pentobarb anesthetized and tracheal cannulated animals; and showed pretreatment blockade by continuous release of CGRP(8-37) from subcutaneously (s.c.) implanted osmotic 30 pumps. Hall et al Br JPharmacol 1995 114, 592-7 and Hall et al Br JPharmacol 1999 126, 280-4 inter alia used topical CGRP to increase hamster cheek pouch arteriole diameter, and i.d. CGRP to increase blood flow in rat dorsal skin of sodium pentobarb anesthetized animals outfitted with cannulated jugular veins for anesthetic WO 2005/065779 PCT/US2003/038799 4 and drug delivery. The effect was blocked by pretreatment with i.v. CGRP(8-37). Doods et al. Br J Pharmacol. 2000 Feb; 129(3):420-3 inter alia drilled into the skull of the marmoset (new world monkey) and used brain electrodes to produce electrical stimulation of the trigeminal ganglion and measured facial blood flow in an invasive 5 terminal procedure involving neuromuscular blockade and artificial ventilation of sodium pentobarbital anesthetized primates. Increase in flow was blocked by pre treatment of a small molecule CGRP antagonist. See also WO 03/272252 Isolated DNA Molecules Encoding Humanized Calcitonin Gene-Related Peptide Receptor, Related Non-Human Transgenic Animals and Assay Methods. Thus the method of 10 the present invention procedure being inter alia a non-invasive survival model in primates measuring exogenous CGRP-induced changes in facial blood flow and demonstrating pre- and post-treatment effects of peptide and small molecule CGRP antagonists in spontaneously breathing isoflurane anesthetized marmosets who recover from the procedure offers significant advantages. 15 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 20 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 98/11128 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 25 99/52875 and WO 01/25228 and equivalents. See also U.S. 6,344,449, U.S. 6,313,097, U.S. 6,521,609, U.S. 6,552,043, US 20030181462, US20030191068 and WO 03/076432 and related applications. Thus, novel CGRP-receptor antagonists effective for the treatment of neurogenic inflammation, migraine and other disorders would be greatly advantageous. 30 Summary of the Invention Thus according to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I) WO 2005/065779 PCT/US2003/038799 5 Q D vm U N (l) and pharmaceutically acceptable salts and solvates thereof wherein 5 V is -N(R')(R 2 ) or OR4
R
4 is H, Ci.
6 alkyl, C1Ahaloalkyl or (Clalkylene)o.1R 4 '
R
4 ' is C 3
_
7 cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2. I ]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, 10 pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino 15 or dioxolanyl; and
R
4 ' is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, Cl.4alkyl, C 1
.
4 haloalkyl, Ci 4 alkoxy, hydroxy, amino, C 3
_
7 cycloalkyl, CI 3 alkylamino, C 1 . 20 3 dialkylamino, (C 1
.
3 alkyl)o- 2 ureido, phenyl and benzyl; and
R
4 ' optionally contains 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure of R4 25 R' and R 2 are each independently L', wherein L' is selected from the group consisting of H, CI- 6 alkyl, C 2
-
6 alkenyl, C 2
.
6 alkynyl, -C 1 . 6 alkylene-amino(C 1
-
3 alkyl) 2 , C 3
-
7 cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, 30 imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, WO 2005/065779 PCT/US2003/038799 6 pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and 5 dioxolanyl; and
R
1 and R 2 are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C 1 . 4 alkyl, C 14 haloalkyl, C 1 4alkoxy, hydroxy, amino, C 3 10 7 cycloalkyl, C 13 alkylamino, C 1 3 dialkylamino, (Cl 3 alkyl)o- 2 ureido, phenyl and benzyl;
R
1 and R 2 optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising R' and R 2 ; 15 wherein L' is optionally and independently interrupted from the nitrogen to which it is attached by L 2 , wherein L 2 is independently CI 3 alkylene or C 3 alkylidene; or RI and R 2 together with the nitrogen to which they are attached form X, 20 wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y 25 is dioxolanyl, C 1
.
9 alkyl, C 2
.
9 alkenyl, C 2 9 alkynyl, C I4alkylamino, C I4dialkylamino, C I 4 alkoxy, C 3
.
7 cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, 30 imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, WO 2005/065779 PCT/US2003/038799 7 piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z 5 is -NHC(O)-, -NHC(O)NH-,
NC(O)NH
2 , -NH-, -Cl 3 alkylene-, -Czi 3 alkylene-, -Cl. 3 alkenylene-NHC(O)O-CN 3 alkylene-; and 10 optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C 1 . 4 alkyl, amino, C 1
.
3 alkylamino, 15 -C 1
.
6 alkylene-amino(Ci- 3 alkyl) 2 , (C I- 3 alkyl)o- 2 ureido, phenyl and benzyl; X and Y optionally and independently contain 1 or 2 carbonyls wherein 20 the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y; provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then 25 X and Y optionally share one carbon atom and together form a spirocyclic moiety; Q is Q t orQ; wherein 30 Q' is (SY),R 3 ; and Q" is NH(SY),R 3 , NHC(O)(S )SR', NHC(O)O(S ),R 3 , NHC(O)NH(S ),R 3 , O(SY),R 3 , (SY)SNHR 3
,
WO 2005/065779 PCT/US2003/038799 8
(SY),NHC(O)R
3 , (SY),NHC(O)OR, (SY),NHC(O)NHR 3 or (SY)sOR 3 ; wherein S' is C 1
.
3 alkylene or CI- 3 alkylidene and s is 0 or 1; 5 U is CH 2 or NH; provided that if Q is Q", then U is CH 2 ;
R
3 is R 3 a or R b wherein
R
3 a is 10 (i) 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 15 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings; (ii) a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of 0, N and S, optionally containing 20 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; (iii) C 3
.
7 cycloalkyl; (iv) carbazolyl, fluorenyl, phenyl, -0-phenyl, -0-C 25 4 alklylene-phenyl, or napthyl; or (v) C1.galkyl, C 2
.
7 alkenyl, -C(O)R", CHC(O)O-R",
CH(CH
3 )C(0)O-R",-C(O)O-R 3 or C 2
.
7 alkynyl; and wherein R 3 a is optionally substituted with 1 to 3 of the same or different substituents selected from the group 30 consisting of benzyl, phenyl, -0-phenyl, -O-C 1 . 3 alkylenephenyl, -CI.
3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, Ci- 6 alkyl, C 1 3 mono-bi-tri-haloalkyl, Ci- 3 mono-bi-tri-haloalkyloxy, (C 1 3 alkyl)1-2amine, WO 2005/065779 PCT/US2003/038799 9 -OR", -C(O)R , -C(O)O-R', -O-C(O)Rr, -N(R3)2,
-C(O)N(R')
2 , -N(R 3 ')C(O)(R")2, -N(R')C(O)N(R )2,
-N(R)C(O)OR
3 , -O-C(O)N(R') 2 , -N(R")S0 2 R",
-SO
2
N(R")
2 and -S0 2 R"; 5 R 3 'is H or -CI- 6 alkyl; provided that if R3a is , -C(O)R , CHC(O)O-R",
CH(CH
3
)C(O)O-R
3 or -C(O)O-R , then said -C(O)R", CHC(O)O-R", CH(CH 3
)C(O)O-R
3 or
-C(O)O-R
3 are unsubstituted; 10 R 3 b iR 3 a but is not phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4 tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-iH indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1 dimethylethoxycarbonyl)- 1 H-indol-3-yl, 4-imidazolyl, I -methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 15 1H-indazol-3-yl, 1-methyl-IH-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted in the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or 20 unbranched alkyl groups, C 3
-
8 -cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, 25 amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, 30 trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups; WO 2005/065779 PCT/US2003/038799 10 wherein said substituents may be the same or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups may in turn additionally be substituted in the 5 phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group; D is 0, NCN or NSO 2
C
1
-
3 alkyl; A is C, N or CH; 10 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; 15 E is N, CH or C; p is 0 or 1; if p is 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 20 containing one to four of the same or different heteroatoms selected from the group consisting of 0, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of 25 said fused heterocycle; AY is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of 0, N and S; and optionally containing 1 to 2 carbonyls, wherein the 30 carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle; wherein A' and A' are optionally substituted with C 1 . 4 alkyl, C 1 4alkoxy, C 14 haloalkyl, cyano, C 3
-
WO 2005/065779 PCT/US2003/038799 11 7cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, 5 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 G, J and A together are GJA' or GJA"; 10 wherein GJA' is A' or AY; and GJA" is Ax or AY; provided that Ax is not a 1,3-diaza-fused heterocycle; 15 and AY is not a 1,3-diaza-heterocycle; and further provided that if Q is Q", then R 3 is R3a; and if Q is Q', then 20 R3 is R b ; or R is R , p is 0 and G, J and A together form GJA". According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and R 3 is R 3 b. 25 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q', R 3 is R 3 a and p is 0 such that G, J and A together form GJA". According to another embodiment of the first aspect of the present invention 30 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and Q' is (SI),R 3 and s is 0.
WO 2005/065779 PCT/US2003/038799 12 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and Q' is (SY),R 3 , S' is CI-alkylene and s is 1. According to another embodiment of the first aspect of the present invention 5 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and Q' is (S ),R , Sy is C 1 3 alkylidene and s is 1. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and U is CH 2 . 10 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q', Q' is (SY), R 3 , s is 0 and U is CH 2 . According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 15 present invention wherein Q is Q', Q' is (SY), R 3 , Sy is CI 3 alkylene, s is land U is
CH
2 . According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q', Q' is (SY), R 3 , S' is C 1 3 alkylidene, s is land U is 20 CH2 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and U is NH. According to another embodiment of the first aspect of the present invention 25 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q', Q' is (SY), R 3 , s is 0 and U is NH. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q', Q' is (SY), R 3 , Sy is C 3 alkylene, s is land U is 30 NH. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the WO 2005/065779 PCT/US2003/038799 13 present invention wherein Q is Q', Q' is (SY), R3, Sy is C 3 alkylidene, s is land U is NH. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 5 present invention wherein Q is Q". According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NH(SY),R 3 . According to another embodiment of the first aspect of the present invention 10 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NH(S )SR 3 and s is 0. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NH(SY)sR , Sy is C 13 alkylene and s is 1. 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NH(SY),R 3 , Sy is C 1 3 alkylidene and s is 1. According to another embodiment of the first aspect of the present invention 20 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(SY),R 3 . According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(S ),R 3 and s is 0. 25 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(S ),R 3 , Sy is C 1
.
3 alkylene and s is 1. According to another embodiment of the first aspect of the present invention 30 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)(S ),R 3 , Sy is C 1 3 alkylidene and s is 1.
WO 2005/065779 PCT/US2003/038799 14 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)O(S ),R 3 . According to another embodiment of the first aspect of the present invention 5 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)O(S )SR 3 and s is 0. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)O(S ),R 3 , Sy is C 1
.
3 alkylene and 10 s is 1. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)O(S ),R 3 , Sy is C 1 3 alkylidene and s is 1. 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)NH(S )R 3 . According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 20 present invention wherein Q is Q" and Q" is NHC(O)NH(S ),R 3 and s is 0. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)NH(S ),R 3 , Sy is C 1 3 alkylene and s is 1. 25 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and Q" is NHC(O)NH(S ),R 3 , Sy is C 1
.
3 alkylidene and s is 1. According to another embodiment of the first aspect of the present invention 30 are provided compounds according to the first embodiment of the first aspect of the 4 present invention wherein V is OR.
WO 2005/065779 PCT/US2003/038799 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is OR 4 and R4 is Ci- 6 alkyl. According to another embodiment of the first aspect of the present invention 5 are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R')(R 2 ). According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein 10 V is -N(RI)(R 2 ) or OR 4 ;
R
4 is H, C 1
.
6 alkyl, C 14 haloalkyl, (CAalkylene)o- 4
R
4
R
4 ' is C 3
.
7 cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2. 1 ]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, 15 pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino 20 or dioxolanyl; and
R
4 ' is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C 1 Aalkyl, C 1 .4haloalkyl, Cl4alkoxy, hydroxy, amino, C 3
.
7 cycloalkyl, CI_ 3 alkylamino, C 1 . 25 3 dialkylamino, (CI 3 alkyl)o- 2 ureido, phenyl and benzyl;
R
4 ' optionally contains I or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure of R 4 '; R1 and R 2 are each independently L 1 , wherein L' is selected from the 30 group consisting of H, C 1
.
6 alkyl, -Ci- 6 alkylene-amino(C 3 alkyl) 2 , C 3
.
7 cycloalkyl, phenyl, adamantyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, WO 2005/065779 PCT/US2003/038799 16 imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, 5 piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and Rl and R2 are each optionally and independently substituted with I or 2 of the same or different substituents selected from the group consisting of halo, cyano, C 1 . 10 4 alkyl, C 1 .4haloalkyl, C 1 Aalkoxy, hydroxy, amino, C 3 . 7 cycloalkyl, C 1 3 alkylamino, CI- 3 dialkylamino, (Cl 3 alkyl)0- 2 ureido, phenyl and benzyl; R' and R2 optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a 15 member of the heterocycles comprising R and R 2 ; wherein Ll is optionally interrupted from the nitrogen to which it is attached by L 2 , wherein L 2 is C 1
.
3 alkylene; or R' and R 2 together with the nitrogen to which they are attached form X, 20 wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y 25 is dioxolanyl, C 1 4 alkyl, C 1 4 alkylamino, C 4 dialkylamino, CI-4alkoxy, C 3
.
7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, 30 pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, WO 2005/065779 PCT/US2003/038799 17 piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z 5 is -NHC(O)O-, -NHC(O)NH-,
NC(O)NH
2 , -NH-, -C 1 . 3 alkylene-, -C 3 alkylene
NHC(O)O-C
1
.
3 alkylene-; and optionally and independently substituted 10 with 1 or 2 of the same or different substituents selected from the group consisting of C 1 . 4 alkyl, amino, C1.
3 alkylamino,
-C
1
.
6 alkylene-amino(CI- 3 alkyl) 2 , 15
(C
1 3 alkyl)o- 2 ureido, phenyl and benzyl; X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl 20 is a member of the heterocycles comprising X and Y; provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share one carbon 25 atom and together form a spirocyclic moiety. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein RW is H, C 1
.
6 alkyl, C14haloalkyl or (C 1 4alkylene)o.iR'; R 30 is C 3 _7cycloalkyl, 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, WO 2005/065779 PCT/US2003/038799 18 triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and R 4 ' is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, Cl4alkyl, ClAhaloalkyl, Cl-alkoxy, hydroxy, amino, C 3 5 7 cycloalkyl, Cl 13 alkylamino, C I 3 dialkylamino, (C 3 alkyl)o-2ureido, phenyl and benzyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 4 is H, CI.
6 alkyl, C 1 4 haloalkyl or (Cl-alkylene)o.1R 4 ; R4' 10 is C 3
.
7 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, 15 piperazinyl, morpholino, thiomorpholino or dioxolanyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 4 is H, C 1 6 alkyl or (C 1 4 alkylene)o.
1
R
4 ; R 4 is C 3 . 7 cycloalkyl. 20 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R 1
)(R
2 ) and
R
1 and R 2 are each independently L', wherein L' is selected from the group consisting of H, C 1 6 alkyl, -C 1
.
6 alkylene-amino(C 25 3 alkyl)2, C 3
.
7 cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, 30 isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; or WO 2005/065779 PCT/US2003/038799 19 R' and R2 together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, 5 diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C 14 alkyl, Ci- 4 alkoxy, C 3 7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, 10 pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, 15 piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y optionally share one carbon atom and together form a 20 spirocyclic moiety. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R')(R 2 ) and R' and R 2 are each independently L', wherein L' is selected from the 25 group consisting of H, C - 6 alkyl, or Ri and R2 together with the nitrogen to which they are attached form X, wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is 30 dioxolanyl, C Ialkyl or piperidinyl; and wherein X and Y optionally share one carbon atom and together form a spirocyclic moiety.
WO 2005/065779 PCT/US2003/038799 20 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R')(R 2 ) and wherein R 1 and R 2 are each independently L', wherein L' is selected from the group consisting of H, C 1
.
6 alkyl. 5 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R')(R 2 ) and wherein
R
1 and R 2 together with the nitrogen to which they are attached form X, 10 wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, Ci-4alkyl or piperidinyl; and wherein X and Y optionally share one carbon atom and together form a 15 spirocyclic moiety. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R')(R 2 ) and wherein
R
1 and R 2 together with the nitrogen to which they are attached form 20 X, wherein X is piperidinyl; wherein X is substituted with Y, wherein Y is piperidinyl. According to another embodiment of the first aspect of the present invention 25 are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R 1
)(R
2 ) and wherein R' and R 2 together with the nitrogen to which they are attached form X, wherein X is morpholino; 30 wherein X is substituted with Y, wherein Y is Ci-alkyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R')(R 2 ) and wherein WO 2005/065779 PCT/US2003/038799 21 R' and R 2 together with the nitrogen to which they are attached form X, wherein X is piperidinyl; wherein X is substituted with Y, wherein Y is C 1 alkyl. 5 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N(R' )(R 2 ) and wherein R' and R 2 together with the nitrogen to which they are attached form X, 10 wherein X is piperidinyl; wherein X is substituted with Y, wherein Y is dioxolanyl; and wherein X and Y share one carbon atom and together form a spirocyclic moiety. 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein X and Y are not interrupted with Z. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 20 present invention wherein X and Y are not interrupted with Z; and X and Y share one carbon atom and together form a spirocyclic moiety According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 a 25 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 b. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 30 present invention wherein R 3 a is 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.
WO 2005/065779 PCT/US2003/038799 22 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is 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 5 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. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 10 present invention wherein R a is 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; wherein R 3 a is optionally substituted with 1 15 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -0-phenyl, -0-CI- 3 alkylphenyl, -C 1 3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, CI- 3 mono-bi-tri-haloalkyl, C 1 3 mono-bi-tri-haloalkyloxy, C 1 6 alkoxy, (C I 3 alkyl) 1 2 amine, -OR , -C(O)R , -C(O)O-R", -O-C(O)R,-N(R3')2,
-C(O)N(R
3
)
2 , -N(R 3
)C(O)(R
3 )2, -N(R 3
)C(O)N(R
3
)
2 , -N(R")C(O)ORr, -0 20 C(O)N(R 3
-)
2 , -N(R")S0 2 R , -SO 2
N(R
3
)
2 and -S0 2
R
3 '; R3'is H or -CI.
6 alkyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 a is a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of 0, N 25 and S. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of 0, N 30 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. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the WO 2005/065779 PCT/US2003/038799 23 present invention wherein R 3 a is a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of 0, 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; wherein R 3 a is optionally 5 substituted with I to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -0-phenyl, -O-CI- 3 alkylphenyl, -C 1
.
3 alkylene-OC(O) phenyl, cyano, amino, nitro, halo, C 1
-
3 mono-bi-tri-haloalkyl, CI- 3 mono-bi-tri haloalkyloxy, Ci- 6 alkoxy, (CI- 3 alkyl) 1
-
2 amine, -OR 3 , -C(O)R 3 , -C(O)O-R, -0 C(O)R', -N(R") 2 , -C(O)N(R 3
')
2 , -N(R")C(O)(R") 2 , -N(R")C(O)N(R 3
)
2 , 10 -N(R")C(O)OR", -0-C(O)N(R)2, -N(R")S0 2 R", -SO 2
N(R
3
)
2 and -SO 2 R";
R
3 is H or -C1.
6 alkyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is C 3
-
7 cycloalkyl. 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 , is C 3 7 cycloalkyl; wherein R3a is optionally substituted with I to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -0-phenyl, -O-C 1
.
3 alkylphenyl, -C 1 3 alkylene-OC(O)-phenyl, cyano, 20 amino, nitro, halo, C 1
-
3 mono-bi-tri-haloalkyl, CI- 3 mono-bi-tri-haloalkyloxy, C 1 6 alkoxy, (CI- 3 alkyl) 1 2 amine, -OR 3 , -C(O)R , -C(O)O-R", -O-C(O)R",-N(R3)2,
-C(O)N(R
3
)
2 , -N(R 3
)C(O)(R
3
)
2 , -N(R 3
)C(O)N(R
3
)
2 , -N(R 3
)C(O)OR
3 , -0
C(O)N(R
3
')
2 , -N(R)S0 2 R , -SO 2
N(R")
2 and -S0 2 R"; Rris H or -C 1 6 alkyl. According to another embodiment of the first aspect of the present invention 25 are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 , is carbazolyl, fluorenyl, phenyl, -0-phenyl, -O-C 4 alklylene-phenyl, or napthyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 30 present invention wherein R 3 , is carbazolyl, fluorenyl, phenyl, -0-phenyl, -O-C 4 alklylene-phenyl, or napthyl; wherein R 3 a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, 0-phenyl, -O-CI- 3 alkylphenyl, -C 1 3 alkylene-OC(O)-phenyl, cyano, amino, nitro, WO 2005/065779 PCT/US2003/038799 24 halo, Ci 3 mono-bi-tri-haloalkyl, CI 3 mono-bi-tri-haloalkyloxy, C 1
.
6 alkoxy, (C1 3 alkyl) 1
-
2 amine, -OR , -C(O)R , -C(O)O-Rr, -O-C(O)R", -N(R 3
)
2 , -C(O)N(R 3
)
2 ,
-N(R")C(O)(R
3
)
2 , -N(R 3 )C(O)N(R3') 2 , -N(R")C(O)OR 3 , -O-C(O)N(R 3
)
2 , -N(R")S0 2 R", -SO 2
N(R
3
)
2 and -S0 2
R
3 ; R is H or -CI- 6 alkyl. 5 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is CI-salkyl, C 2
.
7 alkenyl, -C(O)R", -C(O)O-R 3 or C 2 7 alkynyl. According to another embodiment of the first aspect of the present invention 10 are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 a is C 1
.
8 alkyl, C 2
.
7 alkenyl, -C(O)R", -C(O)O-R 3 or C 2 7 alkynyl; wherein R3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -0-phenyl, -O-C 1 . 3 alkylphenyl, -CI.
3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halo, C 1
.
3 mono-bi 15 tri-haloalkyl, C 1
.
3 mono-bi-tri-haloalkyloxy, C 1
.
6 alkoxy, (C 1
.
3 alkyl)i- 2 amine, -OR", -C(O)R , -C(O)O-R 3 , -O-C(O)R , -N(R") 2 , -C(O)N(R 3
)
2 , -N(R 3 )C(O)(R")2,
-N(R
3
)C(O)N(R
3
)
2 , -N(R 3 )C(O)OR", -O-C(O)N(R") 2 , -N(R")S0 2 R",
-SO
2
N(R")
2 and -S0 2 RY; R 3 is H or -C 1
.
6 alkyl; provided that if R 3 a is -C(O)R , CHC(O)O-R", CH(CH 3 )C(O)O-R or -C(O)O-R , then said -C(O)R , CHC(O)O 20 R 3 , CH(CH 3 )C(O)O-R 3 or -C(O)O-R 3 ' are unsubstituted. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R3a and R 3 a is phenyl, hydroxyphenyl, azetidmyl, napthyl, CI- 6 alkyl, C2.
6 alkenyl, C 2
-
6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, 25 quinolinyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, isoquinolinyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, indazolyl, dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzoxazolyl, 30 benzotriazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, benzothienyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzofuranyl, benzdioxolanyl, dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, WO 2005/065779 PCT/US2003/038799 25 pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl, piperazinyl or morpholino; optionally substituted as provided in the first embodiment of the first aspect. 5 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 a and R 3 a is phenyl, napthyl, indazolyl, benzimidazolinyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl, benzdioxolanyl, dihydroindolonyl, indolyl, furanyl, thienyl, pyridyl, purinyl, 10 carbazolyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 a and R 3 a is dihydro-benzthiazolonyl, 15 hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, benzothienyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzofuranyl, dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl or indazolyl; optionally substituted as provided in the first embodiment of the first aspect. 20 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 ' and R 3 ' is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidine, halopurinyl, C 1 3 alkyl nitroaminopyrimidine, triazolopyrimidinyl, pyridyl, indazolyl, phenyl or 25 benzdioxolanyl; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 a and R 3 a is naphthyl, phenyl-O-phenyl, or thienyl; 30 optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 b.
WO 2005/065779 PCT/US2003/038799 26 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 b and R 3 b is 5 1 H-Indol-5-yl HN TY 5 1H-Indazol-5-yl HN-N Ty ~5 10 1H-Benzotriazol-5-yl HN-N Ty N 1,3-Dihydro-indol-2-on-5-yl 0 HN 5 15 ;ull 3H-Benzooxazol-2-on-6-yl WO 2005/065779 PCT/US20031038799 27 0 HNK Ty 0 1 ,3-Dihydro-benzoimidazol-2-on-5-yl 0 HN-4 Ty, 5 1NH 5 1-Methyl-i ,3-dihydro-benzoimidazol-2-on-6-yl 0 HN Ty N 3,4-Dihydro- 1H-quinolin-2-on-6-yl 0 HN 10 1 ,4-Dihydro-benzo[d][l,3]oxazin-2-on-6-yl 0 HN l 68~ WO 2005/065779 PCT/US2003/038799 28 3,4-Dihydro-1 H-quinazolin-2-on-6-yl 0 HN NH 6 3-Methyl-3,4-dihydro-IH-quinazolin-2-on-6-yl 0 HN'k N 5 ;or 4H-Benzo[1,4]oxazin-3-on-7-yl 0 HN Ty 0 7 10 wherein T is H, Cl 4 alkyl, F, Cl, Br or nitrile. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3 b and R 3 b is azetidinyl, C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2 6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, dihydroisoquinolinonyl, 15 hydroisoquinolinonyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, 1 H indazol-5-yl, dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranonyl, 20 hydrobenzofuranonyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, WO 2005/065779 PCT/US2003/038799 29 pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; optionally substituted as provided in the first embodiment of the first aspect. 5 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 isR 3 b and R 3 b is dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, 10 hydrobenzothiophenonyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, IH indazol-5-yl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or 15 morpholino; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 isR 3 b and R 3 b is azetidinyl, C i- 6 alkyl, C 2
-
6 alkenyl, C 2 20 6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, IH indazol-5-yl, dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, 25 dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention 30 are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 isR 3 b and R 3 b is azetidinyl, C 1 aalkyl, C 2
-
6 alkenyl, C 2 6 alkynl, dihydroquinolinonyl, hydroquinolinonyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, dihydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, WO 2005/065779 PCT/US2003/038799 30 dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, 1 H-indazol-5-yl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, 5 imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 10 present invention wherein R 3 IS R 3 b and R 3 b is benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, purinyl, carbazolyl; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 15 present invention wherein R3 is R 3 b and Rlb is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C j 3 alkyl nitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, 1H-indazol-5-yl, phenyl or benzdioxolanyl. According to another embodiment of the first aspect of the present invention 20 are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and wherein said compounds have an absolute configuration of R. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 25 present invention wherein Q is Q' and wherein said compounds have an absolute configuration of S. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q" and wherein said compounds have an absolute 30 configuration of R. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the WO 2005/065779 PCT/US2003/038799 31 present invention wherein Q is Q" and wherein said compounds have an absolute configuration of S. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 5 present invention wherein n and n are each 1. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein D is 0. According to another embodiment of the first aspect of the present invention 10 are provided compounds according to the first embodiment of the first aspect of the present invention wherein A is C. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein A is CH. 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein A is N. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 20 present invention wherein E is N. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein E is CH. According to another embodiment of the first aspect of the present invention 25 are provided compounds according to the first embodiment of the first aspect of the present invention wherein E is C. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein said compounds exhibit as described herein a CGRP 30 Binding IC 50 of less than 10 nM. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the WO 2005/065779 PCT/US2003/038799 32 present invention wherein said compounds exhibit as described herein a CGRP Binding IC 50 of less than 100 nM. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 5 present invention wherein said compounds exhibit as described herein a CGRP Binding IC 50 of less than 1000 nM. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 1; and G, J and E together form Ax or A . 10 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 1; and G, J and E together form Ax. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 15 present invention wherein p is 1; and G, J and E together form Ay. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein Ax 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 20 or different heteroatoms selected from the group consisting of 0, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 25 present invention wherein Ax 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 0, N and S. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 30 present invention wherein 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 0, N and S and wherein A' is substituted with phenyl.
WO 2005/065779 PCT/US2003/038799 33 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein A' is a fused heterocycle described herein. According to another embodiment of the first aspect of the present invention 5 are provided compounds according to the first embodiment of the first aspect of the present invention wherein AY is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of 0, N and S; and optionally containing I to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle. 10 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein AY is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of 0, N and S. According to another embodiment of the first aspect of the present invention 15 are provided compounds according to the first embodiment of the first aspect of the present invention wherein AY is a 4 to 6 membered heterocycle containing one to three heteroatoms selected from the group consisting of 0, 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; and wherein AY is substituted with phenyl. 20 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein AY is a 4 to 6 membered heterocycle described herein. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 25 present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA' or GJA". According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 30 present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are GJA'.
WO 2005/065779 PCT/US2003/038799 34 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system 5 containing A and wherein G, J and A together are GJA". According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system 10 containing A and wherein G, J and A together are GJA' and GJA' is A*. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system 15 containing A and wherein G, J and A together are GJA' and GJA' is A. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system 20 containing A and wherein G, J and A together are GJA" and GJA" is Ax. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system 25 containing A and wherein G, J and A together are GJA" and GJA" is Ay. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system 30 containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, WO 2005/065779 PCT/US2003/038799 35 dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein said 5 heterocycle is optionally substituted with C 1 alkyl, CI 4 alkoxy, C 14 haloalkyl, cyano,
C
3
.
7 cycloalkyl, phenyl, halophenyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino. According to another embodiment of the first aspect of the present invention 10 are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, 15 dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, 20 imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein said heterocycle is optionally substituted with CI 4 alkyl, C 1 4alkoxy, C 14 haloalkyl, cyano,
C
3 7 cycloalkyl, phenyl, halophenyl, furanyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino. According to another embodiment of the first aspect of the present invention 25 are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, 30 dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein said WO 2005/065779 PCT/US2003/038799 36 heterocycle is optionally substituted with Cl-alkyl, CI 4 alkoxy, C 1 4 haloalkyl, cyano,
C
3
.
7 cycloalkyl, phenyl, halophenyl, piperazinyl or morpholino. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 5 present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, 10 dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino. 15 According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from 20 the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl and dihydrobenzoxazinonyl. According to another embodiment of the first aspect of the present invention are provided compounds according to the first embodiment of the first aspect of the 25 present invention wherein p is 0 such that G and J arc each attached to A, then G, J and A together form a spirocyclic ring system with said rings of said system containing A and wherein G, J and A together are form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl and 30 dihydrobenzoxazinyl. According to various embodiments of a second aspect of the present invention are provided pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
WO 2005/065779 PCT/US2003/038799 37 According to various embodiments of a third aspect of the present invention are provided methods of treating inflammation (particularly neurogenic inflammation), headache (particularly migraine), pain, thermal injury, circulatory shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid/ 5 cranial hemorrhage, tumor growth, flushing associated with menopause and other conditions the treatment of which can be effected by the antagonism of the CGRP receptor by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein. According to various embodiments of a fourth aspect of the present invention 10 are uses of the compounds of the present invention selected from the group consisting of (a) immune regulation in gut mucosa (b) protective effect against cardiac anaphylactic injury (c) stimulating or preventing interleukin- I b(IL- lb)-stimulation of bone resorption (d) modulating expression of NK1 receptors in spinal neurons and (e) airway inflammatory diseases and chronic obstructive pulmonary disease 15 including asthma. See (a) Calcitonin Receptor-Like Receptor Is Expressed on Gastrointestinal Immune Cells. Hagner, Stefanie; Knauer, Jens; Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick. Institute of Physiology, Philipps University, Marburg, Germany. Digestion (2002), 66(4), 197 203; (b) Protective effects of calcitonin gene-related peptide-mediated evodiamine on 20 guinea-pig cardiac anaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan, Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian. School of Pharmaceutical Sciences, Department of Pharmacology, Central South University, Xiang-Ya Road 88, Changsha, Hunan, Naunyn-Schmiedeberg's Archives of Pharmacology (2003), 367(3), 306-311; (c) The experimental study on the effect calcitonin gene-related 25 peptide on bone resorption mediated by interleukin-1. Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican. Department of Orthopedics, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Peop. Rep. China. Journal of Tongji Medical University (2001), 21(4), 304-307, (d) Calcitonin gene-related Peptide regulates expression of neurokininl receptors by rat spinal 30 neurons. Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG. J. Neurosci. 2003 23 (5): 1816-1824. epartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, WO 2005/065779 PCT/US2003/038799 38 Kansas 66160 (e) Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice. Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi. 5 Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. American Journal of Physiology (2002), 283(5,Pt. 1), L963 L970; (/) Calcitonin gene-related peptide as inflammatory mediator. Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. Charite Campus Virchow, Department of Pediatric Pneumology and Immunology, Division of Allergy 10 Research, Humboldt-University Berlin, Berlin, Germany. Pulmonary Pharmacology & Therapeutics (2003), 16(3), 121-130; and (g) Pharmacological targets for the inhibition of neurogenic inflammation. Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolcsanyi, Janos. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung. Current Medicinal Chemistry: 15 Anti-Inflammatory & Anti-Allergy Agents (2003), 2(2), 191-218 all incorporated by reference herein. According to various embodiments of a fifth aspect of the present invention are provided combinations of the compounds of the present invention with one or more agents selected from the group consisting of COX-2 inhibitors, NSAIDS, 20 aspirin, acetaminophen, triptans, ergotamine and caffeine for the treatment of migraine. According to a sixth aspect of the present invention are provided in vivo non terminal methods of identifying anti-migraine compounds. According to the first embodiment of the sixth aspect of the present invention 25 is provided an in vivo non-terminal method of identifying anti-migraine compounds comprising administering a CGRP-receptor agonist to a mammal in an amount capable of inducing an increase in blood flow, followed by administering a test compound in an amount capable of reversing said CGRP-induced increase in blood flow, wherein said mammal is a transgenic mammal with humanized RAMP I having 30 Trp74 or a mammal endogenously expressing RAMP 1 having Trp74. According to another embodiment of the sixth aspect of the present invention is provided an in vivo non-terminal method of identifying anti-migraine compounds comprising administering to a mammal a test compound prior to the delivery of a WO 2005/065779 PCT/US2003/038799 39 CGRP-receptor agonist wherein said CGRP-receptor agonist is administered in an amount capable of inducing an increase in blood flow and wherein said test compound is administered in an amount capable of suppressing said CGRP-induced increase in blood flow, wherein said mammal is a transgenic mammal with 5 humanized RAMP 1 having Trp74 or a mammal endogenously expressing RAMP 1 having Trp74. According to another embodiment of the sixth aspect of the present invention is provided an in vivo non-terminal method of identifying anti-migraine compounds comprising administering to a mammal a CGRP-receptor agonist in an amount 10 capable of inducing an increase in peripheral artery diameter, followed by administering a test compound in an amount capable of reversing said CGRP-induced increase in peripheral artery diameter, wherein said mammal is a transgenic mammal with humanized RAMP 1 having Trp74 or a mammal endogenously expressing RAMP 1 having Trp74. 15 According to another embodiment of the sixth aspect of the present invention is provided an in vivo non-terminal method of identifying anti-migraine compounds comprising administering to a mammal a test compound prior to the delivery of a CGRP-receptor agonist wherein said CGRP-receptor agonist is administered in an amount capable of inducing an increase in peripheral artery diameter and wherein 20 said test compound is administered in an amount capable of suppressing said CGRP induced increase in peripheral artery diameter, wherein said mammal is a transgenic mammal with humanized RAMP 1 having Trp74 or a mammal endogenously expressing RAMP I having Trp74. According to other embodiments of the sixth aspect of the present invention 25 are provided in vivo non-terminal methods of identifying anti-migraine compounds as described herein wherein said blood flow is facial blood flow. According to other embodiments of the sixth aspect of the present invention are provided in vivo non-terminal methods of identifying anti-migraine compounds as described herein wherein said mammal endogenously expressing RAMP I having 30 Trp74 is a non-human primate. According to other embodiments of the sixth aspect of the present invention are provided in vivo non-terminal methods of identifying anti-migraine compounds WO 2005/065779 PCT/US2003/038799 40 as described herein wherein said mammal endogenously expressing RAMP 1 having Trp74 is man. According to other embodiments of the sixth aspect of the present invention are provided in vivo non-terminal methods of identifying anti-migraine compounds 5 as described herein wherein said mammal endogenously expressing RAMP 1 having Trp74 is a non-human primate and said non-human primate is a marmoset. According to other embodiments of the sixth aspect of the present invention are provided in vivo non-terminal methods of identifying anti-migraine compounds as described herein wherein said anti-migraine compounds are CGRP-receptor 10 antagonists. Other embodiments of the present invention may comprise a suitable combination of two or more of the embodiments and/or aspects disclosed herein. Yet other embodiments of the present invention may comprise a suitable subset of an embodiment and/or aspect disclosed herein. 15 Still yet other embodiments and aspects of the invention will be apparent according to the description provided below. Brief Description of the Figures Figure 1. Schild Analysis. 20 Dose response of CGRP stimulated cAMP production in the absence (filled squares) and presence (all others) of increasing concentrations (left-to-right) of the CGRP antagonist Example 2. Inset is Schild plot of log dose ratio minus 1 (Y-axis) against log concentration of the antagonist Example 2 (X-axis): Slope = 0.94, Kb = 0.16 nM. 25 Figure 2. Direct Validation of Facial Blood Flow as Surrogate for Intracranial Artery Dilation in the Rat. Intravenous delivery of i.v. haxCGRP induces comparable percent increases (100 120% of baseline) in rat middle meningeal artery diameter and rat facial blood flow (left and right striped bars, respectively). Pretreatment with the peptide antagonist 30 CGRP(8-37) produces a 50% inhibition of subsequent i.v. haCGRP administration for both measures (filled bars). Intracranial artery diameter and facial blood flow WO 2005/065779 PCT/US2003/038799 41 were measured concurrently in each animal (n = 5 rats). Data are mean sem * p < 0.05, ** p < 0.01 vs corresponding haCGRP alone. Figure 3. Dose-Response for hc.CGRP in Non-Human-Primate Laser Doppler Facial 5 Blood Flow. Delivery of haCGRP induces dose-dependent increase in laser Doppler facial blood flow in non-human primates (e.g., common marmoset). Animals (n= 6) received increasing doses of hcCGRP at 30 min intervals. Data are peak % change from baseline ± sem, with each animal serving as its own control. 10 Figure 4. Inhibitition of CGRP-Induced Changes in Non-Human Primate Facial Blood Flow. The novel CGRP antagonist Example 2 (filled bars) delivered prior to haCGRP (striped bar), dose-dependently inhibits the CGRP-induced increase in laser Doppler 15 facial blood flow. Vehicle (open bar) was without effect. Data are mean ± sem (n = 5-6 primates per group). *p <0.05 compared CGRP alone. Figure 5. Effect of CGRP Antagonist on Non-Human Primate Blood Pressure. In contrast to the dose-dependent inhibition of primate facial blood flow (see Figure 20 4.), Example 2 has negligible effect on blood pressure (parallel studies in separate animals, n=6). Animals received repeat doses of Example 2 at 20 min intervals. BP data are mean ± sem over 20 min period measured by arm cuff Detailed Description of the Invention 25 The description of the invention herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substitutent at any given location. As used herein, "heterocyclic" or "heterocycle" includes cyclic moieties containing one or more heteroatoms, (e.g., 0, N or S) said heterocycles include those 30 that are aromatic and those that are not, i.e., "alicyclic", unless otherwise specified. As used herein, the term "fused bicyclic system" when describing for example a 5.6-fused bicyclic system containing 1 to 4 nitrogen atoms includes aromatic and WO 2005/065779 PCT/US2003/038799 42 alicyclic systems, e.g. indolizine, indole, isoindole, 3H-indole, indoline, indazole or benzimidazole. If a substitutent is named generically, then any and all species of that genus comprise that aspect of the invention. For example, a substituent generically named 5 as "pyrrolonyl" (the radical of "pyrrolone", a pyrrole having a carbonyl) includes pyrrol-2-onyls wherein the carbonyl is adjacent to the nitrogen and pyrrol-3-onyls wherein the carbonyl and nitrogen have an intervening methylene. Similarly, the present invention comprises that a substituent may be attached at any and all suitable points of attachement on said substituent unless otherwise 10 specified. However, it is also understood that the compounds encompassed by the present invention are those that are chemically stable, i.e., heteroalicyclic substituents of the present invention should not be attached in such a way that a heteroatom in said heteroalicyclic substituent is alpha to a point of attachment wherein said point of 15 attachment is also a heteroatom. An embodiment or aspect which depends from another embodiment or aspect, will describe only the variables having values or provisos that differ from the embodiment or aspect from which it depends. If for example a dependent embodiment only addresses R 2 , then the variables and provisos not related to R2 20 should reflect that of the embodiment from which it depends. If a variable is quantified with a value of zero, then a bond attaching said variable should no longer be represented. As used herein, "alkylene" means a divalent alkane, i.e., an alkane having two hydrogen atoms removed from said alkane (said hydrogen removed from two 25 different carbon atoms when said alkane contains more than one carbon atom), e.g.,
-CH
2
CH
2
CH
2 - . As used herein, "alkylidene" means an alkane having two hydrogen atoms removed from one carbon atom in said alkane, e.g.,
H
WO 2005/065779 PCT/US2003/038799 43 It should be understood that the alternating double bond designations in the six-membered ring of the 5,6-membered fused structure represented in Formula (I) are relative and represent the delocalized a orbital electrons of said ring. As used herein, "aryl" or "ar-" includes phenyl or napthyl. 5 As used herein, "heterocyclic" or "heterocyclo" includes both heteroaryl and heteroalicyclic. As used herein, "halo" or "halogen" includes fluoro, chloro, bromo and iodo and further means one or more of the same or different halogens may be substituted on a respective moiety. 10 Unless specificied otherwise, acyclic hydrocarbons such as alkyl, alkoxy, alkenyl and alkynyl may be branched or straight chained. It is to be understood that the present invention may include any and all possible stereoisomers, geometric isomers, diastereoisomers, enantiomers, anomers and optical isomers, unless a particular description specifies otherwise. 15 As used herein, "Trp74", means that the 74 th residue in RAMP I is tryptophan (Mallee et al. JBiol Chem 2002, 277, 14294-8) incorporated by reference herein. As used herein "anti-migraine compound" includes any compound, peptide or peptide fragment (modified or unmodified) capable of reversing or attenuating CGRP-receptor mediated vasodilation, (e.g., CGRP-receptor antagonists). 20 As used herein "test compound" includes any compound, peptide or peptide fragment (modified or unmodified) being tested to determine if it is capable of reversing or attenuating CGRP-receptor mediated vasodifation, (e.g., putative CGRP receptor antagonists). As used herein, "CGRP-receptor agonist" includes any compound, peptide or 25 peptide fragment (modified or unmodified) capable of inducing CGRP-receptor mediated vasodilation particularly by example oCGRP or pCGRP; other members of the calcitonin family, e.g, adrenomedullin; N-terminal CGRP fragments, e.g, CGRP(l-12) CGRP(1-15) and CGRP(1-22); C-terminal amide (NH2) versions of CGRP e.g., CGRP(1-8+NH2), CGRP(1-13+NH2) or CGRP(1-14+NH2); and non 30 naturally occurring CGRP analogues e.g., [Ala' p(CH2NH)Cys 2 ]hCGRP which contains a pseudopeptide bond between Ala' and Cys 2 . See Maggi CA, Rovero P, Giuliani S, Evangelista S, Regoli D, Meli A. Biological activity of N-terminal fragments of calcitonin gene-related peptide. Eur J Pharmacol. 1990 Apr 10;179(l- WO 2005/065779 PCT/US2003/038799 44 2):217-9; Qing X, Wimalawansa SJ, Keith IM. Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonary hypertension in rats. Regul Pept. 2003 Jan 31; 110(2):93-9; and Dennis T, Fournier A, St Pierre S, Quirion R. Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for 5 receptor multiplicity. J Pharmacol Exp Ther. 1989 Nov;251(2):718-25 incorporated by reference herein. The compounds of this invention may exist in the form of pharmaceutically acceptable salts. Such salts may include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for 10 example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid. Further, in case the compounds of this invention contain an acidic group, the acidic group may exist in the form of alkali metal salts such as, for example, a potassium salt and a sodium salt; alkaline earth metal salts such as, for example, a magnesium salt and a calcium salt; and salts with organic bases such as a 15 triethylammonium salt and an arginine salt. In the case of a sublingual formulation a saccharin salt or maleate salt may be of particular benefit. The compounds of the present invention may be hydrated or non-hydrated. The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release 20 formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts. The compounds can be administered alone, but generally will be administered with a pharmaceutical carrier 25 selected upon the basis of the chosen route of administration and standard pharmaceutical practice. Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage 30 regimen. While dosing from 0.01 mg/kg to 30 mg/kg is envisaged for compounds of the present invention, the dosage and dosage regimen and scheduling of a compounds of the present invention must in each case be carefully adjusted, utilizing sound WO 2005/065779 PCT/US2003/038799 45 professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of the disease condition. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level which will produce effective beneficial effects 5 without causing any harmful or untoward side effects. Synthesis Compounds of the present invention may be synthesized according to the general schemas provided below. Variables provided in the schema below are 10 defined in accordance with the description of compounds of the above Formula unless otherwise specified. The compounds of the present invention may be prepared according to Scheme 1 or Scheme 2. It may also be possible to use variations of said schemes to prepare the compounds of the present inventions, said variations known to those of ordinary skill in the art. 15 Scheme 1. Synthesis of Formula I Compounds Q R2 Q HO NPG R/ N PG 0 H 0 H IIIl 2 Q D R2 Q 1N N /N - N R Nk NA-C I / -I 2 HH IV 20 The synthesis described in Scheme 1 begins with a compound of Formula II, which is an amino acid with a protected amino terminus. Common amino protecting groups (PG) include BOC, CBZ, and FMOC and their addition and removal are well known in the field. The carboxylic acid moiety of a Formula II compound is coupled WO 2005/065779 PCT/US2003/038799 46 with an amine of formula HNR 1
R
2 using standard peptide coupling reagents to form an amide of Formula III. The amino protecting group is removed resulting in a Formula IV compound. This compound is then coupled with an amine of Formula V (see below) in a mixed urea or urea isostere reaction, generating a Formula I 5 compound. Mixed urea formation is conveniently carried using phosgene, disuccinimidyl carbonate, carbonyl diimidazole or other equivalents. Formation of urea isosteres, such as cyanoguanidines and sulfonylguanidines, are known in the literature. 10 Scheme 2. Synthesis of Formula I Compounds Q Q D MeO MeO
NA
0 0 H V V1 R2 Q D Q D N _HO' 'N RI/ N N AH N N O H O .~H \{ K The synthesis described by Scheme 2 begins with a compound of Formula V, which is an amino acid with a protected carboxylate terminus. The protection is 15 generally a methlyl ester, but other protecting groups such as ethyl, t-butyl, and benzyl esters may also be used. The Formula V compound is coupled with an amine of Formula VIII (see below) in a mixed urea or urea isostere reaction, as above, to generate a Formula VI compound. The Formula VI compound is converted to a free acid compound of Formula VII which is then coupled with an amine of Formula 20 HNR'R 2 to generate a Formula I compound. Scheme 3. Synthesis of Formula I Compounds WO 2005/065779 PCT/US2003/038799 47 Q D Q D HO 40 N N A- R O H H VIII The synthesis described by Scheme 3 begins with a compound of Formula VII from Scheme 2. The Formula V compound is coupled with an alcohol, R 4 -OH. Such ester-forming reactions are well known in the art and can be carried out, for example, 5 with carbodiimide coupling agents such as N,N-dicyclohexylcarbodiimide. In addition, it is often advantageous, especially for esters of secondary and tertiary alcohols, to include additives that accelerate acylations such as 4 dimethylaminopyridne. 10 Preparation of HNR'R 2 and Formula VIII amines Formula VIII and HNR 1
R
2 amines are commercially available, made by literature methods or described herein. HN A- VIII 15 Preparation of Formula II and Formula V amino acids R HO N.PG II MeO 2 V 0 H Y1 made as described in Scheme 4. 20 WO 2005/065779 PCT/US2003/038799 48 Scheme 4. Synthesis of Formula II and Formula V Compounds R3
R
3 -CHO OMe RO NPG IX 0 -- 1~ 0 H O-Me 00 H R 3 R 3 HO N-,P G R 40 : N' PG O H 0 H II R30XII
R
4 0
NH
2 0 V The synthesis described in Scheme 4 begins with an aldehyde of Formula IX, 5 which is reacted with a glycine phosphonate of Formula X in a Wadsworth-Emmons coupling reaction. The compound of Formula X is deprotonated with a base such as diazabicycloundecene or tetramethylguanidine or other organic or inorganic bases well known in the art. The double bond of the resulting Formula XI compound is reduced to give compounds of Formula XII. Reduction can be carried out to give 10 either a racemate or by use of a stereoselective catalyst to give either enantiomer of Formula XII. Such reductions can result from transfer hydrogenation from hydrogen donors such as formic acid or cyclohexadiene, or hydrogenation using gaseous hydrogen, both in the presence of a suitable catalyst. Compounds of Formula II are prepared by acid or base hydrolysis of the ester. Compounds of Formula V are 15 prepared by removal of the protecting group (PG) using methods well known in the art. Other amino acid derivatives of Formula XII may be prepared as shown in Scheme 5.
WO 2005/065779 PCT/US2003/038799 49 Scheme 5. Synthesis of Formula XII
R
3 H R3
R
4 0 PG x v R 4 P H N 0 O H XIIIXI 5 Where, for the purposes of Scheme 5, compounds of Formula XIV are nucleophilic compounds such as amines or alcohols that are able to participate in a Michael Reaction with a compound of Formula XIII as shown. Other compounds of Formula I may be prepared according to Scheme 6 or Scheme 7. It may also be possible to use variations of said schemes to prepare the 10 compounds of the present inventions, said variations known to those of ordinary skill m the art.
WO 2005/065779 PCT/US2003/038799 50 Scheme 6. Synthesis of Formula I Compounds RK3CHO R 3 COOld- R3 COOH- R 3 0 IX XV Bn cN)O 0 XVI I 0 R 2 0 RNH R 0 N OH 0I N R 0 0 0 XIX XVIII xvi G R Vill R 2 N) , A /"G R' 0 OH R 0 x The synthesis described in Scheme 6 begins with commercially available or synthesized aldehydes. The two-carbon homologation and double-bond reduction 5 which are well-known in the literature and lead to compounds of Formula XV. Some Formula XV compounds are also commercially available and others may be prepared by other methods well known in the art. Preparation of compounds of Formula XVI and XVII are known in the literature as substrates and products of the Evans chiral asymmetric synthesis. Hydrolysis leads to compounds of Formula XVIII. As with 10 compounds of Formula VII in Scheme 2, these carboxylic acids can react with amines of formula R1R 2 NH to afford compounds of Formula XIX using well known amide coupling protocols. Hydrolysis of the tert-butyl ester leads to compounds of Formula XX, which can be further coupled with compounds of Formula VIII to afford Formula I compounds. 15 WO 2005/065779 PCT/US2003/038799 51 Scheme 7. Synthesis of Formula I Compounds
R
3 3 RNCHO O OH 0 OH IX OOMe OMe O OMe XXI xxn OMe HN A-E VIll HO N A-p MeO N A O M a XXNV XXIII
R
2
R
4 -OH R N NH
R
2 R 3 N0- 0 p Scheme 7 also starts with commercially available or synthesized aldehydes. 5 These are reacted with dimethyl succinate in the presence of bases to give compounds of Formula XXI. The double bond of the Formula XXI compound is reduced to give compounds of Formula XXII. Reduction can be carried out to give either a racemate or by use of a stereoselective catalyst to give either enantiomer of Formula XXII. Such reductions can result from transfer hydrogenation from 10 hydrogen donors such as formic acid or cyclohexadiene, or hydrogenation using gaseous hydrogen, both in the presence of a suitable catalyst. Amide coupling with amines of Formula VIII lead to compounds of Formula XXIII using well known amide synthesis protocols. Hydrolysis of methyl ester leads to Formula XXIV compounds, which are further coupleded with various amines or alcohols to give 15 amides of Formula I and esters of Formula I, respectively. Compounds of Formula I may also be prepared according to Scheme 8.
WO 2005/065779 PCT/US2003/038799 52 Scheme 8. Synthesis of Formula I Compounds >O 0 N OH 0 0 XXV O NH O0H O NH 0 N N A-p HO N A XXVII I XXVI
NH
2 N R 2 NH A N1 N A-p
N\A
XXVIII 5 The synthesis described in Scheme 8 begins with a commercially available N tert-butyloxycarbonyl-L-aspartic acid benzyl ester. Differently protected aspartic acid derivatives may also be used for synthetic convenience. The beta carboxyl group is coupled with amines of Formula VIII using standard peptide coupling protocols. The alpha-carboxyl protecting group of the Formula XXV compound is removed by 10 hydrogenolysis giving compounds of Formula XXVI. These are further coupled with amines of the formula HNR'R 2 to give compounds of formula XXVII. The amino protecting group is removed by treatment with strong acids such as trifluoroacetic acid or hydrogen chloride in organic solvents. The resulting compounds of Formula XXVIII are then reacted with a variety of electrophilic reagents to generate Formula I 15 compounds. For example, they can be coupled with halo-aromatic compounds using known methods involving heating at various temperatures or by catalysis with transition metals such as palladium or copper, either in stoichiometric amounts or as catalysts. They can also react with various aldehydes or ketones under reductive alkylation conditions, well described in the art. They can also react with isocyanates, WO 2005/065779 PCT/US2003/038799 53 acyl chlorides, or carbamoyl chlorides to generate urea, amide or carbamate derivatives, respectively. It is understood that the sequence of the modifications described above can be changed depending on the selection of protecting groups and the order of their removal. 5 Compounds of Formula I may also be prepared according to Scheme 9. Scheme 9. Synthesis of Formula I Compounds O
R
3 . CZn 0R 3 , O ., R3 N Ot NH O 0 OEt NH 2 0 O OEt OEt XXIX XXX R3 HN NH 0 EtO Vl OH O OEt XXXII XX
R
2
R
3
R
3 ,NH O NH NH O NHO, IN( A- NHOi E/ HO NIAN R N A-E 0 "4 n -J , XXXIII 10 The synthesis described in Scheme 9 begins with an imine of Formula XXIX, prepared by condensation of ethyl glyoxalate and amines of formula R3-NH 2 . These are reacted with 2-tert-butoxy-2-oxoethylzinc chloride to give compounds of Formula XXX. Treatment wit strong acids removes the tert-butyl ester protecting 15 group to give free acids of Formula XXXI which are coupled to amines of Formula VIII to yield compounds of Formula XXXII. The ethyl ester is hydrolyzed with a metal hydroxide salt or aqueous base to give free alpha-acids of Formula XXXIII. These, in turn are coupled with amines of the formula HNR'R 2 to give compounds of formula I.
WO 2005/065779 PCT/US2003/038799 54 Ureidoamide Intermediates and Examples General. 'H- and 13 C-NMR spectra were run on a Bruker 500 or 300 MHz instrument and chemical shifts were reported in ppm (6) with reference to 5 tetramethylsilane (8 0.0). All evaporations were carried out under reduced pressure. Unless otherwise stated, LC/MS analyses were carried out on a Shimadzu instrument using a YMC C18 column (3 x 50 mm) employing a 2 min linear gradient of 0% tol00% solvent B in A in a 3 min run. For LC/MS and for Shimadzu Preparative HPLC system, Solvent A-was: 10% methanol/90% water/0.1% 10 trifluoroacetic acid, and solvent B was 90% methanol/I 0% water/0. 1% trifluoroacetic acid with a UV detector set at 220 nm. I-Benzyl-2',3'-dihydro-2'-oxospiro-[piperidine-4,4'(1'H)-quinazoline 0 HN NH N 15 Polyphosphoric acid (113 g) was heated to 100-1 10 0 C and stirred while 1 benzyl-piperidin-4-one (9.27 ml, 50 mmol) was added. Immediately afterwards, phenyl urea (9.55 g, 70. mmol) was added in portions small enough to avoid excessive foaming. The mixture was heated at 150-160'C overnight. Water (200 mL) was then added slowly to the mixture which had been allowed to cool to 100 20 1 10 0 C (at lower temperatures the mixture becomes too viscous to stir). The resulting solution was neutralized with 1ON NaOH to ca. pH 8, and then extracted wth chloroform. The organic phase was dried over magnesium sulfate and then concentrated to give the crude product which was purified by flash column chromatography on silica gel (6:4 ethyl acetate/hexanes) to give the desired product 25 (9.0 g, 58% ). Mass spec.: 308.25 (MH)*.
WO 2005/065779 PCT/US2003/038799 55 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'(1'H)-quinazoline 0 HN NH HN To a solution of 1-benzyl-2',3'-dihydro-2'-oxospiro-[piperidine-4,4'(l'H) quinazoline (1.00 g) in degassed methanol ( 50 ml ) and 6N hydrochloric acid (2.0 5 ml) was added 10% palladized charcoal (150 mg ). The mixture was shaken on a Parr apparatus under an atmosphere of hydrogen at 60 psi overnight. LC/MS showed incomplete reaction. More 10% palladized charcoal (200 mg) was added, and the mixture was shaken for 2 more days. At that point, all starting material was consumed. The mixture was filtered and the filtrate concentrated to give 531 mg of 10 the desired compound (64%). Mass spec.: 218.12 (MH)+. 4-Amino-4-cyano-piperidine- I -carboxylic acid tert-butyl ester NC NH 2 N 0 To a well stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 15 (9.0 g, 45.3 mmol) in methanol was added ammonium chloride (2.66 g, 49.8 mnol) at room temperature and stirred for 1 h. Sodium cyanide (2.44 g, 49.8 mmol) was added and stirring was continued for additional 16 h. The reaction mixture was quenched with 5% aqueous sodium hydrogencarbonate (50 mL), diluted with water, and the methanol removed by rotary evaporation. The cyanoamine was extracted with 20 methylene chloride (3x 100 mL), dried over sodium sulfate, and the solvents evaporated to give the desired compound as an oil in 91% yield. 'H-NMR (300 MHz, CDCl 3 ): 8 3.95 - 3.90 (in, 1 H), 3.80 - 3.71 (in, 1 H), 3.42 - 3.06 (in, 2 H), 2.04 - 1.94 (in, 1 H), 1.71 - 1.50 (in, 3 H). Mass spec.: 226 (MH)*.
WO 2005/065779 PCT/US2003/038799 56 2-Phenyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, hydrochloride HN 0 N N H To a solution of 4-amino-4-cyano-piperidine-1 -carboxylic acid tert-butyl ester (1.0 g, 4.44 mmol) in methylene chloride (30 mL) was added triethylamine (1.24 mL, 5 8.88 mol), followed by benzoyl chloride (936 mg, 6.66 mmol). After 30 mmi, 4 (dimethylamino)pyridine (40 mg, 0.33 mmol) was added and stirring continued for additional 12 h. The reaction mixture was then quenched with 1 M sodium hydroxide (10 mL), diluted with ethyl acetate (100 mL), and separated. The organic layer was washed sequentially with I M sodium hydroxide (40 mL), aqueous sodium 10 hydrogencarbonate (50 mL), and brine (50 mL) then dried over sodium sulfate. The desired product, 4-benzoylamino-4-cyano-piperidine- 1 -carboxylic acid tert-butyl ester was obtained in 90% yield through crystallization using 30% ethyl acetate in hexane as a solvent. To a solution of 4-benzoylamino-4-cyano-piperidine- 1 -carboxylic acid tert 15 butyl ester (1.3 g, 4 mmol) in ethanol (10 mL) was added 6M sodium hydroxide (1.5 mL) followed by 30% hydrogen peroxide. The reaction mixture was then refluxed for 3 h. The reaction mixture was then diluted with water (30 mL), and the ethanol removed. The residue was diluted with ethyl acetate (100 mL). The organic phase was washed with brine (30 mL) and dried over sodium sulfate. The desired product, 20 4-oxo-2-phenyl-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester was obtained in 80% yield through crystallization from 30% ethyl acetate in hexane. The tert-butyl ester was then dissolved in methylene chloride (5 mL) and a saturated solution of hydrogen chloride in dioxane (25 mL)was added. After 2 h, the solvent was removed to give 2-phenyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, hydrochloride 25 as white powder in 95% yield. 'H-NMR (500 MHz, CD 3 0D): 8 8.23 - 8.21 (m, 2 H), 7.96 - 7.92 (in, 1 H), 7.79 - 7.76 (in, 2 H), 3.68 - 3.64 (m, 3 H), 3.31 - 3.30 (in, 1 H), 2.47 - 2.44 (m, 4 H). Mass spec.: 230 (MH)*.
WO 2005/065779 PCT/US2003/038799 57 5-Formyl-indazole-1-carboxylic acid tert-butyl ester 0 N/ H 'N A methylene chloride (2 mL) solution of di-tert-butyldicarbonate (388 mg, 5 1.78 mmol) was added dropwise at room temperature to a solution of lH-indazole-5 carbaldehyde (273 mg, 1.87 mmol), 4-dimethylaminopyridine (114 mg, 0.94 mmol), and triethylamine (0.26 mL, 1.87 mmol) in methylene chloride (10 mL). The resulting bright yellow solution was stirred at room temperature for 16 h. Solvents were removed in vacuo and the residue was subjected to flash chromatography with 10 silica gel (25 g) and ethyl acetate/hexanes (1:1) containing 1% triethylamine as eluent to afford the title compound as a brownish yellow liquid (414 mg, 90%). 'H-NMR (CDCl 3 , 500 MHz) 6 10.08 (s, 1H), 8.38 (s, lH), 8.34 (s, 1H), 8.25 (d, J= 8.5 Hz, 1H), 8.04 (d, J= 8.8 Hz, 1H), 1.71 (s, 9H). 1 3 CNMR (CDCl 3 , 125 MHz) 6 191.8, 149.0, 142.5, 140.6, 133.0, 128.3, 126.4, 125.8, 115.3, 85.7, 27.8. 15 5-(2-Benzyloxycarbonylamino-2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester N HN OCH 3 ON O 04 A solution of N-(benzyloxycarbony)-ac-phosphonoglycine trimethyl ester 20 (5.50 g, 16.6 mmol) and tetramethylguanidine (1.99 mL, 15.9 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at -78'C for 20 min. To this was added a solution of 5-formyl-indazole-1-carboxylic acid tert-butyl ester (3.72 g, 15.1 mmol) in tetrahydrofuran (25 mL) slowly via syringe over 10 min. The reaction mixture WO 2005/065779 PCT/US2003/038799 58 was stirred at -78*C for 4 h and then allowed to warm to room temperature overnight. The solvent was evaporated and the resulting residue subjected to flash column chromatography on silica gel (1:2 ethyl acetate/hexane) giving the title compound as a white foam (5.77 g, 85%). 1 H-NMR (CDC1 3 , 500 MHz) 6 8.09 (d, J= 9.0 Hz, 5 IH), 8.08 (s, 1H), 7.84 (s, 1H), 7.67 (d, J= 9.0 Hz, 1H), 7.47 (s, 1H), 7.30 (br s, 5H), 6.43 (br s, 1H), 5.09 (s, 2H), 3.84 (s, 3H), 1.72 (s, 9H). Mass spec.: 452 (MH)*. (±)-5-(2-Amino-2-methoxycarbonyl-ethyl)-indazole- 1 -carboxylic acid tert-butyl ester N o
H
2 N OCH 3 0 10 A mixture of 5-(2-benzyloxycarbonylamino-2-methoxycarbonyl-vinyl) indazole- 1 -carboxylic acid tert-butyl ester (524 mg, 1.16 mmol) and 10% palladium on carbon (60 mg) in methanol (20 mL) was shaken for 4.5 h under 50 psi hydrogen gas using a Parr hydrogenator. The reaction mixture was evacuated and purged with nitrogen. Then, the reaction mixture was filtered through a pad of celite and the pad 15 was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (351 mg, 95%). 'H-NMR (CDCl 3 , 500 MHz) 8 8.12-8.10 (in, 2H), 7.55 (br s, IH), 7.37 (dd, J= 8.9, 1.5 Hz, IH), 3.77-3.75 (m, 1H), 3.70 (s, 3H), 3.19 (dd, J 13.7, 5.5 Hz, 1H), 2.99 (dd, J = 13.7, 8.0 Hz, 1H), 1.72 (s, 9H). Mass spec.: 320 (MH)*. 20 (±)-5-(2-Methoxycarbonyl-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine 1 -carbonyl] -amino} -ethyl)-indazole- 1 -carboxylic acid tert-butyl ester
N
0O N /0 o N O
H
3 CO H N NH 0 WO 2005/065779 PCT/US2003/038799 59 A solution of 5-(2-amino-2-methoxycarbonyl-ethyl)-indazole-1-carboxylic acid tert-butyl ester (307 mg, 0.96 mmol), NN-disuccinimidyl carbonate (246 mg, 0.961 mmol), and NN-diisopropylethylamine (0.67 mL, 3.84 mmol) in methylene chloride was stirred for 30 min at room temperature. 3-piperidin-4-yl-3,4-dihydro 5 1H-quinazolin-2-one (238 mg, 1.03 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue subjected to flash chromatography using methylene chloride/methanol/triethylamine (93:5:2) as eluent, giving the product (259 mg, 47%). 'H-NMR (CDC1 3 , 300 MHz) 6 8.13-8.10 (in, 2H), 7.48 (br s, 1H), 7.31 (dd, J = 8.8, 1.6 Hz, I H), 7.16 (t, J= 8.0 Hz, 10 1H), 7.05 (d, J= 7.0 Hz, 1H), 6.94 (t, J = 7.7 Hz, I H), 6.82 (s, lH), 6.66 (d, J = 8.0 Hz, 1H), 4.98 (d, J = 7.7 Hz, 1H), 4.87-4.81 (in, 1H), 4.58-4.49 (in, 1H), 4.26 (s, 2H), 4.05-3.97 (in, 2H), 3.74-3.67 (in, 4H), 3.29-3.23 (in, 2H), 2.93-2.84 (in, 2H), 1.76 1.62 (in, IH), 1.70 (s, 9H), 1.48-1.42 (in, 1H). Mass spec.: 577 (MH)*. 15 2-Trimethylsilanyl-ethanesulfonyl chloride i SO2C1 Sulfuryl chloride (43 ml, 539 mmol) was added in 3 min to a clear solution of triphenylphosphine (129 g, 490 mmol) in methylene chloride (200 mL) at 0 0 C in a flame-dried three-neck round bottom flask. After stirring at 0 0 C for 5 min, the ice 20 water bath was removed and sodium 2-trimethylsilylethanesulfonate (50 g, 245 mmol) was added in portions over 10 min. The resulting white suspension was stirred at room temperature for 16 h, then it was filtered through a pad of celite. The filtrate was concentrated to ca 50 mL, ethyl acetate/hexanes (1:3, 1000 mL) and celite (40 g) were added. The mixture was stirred at room temperature for 15 min and 25 filtered through a pad of celite. Solvents were removed in vacuo and the residue was loaded onto a pre-wetted column with silica gel (300 mL) using 1:3 ethyl acetate/hexanes as the eluent. Solvents were removed and the title compound was obtained as a light tan liquid (41.9g, 85%). If not used immediately, the final product should be stored under nitrogen in the freezer or refrigerator to minimize 30 decomposition. 'H-NMR (CDCl 3 , 500 MHz) 8 3.61-3.57 (in, 2H), 1.32-1.27 (in, 2H), 0.10 (s, 9H).
WO 2005/065779 PCT/US2003/038799 60 1-(2-Trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carboxylic acid ethyl ester CO 2 Et o'' Si A solution of 1H-indole-5-carboxylic acid ethyl ester (10.31g, 58.8 mmol) in 5 dimethylformamide (50 mL) was added dropwise at 0 0 C to a mixture of sodium hydride (1.83g, 76.4 mmol) in dimethylformamide (150 mL). The resulting mixture was stirred at 0 0 C for 30 min, then a solution of 2-trimethylsilanyl-ethanesulfonyl chloride (17.7 g, 88.2 mmol) in dimethylformamide (1OOmL) was added slowly at 0 0 C to the above mixture. After 2 h, sat. aqueous ammonium chloride (200 mL) was 10 added, and the mixture was extracted with ethyl acetate (300 mL). After separation, the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), and dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using 1:1.5 methylene chloride/hexanes as eluent 15 to afford the title compound as a white solid (15.8 g, 79%). 'H-NMR (CDCl 3 , 500 MHz) 8 8.36 (d, J= 1.5 Hz, IH), 8.03 (dd, J = 9.0, 2.0 Hz, 1H), 7.92 (d, J= 8.5 Hz, 1H), 7.50 (d, J= 3.5 Hz, 1H), 6.75 (d, J = 3.5 Hz, IH), 3.94 (s, 3H), 3.21 - 3.18 (in, 2H), 0.84 - 0.80 (m, 2H), -0.06 (s, 9H). 13 C-NMR (CDC1 3 , 125 MHz) 6 167.3, 137.7, 130.3, 128.3, 125.9, 125.5, 124.0,112.8,108.3,52.2,51.2, 10.1,-2.1. Mass 20 spec. 354.12 (MH)*.
WO 2005/065779 PCT/US2003/038799 61 Similarly prepared: 1-(2-Trimethylsilanyl-ethanesulfonyl)- 1 H-indazole-5-carboxylic acid ethyl ester
CO
2 Et N Si 'H-NMR (CDC1 3 , 500 MHz) 8 8.51 (s, lH), 8.34 (s, 1H), 8.21 (dd, J = 8.9, 1.5 Hz, 5 1H), 8.12 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H), 3.42 - 3.39 (in, 2H), 0.86 - 0.82 (in, 2H), -0.02 (s, 9H). "C-NMR (CDC 3 , 125 MHz) 8 166.4, 143.1, 141.2, 130.1, 126.5, 125.0, 124.2, 112.9, 52.5, 51.3, 9.8, -2.1. Mass spec. 355.13 (MH)*. [1 -(2-Trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl] -methanol / ~ OH 00 H Si 10 A solution of diisobutylaluminum hydride (82.9 mL, IM in toluene, 82.9 mmol) was added slowly at 0*C to the solution of 1-(2-trimethylsilanyl ethanesulfonyl)-1H-indole-5-carboxylic acid ethyl ester (8.81g, 25.9 mnol) in toluene (200mL). After it was stirred at 0 0 C for 45 min, the reaction was quenched 15 by the addition of methanol (26mL), pulverized sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed up to room temperature in I h and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a very viscous liquid, which solidified upon cooling. A white solid (8.08 g, 100% yield). 'H-NMR (CDCl 3 , 500 MHz) 8 7.87 (d, J = 8.5 Hz, 1H), 7.62 20 (s, 1H), 7.44 (d, J = 3.7 Hz, 1H), 7.35 (dd, J 8.6, 1.5 Hz, 11H), 6.66 (d, J 3.7 Hz, 1H), 4.79 (s, 2H), 3.18 - 3.14 (m, 2H), 1.73 (s, 1H), 0.85 - 0.82 (in, 2H), -0.06 (s, 9H). Mass spec. 312.14 (MH)+.
WO 2005/065779 PCT/US2003/038799 62 [1 -(2.-Trimethylsilanyl-ethanesulfonyl)-IH-indazol-5 -yl] -methanol / ~ OH NI N H 0, Si A solution of 1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazole-5-carboxylic acid ethyl ester (azeotropically dried with toluene (2x), 5.77g, 16.9 mmol) in 5 tetrahydrofuran (50 mL) was added at 0 0 C to a mixture of lithium borohydride (3.68g, 169 mmol) in tetrahydrofuran (100 mL). The mixture was warmed up to room temperature and stirred for 14h. It was cooled to 0 0 C and lithium borohydride (3.5g) was added. The mixture was warmed up to room temperature and stirred for 14h. It was re-cooled to 0 0 C and sat. aqueous ammonium chloride (25 mL) was 10 added slowly. The resulted white suspension was filtered through a pad of celite, solvents were removed and the residue was subjected to flash chromatography using ethyl acetate/hexanes (1:1.5) with 1% triethylamine to afford the title compound as a white solid (3.8g, 72%). 'H-NMR (CD 3 0D, 500 MHz) 6 8.41 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.85 (s, 1H), 7.61 (dd, J= 8.5, 1.2 Hz, IH), 4.76 (s, 2H), 3.49 - 3.46 (m, 15 2H), 0.76 - 0.72 (m, 2H), -0.03 (s, 9H); "C-NMR (CD 3 0D, 125 MHz) 6 141.2, 140.9, 138.3, 129.2, 125.8, 119.6, 112.7, 63.8, 50.8, 9.9, -3.2. Mass spec. 313.12 (MH)+. 1-(2-Trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carbaldehyde 0 H 0 , si 20 A solution of [1 -(2-trimethylsilanyl-ethanesulfonyl)- I H-indol-5-yl]-methanol (2.lg, 6.74 mmol) in methylene chloride (30 mL) was added at 0 0 C to a mixture of activated manganese dioxide (22g, azeotropically dried with toluene (2x)) and WO 2005/065779 PCT/US2003/038799 63 methylene chloride (70 mL) in a 500 mL round bottom flask. The reaction mixture was stirred at 0 0 C for 30 min and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a white solid (1.8g, 80%). 'H NMR (CDCl 3 , 500 MHz) 5 10.06 (s, 1H), 8.15 (s, 1H), 8.01 (d, J= 8.6 Hz, 1H), 7.87 5 (dd, J= 8.6, 1.5 Hz, 1H), 7.54 (d, J= 3.4 Hz, 1H), 6.80 (d, J = 3.6 Hz, lH), 3.24 3.20 (in, 2H), 0.86 - 0.82 (in, 2H), -0.06 (s, 9H). "C-NMR (CDC1 3 , 125 MHz) 8 191.9, 138.5, 132.3, 130.7, 128.8, 125.3, 125.1, 1134.6, 108.4, 51.4, 10.2, -2.1. Mass spec. 310.12 (MH)*. 10 Similarly prepared: 1-(2-Trimethylsilanyl-ethanesulfonyl)- 1H-indazole-5-carbaldehyde 0 N H oNs s\ Si Mass spec. 311.10 (MH)*. 15 2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)- I H-indol-5-yl] acrylic acid methyl ester 0 o N O H3CO 00 oN Si 1,1,3,3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-a-phophonoglycine trimethyl 20 ester (1.88g, 5.69 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 15 min and cooled to -78 0 C, and a solution of 1-(2- WO 2005/065779 PCT/US2003/038799 64 trimethylsilanyl-ethanesulfonyl)-IH-indole-5-carbaldehyde (1.6g, 5.17 mmol) in tetrahydrofuran (15 mL) was added slowly. The resulting reaction mixture was stirred at -78'C for 2h and then warmed to room temperature in 3h. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica 5 gel using methylene chloride/hexanes (1:1.5) with 1% triethylamine as eluent to afford the title compound as a 92:8 Z/E mixture (determined by integration of
CO
2
CH
3 , for Z isomer at 3.79 ppm, and E isomer at 3.65 ppm). For the Z isomer: 1 H-NMR (CD 3 CN, 500 MHz) 8 7.96 (s, 1H), 7.91 (d, J= 8.5 Hz, IH), 7.66 (d, J= 8.5 Hz, 1 H), 7.56 (d, J= 3.7 Hz, 1H), 7.51 (s, 1H), 7.43 - 7.35 (m, 5H), 7.67 (d, J= 3.7 10 Hz, 1 H), 5.16 (s, 2H), 3.79 (s, 3H), 3.42 - 3.38 (m, 2H), 0.87 - 0.83 (in, 2H), -0.04 (s, 9H). Mass spec. 515.20 (MH)
T
. Similarly prepared: 2-Benzyloxycarbonylamino-3-[I-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5 15 yl]-acrylic acid methyl ester 0 H N H3 CO N : I\ ' N . Si' Flash chromatography on silica gel using methylene chloride containing 1% triethylamine as eluent afforded the title compound as a 95:5 Z/E mixture (determined by the integration of -CH=C(COMe)(NHCBz), 3.72g, 92%). For the Z 20 isomer: 'H-NMR (CD 3 CN, 500 MHz) 8 8.39 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.84 (dd, J= 8.8, 1.2 Hz, 1H), 7.51 (s, 1H), 7.43 - 7.35 (in, 5H), 5.14 (s, 2H), 3.81 (s, 3H), 3.51 - 3.47 (m, 2H), 0.83 - 0.79 (m, 2H), -0.02 (s, 9H). Mass spec. 516.18 (MH)*.
WO 2005/065779 PCT/US2003/038799 65 (*)-2-Amino-3-[I-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-propionic acid methyl ester 0 H
H
3 CO N O 0 0 N Si To a flame dried 500 mL of round bottom flask was added 2 5 benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl] acrylic acid methyl ester (2.24h, 4.36 mmol), methanol (100 mL) and 10% palladium on charcoal (0.5 2 g). The mixture was degassed and purged with hydrogen five times. It was stirred at room temperature for 1 h and filtered through a pad of celite. Solvents were removed and the residue was subjected to flash chromatography using 10 ethyl acetate/hexanes (1:1 and 2:1) containing 1% triethylamine to afford the tile compound as a colorless viscous liquid (1.27g, 76%), which solidified upon cooling. 'H-NMR (CD 3 CN, 500 MHz) 8 7.82 (d, J= 8.2 Hz, IH), 7.51 - 7.49 (m, 2H), 7.22 (dd, J 8.6, 1.5 Hz, IH), 6.72 (d, J = 3.7 Hz, 1H), 3.70 (dd, J= 7.3, 6.1 Hz, IH), 3.65 (s, 3H), 3.38 - 3.34 (in, 2H), 3.08 (dd, J = 13.4, 5.8 Hz, 1H), 2.95 (dd, J= 13.4, 7.3 15 Hz, 1H), 0.82 - 0.79 (in, 2H), -0.05 (s, 9H). 13 C-NMR (CDCl 3 , 125 MHz) 6 176.0, 134.4,133.4, 131.1, 127.9, 126.4, 122.4, 113.1, 107.7, 56.6, 51.7, 50.8, 41.3, 10.1, 2.7. Mass spec. 383.16 (MH)*. Similarly prepared: 20 (±)-2-Amino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 66 0 H N 0O
H
3 CO Th Y 0 N ON Si 'H-NMR (CD 3 CN, 500 MHz) 5 8.34 (s, 1H), 7.98 (d, J 8.6 Hz, 1H), 7.69 (s, 1H), 7.46 (dd, J= 8.6, 1.5 Hz, 1H), 3.71 (dd, J = 7.3, 5.8 Hz, 1H), 3.65 (s, 3H), 3.48 - 3.44 (in, 2H), 3.12 (dd, J= 13.7, 5.8 Hz, 1H), 2.97 (dd, J = 13.7, 7.6 Hz, 1H), 0.83 - 0.79 5 (m, 2H), -0.02 (s, 9H). 1 3 C-NMR (CDCl 3 , 125 MHz) 5 175.9, 141.1, 140.5, 134.6, 131.5, 126.0, 122.2, 112.7, 56.4, 51.8, 51.1, 40.9, 9.8, -2.6. Mass spec. 384.15 (MH)*. (R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol 10 5-yl]-propionic acid methyl ester
N
I
N
7 S 0 Si HN OCH 3 0 In a glove bag that was subjected to 3 vacuum/nitrogen purge cycles, an AIRFREE* (Schlenk) reaction flask equipped with stir bar was charged with (-)-1,2 bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene) rhodium (I) 15 trifluoromethylsulfonate (123 mg, 0.17 mmol, 5 mol%), sealed with a rubber septum, and removed from the glove bag. The 2-benzyloxycarbonylamino-3-[I-(2 trimethylsilanyl-ethanesulfonyl)- 1H-indazol-5-yl]-acrylic acid methyl ester (1.75 g, 3.40 mmol) was weighed into a second AIRFREE* (Schlenk) reaction flask equipped with stir bar and sealed with a rubber septum. After 3 vacuum/nitrogen purge cycles, 20 it was dissolved in a mixture of anhydrous methanol (75 mL ) and anhydrous WO 2005/065779 PCT/US2003/038799 67 methylene chloride (15 mL). Both solvents were deoxygenated prior to addition by sparging with nitrogen for at least 1 h. Once in solution, the mixture was again subjected to 3 vacuum/nitrogen purge cycles. The dehydroamino acid solution was introduced into the AIRFREE* (Schlenk) reaction flask containing the catalyst via 5 cannula. The reaction mixture was subjected to 5 vacuum/hyrogen purge cycles before opening the flask to 1 atm. of hydrogen (balloon). After 16 h, the reaction mixture was purged with 3 vacuum/nitrogen purge cycles . The solvent was evaporated and the residue was subjected to column chromatography (gradient 1:4 ethyl acetate/hexanes to 1:2 ethyl acetate/hexanes) to give 1.5 g (85%) of the title 10 compound as a white solid with 98.4% ee as determined by HPLC analysis using a Chirocel OD column with 80% hexane/20% ethanol as fluent (retention times: 13.9 min for title compound and 11.2 min for S-enantiomer). 'H-NMR (CDCl 3 , 300 MHz) 8 8.17 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.35-7.25 (in, 6H), 5.29 5.24 (in, 1H), 5.08 (dd, J= 19.0, 12.1 Hz, 2H), 4.73-4.67 (in, 1H), 3.73 (s, 3H), 3.38 15 3.32 (in, 2H), 3.29 (dd, J = 14.2, 5.6 Hz, 1H), 3.19 (dd, J = 13.9, 5.6 Hz, IH), 0.91 0.85 (in, 2H), -0.02 (s, 9H). Mass spec.: 518 (MH)+. (R)-2-Amino-3-[L -(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester
N
OS O. 0 - 0 Si 20 /S H 2 N OCH 3 A mixture of (R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl ethanesulfonyl)-lH-indazol-5-yl]-propionic acid methyl ester (1.24 g, 2.40 mmol) and 10% palladium on carbon (124 mg) in methanol (50 mL) was agitated for 2 h under 50 psi hydrogen using a Parr hydrogenator. The reaction mixture was purged 25 with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give 879 mg (96%) of the title compound as a sticky gum. 'H-NMR (CDCl 3 , 300 MHz) 8 8.21 (s, 1H), 8.02 (d, J = 8.8 Hz, I H), 7.59 (s, I H), 7.38 (d, J= 8.8 Hz, 1H), 3.72 (s, 3H), 3.38-3.32 (in, 2H), 3.21 (dd, J WO 2005/065779 PCT/US2003/038799 68 13.9, 5.1 Hz, IH), 2.98 (dd, J 13.9, 7.9 Hz, 1H), 0.91-0.85 (m, 2H), -0.02 (s, 9H). Mass spec.: 384 (MH)* 7-Methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazole-5-carbaldehyde si _N 0 I~ It H N-S 0 50 To a suspension of 7-methylindazole 5-aldehyde (3.0 g, 18.7 mmol) in methylene chloride (150 mL) was added triethylamine (7.83 mL, 56.2 mL, 3 equiv) followed by dropwise addition of neat 2-trimethylsilanyl-ethanesulfonyl chloride (5.60 g, 28.1 mmol, 1.5 equiv). The mixture gradually became homogeneous and 10 was allowed to stir at room temperature for 16 h. The solution was concentrated to a minimum amount of methylene chloride and then subjected to flash column chromatography on silica gel (1:4 ethyl acetate/hexanes) to give 4.7 g (77%) of the product as a pale yellow solid. 'H-NMR (CDCl 3 , 300 MHz) 5 9.98 (s, 1H), 8.77 (s, 1H), 8.09 (s, 1H), 7.64 (s, 1H), 3.64-3.58 (in, 2H), 2.65 (s, 3H), 0.88-0.82 (in, 2H), 15 0.01 (s, 9H). 2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)- 2
H
indazol-5-yl]-acrylic acid methyl ester 0
OCH
3 0 N HN 0 07 0~ 20 To a solution of N-(benzyloxycarbonyl)--phosphonoglycine trimethyl ester (4.93 g, 14.9 mmol, 1.1 equiv) in anhydrous tetrahydrofuran (75 mL) was added tetramethylguanidine (1.78 mL, 1.05 equiv). The mixture was stirred at room temperature under nitrogen for 5 min and was then cooled to -78*C. After stirring for 15 min at -78*C, a solution of 7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H 25 indazole-5-carbaldehyde in tetrahydrofuran (25 mL) was added. The reaction mixture was allowed to slowly warm to room temperature overnight. Although the WO 2005/065779 PCT/US2003/038799 69 reaction was incomplete, the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and washed with 1 M sulfuric acid. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Flash column chromatography (1:4 ethyl acetate/hexanes) gave 2.66 g (37 %) of the product as 5 white glass foam. 'H-NMR (CDCl 3 , 300 MHz) 8 8.48 (s, lH), 7.62 (s, 1H), 7.38 7.25 (m, 7H), 6.48 (bs, 1H), 5.10 (s, 2H), 3.83 (s, 3H), 3.58-3.52 (in, 2H), 2.51 (s, 3H), 0.89-0.83 (in, 2H), 0.02 (s, 9H). Mass spec.: 530 (MH)+. (R)-2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl) 10 2H-indazol-5-yl]-propionic acid methyl ester Si 0 NH N \\ O .- o N~ ~ O OMe In a glove bag that was subjected to 3 vacuum/nitrogen purge cycles, an AIRFREE* (Schlenk) reaction flask equipped with stir bar was charged with (-)-1,2 bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene) rhodium (I) 15 trifluoromethylsulfonate (259 mg, 0.36 mmol, 9 mol-%), sealed with a rubber septum, and removed from the glove bag. The 2-benzyloxycarbonylamino-3-[7 methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl] -acrylic acid methyl ester (2.03 g, 3.83 mmol) was weighed into a second AIRFREE* (Schlenk) reaction flask equipped with stir bar and sealed with a rubber septum. After 3 20 vacuum/nitrogen purge cycles, it was dissolved in anhydrous methanol (80 mL, deoxygenated prior to addition by sparging with nitrogen for at least 1 h). Once in solution, it was again subjected to 3 vacuum/nitrogen purge cycles. The dehydroamino acid solution was transferred via cannula to the AIRFREE* (Schlenk) reaction flask containing the catalyst. The reaction mixture was purged with 5 25 vacuum/hydrogen purge cycles before opening the flask to a balloon of hydrogen (1 atm). After 2.5 h, the reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The solvent was evaporated and the residue was subjected to column chromatography (gradient 1:4 ethyl acetate/hexanes to 1:2 ethyl acetate/hexanes) to WO 2005/065779 PCT/US2003/038799 70 give 1.4 g (68%; ee = 99.2%) of the title compound as a white solid. 'H-NMR (CDC1 3 , 300 MHz) 8 8.43 (s, 1H), 7.34 (s, 5H), 7.19 (s, 1 H), 6.87 (s, I H), 5.24 (d, J 8.1 Hz, 1H), 5.08 (dd, J= 18.3, 12.1 Hz, 2H), 4.67 (dd, J 13.9, 6.2 Hz, 1 H), 3.73 (s, 3H), 3.57 -3.51 (in, 2H), 3.16 (dd, J 14.0, 5.9 Hz, 1H). 3.06 (dd, J= 13.9, 6.6 Hz, 5 1 H), 2.55 (s, 3H), 0.89-0.83 (in, 2H), 0.01 (s, 9H). "C-NMR (CDC1 3 , 75 MHz) 6 172.0, 155.7, 151.7, 136.2, 132.2, 129.8, 129.5, 128.6, 128.4, 128.2, 125.1, 121.1, 118.1, 67.1, 54.7, 52.5, 51.1, 38.6, 17.1, 9.7, -2.0. Mass spec.: 532 (MH)*. (R)-2-Amino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl] 10 propionic acid methyl ester 0 S _ 1 \ oue
'I
H
2 N 0 2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilanyl ethanesulfonyl)-2H-indazol-5-yl]-propionic acid methyl ester, (1.35 g, 2.54 mmol) and 10% palladium on carbon (135 mg) in methanol (40 mL) were agitated for 3.0 h 15 under 55 psi hydrogen using a Parr apparatus. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (1.01 g, quantitative yield) as a sticky gum. 'H-NMR (CDCl 3 , 300 MHz) 6 8.45 (s, 1H), 7.29 (s, 1H), 20 6.97 (s, IH), 3.79-3.73 (in, 1H), 3.73 (s, 3H), 3.56-3.50 (in, 2H), 5.12 (dd, J= 13.5, 5.12 Hz, 1H), 4.85 (dd, J= 13.5, 8.1 Hz, 1H), 2.58 (s, 3H), 0.87-0.81 (m, 2H), 0.01 (s, 9H). "C-NMR (CDCl 3 , 75 MHz) 8 175.5, 151.8, 133.7, 129.9, 129.4, 125.0, 121.3, 117.9, 55.5, 52.1, 51.1, 41.4, 17.1, 9.8, -2.1. Mass spec.: 398 (MH)*. 25 (R)-3-[7-Methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl]-2-{[4-(2 oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carbonyl]-amino} propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 71 \ ./ 5' HN O 0 N N-s/N N / NH 0 0
OCH
3 A mixture of 2-amino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H indazol-5-yl]-propionic acid methyl ester (500 mg, 1.26 mmol), NN diisopropylethylamine (0.66 mL, 3.77 mmol) and disuccinimidylcarbonate (322 mg, 5 1.26 mmol) were stirred together in methylene chloride (20 mL) for 30 min at room temperature. Then, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (444 mg, 1.35 mmol) was added and the reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated and the residue was subjected to flash column chromatography (1:4 acetone/ethyl acetate) to give 490 mg (60 % yield) of 10 the title compound as a white solid. 'H-NMR (CDC 3 , 300 MHz) 8 8.47 (s, 1H), 7.23 (s, 1H), 7.19-7.14 (m, IH), 7.04 (d, J= 7.3 Hz, 1H), 6.97-6.93 (m, 2H), 6.77 (s, 1H), 6.65 (d, J= 7.7 Hz, 1H), 4.99 (d, J = 7.3 Hz, 1H), 4.81 (dd, J = 13.5, 6.2 Hz, 1H), 4.58-4.46 (in, 1H), 4.27 (s, 2H), 4.10-3.98 (in, 2H), 3.73 (s, 2H), 3.57-3.51 (in, 2H), 3.14-3.11 (in, 2H), 2.95-2.83 (m, 2H), 2.58 (s, 3H), 1.77-1.65 (m, 4H), 0.92-0.84 (in, 15 2H), -0.01 (s, 9H). Mass spec.: 655 (MH)*. Similarly prepared: (±)-2- {[4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yi)-piperidine- 1 -carbonyl]-amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)- 1 H-indol-5-yl] -propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 72 H N N
H
3 CO 0 N Si 'H-NMR (CD 3 0D, 500 MHz) 8 7.85 (d, J 8.2 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J= 3.7 Hz, 1H), 7.27 (dd, J = 8.6, 1.5 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz,IH), 6.95 (t, J = 7.6 Hz, IH), 6.79 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 3.7 Hz, IH), 5 4.44 - 4.38 (in, 1H), 4.26 (s, 2H), 4.13 - 4.08 (m, 2H), 3.73 (s, 3H), 3.34 - 3.29 (m, 4H), 3.13 (dd, J = 13.5, 9.4 Hz, 1H), 2.89 - 2.79 (in, 2H), 1.76 -1.70 (in, 1H), 1.63 1.59 (m, 3H), 0.76 - 0.72 (in, 2H), -0.07 (s, 9H); Mass spec.: 640.40 (MH)*. (R)-2-{ [4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amimo)-3 10 [1-(2-trimethylsilanyl-ethanesulfonyl)-IH-indazol-5-yl]-propionic acid methyl ester 0
OCH
3 N HN O N N OO N4$ NH 'Si A solution of (R)-2-Amino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H indazol-5-yl]-propionic acid methyl ester (764 mg, 1.99 mmol), NN diisopropylethylamine (1.10 mL, 5.97 mmol) and disuccinimidylcarbonate (509 mg, 15 1.99 mmol) in methylene chloride (20 mL) was stirred for 40 min at room temperature. Then, 3-piperidin-4-yl-3,4-dihydro-IH-quinazolin-2-one (70% pure, 703 mg, 2.13 mmol) was added and the reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated in vacuo and the residue WO 2005/065779 PCT/US2003/038799 73 was subjected to flash column chromatography (1:4 acetone/ethyl acetate) to give 1.15 g (90 %) of the title compound. 1 H-NMR (CDC1 3 , 300 MHz) 6 8.21 (s, 1 H), 8.01 (d, J= 8.5 Hz, 1H), 7.53 (s, IH), 7.32 (d, J 8.5 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.06 (d, J= 7.6 Hz, 1H), 6.95 (d, J= 7.6 Hz, 1H)1, 6.76 (s, 1H), 6.65 (d, J= 7.9 5 Hz, lH), 5.01 (d, J= 7.6 Hz, 1H), 4.84 (dd, J= 13.1, 6.0 Hz, 1H), 4.56-4.49 (m, I H), 4.28 (s, 2H), 4.13-3.98 (m, 2H), 3.73 (s, 3H), 3.39-3.35 (m, 2H), 3.28 (dd, J= 14.0, 6.1 Hz, 1H), 3.24 (dd, J = 13.7, 5.8 Hz, 1H), 2.94-2.87 (m, 2H), 1.75-1.67 (m, 4H), 0.91-0.87 (m, 2H), -0.02 (s, 9H). Mass spec.: 641 (MH)*. 10 Similarly prepared: (±)-2- {[4-(2-Oxo-2,3-dihydro-benzoimidazol-I -yl)-piperidine- 1 -carbonyl]-amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-propionic acid methyl ester NH o NN 0Y N NH
CO
2 Me o0/ Si 15 'H-NMR (CD 3 CN, 500 MHz) 8 9.78 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 3.7 Hz, 1H), 7.28 (dd, J = 8.5, 1.5 Hz, 1H), 7.10 - 7.08 (m, 1H), 7.05 7.03 (m, 1H), 6.99 - 6.97 (m, 2H), 6.70 (d, J = 3.7 Hz, 1H), 5.91 (d J= 7.9 Hz, 1H), 4.66 (q, J= 8.2 Hz, 1H), 4.45 - 4.39 (m, 1H), 4.14 (br s, lh), 3.68 (s, 3H), 3.36 - 3.32 (m, 2H), 3.27 (dd, J= 14.0, 5.5 Hz, 1H), 3.18 (dd, J = 13.7, 8.5 Hz, 1H), 2.90 - 2.84 20 (m, 2H), 2.55 (br s, 1H), 2.36 - 2.21 (m, 2H), 1.74 - 1.70 (m, 2H), 0.82 - 0.78 (m, 2H), -0.09 (s, 9H). Mass spec. 626.26 (MH)*. (±)-2-{[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-amino}-3 [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 74 0 NH N N NNH N CO 2 Me 00 o/ si 'H-NMR (CD 3 CN, 500 MHz) S 9.61 (br s, 1H), 8.35 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.51 (dd, J = 8.8, 1.5 Hz, 1H), 7.10 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 7.00 - 6.97 (m, 2H), 5.90n(d, J = 7.9 Hz, 1H), 4.67 4.62 (m, 1H), 4.42 -4.36 (m, 5 1H), 4.13 - 4.07 (br s, 1H), 3.68 (s, 3H), 3.45 - 3.42 (m, 2H), 3.30 (dd, J = 14.0, 5.8 Hz, IH), 3.20 (dd, J = 13.7, 8.8Hz, 1H), 2.89 - 2.84 (m, 2H), 2.52 (br s, 1H), 2.33 2.23 (m, 2H), 1.72 - 1.69 (m, 2H), 0.80 - 0.76 (m, 2H), -0.07 (s, 9H). Mass spec. 627.25 (MH)*. 10 (±)-2- {[4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl)-propionic acid methyl ester H
H
3 CO0 N 00 N -2 0 'H-NMR (CD 3 0D, 500 MHz) 8 7.85 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J 3.7 Hz, 1H), 7.27 (dd, J= 8.6, 1.5 Hz, 1H), 7.16 (t, J= 7.6 Hz, 1H), 7.10 (d, J= 7.6 15 Hz,1H), 6.95 (t, J= 7.6 Hz, 1H), 6.79 (d, J= 8.0 Hz, 1H), 6.73 (d, J= 3.7 Hz, 1 H), 4.44 - 4.38 (m, 1 H), 4.26 (s, 2H), 4.13 - 4.08 (m, 2H), 3.73 (s, 3H), 3.34 - 3.29 (m, 4H), 3.13 (dd, J= 13.5, 9.4 Hz, I H), 2.89 - 2.79 (m, 2H), 1.76 -1.70 (m, 1H), 1.63 1.59 (m, 3H), 0.76 - 0.72 (m, 2H), -0.07 (s, 9H). Mass spec. 640.40 (MH)*.
WO 2005/065779 PCT/US2003/038799 75 (±)-2- {[4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester H 0 N oN N
H
3 CO yC 0 -- N N Si fl 0 5 IH-NMR (CD 3 0D, 500 MHz) 8 8.39 (d, J = 0.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, IH), 7.75 (s, 1H), 7.52 (dd, J = 8.5, 1.5 Hz, 1H), 7.14 - 7.10 (m, 2H), 6.94 (t, J = 7.5 Hz, IH), 6.78 (d, J = 7.5 Hz, 1H), 4.63 - 4.60 (in, lh), 4.43 - 4.37 (m, 1H), 4.27 (s, 2H), 4.11 (br s, 1H), 4.08 (br s, 1H), 3.71 (s, 3H), 3.47 - 3.43 (in, 2H), 3.37 - 3.33 (m, 1H), 3.18 (dd, j = 13.5, 10.0 Hz, 1H), 2.87 - 2.79 (in, 2H), 1.73 - 1.59 (in, 4H), 0.80 10 - 0.75 (in, 2H), -0.05 (s, 9H); 13 C-NMR (CD 3 0D, 125 MHz) 8 173.7, 155.5, 158.1, 141.0, 140.6, 137.2, 134.4, 131.3, 128.2, 126.1, 125.8, 122.2, 121.9, 118.3, 113.4, 112.6, 55.9, 52.1, 51.7, 50.8, 48.9, 48.6, 48.4, 48.2, 48.0, 47.9, 47.7, 47.5, 43.8, 43.7, 43.1, 37.2, 28.5, 9.8, -3.2. Mass spec.: 641.40 (MH)*. 15 Example 1 (±)-3-(1H-Indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 carbonyl]-amino} -propionic acid
N
HN /\ 0 N N 0 HO H N NH 0 A solution of 5-(2-methoxycarbonyl-2- {[4-(2-oxo- 1,4-dihydro-2H 20 quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -ethyl)-indazole- 1 -carboxylic acid WO 2005/065779 PCT/US2003/038799 76 tert-butyl ester (168 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL) in methanol (5 mL) was cooled to 0 0 C. A solution of lithium hydroxide monohydrate (49 mg, 2.04 mmol) in water (5 mL) was added. The reaction mixture was stirred at 0 0 C for 6 h and then placed in the freezer for a further 16 h. The solvents were 5 removed in vacuo and the residue dissolved in water (15 mL). The pH of the aqueous solution was adjusted to ca. 1 with IN hydrochloric acid. The resulting white solid precipitated was collected by filtration. The solid was dried under vacuum to give the title compound (108 mg, 80%). 'H-NMR (DMSO-d 6 , 300 MHz) 5 12.94 (bs, 1H), 9.19 (s, 1H), 8.01 (s, 1H), 7.61 (s, IH), 7.46 (d, J= 8.4 Hz, IH), 10 7.28 (dd, J= 8.5 , 1.5 Hz, IH), 7.13-7.06 (in, 2H), 6.86 (t, J 7.0 Hz, 1H), 6.76-6.72 (in, 2H), 4.32-4.24 (m, 2H), 4.09-4.02 (in, 4H), 3.17-2.97 (m, 2H), 2.72-2.59 (in, 2H), 1.57-1.35 (m, 4H). IR (KBr, cm-1) 3424, 2963, 2930, 1660, 1628, 1505, 1474, 1446, 753. Mass spec.: 463 (MH)*. 15 (R)-2-{[4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid 0 -Si seO / 'N-N H NCO OH H A solution of (R)-2- { [4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine 1 -carbonyl) -amino} -3-[I-(2-trimethylsilanyl-ethanesulfonyl)- I H-indazol-5-yl] 20 propionic acid methyl ester (775 mg, 1.21 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was cooled to 0 0 C. A solution of lithium hydroxide monohydrate (115 mg, 4.84 mmol) in water (3 mL) was added. The reaction mixture was stirred at 0 0 C for 2 h and then placed in the freezer at -15'C for 16 h. While cooling the reaction mixture with an ice bath, the pH was increased to ca. 7 by addition of 1N 25 hydrochloric acid (3.8 mL). Organic solvents were removed under vacuum. The resulting aqueous solution was extracted with ethyl acetate after additon of more IN WO 2005/065779 PCT/US2003/038799 77 hydrochloric acid (0.5 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give 684 mg (90%) of the title compound as a white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) 8 9.21 (s, 1H), 8.58 (s, 1H), 7.90 (d, J 8.4 Hz, lH), 7.78 (s, lH), 7.56 (d, J = 8.1 Hz, 1H), 7.13-7.09 (m, 2H), 6.88-6.83 (in, 5 1H), 6.76-6.74 (m, 2H), 4.33-4.27 (m, 2H), 4.18 (s, 2H), 4.09-3.96 (m, 3H), 3.57 3.51 (in, 2H), 3.25-3.04 (m, 2H), 2.74-2.60 (in, 2H), 1.54-1.43 (m, 4H), 0.70-0.64 (in, 2H), -0.08 (s, 9H). Mass spec.: 627 (MH)*. Similarly prepared: 10 ( )-2-{[4-(2-Oxo-2,3-dihydro-benzoimidazol- 1 -yl)-piperidine- 1 -carbonyl] -amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-lH-indol-5-yl]-propionic acid NH 0 NN NH N0 2 H o0 / Si si Mass spec. 612.25 (MH) 4 . 15 (±)-2-{[4-(2-Oxo-2,3-dihydro-benzoimidazol- 1 -yl)-piperidine- 1 -carbonyl] -amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-IH-indazol-5-yl]-propionic acid NH 0 N N / .~ NH N ~C0 2 H Si WO 2005/065779 PCT/US2003/038799 78 Mass spec. 613.26 (MH)*. (±)-2- {[4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -3 [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid H 0N 0 H N HO N N 0 , N N Si 5 1 H-NMR (CD 3 CN, 500 MHz) 8 8.37 (s, 1H), 8.08 (s, 1H), 8.01 (d, J 8.5 Hz, IH), 7.77 (s, 1 H), 7.53 (dd, J = 8.5, 1.5 Hz, 1H), 7.19 (t, J 7.3 Hz, 1H), 7.14 (d, J= 7.3 Hz, 1H), 6.98 (td,j 7.6, 1.2 Hz, 1 H), 6.79 (d, j = 8.0 Hz, 1 H), 6.28 (br s, 3H), 4.54 - 4.49 (in, IH), 4.37 - 4.32 (in, IH), 4.30 (s, 2H), 3.98 - 3.92 (m, 2H), 3.45 - 3.41 10 (m, 2H), 3.37 (dd, j = 14.0, 4.9 Hz, 1H), 3.20 (dd, J= 14.0, 9.7 Hz, 1H), 2.84 - 2.77 (m, 2H), 1.65 - 1.57 (in, 4H), 0.79 - 0.76 (m, 2H), -0.05 (s, 9H). Mass spec.: 627.30 (MH)*. (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid {2 15 [1,4']bipiperidinyl-1'-yl-2-oxo- 1-I -(2-trimethylsilanyl-ethanesulfonyl)- 1H-indazol 5-ylmethyl]-ethyl } -amide 0 -No N HN N -Sis N NH /1 WO 2005/065779 PCT/US2003/038799 79 To a solution of (R)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino) -3-[1-(2-trimethylsilanyl-ethanesulfonyl)- 1 H-indazol 5-yl]-propionic acid (554 mg, 0.88 mmol) and NN-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) was added a solution of 4 5 piperidinopiperidine (164 mg, 0.97 mmol) and PyBOP* (460 mg, 0.88 mmol) in methylene chloride (15 mL). The reaction mixture was stirred for 16 h at room temperature. It was then concentrated to approximately 2 mL and subjected to flash column chromatography using methylene chloride/methanol/triethylamine (94:5:1) as eluent to give 599 mg (87%) of the title compound as a white solid. 1 H-NMR 10 (CD 3 CN, 300 MHz) 8 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7.96 (in, 1H), 7.74 (s, 0.5H), 7.71 (s, 0.5H), 7.55-7.46 (m, 1H), 7.21-7.12 (m, 2H), 6.97-6.92 (in, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.71 (t, J = 8.1 Hz, 1H), 5.00 (dd, J 15.0, 8.1 Hz, 1H), 4.63 4.51 (in, 1H), 4.39-4.29 (m, 1H), 4.29 (s, 2H), 4.10-3.96 (in, 3H), 3.46-3.40 (m, 2H), 2.92-2.70 (in, 8H), 2.58-2.37 (in, 5H), 1.74-1.40 (m, 13H), 0.80-0.74 (in, 2H), -0.04 15 (s, 9H). Mass spec.: 778 (MH)*. Similarly prepared: (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1 -yl)-piperidine-1 -carboxylic acid {2 [1,4']bipiperidinyl-l'-yl-2-oxo- 1-[i-(2-trimethylsilanyl-ethanesulfonyl)- IH-indol-5 20 ylmethyl]-ethyl} -amide 0 N N N HN 0 TMS N /L NH 'H-NMR (CD 3 CN, 500 MHz) 8 9.42 (br s, 1H), 7.80 (d, J 8.5 Hz, 0.6 H), 7.78 (d, J = 8.2 Hz, 0.4 H), 7.50 (s, 1H), 7.43 (t, J = 3.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 0.6 H), 7.23 (d, J = 8.5 Hz, 0.4 H), 7.10 - 7.07 (m, 1H), 7.02 - 6.95 (in, 3H), 6.69 (s, 0.4 H), 25 6.68 (s, 0.6 H), 5.88 (d, J = 8.5 Hz, 0.6 H), 5.85 (d, J = 8.4 Hz, 0.4 H), 5.04 - 4.98 (in, 1H), 4.49 (s, 0.4 H), 4.46 (s, 0.6 H), 4.36 - 4.30 (m, 1H), 4.11 - 4.07 (in, 1H), WO 2005/065779 PCT/US2003/038799 80 3.97 - 3.91 (i, 1H), 3.31 - 3.28 (m, 2H), 3.11 - 3.05 (m, 6 H), 2.87 - 2.80 (m, 2H), 2.43 - 2.07 (m, 8 H), 1.78 - 1.74 (m, 4H), 1.71 - 1.65 (m, 2H), 1.46 - 1.40 (m, 2H), 1.37 - 1.31 (m, 2H), 0.80 - 74 (m, 2H), -0.10 (s, 9H). LC/MS: tR = 2.47 min, 762.37 (MH)*. 5 (+)-4-(2-Oxo-2,3 -dihydro-benzoimidazol- I -yl)-piperidine- 1 -carboxylic acid {2 [1,4']bipiperidinyl- 1-yl-2-oxo- 1-[1 -(2-trimethylsilanyl-ethanesulfonyl)- I H-indazol 5-ylnethyl] -ethyl} -amide 0 O N N N DDH N ODN SN o I TMS N /NH 10 'H-NMR (CD 3 CN, 500 MHz) 8 9.67 (s, IH), 8.32 (s, 1H), 7.96 (d, J 8.7 Hz, 0.55 H), 7.93 (d, J = 8.6 Hz, 0.45 H), 7.70 (s, IH), 7.51 (d, J = 8.6 Hz, 0.55 H), 7.47 (d, J = 8.8 Hz, 0.45 H), 7.08 - 7.05 (m, IH), 7.03 - 6.99 (m, 1H), 6.98 - 6.94 (m, 2H), 6.01 (d, J = 7.9 Hz, 0.45 H), 5.96 (d, J = 7.9 Hz, 0.55 h), 5.05 - 5.00 (m, 1H), 4.49 4.46 (m, LH), 4.35 - 4.29 (m, 1H), 4.10 - 4.05 (m, 1H), 4.00 - 3.93 (m, 1H), 3.40 15 3.36 (m, 2H), 3.17 - 3.30 (m, 6H), 2.91 - 2.71 (m, 2H), 2.52 - 2.13 (m, 8H), 1.76 9br s, 4H), 1.69 - 1.65 (m, 2H), 1.44 - 1.41 (m, 2H), 1.34 - 1.30 (m, 2H), 0.77 - 0.71 (m, 2H), -0.08 (s, 9H). LC/MS: tR 2.35 min, 763.35 (MH)*. (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2 20 [1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5 ylmethyl]-ethyl} -amide WO 2005/065779 PCT/US2003/038799 81 H 0 N N 0 H N 'rN N 0 'H-NMR (CD 3 CN, 500 MHz) 8 8.17 (s, 0.6H), 8.16 (s, 0.4H), 7.84 (d, J 8.5 Hz, 0.6 H), 7.81 (d, J = 8.5 Hz, 0.4 H), 7.54 (s, 0.4 H), 7.53 (s, 0.6H), 7.48 (t, J = 4.1 Hz, 1H), 7.31 (dd, J = 8.5, 1.5 Hz, 0.6 H), 7.28 (dd, J = 8.5, 1.5 Hz, 0.4 H), 7.18 (t, j = 7.4 5 Hz, 1H), 7.09 - 7.06 (in, 1H), 6.93 (t, J = 7.3 Hz, IH), 6.83 (d, J = 7.9 Hz, I H), 6.72 (d, J = 3.6 Hz, IH), 6.09 (d, J = 8.2 Hz, IH), 5.05 - 4.99 (in, 1H), 4.53 - 4.50 (m, 1H), 4.40 - 4.34 (in, 1H), 4.26 (s, 1.2H)< 4.24 (s, 0.8H), 3.99 - 3.94 (in, 1H), 3.35 3.30 (in, 2H), 3.15 - 3.07 (in, 3H), 3.08 - 3.03 (in, 1H), 2.81 - 2.73 (m, 3H), 2.55 2.37 (m, 6H), 2.21 - 2.16 (m, 1H), 2.13 - 2.08 (in, 1H), 1.69 - 1.57 (in, 4H), 1.51 10 1.45 (m, 4H), 1.41 - 1.35 (in, 4H), 0.83 - 0.74 (in, 2H), -0.06 (s, 9H). Mass spec.: 776.44 (MH)*. (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2 [1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol 15 5-ylmethyl]-ethyl} -amide H o N YI N 0 H N N N N NN 0 Purified by silica gel chromatography using methylene chloride:imethanol/triethylamine (90:10:0.5) as eluent. 'H-NMR (CD 3 CN, 500 MHz) WO 2005/065779 PCT/US2003/038799 82 8 8.36 (s, 1H), 8.04 (s, IH), 8.01 (d, J= 8.8 Hz, 0.6H), 7.97 (dd, J = 8.8 Hz, 0.4 H), 7.74 (s, I H), 7.54 (dd, J= 8.5, 1.5 Hz, 0.6 H), 7.51 (dd, J= 8.5, 1.5 Hz, 0.4 H), 7.18 (t, J= 7.4 Hz, IH), 7.11 (t, J= 7.3 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.9 Hz, IH), 6.05 (d, J= 8.5 Hz, 0.4 H), 6.02 (d, J= 8.5 Hz, 0.6 H), 5.06 - 5.01 (m, 1H), 5 4.52 - 4.50 (m, 1H), 4.39 - 4.34 (m, 1H), 4.27 (s, 1.2 H), 4.25 (s, 0.8 H), 4.00 - 3.97 (m, 2H), 3.45 - 3.40 (m, 2H), 3.20 - 3.08 (m, 2H), 2.81 - 2.74 (m, 2H), 2.56 - 2.39 (m, 8H), 2.27 - 2.24 (m, IH), 2.20 - 2.16 (m, 1H), 1.68 - 1.57 (m, 4H), 1.52 - 1.45 (m, 4H), 1.41 - 1.34 (m, 4H), 1.06 - 1.01 (m, IH), 0.80 -0.75 (m, 2H), -0.07 (s, 9H). Mass spec.: 777.40 (MH)*. 10 (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid {2-(4 isobutyl-piperazin-1-yl)-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5 ylmethyl]-ethyl} -amide O NH 0 N N NH 0 N 0 N S N Si 15 'H-NMR (CD 3 CN, 500 MHz) 8 9.75 (s, IH), 7.82 (d, J 8.2 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.28 (d, J = 8.5 Hz, IH), 7.12 - 7.09 (m, 1H), 7.04 - 7.02 (m, IH), 7.00 - 6.97 (m, 2H), 6.72 (d, J = 3.7 Hz, 1H), 5.97 (d, J = 8.2 Hz, 1H), 5.01 (dd, J = 14.6, 7.2 Hz, I H), 4.40 - 4.34 (m, 1H), 4.15 - 4.08 (m, 2H), 3.58 - 3.54 (m, 1H), 3.50 - 3.45 (m, 2H), 3.39 - 3.35 (m, IH), 3.36 - 3.32 (m, 2H), 3.14 - 3.10 (m, 20 8H), 2.89 - 2.83 (m, 2H), 2.34 - 2.23 (m, 4H), 2.17 - 2.13 (m, 1H), 0.85 (d, J = 6.7 Hz, 6H), 0.83 - 0.80 (m, 2H), -0.06 (s, 9H). Mass spec.: 736.40 (MH)*. ( )-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid {2-(1,4 dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H 25 indol-5-ylmethyl]-ethyl}-amide WO 2005/065779 PCT/US2003/038799 83 0 NH 0O N N eN 0O Nq O O 00 Si 'H-NMR (CD 3 CN, 500 MHz) 8 9.27 (s, 1H), 7.82 (d, J 8.5 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 3.6 Hz, IH), 7.28 (dd, J = 8.5, 1.5 Hz, 1H), 7.13 - 7.10 (m, 1H), 7.06 7.03 (m, 1H), 7.01 - 6.98 (m, 2H), 6.72 (d, J = 3.6 Hz, 1H), 5.95 (d, J = 8.0 Hz, 1H), 5 5.05 (dd, J = 15.0, 7.3 Hz, 1H), 4.41 - 4.34 (m, 1 H), 4.14 - 4.08 (m, 2H), 3.90 - 3.86 (m, 3H), 3.68 - 3.64 (m, 1H), 3.60 - 3.56 (m, 2H), 3.45 - 3.40 (m, 1H), 3.35 - 3.31 (m, 2H), 3.15 (dd, J = 13.4, 7.1 Hz, 1 H), 3.05 (dd, J = 13.4, 7.0 Hz, IH), 2.89 - 2.83 (m, 2H), 2.34 - 2.19 (m, 3H), 1.73 - 1.70 (m, 2H), 1.64 - 1.56 (m, 2H), 1.53 - 1.49 (m, 1H), 1.29 - 1.26 (m, IH), 0.84 - 0.80 (m, 2H), -0.05 (s, 9H). Mass spec.: 737.37 10 (MH)*. (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid {2-(4 isobutyl-piperazin-1-yl)-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol 5-ylmethyl]-ethyl} -amide 0 NH 0 N NH NO OO N Si 15 'H-NMR (CD 3 CN, 500 MHz) 8 9.84 (s, 1H), 8.37 (s, IH), 7.98 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.52 (dd, J = 8.8, 1.5 Hz, 1H), 7.11 - 7.09 (m, 1H), 7.06 - 7.03 (m, 1 H), WO 2005/065779 PCT/US2003/038799 84 7.02 - 6.98 (m, 2H), 5.97 (d, J = 8.2 Hz, 1H), 5.02 (dd,J = 14.3, 7.3 hz, IH), 4.39 4.33 (m, 1H), 4.14 - 4.07 (m, 2H), 3.53 - 3.50 (m, 3H), 3.46 - 3.42 (m, 2H), 3.45 3.39 (m, IH), 3.20 - 3.06 (m, 5H), 2.89 - 2.83 (m, 2H), 2.30 - 2.27 (m, 4H), 2.21 2.17 (m, IH), 1.74 - 1.70 (m, 3H), 0.86 (d, J = 6.7 Hz, 6H), 0.81 - 0.77 (m, 2H), 5 0.04 (s, 9H). Mass spec.: 737.40 (MH)*.
(±)-
4
-(
2 -Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid {2-(1,4 dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-1-[1-( 2 -trimethylsilanyl-ethanesulfonyl)-I
H
indazol-5-ylmethyl]-ethyl} -amide 0 NH 0 NN N' NH /N 0 N Si 10 'H-NMR (CD 3 CN, 500 MHz) 8 9.34 (s, IH), 8.36 (s, 1H), 7.97 (d, J 8.5 Hz, 1H), 7.74 (s, 1H), 7.52 (dd, J = 8.5, 1.5 Hz, I H), 7.11 - 7.08 (m, 1H), 7.06 - 7.03 (m, IH), 7.02 - 6.98 (m, 2H), 5.98 (d, J = 8.2 Hz, IH), 5.06 (dd, J = 14.6, 7.3 Hz, 1H), 4.39 4.32 (m, IH), 4.13 - 4.03 (m, 2H), 3.92 - 3.88 (m, 2H), 3.71 - 3.66 (m, I H), 3.63 15 3.53 (m, 2H), 3.48 - 3.45 (m, IH), 3.44 - 3.40 (m, 2H), 3.19 (dd, j = 13.4, 6.5 Hz,1H), 3.08 (dd, J = 13.7, 7.3 Hz, 1H), 2.85 (t, J = 12.8 Hz, 2H), 2.32 - 2.20 (m, 4H), 1.73 - 1.70 (m, 2H), 1.67 - 1.51 (m, 3H), 1.38 - 1.33 (m, 1H), 0.81 - 0.77 (m, 2H), -0.04 (s, 9H). Mass spec.: 738.32 (MH)*. 20 Example 2 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide
()
WO 2005/065779 PCT/US2003/038799 85 0 N N N NNNH Q0 NA'NH A solution of (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-2-oxo-1-[l-(2-trimethylsilanyl ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide (568 mg, 0.73 mmol) and 5 cesium fluoride (1.11 g, 7.31 mmol) was heated at 80'C in acetonitrile (50 mL) for 4.5 h. The reaction mixture was concentrated and the residue was subjected to flash column chromatography (methylene chloride/methanol/triethylamine, 94:5:1) to give 280 mg (63% yield) of the title compound as a white solid with 98.2% ee as determined by HPLC analysis using a Chirocel OD column with 20% B (A = ethanol, 10 B = 0.05% diethylamine in hexanes) as eluent (Retention times: 9.51 min for title compound and 15.9 min for S-enantiomer). 'H-NMR (CD 3 0D, 500 MHz) 5 8.04 (s, 0.75H), 8.03 (s, 0.25H), 7.67 (s, 0.75H), 7.65 (s, 0.25H), 7.56 (d, J= 8.5 Hz, 0.75H), 7.51 (d, J= 8.5 Hz, 0.25H), 7.41 (d, J= 8.5 Hz, 0.75H), 7.31 (d, J= 8.5 Hz, 0.25H), 7.19-7.12 (m, 2H), 6.97-6.94 (m, 1H), 6.80 (d, J = 7.9 Hz, IH), 5.08-5.05 (in, 1H), 15 4.60-4.53 (in, 1H), 4.48-4.40 (in, 1H), 4.37 (s, 1.5H), 4.26 (s, 0.5H), 4.24-4.14 (in, 2H), 4.06-3.97 (in, IH), 3.15 (d, J = 7.9 Hz, 1.5H), 3.12-3.05 (m, 0.5H), 2.94-2.86 (in, 3H), 2.57-2.51 (in, 1.5H), 2.47-2.42 (m, 1H), 2.37-2.33 (in, 0.75H), 2.03-2.02 (m, 1.5H), 1.87-1.75 (m, 3.75H), 1.73-1.68 (in, 2H), 1.67-1.54 (in, 3H), 1.53-1.44 (m, 4H), 1.43-1.34 (in, 2H), 1.30-1.26 (in, 1H), 0.83-0.77 (in, 0.75H), 20 -0.16 to -0.24 (in, 0.75H). Mass spec.: 613 (MH)+. Similarly prepared: Example 3 (+)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid [2 25 [1,4']bipiperidinyl-l'-yl-1-(1H-indol-5-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 86 NH O NN NH <N 0 Na N 'H-NMR (DMSO-d 6 , 500 MHz) 8 10.99 (s, 0.6 H), 10.96 (s, 0.4 H), 10.85 (s, IH), 7.41 (s, 0.4H), 7.36 (s, 0.6H), 7.33 (d, J = 8.0 Hz, 0.6H), 7.29 - 7.26 (m, 1H), 7.16 7.14 (in, IH), 7.10 (d, J = 7.6 Hz, 0.4 H), 7.02 - 6.96 (in, 4H), 6.81 (br s, 1H), 6.37 5 6.35 (in, 1H), 4.86 (q, J = 8.0 Hz, 0.6 H), 4.80 (q, J = 7.5 Hz, 0.4 H), 4.45 (br s, 1H), 4.38 - 4.32 (m, 1H), 4.21 - 4.16 (m, 1H), 3.98 (br s, 1H), 3.18 (d, J = 5.2 Hz, 0.6H), 3.04 - 2.92 (m, 2.4 H), 2.82 - 2.74 (in, 4H), 2.37 - 2.33 (m, 2H), 2.25 - 2.08 (in, 4H), 2.04 - 1.90 (in, 2H), 1.47 - 1.24 (m, 10H), 0.75 - 0.71 (m, 1H). LC/MS: tR 1.90 min, 598.42 (MH)*. 10 Example 4 (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol- 1 -yl)-piperidine- I -carboxylic acid [2 [1,4']bipiperidinyl- l'-yl-1 -(1H-indazol-5-ylmethyl)-2-oxo-ethyl] -amide O NH / . O N N NIN 0 NrD HNH NN H Na 15 'H-NMR (DMSO-d 6 , 500 MHz) 6 10.70 (s, IH), 8.22 (d, J 8.2 Hz, 0.6H), 8.11 (s, 0.4H), 8.00 (s, 0.6H), 7.89 (d, J = 9.1 Hz, 0.4 H), 7.62 - 7.57 (m, 1H), 7.50 - 7.43 (in, 1H), 7.30 - 7.26 (in, 1H), 7.14 - 7.08 (in, 1H), 6.99 - 6.95 (m, 2H), 6.85 (br s, 1H), 4.89 - 4.80 (m, 1H), 4.45 - 4.31 (m, 2H), 4.18 - 4.00 (m, 2H), 3.26 - 3.16 (in, 1H), WO 2005/065779 PCT/US2003/038799 87 3.09 - 2.96 (m, 2H), 2.82 - 2.73 (m, 4H), 2.38 - 2.34 (m, 2H), 2.24 - 2.08 (m, 4H), 2.03 - 1.88 (m, 2H), 1.47 - 1.22 (m, 1OH), 0.90 - 0.84 (m, 1H). LC/MS: tR " 1.73 min, 599.32 (MH)*. 5 Example 5 (+)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(1 H-indol-5-ylmethyl)-2-oxo-ethyl]-amide H QyN D 0 N N N H A mixture of 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-1I 10 carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2-trimethylsilanyl ethanesulfonyl)-1IH-indol-5 -ylmethyl] -ethyl} -amide (52 mg, 0.067 mmol), cesium fluoride (51 mg, 0.33 mmol) in acetonitrile (5 mL) was heated at 80'C for 4h. The solvents were removed in vacuo and the residue was subjected to chromatography on silica gel using methylene chloride/methanol/triethylamine (93:5:2) as eluent to 15 afford the title compound as a white solid (70% yield). 1H-NMR (CD3CN, 500 MHz) 8 9.30 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.39 (d, J = 8.2 Hz, 0.6H), 7.36 (d, J = 8.2 Hz, 0.4 H), 7.24 - 7.21 (m, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.12 - 7.09 (m, 1H), 7.06 (d, J = 8.2 Hz, 0.6 H), 7.02 (d, J = 8.2 Hz, 0.4 H), 6.95 (t, J = 7.4 Hz, 1, 4.04 3.93 (m, I1H), 3.07 - 3.02 (m, 1.6H), 2.95 (dd, J = 13.7, 7.1 Hz, 0.4 H), 2.85 - 2.72 20 (m, 3H), 2.56 - 2.37 (m, 3H), 2.42 - 2.37 (m, 1H), 1.99 - 1.95 (m, 7H), 1.76 - 1.51 (m, 8H), 1.45 - 1.40 (m, 3H). LC/MS: tR = 1.91 min, 612.44 (MH)*. Example 6 ( )-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 25 [1,4']bipiperidinyl-l'-yl-1-(lH-indazol-5-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 88 H N H N N NNN N H Purified by silica gel chromatography using methylene chloride:methanol:triethylamine (93:5:2) as fluent to afford the title compound as a white solid (90% yield). 'H-NMR (CD 3 0D, 500 MHz) 8 8.04 (s, 0.7 H), 8.02 (s, 0.3 5 H), 7.67 (s, 0.7 H), 7.65 (s, 0.3H), 7.56 (d, J= 8.5 Hz, 0.7 H), 7.51 (d, J= 8.5 Hz, 0.3 H), 7.40 (d, J = 8.5 Hz, 0.7 H), 7.33 (d, J= 8.5 Hz, 0.3 H), 7.19 - 7.12 (m, 2H), 6.97 - 6.94 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.08 - 5.05 (in, lH), 4.59 - 4.54 (m, 1H), 4.48 - 4.42 (m, IH), 4.37 (s, 1 H), 4.27 - 4.20 (m, 2H), 4.04 (d, J = 13.4 Hz, 0.3 H), 3.99 (d, J= 13.4 Hz, 0.7 H), 3.19 - 3.08 (m, 2H), 2.94 - 2.86 (m, 3H), 2.57 (br s, 10 2H), 2.51 - 2.36 (m, 2H), 2.07 - 2.05 (m 1 H), 1.90 -1.31 (m, 16 H). LC/MS: tR 1.85 min, 613.44 (MH)+. The (R)-enantiomer, whose discrete synthesis is described above (Example 1), was obtained by chiral separation of the racemate by employing the following conditions: Chiracel OD prep column, 50 x 500 mm, 20 um; A = EtOH, B= 0.05%diethylamine/hexane; 20%B @ 65 m/min for 45 min; retention 15 times: 20.5 min for R and 32.8 min for S enantiomers. Example 7 (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol- 1 -yl)-piperidine- 1 -carboxylic acid [1 -(1 H indol-5-ylmethyl)-2-(4-isobutyl-piperazin- I -yl)-2-oxo-ethyl]-amide NH HN 20 H N LC/MS: tR 2.05 min, 572.31 (MH)'.
WO 2005/065779 PCT/US2003/038799 89 Example 8 (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid [2-(1,4 dioxa-8-aza-spiro[4.5]dec-8-yl)-1-(1H-indol-5-ylmethyl)-2-oxo-ethyl]-amide 0 NH o N N NH H_0 5 0j LC/MS: tR 2.35 min, 573.26 (MH)*. Example 9 (±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid [1-(1H 10 indazol-5-ylmethyl)-2-(4-isobutyl-piperazin-1-yl)-2-oxo-ethyl]-amide 0 ONH N/ 0 N N NH N: N 0 N H N LC/MS: tR= 1.86 min, 573.28 (MH)*. Example 10 15 (+)-4-(2-Oxo-2,3-dihydro-benzoimidazol- 1 -yl)-piperidine- 1 -carboxylic acid [2-(1,4 dioxa-8-aza-spiro[4.5]dec-8-yl)- 1 -(1 H-indazol-5-ylmethyl)-2-oxo-ethyl] -amide WO 2005/065779 PCT/US2003/038799 90 0 ~N 0 YNa NNH N 0 N H 0 LC/MS: tR 2.18 min, 574.23 (MH)*. Example 11 5 (+)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(1,4 dioxa-8-aza-spiro[4.5]dec-8-yl)-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide
N
HN N N NH 0 a 0 To a solution of the 3-(lH-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (95 mg, 0.21 mmol) 10 and NN-diisopropylethylamine (0.14 mL, 0.82 mmol) in dimethylformamide (5 mL) was added a solution of 1,4-dioxa-8-azaspiro[4,5]decane (32 mg, 0.23 mmol) and PyBOP* (107 mg, 0.21 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 16 h at room temperature. All solvent was removed using high vacuum. The residue was subjected to flash column chromatography using 15 methylene chloride/methanol/ triethylamine (93:5:2) to give the title compound as a white solid (67 mg, 56% yield). 'H-NMR (CDCl 3 , 500 MHz) S 10.52 (s, 1H), 7.97 (s, 1H), 7.54 (s, IH), 7.37 (d, J= 8.6 Hz, I H), 7.20 (d, J= 10.7 Hz, lH), 7.16 (t, J= 7.2 Hz, IH), 7.04 (d, J 7.6 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J = 8.6 Hz, I H), 6.67 (d, J = 7.6 Hz, 1H), 5.64 (d, J= 7.9 Hz, 1H), 5.16 (dd, J= 15.0, 6.7 Hz, 1H), 4.56-4.49 (m, 20 1H), 4.25 (s, 2H), 4.11 (br t, J= 15.6 Hz, 2H), 3.92-3.84 (m, 4H), 3.73-3.69 (m, 1H), WO 2005/065779 PCT/US2003/038799 91 3.60-3.56 (in, 1H), 3.48-3.43 (i, I H), 3.22-3.17 (m, 1H), 3.11 (d, J 6.7 Hz, 2H), 2.90-2.85 (m, 2H), 2.68-2.60 (in, 4H), 1.67-1.61 (in, 2H), 1.54-1.49 (in, 2H). Mass spec.: 588 (MH)*. 5 4-Bromo-2,6-dimethylphenyldiazo-t-butyl sulfide S NN Br 4-Bromo-2,6-dimethylaniline (20.00 g, 100 mmol) was ground to a powder with a mortar and pestle and then suspended in 24% hydrochloric acid (41 mL). The stirred mixture was cooled to -20'C and treated with sodium nitrite (7.24 g, 1.05 10 equiv) in water (16 mL), dropwise over 40 min while the temperature was maintained below -5'C. After a further 30 min at -5 0 C to -20'C, the mixture was buffered to ca. pH 5 with solid sodium acetate. This mixture (kept at ca. -1 0 C) was added in portions to a stirred solution of t-butyl thiol (11.3 mL, 1 equiv) in ethanol (100 mL) at 0 0 C over ca. 10 min. Following addition, the mixture was stirred at 0 0 C for 30 min 15 and then crushed ice (ca. 150 mL) was added. The mixture was stored in the refrigerator overnight. The resulting light-brown solid was collected by filtration, washed with water, and dried under high vacuum for several h. (26.90 g, 89%). The compound appeared to be stable as a solid but underwent significant decomposition when recrystallization from ethanol was attempted. 'H 20 NMR (CDC 3 , 500 MHz) 8 1.58 (9H, s), 1.99 (6H, s), 7.21 (2H, s). Mass spec.: 303.05 (MH)+. 5-Bromo-7-methylindazole HN-N Br WO 2005/065779 PCT/US2003/038799 92 Into a flame-dried round bottom flask, 4-bromo-2,6-dimethylphenyldiazo-t butyl sulfide (12.50 g, 41.5 mmol) and potassium t-butoxide (46.56 g, 10 equiv) were combined. A stir bar was added and the mixture placed under nitrogen. To this was added dry DMSO (120 mL). The mixture was stirred vigorously overnight at rt. The 5 reaction mixture was then carefully poured into a mixture of crushed ice (400 mL) and 10% hydrochloric acid (200 mL). The resulting suspension was left to stand at 4'C overnight and the solid was collected by filtration and washed with water. The crude solid was dissolved in 5:1 methylene chloride/methanol and the solution dried over magnesium sulfate and evaporated to give the product as an off-white solid 10 (7.60 g, 87%). 'H-NMR (CDCl 3
/CD
3 0D, 500 MHz) 8 2.51 (3H, s), 7.22 (1H, s), 7.69 (1H, s), 7.94 (1H, s). Mass spec.: 211.03 (MH)*. 7-methylindazole-5-carboxaldehyde HN-N H 0 15 5-Bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in mineral oil, 1.27 g, 1.1 equiv) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred 20 mixture was cooled to -70'C and a solution of sec-butyllithium in cyclohexane (1.4M, 45 mL, 2.2 equiv) was added over several minutes. After 1 h at -70-C, dimethylformamide (10 mL) was added over several minutes. The mixture was allowed to warm to room temperature and was stirred overnight. It was then cooled to 0 0 C and carefully treated with 1N hydrochloric acid (60 mL). After a few minutes, 25 solid sodium bicarbonate was added to basify the mixture to pH 9-10. The layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were extracted with 0.8M sodium hydrogen sulfate (3 x 125 mL). The combined aqueous phases were washed with ethyl acetate (100 mL) and then the pH was adjusted to ca. 10 with solid sodium hydroxide. The resulting WO 2005/065779 PCT/US2003/038799 93 suspension was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were washed with brine, dried (magnesium sulfate) and evaporated to give the product as a light-tan solid (3.01 g, 65%). 'H-NMR (CDC1 3 , 500 MHz) 8 2.63 (3H, s), 7.73 (1H, s), 8.12 (1H, s), 8.25 (1 H, s), 10.03 (11H, s). Mass spec.: 161.06 (MH)*. 5 2-Benzyloxycarbonylamino-3-(7-methyl- 1 H-indazol-5 -yl)-acrylic acid methyl ester HN-N H IN 0 0
H
3 CO 0 A stirred solution of N-benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (5.51 g, 1.2 equiv.) in tetrahydrofuran (30 mL) at room temperature was treated 10 with tetramethylguanidine (1.91 mL, 1.1 equiv). After 10 min, 7-methylindazole-5 carboxaldehyde (2.22 g, 13.86 mmol) in tetrahydrofuran (20 mL) was added. Disappearance of starting material was monitored by TLC and LC/MS. After 5 days at room temperature, the solvent was evaporated and the residue dissolved in ethyl acetate. The solution was washed with 2% phosphoric acid and brine, dried 15 (magnesium sulfate) and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 1) 1:1 and 2) 2:1 ethyl acetate/hexane, to give the product as a colorless foam (4.93 g, 97%). 'H-NMR (CDCl 3 , 500 MHz) 8 2.43 (3H, s), 3.80 (3H, s), 5.12 (2H, s), 6.66 (1H, s), 7.28 (5H, brs), 7.33 (1H, s), 7.47 (1H, s), 7.74 (1H, s), 7.96 (11H, s). Mass spec.: 366.16 (MH)+. 20 (±)-2-Amino-3 -(7-methyl-I H-indazol-5-yl)-propionic acid methyl ester HN-N
NH
2 0 0 A solution of 2-benzyloxycarbonylamino-3-(7-methyl-1H-indazol-5-yl) acrylic acid methyl ester (4.93 g, 13.49 mmol) in methanol (125 mL) was degassed WO 2005/065779 PCT/US2003/038799 94 by bubbling nitrogen through it for 30 min and then 10% palladium on charcoal (0.6 g) was carefully added. The mixture was hydrogenated at 40 psi in a Parr shaker apparatus overnight. The catalyst was removed by filtration through a pad of elite and the filtrate was concentrated in vacuo to give the product as a colorless foam 5 (3.62 g, quant.). 'H-NMR (CD 3 0D, 500 MHz) 8 2.45 (3H, s), 2.99 (1H, Abq), 3.22 (IH, Abq), 3.74 (3H, s), 3.89 (1H, m), 6.91 (1H, s), 7.31 (1H, s), 7.73 (1 H, s). Mass spec.: 234.11 (MH)+. Example 12 10 (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid methyl ester HN-N H O N H N N 0 0 A stirred solution of (±)-2-amino-3-(7-methyl- 1 H-indazol-5-yl)-propionic acid methyl ester (162.9 mg, 0.698 mmol) in methylene chloride (3 mL) at room 15 temperature was treated with carbonyl diimidazole (113.2 mg, I equiv). After 1.5 h at room temperature, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (161.5 mg, I equiv.) was added. The mixture was stirred at room temperature overnight. A white precipitate had formed that was shown to be the desired product. The solvent was evaporated and the residue triturated with methylene chloride. The product was 20 collected by filtration, washed with methylene chloride and dried in vacuo to give a white solid (241.5 mg, 71%). Some product remained in the mother liquors. ' H NMR (dimethylformamide-d 7 , 500 MHz) 6 1.75 (4H, in), 2.78 (3H, s), 2.7-3.1 (4H, in), 3.35 (2H, in), 3.86 (3H, s), 4.44 (2H, s), 4.57 (1H, m), 4.72 (1H, m), 7.11 (3H, m), 7.31 (1H, s), 7.34 (2H, in), 7.72 (1H, s), 9.34 (1H, s). Mass spec.: 491.13 (MH)*. 25 WO 2005/065779 PCT/US2003/038799 95 Similarly prepared: Example 13 3-(7-Methyl-1H-indazol-5-yl)-2-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H) quinazoline)carbonyl amino]-propionic acid methyl ester N-NH / 0 HN NH HN N 0 5 0 0 1 H-NMR (DMSO-d 6 ) 61.59 (4H, n), 2.46 (3H, s), 3.00 -3.08 (4H, m), 3.6 ( 3H, s), 3.78-3.81 (2H, in), 4.30-4.32 (1 H, m),6.78-6.
8 8 (4H, m), 7.03 (1 H, s), 7.10 (IH, m),7.13 (1H, s),7.41 ( 1H,s), 7.96 (1 H, s), 9.12 (1H, s). Mass spec.: 477.11 (MH)*. 10 Example 14 3-(7-Methyl-1H-indazol-5-yl)-2-(1,2-dihydro-2-oxospiro-4H-3,1-dihydro benzoxazine-4'4-piperidine-carbonylamino)-propionic acid methyl ester N-NH / 0 0 NH H N N 0
H
3 CO 0 Mass spec.: 478.15 (MH)*. 15 3-(7-Methyl-1H-indazol-5-yl)-2{3',4'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H) quinolinecarbonyl amino}-propionic acid methyl ester N-NH / 0 NH N N 0
H
3 CO 0 'H-NMR (DMSO-d 6 ) 8 1.42-1.56 (4H, m), 2.47 (3H, s), 2.50-2.54 (1H, d), 2.60-2.64 20 (1H, d), 2.98-3.06 4H, m), 3.60 (3H, s) 3.80 (2H, m), 4.30 (11H, m), 6.86 (2H, d), 6.95 WO 2005/065779 PCT/US2003/038799 96 (2H, m), 7.15 (1H, m), 7.40 (1H, s), 7.95 (1H, s), 8.32 (1H, s), 10.14 (IH, s), 13.05 (1H, s). Mass spec.: 476.17 (MH)*. 3-(7-Methyl-1H-indazol-5-yl)-2-[2'-phenyl-l',3',8'-triaza-spiro(4',5')deo-1-ene-8 5 carbonyl amino]-propionic acid methyl ester HN-N NI 0 H NH N N N rCP 0
H
3 CO 0 'H-NMR (DMSO-d6) 5 1.50 (2H, m), 1.68 (2H, m), 2.46 (3H, s was overlapped with DMSO), 3.05 (2H, m), 3.30 (2H, m), 3.60 (3H, s), 3.86 (2H, in), 4.28 (1H, m), 6.98 (1H, d), 7.04 (1H, s), 7.40 (11, s), 7.58 (2H, m), 7.65 (1H, m), 8.00 (1H, s), 8.04 (2H, 10 m). Mass spec.: 489.15 (MH)*. Example 15 (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid HN-N H NyN 15 HO 0 A suspension of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester (240.0 mg, 0.489 mmol) in 1:1 tetrahydrofuran/methanol (20 mL) at room temperature was treated with a solution of lithium hydroxide (140.5 mg, 7 equiv) in 20 water (10 mL). Within 1 min, the mixture became homogeneous and it was left to stand at 4C overnight. The solvents were evaporated at ca. 30'C and the pH was adjusted to ca. 1 with IN hydrochloric acid. The resulting white suspension was stored at 4'C for several hours and the product was collected by filtration, washed with a small amount of water, and dried in vacuo (169.0 mg, 73%). Solid sodium WO 2005/065779 PCT/US2003/038799 97 chloride was added to the filtrate resulting in precipitation of more product (5.2 mg, total yield 75%). 'H-NMR (CD 3 0D, 500 MHz) 8 1.2-1.7 (4H, m), 2.58 (3H, s), 2.5 3.2 (4H, m), 3.35 (2H, m), 4.15 (2H, m), 4.36 (1H, m), 4.60 (1H, m), 6.79 (1H, d), 6.96 (1H, t), 7.18 (3H, m), 7.49 (1H, s), 8.00 (1H, s). Mass spec.: 477.13 (MH)+. 5 Similarly prepared: 3-(7-Methyl-I H-indazol-5-yl)-2-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-(1 H) quinazolinecarbonyl amino)-propionic acid N-NH / 0 HN 'NH 0 HO 0 10 'H-NMR (DMSO-d6) 8 1.58 (4H, m), 2.46 (3H, s), 3.00-3.23 (3H, in), 3.78-3.91 (3H, m), 3.88 (2H, m) 4.28 (1H, s), 6.70 (1H, d), 6.75-6.85 ( 3H, m), 7.04 (1H, d), 7.11 (1H, n) 7.18 (1H, s), 7.96 (IH, s), 13.02 (lH, m). Mass spec.: 463.09 (MH)*. 3-(7-Methyl-1H-indazol-5-yl)-2-(1,2-dihydro-2-oxospiro-4H-3,1-dihydro 15 benzoxazine-4'4-piperidine-carbonylamino)-propionic acid methyl ester N -NH o0 S NN 0 HO 0 'H-NMR (DMSO-d6) 8 1.63-1.98 (4H, m), 2.46 (3H, s, 7-Me was overlapped with DMSO), 2.98-3.32 (4H, m), 3.90 (2H, m), 4.28 (IH, m), 6.78 (1H, d), 6.87 (2H, in), 6.96 (1H, m), 7.05 (1H, s), 7.24 (lH, m), 7.41 (1H, s), 7.96 (1H, s),10.22 (1H, s) 20 12.42 (1 H, br. ) 13.02 (1H, m). Mass spec.: 464.07 (MH)+. 3-(7-Methyl-1H-indazol-5-yl)-2{3',4'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H) quinoline- carbonyl amino}-propionic acid WO 2005/065779 PCT/US2003/038799 98 N -NH 0 NH H N N 0 HO 0 1 H-NMR (DMSO-d 6 ) 8 1.39-1.45 (2H, m), 1.53-1.56 (2H, n), 2.46 (3H, s), 2.50-2.54 (1H, d), 2.60-2.63 (1H, d), 2.88-3.00(3H, m), 3.09-3.11 (1H, m), 3.78-3.81 (2H, m), 4.27 (f H, m), 6.69-6.70 (1H, d), 6.86-6.87 (1H, d), 6.93-6.94 (1H, m)6.99-7.00 (1 H, 5 m), 7.05 (11H, m), 7.41 (1H, s), 7.95 (11H, s), 10.13 (11H, s), 12.50 (1H, m), 13.03 (11H, m). Mass spec.: 462 (MH)*. 3-(7-Methyl- 1 H-indazol-5-yl)-2-[2'-phenyl- 1',3',8'-triaza-spiro(4',5')deo- 1 -ene-8 carbonyl amino]-propionic acid H N-N N' 0 H 40 wNH N N N H0 10 HO 0 'H-NMR (DMSO-d 6 ) 8 1.36 (2H, m), 1.63 (2H, m), 2.46 (3H, s was overlapped with DMSO), 2.98-3.03 (2H.m), 3.09-3.11 (2H, m), 3.86 (2H, m), 4.21 (11H, m), 6.69 (1H, m), 7.04 (1 H, s), 7.40 (1H, s), 7.52-7.58 (3H, m), 7.99 (3H, m), 11.55 (1 H, m), 13.00 (1H, m). Mass spec.: 475.08 (MH)*. 15 Example 16 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 99 HN-N H 0 N H N N NN N 0 N0 A stirred solution of (±)-3-(7-methyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -propionic acid (65.7 mg, 0.138 mmol) in 2:1 dimethylformamide/methylene chloride (1.5 mL) at 0*C was 5 treated with 4-(1 -piperidyl)-piperidne (46.5 mg, 2 equiv), diisopropylethylamine (0.048 mL, 2 equiv) and PyBOP* (75.5 mg, 1.05 equiv). The ice bath was allowed to melt and the mixture was stirred at room temperature overnight. The solvents were removed under high vacuum and the residue was purified by flash chromatography on silica gel, eluting with 18:1 methylene chloride/methanol containing 1% 10 triethylamine, to give the product as a pale-yellow solid (80.4 mg, 93%). 'H-NMR
(CD
3 0D, 500 MHz) 8 -0.28 (1H, in), 0.75 (1H, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m), 2.59 (3H, s), 2.68 (2H, m), 2.90 (4H, m), 3.08 (4H, m), 3.9-5.1 (4H, several in), 6.81 (1H, d), 6.96 (1 H, t), 7.16 (3H, in), 7.49 (1H, s), 8.03 (1H, s). Mass spec.: 627.29 (MH)+. 15 Similarly prepared: Example 17 (±)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carboxylic acid [1 -(7 methyl-1H-indazol-5-ylmethyl)-2-oxo-2-piperidin-1 -yl-ethyl)-amide HN-N H 0 N NN Y Y N O0 20 WO 2005/065779 PCT/US2003/038799 100 H-NMR (CD 3 0D, 500 MHz) 8 0.87 (1H, m), 1.33 (1H, m), 1.47 (2H, m), 1.80 (6H, m), 2.57 (3H, s), 2.89 (2H, m), 3.06 (2H, in), 3.18 (4H, m), 3.40 (2H, m), 3.61 (1 H, m), 4.16 (1H, m), 4.28 (1H, Abq), 4.43 (1 H, m), 5.02 (1H, m), 6.51 (1 H, d), 6.79 (1H, d), 6.96 (1 H, t), 7.11 (1H, d), 7.15 (1H, t), 7.48 (1 H, s), 8.01 (1 H, s). Mass 5 spec.: 544.24 (MH) . Example 18 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1 dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-amide H N H 0 N N H N 0 10 'H-NMR (CD 3 0D, 500 MHz) 8 1.12 (2H, d), 1.64 (2H, m), 2.57 (3H, s), 2.74 (IH, m), 2.87 (3H, s), 2.89 (3H, s), 2.86 (2H, m), 3.07 (2H, m), 3.20 (1H, m), 4.17 (1H, m), 4.25 (1H, Abq), 4.43 (1 H, m), 4.97 (1H, m), 6.79 (1H, d), 6.95 (1H, t), 7.0-7.4 (3H, m), 7.48 (1H, d), 8.01 (1 H, s). Mass spec.: 504.15 (MH)*. 15 Example 19 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(7 methyl-iH-indazol-5-ylmethyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide HN-N H 0 N NI 0 N H N yN N O0 N II 20 1 H-NMR (CD3OD, 500 MHz) 8 1.30 (2H, m), 1.66 (2H, m), 1.78 (1H, m), 1.90 (11H, m), 2.00 (3H, s), 2.19 (1H, m), 2.35 (1H, m), 2.58 (3H, s), 2.88 (2H, in), 3.09 (2H, d), 3.10-3.45 (3H, m), 3.66 (1H, m), 4.19 (2H, d), 4.20 (2H, s), 4.43 (1H, m), 4.98 (1H, WO 2005/065779 PCT/US2003/038799 101 t), 6.80 (IH, d), 6.95 (1H, t), 7.11 (2H, m), 7.16 (IH, t), 7.47 (1H, s), 8.02 (1H, s). Mass spec.: 559.23 (MH)*. Example 20 5 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(7 methyl-iH-indazol-5-ylmethyl)-2-oxo-2-pyrrolidin-1-yl-ethyl]-amide HN-N H 0 N NyN N O0 'H-NMR (CD 3 0D, 500 MHz) 8 1.40-1.90 (5H, m), 2.02 (31H, brs), 2.57 (3H, s), 2.86 (1H, m), 2.89 (2H, q), 3.09 (2H, m), 3.16 (1H, m), 3.25 (2H, m), 3.40 (11H, m), 3.56 10 (1H, m), 4.17 (2H, d), 4.27 (2H, s), 4.40 (IH, m), 4.69 (IH, t), 6.80 (1H, d), 6.95 (1H, t), 7.10 (1H, s), 7.16 (1H, m), 7.48 (1H, s), 7.53 (IH, m), 8.01 (1H, s). Mass spec.: 530.19 (MH)*. Example 21 15 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(7 methyl-iH-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-amide HN-N H 0 N N H N N N N 0
N
WO 2005/065779 PCT/US2003/038799 102 'H-NMR (CD 3 OD, 500 MHz) 5 1.38(11H, t), 1.68 (2H, m), 1.81 (1H, m), 2.30(11H, m), 2.53 (3H, s), 2.95 (4H, m), 3.13 (2H, d), 3.22 (lH, m), 3.35-3.65 (4H, m), 3.79 (1H, m), 4.18 (2H, d), 4.31 (2H, s), 4.42 (11H, m), 4.99 (1H, t), 6.64 (2H, d), 6.80 (11H, d), 6.89 (1H, m), 6.96 (1H, t), 7.14 (3H, m), 7.51 (1H, s), 7.99 (1H, s), 8.10 (2H, d), 5 8.16 (1H, m). Mass spec.: 622.26 (MH)*. Example 22 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(7 methyl-1H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-amide H N-N H 0 N H N N N 0 N N 10 IH-NMR (CD 3 0D, 500 MHz) 5 1.27 (1H, m), 1.38 (IH, m), 1.67 (2H, m), 1.84 (1H, m), 2.54 (3H, s), 2.65 (IH, m), 2.88 (2H, m), 3.15 (4H, m), 3.35 (IH, m), 3.58 (3H, m), 3.77 (1H, m), 4.18 (2H, d), 4.30 (2H, s), 4.42 (1H, m), 5.01 (11H, t), 6.62 (1H, d), 6.70 (1H, t), 6.80 (1H, d), 6.95 (1H, t), 7.10 3H, m), 7.50 (1H, s), 7.54 (1H, t), 7.99 15 (1H, s), 8.05 (11H, 7). Mass spec.: 622.25 (MH)[. Example 23 (±)-I-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1,4-bipiperidin]-1-yl-2-oxoethyl]-2',3' dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide HN-N 0 H N NNH N 20 WO 2005/065779 PCT/US2003/038799 103 1 H-NMR (DMSO-d 6 , 500 MHz) 8 1.2-1.73 (14H, m), 2.46 ( 3H, s), 2.75-3.24 (12H, m), 3.87 (2H, m), 4.45 (1 H, m), 4.78-4.85 (1H, m), 6.80 (1H,m), 6.86 (11H, m), 7.05 ( I H, m), 7.12 ( l H, m), 7.21 (1 H, m), 7.27 (2H, m), 7.98 (1 H, m), 9.23 (11H, m). Mass spec.: 613.25 (MH)* 5 Example 24 (±)-1-(7-Methyl-IH-indazol-5-ylmethyl)-2-(1-piperidinyl)-2-oxoethyl]-2',3'-dihydro 2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide HN-N 0 N NH H N 0 N 0 10 'H-NMR (CD 3 0D, 500 MHz) 8 0.87 ( 1H, m), 1.28-1.47 (5H, m), 1.74-1.85 (4H, m), 2.53 (3H, s), 3.02-3.38 (8H, m), 3.92 (2H, m), 5.02 (1H, m), 6.82 (1H, d), 6.99 (1H, d), 7.04-7.09 (2H, m), 7.17 (1H, m), 7.32 (2H, s), 7.45 (11H, s), 7.96 (1H, s). Mass spec.: 530.17 (MH)*. 15 Example 25 (±)-1-(7-Methyl-IH-indazol-5-ylmethyl)-2-[1,4-bipiperidin]-1-yl-2-oxoethyl]-l',2' dihydro-2'--oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide HN-N 0 ~N H OA NH N N N O QN 'H-(DMSO-d 6 , 500 MHz) S 1.88 (14H, m), 2.64 (3H, s), 2.78 (12H,m), 4.0 (2H, m), 20 4.4 (IH, m),4.85 (LH, m), 6.80-6.88 (211, m), 7.03 (2H, m), 7.11 (1H, m), 7.23 (1H, m), 7.36 (2H, m), 7.97 (1H, m). Mass spec.: 614.73 (MH)*.
WO 2005/065779 PCT/US2003/038799 104 Example 26 (±)-1-(7-Methyl-IH-indazol-5-ylmethyl)-2-(1-piperidinyl)-2-oxoethyll-1',2'-dihydro 2'--oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide HN-N 0 ''H O NH N N 5 NO 'H-NMR (DMSO-d 6 , 500 MHz) 8 1.15-1.91 (1OH, m), 2.47 (3H, s), 2.95-3.05 (6H, m) 3.40 ( 4H, m) 3.95 (2H, d), 4.81(1H, m), 6.81 (1H, d), 6.88 (1H, d), 6.94 (11H, m), 6.99 (IH, m), 7.04 (1H, s), 7.24 (IH, m), 7.37 (IH, s), 7.96 (1H, s). Mass spec.: 531.23 (MH)*. 10 Example 27 (±)-[1-Dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-l',2'-dihydro-2' oxospiro-[4H-3',I-benzoxazine-4,4'-piperidine]-1-carboxamide HN-N 0 N YN -0 N 0 15 'H-NMR (DMSO-d,, 500 MHz) 5 1.68-1.88 (4H, m), 2.47 (3H, m), 2.79 (6H, s), 2.89-3.04 (4H, m), 3.96 (2H, d), 4.75 (1H, m), 6.81 (1H, d), 6.88 (1H, m), 6.93 (1H, m), 6.98 (1H, m), 7.05 (1H, s), 7.24 (1H, m), 7.43 (1H, s), 7.97 (1H, m), 8.32 (1H, s). Mass spec.: 491.14 (MH)*. 20 Example 28 (±)-[1-(2-adamantyl-carbamoyl)-2-(7-methyl-1H-indazol-5-yI)-ethyl]-l',2'-dihydro 2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide WO 2005/065779 PCT/US2003/038799 105 HN-N -' 0 H OA NH N N HN O 'H-NMR (DMSO-d,, 500 MHz) 8 1.40-1.95 (15H, in), 2.46 (3H, m), 2.89-3.07 (4H, in), 3.81 (1H, m), 3.90 (2H, in), 4.48 (1H, in), 6.74 (2H, in), 6.86 (1H, d), 6.97 (1H, in), 7.11 (1H, s), 7.24 (1H, in), 7.36 (1H, s), 7.44 (1H, s), 7.96 (1H, s). Mass Spec.: 5 597.27 (MH)*. Example 29 (±)- 1',2'-Dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4'-piperidine- I -carboxylic acid [1 -(7-methyl-I H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazin- 1 -yl)-ethyl] 10 aide HN-N 0 H N H N N _0 NO N LC/MS: tR = 1.56 min, 609.14 (MH)*. Example 30 15 (±)-1',2'-Dihydro-2'-oxospiro-[4H-3',I-benzoxazine-4,4'-piperidine-1-carboxylic acid {2-(7-methyl- I H-indazol-5 -yl)-1 -[(pyridin-4-ylmethyl)-carbamoyl]-ethyl } -amide WO 2005/065779 PCT/US2003/038799 106 HN-N 0 / O NH N N '0 N N O LC/MS: tR = 1.49 min, 553.12 (MH)*. Example 31 5 (±)-1-(7-Methyl-I H-indazol-5-ylmethyl)-2-[1,4-bipiperidin]-1-yl-2-oxoethyl]3',4' dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinoline]-1-carboxamide HN-N 0 H NH N N NO NO 'H-NMR (DMSO-d 6 , 500 MHz) 5 1.20-2.00 ( 14H, m), 2.46 (3H, s), 2.38-3.03 (12H, m), 3.87 (2H, m), 4.34 (1H, m), 4.76-4.87 (1H, m), 6.65 (IH, m), 6.82-7.64 (3H, m), 10 7.13-7.23 (2H, m), 7.36 (3h, m), 7.96 (1H, s). Mass spec.: 612.32 (MH)*. Example 32 (±)- 1-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1-piperidinyl]-2-oxoethyl]3',4'-dihydro 2'-oxospiro-[piperidine-4,4'-(H)-quinoline]-1-carboxamide HN-N 0 H NH N N 15 N 0 WO 2005/065779 PCT/US2003/038799 107 IH-NMR (DMSO-d 6 , 500 MHz) 8 1.10-1.68 (10H, m), 2.46 (3H, s), 2.50-2.60 (2H, m), 2.82-2.97 (4H, m), 3.39 (2H, m), 3.85 (2H, m), 4.80 (1H, m), 6.68 (1H, m), 6.87 (1H, d), 6.94 (1H, m), 7.03 (1H, s), 7.06 (1H, m), 7.15 (1 H, m), 7.37 (1H, s), 7.40 (1H, s), 7.96 (1H, s). Mass spec.: 529.25 (MH)+. 5 Example 33 (±)-[1-Dimethylcarbmoyl-2-(7-methyl-1H-indazol-5-yl)-ethy]1-3',4'-dihydro -2' oxospiro- [piperidine-4,4'-(1H)-quinoline]-1-carboxamide HN-N 0 H NH N N F0 N 0 10 'H-NMR (DMSO-d 6 , 500 MHz) 8 1.43 (2H, m), 1.56 (2H, in), 2.46 (3H, s), 2.56 (2H, m), 2.79 (3H, s), 2.90 (5H, m), 3.84 (2H, m), 4.73 1 H, m), 6.69 (1 H, d), 2.69 (1H, d), 6.94 (1H, m), 7.05 (2H, m), 7.14 (1H, m), 7.37 (1H, s), 7.42 (IH, s), 7.96 (1H, s). Mass spec.: 489.2 (MH)*. 15 Example 34 (±)-4-Oxo-2-phenyl-1,3,8-triaza-spiro[4,5]dec-1-ene-8-carboxylic acid{ 1-(7-methyl IH-indazol-5- yl methyl)-2-[1,4]bipiperidinyl-l'-yl-2-oxo-ethyl}-amide HN-N N) 0 H NH N N N N 'H-NMR (DMSO-d 6 , 500 MHz) 8 1.34-2.00 (14H, m), 2.48 (3H, s overlapped with 20 DMSO), 2.70-3.30 (12H, m), 3.90 (2H, m), 4.40 (1H, m), 4.82 (IH, m), 6.82 (1H, WO 2005/065779 PCT/US2003/038799 108 m), 7.04 (1H, s), 7.37 (2H, m), 7.56 (3H, m), 7.98 (3H, m). Mass spec.: 625.29 (MH)'. Example 35 5 (±)-4-Oxo-2-phenyl-1,3,8-triaza-spiro[4,5]dec-1-ene-8-carboxylic acid{ 1-(7-methyl 1H-indazol-5- yl methyl)-2-[1-piperidinylyl]-2-oxo-ethyl}-amide HN-N Nj 0 H r NH N N N N O 'H-NMR (DMSO-d, 500 MHz) 8 1.10-1.62 (6H, m), 1.73 (4H, m), 2.48 (3H, s), 3.00 (6H, m), 3.39 (2H, m), 3.93 (2H, m), 4.82 (1H, m), 6.78 (1H, m), 7.05 (1H, s), 10 7.37 (2H, s), 7.40 (1H, s), 7.53 (2H, m), 7.98 (2H, m). Mass spec.: 543.26 (MH) . Example 36 (±)-4-Oxo-2-phenyl-1,3,8-triaza-spiro[4,5]dec-1-ene-8-carboxylic acid[l dimethylcarbamoyl -2-(7-methyl- 1 H-indazol-5- yl)-ethyl]amide HN-N NH H N N N N 00 15 'H-NMR (DMSO-d 6 , 500 MHz) 8 1.28-1.61 (4H, m), 2.78 (4H, m), 2.90 (6H, m), 3.94 (2H, m), 4.74 (11H, m), 6.77 (1 H, m), 7.05 (1H, s), 7.37 (4H, s), 7.42 (1H, s), 7.52 (2H, m), 7.98 (2H, m). Mass spec.: 502.21 (MH)*.
WO 2005/065779 PCT/US2003/038799 109 Example 37 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(1H indazol-5-ylmethyl)-2-oxo-2-[ 4
-(
2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 yl]-ethyl }-amide HN-N H 0 N H N N N O0 "N NIO 5 H LC/MS: tR = 1.51 min, 674 (MH)~ Example 38 4-(3-(1 H-Indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 10 carbonyl]-amino} -propionyl)-piperazine-1-carboxylic acid benzyl ester HN-N H 0 N N H N N O N N 0 0 LC/MS: tR= 1.74 min, 665 (MH)*. Example 39 15 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carboxylic acid [1 -(1 H indazol-5-ylmethyl)-2-oxo-2-piperazin- I -yl-ethyl] -amide WO 2005/065779 PCT/US2003/038799 110 HN-N H O N N IH N 0 HN To a degassed solution of 4-(3-(1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidine-1 -carbonyl]-amino} -propionyl)-piperazine- 1 carboxylic acid benzyl ester ( 280 mg, 0.42 mmol ) in methanol (50 ml) was added 5 10% palladized charcoal (50 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen at 50 psi for 3 h. The mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the desired product in 91% yield. LC/MS: tR 1.22 min, 531 (MH)*. 10 Example 40a 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid {1-(1H indazol-5-ylmethyl)-2-[4-(2-methyl-butyl)-piperazin-1-yl]-2-oxo-ethyl}-amide H N H 0 N H N H N N N 0 N.) A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 15 carboxylic acid [1-(1H-indazol-5-ylmethyl)-2-oxo-2-piperazin-1-yl-ethyl]-amide (100 mg, 0.188 mmol) in methanol (25 mL) was treated with 2-methyl-butyraldehyde (0.03 ml, 0.376 mmol). After lh at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was allowed to stir overnight. The solution was filtered through an SCX cartridge. The cartridge was eluted first with 20 methanol and then with a 1M solution of ammonia in methanol. The solvent was removed in vacuo to give the desired product in 50% yield. LC/MS: tR 1.31 min, 601 (MH)*.
WO 2005/065779 PCT/US2003/038799 1l General Experimental Procedure for the Preparation of Examples 40b-40k. The appropriate aldehyde (0.04 mmol) was added to a solution of Example 39 5 piperazine (0.02 mmol) in methanol (2.0 mL) and the resulting solution was shaken at room temperature for 1 h. Sodium triacetoxyborohydride (0.2 mmol) was then added and the solution allowed stir overnight at room temperature. The solution was then filtered through a SCX cartridge and the cartridge washed with methanol and an ammonia/methanol solution. The ammonia/methanol solution was concentrated in 10 vacuo and the crude products were purified by preparative HPLC to the afford the products listed in Table 1. Table 1. Examples 40b-40k. HPLC Mass spec Example No. Structure Retention M (MH) time (min) HN-N H N 40b y N 2.62 629 N O Me N ) H-N H 0YN N 40c HN 1.41 587 0 N 0* Me N,) HN-N H 0 H ,N 40d H N 1.27 573 H-N O Me N 1 N H 40e NN 1*74 611 N O0 WO 2005/065779 PCT/US2003/038799 112 HPLC Mass spec Example No. Structure Retention M
(MH)
time (min) HN-N 40f 2 N 1.89 643 Et $ N 0 Me N HN- H 0H - N N 40g N 1.48 610 ^ N O0 H HN- H N 40h 2.19 614 N 0 Me 2 N N HN-NH NH - N N 40i| N 2.36 629 Et N 0 i-Pr )~N HN-N H 40j N y . 1.66 647 0 N 0 Ph N HNN H 0H - N N 40k N 2.61 545 IH <N O 0 MeN Example 41a 3-(7-Methyl-lH-indazol-5-yl)-2- {[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid cyclohexyl ester WO 2005/065779 PCT/US2003/038799 113 HN-N H 0 N N H N YNr 01 0 To a stirred solution of (±) -2-amino-3-(7-methyl- I H-indazol-5-yl)-propinic acid (20 mg, 0.042 mmoles), 4-(dimethylamino)pyridine (2.5 mg, 0.02 mmoles), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 5 mmoles) in methylene chloride (2 mL) and dimethylforamide (1 mL), was added cyclohexanol (13.3 L, 0.126 mmoles). The reaction mixture was stirred at 50-55'C for 4 h. The solvent was removed under reduced pressure, the the residue purified by preparative TLC on silica gel (9:1 chloroform/methanol) to give the desired product as white solid (9.4 mg, 40%). 'H-NMR (CD 3 0D, 500 MHz) 8 1.32-1.87 (14H, in), 10 2.57 (3H, s), 2.86 (2H, in), 3.11-3.26 (2H, in), 4.13-4.22 (3H, in), 4.46 (1H, in), 4.55 (lH, in), 4.80 (1H, in), 6.79 (1H, d), 6.97 (1H, in), 7.08-7.18 (2H, in), 7.35 ( 1H, s), 7.47 (1H, s), 8.01-8.02 (1H, in). Mass spec.: 559.22 (MH)*. Similarly prepared: 15 Example 41b 3-(7-Methyl-1H-indazol-5-yl)-2- { [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1-benzyl-piperidin-4-yl ester H N H ON H N N N IH N 0 0 LC/MS: tR 1.76 min, 650.30 (MH)+. 20 Example 41c 3-(7-Methyl-1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1-methyl-piperidin-4-yl ester WO 2005/065779 PCT/US2003/038799 114 HN -N H 0 N N H N NyN 0 0 LC/MS: tR 1.59 min, 574.27 (MH)*. Example 41d 5 3-(7-Methyl-I H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 4-phenyl-cyclohexyl ester HN-N H 0 N N H N N 0 0 LC/MS: tR 2.69 min, 635.29 (MH)*. 10 Example 41e 3-(7-Methyl-iH-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino }-propionic acid (R)- 1 -pyridin-4-yl-ethyl ester HN-N H 0 N N H N yN N 0 0 N O LC/MS: tR = 1.66 min, 582.22 (MH)*. 15 Example 41f 3-(7-Methyl- I H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino } -propionic acid (S)-1-pyridin-4-yl-ethyl ester WO 2005/065779 PCT/US2003/038799 115 HN-N H 0 N N NN /rN H N N N .0 LC/MS: tR 1.65 min, 582.23 (MH)*. 4-Bromo-2-chloro-6-methylphenyldiazo-t-butyl sulfide S N. C1 5 Br 4-Bromo-2-chloro-6-methylaniline (4.0 g, 18.3 mmol) was suspended in 24% hydrochloric acid (5 mL). The stirred mixture was cooled to -20'C and treated with sodium nitrite (1.32 g, 1.05 equiv.) in water (2 mL), dropwise over 10 min while the temperature was maintained below -5'C. After a further 30 min at -5 0 C to -20 0 C, the 10 mixture was buffered to ca. pH 5 with solid sodium acetate. This mixture (kept at ca. -10*C) was added in portions to a stirred solution of t-butyl thiol (2.06 mL, 1 equiv.) in ethanol (18.5 mL) at 0 0 C over ca. 10 min. Following addition, the mixture was stirred at 0 0 C for 30 min and then crushed ice (ca. 50 mL) was added. The mixture was stored in the refrigerator overnight. The resulting light-brown solid was 15 collected by filtration, washed with water, and dried under high vacuum for several hours (4.60 g, 78%). Mass spec.: 323.03 (MH)+. 5-Bromo-7-chloroindazole HN-N CI Br WO 2005/065779 PCT/US2003/038799 116 Into a flame-dried round bottom flask, 4-bromo-2,-chloro-6 methylphenyldiazo-t-butyl sulfide (4.60 g, 14.4 mmol) and potassium t-butoxide (16.1 g, 10 equiv) were combined. A stir bar was added and the mixture placed under nitrogen. To this was added dry DMSO (50 mL). The mixture was stirred 5 vigorously for 10 min at room temperature. The reaction mixture was then carefully poured into a mixture of crushed ice (150 mL) and 10% hydrochloric acid (74 mL). The resulting suspension was left to stand at 4'C overnight and the solid was collected by filtration and washed with water. The solid was collected and dried in vacuo to give 2.86 g (86%) as a beige solid. 'H-NMR (CDC1 3 , 500 MHz) 8 7.52 (d, 10 J=1.5, 1H), 7.82 (d, J=1.5, 1H), 8.08 (s, IH). Mass spec.: 230.90 (MH)*. 7-Chloroindazole-5-carboxaldehyde HN-N ci H 0 5-Bromo-7-chloroindazole (2.0 g, 8.7 mmol) and sodium hydride (221 mg, 15 1.1 equiv) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to -78'C and a solution of tert-butyllithium in pentane (1.7 M, 10.5 mL, 2.0 equiv) was added over 20 several minutes. After 30 min at -78'C, the reaction was gradually warmed to to 50'C, kept there for 15 min, and recooled to -78'C. Dimethylformamide (2.8 mL) was slowly added and the mixture allowed to warm to -50'C. The solution was quickly transferred to a separatory funnel containing diethyl ether and water. The aqueous was made acidic by the addition of 1 M potassium hydrogen sulfate and 25 neutralized by the addition of sodium bicarbonate. The aqueous was extracted with diethyl ether (3x) which was washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.7g (100%) of nearly pure material. An analytically pure sample was obtained by recrystallization from hot methanol. H- WO 2005/065779 PCT/US2003/038799 117 NMR (CDC1 3 , 500 MHz) 8 7.97 (s, IH), 8.20 (s, 1H), 8.30 (s, 1H), 10.02 (s, IH). Mass spec.: 181.09 (MH)+. 2-Benzyloxycarbonylamino-3-(7-chloro-1 H-indazol-5-yl)-acrylic acid methyl ester HN-N CI H N 0 5 0 0 A stirred suspension of potassium tert-butoxide (375 mg, 1.2 equiv.) in methylene chloride (20 mL) was cooled to -20*C and treated with a solution of N benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (1.11 g, 1.2 equiv.) in methylene chloride (5 mL). After 10 min, 7-chloroindazole-5-carboxaldehyde (0.50 10 g, 2.79 mmol) in methylene chloride (5 mL) was added. The reaction was allowed to gradually warm to room temperature and was stirred for 3 days. The reaction was poured into a separatory funnel containing water and diethyl ether. The aqueous was extracted with diethyl ether (3x) which was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography gave 0.40 g (37%) of 15 product along with 0.20 g (40%) of starting material. 'H-NMR (CDC 3 , 500 MHz) 5 3.64 (s, 3H), 5.11 (s, 2H), 6.44 (bs, lH), 7.30 (bs, 5H), 7.43 (s, 1H), 7.62 (s, 1H), 7.80 (s, 1H), 8.07 (s, 1H). Mass spec.: 386.16 (MH)*. (±)-2-Amino-3-(7-chloro-1H-indazol-5-yl)-propionic acid methyl ester HN-N C I
NH
2 20 0 0 A solution of 2-benzyloxycarbonylamino-3-(7-chloro-IH-indazol-5-yl) acrylic acid methyl ester (300 mg, 0.78 mmol) in methanol (10 mL) was treated with trifluoroacetic acid (0.2 mL), flushed with nitrogen, and treated with 10% palladium on charcoal (30 mg). The flask was flushed with hydrogen and allowed to stir under WO 2005/065779 PCT/US2003/038799 118 an atmosphere of hydrogen. After 4 days, all starting material had been consumed. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 78 mg (40%). 'H-NMR (CDCl 3 , 500 MHz) 8 1.31 (bs, 3H), 2.95 (dd, J=13.7, 7.9, 1 H), 3.18 (dd, J=13.7, 5.2, 1H), 3.48 (s, 3H), 3.78 5 (dd, J=7.9, 5.2, 1H), 7.23 (s, IH), 7.46 (s, 1H), 8.00 (s, 1H). Mass spec.: 254.06 (MH)+. Example 42 (±)-3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 10 piperidine-1-carbonyl]-amino}-propionic acid methyl ester HN - H CI 0 N N IH NyN
H
3 CO 0 A stirred solution of (±)-2-amino-3-(7-chloro- 1 H-indazol-5-yl)-propionic acid methyl ester (78 mg, 0.31 mmol) in tetrahydrofuran (2 mL) at 0 0 C was treated with carbonyl diimidazole (50 mg, 1 equiv). The reaction was stirred for 5min, warmed to 15 room temperature, stirred 10 min, and treated with 3-piperidin-4-yl-3,4-dihydro-1H quinazolin-2-one (78 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 148 mg (94%) as a white powder. 'H-NMR (DMSO-d 6 , 500 MHz) 8 1.46 (m, 4H), 2.55-2.80 (in, 2H), 3.05 (dd, J=13.7, 10.7, 1H), 3.15 (m, 1H), 20 3.62 (s, 3H), 4.04 (d, J=13.4, 2H), 4.11 (s, 2H), 4.22-4.39 (m, 2H), 6.76 (d, J=7.9, 1H), 6.87 (dd, J=7.3, 7.3, 1H), 6.90 (d, J=8.2, 1H), 7.08 (d, J=7.6, IH), 7.12 (dd, J=7.6, 7.6, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.15 (s, 1H), 9.18 (s, I H), 13.48 (s, IH). Mass spec.: 511.18 (MH)*. 25 Example 43 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-1-(7-chloro-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 119 HN-N H CI 0 N NN / ~ H N N N 0 A suspension of (±)-3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester (15 mg, 0.029 mmol) in 1:1 tetrahydrofuran /methanol (1 mL) at room temperature was 5 treated with a solution of lithium hydroxide (3.0 mg, 2.5 equiv) in water (0.25 mL), and the resulting solution was stirred for 1.5 h. The solution was cooled to 0 0 C, treated with aqueous I M potassium hydrogen sulfate (60 pL, 2.0 equiv), and concentrated to give the crude acid which was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially 10 treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (10.1 mg, 2 equiv), diisopropylethylamine (10 gL, 2 equiv), and PyBOP* (16.5 mg, 1.1 equiv). The solution was stirred 30 min and concentrated. The product was purified by column chromatography to give 14.7 mg (77%, 2 steps). 'H-NMR (CDCl 3 , 500 MHz) 8 1.30-1.60 (in, 8H), 1.65-1.88 (m, SH), 2.14 (in, 1H), 2.23 (m, lH), 2.30-2.70 (m, 7H), 15 2.80-3.20 (in, 5H), 3.94 (d, J=13.4, 13.1, 1H), 4.10-4.30 (in, 4H), 4.55 (m, 1H), 4.62 (dd, J=13.1, 12.8, 1H), 5.19 (in, 1H), 5.91 (dd, J=30.2, 22.3, 1H), 6.70 (d, J=7.6, 1H), 6.92 (dd, J=7.6, 7.3, 1H), 7.01 (dd, J, 7.9, 7.6, 1H), 7.13 (s, 0.4H), 7.15 (dd, J=7.9, 7.6, 1H), 7.24 (s, 0.6H), 7.33 (s, 0.4H), 7.43 (s, 0.6H), 7.49 (bs, 1H), 7.91 (s, 0.4H), 7.95 (s, 0.6H), 11.25 (bd, J=50.7, 1H). Mass spec.: 647.37 (MH)*. 20 4-Bromo-2-ethyl-6-methyl-phenylamine
NH
2 Br WO 2005/065779 PCT/US2003/038799 120 2-Ethyl-6-methyl-phenylamine (14 mL, 100 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and water (220 mL) and cooled to 0 0 C. To this was added bromine (5.1 mL, 1 equiv.) dropwise. There was rapid formation of a white precipitate. The precipitate was filtered and washed with diethyl ether. The 5 precipitate was suspended in water and neutralized with aqueous potassium carbonate. An oil formed which was extracted into diethyl ether. The ethereal was dried over potassium carbonate, filtered, and concentrated to give 7.0 g (33%) as a purple oil which was used without purification. Mass spec.: 214.01 (MH)*. 10 4-Bromo-2-ethyl-6-methylphenyldiazo-t-butyl sulfide S N Br 4-Bromo-2-ethyl-6-methylaniline (7.0 g, 33 mmol) was suspended in 7.8 M hydrochloric acid (30 mL). The stirred mixture was cooled to -20'C and treated with sodium nitrite (2.27 g, 1.05 equiv.) in water (5 mL), dropwise over 10 min while the 15 temperature was maintained below -5'C. After a further 30 min at -5'C to -20'C, the mixture was buffered to ca. pH 5 with solid sodium acetate. This mixture (kept at ca. -10 C) was added in portions to a stirred solution of t-butyl thiol (3.7 mL, 1 equiv.) in ethanol (50 mL) at 0 0 C over ca. 10 min. Following addition, the mixture was stirred at 0 0 C for 30 min and then crushed ice (ca. 50 mL) was added. The mixture was 20 stored in the refrigerator for 2 h. The resulting light-brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours (9.47 g, 92%). Mass spec.: 315.05 (MH)*. 5-Bromo-7-ethyl- I H-indazole HN -- N 2N 25 Br WO 2005/065779 PCT/US2003/038799 121 To a stirred solution of potassium t-butoxide (33.6 g, 10 equiv.) in DMSO (200 mL) was added a solution of 4-bromo-2-ethyl-6-methylphenyldiazo-t-buty sulfide (9.4 g, 30 mmol) in DMSO (100 mL) via cannula. The mixture was stirred vigorously for 1 h. The reaction mixture was then carefully poured into a mixture of 5 crushed ice (500 mL), concentrated hydrochloric acid (25 mL), and water (100 mL). The resulting precipitate was filtered, washed with water, dissolved in methanol, and concentrated to give 5.7 g (85%) as a tan solid. 'H-NMR (CDCl 3 , 500 MHz) 6 1.39 (t, J=7.6, 3H), 2.92 (q, J=7.6, 2H), 7.30 (s, IH), 7.75 (s, IH), 8.04 (s, 1H). Mass spec.: 225.00 (MH)*. 10 7-Ethyl-1 H-indazole-5-carbaldehyde HN -N H 0 5-Bromo-7-ethyl-1H-indazole (2.0 g, 8.9 mmol) and sodium hydride (226 mg, 1.1 equiv.) were weighed into a flame-dried round-bottom flask containing a 15 magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 15 min. The stirred mixture was cooled to -78'C and a solution of tert-butyllithium in pentane (1.7 M, 10.5 mL, 2.0 equiv.) was added over several minutes. After 15 min at -78'C, the reaction was gradually warmed to to -50'C, and recooled to -78'C. 20 Dimethylformamide (2.8 mL) was slowly added and the mixture allowed to warm to -50'C. The solution was quickly transferred to a stirred solution of water 300 mL and I M potassium hydrogen sulfate (25 mL). The resulting suspension was extracted with diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography gave 160 mg (10%) as a white 25 solid. 'H-NMR (CD 3 0D, 500 MHz) 8 1.38 (t, J=7.6, 3H), 2.98 (q, J=7.6, 2H), 7.71 (s, 1H), 8.22 (s, 1H), 8.24 (s, 1H), 9.96 (s, 1H). Mass spec.: 175.08 (MH)*. 2-Benzyloxycarbonylamino-3-(7-ethyl-i H-indazol-5-yl)-acrylic acid methyl ester WO 2005/065779 PCT/US2003/038799 122 HN-N H N 0 0 0 To a stirred solution of N-benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (0.61 g, 2.0 equiv.) and 7-ethyl-IH-indazole-5-carbaldehyde (160 mg, 0.92 mmol) in tetrahydrofuran (5 mL) at 0*C was added tetramethylguanidine (0.22 mL, 5 1.9 equiv.). The reaction was allowed to slowly warm to room temperature overnight. The reaction was concentrated, dissolved in diethyl ether, washed with water, then brine, dried (magnesium sulfate), and concentrated. The residue was purified by column chromatography to give 333 mg (95%) as an oil. 1 H-NMR
(CDC
3 , 500 MHz) 8 1.33 (t, J=7.6, 3H), 2.86 (q, J=7.3, 2H), 3.83 (s, 3H), 5.11 (s, 10 2H), 6.39 (bs, 1H), 7.29 (bs, 5H), 7.43 (s, 1H), 7.50 (s, 1H), 7.78 (s, 1H), 8.04 (s, IH). Mass spec.: 380.17 (MH)*. (±)-2-Amino-3 -(7-ethyl-i H-indazol-5-yl)-propionic acid methyl ester HN-N
NH
2 0 0 15 To a solution of 2-benzyloxycarbonylamino-3-(7-ethyl-1H-indazol-5-yl) acrylic acid methyl ester (330 mg, 0.78 mmol) in methanol (5 mL) under nitrogen was added palladium on charcoal (10%, 33 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 20 210 mg (98%) which was used without purification. 'H-NMR (CDCl 3 , 500 MHz) 8 1.34 (t, J=7.6, 3H), 2.85 (q, J=7.6, 2H), 2.96 (dd, J=13.7, 7.6, 1H), 3.19 (dd, J=13.7, 8.6, 1H), 3.48 (s, 2H), 3.73 (s, 3H), 3.80 (dd,J=7.6, 5.2, 1H), 6.99 (s, 1H), 7.38 (s, 1H), 7.97 (s, IH). Mass spec.: 248.15 (MH)+.
WO 2005/065779 PCT/US2003/038799 123 Example 44 (±)-3-(7-Ethyl-IH-indazol-5-yl)-2-{
[
4
-(
2 -oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino} -propionic acid methyl ester HN-N \ H O N N N
H
3 CO 0 5 A stirred solution of (±)- 2 -amino-3-(7-ethyl-1H-indazol-5-yl)-propionic acid methyl ester (100 mg, 0.41 mmol) in tetrahydrofuran (2 mL) at 0 0 C was treated with carbonyl diimidazole (66 mg, 1 equiv). The reaction was stirred for 5 min, warmed to room temperature, stirred for 15 min, and then treated with 3-piperidin-4-yl-3,4 dihydro-1H-quinazolin-2-one (103 mg, 1.1 equiv). The mixture was stirred at room 10 temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 188 mg (92%) as a white solid. 'H-NMR (CDCl 3 , 500 MHz) 8 1.36 (t, J=7.6, 3H), 1.69 (m, 4H), 2.86 (in, 2H), 2.90 (q, J=7.6, 2H), 3.22 (dd, J=5.5, 4.9, 2H), 3.75 (s, 3H), 4.03 (dd, J=44.0, 13.7, 2H), 4.26 (s, 2H), 4.51 (m, 1H), 4.84 (in, IH), 5.02 (m, 1 H), 6.70 (d, J=7.9, 1H), 6.90-7.05 (in, 4H), 7.16 15 (dd, J=7.6, 7.6, 1H), 7.34 (s, 1H), 8.03 (s, 1H). Mass spec.: 505.29 (MH)*. Example 45 (±)-4-(2-Oxo-1, 4 -dihydro- 2 H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl- 1'-yl- 1-(7-ethyl-I H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide HN-NH 0 N NyN N 0 O 20 To a solution of (±)-3-(7-ethyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro 2 H-quinazolin-3-yl)-piperidine-1 -carbonyl]-amino} -propionic acid methyl ester (15 I H WO 2005/065779 PCT/US2003/038799 124 mg, 0.03 mmol) in methanol (0.6 mL) was added a solution of lithium hydroxide monohydrate (3.0 mg, 2.5 equiv) in water (0.1 mL), and the resulting solution was stirred for 6 h. The solution was cooled to 0*C, treated with aqueous 1 M potassium hydrogen sulfate (60 .tL, 2.0 equiv), and concentrated to give the crude acid which 5 was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.4 mL), cooled to 0*C, and sequentially treated with methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), diisopropylethylamine (12 iiL, 2.3 equiv.), and PyBOP* (19 mg, 1.2 equiv). The solution was stirred for 15 min at 0 0 C, warmed to room temperature, stirred 1.5 h, and concentrated. The 10 product was purified by column chromatography to give 14.5 mg (76%, 2 steps). 1
H
NMR (CDCl 3 , 500 MHz) 8 1.28-1.48 (in, 10H), 1.52 (in, 2H), 1.60-1.82 (in, 6H), 1.95 (m, 1.4H), 2.06 (m, 1.611), 2.20-2.50 (in, 5H), 2.77-2.93 (in, 5H), 2.96-3.17 (m, 2H), 3.76 (d, J=13.4, 0.4H), 3.86 (d, J=13.7, 0.6H), 4.10-4.20 (in, 2H), 4.26 (s, 2H), 4.57 (in, 2H), 5.10-5.24 (in, 1H), 5.67 (d, J=8.2, 0.6H), 5.74 (d, J=7.9, 0.4H), 6.67 15 (d, J=7.9, IH), 5.67 (d, J=8.2, 0.6H), 5.74 (d, J=7.9, 0.4H), 6.67 (d, J=7.9, IH), 6.93 (dd, J=7.6, 7.3, 1H), 6.96 (s, 0.4H), 7.03 (dd, J=7.0, 6.7, 1H), 7.09 (in, 1.6H), 7.15 (dd, J=7.0, 6.7, 1H), 7.31 (s, 0.411), 7.38 (s, 0.6H), 7.94 (s, 0.4H), 7.95 (s, 0.6H). Mass spec.: 641.50 (MH)*. 20 (3,4-Dinitro-phenyl)-methanol 0 2 N OH 0 2 N Borane-tetrahydrofuran complex (IM in tetrahydrofuran, 800 mL, 800 mmol) was added at -20'C over 45 min to a solution of 3,4-dinitrobenzoic acid (93.5 g, 441 mmol) in tetrahydrofuran (300 mL). The resulting mixture was stirred at -20*C for 1 25 h and then warmed to room temperature and stirred overnight. It was quenched by the addition of 32 mL of 1:1 acetic acid/water. Solvents were removed in vacuo and the residue was poured into an ice-cold 1000 mL of sat. sodium bicarbonate with vigorous stirring over 15 min. The mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with sat. sodium bicarbonate, brine 30 and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a light yellow solid (100%). 'H-NMR (CDCl 3 , 500 MHz) 6 WO 2005/065779 PCT/US2003/038799 125 7.91(d, J 8.0 Hz, IH), 7.89 (s, 1H), 7.71 (dd, J = 8.5, 1.0 Hz, 1H), 4.87 (s, 2H), 2.30 (s, 1H). 3,4-Dinitro-benzaldehyde 0 2 N CHO 5 0 2 N A solution of (3,4-dinitro-phenyl)-methanol (95.3g, 481 mmol) in methylene chloride (500 mL) was added all at once to a suspension of pyridinium chlorochromate (156 g, 722 mmol) in methylene chloride (900 mL). The mixture was stirred at room temperature for 1.5 h and then ether (1500 mL) was added. The 10 supernatant was decanted from the resulting black gum, and the insoluble residue was washed thoroughly with methylene chloride (3 x 250 mL). The combined organic solution were filtered through a pad of florisil to afford a light bright yellow clear solution. Solvents were removed in vacuo and the residue was purified by silica gel chromatography using methylene chloride as eluent to afford the title compound as a 15 yellow solid (71%). 'H-NMR (CDCl 3 , 300 MHz) 5 8.45 (d, J 1.5 Hz, 1H), 8.28 (dd, J 8.1, 1.5 Hz, IH), 8.07 (d, J= 8.1 Hz, 1H). "CNMR (CD 3 0D, 125 MHz) 8 187.7, 139.2, 134.2, 126.2, 125.7. 2-Benzyloxycarbonylamino-3-( 3 ,4-dinitro-phenyl)-acrylic acid methyl ester 0 2 N CO 2 Me 2 . I NH Cbz 20 0 2 N 1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-alpha-phophonoglycine trimethyl ester (114.lg, 344 mmol) in tetrahydrofuran (800 mL). The mixture was stirred at room temperature for 15 min and cooled to -78 0 C. A solution 3,4-dinitro 25 benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was slowly added via cannula. The resulting mixture was stirred at -78'C for 2h and then allowed to warm to room temperature overnight. Solvents were removed in vacuo, and the yellow residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of IN sulfuric acid, water twice, brine and dried over sodium sulfate. After filtration, 30 solvents were removed in vacuo and the residue was crystallized from ethyl acetate WO 2005/065779 PCT/US2003/038799 126 (20 g crude product/100 mL of ethyl acetate). The yellow crystals were collected and further purified by chromatography on silica gel using methylene chloride as eluent. The title compound was obtained a s yellow crystals (77%). 'H-NMR (CDCl 3 , 500 MHz) 8 7.85 (d, J= 1.5 Hz, 1H), 7.74 (d, J= 8.0 Hz, lH), 7.62 (dd, J= 8.5, 1.5 Hz, 5 1H), 7.35 - 7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H), 6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H). Similarly prepared: 2-Benzyloxycarbonylamino-3-(3-hydroxy-4-nitro-phenyl)-acrylic acid methyl ester HO CO 2 Me x NHCbz 10 0 2 N 'H-NMR (CDCl 3 , 500 MHz) 5 7.93 (d, J = 9.0 Hz, 1H), 7.32 (br s, sH), 7.28 (br s, 2H), 7.17 (s, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.0, 2.0 Hz, 1H), 6.74 (br s, 1H), 5.06 (s, 2H), 3.86 (s, 3H). 15 (R)-2-Benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-propionic acid methyl ester H 0 2 N
CO
2 Me 0 2 N
-
NHCbz An oven-dried 500 mL Shlenck flask was put into a glove-bag filled with nitrogen. After the glove-bag was evacuated and filled with nitrogen (3x), the flask was sealed and taken out of the glove-bag and weighed. It was put back into the 20 glove-bag and evacuated and filled with nitrogen (3x), then it was charged with (-) 1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadienene)rhodium (I) trifluoromethanesulfonate. The flask was sealed and taken out of the glove-bag and weighed (784 mg, 1.08 mmol). 2-Benzyloxycarbonylamino-3-(3,4-dinitro-phenyl) acrylic acid methyl ester (8.72 g, 21.7 mmol) was added to another 500 mL of 25 Schlenck flask and was evacuated and filled with nitrogen (3x). Methylene chloride (350 mL, degassed with nitrogen for 2 h) was added and the resulting solution was transferred to the catalyst flask via cannula. The flask was purged and filled with hydrogen (4x) and the mixture was stirred at room temperature for 4h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography WO 2005/065779 PCT/US2003/038799 127 using ethyl acetate/hexanes (1:1) as eluent to afford the title compound as a light tan gummy solid (99% yield and 99.2% ee determined by HPLC analysis using the following conditions: Chiralpak AD column (4.6 x 250 mm, 10 um; A = ethanol, B = hexane; 40% B @ 1.0 mL/min for 14 min; retention times: 10.9 min for R 5 enatiomer and 6.9 min for S enatiomer). 'H-NMR (CDCl 3 , 500 MHz) 8 7.80 (d, J 8.0 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.38 - 7.31 (in, 5H), 5.37 (d, J 6.0 Hz, 1H), 5.13 - 5.05 (in, 2H), 4.68 (d, J= 6.0 Hz, 1H), 3.71 (s, 3H), 3.36 (dd, J= 13.5, 5.0 Hz, IH), 3.17 (dd, J = 13.5, 6.0 Hz, 1H). 10 Similarly prepared: (R)-2-Benzyloxycarbonylamino-3-(3-hydroxy-4-nitro-phenyl)-propionic acid methyl ester H HO CO 2 Me 02N / NHCbz 'H-NMR (CDCl 3 , 500 MHz) 8 7.97 (d, J = 9.0 Hz, 1H), 7.36 - 7.30 (in, 5H), 6.90 (s, 15 1H), 6.71 (d, J = 8.5 Hz, 1H), 5.29 (d, j = 7.0 Hz, 1H), 5.11 (d, J = 12.5 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 4.68 (dd, j = 13.0, 6.0 Hz, 1 H), 3.74 (s, 3H), 3.20 (dd,j = 13.5, 5.0 Hz, 1H), 3.05 (dd, J= 13.5, 6.0 Hz, 1H). (R)-2-Benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester H
H
2 N - CO 2 Me - N H Cbz 20
H
2 N Solid ammonium formate (2.27 g, 36 mmol) was added in small portions at 0 0 C to a methanol (50 mL, degassed with nitrogen for 2 h) suspension of (R)-2 benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-propionic acid methyl ester (1.45 g, 3.6 mmol) and zinc powder (1.41 g, 21.6 mmol). The resulting mixture was stirred at 25 room temperature overnight. The solvents were removed in vacuo and then toluene (30 mL, degassed) and ethyl acetate (30 mL, degassed) were added, followed by acetic acid (3 mL). The mixture was further diluted until all organic solids dissolved, then it was washed with water, brine and dried over sodium sulfate. After filtration, WO 2005/065779 PCT/US2003/038799 128 solvents were removed in vacuo to afford the title compound containing I equivalent of acetic acid as a reddish gummy solid (85%). Mass Spec.: 344.18 (MH)*. (R)-2-Benzyloxycarbonylamino-3-(2-methyl-1 H-benzoimidazol-5-yl)-propionic acid 5 methyl ester H Me/N H-CO 2 Me Ne , NHCbz H A solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl) propionic acid methyl ester-acetic acid (640 mg) in acetic acid (8 mL) was heated at 130'C for 4h. The mixture was then poured into water and cooled to 0 0 C. The pH 10 was adjusted to 8 by gradual addition of solid sodium bicarbonate. The mixture was then extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were washed with water, brine and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a brownish foamy solid (95%). 'H NMR (CDC1 3 , 500 MHz) 5 7.39 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.26 - 7.22 (m, 15 5H), 7.06 (d, J = 8.0 Hz, 1H), 5.03 (d, J= 12.5 Hz, 1H), 4.99 (d, J= 13.0 hz, 1H), 4.51 (dd, J= 8.5, 5.5 Hz, 1H), 3.70 (s, 3H), 3.27 (dd, J= 13.5, 5.0 Hz, 1H), 3.03 (dd, J= 14.0, 9.0 Hz, 1H), 2.55 (s, 3H). Mass spec.: 368.19 (MH)+. (R)-2-Benzyloxycarbonylamino-3-{2-methyl-3-(2-trimethylsilanyl-ethanesulfonyl) 20 3H-benzoimidazol-5-yl]-propionic acid methyl ester and (R)-2-Benzyloxycarbonylamino-3-[2-methyl- 1 -(2-trimethylsilanyl-ethanesulfonyl) 1H-benzoimidazol-5-yl]-propionic acid methyl ester SES H HCO 2 Me e N CO 2 Me N HCbz Me N / NH CbzNNHb SES 25 To a suspension of (R)-2-benzyloxycarbonylamino-3-(2-methyl- 1 H benzoimidazol-5-yl)-propionic acid methyl ester (533 mg, 1.96 mmol), and sodium carbonate in acetonitrile (20 mL) was added neat 2-trimethylsilanyl-ethanesulfonyl chloride all at once. The mixture was stirred at room temperature overnight.
WO 2005/065779 PCT/US2003/038799 129 Solvents were removed and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (1:2) as eluent to afford the title compound as a waxy solid (1:1 mixture of N1 and N3 isomers, 66%). 1 H-NMR (CDCl 3 , 500 MHz) 8 7.68 (d, J= 8.5 hz, 0.5H), 7.55 (d, J= 8.5 Hz, 0.5 H), 7.53 (s, 0.5H), 7.41 (s, 0.5 H), 7.34 5 7.29 (m, 5H), 7.06 - 7.04 (m, 1H), 5.22 (d, J = 8.0 Hz, 0.5 H), 5.17 (d, J= 7.5 Hz, 0.5 H), 5.11 - 5.07 (m, 2H), 4.72 - 4.69 (m, 1H), 3.75 (s, 1.5 H), 3.72 (s, 1.5 H), 3.24 3.17 (m, 2H), 2.79 (s, 3H), 0.92 - 0.83 (m, 2H), -0.02 (s, 4.5 H), -0.05 (s, 4.5H). Mass spec.: 532.26 (MH)*. 10 (R)-2-Amino-3-[2-methyl-1-( 2 -trimethylsilanyl-ethanesulfonyl)-1H-benzoimidazol 5-yl]-propionic acid methyl ester and (R)-2-Amino-3-[2-methyl-3-( 2 -trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol 5-yl]-propionic acid methyl ester H N CO 2 Me SES H Me N CO 2 Me
SNH
2 Me NH2 15 N NHN A methanol (50 mL) suspension of (R)-2-benzyloxycarbonylamino-3-[2 methyl-3-( 2 -trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol-5-yl]-propionic acid methyl ester and (R)- 2 -Benzyloxycarbonylamino-3-[2-methyl-1-(2-trimethylsilanyl ethanesulfonyl)- 1 H-benzoimidazol-5-yl] -propionic acid methyl ester (1:1 mixture, 20 600 mg), and 10% palladium on charcoal (180 mg) was agitated on a Parr apparatus overnight under 40 psi of hydrogen at room temperature. After replacing the hydrogen atmosphere with nitrogen, the mixture was filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a tan solid (80%). H-NMR (CD 3 0D, 500 MHz) 5 7.81 (d, J 8.5, 0.5 Hz, 0.5 H), 7.70 (s, 0.5 H), 7.58 25 (d, J= 8.5 Hz, 0.5 H), 7.49 (s, 0.5 H), 7.25 (d, J= 9.0 Hz, 1H), 3.89 (dd, J = 14.0, 6.5 Hz, 1H), 3.75 (s, 1.5 H), 3.72 (s, 1.5 H), 3.55 - 3.51 (m, 2H), 3.18 (d, J= 6.0 Hz, 1H), 3.22 - 3.18 (m, 0.5 H), 3.14 - 3.09 (m, 0.5 H), 2.81 (s, 1.5 H), 2.80 (s, 1.5 H), 0.92 - 0.88 (m, 2H), 0.02 (s, 4.5 H), 0.01 (s, 4.5 H); ' 3 CNMR (CD 3 0D, 125 MHz) S 174.3, 174.1, 153.5, 153.3, 141.7, 140.6, 133.9, 133.82, 133.78, 132.7, 126.5, 126.3, WO 2005/065779 PCT/US2003/038799 130 119.7, 119.0, 114.1, 113.4, 55.6, 51.8, 51.7, 51.6, 40.2, 39.8, 15.83, 15.77, 9.9, -3.07, -3.11. Mass spec.: 398.20 (MH)*. (R)-3-[2-Methyl-1-(2-trimethylsilanyl-ethanesulfonyl)-1H-benzoimidazol-5-y1]-2 5 {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} propionic acid methyl ester and (R)-3-[2-Methyl-3-(2-trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol-5-yl]-2 {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} 10 propionic acid methyl ester H SES H e N CO 2 Me N CO Me SES N N 0 N 0 N HN HN Prepared as described above for (R)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin 3-yl)-piperidine- I -carbonyl]-amino} -3-[1-(2-trimethylsilanyl-ethanesulfonyl)- I H indazol-5-yl]-propionic acid methyl ester. Purified by silica gel chromatography 15 using ethyl acetate with 1% triethylamine as fluent to afford the title compound as an off-white solid (87%). 'H-NMR (CD 3 0D, 500 MHz) 8 7.82 (d, J = 8.5 Hz, 0.5 H), 7.80 (s, 0.5 H), 7.59 (d, J = 8.0 Hz, 0.5 H), 7.55 (s, 0.5 H), 7.33 - 7.30 (in, 1H), 7.16 (t, J= 8.0 Hz, 1H), 7.12 (t, J = 7.5 Hz, IH), 6.95 (t, J = 7.5 Hz, lH), 6.79 (d, J = 7.5 Hz, IH), 4.60 - 4.55 (m, IH), 4.45 - 4.40 (in, 1H), 4.29 - 4.27 (in, 2H), 4.15 - 4.10 20 (in, 2H), 3.77 (s, 1.5 H), 3.74 (s, 1.5 H), 3.56 - 3.51 (m, 2H), 3.35 - 3.31 (in, 2H), 3.21 - 3.15 (in, I H), 2.91 - 2.80 (in, 2H), 2.78 (s, 1.5 H), 2.77 (s, 1.5 H), 1.76 - 1.73 (m, 1H), 1.66 - 1.61 (m, 2H), 0.92 - 0.87 (m, 2H), 0.009 (s, 4.5 H), -0.007 (s, 4.5 H). "CNMR (CD 3 OD, 125 MHz) 173.8, 173.7, 158.2, 158.1, 155.6, 153.4, 153.2, 141.6, 140.3, 137.2, 135.3, 135.1, 133.7, 132.5, 128.2, 126.4, 126.3, 125.7, 122.13, 122.10, WO 2005/065779 PCT/US2003/038799 131 119.6, 118.8, 118.4, 114.0, 113.4, 113.2, 57.3, 56.2, 51.9, 51.7, 51.5, 43.8, 43.7, 42.9, 37.6, 37.2, 28.4, 17.4, 15.7, 15.6, 9.9, -3.1, -3.2. Mass spec.: 655.36 (MH)*. (R)-3-(2-Methyl-1H-benzoimidazol-5-yl)-2- {[4-(2-oxo-1,4-dihydro-2H-quinazolin 5 3-yl)-piperidine- 1 -carbonyl] -amino} -propionic acid H N C0 2 H Me/ Ne Do" H N 0 H N 0 N The 1:1 mixture of (R)-3-[2-Methyl- 1 -(2-trimethylsilanyl-ethanesulfonyl) IH-benzoimidazol-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 carbonyl]-amino} -propionic acid methyl ester and (R)-3-[2-Methyl-3-(2 10 trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol-5-yl]-2-{[4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidine-1 -carbonyl]-amino}-propionic acid methyl ester was treated as described above for (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino } -3-[1-(2-trimethylsilanyl-ethanesulfonyl)- 1 H-indazol 5-yl]-propionic acid. The hydrolysis conditions (lithium hydroxide/methanol 15 tetrahydrofuran-water (1:1:1) at -15 'C ovemight were used. The title compound was obtained as a white solid (25%). Mass spec.: 477.24 (MH) *. Example 46 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carboxylic acid [2 20 [1,4']bipiperidinyl-l'-yl-1-(2-methyl-i H-benzoimidazol-5-ylmethyl)-2-oxo-ethyl] amide WO 2005/065779 PCT/US2003/038799 132 0 N I-N-N N N I; HN 0 NN H 'If N Of NH Prepared as described above for (R)-4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-1I'-yl-2-oxo-1-[i-(2 trimethylsilanyl-ethanesulfonyl)- 1H-indazol-5-ylmethyl]-ethyl} -amide. Purified by 5 silica gel chromatography using methylene chloride:methanol:triethylamine (93:5:2) as eluent to give a white solid. This was dissolved in ethyl acetate (60 mL) and washed with a 1:1 sat. sodium bicarbonate/brine twice and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a white solid (11% yield). LC/MS: tR = 1.59 min, 627.34 (MH)*. 10 (R)-3-(4-Amino-3-hydroxy-phenyl)-2-benzyloxycarbonylamino-propionic acid methyl ester hydochloride H HO CO 2 Me H2N NHCbz HCI Powdered iron (3.7 g, 66.4 mmol) and ammonium chloride (5.9 g, 111 mmol) 15 were added at 0 0 C to a solution of (R)-2-benzyloxycarbonylamino-3-(3-hydroxy-4 nitro-phenyl)-propionic acid methyl ester (2.07 g, 5.53 mmol) in degassed 1:1 methanol/water (400 mL). The resulting mixture was stirred at room temperature for 48 h. Trifluoroacetic acid (7 mL) was added, and the mixture was swirled until it was a clear dark red solution containing a suspension of unreacted iron powder. The 20 mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 x 150 mL), the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, hydrochloric acid (4.2 mL, 4M in dioxane) was added. Solvents were removed in vacuo, and the title compound WO 2005/065779 PCT/US2003/038799 133 was obtained as a tan foamy solid (80%). 1 H-NMR (CD 3 0D, 500 MHz) 8 7.34 7.28 (in, 5H), 7.20 (d, J= 8.0 hz, 1H), 6.88 (s, 1H), 6.78 (d, J = 7.5 Hz, 1H), 5.05 5.00 (in, 2H), 4.42 (dd, J= 8.5, 5.0 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 1H), 3.33 (br s, 2H), 3.11 (dd, J= 14.0, 5.0 hz, IH), 2.90 (dd, J= 13.5, 9.0 Hz, 1H). "'CNMR 5 (CD 3 0D, 125 MHz) 172.5, 157.4, 151.2, 140.2, 137.0, 128.5, 128.0, 127.7, 123.8, 120.9, 117.0, 116.9, 67.2, 55.7, 52.0, 37.2. Mass spec.: 345.20 (MH)*. (R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester H 0
HCO
2 Me oH~<I N NH~b 10 H A methylene chloride (15 mL) solution of carbonyl diimidazole (498 mg, 3.07 mmol) was added at 0 0 C to a solution of (R)-3-(4-amino-3-hydroxy-phenyl)-2 benzyloxycarbonylamino-propionic acid methyl ester (1.1 7g, 3.07 mmol), diisopropylethylamine (1.60 mL, 9.21 mmol), and methylene chloride (85 mL). The 15 mixture was stirred at 0 0 C for 4 h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate/hexanes as eluent to afford the title compound as a white solid (51%). 'H-NMR (CDCl 3 , 500 MHz) 8 9.07 (s, IH), 7.37 - 7.29 (m, 5H), 6.96 (s, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.36 (d, J = 8.0 Hz, 1H), 5.11 (d, J 12.0 Hz, 1H), 5.07 (d, J = 20 12.5 Hz, IH), 4.65 (dd, J= 13.5, 5.5 Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J= 14.0, 5.5 Hz, 1H), 3.07 (dd, J= 14.0, 6.0 Hz, 1H). 13 CNMR (CDCl 3 , 125 MHz) 5 171.9, 155.7, 155.5, 144.1, 136.2, 130.8, 128.6, 128.42, 128.38, 128.2, 125.1, 111.1, 109.8, 67.2, 55.1, 52.6, 38.3. Mass spec.: 371.18 (MH)+. 25 (R)-2-Amino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester H O H CO 2 Me N NH 2 H A solution of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro benzooxazol-6-yl)-propionic acid methyl ester (310 mg) in 4.4% formic acid in WO 2005/065779 PCT/US2003/038799 134 methanol ( 20 ml, freshly prepared in degassed methanol) was added via cannula to a suspension of 10% palladium on charcoal in 4.4% formic acid in methanol ( 20 ml, freshly prepared in degassed methanol). The resulting mixture was stirred at room temperature for 4 h. After filtration through a pad of celite, the solvents were 5 removed in vacuo giving a tan solid. The solid was dissolved in a mixture of ethyl acetate (50 mL), toluene (10 mL) and ethanol (40 ml), and solid sodium bicarbonate (3.1 g) was added. The mixture was stirred at room temperature for 2h and filtered. Solvents were removed in vacuo to afford the title compound. 'H-NMR (CD 3 oD, 500 MHz) 6 8.41 (br s, 2H), 7.17 (s, 1 H), 7.09 (br s, 2H), 4.32 (s, 1H), 3.83 (s, 3H), 10 3.33 (s, IH), 3.30 (s, 1H), 3.22 (s, IH). Mass spec.: 237.20 (MH) 4 . (R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino } -propionic acid methyl ester H o HH CO 2 Me H 0YN 0 N 15 Prepared as described above for (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin 3-yl)-piperidine- 1 -carbonyl] -amino) -3-[1-(2-trimethylsilanyl-ethanesulfonyl)- 1H indazol-5-yl]-propionic acid methyl ester. Purified by silica gel chromatography using methylene chloride:methanol:triethylamine (93:5:2) as eluent to afford the title compound as a white solid (33%). 'H-NMR (CD 3 0D, 500 MHz) 6 7.17 - 7.13 (m, 20 3H), 7.08 (d, J = 7.9 hz, 1H), 7.03 (d, J= 8.0 Hz, 1H), 6.95 (t, J= 7.0 Hz, 1H), 6.79 (d, J= 8.0 Hz, I H), 4.55 - 4.51 (in, I H), 4.44 - 4.41 (m, I H), 4.33 (s, 2H), 4.14 4.10 (m,2H), 3.74 (s, 3H), 3.33 (br s, 2H), 3.23 (dd, j = 13.7, 5.2 Hz, 1H1), 3.03 (dd, J = 14.0, 9.7 Hz, 1H), 2.92 - 2.82 (in, 2H), 1.79 - 1.63 (m, 4H). 3 CNMR (CD 3 0D, 125 MHz) 173.8, 158.2, 156.2, 155.6, 144.4, 137.1, 132.7, 129.3, 128.2, 125.7, 25 125.0, 122.2, 118.4, 113.4, 110.6, 109.6, 56.2, 52.0, 51.7, 43.8, 42.9, 37.3, 28.4. Mass spec.: 494.30 (MH)*.
WO 2005/065779 PCT/US2003/038799 135 (R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine-1 -carbonyl]-amino} -propionic acid H 0 ~ C0 2 H N 0' HN 0 H N 0 N HN 5 Prepared as described above for (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin 3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H indazol-5-yl]-propionic acid. The hydrolysis conditions (lithium hydroxide/methanol-tetrahydrofuran-water (1:1:1) at -1 5C overnight were used. The title compound was obtained as a white solid (95%). Mass spec.: 480.30 (MH)*. 10 Example 47 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl- l'-yl-2-oxo- 1-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-ethyl] amide oNN N N 0 NH 15 Prepared as described above for (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2- WO 2005/065779 PCT/US2003/038799 136 trimethylsilanyl-ethanesulfonyl)-1H-indazol-5 -ylmethyl]-ethyl } -amide. The crude product was purified by silica gel chromatography using methylene chloride:methanol:triethylamine (93:5:2) as eluent to give a white solid. This was dissolved in ethyl acetate (60 mL) and washed with a 1:1 sat. sodium 5 bicarbonate/brine twice and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a white solid (70%). 'H-NMR (CD 3 0D, 500 MHz) 8 7.20 - 7.14 (m 4H), 7.08 (d, J= 9.0 Hz, 1H), 6.96 (td, J = 7.5, 1.0 Hz, IH), 6.79 (d, J 8.0 Hz, 1H), 4.99 - 4.94 (in, 1H), 4.61 - 4.58 (m, 1H), 4.47 - 4.43 (m, 1H), 4.39 (s, IH), 4.23 - 4.16 (in, 2H), 4.08 - 4.04 (m, 1H), 3.06 - 2.88 (in, 5H), 2.74 10 - 2.69 (m, 2H), 2.59 - 2.52 (in, 2H), 2.41 - 2.33 (in, 2H), 1.96 - 1.89 (in, IH), 1.88 1.47 (in, 16H). LC/MS: tR = 1.86 min, 630.31 (MH)+. (R)-3-(1H-Benzotriazol-5-yl)-2-benzyloxycarbonylamino-propionic acid methyl ester H N CO 2 Me N" N NHCbz H 15 To a solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl) propionic acid methyl ester mono acetate (2.68 g, 6.65 mmol) in acetic acid (30 mL) and water (40 mL), at room temperature was added a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL), dropwise over several minutes. The resulting mixture was stirred at room temperature for 20 min, then cooled to 0 0 C, concentrated 20 ammonium hydroxide was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice in the presence of solid sodium chloride, and the organic layers were dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (6:4) as eluent to afford the title compound as a tan solid (94% yield). 1 H-NMR 25 (CD 3 0D, 500 MHz) 5 7.75 (d, J= 8.5 Hz, IH), 7.58 (s, 1H), 7.31 - 7.25 (m, 5H), 7.18 (d, J= 8.5 Hz, 1H), 5.39 (d, J= 8.0 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 5.05 (d, J = 12.0 Hz, IH), 4.74 (dd, j = 13.5, 6.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J = 14.0, 5.5 Hz,1H), 3.22 (dd, J = 13.5, 6.0 Hz, 1H). "CNMR (CD 3 0D, 125 MHz) 8 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spec. 355.18 (MH) 4 . 30 WO 2005/065779 PCT/US2003/038799 137 (R)-2-Amino-3-(1H-benzotriazol-5-yl)-propionic acid methyl ester H N CO 2 Me N NH 2 H Prepared as described above for (R)-2-amino-3-(2-oxo-2,3-dihydro benzooxazol-6-yl)-propionic acid methyl ester. 'H-NMR (CD 3 0D, 500 MHz) 8 8.38 5 (br s, 2H), 7.89 (d, J= 7.5 Hz, 1 H), 7.81 (s, 1H), 7.40 (d, J= 7.5 Hz, 1H), 4.44 (s, 1H), 3.81 (s, 3H), 3.48 - 3.45 (m, IH), 3.40 - 3.37 (m, IH), 3.33 (br s, 1H). 13 CNMR (CD 3 0D, 125 MHz) 8 169.8, 139.4, 138.9, 133.0, 127.6, 115.52, 115.47, 54.3, 52.6, 36.7. Mass spec. 221.15 (MH)+. 10 Example 48 (R)-3-(1H-Benzotriazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino) -propionic acid methyl ester H N
CO
2 Me N HHN 0 N N 0 NH Prepared as described above for (R)-2- {[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 15 piperidine- 1 -carbonyl]-amino} -3-[1-(2-trimethylsilanyl-ethanesulfonyl)- 1H-indazol 5-yl]-propionic acid methyl ester except that carbonyl diimidazole was used in place of NN-disuccinimidyl carbonate (DSC). 'H-NMR (CD 3 0D, 300 MHz) 5 7.82 (d, J= 8.4 Hz, IH), 7.24 (s, 1H), 7.39 (dd, J= 8.7, 1.2 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.94 (td, J = 7.5, 0.9 Hz, 1H), 6.75 (d, J = 7.8 Hz,1H), 4.67 - 4.60 (m, IH), 4.39 - 4.31 (m, 20 1H), 4.15 (s, 2H), 4.08 - 4.03 (m, 2H), 3.72 (s, 3H), 3.38 (dd, J = 13.9, 5.5 Hz, 1H), 3.32 - 3.29 (m, lH), 3.17 (dd, J= 13.9, 10.3 Hz, 1H), 2.87 - 2.71 (m, 2H), 1.64 1.48 (m, 4H). Mass spec. 478.30 (MH)*. Example 49 WO 2005/065779 PCT/US2003/038799 138 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(1H benzotriazol-5-ylmethyl)-2-[1,4']bipiperidinyl-l'-yl-2-oxo-ethyl]-amide 0 N N N NN N -I, I-N 0O NN H N Y0 NH Prepared as described above for (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3 5 yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-2-oxo-1-[1-(2 trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide. Purified by silica gel chromatography using methylene chloride/methanol/triethylamine (93:5:2) as fluent. 'H-NMR (CD 3 0D, 500 MHz) 8 7.83 d, J= 8.2 Hz, 0.75H), 7.79 (d, J= 8.5 Hz, 0.25H), 7.71 (s, 0.25H), 7.69 (s, 0.75H), 7.33 (d, J = 9.2 Hz, 1H), 7.16 - 7.12 (m, 10 2H), 6.96 - 6.91 (in, 1H), 6.78 (d, J= 8.0 Hz, 0.75H), 6.77 (d, J = 8.0 Hz, 0.25H), 5.07 - 5.03 (in, IH), 4.58 - 4.55 (in, 1H), 4.45 - 4.40 (in, IH), 4.34 (s, 1.25H), 4.24 (s, 0.75H), 4.20 - 4.05 (in, 2.25H), 4.00 - 3.96 (in, 0.75H), 3.24 - 3.09 (in, 2H), 2.91 - 2.78 (m, 4H), 2.64 - 2.61 (m, 2H), 2.56 - 2.42 (in, 2H), 2.15 - 2.10 (m, 1.25H), 2.02 - 1.98 (in, 1.75H), 1.95 - 1.90 (in, IH), 1.68 - 1.60 (in, 8H), 1.54 - 1.46 (m, 15 6H). LC/MS: tR - 1.86 min, 614.28 (MH) 4 . (R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro- I H-indol-5-yl)-propionic acid methyl ester H
CO
2 Me N =<'- -NHCbz H 20 PyHBr 3 (1.28 g, 4.02 mmol) was added in small portions over 30 min to a solution of (R)-2-benzyloxycarbonylamino-3-(lH-indol-5-yl)-propionic acid methyl ester (0.47 g, 1.34 rnmol) in t-butanol (10 mL) while the reaction temperature was maintained between 25-30*C. The resulting mixture was stirred at room temperature WO 2005/065779 PCT/US2003/038799 139 for 3.5 h. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate (2x). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, solvents were removed and the residue was azeotropically dried with anhydrous ethanol. The residue was dissolved in glacial 5 acetic acid (10 mL) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred at room temperature overnight. After the acetic acid was removed in vacuo, the residue was purified by flash chromatography on silica gel using ethyl acetate/hexanes [(1:3) first and then (3:2)] as eluent to afford the title compound as a white solid (41% for 2 steps). IH-NMR (CDC1 3 , 500 MHz) 8 8.03 (s, 1H), 7.36 10 7.31 (in, 5H), 6.94 (s, IH), 6.91 (d, J 8.0 Hz, IH), 6.73 (d, J= 7.5 Hz, 1H), 5.26 (d, J = 8.0 Hz, IH), 5.11 (d, J= 12.0 Hz, lH), 5.05 (d, j = 12.5 Hz, lH), 4.61 (dd, J = 13.5, 6.0 hz, 1H), 3.72 (s, 3H), 3.45 (s, 2H), 3.10 (dd, J= 14.0, 5.5 Hz, lH), 3.00 (dd, J= 14.0, 6.0 Hz, IH). 1CNMR (CDCl 3 , 125 MHz) S 177.7, 172.2, 155.7, 141.7, 136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1, 55.1, 52.5, 38.0, 15 36. Mass spec. 369.20 (MH)+. (R)-2-Amino-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)-propionic acid methyl ester H 0 HNN C0 2 Me N - NH 2 H Prepared as described above for (R)-2-amino-3-(2-oxo-2,3-dihydro 20 benzooxazol-6-yl)-propionic acid methyl ester. 'H-NMR (CD 3 0D, 500 MHz) 8 8.48 (br s, 2H), 7.16 (s, 1 H), 7.10 (s, IH), 6.89 (s, IH), 4.21 (s, 1H), 3.81 (s, 3H), 3.54 (s, 1H), 3.33 (s, 2H), 3.20 (s, 1H), 3.12 (s, IH). "CNMR (CD 3 0D, 125 MHz) S 178.9, 170.7, 143.3, 129.0, 128.6, 126.9, 125.6, 110.0, 57.3, 54.6, 52.3, 37.0. Mass spec. 235.30 (MH)*. 25 (R)-3-(2-Oxo-2,3-dihydro-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin 3 -yl)-piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 140 H O
CO
2 Me NHN 0 H NH A solution of phosgene in toluene (2M, 0.158 mL, 0.30 mmol) was added to a vigorously stirred mixture of (R)- 2 -amino-3-(2-oxo-2,3-dihydro-1H-indol-5-yl) propionic acid methyl ester (70 mg, 0.25 mmol) in methylene chloride (15 mL) and 5 saturated sodium bicarbonate (7.5 mL). After the mixture was stirred at room temperature for 30 min, 3 -piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 h, diluted with ethyl acetate, and washed with 0.25 N hydrochloric acid that had been saturated with solid sodium chloride. The organic layers were dried over 10 sodium sulfate. After filtration, solvents were removed to afford the title compound as a tan viscous oil. LC/MS: tR = 2.01 min, 492.10 (MH)*. Example 50 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 15 [1,4']bipiperidinyl-l'-yl-2-oxo-1-( 2 -oxo-2,3-dihydro-IH-indol-5-ylmethyl)-ethyl] amide 0 MO N No HN N N
NH
WO 2005/065779 PCT/US2003/038799 141 Prepared as described above for (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2 trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl} -amide. Purified by flash chromatography on silica gel using methylene chloride/methanol/triethylamine 5 (93:5:2) as eluent. 'H-NMR (CD 3 0D, 500 MHz) 5 7.20 - 7.09 (in, 4H), 6.97 (t, J = 7.3 Hz, 1H), 6.88 (d, J 7.9 Hz, 0.65 H), 6.84 (d, J= 7.6 Hz, 0.35 H), 6.80 (d, J = 7.7 Hz, 1H), 5.51 (s, 0.65 H), 5.23 (s, 0.35 H), 4.99 - 4.95 (in, 0.65 H), 4.92 - 4.88 (m, 0.35 H), 4.60 - 4.56 (m, 1.65 H), 4.46 - 4.41 (m, 1.35 H), 4.39 (s, 1.3 H), 4.36 (s, 0.7 H), 4.24 - 4.17 (in, 2H), 4.05 - 4.02 (in, 1H), 3.65 - 3.61 (m, 2H), 3.52 - 3.47 (m, 10 1H), 3.20 - 3.16 (in, 1H), 3.00 - 2.88 (in, 2H), 2.70 - 2.64 (m, 2H), 2.53 - 2.46 (in, 211), 2.40 - 2.34 (in, 2H), 1.94 - 1.46 (in, 15H), 1.39 - 1.36 (in, 2H). LC/MS: tR 1.83 min, 628.40 (MH)+. 2-(Di-tert-butoxycarbonylamino)-acrylic acid methyl ester 0 0 Boc 2 N
OCH
3 + Boc 2 N
OCH
3 15 OBoc To a solution of 2-tert-butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (10.0 g, 39 mmol) and di-tert-butyl-dicarbonate (21.8 g, 2.6 equiv.) in acetonitrile (40 mL) was added 4-dimethylaminopyridine (0.48 g, 0.1 equiv) at room temperature. The solution was stirred overnight and concentrated. The residue was 20 dissolved in diethyl ether, washed sequentially with 1 M potassium hydrogen sulfate (2x), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give 15.6 g (quant.) as an oil. Inspection of the 1H NMR showed a mixture of the title compound and 2-(di-tert-butoxycarbonylamino)-3-tert butoxycarbonyloxy-propionic acid methyl ester. As it was later found that both react 25 with secondary amines to give the same products, the mixture was used without separation. 2-(Di-tert-butoxycarbonylamino)-acrylic acid methyl ester: 1 H-NMR (CDCl 3 ) 8 1.45 (s, 18H), 3.78 (s, 3H), 5.63 (s, 1H), 6.33 (s, 1H). Mass spec.: 324.14 (M+Na)+. 2-(Di-tert-butoxycarbonylamino)-3-tert-butoxycarbonyloxy-propionic acid methyl ester: 1 H-NMR (CDCl 3 , 500 MHz) 8 1.46 (s, 9H), 1.49 (s, 18H), 3.72 (s, WO 2005/065779 PCT/US2003/038799 142 3H), 4.42 (dd,J=11.6, 9.2, 1H), 4.75 (dd,J=11.3, 4.6, 1H), 5.30 (dd,J=9.2, 4.6, 1H). Mass spec.: 442.21 (M+Na) t . (+)-3-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-2-(di-tert-butoxycarbonylamino) 5 propionic acid methyl ester 0 Boc 2 N
OCH
3 N o To a solution of 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (900 mg, 3.0 mmol), and 4-benzyloxy-1 H-pyridin-2-one (630 mg, 1.03 equiv) in acetonitrile (2.5 mL) was added cesium carbonate (100 mg, 0.10 equiv). The 10 resulting suspension was heated to 80'C via microwave for 2 h. The reaction was concentrated, dissolved in water, and extracted with methylene chloride (3x). The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 1.47 g (97%) which was used without purification. Mass spec.: 503.56 (MH)+. 15 (±)-4-Benzyloxy-1-[3-[1,4']bipiperidinyl-1'-yl-2-(di-tert-butoxycarbonylamino)-3 oxo-propyl]-1H-pyridin-2-one 0 N (Boc)2N N /0 To a stirred solution of 3-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-(di-tert 20 butoxycarbonylamino)-propionic acid methyl ester (1.47 g, 2.9 mmol) in methanol (17 mL) was added a solution of lithium hydroxide monohydrate (0.50 g, 4 equiv) in water (2.85 mL). The reaction mixture was stirred for 3 h at room temperature, cooled to 0 0 C, treated with concentrated hydrochloric acid (0.99 mL), and WO 2005/065779 PCT/US2003/038799 143 concentrated to afford the crude acid, half of which was taken on in the following step. The crude acid was dissolved in methylene chloride (6 mL), cooled to 0 0 C and treated sequentially with 4-piperidyl-piperidine (0.25 g, 1 equiv), triethylamine (0.31 mL, 2.5 equiv), and bis-2-oxo-3-oxazolidinyl)phoshinic chloride (0.38 g, I equiv). 5 The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated, and purified by Prep HPLC to afford 489 mg (52%, 2 steps). Mass spec.: 639.41 (MH)*. Example 51 10 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4 benzyloxy-2-oxo-2H pyridin-1-ylmethyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl] amide H C N YO N N Nk aNI N 0 b To a stirred solution of 4-benzyloxy-1-[3-[1,4']bipiperidinyl-1'-yl-2-(di-tert 15 butoxycarbonylamino)-3-oxo-propyl]-1 H-pyridin-2-one in methylene chloride (3 mL) was added trifluoroacetic acid (1 mL) at 0 0 C. After 2 h, the reaction was concentrated to afford the crude amine (151 mg, 97%) as its trifluoroacetic acid salt [Mass spec.: 439.61 (MH)*] which was split into two portions, using half in the following procedure. To a solution of the crude amine (75 mg, 0.11 mmol) and 20 diisopropylethylamine (80 .tL, 4 equiv) in methylene chloride (3 mL) at 0 0 C was added carbonyl diimidazole (29 mg, 1.6 equiv, in 2 portions). After stirring for 10 min, the solution was treated with 3-piperidin-4-yl-3,4-dihydro-IH-quinazolin-2 acetic acid (40 mg, 1.15 equiv). The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep TLC to give WO 2005/065779 PCT/US2003/038799 144 40.8 mg (53%). 'IH-NMR (CD 3 0D, 500 MHz) 8 1.25-1.56 (m, 4H), 1.56-1.84 (m, 9H), 1.90-2.08 (m, 2H), 2.60-2.95 (m, 8H), 3.11 (dd, J=24.1, 12.8, 1H), 3.89 (ddd, J=22.0, 13.2, 9.2, 1H), 4.10 (dd, J=14.3, 14.1, 2H), 4.27-4.54 (m, 5H), 4.60 (bd, J=11.9, 1H), 5.08 (dd, J=13.2, 12.2, 2H), 5.26 (ddd, J=9.4, 9.4, 4.8, 1 H), 6.05 (dd, 5 J=13.7, 2.7, 1H), 6.16 (m, 1H), 6.77 (d, J=8.0, 1H), 6.84 (ddd, J=7.6, 7.6, 2.1, 1H), 7.04 (d, J=z7.6, 1H), 7.12 (dd, J=7.6, 7.4, 1 H), 7.28-7.43 (in, 5H), 7.48 (d, J=7.6, 1H). Mass spec.: 696.85 (MH)*. Example 52 10 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl)-2-oxo-ethyl] amide HH N N N N N OH A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 15 carboxylic acid [1-(4-benzyloxy-2-oxo-2H-pyridin-1-ylmethyl)-2-[1,4']bipiperidinyl l'-yl-2-oxo-ethyl]-amide (29 mg) and 10% palladium on charcoal (5 mg) in methanol (1 mL) was placed under an atmosphere of hydrogen. After 1 h at room temperature, the reaction was flushed with nitrogen, filtered through celite, and concentrated to give the product. 'H-NMR (CD 3 0D, 500 MHz) 8 1.40-1.85 (m, 12H), 2.04 (dd, 20 J=27.4, 17.0, 2H), 2.66 (dd, J=21.1, 11.0, 1H), 2.80-3.19 (m, 8H), 3.95 (ddd, J=49.8, 12.5, 7.9, 1H), 4.07-4.28 (m, 3H), 4.34 (bs, 2H), 4.36-4.59 (m, 2H), 4.63 (bd, J=12.8, 1H), 5.20 (m, 1H), 5.75 (dd, J=7.3, 2.1, 1H), 5.97 (dd, J=8.9, 7.6, 1 H), 6.78 (d, J=7.6, 1H), 6.93 (dd, J=7.6, 7.3, 1H), 7.08-7.18 (m, 2H), 7.33 (dd, J=18.3, 11.0, 1H). Mass spec.: 606.32 (MH)*. 25 WO 2005/065779 PCT/US2003/038799 145
(±)-
2 -(Di-tert-butoxycarbonylamino)-3-(4-hydroxy-piperidin- I -yl)-propionic acid methyl ester 0 Boc 2 N OMe N OH To a solution of 2 -(di-tert-butoxycarbonylamino)-acrylic acid methyl ester 5 (1.0 g, 3.0 mmol) in acetonitrile (10 mL) was added piperidin-4-ol (0.33 g, 1.1 equiv). A gentle stream of nitrogen was placed over the reaction while it stirred overnight. The crude oil which resulted was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.38 g (quant.) as an oil which was used without purification. Mass spec.: 403.42 (MH)*. 10 (±)-1-[1, 4 ']Bipiperidinyl-l'-yl- 2 -(di-tert-butoxycarbonylamino)-3-(4-hydroxy piperidin-I -yl)-propan-1-one 0 Boc 2 N NN HO N To a solution of 2 -(di-tert-butoxycarbonylamino)-3-(4-hydroxy-piperidin- 1 15 yl)-propionic acid methyl ester (1.0 g, 2.5 mmol) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (400 mg, 3.9 equiv) in water (1 mL). The reaction was stirred 6 h, cooled to 0 0 C, neutralized with concentrated hydrochloric acid, and concentrated. The crude acid was used without purification. The crude acid was suspended in methylene chloride (25 mL), treated with a few drops of 20 methanol to aid in dissolving the acid, and cooled to 0 0 C. The resulting suspension was treated sequentially with 4 -piperidyl-piperidine (0.53 g, 1.25 equiv), triethylamine (0.70 mL, 2. equiv), and bis- 2 -oxo-3-oxazolidinyl)phoshinic chloride (0.80 g, 1.25 equiv). The reaction was allowed to warm to room temperature overnight. The reaction was concentrated and then purified by Prep HPLC to afford 25 310 mg (23%, 2 steps). Mass spec.: 539.49 (MH)+.
WO 2005/065779 PCT/US2003/038799 146 (4)-2-Amino- -[1,4']bipiperidinyl-1'-yl-3-(4-hydroxy-piperidin- 1 -yl)-propan- 1-one 0
H
2 N N HO N N HOO To a solution of 1-[1,4']bipiperidinyl-l'-yl-2-(di-tert-butoxycarbonylamino) 3-(4-hydroxy-piperidin- 1 -yl)-propan-1-one (310 mg, 0.58 mmol) in methylene 5 chloride (5 mL) at 0 0 C was added trifluoroacetic acid (2.0 mL). The ice bath was removed and the reaction stirred for 30 min. The reaction was concentrated to afford the product as its trifluoroacetic acid salt (400 mg, quant.) which was used without purification. Mass spec.: 339.46 (MH)*. 10 (±)- [2-[1,4']Bipiperidinyl-l'-yl-l-(4-hydroxy-piperidin-1-ylmethyl)-2-oxo-ethyl] carbamic acid tert-butyl ester 0 BocHN N HO N N HOJ: To a solution 2-amino- 1-[1,4']bipiperidinyl- l'-yl-3-(4-hydroxy-piperidin- 1 yl)-propan-1-one (trifluoroacetic acid salt, 300 mg, 0.58 mmol) and 15 diisopropylethylamine (0.30 mL, 4 equiv) in tetrahydrofuran (5 mL) was added di tert-butyl-dicarbonate (128 mg, I equiv). The resulting solution was stirred at room temperature for I h, and concentrated. The residue was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to afford to 248 mg (98%) which was used without purification. Mass spec.: 439.65 20 (MH)*. (±)- [2-[1,4']Bipiperidinyl-1'-yl-2-oxo-1-(4-oxo-piperidin-1-ylmethyl)-ethyl] carbamic acid tert-butyl ester WO 2005/065779 PCT/US2003/038799 147 0 BocHN N O N N To a solution of 1-[1,4']bipiperidinyl- l'-yl-2-(di-tert-butoxycarbonylamino)-3-(4 hydroxy-piperidin-1-yl)-propan-1-one (200 mg, 0.37 mmol) in methylene chloride (4 mL) was added Dess-Martin periodinane (316 mg, 2 equiv) in two portions. After 1 5 h, the reaction was quenched by the addition of saturated sodium bicarbonate, and extracted into methylene chloride (3x). The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 187 mg (94%) which was used without purification. Mass spec.: 437.63 (MH)*. 10 (+)-1-(2-Amino-3-[1,4']bipiperidinyl-l'-yl-3-oxo-propyl)-piperidin-4-one 0
H
2 N N o N N To a solution of [2-[1,4']bipiperidinyl-l'-yI-2-oxo-1-(4-oxo-piperidin-1 ylmethyl)-ethyl]-carbamic acid tert-butyl ester (100 mg, 0.23 mmol) in methylene chloride (5 mL) at 0 0 C was added trifluoroacetic acid. The ice bath was removed, 15 stirring continued for 1 h, and the reaction concentrated to give 150 mg (96%) as its trifluoroacetic acid salt which was used without purification. Mass spec.: 337.64 (MH)*. Example 53 20 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(4-hydroxy-piperidin-1-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 148 H NO N N O N N OH To a solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-l-(4-hydroxy-piperidin-1-ylmethyl)-2 oxo-ethyl]-amide (3 trifluoroacetic acid salt, 200 mg, 0.39 mmol) in methylene 5 chloride (5 mL) at 0 0 C was added diisopropylethylamine (0.27 mL, 3.9 equiv), and carbonyl diimidazole (63 mg, 1 equiv). After stirring for 15 min, the solution was treated with 3-piperidin-4-yl-3,4-dihydro- 1 H-quinazolin-2-one (acetic acid salt, 142 mg, 1.25 equiv). The solution was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by Prep TLC to give 130 mg 10 (56%) as an oil. LC/MS: tR:= 1.17 min, 596.44 (MH)*. 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester 0 O N Me 2 N 15 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (10 g, 50 mmol) was dissolved in dimethyl formamide dimethylacetal (50 mL) and heated to reflux for 1.25 h. The solution was cooled, concentrated, and purified by flash chromatography to give 2.55 g (19%). Mass spec.: 255.16 (MH)+. 20 1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 0 O N NH
N
WO 2005/065779 PCT/US2003/038799 149 To a solution of 3 -dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). The solution was heated to reflux, immediately allowed to cool to room temperature, and concentrated to give 1.4 g (63%) which was 5 used without purification. Mass spec.: 224.11 (MH)*. 4,5,6,7-Tetrahydro- 1 H-pyrazolo[4,3-c]pyridine HN NH _N 1, 4
,
6
,
7 -Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 10 (0.70 g, 3.1 mmol) was dissolved in trifluoroacetic acid (10 mL) at 0 0 C, stirred for 1 h, and was concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-hydrochloride salt precipitated out as a white solid which was filtered to give 510 mg (83%). The free base was prepared as needed by dissolving the salt in water, loading it onto an SCX column, flushing 15 with methanol, and then eluting with 2 M ammonia in methanol.
(±)-
2 -(Di-tert-butoxycarbonylamino)-3-(1, 4
,
6
,
7 -tetrahydro-pyrazolo[4,3-c]pyridin-5 yl)-propionic acid methyl ester 0 Boc 2 N We N NH N 20 To a solution of 4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (160 mg) in 2.5 mL methanol was added 2 -(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (400 mg). The reaction was concentrated to approximately 1.5 mL by application of a gentle stream of nitrogen. The solution was stirred at room temperature overnight. The reaction was concentrated, dissolved in ethyl acetate, 25 washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was pure enough to use without purification. 1 H-NMR (CDCl 3 , 500 MHz) S 1.44 (s, 9H), 2.73 (m, 3H), 2.91 (m, lH), 3.06 (dd, J=13.4, 8.6, IH), 3.22 (dd, WO 2005/065779 PCT/US2003/038799 150 J=13.4, 8.2, 11-1), 3.54 (d,J=13.4, lH), 3.63 (d,J=13.4, 1H), 3.71 (s, 3H), 5.11 (dd, J=8.5, 5.2, 1H), 7.25 (s, IH). Mass spec.: 425.23 (MH)*. (±)-2-Amino-3-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid 5 methyl ester 0
H
2 N OMe N NH N To a solution of 2-(di-tert-butoxycarbonylamino)-3-(1,4,6,7-tetrahydro pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.55 g, 1 equiv.) in methylene chloride (5 mL, O 0 C) was added trifluoroacetic acid (1.5 mL). The ice 10 bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and passed onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2 M ammonia in methanol to afford the product as its free base (275 mg, 95%). 'H-NMR (CDCl 3 , 500 MHz) 5 2.71 (dd, J=12.8, 8.6, lH), 2.74-2.91 (in, 6H), 3.48 (s, 15 2H), 3.54 (d, J=13.4, 1H), 3.62 (d, J=13.4, IH), 3.69 (dd, J=8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spec.: 225.16 (MH)*. 3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester 0 O N 0 20 To a solution of 4-oxo-piperidine-I -carboxylic acid tert-butyl ester (16 g, 80 mmol) in tetrahydrofuran (400 mL) at 0'C was added sodium hydride (4.1 g, 2.1 equiv) in 4 portions. To this was added iodomethane (12.5 mL, 2.5 equiv) dropwise. The reaction was allowed to gradually warm to room temperature and stirred overnight. The reaction was concentrated, dissolved in diethyl ether, washed with 25 brine, dried over magnesium sulfate, and concentrated. The product was crystallized from hot pentane (2X) to give 5.9 g (32%). 'H-NMR (CDCl 3 , 500 MHz) 8 1.09 (s, WO 2005/065779 PCT/US2003/038799 151 6H), 1.47 (s, 9H), 2.47 (dd, J=6.4, 6.4, 2H), 3.41 (m, 2H), 3.70 (in, 2H). Mass spec.: 250.12 (M+Na)*. 5-Dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert 5 butyl ester 0 O N 0 Me 2 N 3,3-Dimethyl-4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (5 g, 22 mmol) was dissolved in dimethyl formamide dimethylacetal (25 mL) and heated at reflux for 2 h. The reaction mixture was then heated to 130'C for 1 h via microwave, 10 and concentrated to give 6.43 g (quant.) as an oil which used without purification. 'H-NMR (CDCl 3 , 500 MHz) 5 1.07 (s, 6H), 1.45 (s, 9H), 3.06 (s, 6H), 3.37 (in, 2H), 4.57 (m, 2H), 7.41 (bs, 1H). 7,7-Dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl 15 ester O N NH N To a solution of 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1 carboxylic acid tert-butyl ester (6.35 g, 22 mmol) in methanol (15 mL) was added hydrazine hydrate (1.2 mL, 1.1 equiv). The solution was stirred at room temperature 20 overnight and concentrated to give 5.3 g (94%) which was used without purification. Mass spec.: 252.19 (MH)*. 7,7-Dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine H N NH
N
WO 2005/065779 PCT/US2003/038799 152 To a solution of 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5 carboxylic acid tert-butyl ester (5.3 g, 21 mmol) in methylene chloride (10 mL) at 0 0 C was added trifluoroacetic acid (5 mL). The reaction was allowed to warm to room temperature, stirred 15 min, and treated with additional trifluoroacetic acid (5 5 mL). After I h, the reaction was concentrated, dissolved in ethanol (10 mL), cooled to 0*C, treated with concentrated hydrochloric acid (3 mL), and concentrated. The resulting solid was triturated with ethanol, and filtered to give 3.02 g (64%) as its bis hydrochloride salt. The free base was prepared as needed by dissolving the salt in water, loading it onto an SCX column, flushing with methanol, and then eluting with 10 2M ammonia in methanol. 1 H-NMR (D 2 0, 500 MHz) 5 1.49 (s, 6H), 3.46 (s, 2H), 4.39 (s, 2H), 7.86 (s, 1H). Mass spec.: 152.14 (MH)+. (d)-2-(Di-tert-butoxycarbonylamino)- 3-(7,7-dimethyl-1,4,6,7-tetrahydro pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester 0 Boc 2 N OMe N NH 15 N To a solution of 7,7-dimethyl-4,5,6,7-tetrahydro-IH-pyrazolo[4,3-c]pyridine (160 mg) in methanol (3 mL) was added 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (331 mg). A gentle stream of nitrogen was applied and the reaction stirred overnight. In the morning, the volume was greatly reduced. The last traces of 20 solvent were removed under high vacuum to give 490mg (quant.) which was used without purification. 'H-NMR (CDCl 3 , 500 MHz) 8 1.24 (s, 3H), 1.26 (s, 3H), 1.38 (s, 18H), 2.33 (d, J=11.3, 1H), 2.57 (d, J=11.3, 1 H), 3.09 (dd, J=13.1, 5.5, 1H), 3.15 (dd, J=13.4, 9.5, 11), 3.35 (d, J=12.8, IH), 3.57 (d, J=12.8, 1H), 3.68 (s, 3H), 5.13 (dd, J=9.5, 3.7, 1H), 7.16 (s, 1H). Mass spec.: 453.30 (MH)*. 25 ( )-2-Amino-3 -(7,7-dimethyl- 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl) propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 153 0
H
2 N OMe N NH N To a solution of 2 -(di-tert-butoxycarbonylamino)- 3-(7,7-dimethyl-1,4,6,7 tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.49 g, 1 equiv) in methylene chloride (5 mL, O'C) was added trifluoroacetic acid (1.5 mL). The ice 5 bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and loaded onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2M ammonia in methanol to afford the product as its free base (250 mg, 94%). 1 H-NMR (CDC 3 , 500 MHz) 5 1.27 (s, 3H), 1.28 (s, 3H), 2.41 (d, J= 11.3, 1H), 2.50 10 (d, J= 11.3, 1H), 2.69 (dd, J=12.5, 7.9, 1H), 2.82 (dd, J=12.5, 5.2, 1H), 3.45 (d, J=12.8, 1H), 3.52 (d, J=12.8, 1H), 3.67 (m, 1H), 3.69 (s, 3H), 7.19 (s, IH). Mass spec.: 253.16 (MH)*. (±)-2- {[4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carbonyl]-amino} -3 15 (1, 4
,
6 ,7-tetrahydro-pyrazolo[4, 3 -c]pyridin-5-yl)-propionic acid methyl ester H NN O e NH 0 ,N NH 0 N N H N To a solution of 2-amino-3-(1, 4
,
6
,
7 -tetrahydro-pyrazolo[4,3-c]pyridin-5-yl) propionic acid methyl ester (260 mg, 1 equiv) in methylene chloride (2 mL, O'C) was added carbonyl diimidazole (188 mg, I equiv). After 15 min, 3-piperidin-4-yl-3,4 20 dihydro- 1 H-quinazolin-2-one (295 mg, 1.1 equiv) was added in one portion. The ice bath was removed and stirring continued overnight. The reaction was concentrated and purified by column chromatography to give 118 mg (21%). 'H-NMR (CDCl 3 , 500 MHz) 8 1.60-1.80 (in, 4H), 2.70-3.05 (m, 8H), 3.45 (s, 2H), 3.56 (d, J=13.4, WO 2005/065779 PCT/US2003/038799 154 1H), 3.62 (d, J=13.4, 1H), 3.75 (s, 3H), 4.02 (d, J=13.1, IH), 4.10 (d, J=12.5, 1H), 4.24 (s, 2H), 4.45-4.57 (m, 2H), 5.79 (bs, 1H), 6.68 (d, J=7.94, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 7.00 (d, J=7.3, 1H), 7.13 (dd, J=7.6, 7.3, 1H), 7.25 (s, 1H), 7.82 (s, 1H). Mass spec.: 482.27 (MH)*. 5 Example 54 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-2-oxo-1-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5 ylmethyl)-ethyl]-amide N N N N 10 N To a solution of 2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 carbonyl]-amino} -3-(1,4,6,7-tetrahydro-pyrazolo [4,3-c]pyridin-5-yl)-propionic acid methyl ester (16 mg, 1 equiv) in methanol (0.6 mL) was added lithium hydroxide monohydrate (3 mg, 2.2 equiv) in water (0.1 mL) and stirred for 4 h at room 15 temperature. The solution was cooled to 0 0 C, treated with aqueous I M potassium hydrogen sulfate (60 p1, 1.8 equiv), and concentrated to give the crude acid which was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (11 mg, 2 equiv), diisopropylethylamine (12 RL, 2 20 equiv), and PyBOP* (19 mg, 1.1 equiv). The solution was stirred 30 min and concentrated. The product was purified by column chromatography to give 17.6 mg (85%, 2 steps). 'H-NMR (CDC 3 , 500 MHz) 8 1.30-1.60 (m, 9H), 1.62-1.78 (in, 5H), 1.81 (bd, J=11.0, 2H), 2.23-2.49 (in, 6H), 2.55-3.10 (m, 1 1H), 3.59 (d, J=7.3, 2H), 4.00-4.20 (in, 3H), 4.23 (s, 2H), 4.50 (m, 1H), 4.63 (m, IH), 5.03 (m, IH), 5.71 (d, 25 J=7.3, 1H), 6.67 (d, J=7.9, 1H), 6.91 (dd, J=7.6, 7.3, 1 H), 7.02 (dd, J=7.9, 7.3, 1H), WO 2005/065779 PCT/US2003/038799 155 7.14 (dd, J=7.6, 7.6, IH), 7.24 (s, IH), 7.39 (s, 1H), 10.76 (bs, 1H). Mass spec.: 618.34 (MH)*. Example 55 5 (±)-3-(7,7-Dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-{ [4-(2-oxo 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carbonyl] -amino} -propionic acid methyl ester H NOe NN OMe 0 N NH N To a solution of 2-amino-3-(7,7-dimethyl- 1,4,6,7-tetrahydro-pyrazolo[4,3 10 c]pyridin-5-yl)-propionic acid methyl ester (250 mg, 1 equiv) in tetrahydrofuran (4 mL, 0*C) was added carbonyl diimidazole (162 mg, 1 equiv). After 5 min, the ice bath was removed and the reaction stirred at room temperature for 30 min. To this was added 3-piperidin-4-yl-3,4-dihydro-IH-quinazolin-2-one (250 mg, 1.1 equiv) in one portion, and the reaction stirred overnight. The reaction was concentrated and 15 purified by column chromatography to give 228 mg (45%). 'H-NMR (CDC1 3 , 500 MHz) 8 1.30 (s, 3H), 1.31 (s, 3H), 1:60-1.80 (in, 4H), 2.43 (d, J= 11.6, 1H), 2.53 (d, J=11.3, 1H), 2.80-2.95 (in, 4H), 3.51 (dd, J=20.4, 13.1, 2H), 3.74 (s, 3H), 4.00 (d, J=1 3.7, 1H), 4.10 (d, J=12.2, 1H), 4.25 (dd, J=16.2, 14.4, 2H), 4.86 (m, 2H), 6.66 (d, J=7.6, 1H), 6.92 (dd, J=7.6, 7.3, 1H), 7.02 (d, J=7.3, 1H), 7.14 (dd, J=7.6, 7.6, 20 1H), 7.24 (s, IH). Mass spec.: 510.27 (MH)+. Example 56 (+)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-1-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5 25 ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 156 H N N N H N N N N N Nq H To a solution of 3-(7,7-dimethyl-1, 4 ,6, 7 -tetrahydro-pyrazolo[4,3-c]pyridin-5 yl)-2-{ [ 4 -(2-oxo- 1, 4 -dihydro-2H-quinazolin-3-yl)-piperidine- I -carbonyl]-amino} propionic acid methyl ester (20 mg, 1.0 equiv) in methanol (0.6 mL) was added 5 lithium hydroxide monohydrate (4 mg, 2.2 equiv) in water (0.1 mL) and stirred for 4 h at room temperature. The solution was cooled to 0"C, treated with aqueous IM potassium hydrogen sulfate (75 sl, 1.8 equiv), and concentrated to give the crude acid which was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride 10 (0.15 mL), 4-piperidyl-piperidine (13 mg, 2 equiv), diisopropylethylamine (14 gL, 2 equiv), and PyBOP* (22 mg, 1.1 equiv). The solution was stirred 1.5 h and concentrated. The product was purified by column chromatography to give a product which was tainted with HOBT. The HOBT was removed by passing the product through a plug of basic alumina, eluting with 10% methanol in methylene chloride. 15 Concentration gave 18.3 mg (72%, 2 steps). 'H-NMR (CDC 3 , 500 MHz) 6 1.25-1.32 (m, 6H), 1.40 (m, 4H), 1.54 (in, 5H), 1.65 (m, 4H), 1.83 (m, 2H), 2.30-2.56 (m, 8H), 2.81 (m, 4H), 3.04 (dt, J=57.1, 12.2, lH), 3.43-3.60 (in, 2H), 4.00-4.17 (m, 2H), 4.18-4.26 (m, 3H), 4.49 (in, 1 H), 4.62 (in, 1H), 5.03 (in, IH), 5.80 (dd, J=16.8, 9.8, 1H), 6.69 (d, J=7.9, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 6.99 (dd, J=7.6, 7.3, 1H), 7.13 20 (dd, J=7.6, 7.6, 1H), 7.19 (s, lH), 7.66 (bd, J=12.8, 1H). Mass spec.: 646.43 (MH)+. 2 -Benzyloxycarbonylamino-3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester
CO
2 Me CBZHN N N / OMe WO 2005/065779 PCT/US2003/038799 157 To a suspension of potassium tert-butoxide (1.23 g, 1.5 equiv) in methylene chloride (70 mL, -20*C) was added a solution of N-benzyloxycarbonyl-a phosphonoglycine trimethyl ester (3.63 g, 1.5 equiv) in methylene chloride (15 mL). The resulting solution was stirred 5 min and treated with the 6-methoxy-pyridine-3 5 carbaldehyde (1.0 g, 7.3 mmol) in methylene chloride (15 mL). After stirring for 1.5 h, the reaction was warmed to 0 0 C and stirred I h. The reaction was quickly poured into a separatory funnel containing ethyl acetate and water. Brine was added to aid in separation of the layers. The aqueous was extracted with ethyl acetate (3x) which were in turn washed with brine, dried over magnesium sulfate, and concentrated to 10 give 2.63 g (quant.) which was used without purification. Mass spec.: 343.08 (MH)*. (+)-2-Amino-3-(6-methoxy-pyridin-3-yl)-propionic acid methyl ester
CO
2 Me
H
2 N N / OMe A flask containing 2-benzyloxycarbonylamino-3-(6-methoxy-pyridin-3-yl) 15 acrylic acid methyl ester (620 mg), palladium on charcoal (10%, 100 mg), ethyl acetate (10 mL) and methanol (20 mL) was flushed with nitrogen, then hydrogen, before finally affixing a balloon of hydrogen. The reaction was allowed to stir overnight. The flask was flushed with nitrogen, filtered through celite, and concentrated to give 390 mg (quant.) which was used without purification. Mass 20 spec.: 211.11 (MH)*. (±)-3-(6-Methoxy-pyridin-3-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl) piperidine-1-carbonyll-amino}-propionic acid methyl ester H N 0 H N N CO 2 Me 0 N OMe WO 2005/065779 PCT/US2003/038799 158 To a solution of 2-amino-3-(6-methoxy-pyridin-3-yl)-propionic acid methyl ester (130 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, 0 0 C) was added N,N'-disuccinimidyl carbonate (158 mg). After 30 min, 3-piperidin 4-yl-3,4-dihydro-1H-quinazolin-2-one (120 mg) in methylene chloride (1 mL) was 5 added via canula. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep HPLC to give 160mg (55%). Mass spec.: 468.19 (MH)*. Example 57 10 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(6-methoxy-pyridin-3-ylmethyl)-2-oxo-ethyl]-amide H N N N N OMe To a solution of 3-(6-methoxy-pyridin-3-yi)-2- {[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -propionic acid methyl ester (160 15 mg) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (29 mg) in water (1 mL). The reaction was stirred at room temperature for 4 h and cooled to 0 0 C. The reaction was treated with IN hydrochloric acid (0.6 mL), concentrated. The residue obtained was dissolved in methylene chloride (5 mL), and treated sequentially with 4-piperidyl-piperidine (75 mg), triethylamine (0.14 mL), 20 and bis-2-oxo-3-oxazolidinyl)phoshinic chloride (104 mg). The reaction was stirred overnight, concentrated, and purified by prep HPLC to give 94 mg (45%). LC/MS: tR 1.86 min, 604.51 (MH)*. 2-Benzyloxycarbonylamino-3-(2-methoxy-pyrimidin-5-yl)-acrylic acid methyl ester WO 2005/065779 PCT/US2003/038799 159
CO
2 Me CBZHN N N OMe To a suspension of potassium t-butoxide (1.23 g) in methylene chloride (70 mL, -30'C) was added a solution of N-benzyloxycarbonyl-ac-phosphonoglycine trimethyl ester (3.63 g) in methylene chloride (15 mL). The resulting solution was 5 stirred 5 mm and treated with the 2-methoxy-pyrimidine-5-carbaldehyde (1.0 g) in methylene chloride (15 mL). After stirring for 1.5 h, the reaction was warmed to 0*C and stirred 1 h. The reaction was quickly poured into a sep funnel containing ethyl acetate and water. Brine was added to aid in separation of the layers. The aqueous was extracted with ethyl acetate (3X) which were in turn washed with brine, dried 10 over magnesium sulfate, and concentrated. The crude product was recrystallized from hot methanol to give 1.4g of pure material. Mass spec.: 344.10 (MH)*. ( )-2-Amino-3-(2-methoxy-pyrimidin-5-yl)-propionic acid methyl ester
CO
2 Me
H
2 N N ,-N OMe 15 A flask containing amino ester (700 mg), palladium on charcoal (10%, 100 mg) and methanol (20 mL) was flushed with nitrogen, then hydrogen, before finally affixing a balloon of hydrogen. The reaction was allowed to stir overnight. The flask was flushed with nitrogen, filtered through celite, and concentrated to give 379 mg (88%) which was used without purification. Mass spec.: 212.08 (MH)*. 20 (+)-3-(2-Methoxy-pyrimidin-5-yl)-2- {[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 160 H N "r0 H N N CO 2 Me 0 N N OMe To a solution of 2-Amino-3-(2-methoxy-pyrimidin-5-yl)-propionic acid methyl ester (125 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, OC) was added N,N'-disuccinimidyl carbonate (155 mg). After 30 min, 3 5 piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (120 mg) in methylene chloride (2 mL) was added via canula. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep HPLC to give 99mg (36%). Mass spec.: 469.10 (MH)+. 10 Example 58 (±)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(2-methoxy-pyrimidin-5-ylmethyl)-2-oxo-ethyl]-amide H ~O N ~H0 N O N N N N OMe To a solution of 3-(2-methoxy-pyrimidin-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H 15 quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (99 mg) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (18 mg) in water (1 mL). The reaction was stirred at room temperature for 4 h and cooled to 0 0 C. The reaction was treated with IN hydrochloric acid (0.4 mL), concentrated. The residue obtained was dissolved in methylene chloride (3 mL), and treated 20 sequentially with 4-piperidyl-piperidine (50 mg), triethylamine (88 gL), and bis-2 oxo-3-oxazolidinyl)phoshinic chloride (71 mg). The reaction was stirred overnight, WO 2005/065779 PCT/US2003/038799 161 concentrated, and purified by prep HPLC to give 103 mg (45%). LCIMS: t R 1.23 min, 605.54 (MH)*. 2-Benzyloxy-5-bromo-pyridine Br o 5N A suspension of 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-1 8-crown-6 (0.14 g, .05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide (1.1 g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in 10 water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85%) which was used without purification. Mass spec.: 264.25 (MH)*. 6-Benzyloxy-pyridine-3-carbaldehyde N. 0 15 To a solution of 2-benzyloxy-5-bromo-pyridine (1.64 g, 6.2 mmol) in tetrahydrofuran (25 mL, -78'C) was added n-butyllithium (2.5 M in hexane, 2.61 mL, 1.05 equiv). After 1 h at -78'C, dimethylformamide (0.97 mL, 2 equiv) was added and the mixture stirred for 30 min. The reaction was quickly poured into a stirred 20 solution of 5% aqueous sodium bicarbonate (50 mL) and extracted with diethyl ether (3x). The ethereal was washed with brine, dried over magnesium sulfate, and concentrated to give 1.16 g (quant.) which was used without purification. Mass spec.: 186.34 (MH)+. 25 2-Benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-acrylic acid methyl ester WO 2005/065779 PCT/US2003/038799 162 0 HN
CO
2 Me N To a stirred suspension of potassium tert-butoxide (0.440 g, 1.7 equiv) in methylene chloride (25 mL) at -20 9 C was added N-benzyloxycarbonyl-ax phosphonoglycine trimethyl ester (1.3 g, 1.7 equiv) in methylene chloride (5 mL). 5 The resulting solution was stirred for 5 min and treated with the 6-benzyloxy pyridine-3-carbaldehyde (0.49 g, 2.28 mmol) in methylene chloride (5 mL). The reaction was stirred at -20'C for 1 h, allowed to gradually warm to 0 0 C, and poured into a separatory funnel containing water and diethyl ether. The reaction was extracted with diethyl ether (2x), washed with brine, dried over magnesium sulfate, 10 and concentrated to give 0.98 g (quant.) as an oil which was used without purification. Mass spec.: 419.32 (MH)*. ( )-2-Benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester 0 HN
CO
2 Me
N
15 A flask was charged with 2-benzyloxycarbonylamino-3-(6-benzyloxy pyridin-3-yl)-acrylic acid methyl ester (0.50 g, 1.2 mmol), Wilkinson's catalyst (200 mg, 0.2 equiv), methanol (5 mL), and toluene (3 mL). The flask was flushed with nitrogen, then hydrogen, heated to 35'C, and allowed to stir under an atmosphere of WO 2005/065779 PCT/US2003/038799 163 hydrogen for 4 days. The reaction was flushed with nitrogen, diluted with methanol, filtered, and concentrated to afford the crude product which was purified by column chromatography to give 145 mg (29%). 5 (±)-2-Amino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester
H
2 N
CO
2 Me
N
To a stirred solution of 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3 yl)-propionic acid methyl ester (130 mg, 0.31 mmol) in methylene chloride (5 mL, 0 0 C) was added trimethylsilyl iodide (44 gL, 1.0 equiv). The ice bath was removed 10 and stirring continued for I h. Reaction was poured into saturated sodium bicarbonate, extracted with ethyl acetate (3x), washed with brine, dried over magnesium sulfate, and concentrated to give 81mg (91%) which was used without purification. Mass spec.: 287.37 (MH)+. 15 (±)-3-(6-Benzyloxy-pyridin-3-yl)-2- {[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl] -amino} -propionic acid methyl ester H N N
OCH
3 0 " O N' 0 N 0 To a stirred solution of 2-amino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester (60 mg, 0.21 mmol) in methylene chloride (1 mL, 0*C) was added 20 carbonyl diimidazole (34 mg, 1.0 equiv.). After 15 min, a solution of 3-piperidin-4 yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 1.2 equiv.) in methylene chloride (0.5 mL) was added via canula. The ice bath was removed and stirring continued WO 2005/065779 PCT/US2003/038799 164 overnight. The reaction was concentrated and purified by column chromatography to give 59 mg (52%). Mass spec.: 544.49 (MH)'. Example 59 5 (±)-4-(2-Oxo-1, 4 -dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(6 benzyloxy-pyridin-3-ylmethyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide H N 0 N N N N 0 NC N O To a stirred solution of 3-(6-benzyloxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidine- -carbonyl]-amino} -propionic acid methyl 10 ester (59 mg, 0.11 mmol) in methanol (3 mL) was added a solution of lithium hydroxide monohydrate (9.1 mg, 2 equiv) in water (0.5 mL). The reaction was stirred 2 h at room temperature, cooled to 0*C, quenched by addition of IN hydrochloric acid (0.15 mL), and concentrated. The crude product was used without purification. The crude acid was dissolved in methylene chloride (2 mL, OC), and 15 treated sequentially with 4 -piperidino-piperidine (34 mg, 1.8 equiv), triethylamine (35 gL, 2.3 equiv.), and bis-2-oxo-3-oxazolidinyl)phoshinic chloride (34 mg, 1.2 equiv). The ice bath was removed and the reaction allowed to stir overnight. The reaction was concentrated and purified by Prep TLC to give 30.3 mg (41%). LC/MS: tR = 1.49 min, 680.29 (MH)*. 20 Example 60 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-2-oxo-1-(6-oxo-1, 6 -dihydro-pyridin-3-ylmethyl)-ethyl) amide WO 2005/065779 PCT/US2003/038799 165 H N -f 0 N N N N N 0 H A flask was charged with 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carboxylic acid [1-(6-benzyloxy-pyridin-3-ylmethyl)-2 [1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide (27 mg, 0.04 mmol), palladium on 5 charcoal (10%, 4 mg), and methanol (1 mL). The flask was flushed with nitrogen, then hydrogen, and allowed to stir under an atmosphere of hydrogen overnight. The flask was flushed with nitrogen, and the reaction filtered through celite to give 22.1 mg (94%). LC/MS: tR 0.93 min, 590.32 (MH)+. 10 Piperidine-1,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester oo N To a solution of ethyl isonipecotate (5.00 g, 0.032 mol) and triethylamine (4.9 mL, 0.035 mmol) in dichloromethane (25 mL) at 0 0 C was slowly added a solution of di-tert-butyldicarbonate (7.2 g, 0.033 mol) in dichloromethane (25 mL). The reaction 15 mixture was stirred at room temperature overnight, then washed with potassium hydrogen sulfate three times and with brine once. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give the desired product (8.23 g, 100%) as colorless oil. 1H NMR (C 6
D
6 , 500 MHz) S 3.88 (q, J= 7.5 Hz, 2H), 2.52 (in, I H), 1.60-1.48 (in, 8H), 1.42 (s, 9H), 0.92 (t, 3H). Mass spec.: 20 280.44 (M+Na)*. 4-(2-Nitro-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester WO 2005/065779 PCT/US2003/038799 166 0 N02 N O ko To a solution of piperidine- 1,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester (8.23 g, 0.032 mol) in tetrahydrofuran (85 nL) was slowly added a solution of sodium bis(trimethylsilyl)amide (44 mL, 0.044 mol). After the resulting mixture had 5 been stirred at -78'C for 1 h, a solution of 2-nitrobenzyl bromide (8.21 g, 0.038 mol) was added. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. It was then concentrated and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The 10 final product was purified from the complex reaction mixture by way of column chromatography on silica gel (eluent - hexanes - ethyl acetate 4:1) to give the desired product (1.61 g, 13%) as brown oil. Mass spec.: 415.38 (M+Na)+. 4-(2-Amino-benzyl)-piperidine- 1,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester 0
NH
2 N 15 A mixture of 4-(2-nitro-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.61 g, 4.102 mmol) and 10% palladium on charcoal (0.10 g) in ethanol (190 mL) was hydrogenated at 50 psi overnight. The resultant mixture was filtered through a plug of celite, and the filtrate concentrated under vacuum to 20 provide the desired product (1.29 g, 99%) as colorless oil. Mass spec.: 363.45 (MH)*. 4-(2-Amino-benzyl)-piperidine-4-carboxylic acid ethyl ester hydrochloride WO 2005/065779 PCT/US2003/038799 167 0
NH
2 N H - HCI To a solution of 4-(2-amino-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert butyl ester 4-ethyl ester (1.29 g, 4.102 mmol) in dichloromethane (15 mL) was added a 4.OM solution of hydrogen chloride in dioxane (5 mL). The resulting solution was 5 stirred at room temperature overnight. The concentration of the solution under vacuum provided the title compound (1.23 g, 100%) as white solid, which was used in the next step without purification. Mass spec.: 263.40 (MH). 3,4-Benzo-2,9-diazaspiro[5.5]undeca- 1-one H N 0 HN 10 A solution of 4-(2-amino-benzyl)-piperidine-4-carboxylic acid ethyl ester hydrochloride (1.23 g, 4.102 mmol) was dissolved in methanol and the resulting solution was stirred at room temperature overnight. The solution was diluted by half with water and passed through a short plug of the hydroxide form of AG* 1-X2 ion 15 exchange resin (100-200 mesh), eluting with 50% aqueous methanol. The evaporation of the collected fractions gave the desired product (0.89 g, 100%) as white solid. 'H-NMR (CD 3 0D, 500 MHz) 8 7.23 (in, 2H), 7.05 (d, J= 7.5 Hz, 1H), 6.89 (d, J= 8.0 Hz, 1H), 3.46-3.41 (m, 2H), 3.34-3.30 (m, 2H), 2.14-2.09 (m, 2H), 1.73-1.67 (m, 4H). Mass spec.: 217.46 (MH) 4 . 20 (R)-2-Amino-3-benzo[b]thiophen-3-yl- 1-[1,4']bipiperidinyl- '-yl-propan- 1-one, dihydrochloride WO 2005/065779 PCT/US2003/038799 168 N N 0 NH 2 To a well stirred solution of 3-benzo[b]thiophen-3-yl-(2R)-2-tert butoxycarbonylamino-propionic acid (1.0 g, 3.1 mmol) in methylene chloride (30 mL) at room temp was added 4-piperidinopiperidine (573 mg, 3.4 mmol), 5 triethylamine (1.3 mL, 9.3 mmol) followed by 3-(diethoxyphosphoryloxy)-1,2,3 benzotriazin-4(3H)-one (1.02 g, 3.4 mmol). After 3 h, the reaction mixture was treated with aqueous sodium hydrogencarbonate (15 mL), brine (20 mL) and dried (sodium sulfate). The crude mixture was purified by flash chromatography using 5% methanol in methylene chloride to give (1 R)-1 -benzo[b]thiophen-3-ylmethyl-2 10 -[1,4']bipiperidinyl-l'-yl-2-oxo-ethyl)-carbamic acid tert-butylester in 82% yield. (1R)-1-Benzo[b]thiophen-3-ylmethyl-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl) carbamic acid tert-butylester (1.2 g, 2.54 mmol) in methylene chloride (5 mL) was added to a saturated solution of hydrogen chloride in dioxane (20 mL) and stirred for 2 h. The solvents were removed to give (2R)-2-amino-3-benzo[b]thiophen-3-yl-1 15 [1,4']bipiperidinyl- '-yl-propan- 1 -one,dihydrochloride in 98% yield. 1 H-NMR (500 MHz, CD 3 0D): 6 7.98 - 7.88 (in, 2 H), 7.55 - 7.40 (m, 3 H), 4.85 - 4.83 (m, 1 H), 3.66 - 2.68 (m, 9 H), 1.92 - 1.44 (m, 12 H). Mass spec.: 372 (MH)*. Example 61 20 (R)-1-Oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid (1-benzo [b] thiophen-3-ylmethyl-2-[1,4'] bipiperidinyl-l'-yl-2-oxo-ethyl)-amide ND NO S O NH NH 0 0 WO 2005/065779 PCT/US2003/038799 169 To a solution of 2 -amino-3-benzo[b]thiophen-3-yl-1-[1,4'] bipiperidinyl-l'-yl propan-1-one (50.0 mg, 0.135 mmol) in 1,2-dichloroethane (1.5 mL) were added N,N'-disuccinimidyl carbonate (34.6 mg, 0.135 mmol) and diisopropylethyl amine (0.09 mL, 0.500 mmol). The resulting solution was stirred for 1 h, at which point 3,4 5 benzo-2,9-diazaspiro[5.5]undeca-1-one (30.4 mg, 0.140 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated. The purification was achieved by way of reversed-phase preparative HPLC to give the desired product (75.5 mg, 77%) as brown oil. 'H-NMR (CD 3 0D, 500 MHz) 8 7.92 7.85 (m, 2H), 7.44-7.34 (m, 3H), 7.21-7.16 (in, 2H), 7.00 (t, J= 7.0 Hz, 1H), 6.86 (t, 10 J= 8.5 Hz, 1H), 5.15-5.02 (m, 1H), 4.72-4.45 (in, IH), 3.95-3.20 (m, 8H), 3.18-2.92 (m, 4H), 2.92-2.75 (m, 2H), 2.75-2.63 (m, 1H), 2.40-2.30 (in, 1H), 2.08-1.64 (m, 8H), 1.58-1.20 (in, 6H). Mass spec.: 614.37 (MH)*. Example 62 15 N-[(1R)-1-(Benzo[b]thien-3-ylmethyl)-2-[1,4-bipiperidin]-1-yl-2-oxoethyl]-3',4' dihydro-2-oxospiro-[piperidine-4,4'(1H)-quinoline]-1-carboxamide 0 S NH H N N N N 0 Prepared as described for (R)-l-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3 ene-9-carboxylic acid (1-benzo [b] thiophen-3-ylmethyl-2-[1,4'] bipiperidinyl-l'-yl 20 2-oxo-ethyl)-amide from 3',4'-dihydro-2-oxospiro-[piperidine-4,4'(1 H)-quinoline (M.S. Chambers, et al., J. Med. Chem., 1992, 35, 2033-2039; WO-94/13696). 'H NMR (CDCl 3 , 500 MHz) 8 -0.35 (1H, m), 0.79 (1H, in), 1.2-2.1 (12H, in), 2.22 (5H, m), 2.38 (2H, in), 2.74 (2H, ABq), 3.19 (3H, m), 3.33 (2H, in), 3.65 (1H, d), 3.80 (1H, m), 3.93 (11H, t), 4.49 (1H, d), 5.31 (1H, t), 5.96 (1H, t), 6.89 (1H, d), 7.05 (1H, 25 t), 7.18 (1H, d), 7.26 (11H, m), 7.33 (1H, m), 7.40 (1H, m), 7.78 (1H, in), 7.96 (1H, Abq), 9.01 (1H, brs), 9.17 (lH, brs). Mass spec.: 614.36 (MH)*.
WO 2005/065779 PCT/US2003/038799 170 Example 63 N-[(1R)-1-(Benzo[b]thien-3-ylmethyl)-2-[1,4-bipiperidin]-1-yl-2-oxoethyl]-2',3' dihydro-1-oxospiro-[piperidine-4,4'( 1H)-isoquinoline]-1-carboxamide H S N 0 H N N N O0 NO0 5 Prepared as described for (R)-1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9 carboxylic acid (1-benzo [b] thiophen-3-ylmethyl-2-[1,4'] bipiperidinyl-l'-yl 2-oxo-ethyl)-amide from 2',3'-dihydro- 1 -oxospiro-[piperidine-4,4'(1 H) isoquinoline (M.S. Chambers, et al., J. Med. Chem., 1992, 35, 2033-2039; WO-94/13696). 'H-NMR (CDCl 3 , 500 MHz) 6 0.01 (1H, m), 0.78 (11H, m), 10 1.1-2.0 (12H, m), 2.15-2.30 (5H, m), 2.74 (1H, t), 3.0-3.6 (9H), 3.89(2H, m), 4.46 (11H, d), 5.29 (1H, m), 5.62 (1H, d), 6.47 (1H, brs), 7.38 (5H, m), 7.51 (1H, m), 7.77 (11H, m), 7.85 (1 H, m), 8.11 (I H, d). Mass spec.: 614.42 (MH)*. 15 Example 64 N-[(1R)-1-(Benzo[b]thien-3-ylmethyl)-2-[1,4'-bipiperidin]-1'-yl-2-oxoethyl]-1,2 dihydro-2-oxospiro-[4H-3,1-benzoxazine-4,4'-piperidine]-l'-carboxamide s 0 N N0 OA NH N N 0 H 6 Prepared as described for (R)-1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3 20 ene-9-carboxylic acid (1-benzo [b] thiophen-3-ylmethyl-2-[1,4'] bipiperidinyl-l'-yl 2-oxo-ethyl)-amide from 1,2-dihydro-2-oxospiro-[4H-3,1-benzoxazine-4,4'- WO 2005/065779 PCT/US2003/038799 171 piperidine (prepared as described in Takai, et al.; Chem. Pharm. Bull. 1985, 33, 1129-1139) to give the title compound (76%). Mass spec.: 616 (MH)+. Rf= 1.42. Succinate Intermediates and Examples 5 3-Benzo[b]thiophen-3-yl-acrylic acid COOH A suspension of 1-benzothiophene-3-carbaldehyde (4.9 g, 0.03 mol), malonic acid (6.6 g, 0.06 mol) and piperidine (1 mL) in 100 mL anhydrous pyridine was 10 heated at I 10 C overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in 100 mL of water and 1 N hydrochloric acid was added to adjust the pH of this solution to ca. 3. The suspension was filtered and the yellow solid was collected, washed with water (3 x 50 mL) and concentrated in vacuo to give the indicated product with 95% purity 15 (5.
6 5g, 91%). 3 -Benzo[b]thiophen-3-yl-propionic acid S COOH A suspension of 3 -benzo[b]thiophen-3-yl-acrylic acid: (5.6 g, 0.027 mol) and 20 10% Pd/C (600 mg) in 1:1 methanol/ethyl acetate (50 mL) was hydrogenated in a Parr apparatus at 50 psi overnight. The mixture was filtered and concentrated to give the crude product without further purification (ca. 100% conversion). Mass spec.: 205(MH)-. 25 3-( 3 -Benzo[b]thiophen-3-yl-propionyl)-4(R)-benzyl-oxazolidin-2-one S Bn O WO 2005/065779 PCT/US2003/038799 172 To a solution of 3-benzo[b]thiophen-3-yl-propionic acid (2.1g, 0.010 mol), triethylamine (4.12 g, 0.040 mol) in anhydrous tetrahydrofuran (100 mL) at 0 0 C was added pivaloyl chloride (1.38 mL, 0.011 mol). After stirring for 1.5 h at 0*C, lithium chloride (0.475 g, 0.011 mol) and (R)-4-benzyl-2-oxazolidinoe (1.988 g, 0.011 mol) 5 were added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. Then the mixture was washed with water (3 x 150 mL). The organic layer was separated, dried, and evaporated to give the crude product. The title product was obtained as a brown oil (90%) by flash chromatography on silica gel eluting with 100% methylene chloride. This compound was used immediately in the 10 following procedure. 3(S)-Benzo[b]thiophen-3-ylmethyl-4-(4-benzyl-2-oxo-oxazolidin-3-yl)-4-oxo butyric acid tert-butyl ester - Bn N 15 To a solution of 3-(3-benzo[b]thiophen-3-yl-propionyl)-4-benzyl-oxazolidin 2-one (3.35 g, 9.18 mmol) in 100 mL anhydrous tetrahydrofuran at -78*C was added lithium diisopropyl amide in tetrahydrofuran (6.1 mL, 11.01 mmol) and the reaction mixture was stirred for 30 min Following addition of t-butyl bromoacetate (1.62 mL, 11.01 mmol) at -78'C, the mixture was stirred overnight while it was allowed to 20 warm to room temperature. The solvent was evaporated and the residue diluted with ethyl acetate. The organic layer was washed with water (3 x 100 mL), dried, filtered, and concentrated to give the crude product. The title product was obtained by filtration through a pad of silica, eluting with methylene chloride (49 %). 25 2(S)-Benzo[b]thiophen-3-ylmethyl-succinic acid, 4-tert-butyl ester WO 2005/065779 PCT/US2003/038799 173 S , HO 0 To a stirred solution of 3-benzo[b]thiophen-3-ylmethyl-4-(4-benzyl-2-oxo oxazolidin-3-yl)-4-oxobutyric acid tert-butyl ester (2.15 g, 4.49 mmol) in tetrahydrofuran (50 mL) and water (30 mL) at 0*C was added 30 % aqueous 5 hydrogen peroxide (1 mL) followed by lithium hydroxide (0.2155 g, 8.98 mmol). The reaction mixture was stirred overnight. Tetrahydrofuran was removed in vacuo and the resulting solution was acidified with 10% citric acid, and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with sodium bisulfite solution, dried and concentrated to give the title product. 10 3(S)-Benzo[b]thiophen-3-ylmethyl-4-[1,4']bipiperidinyl-1'-yl-4-oxo-butyric acid tert butyl ester S 0 N N 0 C-C 0 A solution of 2-benzo[b]thiophen-3-ylmethyl-succinic acid 4-tert-butyl ester 15 (1.8420 g, 5.76 mmol), piperidylpiperidine (1.2240 g, 7.28 mmol) and triethylamine (0.7353 g, 7.28 nimol) in 100 mL methylene chloride was treated with 3 (diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 1.8953 g, 6.34 mmol). The mixture was stirred overnight and then washed with water (3 x 40 mL). The organic layer was dried, filtered, and concentrated in vacuo to give the crude 20 product. This was further purified by flash chromatography on silica gel, eluting with 0-10% 2 M ammonia in methanol/methylene chloride, to give the desired product. This product was carried on without further purification. 3(S)-Benzo[b]thiophen-3-ylmethyl-4-[1,4']bipiperidinyl-l'-yl-4-oxo-butyric acid WO 2005/065779 PCT/US2003/038799 174 S 0 N N O OH A solution of 3 -benzo[b]thiophen-3-ylmethyl-4-[1,4']bipiperidinyl-' 1-yl-4 oxo-butyric acid tert-butyl ester in 15 mL methylene chloride was treated with trifluoroacetic acid (3 mL) and the reaction mixture was stirred overnight at room 5 temperature. The solvent was evaporated to give the corresponding trifluoroacetate salt of the title product (99%). Example 65 1-[1,4']Bipiperidinyl-l'-yl- 2
-(
3 (S)-Benzo[bthiophen-3-ylmethyl)-4-[1',2'-dihydro-2' 10 oxospiro-[4H-3', 1-benzoxazine-4,4'-piperidinyl]-butane- 1,4-dione N NH N 0 A solution of 3-benzo[b]thiophen-3-ylmethyl-4-[1,4']bipiperidinyl-l'-yl-4 oxo-butyric acid (25.0 mg, 0.060 mmol), 1, 2 -dihydro-2-oxospiro-4H-3,1-dihydro benzoxazine-4'4-piperidine (15.7 mg, 0.072 mmol) and triethylamine (7.3 mg, 0.072 15 mmol) in 5 mL methylene chloride at room temperature was treated with 3 (diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 21.5 mg, 0.072 mmol). The solution was stirred overnight and then washed with water (3 x 5 mL). The organic layer was dried, concentrated, and the crude product was purified by flash chromatography on silica gel, eluting with 0-10% 2M ammonia in 20 methanol/methylene chloride, to give the desired product in 60% yield. LC/MS: tR=1.
3 4 min, 615.45 (MH) t
.
WO 2005/065779 PCT/US2003/038799 175 2-(7-Methyl-IH-indazol-5-ylmethylene)-succinic acid 1-methyl ester OH NI 0 N NO
OCH
3 H To a mixture of 7-methyl indazole aldehyde (0.2619 g, 1.64 mmol) and 5 DBE-4 dibasic ester (dimethyl succinate) (0.32 mL, 2.45 mmol) in t-butanol (20 mL) was added potassium t-butoxide (0.4036 g, 3.60 mmol). The reaction mixture was heated at 50'C for 2h under nitrogen. After a further 16h at room temperature, the solvent was removed in vacuo and the residue was taken up in water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The aqueous layer was acidified with I N 10 hydrochloric acid to pH 3 ~ 4 and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate solution was dried and concentrated in vacuo to give the crude product as a yellow solid (99%, cis/trans isomer approximately 40:60). The crude mixture was carried to next step without further purification. Mass spec.: 275 (MH)*. 15 (±)-2-(7-Methyl- I H-indazol-5-ylmethyl)-succinic acid 1-methyl ester OH N'I N 0
OCH
3 H A suspension of 2-(7-methyl-IH-indazol-5-ylmethylene)-succinic acid 1 methyl ester (0.4440 g, 1.62 mmol) and 10% Pd/C (0.04 g) in ethyl acetate (15 mL) 20 and methanol (5 mL) was hydrogenated in a Parr apparatus overnight at 50 psi. The reaction mixture was filtered through a pad of celite and the filtrate evaporated to give the desired product as a yellow solid (100%). Mass spec.: 277 (MH) . Example 66 25 (±)-2-(7-Methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1',2'-dihydro-2'-oxospiro-[4H-3',1 benzoxazine-4,4'-piperidinyl]-butyric acid methyl ester WO 2005/065779 PCT/US2003/038799 176
OCH
3 Y 0 N N 0 H N 0 N H A solution of 2-(7-methyl-IH-indazol-5-ylmethyl)-succinic acid 1-methyl ester (0.2253 g, 0.82 mmol), 1,2-dihydro-2-oxospiro-4H-3,1-dihydro-benzoxazine 4'4-piperidine (0.1938 g, 0.89 mmol) and triethylamine (0.099 g, 0.98 mmol) in 5 methylene chloride (15 mL) was treated with 3-(diethoxyphosphoryloxy)- 1,2,3 benzotriain-4(3H)-one (DEPBT, 0.2685 g, 0.90 mmol). The mixture was stirred overnight and then washed with water (3 x 5 mL). The organic layer was dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-10% 2M ammonia in methanol/methylene chloride, to afford the 10 desired product (53%). LC/MS: tR 1.40 min, 477.28 (MH)*. Similarly prepared: Example 67 ( )-2-(7-Methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo- 1,4-dihydro-2H 15 quinazolin-3-yl)-piperidin- I -ylj-butyric acid methyl ester H o N N NN N 0 OCH 3 H H-NMR (400 MHz, CDCl 3 ) S 8.02 (lH, s), 7.98(1H, in), 7,90 (1H, in), 7.35 - 6.89 (4H, in), 6.72 (1 H, m), 4.71(1H, in), 4.57(1H, in), 4.27 (1H, s), 4.22 (1H, in), 3.85 (1H, in), 3.65 (3H, m), 3.30 (1H, in), 3.11(2H, m), 2.83 (2H, m), 2.81 - 2.54 (4H, in), 20 2.35 (1H, in), 1.7 3 - 1.67 (4H, i). Mass spec.: 490.32 (MH)*.
WO 2005/065779 PCT/US2003/038799 177 (±)-2-(7-Methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[ 1',2'-dihydro-2'-oxospiro-[4H-3',1 benzoxazine-4,4'-piperidinyl]-butyric acid OH N0 N O H N 0 A solution of 2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4-[1',2'-dihydro-2' 5 oxospiro-[4H-3',I-benzoxazine-4,4'-piperidinyl]-butyric acid methyl ester (0.1911 g, 0.40 mmol) and lithium hydroxide (19.3 mg, 0.80 mmol) in tetrahydrofuran (10 mL) and water (8 mL) was stirred overnight at room temperature. The reaction mixture was acidified with IN hydrochloric acid to ca. pH 1 and concentrated to remove tetrahydrofuran in vacuo to afford a white solid precipitate which was collected by 10 filtration. The solid was washed twice with small amounts of water and dried in vacuo overnight (100%). Mass spec.: 477 (MH) t . Example 68 (±)-1-[1,4']Bipiperidinyl-l'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[l',2'-dihydro 15 2 '-oxospiro-[4H-3',1 -benzoxazine-4,4'-piperidinyl]-butane-1,4-dione 0 0 NH O N N |~ H 0 N N A solution of 2-(7-methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[1',2'-dihydro-2' oxospiro-[ 4 H-3
'
,l-benzoxazine-4,4'-piperidinyl]-butyric acid (0.020 g, 0.04 mmol), piperidylpiperidine (0.0087 g, 0.05 mmol) and triethylamine (0.09 g, 0.08 mmol) in 20 methylene chloride (5 mL) at room temperature was treated with 3- WO 2005/065779 PCT/US2003/038799 178 (diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 0.0155 g, 0.05 mmol). The mixture was stirred overnight and then washed with water (3 x 5 mL). The organic layer was dried and the solvents were removed in vacuo. The crude product was purified by preparative TLC on silica gel (10% 2 M ammonium 5 hydroxide/methanol in methylene chloride) to give the desired product (36%). LC/MS: tR=1.1 8 min, 613.47 (MH)*. Similarly prepared: Example 69 10 (±)-1-[1,4']Bipiperidinyl-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin- 1 -yl] -butane-1,4-dione H o N o N N| N 0 N H N 'H-NMR (400 MHz, CDCl 3 ) 8 7.99 (1H, m), 7.62 (1H, i), 7.38 (1H, m), 7.14(11H, m), 7.04 - 6.90 (3H, in), 6.70 (2H, d, J=8.0 Hz), 4.70-4.58 (3H, m), 4.24 (2H, in), 15 4.00 (2H, m), 3.70 (1H, m), 3.18 - 2.72 (5H, in), 2.64 - 2.22 (8H, m), 2.18 - 0.82 (17H, m). Mass spec.: 626.34 (MH)*. Example 70 (+)-1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(7-methyl-1H-indazol-5- ylmethyl)-4 20 [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl] -butane- 1,4-dione WO 2005/065779 PCT/US2003/038799 179 H 0 N 0 N N | 'N N 0 N H 0 'H-NMR (400 MHz, CDC1 3 ) 8 8.06 (1H, s), 7.75 (1H, m), 7.36 (1H, m), 7.14 (IH, m), 7.01 - 6.79 (3H, m), 6.70 (1H, m), 4.70 - 4.49 (2H, m), 4.23 (2H, m), 3.98 (1H, m), 3.87 (3H, m), 3.65 - 3.44 (4H, m), 3.26 (1H, m), 3.10 - 2.88 (3H, m), 2.75 (1 H, 5 m), 2.51 (3H, s), 2.35 (lH, m), 2.00 (lH, m), 1.70 - 1.00 (9H, m). Mass spec.: 601.38 (MH)*. Example 71 (±)-1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(7-methyl- 1 H-indazol-5- ylmethyl)-4 10 [1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4'-piperidinyl]-butane- 1,4-dione 0 O NH ON N 0 N 'H-NMR (400 MHz, CDC1 3 ) 8 9.27 (1H, m), 8.00 (IH, s), 7.37 (1H, m), 7.23 (1 H, m), 7.10 - 6.99 (3H, m), 6.87 (1H, m), 4.54 (IH, m), 3.97 - 3.50 (10H, m), 3.30 (1H, m), 3.16 - 2.76 (4H, m), 2.53 (3H, s), 2.35 (IH, m), 2.20 - 1.00 (9H, m). Mass spec.: 15 588.36 (MH)*. Example 72 (±)-N,N-Dimethyl-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyranide WO 2005/065779 PCT/US2003/038799 180 H O N o N N 'N O N H LC/MS: tR-.
3 6 min, 525.35 (M+Na)*. Example 73 5 (±)- 1 -(2,6-Dimethyl-morpholin-4-yl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-[4-(2 oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1,4-dione H N o N Nj 'N 0 N H LC/MS: tR=1.
4 1 min, 573.39 (MH)*. 10 Example 74 (±)-2-(7-Methyl-IH-indazol-5-ylmethyl)-1-(4-methyl-piperidin-1-yl)-4-[4-(2-oxo 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1 -yl]-butane- 1,4-dione H 0 N 0 N N 'N 0 N
H
WO 2005/065779 PCT/US2003/038799 181 'H-NMR (400 MHz, CDC 3 ) 5 8.06 (1H, b), 7.60 - 6.73 (7H, m), 4.71 (1H, m), 4.54 (2H, m), 4.26 (2H, m), 4.05 - 3.89 (2H, m), 3.65 (1H, m), 3.09 - 2.81 (4H, m), 2.61 (3H, s), 2.41 (2H, m), 1.76 - 0.51(15H, m). Mass spec.: 557.38 (MH)+. 5 Example 75 (±)-2-(7-Methyl-1H-indazol-5-ylmethyl)-1-morpholin-4-yl-4-[4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione H O <N 0N 0 N N| N 0 N H 0 LC/MS: tR=1.32 min, 545.42 (MH)+. 10 Example 76 (+)-N,N-Dimethyl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[I',2'-dihydro-2' oxospiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butyramide 0 O kNH 0 N NJ 'N O N H 15 LC/MS: tR=1.
2 7 min, 512.30 (M+Na)+. Example 77 (±)-2-(7-Methyl-1H-indazol-5-ylmethyl)-1-(piperidin-1-yl)- 4 -[I',2'-dihydro-2' oxospiro-[4H-3', I -benzoxazine-4,4'-piperidinyl]-butane-1,4-dione WO 2005/065779 PCT/US2003/038799 182 0 O NH ON N" j N0 N 'H-NMR (400 MHz, CDC 3 ) 8 9.26 - 9.01 (1 H, m), 8.09 (1H, s), 7.42 - 6.89 (7H, m), 4.56 (1H, m), 3.84 (1H, m), 3.65 (3H, m), 3.30 (2H, m), 3.05 (3H, m), 2.81 (1H, m), 2.60 (3H, s), 2.39 (1H, m), 2.09 (2H, m), 1.85 (IH, m), 1.43 - 0.79 (9H, m). Mass 5 spec.: 530.34 (MH)+. Example 78 (±)-2-(7-Methyl- IH-indazol-5-ylmethyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidin-1-yl]-1-piperidin-1-yl-butane-1,4-dione H 0 N 0 N NI H 10 H-NMR (400 MHz, CDCl 3 ) 5 8.02 (1H, s), 7.82 (1H, m),7.37 (1H, m), 7.14 (lH, m), 7.04 - 6.90 (3H, m), 6.73 (1H, d, J = 8.0 Hz), 4.69 (1H, m), 4.56 (1H, m), 4.24 (2H, d, J = 7.2 Hz), 4.02 (IH, m), 3.65 (2H, m), 3.33 (3H, m), 3.07 (3H, m), 2.78 (1H, m), 2.55 (3H, s), 2.36 (1H, m), 1.80 - 1.50 (4H, n), 1.43 (4H, b), 1.26 (2H, b), 15 0.81 (2H, b). Mass spec.: 543.40 (MH)*. Example 79 (+)-1-[1,4']Bipiperidinyl-l'-yl- 2 -(1H-indazol-5-ylmethyl)-4-[l',2'-dihydro-2' oxospiro-[4H-3, 1 -benzoxazine-4,4'-piperidinyl]-butane- 1,4-dione WO 2005/065779 PCT/US2003/038799 183 0 0 NH 0 N N 0 N H N 1 H-NMR (400 MHz, CDC1 3 ) 5 8.86 (1H, m), 7.98 (1H, s), 7.54 - 6.85 (7H, m), 4.73 4.48 (3H, m), 3.96 - .80 (3H, in), 3.73 - 3.58 (3H, m), 3.17 - 2.78 (5H, m), 2.55 - 2.24 (5H, m), 2.02 - 1.79 (6H, m), 1.70 - 0.79 (7H, m). Mass spec.: 599.31 (M+Na)*. 5 Example 80 (+)-1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(1H-indazol-5- ylmethyl)-4-[1',2' dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4'-piperidinyl]-butane-1,4-dione 0 O ' NH 0 Nob NO N0 N H0 0 10 LC/MS: t=1.25 min, 574.25 (MH)+. Example 81 (±)-1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-( 1H-indazol-5-ylmethyl)-4-[4-(2-oxo 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- I -yl]-butane- 1,4-dione WO 2005/065779 PCT/US2003/038799 184 H 0 N N NI 0 NN H N 0 LC/MS: tR=1.
3 4 min, 587.38 (MH)*. Example 82 5 (+)-2-(1 H-Indazol-5-ylmethyl)-N,N-dimethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1 -yl]-butyramide H N 0 N N N O N H LC/MS: tR=1.28 min, 489.33 (MH)*. 10 Example 83 (±)-5- {2-([1,4']Bipiperidinyl- 1'-carbonyl)-4-oxo-4-[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-butyl}-indazole-1-carboxylic acid tert-butyl ester O N 0N 0 N N N N 0
ND
WO 2005/065779 PCT/US2003/038799 185 LC/MS: tR=1.47 min, 742.55 (M+Na)*. Example 84 (±)-2-(7-Methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-( 2 -oxo-1,4-dihydro-2H 5 quinazolin-3-yl)-piperidin- 1 -yl]-N-prop-2-ynyl-butyramide 0oyNH o N NI| N 0 N H H LC/MS: tR=1.
3 3 min, 535.32 (M+Na)*. Aspartate Intermediates and Examples 10 (L)-2-tert-Butoxycarbonylamino-4-oxo-4-[4-( 2 -oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidin-1 -yl]-butyric acid benzyl ester 0 O NH 0 ON N 0 0 a N 1 NH To a stirred solution of N-tert-butyloxycarbonyl-L-aspartic acid-alpha-benzyl 15 ester (1.4 g, 4.33 mmol) and 3,4-dihydro-3-(4-piperidinyl-2(I H)-quinazolinone (1.26 g, 4.33 mmol) in methylene chloride (12 mL) was added 3-(diethoxyphosphoryloxy) 1,2,3-benzotriain-4(3H)-one (DEPBT, 1.425 g, 4.76 mmol) in one portion followed by dropwise addition of triethylamine (0.724 mL, 5.20 mmol). The resulting suspension gradually became homogeneous with stirring and was stirred at room 20 temperature overnight (15 h). The mixture was diluted with methylene chloride and WO 2005/065779 PCT/US2003/038799 186 washed with sodium hydroxide (0.5 N) and water. The layers were separated and the organic layer was dried with sodium sulfate, and concentrated in vacuo to give a light yellow foam. The crude product was purified by flash column chromatography (10% methanol in methylene chloride) to give a colorless oil. Mass spec.: 559 (M+Na)*. 5 (L)-2-tert-Butoxycarbonylamino-4-oxo- 4
-[
4
-(
2 -oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidin- 1 -y]-butyric acid 0 0 jNH 0 HO (
-
N N NH To a solution of 2-tert-butoxycarbonylamino-4-oxo-4-[ 4
-(
2 -oxo-1,4-dihydro 10 2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid benzyl ester (1.48 g, 2.76 mmol) in ethyl acetate/methanol (16 mL, 1:1) in a Parr bottle was added 10% palladized charcoal (150 mg) in one portion. Hydrogenation was carried out with a Parr apparatus at 52 psi for 1 h. TLC (10% methanol in methylene chloride) indicated a quantitative conversion. The mixture was filtered and concentrated in vacuo to afford 15 a glassy colorless solid (1.14 g, 93%). Example 85 (L)-{ 1-([1,4']Bipiperidinyl-l'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester WO 2005/065779 PCT/US2003/038799 187 O <NH 0 N NH N N To a stirred solution of 2-tert-butoxycarbonylamino-4-oxo-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid (1.14 g, 2.55 mmol) and 4 piperidinyl-piperidine (525 mg, 2.81 mmol) in methylene chloride (20 mL) was 5 added 3-(diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 840 mg, 2.81 mmol) in one portion followed by dropwise addition of triethylamine (0.427 mL, 3.06 mmol). The resulted mixture was stirred at room temperature overnight (15 h). The mixture was diluted with methylene chloride and washed with sodium hydroxide (0.5 N) solution and water. The layers were separated and the organic 10 layer was dried with sodium sulfate and concentrated in vacuo to give a light yellow foam. The crude product was purified by flash column chromatography (10% (lM ammonia in methanol) in methylene chloride) to give a colorless foam (1.08 g, 71%). 'H-NMR (400 MHz, CDC1 3 ) 5 8.86 - 8.55 (1 H, br), 7.05 (1H, br), 6.93 (1 H, br), 6.82 (1H, br), 6.72 (1 H, d, J = 7.6 Hz), 6.10 - 5.68 (11H, br), 5.20 (1 H, in), 54.70 - 4.40 15 (2H, br), 4.20 (2H, br), 4.01 - 3.82 (2H, br.), 3.10 - 2.88 (3H, br), 2.99 (3H, br), 2.53 (6H, br), 1.90 - 1.10 (23H, m). Mass spec.: 597 (MH)*. (L)-2-Amino-1-[1,4']bipiperidinyl-l'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidin- I -yl]-butane- 1,4-dione
NH
2 0 N NH N 20 20 WO 2005/065779 PCT/US2003/038799 188 To a stirred solution of {1-([1,4']bipiperidinyl-1'-carbonyl)-3-oxo-3-[4-(2 oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidin- 1-yl] -propyl } -carbamic acid tert butyl ester (1.05 g, 1.76 mmol) in methylene chloride (12 mL) was added trifluroacetic acid (2 mL). The mixture was stirred at room temperature until 5 complete conversion (monitored by LCMS, ca. 15 h). The mixture was then diluted with water and sodium hydroxide (1.5 g) was slowly added with stirring. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a light yellow foam (860 mg, 98%). Mass spec.: 497 (MH)+. 10 Example 86 (L)-1-[1,4']Bipiperidinyl-1'-yl-2-(1H-indol-5-ylamino)-4-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione HN NH 0 0 N 0 N L N N H N 15 To a solution of 2-amino- 1-[1,4']bipiperidinyl- l'-yl-4-[4-(2-oxo- 1,4-dihydro 2H-quinazolin-3-yl)-piperidin- 1 -yl]-butane- 1,4-dione (52 mg, 0.105 mmol) and N tert-BOC-5-bromo-indole (prepared as described in Tetrahedron 2000, pp 8473 8482) (31 mg, 0.105 mmol) in tetrahydrofuran (1 mL) in a 5 mL drum vial was added 2-dicyclohexylphosphino-2'-(N, N-dimethylamino)-biphenyl (4.1 mg, 0.0105 mmol), 20 Pd 2 (dba) 3 (4.8 mg, 0.005 mmol), and cesium carbonate (54.6 mg, 0.168 mmol) under nitrogen. The vial was sealed with a teflon*-lined cap. The deep orange-colored reaction mixture was heated at 80'C with stirring. The reaction was continued at 80'C overnight. Conversion reached approximately 50% after 17 h. The solvent was removed in vacuo and the residue dissolved in methylene chloride and filtered. The 25 desired product was purified by prep arative TLC (10% methanol in methylene WO 2005/065779 PCT/US2003/038799 189 chloride) to afford the tert-butyloxycarbonyl-protected product (11 mg, 15%). Mass spec.: 712 (MH)*. This intermediate (11 mg) was dissolved in 3 mL methylene chloride and treated with trifluoroacetic acid (1.5 mL). The colorless solution turned to a tan color and was stirred at room temperature for 1.5 h. The mixture was 5 concentrated in vacuo and dried under high vacuum to a give tan powder (15 mg, 100%). Mass spec.: 612 (MH)+. Example 87 (L)-1-[1,4']Bipiperidinyl-1'-yl-2-(5-chloro-2-nitro-phenylamino)-4-[4-(2-oxo-1,4 10 dihydro-2H-quinazolin-3 -yl)-piperidin- 1 -yl]-butane- 1,4-dione
NO
2 CI NH 0 N 0 N N NH N To a stirred solution of 2-amino-1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3 -yl)-piperidin- 1 -yl]-butane- 1,4-dione (33.7 mg, 0.068 mmol) and 4-chloro-1,2-dinitrobenzene (16.8 mg, 0.075 mmol) in ethanol (0.5 mL) 15 was added a saturated sodium bicarbonate solution (4 drops). The mixture was stirred at room temperature for 70 h to approximately 60% conversion. The product was purified by preparative HPLC to give a yellow solid (17.7 mg, 40%). Mass spec.: 652 (MH)*. 20 Example 88 (L)-1-[1,4']Bipiperidinyl-1'-yl-2-(6-chloro-pyrimidin-4-ylamino)-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione WO 2005/065779 PCT/US2003/038799 190 N' I N N 0 N N "NH N 1 A mixture of 2-amino- 1-[1,4']bipiperidinyl- 1'-yl-4-[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidin-I-yl]-butane-1,4-dione (22.3 mg, 0.045 mmol) and 4, 6 dichloropyrimidine (16 mg, 0.095 mmol) in 2-propanol (0.5 mL) in a microwavable 5 vial was heated at 130'C under microwave irradiation for 40 min. LC/MS indicated 90% conversion. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and 1 N sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (10 % (IN ammonia in methanol) in 10 methylene chloride) to afford a white solid (23 mg, 84%). 'H-NMR (400 MHz,
CDC
3 ) 8 8.36 (1 H, d, J = 12.8 Hz), 8.04 - 7.81 (1H, 2s), 7.14 (1H, t, J 7.6 Hz), 7.10 - 6.80 (2H, in), 6.74 (111, t, J= 8.2 Hz), 6.52 - 6.42 (IH, m), 5.90 - 5.50 (1H, br), 4.85 - 4.40 (3H, m), 4.40 - 4.05 (3H, in), 4.05 - 3.82 (1H, in), 3.20 - 3.00 (2H, m), 3.00 - 2.68 (2H, in), 2.68 - 2.30 (8H, m), 2.05 - 1.90 (2H, in), 1.90 - 0.70 (12H, 15 in). Mass spec.: 609 (MH)*. Similarly prepared: Example 89 (L)-1-[1,4']Bipiperidinyl-l'-yl- 2
-(
2 -chloro-9H-purin-6-ylamino)-4-[4-(2-oxo-1,4 20 dihydro-2H-quinazolin-3-yl)-piperidin- -yl]-butane- 1,4-dione WO 2005/065779 PCT/US2003/038799 191
HN-
N CI N NH 0 0 N N A0N N LC/MS: tR 1. 10 min, 649 (MH)-'. Example 90 5 (L)-2-(4-Amino-6-methyl-5 -nitro-pyrimidin-2-ylamino)- -1-l,4']bipiperidinyl-l1 -yl-4 [4-(2-oxo-1I,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yll-butane-1I,4-dione
NH
2 0 2 N -~N
A
me N NHI 0 0 z N 0kN N N LCIMS: tR =1. 12 min, 649 (MH)j. 10 Example 91 (L)- -11 ,4]Bipiperidinyl-lI'-y1-2-(4,5-diamino-6-methyl-pyrimidin-2-ylamino)-4-I4 (2-oxo- 1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1 -yl]-butane- 1 ,4-dione WO 2005/065779 PCT/US2003/038799 192
NH
2
H
2 N N Me N NH 0 0 Na 0 N NH N To a solution of 2-(4-amino-6-methyl-5-nitro-pyrimidin-2-ylamino)- 1 [1,4']bipiperidinyl-1'-yI-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl] butane-1,4-dione in 2:1 methanol/ethyl acetate (6 mL) in a Parr bottle was added 10% 5 palladized charcoal (60 mg). The mixture was shaken under a hydrogen atmosphere at 55 psi for 20 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a colorless solid (41.2 mg, 49.2% for two steps) . LC/MS: tR = 0.86 min, 619 (MH)*. 10 Example 92 (L)-1-[1,4']Bipiperidinyl-1'-yl-2-(7-methyl-1 H-[1,2,3]triazolo[4,5-d]pyrimidin-5 ylamino)-4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidin- 1-yl] -butane- 1,4 dione N=N HN NN Me N NH 0 0Y- Na 0 N NH N 15 To a stirred solution of 1-[1,4']bipiperidinyl-l'-yl-2-(4,5-diamino-6-methyl pyrimidin-2-ylamino)- 4
-[
4
-(
2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl] butane-1,4-dione (10.6 mg, 0.0125 mmol) in acetic acid (1.5 mL) was added sodium nitrite (24 mg) followed by a few drops of water. The resulting light yellow solution WO 2005/065779 PCT/US2003/038799 193 was stirred at room temperature for 6 h. The reaction mixture was diluted with water and methanol and purified by preparative HPLC to afford a colorless oil/solid (3.0 mg, 28%). LC/MS: tR = 1.07 min, 630 (MH)+. 5 General procedure for the synthesis of Examples 93-95: A mixture of 2-amino-1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione (0.014 mmol), one of a series of aldehydes (0.07 mmol, 5 equiv) and solid anhydrous magnesium sulfate (0.031 mmol, 2.2 equiv) in 1,2-dichloroethane (3.0 mL) was treated with a catalytic amount 10 of acetic acid and was shaken overnight. Sodium cyanoborohydride ( 0.07 mmol, 5 eq) was then added in one portion and the suspension was again shaken overnight. Purification was carried out either by filtration through an SCX cartridge or by preparative HPLC. 15 Example 93 (L)-1-[1,4']Bipiperidinyl-l'-yl-2-((2'-pyridyl)-methyl-amino)-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl] -butane-1,4-dione NH/ NH 0 N N NH N LC/MS: tR 0.87 min, 588 (MH)*. 20 Example 94 (L)-1-[1,4']Bipiperidinyl-l'-yl- 2 -((5'-indazolyl)-methyl-amino)-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin- I -yl]-butane- 1,4-dione WO 2005/065779 PCT/US2003/038799 194 HN-N NH 0 0 l--Na 0 N NH N 16 LC/MS: tR 0.92 min, 626 (MH)*. Example 95 5 (L)-1-[1,4']Bipiperidinyl-1'-yl-2-((3'-methyl-phenyll)-methyl-amino)-4-[4-(2-oxo 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl] -butane-1,4-dione NH 0 0 z ON 0 N N ',N H N LC/MS: tR = 1.08 min, 600 (MH)*. 10 Example 96 (L)-1-[1,4']Bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidin-1-yl]-2-(pyrimidin-4-ylamino)-butane-1,4-dione WO 2005/065779 PCT/US2003/038799 195 N N NH 0 N 06 N O NN NH To a solution of 1-[l,4']bipiperidinyl-l'-yl- 2
-(
6 -chloro-pyrimidin-4-ylamino) 4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1 -yl]-butane- 1,4-dione (21 mg) was dissolved in 4 mL ethyl acetate/methanol (1:1) in a Parr bottle was added 5 10% palladized charcoal (10 mg). Hydrogenation was carried out on a Parr apparatus at 55 psi overnight. The degassed mixture was then filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford a yellow solid (12.4 mg, 45%). Mass spec.: 575 (MH)*. 10 Example 97 (L)-1-[1,4']Bipiperidinyl-l'-yl- 2
-(
4 -hydroxy-cyclohexylamino)-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin- 1 -y ]-butane- 1,4-dione HO NH 0 Na 0 N NH N 1 To a stirred mixture of 2-amino- 1-[1,4']bipiperidinyl- 1'-yl-4-[4-(2-oxo- 1,4 15 dihydro-2H-quinazolin-3 -yl)-piperidin- I -yl]-butane- 1,4-dione (47.9 mg, 0.096 mmol) and 4-hydroxy-cyclohexanone (Synthesis reported in Can. J. Chem. 1994, 72, 1699 - 1704) (11 mg, 0.096 nunol) in methanol (1.0 mL) was added excess zinc chloride followed by sodium cyanoborohydride (5 equiv). The suspension was stirred at room temperature for 6 days. The methanol was removed in vacuo and the 20 residue partitioned between methylene chloride and 1 N sodium hydroxide. The WO 2005/065779 PCT/US2003/038799 196 aqueous layer was extracted with methylene chloride (3x). The combined methylene chloride solution was passed through a celite cartridge and concentrated in vacuo. The residue was purified by preparative TLC (10% (IN ammonia in methanol) in methylene chloride) to afford the desired product as a white solid (15.3 mg, 27%). 5 Mass spec.: 595 (MH)*. Example 98 (L)-1-[1,4']Bipiperidinyl-l'-yl-2-[(1H-imidazol-4-ylmethyl)-amino]-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin- 1 -yl]-butane- 1,4-dione -N H N NH 0 0 N 0 N N NH N 10 To a stirred solution of 2-amino-1-[1,4']bipiperidinyl-l'-yl- 4 -[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl] -butane-1,4-dione (20.6 mg, 0.0415 mmol) and 4-imidazlecarboxyaldehyde (4 mg, 0.0415 mmol) in methylene chloride (1.0 mL) was added sodium cyanoborohydride (8.8 mg, 0.0415 mmol) in one portion. 15 The suspension was stirred at room temperature for 2 days and then partitioned between methylene chloride and iN sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC (10% (IN ammonia in methanol) in methylene chloride) 20 to afford the desired product as a colorless oil that solidified upon standing (6.1 mg, 26%). 'H-NMR (400 MHz, CDCl 3 ) 8 7.61 (1H, d, J= 4.8 Hz), 7.16 (1H, t, J = 7.6 Hz), 7.10 - 6.85 (3H, in), 6.67 (1H, d, J = 8.0 Hz), 4.85 - 4.63 (2H, m), 4.63 - 4.40 (1 H, in), 4.40 - 3.65 (7H, in), 3.25 - 2.40 (1OH, m), 2.15 - 0.70 (18H, m). Mass spec.: 577 (MH)*. 25 WO 2005/065779 PCT/US2003/038799 197 Example 99 (L)-N-{ 1-([1,4']Bipiperidinyl-l'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-propyl}-4-methoxy-benzamide
OCH
3 O NH 0 O N 0 N N N H N 5 To a stirred mixture of 2-amino-i -[1,4']bipiperidinyl- I'-yl-4-[4-(2-oxo- 1,4 dihydro-2H-quinazolin-3-yl)-piperidin- I-yl] -butane-1,4-dione (91.5 mg, 0.184 mmol) andp-anisoyl chloride (34.6 mg, 0.203 mmol) in methylene chloride was added two drops of triethylamine (35 pL). The light yellow solution was stirred at room temperature for 2.5 h to achieve complete conversion. The reaction mixture 10 was washed with sodium hydroxide (IN) and the aqueous layer was then extracted with methylene chloride. The combined organic layers were passed through a celite cartridge and concentrated in vacuo to give a glassy solid. The crude product was purified by flash column chromatography (10% (IN ammonia in methanol) in methylene chloride) to give a glassy solid (92.8 mg, 80%). 'H-NMR (400 MHz, 15 CDCl 3 ) 8 8.55 - 8.47 (1H, d), 8.10 - 7.78 (3H, in), 7.09 (1H, t, J 7.4 Hz), 6.96 6.74 (4H, m), 5.62 - 5.44 (1H, br), 4.75 - 4.40 (3H, m), 4.40 - 4.05 (3H, m), 4.05 3.82 (1H, br), 3.76 (3H, s), 3.18 - 2.88 (3H, m), 2.88 - 2.70 (1H, m), 2.70 - 2.30 (8H, m), 2.05 - 1.19 (14H, m). Mass spec.: 631 (MH) . 20 Example 100 (L)-N-{ 1-([1,4']Bipiperidinyl-l'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-propyl}-4-hydroxy-benzamide WO 2005/065779 PCT/US2003/038799 198 OH O NH 0 O N 0 N N NH N A stirred solution of N- {1-([1,4']bipiperidinyl-1'-carbonyl)-3-oxo-3-[4-(2 oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-propyl } -4-methoxy-benzamide solution in methylene chloride (69 mg) was treated with boron tribromide (1 M in 5 methylene chloride, 0.6 mL), dropwise at room temperature. The resulting suspension was stirred at room temperature for 7 h and then the reaction was quenched with excess triethylamine followed by methanol. The solvents were removed in vacuo and the residue was dissolved in methanol and purified by preparative HPLC. LC/MS: tR 1.03 min, 617 (MH)*. 10 Example 101 (L)-1H-Pyrazole-3-carboxylic acid {1-([1,4']bipiperidinyl-l'-carbonyl)-3-oxo-3-[4 (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-propyl}-amide NH N O NH 0 N NH N 15 To a stirred solution of pyrrazole-3-carboxylic acid (4 mg, 0.036 mmol) and 2-amino-1-[1,4']bipiperidinyl-l'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidin-1-yl]-butane-1,4-dione (13 mg, 0.026 mmol) in methylene chloride (1 mL) WO 2005/065779 PCT/US2003/038799 199 was added 3-(diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 8.6 mg, 0.036 mmol) in one portion followed by one drop of triethylamine. The resulting mixture was stirred at room temperature overnight (15 h). The mixture was then partitioned between sodium hydroxide (0.5 N) and methylene chloride. The layers 5 were separated and the aqueous layer was extracted with methylene chloride (3x). LCMS indicated that the product was remained in the aqueous layer. The product was purified by preparative HPLC to give a yellow oil (17.2 mg, 94%). Mass spec.: 591 (MH)*. 10 General procedure for the synthesis of Examples 102-134: XR O <NH 0 o N 0 N N NH N X = C, 0 The starting amine, 2-amino-l-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, was dispersed in a 96 well mini-reactor (ca. 10 mg each) in 1 mL dichloroethane. Individual acyl chlorides 15 (ca. 2 equiv.) were added followed by a resin-bound solid-phase piperidine base (4 equiv). The block was shaken overnight. Approximately 4 equivalents of tris-amine resin was added to each well and the mini-reactor was shaken for another 5 h. The reaction mixtures were filtered, and purified by either preparative HPLC or filtration through an SCX cartridge or both. HPLC retention times and mass spectral data for 20 each example are listed in Table 2.
WO 2005/065779 PCT/US2003/038799 200 Table 2. Amides and Carbamates HPLC MS Example Structure tR (min) (M+) Chiral N 0 0 N 102 H 1.84 637.38 HN N O 0 Chiral 0N 103 0 1.39 565.45 HN 0 H0 Chiral 104 N 1.89 641.46 0 N N Chiral F1. =0 105 HN 0H1.73 619.42 WO 2005/065779 PCT/US2003/038799 201 HPLC MS Example Structure t(minl) (M+) 0 Chiral 106 1.62 615.41 H H 0 0 2 N C h ira l N 0 H,,F F 107 F 2.25 737.37 NH F 0F Chiral N 1 HNN 0 0 108 NH - 2.12 669.3 0 N 0 q HN Chiral 109 1.59 675.46 H/0 0 0 0 WO 2005/065779 PCT/US2003/038799 202 HPLC MS Example Structure tR (min) (M+) Chiral N NH ON 110 1.62 601.43 HN 0 Chiral N0 H 2.09 669.33 N N 0NC HN~~H NNH 112 01.91 665.36 00 CI O
-
C h i r a l 00 113 HZ 1.68 646.37 CN- N __No _ , _00
%N
WO 2005/065779 PCT/US2003/038799 203 HPLC MS Example Structure t R (Min) (M+) Chiral 0 NN 114 NH N 1.66 645.4 0 O-i Chiral Ho KN O0 115 N" 2.14 690.45 O HN 0 Chiral NO 0 116 0H',. 1.59 607.39 OS 0 Chiral O NI 117 N N ,, 1.59 621.4
SON
WO 2005/065779 PCT/US2003/038799 204 HPLC MS Example Structure tR (min) (M+) rp Chiral O N N NH 118 O H 2.01 735.43 HN 0 O O Chiral HN N O 0 119 NY Na 1.92 679.32 0 NH Br Chiral 120 N 1.22 537.4
H
1 0 Chiral F 0; 121 HN O 2.03 685.4 oce0o, WO 2005/065779 PCT/US2003/038799 205 HPLC MS Example Structure tR (min) (M+) Chiral N 0 IF 122 H 1.79 637.38 N HN'N "O F Chiral N 123 0 1.84 669.3 H4 N N- N-e N CI H Chiral 0 N /1 0 ND ": 0 HN Ng 124 "' H 0 1.53 636.35 QNN ON--C Oi.0 h iralI H IN H S 0 125 N2.04 691.35 0
HN
WO 2005/065779 PCT/US2003/038799 206 HPLC MS Example Structure tR (min) (M+) Q Chiral bN H0 126 1.89 657.35 N N 0 N 0 H CI Chiral 127 N 1.86 649.39 MM10 Chiral O Ng N TNH 0 H 128 N N 1-67 691-2 ON 0 Chiral Cl =0 129 HN O 1.84 635.38 cN 00 - WO 2005/065779 PCT/US2003/038799 207 HPLC MS Example Structure t R (min) (M+) 0N Chiral 130 1.69 617.42 N N O/ 0 a F Chiral 0 NH 131 N 1.74 635.38 N N H 0 Chiral 132 N 1.84 631.44 Br Chiral a O1 <NH 0 ' 133 ""' 1.94 695.28 0 WO 2005/065779 PCT/US2003/038799 208 HPLC MS Example Structure tR (min) (M+) o Chiral 134 1.7 647.41 General procedure for the synthesis of Examples 135-200: HN- R O NH 0 0 N 0 N N NH N 16 5 The starting amine, 2-amino-i-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, was dispersed in a 96 well mini-reactor (ca. 10 mg in each well) in dichloroethane (1 mL). Individual isocyanates (ca. 2 equiv) were added to individual wells. The block was shaken for 2 days. Approximately 4 equivalent of tris-amine resin was added to each well and the 10 mini-reactor was shaken for another two days. The reaction mixtures were filtered, and individual product was purified by either preparative HPLC or filtration through an SCX cartridge or both. HPLC retention times and mass spectral data for each example are listed in Table 3.
WO 2005/065779 PCT/US2003/038799 209 Table 3. Ureas HPL Example Structure C tR (M (min) (MH) Chiral 135 N 1.43 665.84 1 H 0 0 -C~ 0 N O Chiral bN 0 H 0 136 N-', 0 1.56 707.88 0 H~ H 0 0 Chiral N 137 00 1.39 665.84 H4 WO 2005/065779 PCT/US2003/038799 210 HPL Example Structure C tR MS (m ) (MH)* Chiral NO O NO No H H 138 0 1.3 643.83 N N N H __ CQ C h i r a l N 139N 01. 4 6 7 8 0 H Cl Chiral ONH 01,1NH N 140H 1.42 650.22 O MNN 0
H
WO 2005/065779 PCT/US2003/038799 211 HPL MS Example Structure C tR (MH)+ (min) Chiral N 141 0 1.26 629.81 H Q Chiral 142 1.41 643.83 0 O0 HN8 O NI Chiral 143 b 124 615.78 0o H4 N N N
H
WO 2005/065779 PCT/US2003/038799 212 HPL MS Example Structure C tR ( (min) iN Chiral 144 N 1.53 691.88 H0 N-N Chiral HN N 0 NH 145 O N NH 1.21 629.81 H 0 N 0 _aN Q Chiral N 146 HH 1.52 707.88 - N O N Chiral 147 N 1.19 657.82 N N C J-CH N oH WO 2005/065779 PCT/US2003/038799 213 HPL MS Example Structure C tR (MH)+ (mM) N 'Chiral N 0 148 HN 1.44 684.67 HN O N INH NO CI ' Chiral N 149 0 0 1.3 64.8 0 0 Chiral 150 N 1.24 645.81 N H 0 0N4 (:jjNCINH WO 2005/065779 PCT/US2003/038799 214 HPL Example Structure C tR (min) (MH)* KY> Chiral N 151 o 1.33 643.83 N CI Chiral F NH 152 NH 1.56 718.22 N N I H N NQ F F Chiral HN N 0 NH 153 0 N NH 1.55 683.78 0 H N N WO 2005/065779 PCT/US2003/038799 215 HPL MS Example Structure C tR (MH)+ (min) Chiral N H 154 HN N 0 1.37 655.84 OJ NH N NH H Chiral N 155 H O O 1.27 675.83 N N O -- C' O 0 H N 0\ 0 O Chiral CN 0 0 156 H=0 1.26 651.76 HN F0
F
WO 2005/065779 PCT/US2003/038799 216 HPL MS Example Structure C tR (MH)* (min) Chiral N 157 0H 00 1.39 643.83 N N N-HN H Chiral 158 N 1.43 643.83
NN
H CI Chiral NH 159 0 NH 1.57 684.67 /N N-I 4- a NQ N00 WO 2005/065779 PCT/US2003/038799 217 HPL MS Example Structure C tR (MH)* (min) F F Chiral NH NO NH 4H 160 N 1.46 683.78 H O Chiral CN-O-H -NO N 161 o 1.48 684.67 HN Cl C Chiral 162 1.5 657.86 0 H, 0 H4 0 163 H 1.14 651.76 FN
FH
WO 2005/065779 PCT/US2003/038799 218 HPL MS Example Structure C tR (MH)* (min) C1 Chiral CI ~ 164 0<H 1.34 685.66 _ N NH HN Chiral N 165 H H 0 1.26 675.83 0H0 N N Chi ra o H 0 Chiral N N O H N
N
166 ON 1.28 701.87 H H O 0 0 F F Chiral N FI Cl HN yN,, 0 yNH 167 0 l ', H1.52 718.22 0 N __ a___C WO 2005/065779 PCT/US2003/038799 219 HPL Example Structure C tR (min) (MH)* F Chiral IF F HN N 0 NH 168 NH 1.35 669.75 0 N LN Chiral N 169 0N N NH 1.24 649.86 NH NH Chiral N N 00 170 0i-C I 0 ~H11 3. HH 0 WO 2005/065779 PCT/US2003/038799 220 HPL MS Example Structure C tR (MH)+ (min) N OChiral 171 HN 1.31 633.77 F 0 H Chiral 172 HN O 1.34 650.22 C N HChiral 0 Hl 0 173 1.47 684.67 HN 0 Chiral 174 N H 0 1.27 675.83 0 N 0 WO 2005/065779 PCT/US2003/038799 221 HPL MS Example Structure C tR (MH)+ (min)(H O N Chiral N 175 H O01.34 659.83 N N N
H
Br Chiral HN N 0 NH N P ", F Chiral HN N 0 NH 177 0 NH 1.28 633.77 0 N 0 N N o WO 2005/065779 PCT/US2003/038799 222 HPL MS Example Structure C tR + (min) (MH) CI Chiral HN N 0 NH 178 O 1.39 650.22 O H O N N Br Chiral NH O NH N 179 'H N 1.42 694.68 H F Chiral NH HO NN N
HO
WO 2005/065779 PCT/US2003/038799 223 HPL MS Example Structure C tR (m)(MH) Chiral 181 N 1.19 645.81 100 0 H4 0 Chiral N 182 H 0 1.34 687.84 NN 0 H HN / H Chiral 0O N H H 183 N N H 1.08 581.76 0 o N O Chiral 0 CN-O H 2-O-'! 184 HNVo 1.31 651.76 HN F F WO 2005/065779 PCT/US2003/038799 224 HPL MS Example Structure C tR MH)+ (min) (MH O N~ Chiral N 185 H 1.39 643.83 0 Chiral 186 O H 1.33 664.25 NH N-C N-\/I H~-N N§7 C O Chiral HN N 0 NH 187 0 N NH 1.41 680.25 O N N o Chiral CN NoN HN 188 > 1.48 718.22 HN F F
CI
WO 2005/065779 PCT/US2003/038799 225 HPL MS Example Structure C tR (MH)* (min) >Chiral 189 N 1.28 659.83 Ho I 0 N 0 Hx / 0 Chiral 190 1.41 643.83 0 0 NN/O CI Chiral NH NO 0 NH N 191 N,"' 1.41 664.25 00 H CI Chiral HN N 0 NH 192 O N NH 1.41 664.25 o H O N N ® _ WO 2005/065779 PCT/US2003/038799 226 HPL MS Example Structure C tR (mi) (MH)* CI Chiral F NH NO O <NHN 193 N 1.41 668.21 O O N'0 H Br Chiral NH O NH N O 194 H N 1.45 708.71 ao H SF Chiral HN N 0 NH 195 O N NH 1.39 647.8 0 H O N
N
WO 2005/065779 PCT/US2003/038799 227 HPL Example Structure C tR MS (min) (MH)* 0 Chiral 196 1.27 673.82 0 N4 0 0 197 H N 15 . HN C hiral NN 197 0 1.45 691.88 - NN H Chiral ON o NN 0 198N H 1.26 643.83 HN 0 WO 2005/065779 PCT/US2003/038799 228 HPL MS Example Structure C tR + (m)(MH)* (min) Chiral N 199 o N 1.45 693.89 iHH 0 NH YY NH O H Chiral HN 200 >0 1.4 699.78 F F F 2-(1H-Indazol-5-ylamino)-succinic acid 4-tert-butyl ester 1-ethyl ester ,N_ HN NH 0 OEt To a solution/suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in 5 tetrahydrofuran (20 mL) was added ethyl glyoxlate solution (ca. 50% in toluene, 1.7 mL, 1.1 equiv) in one portion followed by magnesium sulfate (4.6 g). The mixture was stirred at room temperature overnight (23 h) and then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was dried by azeotroping with anhydrous benzene and further dried under high vacuum. The 10 residue was then dissolved in tetrahydrofuran (20 mL) and cooled at 0 0 C. A solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was then WO 2005/065779 PCT/US2003/038799 229 slowly added. After stirring at 0 0 C for I h, the mixture was stored at 4*C overnight. The mixture was then diluted with ethyl acetate and quenched with half-saturated ammonium chloride solution along with a minimum amount of 0.5 N HCl to dissolve the precipitated solids. The layers were separated and the aqueous layer was 5 extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride, to afford the desired product (1.3 g, 65%) as a tan oil. 'H-NMR (400 MHz, CDC 3 ) 8 10 7.89 (lH, s), 7.40 - 7.27 (1H, in), 6.98 - 6.77 (2H, in), 4.42 - 4.35 (1 H, in), 4.30 4.12 (3H, in), 2.80 (2H, d, J 4.4 Hz), 1.43 (9H, s), 1.27 - 1.17 (4H, in). Mass spec.: 356.24 (M+Na)*, 278.23 (M t Bu)+, tR 1.287 min. 2-(1H-Indazol-5-ylamino)-succinic acid 1-ethyl ester N. HN NH 0 O OH 15 OEt A stirred solution of 2-(IH-indazol-5-ylamino)-succinic acid 4-tert-butyl ester 1-ethyl ester (123.6 mg, 0.37 mmol) in methylene chloride (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and washed with saturated ammonium chloride 20 solution, water and brine. The organic layer was dried and concentrated to give a dark green oil: LC/MS: tR 0.643 min, 278.19 (MH)*. 2-(1H-Indazol-5-ylamino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidin-1-yl]-butyric acid ethyl ester WO 2005/065779 PCT/US2003/038799 230 /N_ HN NH 0 ON O OEt N NH To a stirred solution of 2 -(l H-indazol-5-ylamino)-succinic acid 1-ethyl ester (84 mg, 0.215 mmol) in methylene chloride (lmL) was added the amine (99 mg, 0.429 mmol, 2 equiv) followed by DEPBT (128 mg, 0.43 mmol, 2 equiv.) and 5 triethylamine (70 iL, 0.47 mmol, 2.2 equiv). The mixture was stirred overnight and then diluted with ethyl acetate and washed with half-saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to a tan oil. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride, to give the desired product (36.2 10 mg, 34.5% for two steps) as a reddish oil. 'H-NMR (400 MHz, CDCl 3 ) 8 7.90 (2H, d, J = 4.4 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.20 - 7.14 (1 H, in), 7.00 - 6.80 (4H, in), 6.70 (1 H, t, J= 6.8 Hz), 4.58 - 4.48 (1H, m), 4.65 - 4.40 (2H, m), 4.34 - 4.05 (3H, m), 4.02 - 3.82 (1 H, m), 3.20 - 2.99 (2H, in), 2.99 - 2.84 (1 H, in), 2.70 - 2.52 (1 H, m),1.80 - 1.50 (5H, in), 1.35 - 1.12 (5H, m). LC/MS: tR 1.130 min, 491.37 (MH)*. 15 2-(1H-Indazol-5-ylamino)-4-oxo-4-[4-(2-oxo-1, 4 -dihydro-2H-quinazolin-3-yl) piperidin-1-yl]-butyric acid HN NH 0 0 N N NH To a solution of the ethyl ester (34 mg, 0.069 mmol) in tetrahydrofuran (0.3 20 mL) was added lithium hydroxide in water(lM, 280 gL, 4 equiv) and the mixture WO 2005/065779 PCT/US2003/038799 231 was stirred at room temperature for 17 h. The solution was dried under a stream of nitrogen. To the residue was added 0.2 mL tettrahydrofuran and 0.2 mL anhydrous benzene and the suspension was blown dry again with a stream of nitrogen. LC/MS: tR = 0.900 min, 463.30 (MH)*. 5 Example 201 (±)- 1-[1,4']Bipiperidinyl-l'-yI-2-(l H-indazol-5-ylamino)-4-[4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1,4-dione /N_ HN NH 0 0 N 0 N N NH N 10 To a solution of 2-(IH-indazol-5-ylamino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidin-1-yl]-butyric acid ethyl ester (0.069 mmol) in dimethylformamide (0.5 mL) in a capped drum vial was added piperidinylpiperidine (14.3 mg, 0.076 mmol, 1.1 equiv), DEPBT (22.8 mg, 1.1 equiv) and triethylamine (8 drops, ca. 160 gL). The mixture was stirred at room temperature overnight. The 15 final product was purified by preparative HPLC to afford the desired product (15 mg, 26% for two steps) as a tan solid. LC/MS: tR = 0.917 min, 613.54 (MH)*. Additional Examples 20 (1 -Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine S N H 2-Nitrobenzaldehyde (1 g, 6.61 mmol) and 4-amino-1-benzylpiperidine (1.35 mL, 6.61 mmol) were combined in ethanol (20 mL). The resulting suspension was WO 2005/065779 PCT/US2003/038799 232 stirred at room temperature for 20 min before a solution of sodium borohydride (0.25 g, 6.61 mmol) in ethanol (5 mL) was added dropwise over 10 min. After the addition was complete, the reaction was stirred for 1 h, cooled to 0 0 C and concentrated ammonium chloride was added to the reaction mixture until no bubbling was 5 observed. The solvents were evaporated in vacuo and the resultant crude mixture was dissolved in water (10 mL) and methylene chloride (10 mL). The layers were separated and the organic layer washed with water (2x) and brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 1.5 g (70%) of the desired product. LC/MS: tR = 0.7 min, 326.18 (MH)+. 10 (2-Amino-benzyl)-(l -benzyl-piperidin-4-yl)-amine N N H (1-Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine (1.2 g, 3.7 mmol) and zinc dust (1 g, excess) were combined in 75% aqueous acetic acid (16 mL) and stirred at 15 60'C for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant crude dissolved in water (10 mL), followed by addition of ammonium hydroxide until pH 3 was attained. The solution was extracted with methylene chloride (3x). The organic layers were pooled together washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 0.8 g 20 (73%) of the desired product. 1 H-NMR (CD 3 0D) 5 2.50 (m, 2H), 3.20 (in, 2H), 3.49 (dd, J=7.0, 7.3, 111), 3.62 (m, 4H), 4.20 (s, 2H), 4.36 (s, 2H), 7.04 (m, 211), 7.32 (dd, J=7.3, 7.6, 1 H), 7.41 (d, J=7.9, 111), 7.50 (m, 5H). Mass spec.: 296.40 (MH)*. 3-(1-Benzyl-piperidin-4-yl)-3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide 0N HN N 25 A solution of (2-amino-benzyl)-(l -benzyl-piperidin-4-yl)-amine (1.0 g, 3.39 mmol) and sulfamide (0.64 g, 6.78 mmol) in pyridine was heated at reflux for 14 h.
WO 2005/065779 PCT/US2003/038799 233 After cooling to room temperature, the solvent was evaporated and the crude product dissolved in water. After being adjusted to pH 9 with 6N sodium hydroxide, the resulting mixture was extracted with methylene chloride (2x). The extracts were washed with water (2x), dried over sodium sulfate, filtered, and concentrated to 5 afford an oily residue which was dissolved in ethyl acetate (4 mL). This solution was mixed with 4N HCl in 1,4-dioxane (2 mL) followed by addition of diethyl ether until precipitation of product occurred. The desired product was obtained by filtration to afford 0.7 g (53%). LC/MS: tR = 0.96 min, 358.16 (MH)*. 10 3-Piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide H o NH HN 'N 3-(1-Benzyl-piperidin-4-yl)-3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2 dioxide (0.46 g, 1.29 mmol) in methanol (10 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 46 mg). The flask was flushed with 15 hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.26 g (75%) of the desired material. 'H-NMR (CD 3 0D) 5 1.53-1.61 (m, 2H), 1.80 (in, 2H), 2.55 (in, 2H), 2.95-3.05 (in, 2H), 3.30 (in, 2H), 3.70 (in, 2H), 4.65 (s, 2H), 6.70 (d, J=7.9, 1H), 7.40 (dd, J=8.2, 6.7, 1H), 7.10 (m, 20 2H). Mass spec.: 268.10 (MH) 4 . 6-Bromo-3-piperidin-4-yl-3,4-dihydro- 1 H-quinazolin-2-one H N Y0 Br NH 3-Piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.87 mmol) was dissolved in acetic acid (2 mL). To this solution was added a solution of bromine 25 (1.8 mL, 35.14 mmol) in acetic acid (0.5 mL) dropwise over 5 min. After stirring for at room temperature for 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and WO 2005/065779 PCT/US2003/038799 234 concentrated to afford 0.16 g (59%) which was used immediately without further purification. LC/MS: tR = 0.91 min, 310.15 (MH)*. 2-Oxo-3-piperidin-4-yl-1,2,3,4-tetrahydro-quinazoline-6-carbonitrile HN CN N 5 H 6-Bromo-3-piperidin-4-yl-3,4-dihydro- 1 H-quinazolin-2-one (0.16 g, 0.52 mmol), zinc cyanide (37 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladiun(0) (60 mg, 0.05 mmol) were combined in dimethylformamide (4 mL). The reaction flask was connected to high vacuum and degassed (3x) by a freeze-thawing method, before 10 being heated at 90*C with stirring under nitrogen for 1 h. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture purified by preparative HPLC to afford 50 mg (38%) of the desired nitrile. 'H-NMR (CD 3 0D) S 1.99 (m, 2H), 2.08-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, IH), 4.40 (m, 1H), 4.47 (s, 2H), 6.93 (d, J=8.1, 1H), 4.10 (m, 2H). Mass spec.: 257.13 (MH)+. 15 N-(1 -Benzyl-piperidin-4-yl)-2-(2-nitro-phenyl)-acetamide
NO
2 H N (2-Nitro-phenyl)-acetic acid (2.0 g, 11.04 mmol), 4-amino-1-benzylpiperidine (2.25 mL, 10.03 mmol), 1-hydroxybenzotriazole (1.49 g, 11.04 mmol) and 1-(3 20 dimethylaminopropyl)-3-ethyl carbodiimide (2.3 g, 12.03 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.1 mmol) and the reaction mixture stirred at 40'C for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate, and concentrated to afford 3.5 g 25 (98%) of the desired product. LC/MS: tR = 1.24 min, 354.30 (MH)*. [2-(2-Amino-phenyl)-ethyl]-(1 -benzyl-piperidin-4-yl)-amine WO 2005/065779 PCT/US2003/038799 235
NH
2 H N N Into a flame dried flask, N-(1-benzyl-piperidin-4-yl)-2-(2-nitro-phenyl) acetamide (3.2 g, 9.06 mmol) and lithium aluminium hydride (1.0 g, 18.12 mmol) were combined. 1,4-Dioxane (15 mL) was added and the mixture slowly brought to 5 reflux over 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0*C and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction. 10 3-(1 -Benzyl-piperidin-4-yl) 1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one N
N
A stirred solution of [ 2 -(2-amino-phenyl)-ethyl]-(l -benzyl-piperidin-4-yl) amine (0.44 g, 1.42 mmol) in tetrahydrofuran (5 mL) at 0*C was treated with carbonyl diimidazole (0.23 g, 1.42 mmol). The reaction was stirred for 30 min at 0*C 15 and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 100 mg (2 1%) of the desired product. LC/MS: tR = 1.29 min, 336.34 (MH)*. 3-Piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one 20 N NH 3-(1-Benzyl-piperidin-4-yl)1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, WO 2005/065779 PCT/US2003/038799 236 filtered through celite, and concentrated. Column chromatography gave 50 mg (68%) of the desired material. LC/MS: tR = 1.07 min, 246.26 (MH) t . 3-[(1-Benzyl-piperidin-4-yl-amino)-methyl]-4-nitro-phenol
NO
2 N N H 5 OH 5-Hydroxy-2-nitro-benzaldehyde (5 g, 29.9 mmol) and 4-amino-1 benzylpiperidine (5.6 mL, 29.9 mmol) were combined in ethanol (30 mL). The resulting suspension was stirred at room temperature for 20 min before a solution of sodium borohydride (1.13 g, 29.9 mmol) in ethanol (10 mL) was added dropwise 10 over 10 min. After the addition was complete, the reaction was stirred at room temperature for 1 h, cooled to 0 0 C and concentrated ammonium chloride added to the reaction mixture until no bubbling was observed. The solvents were evaporated in vacuo and the resultant crude mixture was dissolved in water (30 mL) and methylene chloride (40 mL). The layers were separated and the organic layer washed with 15 water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 5.8 g (57%) of the desired product. LC/MS: tR = 0.95 min, 342.27 (MH)*. 4-Amino-3-[(1 -benzyl-piperidin-4-yl-amino)-methyl]-phenol
NH
2 N ~ N H OH 20 (1-Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine (0.25 g, 0.7 mmol) and zinc dust (0.2 g, excess) were combined in 75% aqueous acetic acid (8 mL) and stirred at 60*C for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant crude mixture dissolved in water (10 mL), followed by addition of ammonium hydroxide until pH 3 was attained. The solution was extracted with 25 methylene chloride (3x). The organic layers were pooled together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 0.18 g (79%) of the desired product.
WO 2005/065779 PCT/US2003/038799 237 3-(1 -Benzyl-piperidin-4-yl)-6-hydroxy-3,4-dihydro- I H-quinazolin-2-one H HOCN A stirred solution of 4-amino-3-[(1-benzyl-piperidin-4-yl-amino)-methyl] 5 phenol (0.16 g, 0.51 mmol) in tetrahydrofuran (3 mL) at 0 0 C was treated with carbonyl diimidazole (52 mg, 0.51 mmol). The reaction was stirred for 30 min at 0 0 C and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 100 mg (57%) of the desired product. LC/MS: tR = 1.09 min, 338.28 (MH)*. 10 6-Hydroxy-3 -piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one H N 0 HOO HNH 3-(1 -Benzyl-piperidin-4-yl)-6-hydroxy-3,4-dihydro- 1 H-quinazolin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium 15 on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 60 mg (81%) of the desired material. LC/MS: tR = 0.75 min, 248.22 (MH)*. 20 N-(1 -Benzyl-piperidin-4-yl)-2-methoxy-6-nitro-benzamide N0 2 0N ~ N
H
WO 2005/065779 PCT/US2003/038799 238 2-Methoxy-6-nitro-benzoic acid (2.0 g, 10.1 mmol), 4-amino-I benzylpiperidine (1.9 mL, 10.1 mmol), 1-hydroxybenzotriazole (1.43 g, 10.5 mmol) and I-(3-dimethylaminopropyl)-3-ethyl carbodilmide (1.9 g, 10.1 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 5 mL. 30.3 mmol) and the reaction mixture stirred at 40'C for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate, and concentrated to afford 3.2 g (86%) of the desired product. LC/MS: tR = 1.10 min, 370.28 (MH)*. 10 (2-Amino-6-methoxy-benzyl)-(1-benzyl-piperidin-4-yl)-amine
NH
2 N H 0 Into a flame dried flask, N-(1 -benzyl-piperidin-4-yl)-2-methoxy-6-nitro benzamide (1.0 g, 2.8 mmol) and lithium aluminium hydride (0.31 g, 8.45 mmol) were combined. To the mixture was added anhydrous 1,4-dioxane (15 mL). The 15 mixture was slowly brought to reflux over 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0 0 C and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction. 20 3-(1 -Benzyl-piperidin-4-yl)-8-methoxy-3,4-dihydro-1 H-quinazolin-2-one 0 H N.- Nr'0 N A stirred solution of (2-amino-6-methoxy-benzyl)-(1 -benzyl-piperidin-4-yl) amine (0.2 g, 0.62 mmol) in tetrahydrofuran (3 mL) at 0*C was treated with carbonyl WO 2005/065779 PCT/US2003/038799 239 diimidazole (99 mg, 0.62 mmol). The reaction was stirred for 30 min at 0 0 C and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 150 mg (68%) of the desired product. LC/MS: tR = 1.41 min, 352.30 (MH)*. 5 8-Methoxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one NH 3-(1-Benzyl-piperidin-4-yl)-8-methoxy-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.28 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with 10 palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 68 mg (93%) of the desired material. LC/MS: tR = 1.11 min, 262.23 (MH)*. 15 N-(1 -Benzyl-piperidin-4-yl)-2-chloro-6-nitro-benzamide N0 2 0N CI 2-Chloro-6-nitro-benzoic acid (1.2 g, 5.97 mmol), 4-amino-1 benzylpiperidine (1.1 mL, 5.97 mmol), 1-hydroxybenzotriazole (0.84 g, 1.05 equiv) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1 g, 1.05 equiv) were 20 combined in ethyl acetate (20 mL). To this solution was added triethylamine (2.5 mL. 3.0 equiv) and the reaction mixture stirred at 40'C for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate, and concentrated to afford 1.9 g (85%) of the desired product. 25 (2-Amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl)-amine WO 2005/065779 PCT/US2003/038799 240
NH
2 N H CI Into a flame dried flask, N-(1 -benzyl-piperidin-4-yl)-2-chloro-6-nitro benzamide (1.67 g, 4.47 mmol) and lithium aluminium hydride (0.51 g, 13.43 mmol) were combined. To this was added anhydrous 1,4-dioxane (15 mL). The mixture 5 was slowly brought to reflux and stirred for 16 h. The reaction mixture was cooled to 0 0 C and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction. 10 3-(1 -Benzyl-piperidin-4-yl)-8-chloro-3,4-dihydro- 1 H-quinazolin-2-one CI N A stirred solution of (2-amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl) amine (0.66 g, 2.0 mmol) in tetrahydrofuran (8 mL) at 0 0 C was treated with carbonyl diimidazole (0.36 g, 2.05 mmol). The reaction was stirred for 30 min at 0 0 C and at 15 reflux for I h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 0.58 g (82%) of the desired product. LC/MS: tR = 1.40 min, 356.25 (MH)+. 2-Chloro-3-piperidin-4-yl-3,4-dihydro- 1 H-quinazolin-2-one C1 N Y 20 NH 3-(1-Benzyl-piperidin-4-yl)-8-chloro-3,4-dihydro-1H-quinazolin-2-one (0.17 g, 0.48 mmol) in methanol (10 mL) was flushed with nitrogen, and treated with palladium on WO 2005/065779 PCT/US2003/038799 241 charcoal (10%, 17 mg). Trifluoroacetic acid (0.2 mL) was added and the mixture flushed with nitrogen then allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 100 mg (79%) of the desired material. 5 LC/MS: tR = 0.99 min, 266.08 (MH)*. 5-Bromo-l H-indole-3-carbonitrile CN Br N H A mixture of 5-bromo-indole-3-carboxaldehyde (5 g, 22.3 mmol), 10 diammonium hydrogen phosphate (15.6 g, 31.8 mmol) in 1 -nitropropane (66 mL) and acetic acid (22 mL) were heated at reflux for 16 h. After cooling to room temperature, the solvents were removed under reduced pressure and water added to the dark residue. After a short while, 5-bromo-1H-indole -3-carbonitrile precipitated rapidly. The solid was filtered, washed severally with water and dried 15 for several hours to afford 4.3 g (86%) of the desired product. 'H-NMR (CD 3 0D) 5 7.40 (m, 2H), 7.77 (s, 1H), 7.97 (s, 1H). Mass spec.: 222.95 (MH)*. 5-Formyl-1 H-indole-3-carbonitrile 0 CN H SN H 20 5-Bromo-1H-indole -3-carbonitrile (4.25 g, 19.23 mmol) and sodium hydride (0.51 g, 21.2 mmol) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (24 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled 25 to -78'C and a solution of sec-butyllithium in cyclohexane (1.4M, 30.2 mL, 2.2 equiv) was added over several minutes. After 1 h at -78'C, dimethylformamide (6.0 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0 0 C and carefully treated with 1 N WO 2005/065779 PCT/US2003/038799 242 hydrochloric acid (45 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column 5 chromatography gave 2.4 g (72%) of pure material. LC/MS: tR = 0.99 min, 171.07 (MH)*. 2-Benzyloxycarbonylamino-3-(3-cyano-1H-indol-5-yl)-acrylic acid methyl ester 'N NH 0 CN N H 10 A stirred solution of N-benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (1.68 g, 5.1 mmol) in tetrahydrofuran (10 mL) at room temperature was treated with tetramethylguanidine (0.6 mL, 1.1 equiv). After 10 min, 5-formyl-1H-indole-3 carbonitrile (0.72 g, 4.24 mmol) was added. After stirring at room temperature for 3 days, the solvent was evaporated and the residue washed with water (2x), brine (2x), 15 dried over sodium sulfate, and concentrated. Column chromatography gave 1.3 g (82%) of pure material. LC/MS: tR = 1.43 min, 376.22 (MH)*. (±)-2-Amino-3-(3-cyano-1 H-indol-5-yl)-propionic acid methyl ester 0 N
NH
2 CN N H 20 2-Benzyloxycarbonylamino-3-(3 -cyano- 1 H-indol-5-yl)-acrylic acid methyl ester (0.5 g, 1.3 mmol) in methanol (8 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 50 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed WO 2005/065779 PCT/US2003/038799 243 with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.3 g (92%) of the desired material. LC/MS: t R = 0.80 min, 244.20 (MH)*. Example 202 5 (±)-3-(3-Cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester o N N NH CN N H A stirred solution of 2 -amino-3-(3-cyano-1H-indol-5-yl)-propionic acid methyl ester (25 mg, 0.11 mmol) in tetrahydrofuran (3 mL) at 0 0 C was treated with 10 carbonyl diimidazole (17.5 mg, 1.1 equiv.). The reaction was stirred for 5 min at 0*C, warmed to room temperature, stirred 10 min, and treated with 3-piperidin-4-yl 3,4-dihydro-1H-quinazolin-2-one (25 mg, 1.1 equiv.). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 40 mg (75%) as a white powder. LC/MS: tR 1.37 15 min, 501.33 (MH)*. Example 203 (±)-4-(2-Oxo-1, 4 -dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1-(3-cyano-1H-indol-5-yl-methyl)-2-oxo-ethyl]-amide H o N o H N NyN 0 N N 20 HN / CN WO 2005/065779 PCT/US2003/038799 244 A solution of 3
-(
3 -cyano- 1 H-indol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (15 mg, 0.03 mmol) in methanol (0.6 mL) at room temperature was treated with a solution of lithium hydroxide monohydrate (3.0 mg, 2.5 equiv.) in water (0.1 mL). The solution 5 was stirred at room temperature for 2 h. The solution was cooled to 0 0 C, and treated with aqueous IM potassium hydrogen sulfate (60 pL, 2.0 equiv.), and the solvents evaporated to give the crude acid which was used immediately without purification. The crude acid was dissolved in dimethylformamide (0.4 mL) cooled to 0 0 C, and sequentially treated with methylene chloride (0.2 mL), 4 -piperidyl-piperidine (11 mg, 10 2.2 equiv), NN-diisopropylethylamine (12 gL, 2.3 equiv) and PyBop (19 mg, 1.2 equiv). The solution was stirred for 15 min at 0*C, warmed to room temperature, stirred 1.5 h, and concentrated. The product was purified by column chromatography to give 10.1 mg (52% 2 steps). 'H-NMR (CD 3 0D) S 1.60-2.10 (in, 14H), 2.53 (d, J=13.0, lH), 2.58 (d, J=12.2, lH), 2.65-3.00 (m, 7H), 3.12 (d,fJ-7.0, 111), 3.17 (d, 15 J=7.0, 1H), 3.84 (s, 1H), 3.46 (bs, lH), 4.08-4.86 (m, 5H), 4.70 (m, 1H), 5.02 (dd, J=8.2, 6.7, 1H), 6.79 (d, J=7.6, IH), 6.9(m, IH), 7.10 (dd, J=7.3, 7.9, 1 H), 9.18 (s, 1H), 7.15 (dd, J=7.3, 7.6, 1H), 7.30 (m, 1H), 7.50 (m, lH), 8.00 (s, 1H). Mass spec.: 647.41 (MH)*. 20 3
-(
4 -Bromo-2-methyl-phenylamino)-2-methyl-acrylic acid ethyl ester 0 N, NH Br To a solution of 4-bromo-2-methyl aniline (7.0 g, 37.8 mmol) in acetonitrile (80 mL) was added, sequentially, concentrated hydrochloric acid (15 mL), water (40 mL) and a solution of sodium nitrite (2.74 g, 39.7 mmol) in water (40 mL) under ice 25 cooling to give the diazonium salt. The solution was transferred dropwise to a solution of 50% potassium hydroxide (16 mL) and ethyl-2-methyl acetoacetate (5.38 mL, 38 mmol) in ethanol (50 mL) at 0 0 C. After the addition was complete, the WO 2005/065779 PCT/US2003/038799 245 reaction mixture was poured into ice-water (150 mL) and extracted with ethyl acetate. The organic layer was washed with brine (2x), dried over sodium sulfate, filtered, and concentrated to give 7.5 g (66%) of the title compound which was used immediately without purification. 'H-NMR (CD 3 0D) S 1.80 (t, J=7.0, 3H), 2.13 (s, 5 3H), 2.29 (s, 3H), 4.26 (dd, J=5.8, 7.0, 1 H), 4.30 (dd, .J5.8, 7.0, 1 H), 7.26 (in, 2H), 7.43 (in, 1H). Mass spec.: 323.07 (MNa)*. 5-Bromo-7-methyl- 1 H-indole-2-carboxylic acid ethyl ester Br o 10 A solution ofp-toluenesulfonic acid monohydrate (4.26 g, 75 mmol) in toluene (80 mL) was heated at reflux under a dean-stark water separator for 1.5 h. To this solution was added a solution of 5-bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester (7.5 g, 25.0 mmol) in toluene (40 mL) and the reaction mixture heated at reflux for 5 h. After cooling to room temperature, the reaction mixture was poured in 15 to ice-water (120 mL) and extracted twice with ethyl acetate. The organic layers were pooled together and washed with sodium bicarbonate (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated. Column chromatography on silica gel afforded 5.5 g (78%) of the title compound. 'H-NMR (CD 3 0D) 8 1.35 (t, J=7.0, 3H), 2.52 (s, 3H), 4.36 (q, J=7.0, 2H), 7.13 (s, IH), 7.14 (s, 1H), 7.70 (s, 1H), 11.90 20 (s, 1H). Mass spec.: 284.09 (MH)*. 5-Bromo-7-methyl- 1 H-indole Br N H 5-Bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester (5.3 g, 18.7 25 mmol) was added to a potassium hydroxide solution in 1:1 water/ethanol mixture (20 mL) and heated at reflux for 12 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant residue transferred to a 6N hydrochloric acid solution (20 mL). The white precipitate that formed was filtered, washed severally with water, and dried for several hours. The crude solid was dissolved in WO 2005/065779 PCT/US2003/038799 246 quinoline (14 mL) and heated at reflux for 4 h. After cooling to room temperature, the crude mixture was poured into a mixture of ice water (100 mL) and concentrated hydrochloric acid (16 mL), extracted with ethyl acetate (2x), brine (2x), dried over sodium sulfate, and concentrated. Attempts to recrystallize the desired product from 5 isopropanol resulted in significant decomposition. The title compound was obtained by flash chromatography on silica get to afford 1.5 g (38%, 2 steps). LC/MS: tR 1.72 min, 210.05 (MH)*. 5 -Bromo-7-methyl- 1 H-indole-3 -carboxaldehyde H 0 Br N 10 H 5-Bromo-7-methyl-1H-indole (1.2 g, 5.71 mmol) was dissolved in acetonitrile (6 mL) and transferred slowly to a solution of bromomethylene dimethyl ammonium bromide (1.36 g, 6.28 mmol) in acetonitrile (9 mL) at -10 0 C to 0 0 C. The reaction was stirred at 0 0 C for 2 h and at room temperature for 30 min. The solvents were 15 evaporated and the crude mixture dissolved in water and stirred at 50'C for 4 h. After cooling to room temperature, the crude mixture was extracted with ethyl acetate (2x). The organic layers were pooled together and washed with brine (2x), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel afforded 0.7 g (52%, 2 steps) of the desired compound. 'H-NMR 20 (CD 3 0D) 8 2.50 (s, 3H), 7.24 (s, 1H), 8.34 (in, IH), 9.93 (s, 1H). Mass spec.: 238.05 (MH)+ 5-Bromo-7-methyl-1H-indole-3-carbonitrile CN Br N H 25 A mixture of 5-bromo-indole-3-carboxaldehyde (0.7 g, 2.94 mmol), diammonium hydrogen phosphate (2.05 g, 15.5 mmol) in 1-nitropropane (9 mL) and acetic acid (3 mL) were heated at reflux for 16 h. After cooling to room temperature, WO 2005/065779 PCT/US2003/038799 247 the solvents were removed under reduced pressure and water added to the dark residue. After a short while, 5-bromo-lH-indole-3-carbonitrile precipitated rapidly, was filtered, washed severally with water and dried for several hours to afford 0.6 g (87%) of the desired nitrile. LC/MS: tR = 1.71 min, 235.01 (MH)*. 5 5-Formyl-7-methyl-1H-indole-3-carbonitrile 0 CN H N H 5-Bromo-7-methyl-1H-indole -3-carbonitrile (0.58 g, 2.46 mmol) and sodium hydride (68 mg, 2.7 mmol) were weighed into a flame-dried round-bottom flask 10 containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (9 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to -78*C and a solution of sec-butyllithium in cyclohexane (1.4M, 3.8 mL, 2.2 equiv) was added over several minutes. After 1 h at -78'C, dimethylformamide 15 (0.9 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0 0 C and carefully treated with IN hydrochloric acid. After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with 20 water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography gave 60 mg (14%) of desired product and 0.4 g of unreacted starting material. LC/MS: tR = 1.21 min, 185.10 (MH)+. 2-Benzyloxycarbonylamino-3-(3-cyano-7-methyl-1H-indol-5-yl)-acrylic acid methyl 25 ester WO 2005/065779 PCT/US2003/038799 248 0 0 0 NH 0 CN N H A stirred solution of N-benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (180 mg, 0.54 mmol) in tetrahydrofuran (3 mL) at room temperature was treated with tetramethylguanidine (40 gL, 1.1 equiv). After 10 min, 5-formyl-7-methyl-1H 5 indole-3-carbonitrile (50 mg, 0.27 mmol) was added. After stirring at room temperature for 3 days, the solvent was evaporated and the residue washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography gave 100 mg (95%) of pure material. LC/MS: tR = 1.59 min, 390.24 (MH)*. 10 (E)-2-Amino-3-(3-cyano-7-methyl-1H-indol-5-yl)-propionic acid methyl ester 0 0
NH
2 CN N H 2-Benzyloxycarbonylamino-3-(3-cyano-7-methyl-1H-indol-5-yl)-acrylic acid methyl ester (0.1 g, 0.26 mmol) in methanol (2.5 mL) was flushed with nitrogen, and treated 15 with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 60 mg (90%) of the desired material. LC/MS: tR = 0.93 min, 258.22 (MH)*. 20 Example 204 WO 2005/065779 PCT/US2003/038799 249 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(3-cyano-7-methyl-1H-indol-5-yl-methyl)-2-oxo-ethyl] amide HN H CN 0 N N 0 5 Prepared as describe above for Example 203: 'H-NMR (CD 3 0D) 6 1.55-2.10 (m, 16H), 2.50 (s, 3H), 2.80-3.20 (in, 9H), 4.10-4.40 (in, 7H), 4.90 (m, 3H), 6.72 (d, J=7.9, lH), 6.93 (dd, J=8.5, 8.5, 1 H), 7.40 (s, 1H), 7.88(s, 1H), 7.90 (s, 1H), 7.99 (s, I H). Mass spec.: 651.57 (MH)*. 10 4-Bromo-2-isopropyl-6-methyl-phenylamine
NH
2 Br 2-Isopropyl-6-methyl-phenylamine (5 g, 33.5 mmol) was dissolved in acetic acid (20 mL). To this solution was added a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (5 mL) dropwise over 10 min. After stirring for I h at room 15 temperature, the reaction mixture was diluted with methylene chloride, washed with water (2x), saturated sodium thiosulfate (2x), saturated sodium bicarbonate (2x), and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel afforded 7.6 g (quantitative) of the desired product. LC/MS: tR = 1.37 min, 230.07 (MH)*. 20 4-Bromo-2-isopropyl-6-methyl-phenyldiazo-t-buty sulfide WO 2005/065779 PCT/US2003/038799 250 N 1 Br 4-Bromo-2-isopropyl-6-methyl-phenylamme (7.6 g, 33.5 mmol) was suspended in 24% hydrochloric acid (15 mL). The stirred mixture was cooled to 20'C and treated with sodium nitrite (2.4 g, 1.05 equiv.) in water (5 mL), dropwise 5 over 30 min while the temperature was maintained below -5'C. After a further 30 min at -5'C to -20'C, the mixture was buffered to ca. pH 5 with solid sodium acetate. This mixture (kept at ca. -1 O'C) was added in portions to a stirred solution of t-butyl thiol (3.77 mL, 1.0 equiv.) in ethanol (25 mL) at 0 0 C over ca. 30 min. Following addition, the mixture was stirred at 0 0 C for 30 min and then crushed ice (ca. 50 mL) 10 was added. The resulting light-brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours to afford 7.9 g (72%) of the desired product. 'H-NMR (CDCl 3 ) 8 1.15 (t, J=6.7, 3H), 1.58 (s, 9H), 2.00 (s, 3H), 2.54 (m, 1H), 7.20 (s, 1H), 7.28 (s, 1H). Mass spec.: 331.08 (MNa)*. 15 5-Bromo-7-isopropyl- 1 H-indazole HN-N Br A flame-dried round bottom flask was charged with 4-bromo-2,6 diethylphenyldiazo-t-butyl sulfide (7.94 g, 24 mmol) and potassium t-butoxide (27 g, 10 equiv). A stir bar was added and the mixture placed under nitrogen. To this was 20 added dry dimethylsulfoxide (70 mL). The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully poured into a mixture of crushed ice (250 mL) and 10% hydrochloric acid (120 mL). The resulting suspension was collected by filtration and washed severally with water. The solid WO 2005/065779 PCT/US2003/038799 251 was collected and dried in vacuo to give 4.2 g (74%) of the desired product. LC/MS: tR = 1.73 min, 241.06 (MH)*. 7-Isopropyl-1H-indazole-5-carbaldehyde HN -N 5 H O 5-Bromo-7-isopropyl-1H-indazole (3.1 g, 12.1 mmol) and sodium hydride (0.34 g, 1.1 equiv.) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (18 mL) was added. The mixture was stirred at room temperature for 10 15 min, during which time it became homogeneous. The stirred mixture was cooled to -78'C and a solution of sec-butyllithium in cyclohexane (1.4M, 20 mL, 2.2 equiv.) was added over several minutes. After 1 h at -78cC, dimethylfonnamide (3.0 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0 0 C and carefully treated with 1 N hydrochloric acid (35 15 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography gave 2.1 g (92%) of pure material. LC/MS: tR = 1.15 min, 189.12 (MH) t . 20 2 -Benzyloxycarbonylamino-3-(7-isopropyl- I H-indazol-5-yl)acrylic acid methyl ester HN-N N 0 N. 0 00 A stirred solution of N-benzyloxycarbonyl-ax-phosphonoglycine trimethyl ester (0.39 g, 1.2 equiv) in tetrahydrofuran (5 mL) at room temperature was treated 25 with tetramethylguanidine (0.16 mL, 1.1 equiv.). After 10 min, 7-isopropyl- 1 H- WO 2005/065779 PCT/US2003/038799 252 indazole-5-carbaldehyde (0.2 g, 1.06 mmol) was added. After stirring at room temperature for 3 days, the solvent was evaporated and the residue purified by flash chromatography on silica gel to give 0.35 g (84%) of product. LC/MS: tR = 1.61 min, 394.16 (MH)+. 5 (±)-2-Amino-3-(7-isopropyl-1H-indazol-5-yl)propionic acid methyl ester HN-N
NH
2 0 0 A solution of 2-benzyloxycarbonylamino-3-(7-isopropyl-1H-indazol-5 yl)acrylic acid methyl ester (0.35 g, 0.89 mmol) in methanol (7 mL) was flushed with 10 nitrogen, and treated with palladium on charcoal (10%, 35 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.21 g (90%) of the desired material. 15 Example 205 ( )-3-(7-Isopropyl-IH-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -prop ionic acid methyl ester HN-N \ H 0 N N N N 0 0 Prepared as described above for 3-(3-cyano-IH-indol-5-yl)-2-{[4-(2-oxo-1,4 20 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -propionic acid methyl ester. LC/MS: tR = 1.49 min, 519.35 (MH)*. Example 206 WO 2005/065779 PCT/US2003/038799 253 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(7-isopropyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide HN-N H 0 N N H N N 0 N 0 Prepared as described above for Example 203 from 3-(7-isopropyl-1H-indazol-5-yl) 5 2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- I -carbonyl] -amino} propionic acid methyl ester: 'H-NMR (CD 3 0D) 8 1.45 (in, 6H), 1.60-2.05 (in, 14H), 2.20-2.50 (in, 4H), 2.73 (d, J=13.7, 1H), 2.90 (m, 4H), 4.05 (d, J=14.0, 1H), 4.20 (in, 211), 4.35 (s, 1H), 4.65 (dd, J=12.2, 14.3, 1H), 4.95 (m, 2H), 6.79 (d, J=7.9, 1H), 6.92 (dd, J=7.6, 6.1, 1H), 7.13(m, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 8.05(s, 1H). Mass 10 spec.: 655.40 (MH)*. 4-Bromo-2,6-diethylphenyldiazo-t-butyl sulfide N N Br 4-Bromo-2,6-diethylaniline (6.3 g, 27.6 mmnol) was suspended in 24% 15 hydrochloric acid (15 mL). The stirred mixture was cooled to -20'C and treated with sodium nitrite (2.0 g, 1.05 equiv.) in water (5 mL), dropwise over 30 min while the temperature was maintained below -5*C. After a further 30 min at -5 0 C to -20*C, the mixture was buffered to ca. pH 5 with solid sodium acetate. This mixture (kept at ca. -10*C) was added in portions to a stirred solution of t-butyl thiol (3.15 mL, 1.0 20 equiv.) in ethanol (25 mL) at 0 0 C over ca. 30 min. Following addition, the mixture was stirred at 0 0 C for 30 min and then crushed ice (ca. 50 mL) was added. The WO 2005/065779 PCT/US2003/038799 254 resulting light-brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours to afford 6.0 g (66%) of the desired product. 'H-NMR (CDC 3 ) 8 1.15 (t, J=7.6, 6H), 1.50 (s, 9H), 2.27 (m, 4H), 7.21 (s, 2H). Mass spec.: 331.08 (MH)+. 5 5-Bromo-7-ethyl-3-methylindazole HN-N Br A flame-dried round bottom flask was charged with 4-bromo-2,6 diethylphenyldiazo-t-butyl sulfide (4.0 g, 12.1 mmol) and potassium t-butoxide (13.2 10 g, 10 equiv). A stir bar was added and the mixture placed under nitrogen. To this was added dry dimethylsulfoxide (35 mL). The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully poured into a mixture of crushed ice (130 mL) and 10% hydrochloric acid (60 mL). The resulting suspension was collected by filtration and washed severally with water. The solid 15 was collected and dried in vacuo to give 2.85 g (98%) as a beige solid. 'H-NMR
(CD
3 0D) 8 1.32 (t, J=7.6, 3H), 2.50 (s, 3H), 2.88 (in, 2H), 7.25 (s, 1H), 7.68 (s, IH). Mass spec.: 239.26 (MH)+. 7-Ethyl-3-methylindazole-5-carboxaldehyde HN-N 20 H 0 5-Bromo-7-ethyl-3-methylindazole (2.85 g, 11.9 mmol) and sodium hydride (0.31 g, 1.1 equiv.) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (15 mL) was added. The mixture was stirred at room temperature for 25 15 min, during which time it became homogeneous. The stirred mixture was cooled to -78'C and a solution of tert-butyllithium in pentane (1.4M, 18.7 mL, 2.0 equiv) WO 2005/065779 PCT/US2003/038799 255 was added over several minutes. After I h at -78'C, dimethylformamide (2.8 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0 0 C and carefully treated with 1N hydrochloric acid (30 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 5 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography gave 1.5 g (67%) of pure material. LC/MS: t R = 1.15 min, 189.12 (MH)*. 10 2-Benzyloxycarbonylamino-3-(7-ethyl-3-methyl- IH-indazol-5-yl)-acrylic acid methyl ester HN-N H ~N 0 ' N 0 0 0 A stirred solution ofN-benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (3.17 g, 9.57 mmol, 1.2 equiv.) in tetrahydrofuran (15 rnL) at room temperature 15 was treated with tetramethylguanidine (1.1 mL, 1.1 equiv.). After 10 min, 7-ethyl-3 methylindazole-5-carboxaldehyde (1.5 g, 7.98 mmol) was added. After stirring at room temperature for 3 days, the solvent was evaporated and the residue purified by flash chromatography on silica gel to give 2.5 g (80%) of product. LC/MS: tR = 1.61 min, 394.16 (MH)*. 20 (±)-2-Amino-3-(7-ethyl-3 methyl-iH-indazol-5-yl)-propionic acid methyl ester HN--N
NH
2 0 0 2-Benzyloxycarbonylamino-3-(7-ethyl-3-methyl- 1 H-indazol-5-yl)-acrylic acid methyl ester (1.0 g, 2.54 mmol) in methanol (15 mL) was flushed with nitrogen, and WO 2005/065779 PCT/US2003/038799 256 treated with palladium on charcoal (10%, 100 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.6 g (91%) of the desired material. 'H-NMR (CD 3 0D) S 1.32 5 (m, 3H), 2.50 (s, 3H), 2.88 (dd, J=7.3, 7.6, 1H), 2.89 (dd, J=7.6, 7.6, 1H), 3.02 (dd, J=6.4, 7.0, 1H), 3.11 (dd, J=7.6, 5.8, lH), 3.35 (s, 1H), 3.65 (m, 3H), 7.00 (s, lH), 7.33 (s, 1H). Mass spec.: 262.24 (MH)*. Example 207 10 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(7-ethyl-iH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide HN-N H 0 N H N N Y 0 N 0 Prepared as described above for Example 203 from (±)-2-amino-3-(7-ethyl-3 methyl IH-indazol-5-yl)-propionic acid methyl ester. 'H-NMR (CD 3 0D) 6 1.35 (in, 3H), 15 1.85-2.20 (in, 4H), 2.50 (s, 1H), 2.70 (m, 2H), 2.85 (s, 3H), 2.88-3.25 (in, 7H), 3.35 (s, 1H), 3.47 (dd, J=7.3, 7.3, 1H), 4.00-4.40 (in, 7H), 4.70 (in, lH), 5.00 (in, 3H), 6.79 (d, J=7.6, IH), 6.93 (dd, J=7.3, 7.3, 1H), 7.10 (m, 1H), 7.15 (dd, J=7.3, 7.6, 1H), 7.45 (m, 1 H). Mass spec.: 655.50 (MH) . 20 Example 208 (±)-4-(2,2-Dioxo- 1,4-dihydro-2H-2X 6 -benzo[ 1,2,6]thiadiazin-3-yl)-piperidine- 1 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-1(7-methyl-1H-indazol-5-yl-methyl)-2 oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 257 HN-N O H O N N N N N N 0 N0 Prepared as described above for Example 203 from 3-piperidin-4-yl-3,4-dihydro-IH benzo[ 1,2,6]thiadiazine-2,2-dioxide: 'H-NMR (CD 3 0D) 6 1.20-2.10 (m, 12H), 2.20 2.60 (m, 6H), 2.90 (m, 6H), 3.78-4.11 (m, 4H), 4.60 (s, 3H), 4.90 (m, 1H1), 6.70 (d, 5 J=8.1, 1H), 6.79 (dd, J=7.67, 7.3, 1H), 7.44 (s, 1H), 7.10 (m, 1H), 7.13 (m, 3H), 8.03 (s, 1H). Mass spec.: 663.60 (MH)+. Example 209 (±)-4-(2,2-Dioxo- 1,4-dihydro-2H-2X6 -benzo[ 1,2,6]thiadiazin-3-yl)-piperidine- 1 10 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-1(7-ethyl-3-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl]-amide HN--N O H N H N N 0 N O0 Prepared as described above for Example 203 from 3-piperidin-4-yl-3,4-dihydro-1H benzo[1,2,6]thiadiazine-2,2-dioxide: 'H-NMR (CD 3 0D) 6 1.35 (m, 3H), 1.42-2.05 15 (m, 1OH), 2.40 (m, 3H), 2.55 (s, 3H), 2.67-3.12 (m, 7H), 3.85 (m, 111), 3.97 (s, 1H), 4.03 (m, 3H), 4.65 (m, 4H), 4.95 (dd, J-4.9, 5.8, 1H), 6.73 (d, J=7.9, 1H), 6.98 (dd, J=7.3, 6.4, 1H), 7.20 (m, 2H), 7.88 (s, 1H). Mass spec.: 691.51 (MH)+. Example 210 WO 2005/065779 PCT/US2003/038799 258 (±)-2-[4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine- 1 -carbonyl] amino]-3 -(7-methyl-1 H-indazol-5.-yl)-propionic acid methyl ester H N 0 NN" NC"C H N N NH N Prepared as described above for 3-(3-cyano- 1 H-indol-5-yl)-2- { [4-(2-oxo- 1,4 5 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino } -propionic acid methyl ester: LC/MS: tR = 1.34 min, 516.40 (MH) . Example 211 (±)-4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid 10 {2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide H N y0 NC N N N HN N Prepared as described above for Example 203 from 2-oxo-3-piperidin-4-yl-1,2,3,4 tetrahydro-quinazoline-6-carbonitrile: 'H-NMR (CD 3 0D) 8 1.80 (m, 12H), 2.4 0(m, 15 4H), 2.60 (s, 3H), 2.70-3.20 (m, 10H), 4.00-4.30 (m, 6H), 5.00 (m, 1H), 5.50 (s, 2H), 6.90 (d, J=7.8, I H), 7.21 (s, 1H), 7.50 (m, 4H), 8.05 (s, 1 H). Mass spec.: 652.64 (MH)*. Example 212 WO 2005/065779 PCT/US2003/038799 259 (±)-4-(2-Oxo- 1,2,4,5-tetrahydro-benzo[d] [1,3]diazepin-3-yl- 1 -carboxylic acid {2 [1,4']bipiperidinyl-l'-yl-l-(7-methyl-IH-indazol-5-yl methyl)-2-oxo-ethyl}-amide HN' N NH 0 N' 0 NN Prepared as described above for Example 203 from 3-piperidin-4-yl-1,3,4,5 5 tetrahydro-benzo[d][1,3]diazepin-2-one: 'H-NMR (CD 3 OD) 5 1.40-2.00 (m, 12H), 2.30-2.60 (m, 8H), 2.70-3.20 (m, 10H), 3.70 (m, 2H), 3.60 (d, J=9.5, 1H), 4.00-4.30 (m, 4H), 4.70 (m, 1H), 5.00 (m, 1H), 6.90 (m, 2H), 7.10 (m, 3H), 7.20 (s, 1H), 7.50 (s, 111), 8.05 (s, 1H). Mass spec.: 652.64 (MH)*. 10 Example 213 (t)-4-(6-Hydroxy-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine- 1 -carboxylic acid {2-[1,4']bipiperidinyl- '-yl-1 -(7-methyl-i H-indazol-5-yl methyl)-2-oxo-ethyl} amide HN-N OH H N NNN NH 00 N' 0 15 Prepared as described above for Example 203 from 6-hydroxy-3 -piperidin-4-yl-3,4 dihydro-1H-quinazolin-2-one: LC/MS: tR = 1.24 min, 643.62 (MH) 4 . Example 214 WO 2005/065779 PCT/US2003/038799 260 (±)-4-(8-Methoxy-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine- I -carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide HN-N N N I H O N> NH 0 0 0 N N 0 5 Prepared as described above for Example 203 from 8-methoxy-3-piperidin-4-yl-3,4 dihydro-1H-quinazolin-2-one: 'H-NMR (CD 3 0D) 8 1.40-2.00 (m, 12H), 2.40 (m, 2H), 2.50 (s, 3H), 2.80 (m, 3H), 3.00-3.20 (m, 3H), 3.50 (m, 2H), 4.00-4.60 (m, 6H), 5.00 (m, 2H), 6.70 (dd, J=8.5, 10.1, 1H), 6.85 (m, 2H), 7.10 (m, 1H), 7.20 (s, 1H), 7.47 (s, 1H). Mass spec.: 657.41 (MH)*. 10 Example 215 (±)-4-(8-Chloro-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-l-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide HN-N CI H 'N0 N H N N I0 r-N 0 15 N Prepared as described above for Example 203 from 2-chloro-3-piperidin-4-yl-3,4 dihydro-1H-quinazolin-2-one: 'H-NMR (CD 3 0D) 5 1.40-2.00 (m, 14H), 2.30 2.60(m, 8H), 2.80 (m, 4H), 3.50 (m, 3H), 3.98 (s, 1H), 4.10 (m, 4H), 4.40 (m, 2H), 4.60 (m, 1H), 4.95 (m, 1H), 6.95 (dd, J=7.9, 7.9, 1H), 7.10 (m, 1H), 7.26 (dd, J=6.7, 20 7.6, 1H), 7.47 (m, IH), 8.04 (s, 1H). Mass spec.: 661.27 (MH)*.
WO 2005/065779 PCT/US2003/038799 261 Example 216 (±)-N-(3-(7-Ethyl-3-methyl- 1H-indazol-5-yI)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1 yl)propan- 2 -yl)-2', 3 '-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)- I 5 carboxamide HN-N 0 HN NH H N N 0 N N 0O Prepared as described above for Example 203: LC/MS: tR = 1.51 min, 641.63 (MH)+. 10 Example 217 (±)-N-(3-(7-Ethyl-3-methy11H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin- 1 yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1,3]oxazine) 1 -carboxamide HN--N 0 0 "uNH H N N N N 0 15 Prepared as described above for Example 203: LC/MS: tR 1.48 min, 642.61 (MH)+. tert-Butyl 2-fluorophenylcarbamate WO 2005/065779 PCT/US2003/038799 262 Q /NHBoc F To a solution of di-tert-butyldicarbonate (45.2 g, 207 mmol, 1.0 equiv.) in tetrahydrofuran (210 mL) at room temperature was added 2-fluoroaniline (20.0 mL, 207 mmol). The reaction was heated to reflux and held there for 6h. It was cooled, 5 concentrated, dissolved in pentane, washed with 5% citric acid, then I M potassium bisulfate (2x), then water, then 20% potassium hydroxide, then brine, dried over magnesium sulfate, and concentrated to give 48.0 g (quant.) as an amber oil which was used without purification. 'H-NMR (CDC 3 , 500 MHz) 6 1.52 (s, 9H), 6.68 (bs, lH), 6.85-7.20 (m, 3H), 8.07 (dd, J=8.1, 8.1, lH). Mass spec.: 234.18 (MNa)*. 10 2 -(tert-Butoxycarbonylamino)-3-fluoro-benzoic acid
CO
2 H NHBoc F To a solution of tert-butyl 2 -fluorophenylcarbamate (44.0 g, 208 mmol) in tetrahydrofuran (660 mL) at -78'C was added tert-butyllithium in pentane (1.7 M, 15 306 mL, 2.5 equivx) dropwise. After addition was complete, the reaction was stirred at -78'C for 30 min. The solution was allowed to gradually reach -20'C before being recooled to -78'C and transferred via canula to a slurry of carbon dioxide (excess) and tetrahydrofuran (500 mL). The solution was allowed to slowly warm to room temperature. The reaction mixture was concentrated to remove most of the 20 tetrahydrofuran, and poured into a sep funnel containing water and diethyl ether. The layers were separated, and the aqueous extracted with diethyl ether twice more. The ethereals were discarded. The aqueous was acidified with 5% citric acid, extracted with diethyl ether (3x). The ethereal was dried over magnesium sulfate, and concentrated to give a light yellow solid which was recrystallized from hot toluene to 25 give 37.1 g (70%) as a faint yellow solid. 'H-NMR (CDC 3 , 500 MHz) 6 1.50 (s, 9H), 6.25 (bs, 1H), 7.18 (ddd, J=7.9, 7.9, 4.9, 1H), 7.33 (dd, J=9.5, 9.2, lH), 7.79 (d, J=7.9, 1H), 7.94 (s, lH). Mass spec.: 278.21 (MNa)*.
WO 2005/065779 PCT/US2003/038799 263 tert-Butyl 2-(1-benzylpiperidin-4-ylcarbamoyl)-6-fluorophenylcarbamate BnN 0 NHBoc N F H To a solution of 2-(tert-butoxycarbonylamino)-3-fluoro-benzoic acid (37.1 g, 145 mmol), 4-amino-1-benzylpiperidine (35.6 mL, 1.20 equiv.), 1 5 hydroxybenzotriazole (21.6 g, 1.1 equiv.), and triethylamine (44.1 g, 3.0 equiv.) in ethyl acetate (450 mL) was added 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (30.7 g, 1.1 equiv.) in one portion. Initially, everything went into solution, but a precipitate formed very rapidly. The reaction was fitted with a reflux condenser and heated at reflux for 5 h. The reaction was 10 diluted with ethyl acetate, washed with water (2x), then IN sodium hydroxide (2x), then brine, dried over magnesium sulfate, and concentrated to give 67.0 g (quant.) as a white solid which was used without purification. 'H-NMR (CDCl 3 , 500 MHz) 3 1.48 (s, 9H), 1.55 (in, 2H), 1.99 (bd, J=1 1.0, 2H), 2.17 (dd, J=1 1.0, 11.0, 2H), 2.84 (bd, J=1 1.3, 2H), 3.51 (s, 2H), 3.94 (in, lH), 6.13 (bd, J=7.6, 1H), 7.10-7.28 (in, 15 4H), 7.31 (in, 4H), 7.59 (s, 1H). Mass spec.: 428.41 (MH)+. 2-Amino-N-(1 -benzylpiperidin-4-yl)-3-fluorobenzamide BnN 0 NH 2 N &F H To a solution of tert-butyl 2-(1 -benzylpiperidin-4-ylcarbamoyl)-6 20 fluorophenylcarbamate (67.0 g, 157 mmol) in dichloromethane (700 mL) at 0 0 C was added trifluoroacetic acid (100 mL). The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous was extracted with ethyl acetate (2x), which were washed with water (3x), then brine, dried over 25 magnesium sulfate, and concentrated to give 47.6 g (93%) as a white solid which was used without purification. Mass spec.: 328.33 (MH)+.
WO 2005/065779 PCT/US2003/038799 264 N-(2-Amino-3-fluorobenzyl)- 1 -benzylpiperidin-4-amine BnN NH 2 F H To a refluxing suspension of lithium aluminum hydride (16.1 g, 424 mmol, 3.50 equiv.) in dioxane (800 mL) was added a solution of 2-amino-N-(1 5 benzylpiperidin-4-yl)-3-fluorobenzamide (39.7 g, 121 mmol) in dioxane (250 mL) at such a rate that gas evolution was limited to a safe flow. Upon completion of the addition, the resulting suspension was heated at reflux for 4 h. The reaction was cooled to 0 0 C, and quenched by the cautious addition of 20% potassium hydroxide. Upon formation of a white, filterable precipitate, the solid was filtered through a 10 course glass sintered funnel, and the eluent concentrated to give 36.3 g (96%) as a light yellow oil which was used without purification. Mass spec.: 314.29 (MH)+. 3-(1-Benzylpiperidin-4-yl)-8-fluoro-3,4-dihydroquinazolim-2(1H)-one H F ON "aN BnN 15 To a solution of N-(2-amino-3-fluorobenzyl)-1-benzylpiperidin-4-amine (36.3 g, 116 mmol) in tetrahydrofuran (600 mL) at room temperature was added carbonyl diimidazole (20.7 g, 1.10 equiv.) in one portion. The reaction was stirred at room temperature for 3 h, heated at reflux for 30 min, and concentrated. The resulting solid was dissolved in 1:1 diethyl ether/ethyl acetate, washed with water (3x), then 20 brine, dried over magnesium sulfate, and concentrated to give the crude product as a wet, yellow solid. The solid was triturated with diethyl ether and filtered to give 30.0 g (76%) as a white powder. 1 H-NMR (CDCl 3 , 500 MHz) 8 1.68 (in, 2H), 1.86 (dddd, J= 11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, J=1 1.6, 10.1, 2H), 2.98 (d, J=1 1.6, 2H), 3.51 (s, 2H), 4.34-4.44 (m, 3H), 6.71 (bs, 1H), 6.79-6.89 (in, 2H), 6.94 (dd, J=9.2, 9.2, 25 1H), 7.21-7.34 (in, 5H). Mass spec.: 340.30 (MH)*. 8-Fluoro-3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1 H)-one WO 2005/065779 PCT/US2003/038799 265 H F 0 NN H N A 250 mL flask was charged with 3-(1-benzylpiperidin-4-yl)-8-fluoro-3,4 dihydroquinazolin-2(1H)-one (1.40 g, 4.12 mmol) and methanol (25.0 mL). The suspension was heated with a heat gun to aid in dissolution. The flask was flushed 5 with nitrogen, treated with palladium on charcoal (141 mg, 0.032 equiv.), flushed with nitrogen, then hydrogen, and vigorously stirred under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 0.99g (97%) as a white solid which was used without purification. 'H-NMR (CDCl 3 , 500 MHz) 8 1.71 (in, 4H), 2.75 (in, 2H), 3.16 (in, 10 2H), 4.38 (s, 2H), 4.46 (in, 1H), 6.77 (bs, 1H), 6.81-6.89 (m, 2H), 6.95 (in, 1H). Mass spec.: 250.22 (MH)*. 3-(1-Benzylpiperidin-4-yl)-8-fluoroquinazoline-2,4(1H,3H)-dione H F 0 N BnN 0 15 To a solution of 2-amino-N-(1-benzylpiperidin-4-yl)-3-fluorobenzamide (750 mg, 2.29 mmol) in dichloromethane (30.0 mL) at 0 0 C was added triphosgene (227 mg, 0.33 equiv.) as a solution in dichloromethane (5 mL). The ice bath was removed and the reaction heated at reflux for 6h. The reaction was concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate, then water, then brine, dried 20 over magnesium sulfate, and concentrated to give 700 mg of a white solid. The crude product was purified by flash chromatography to give 205 mg (25%) as a white solid. Mass spec.: 354.13 (MH)+. 8-Fluoro-3-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione WO 2005/065779 PCT/US2003/038799 266 H F 0N HN 0 A flask containing a solution of 3-(1 -benzylpiperidin-4-yl)-8 fluoroquinazoline-2,4(1H,3H)-dione (75.0 mg, 0.21 mmol) and palladium on charcoal (8.00 mg, 0.035 equiv) in methanol (3.00 mL) was flushed first with 5 nitrogen, then hydrogen. The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 53 mg (95%) as a white solid which was used without purification. Mass spec.: 264.25 (MH)+. 10 8'-Fluoro-2',3'-dihydro-2'-oxospiro-(I -phenylmethylpiperidine)-4,4'-quinazoline 0 HN NH BnN F A 500 mL 3-neck flask was charged with polyphosphoric acid (110 mL) and fitted with an overhead stirrer, a nitrogen inlet, and a bubbler. The flask was flushed with nitrogen and heated to 105'C in an oil bath. To this was added 1-benzyl-4 15 piperidone (21.0 mL, 115 mmol). To this was added N-(2-Fluorophenyl)urea (21.3 g, 1.2 equiv) in many small portions over 2h. The reaction was heated to 160'C with vigorous stirring. After 2h, the reaction was quenched by pouring over crushed ice and neutralizing with 20% potassium hydroxide. The reaction mixture was extracted with dichloromethane, washed with water, then brine, dried over magnesium sulfate, 20 and concentrated. The whole lot was purified by preparative HPLC (~130 injections) to give a much purer product. The product was repurified by flash chromatography to give a solid which was triturated with diethyl ether and filtered to give 275 mg (0.7%) as a white solid. 'H-NMR (CDCl 3 , 500 MHz) 6 1.91 (dd, J=13.7, 2.1, 2H), 2.10 (ddd, J=13.1, 13.1, 4.3, 2H), 2.27 (ddd, J=12.5, 12.5, 2.1, 2H), 2.86 (m, 2H), 25 3.57 (s, 2H), 5.40 (bs, 1H), 6.90 (bs, 1H), 6.90-7.05 (m, 3H), 7.27 (m, 1H), 7.32 (m, 4H). Mass spec.: 326.13 (MH)+.
WO 2005/065779 PCT/US2003/038799 267 8'-Fluoro-2',3'-dihydro-2'-oxospiro-piperidine-4,4'-quinazoline 0 HN NH HN IF To a solution of 8'-fluoro-2',3'-dihydro-2'-oxospiro-(1 5 phenylmethylpiperidine)-4,4'-quinazoline (250 mg, 0.77 mmol) in methanol (4 mL) and dichloromethane (4 mL) was added palladium on charcoal (30.0 mg, 0.037 equiv.). The reaction was flushed with hydrogen, and stirred under an atmosphere of hydrogen overnight. The balloon was removed, the reaction flushed with nitrogen, filtered through celite, washed with additional methanol, and concentrated to give 10 158 mg (87%) as a white solid which was used without purification. 'H-NMR (CDCl 3
/CD
3 0D, 500 MHz) 8 1.87 (d, J=12.8, 2H), 2.15 (ddd, J=14.0, 14.0, 5.5, 2H), 3.10 (m, 4H), 6.84 (in, 2H), 6.93 (d, J=7.0, 1H). Mass spec.: 236.11 (MH)*. Example 218 15 ( )-N-(3-(7-Ethyl-1H-indazol-5-yl)-I-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H) yl)-l-oxopropan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 carboxamide N-NH H 'NN H N N 0 N N 0 N H Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) 8 1.24 20 (m, 2H), 1.55-2.07 (in, 5H), 2.57 (m, 1H), 2.82 (m, 4H), 3.08 (in, 2H), 3.30 (in, 3H), 3.35 (in, 5H), 3.48 (in, 3H), 3.65 (in, IH), 4.14 (m, 2H), 4.27 (in, 2H), 4.33-4.57 (m, 2H), 5.06 (dd, J=6.7, 6.7, lH), 5.22 (d, J=1.8, 2H), 6.78 (d, J=7.6, 1H), 6.93 (m, 1H), 7.00-7.18 (in, 3.5 H), 7.37 (d, J=9.8, 1H), 7.46 (s, 0.5H), 7.91 (dd, J=10.1, 1.8, 1H). Mass spec.: 596.43 (MH)+.
WO 2005/065779 PCT/US2003/038799 268 Example 219 (h)-N-(3-(7-Ethyl-1H-indazol-5-yl)-I -(6,7-dihydro-7,7-dimethyl-1H-pyrazolo[4,3 c]pyridin-5(4H)-yl)-1-oxopropan-2-yl)-4-(1, 2 -dihydro-2-oxoquinazolin-3(4H) 5 yl)piperidine-1 -carboxamide N-NH H /N 0 N H N N 0 N N 0 N H Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) S 1.11 (in, 3H), 1.50-1.80 (m, 4H), 2.87 (in, 4H), 3.10 (m, 2H), 3.32 (in, 9H), 3.48 (in, 4H), 4.00-4.45 (in, 6H), 5.05-5.25 (in, 2H), 6.77 (d, J=6.1, 1H), 6.93 (m, I H), 7.13 (m, 10 3H), 7.30-7.60 (m, 2H), 7.95 (m, IH). Mass spec.: 624.49 (MH)*. Example 220 (±)-Methyl 2-(4-(8-fluoro-1, 2 -dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 carboxamido)-3-(7-methyl-iH-indazol-5-yl)propanoate N-NH H F N N N 15 MeO 00 Prepared as described above for 3-(3-cyano-1H-indol-5-yI)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino} -propionic acid methyl ester: 'H-NMR (CDCl 3 , 500 MHz) 8 1.53-1.68 (in, 4H), 2.48 (s, 3H), 2.82 (in, 2H), 3.05 (m, 6H), 3.09 (dd, JB=13.7, 6.1, 1H), 3.14 (dd, JAB=14.0, 6.1, 1H), 3.35 (bs, 20 1 H), 3.68 (s, 3H), 3.88-4.02 (m, 2H), 4.22 (d, JAB=15.6, 1H), 4.25 (d, JAB=15.3, 1H), 4.44 (m, lH), 4.71 (dd, J=6.1, 6.1, 1H), 6.78 (d, J=7.3, 1H), 6.84 (ddd, J=7.6, 7.6, 4.9, 1H), 6.88-6.95 (m, 2H), 7.28 (s, 1H), 7.91 (s, 1H). Mass spec.: 509.25 (MH)*.
WO 2005/065779 PCT/US2003/038799 269 Example 221 (+)-4-(8-Fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-IH-indazol 5-yl)-l-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine- 1 5 carboxamide N-NH H F 0 N N H N N 0 N 0 Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) 8 -0.25 (m, IH), 0.82 (m, 1H), 1.25-2.10 (m, 13H), 2.20-2.63 (m, 6H), 2.68-2.98 (m, 4H), 3.00-3.22 (m, 3H), 3.31 (m, 2H), 3.44 (bs, 1H), 4.00-4.50 (m, 6H), 4.64 (m, 1H), 4.96 10 (m, 1H), 6.85-7.05 (m, 3H), 7.08 (s, 0.4H), 7.20 (s, 0.6H), 7.46 (d, J=7.0, 1H), 7.99 (s, 0.4H), 8.05 (d, J=2.4, 0.6H). Mass spec.: 645.58 (MH)*. Example 222 (±)-4-(8-Fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol 15 5-yl)-l-oxo-1-(4-phenylpiperazin-I -yl)propan-2-yl)piperidine-1-carboxanide N-NH H F /0 yN N H N N 0 N 0 N N Prepared as described above for Example 203: 'H-NMR (CDC1 3 , 500 MHz) 8 1.73 (m, 4H), 2.49 (m, 4H), 2.80-3.26 (m, 7H), 3.43 (m, 2H), 3.65-3.95 (m, 3H), 4.14 (dd, J=21.7, 14.3, 2H), 4.32 (s, 2H), 4.51 (m, 1H), 5.15 (dd, J=7.9, 6.4, 1 H), 5.90 (bs, 20 1H), 6.80 (d, J=7.3, 1H), 6.83-7.01 (m, 4H), 7.06 (dd, J=7.6, 7.3, 1H), 7.10 (s, IH), WO 2005/065779 PCT/US2003/038799 270 7.26-7.33 (m, 2H), 7.44 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1 H). Mass spec.: 639.36 (MH)*. Example 223 5 (±)-4-(8-Fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(4 fluorophenyl)piperazin-I -yl)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2 yl)piperidine- 1 -carboxamide N-NH H F /0 yN O N N H ': N N 0 N 0 N F Prepared as described above for Example 203: 'H-NMR (CDCl 3 , 500 MHz) 6 1.73 10 (m, 4H), 2.26 (dd, J=7.9, 7.6, 1H), 2.49 (s, 3H), 2.75-3.05 (m, 4H), 3.09 (m, 2H), 3.19-3.45 (m, 3H), 3.63 (m, 1H), 3.78 (m, 2H), 4.13 (dd, J=16.5, 15.3, 2H), 4.32 (s, 2H), 4.50 (m, 1H), 5.15 (dd, J=8.2, 6.1, 1H), 5.85 (bs, IH), 6.70-6.84 (m, 3H), 6.85 7.02 (m, 5H), 7.09 (s, 1H), 7.43 (s, lH), 7.78 (s, 1H), 8.06 (s, 1H). Mass spec.: 657.35 (MH)*. 15 Example 224 (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(4-(2 fluorophenyl)piperazin-1 -yl)-3-(7-methyl- 1 H-indazol-5-yl)-1 -oxopropan-2 yl)piperidine- 1 -carboxamide N-NH H F 0 N N H N N rl N 0 0 N 20 F WO 2005/065779 PCT/US2003/038799 271 Prepared as described above for Example 203: 1 H-NMR (CDCl 3 , 500 MHz) 8 1.62 1.78 (m, 4H), 2.24 (dd, J=7.9, 8.2, 1H), 2.50 (s, 3H), 2.70-2.85 (m, 2H), 2.85-2.96 (m, 2H), 2.00 (m, 1H), 3.08 (dd, JA3=13.1, 8.6, 1H), 3.12 (m, lH), 3.30 (m, IH), 3.57 (m, 1H), 3.73 (m, 2H), 4.13 (dd, J=19.8, 15.0, 2H), 4.33 (s, 2H), 4.53 (m, 1H), 5.18 5 (dd, J=8.2, 5.8, 1H), 5.82 (bs, 1H), 6.58 (dd, J=8.2, 8.2, 1 H), 6.81 (d, J=7.6, 1H), 6.85-7.05 (m, 5H), 7.09 (s, 1H), 7.44 (s, 1H), 7.58 (s, IH), 8.05 (s, IH). Mass spec.: 657.37 (MH)+. Example 225 10 (±)-4-(8-Fluoro-1, 2 -dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol 5-yl)-l-oxo-1 -( 4 -o-tolylpiperazin-1-yl)propan-2-yl)piperidine-1-carboxamide N-NH H F 0YIN N H N N D 00 N OO N Prepared as described above for Example 203: 'H-NMR (CDC 3 , 500 MHz) 8 1.60 1.79 (m, 4H), 2.03 (dd, J=8.5, 8.2, 1H), 2.22 (s, 3H), 2.49 (s, 3H), 2.54 (dd, J=8.6, 15 8.5, 1H), 2.65 (m, 1H), 2.81 (m, 1H), 2.85-2.97 (m, 2H), 3.05-3.22 (m, 3H), 3.38 (m, 1H), 3.50-3.65 (m, 2H), 3.83 (m, 1H), 4.15 (dd, J=15.9, 15.3,22H), 4.31 (s, 2H), 4.53 (m, 1H), 5.19 (dd, J=7.9, 5.8, 1 H), 5.84 (bs, 1 H), 6.54 (d, J=7.6, 1H), 6.81 (d, J=7.6, I H), 6.89 (ddd, J=7.6, 7.6, 5.2, 1H), 6.96 (m, 2H), 7.00-7.23 (m, 4H), 7.39 (s, I H), 7.43 (s, 1H), 8.04 (s, 1H). Mass spec.: 653.38 (MH)*. 20 Example 226 (±)-Methyl 2-(4-(8-fluoro-1, 2 -dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 carboxamido)-3-(7-ethyl-3-methyl-1H-indazol-5-yl)propanoate WO 2005/065779 PCT/US2003/038799 272 N-NH H F N N N 0 MeO 0 Prepared as described above for 3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidine-l-carbonyl]-amino} -propionic acid methyl ester: 'H-NMR (CD 3 0D, 500 MHz) 8 1.33 (in, 3H), 1.39-1.72 (in, 4H), 2.70-2.95 5 (m, 3H), 3.06 (m, IH), 3.25 (m, 1H), 3.70 (m, 3H), 3.95-4.30 (m 4H), 4.38 (m, 1 H), 4.57 (m, 1H), 6.80-7.05 (in, 3H), 7.08 (s, IH), 7.38 (s, IH). Mass spec.: 537.47 (MH)*. Example 227 10 (±)-N-(3-(7-Ethyl-3-methyl- 1H-indazol-5-yl)-1 -oxo-1-(4-(piperidin-1-yl)piperidin-1 yl)propan-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 carboxamide N-NH H F 0 N N H N N 0 N 0 Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) 8 -0.36 15 (in, 1H), 0.70 (m, 1H), 1.21 (bd, J= 1.9, 1H), 1.28-2.00 (in, 19H), 2.31 (dd, J=1 1.6, 11.3, 1H), 2.40 (dd, J=13.1, 11.6, IH), 2.79-3.16 (m, 7H), 3.72 (in, IH), 3.85-4.03 (in, 1H), 4.10-4.48 (m, 5H), 4.53 (bd, J=11.0, IH), 5.05 (m, LH), 6.85-7.03 (in, 3H), 7.08 (s, 0.2H), 7.18 (s, 0.8H), 7.37 (s, 1H). Mass spec.: 673.42 (MH)*. 20 Example 228 WO 2005/065779 PCT/US2003/038799 273 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- I -(4-(piperidin- 1 yl)piperidin- 1 -yl)propan-2-yl)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamide 0 N H H F 0 N N H N N 0 NN 0 N 5 Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) 8 0.71 (m, 1 H), 1.26 (m, I H), 1.40-2.15 (m, 13H), 2.50-3.29 (m, 9H), 3.32-3.64 (m, 3H), 4.14 (d, JAB=12.8, 1H), 4.17 (d, JAB=1 1.6, 1H), 4.32-4.45 (m, 3H), 4.68 (bd, J=13.4, 1H), 4.92 (m, 1H), 6.87-7.22 (m, 6H). Mass spec.: 648.47 (MH)+. 10 Example 229 (d)-N-(3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1 yl)propan-2-yl)-8'-fluoro-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)-1 carboxamide N-NH 0 HN NH H F N N 0 N 0 15 Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) 8-0.23 (m, 1H), 0.85 (m, 1H), 1.20-2.10 (m, 22H), 2.25-2.55 (m, 7H), 2.58 (s, 3H), 2.74 (d, J=11.3, 1H), 2.94 (dd, J=12.5, 12.2, 2H), 3.00-3.20 (m, 5H), 3.40-3.65 (m, 2H), 3.80-4.15 (m, 4H), 4.55-4.73 (m, 2H), 4.96 (dd, J=7.9, 7.6, IH), 5.01 (dd, J=10.4, WO 2005/065779 PCT/US2003/038799 274 5.8, 1H), 6.65-7.15 (m, 5H), 7.21 (s, 1H), 7.47 (s, I H), 7.96 (m, IH), 8.04 (s, I H). Mass spec.: 631.29 (MH)+. Example 230 5 (±)-4-(8-Fluoro-1,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-IH indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1 carboxamide N-NH H F 0 N N H N N 0 N N 00 Prepared as described above for Example 203: 'H-NMR (CD 3 0D, 500 MHz) 6 -0.26 10 (in, 1H), 0.81 (m, 1H), 1.20-2.10 (in, 1 1H), 2.20-2.80 (in, 9H), 2.90 (in, 3H), 3.10 (in, 3H), 3.34 (in, 1H), 3.44 (in, 1H), 4.06 (bd, J=13.4, 1H), 4.17 (d, JAB=15.9, 1H), 4.22 (d, JA=1 3 .1, 1H), 4.64 (dd, J=24.4, 13.1, 1H), 4.91-5.13 (in, 2H), 7.00-7.25 (m, 2H), 7.44 (in, 2H), 7.81 (m, 1H), 7.92-8.08 (m, IH). Mass spec.: 659.59 (MH)+. 15 (R)-Methyl 2 -amino-3-(2-(trifluoromethyl)-IH-benzo[d]imidazol-5-yl)propanoate F N NH 2 H A mixture of (R)- 2 -benzyloxycarbonylamino-3-(3, 4 -diamino-phenyl)-propionic acid methyl ester (500 mg, 1.20 mmol) and trifluoroacetic acid (6 mL) was heated at 80'C for 16 h. The reaction mixture was poured into ice water (75 mL), neutralized to pH 20 7 with aqueous saturated sodium bicarbonate, and extracted with ethyl acetate (2 x 250 mL). The organic extracts were dried over sodium sulfate, filtered and evaporated to give the title compound as the trifluoroacetic acid salt (459 mg, 84 % yield). 'H-NMR (CDCl 3 , 300 MHz) 8 7.37 (bs, IH) 7.35 (bs, 1 H), 7.17 (d, J= 8.4 WO 2005/065779 PCT/US2003/038799 275 Hz, 1H), 4.70 (s, 2 H), 3.85 (dd, J= 8.4, 4.8 Hz, 1H), 3.77 (s, 3H), 3.30 (dd, J = 13.9, 4.8 Hz, 1H), 2.97 (dd, J= 13.5, 8.4 Hz, 1H). Mass spec.: 288 (MH)+. 5 (R)-Methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido) 3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanoate HN >NH F N.N OH H N N A solution of the amino ester (R)-methyl 2-amino-3-(2-(trifluoromethyl)-1H benzo[d]imidazol-5-yl)propanoate (230 mg, 0.51 mmol), diisopropylethylamine (262 10 mg, 2.03 mmol), and disuccinimidyl carbonate (129 mg, 0.51 mmol) in a mixture of methylene chloride/dimethylformamide (15:1 ratio) was stirred at room temperature for 30 min. To the solution was added 4-(2-keto-1-benzimidazolinyl)piperidine and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was filtered to remove any solids and was then purified by flash column 15 chromatography (95:3:2 methylene chloride/methanol/triethylamine) to give the title compound (215 mg, 77 % yield) as a tan solid. 'H-NMR (CDC1 3 , 300 MHz) 6 7.67 (d, J = 8.4 Hz, 1H), 7.39 (s, IH), 7.21-7.16 (in, 1H), 7.05-6.94 (in, 3H), 6.70-6.68 (m, 2H), 5.11 (d, J= 7.3 Hz, 1H), 4.78 (dd, J = 12.1, 5.5 Hz, IH), 4.42 (d, J= 4.4 Hz, 2H), 4.29 (d, J= 12.1 Hz, 1H), 3.82-3.72 (m, 2H), 3.74 (s, 3H), 3.44 (dd, J= 13.9, 5.5 20 Hz, 1H), 3.22 (dd, J 13.9, 5.5 Hz), 2.95-2.83 (m, 3H), 2.18-2.03 (m, 2H), 1.79-1.68 (m, 2H). Mass spec.: 545 (MH)*. (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2 (trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanoic acid OH H NH 25 N
N
WO 2005/065779 PCT/US2003/038799 276 To a solution of the ester (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoate (220 mg, 0.40 mmol) in tetrahydrofuran and methanol (1:1 mixture, 20 mL) at 0 0 C was added lithium hydroxide (36 mg, 1.51 mmol) in water (10 mL). The 5 mixture was stirred at 0 0 C for 2 h and then stored at -15*C for 16 h. The organic solvents were evaporated. The aqueous solution was extracted with ethyl acetate while adjusting the pH to 4 with IN HC1 (3 mL). The organic extracts were dried over sodium sulfate, filtered, and evaporated to give the title compound (176 mg, 82% yield). LC/MS: t R = 2.01 min, 531 (MH)*. 10 Example 231 N-((R)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-oxo-1-(4-(piperidin-1 yl)piperidin- I -yl)propan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine 1 -carboxamide F F F HN O HN N N N 0 N O NH 15 To a stirred solution of the acid (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamido)-3 -(2-(trifluoromethyl)- 1H-benzo[d] imidazol-5 yl)propanoic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) in methylene chloride (2 mL) was added a solution of PyBOP (33 mg, 0.06 20 mmol) and 4-piperidinopiperidine (12 mg, 0.07 mmol) in methylene chloride (lmL). The reaction mixture was stirred at room temperature for 16 h and was subjected to preparative thin layer chromatography for purification (1:10 2M ammonia in WO 2005/065779 PCT/US2003/038799 277 methanol/methylene chloride) to give the title compound (4.6 mg, 12% yield). 'H NMR (CD 3 0D, 500 MHz) 8 7.73-7.71 (m, 1H), 7.62 (bs, 1H), 7.39-7.36 (m, 1H), 7.19-7.11 (m, 2H), 6.96 (t, J = 7.2 Hz, I H), 6.81 (d, J = 7.9 Hz, 1H), 5.06-5.02 (m, IH), 4.67-4.58 (m, I H), 4.49-4.40 (m, 1H), 4.38 (s, 1H), 4.33 (bs, 1H), 4.25-4.16 (m, 5 2H), 4.10-4.03 (m, IH), 3.22-3.14 (m, 3H), 3.04-2.87 (m, 4H), 2.79-2.71 (m, IH), 2.58-2.48 (m, IH), 2.44-2.33 (m, IH), 2.31-2.22 (m, 1H), 2.04-1.92 (m, IH), 1.86 1.43 (m, 11H), 1.33-1.29 (m, 1H), 0.94-0.84 (m, 1H), -0.04- -0.12(m, 1H). LC/MS: tR = 1.97 min, 681 (MH)+. 10 Example 232 N-((R)-1-(dimethylcarbamoyl)-2-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)ethyl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamide F F F HN HN ON- N N 0 N O NH Prepared as described above for Example 231. 'H-NMR (CD 3 0D, 300 MHz) S 7.69 15 7.56 (m, 2H), 7.34 (d, J 7.7 Hz, 1H), 7.17-7.08 (m, 2H), 6.92 (t, J = 7.7 Hz, 1H), 6.77 (d, J= 8.4 Hz, 1H), 6.56 (d, J= 7.7 Hz, 1H), 5.02-4.97 (m, 1H), 4.46-4.35 (m, IH), 4.29 (s, 2H), 4.15 (d, J = 12.8 Hz, 1H), 3.26-3.11 (m, 5H), 2.87 (s, 6H), 1.86 1.68 (m, 2H), 1.66-1.59 (m, 2H). LC/MS: tR = 2.37 min, 558 (MH)*. 20 Benzyl (R)-1-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6 yl)ethylcarbamate WO 2005/065779 PCT/US2003/038799 278 H o N O N HN H 0 To a dilute solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl) propionic acid methyl ester (600 mg, 1.44 mmol) in tetrahydrofuran (125 mL) was added triethylamine (320 mg, 3.17 mmol) followed by 1,1'-carbonyldiimidazole (280 5 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered to remove solid. The filtrate was evaporated and subjected to flash column chromatography (1:12 methanol/methylene chloride) to give the title compound (313 mg, 59% yield). 'H-NMR (CD 3 0D, 300 MHz) 5 7.28-7.21 (in, 5H), 6.94-6.83 (in, 3H), 5.06-4.95 (m, 2H), 4.46-4.41 (in, 1H), 3.68 (s, 3H), 3.17-3.11 (in, 10 lH), 2.95-2.88 (in, lH). LC/MS: tR 2.11 min, 370 (MH)*. (R)-methyl 2-amino-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propanoate H o N O N
NH
2 H Benzyl (R)-I-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6 15 yl)ethylcarbamate (265 mg, 0.72 mmol) and 10% palladium on carbon (30 mg) in methanol (15 mL) were agitated for 1.5 h under 50 psi hydrogen using a Parr apparatus. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of Celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to 20 give the title compound (168 mg, quantitative yield). 'H-NMR (CD 3 0D, 300 MHz) 6 6.97 (d, J = 8.1 Hz, 1 H), 6.87 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.71-3.64 (in, 1H), 3.67 (s, 3H), 3.04-2.89 (m, 2H). LC/MS: tR = 0.87 min, 236 (MH)*. Example 233 WO 2005/065779 PCT/US2003/038799 279 (R)-methyl 2-(4-(1, 2 -dihydro- 2 -oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido) 3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propanoate H 0 N O N NH NH NN N .O H H 0 O Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 5 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-IH-benzo[d]imidazol-5 yl)propanoate. 'H-NMR (CD 3 0D, 300 MHz) 6 7.16-7.08 (m, 2H), 6.98-6.90 (m, 4H), 6.76 (d, J= 8.1 Hz, 1H), 4.52-4.47 (m, 1H), 4.39-4.35 (m, 1H), 4.27 (s, 2H), 4.13-4.05 (m, 2H), 3.70 (s, 3H), 3.21-3.14 (m, 1H), 3.04-2.96 (m, 1H), 2.89-2.74 (m, 2H), 1.78-1.59 (m, 4H). LC/MS: tR = 1.77 min, 493 (MH)*. 10 (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2,3 dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propanoic acid O H C _ N-# 0 N NH NH OH Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) 15 yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[djimidazol-5 yl)propanoic acid, 'H-NMR (CD 3 0D, 300 MHz) 8 7.16-7.09 (m, 2H), 6.99-6.90 (m, 4H), 6.76 (d, J = 7.3 Hz, 1H), 4.53-4.48 (m, 1H), 4.28 (s, 2H), 4.13-4.03 (m, 2H), 3.07-2.97 (m, 1H), 2.89-2.77 (m, 2H), 1.79-1.60 (m, 4H), 1.28-1.21 (m, IH). LC/MS: tR 1.83 min, 479 (MH)+. 20 Example 234 WO 2005/065779 PCT/US2003/038799 280 N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)- 1 -oxo- 1 (4-piperidin- 1 yl)piperidine- 1 -yl)propan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine 1 -carboxamide 0 N N NH NH O N O H 0 N N 5 Prepared as described above for Example 231. 'H-NMR (CD 3 0D, 300 MHz) 8 7.17 7.10 (in, 2H), 7.01 (s, IH), 6.95-6.90 (in, 3H), 6.78 (d, J 8.1 Hz, 1H), 4.98-4.93 (in, 1H), 4.62-4.55 (m, 1H), 4.41-4.33 (in, 2H), 4.20-4.16 (in, 2H), 4.04-3.96 (in, LH), 3.05-2.85 (in, 7H), 2.71-2.57 (in, 1H), 2.53-2.32 (m, 1H), 1.86-1.76 (in, 2H), 1.70 1.61 (in, 8H), 1.50-1.41 (in, 2H), 1.03-0.89 (m, 1H), 0.10- - 0.02 (in, IH). Mass 10 spec.: 629.22 (MH)*. Example 235 N-((R)-1-(dimethylcarbamoyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6 yl)ethyl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamide - N N 4 .NH NH H 0 ON .. O. 15 / Prepared as described above for Example 231. LC/MS: tR = 1.96 min, 506 (MH)*. (R)-Methyl 2-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H) quinazoline)carbonylamino]-3-2,3-dihydro-2-oxo-IH-benzo[d]imidazol-6 20 yl)propanoate WO 2005/065779 PCT/US2003/038799 281 0 N N NH HN N O 0 Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-bcnzo[djimidazol-5 yl)propanoate. 'H-NMR (DMSO-d6, 500 MHz) 6 10.54 (s, 1H), 10.50 (s, 1H), 9.22 5 (s, 1H), 7.21 (s, IH), 7.13-7.10 (m, 1H), 6.96-6.79 (m, 7H), 4.29-4.25 (in, 1H), 3.82 3.78 (in, 2H), 3.60 (s, 3H), 3.32-3.23 (in, 1H), 3.16-3.14 (i, I H), 3.00-2.90 (m, 2H), 2.08 (s, 1H), 1.67-1.55 (in, 4H). LC/MS: tR = 1.62 min, 479 (MH)*. (R)-2-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H)-quinazoline)carbonylamino] 10 3-2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propanoic acid O HN 0 NH NH HN(NH OH 0 WO 2005/065779 PCT/US2003/038799 282 Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-I -carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoic acid. 'H-NMR (CD 3 0D, 300 MHz) 5 7.19-7.14 (in, 1 H), 7.05-6.95 (in, 5H), 6.81 (d, J = 7.7 Hz, 1H), 5.04-4.90 (in, 1H), 4.57-4.52 (in, 1H), 3.96-3.84 (in, 5 2H), 3.24-3.14 (in, 2H), 3.07-2.95 (in, 1H), 1.94-1.73 (in, 4H). LC/MS: tR = 1.67 min, 465 (MH)*. Example 236 N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]iidazol-6-yl)-1-oxo-1(4-piperidin- 1 10 yl)piperidine- 1 -yl)propan-2-yl)-4-(2',3'-dihydro-2'-oxospiro(piperidine-4,4'-(l H) quinazoline)carboxamide 0 )NH HN HN N N 01 N N 0 NH N O H Prepared as described above for Example 231. LC/MS: tR 1.55 min, 615 (MH)*. 15 4-Acetamido-3-methylbenzoic acid 0 ANH HO 0 WO 2005/065779 PCT/US2003/038799 283 To a suspension of 4-amino-3-methylbenzoic acid (60 g, 0.40 mol) in methylene chloride (800 mL) was added triethylamine (121 g, 1.19 mol). The solution became clear. Then, acetic anhydride (81 g, 0.79 mol) was added and the reaction mixture was stirred for 60 h at room temperature. The solvent was evaporated. The residue 5 was diluted with water (400 mL) and extracted with ethyl acetate (3 x 600 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the title compound as a tan solid (43 g, 56% yield). 'H-NMR (d DMSO, 300 MHz) 5 9.36 (s, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). LC/MS: tR = 1.22 min, 194 (MH)+. 10 4-Acetamido-3-methyl-5-nitrobenzoic acid 0 ANH
NO
2 HO 0 To a solution of 60% nitric acid in sulfuric acid (410 mL) was added 4-acetamido-3 methylbenzoic acid (43 g, 0.22 mol) in small portions over 40 min while cooling with 15 an ice bath. After addition of all amide was complete, the reaction mixture was stirred for 1 h at 0 0 C and then very slowly poured over 1500 mL of ice. The yellow solid was collected by filtration and washed with ice cold water to give the title compound (38 g, 72% yield). 'H-NMR (CD 3 0D, 300 MHz) 5 8.29 (s, lH), 8.18 (s, 1H), 2.39 (s, 3H), 2.16 (s, 3H). Mass spec.: 237 (MH)+. 20 4-Amino-3-methyl-5-nitrobenzoic acid
NH
2
NO
2 HO 0 WO 2005/065779 PCT/US2003/038799 284 A suspension of 4-acetamido-3-methyl-5-nitrobenzoic acid (38 g, 0.16 mol) in 3N hydrochloric acid (800 mL) was heated at reflux for 8 h and then stirred at room temperature for 8 h. The yellow solid was collected by filtration and transferred to a 2 L flask with a mixture of methylene chloride and methanol. The solvent was 5 evaporated under high vacuum to give the title compound (23 g, 74% yield). 1 H NMR (DMSO-d6, 300 MHz) 8 12.79 (bs, 1 H), 8.46 (s, 1H), 7.79 (s, 1H), 7.61 (s, 2H), 2.34 (s, 3H). "C-NMR (d 6 -DMSO, 75 MHz) 8 166.0, 147.0, 135.1, 130.0, 126.4, 125.9, 116.7, 17.9. LC/MS: tR -1.23 min, 195 (MH)~. 10 3-Methyl-4,5-dinitrobenzoic acid
NO
2
NO
2 HO 0 To a suspension of 4-amino-3-methyl-5-nitrobenzoic acid (5.0 g, 25.5 mmol) in trifluoroacetic acid (200 mL) was added hydrogen peroxide (50 wt-% , 15 mL). The reaction mixture was heated at 50'C for 2 h and the solution eventually went from a 15 dark orange clear solution to a pale yellow clear solution. The reaction mixture was slowly poured into ice water (800 mL). The solid was collected by filtration and dried under vacuum to give the title compound as an off-white solid (4.0 g, 70% yield). 'H-NMR (CD 3 0D, 300 MHz) 8 8.59 (s, 1H), 8.40 (s, 1H), 2.45 (s, 3H). 1 3
C
NMR (CD 3 0D, 75 MHz) 8 165.8, 147.4, 142.0, 139.3, 134.8, 134.6, 125.4, 17.2. 20 Mass spec.: 225.14 (MH) . (3-Methyl-4,5-dinitrophenyl)methanol
NO
2
NO
2 HO A solution of 3-methyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran 25 (200 mL) was cooled to -70'C with a dry ice/acetone bath. To this solution was added borane-tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL). The reaction WO 2005/065779 PCT/US2003/038799 285 mixture was allowed to slowly warm to room temperature and was stirred for 16 h. The reaction was incomplete, was again cooled to -50'C and additional borane tetrahydrofuran (1 M in tetrahydrofuran, 35.4 mL) was added. Again, the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction 5 was quenched with a mixture of acetic acid and water (1:1, 30 mL) while cooling at 0 0 C. After stirring for 30 min, all organic solvent was evaporated and the aqueous material was neutralized by pouring into ice cold saturated sodium bicarbonate (350 mL) in small portions. The aqueous layer was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered and 10 evaporated. The residue was subjected to flash column chromatography (1:2 hexanes/ethyl acetate) to give the title compound (3.2 g, 86% yield). 'H-NMR (CDCl 3 , 300 MHz) 8 8.00(s, 1H), 7.62 (s, 1 H), 4.82 (s, 2H), 2.41 (s, 3H). ' 3 C-NMR (CDCl 3 , 75 MHz) 8 144.5, 143.3, 140.9, 134.3, 132.9, 120.8, 63.0, 17.4. 15 3-Methyl-4,5-dinitrobenzaldehyde
NO
2
NO
2 0H In a flame-dried flask, manganese (IV) oxide (36.0 g, 414 mmol) was azeotropically dried with toluene. Then, a solution of (3-methyl-4,5-dinitrophenyl)methanol (3.2 g, 15 mmol) in chloroform (100 mL) was transferred to the flask containing the 20 manganese dioxide. The reaction mixture was heated at 50'C with stirring for 3 h. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite" to remove manganese dioxide and the Celite was washed with chloroform several time. The filtrate was evaporated to give the title compound (1.4 g, 44% yield). 'H-NMR (CDCl 3 , 300 MHz) 8 10.09 (s, 1H), 8.51 (s, I H), 8.16 (s, 1H), 2.51 25 (s, 3H). Benzyl (Z)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl)vinylcarbamate WO 2005/065779 PCT/US2003/038799 286 0 2 N N 0 ..- HN 0 2 N 0 To a solution of N-(benzyloxycarbonyl)-ax-phophonoglycine trimethyl ester (2.4 g, 7.3 mmol) in tetrahydrofuran (40 mL) at -78'C was added 1,1,3,3 tetramethylguanidine (729 mg, 6.33 mmol) and the mixture was stirred for 1 h at 5 78'C. To this mixture was added a solution of 3-methyl-4,5-dinitrobenzaldehyde (1.4 g, 6.7 mmol) in tetrahydrofuran (15 mL). The reaction mixture was allowed to slowly warm to room temperature and was then stirred for 16 h at room temperature. The solvent was evaporated and the residue subjected to flash column chromatography (gradient, 1:2 to 1:1 ethyl acetate/hexanes). The product was then 10 recrystallized from ethyl acetate/hexanes (1:1) to give the title compound (1.7 g, 62% yield). 'H-NMR (CDCl 3 , 300 MHz) 5 8.01 (s, 1H), 7.55 (s, 1H), 7.33-7.22 (m, 6H), 6.94 (bs, 1H), 5.06 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H). 3 C-NMR (CDCl 3 , 75 MHz) 6 164.7, 152.5, 143.1, 140.6, 137.7, 137.0, 135.3, 132.5, 128.8, 128.7, 128.6, 127.1, 123.5, 123.2, 68.3, 53.5, 17.4. Mass spec.: 414.20 (MH)~. 15 Benzyl (R)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl)ethylcarbamate 0 2 N --. 0 HN 0 2 N O In a glove bag that was subjected to 3 vacuum/nitrogen purge cycles, an AIRFREE* (Schlenk) reaction flask equipped with stir bar was charged with (-)- 1,2-bis((2R,5R) 20 2,5-diethylphospholano)benzene(cyclooctadiene) rhodium (I) trifluoromethylsulfonate (125 g, 0.173 mmol, 4 mol%), sealed with a rubber septum, WO 2005/065779 PCT/US2003/038799 287 and removed from the glove bag. The benzyl (Z)-1-(methoxycarbonyl)-2-(3-methyl 4,5-dinitrophenyl)vinylcarbamate (1.65 g, 3.97 mmol) was weighed into a second AIRFREEO (Schlenk) reaction flask equipped with stir bar and sealed with a rubber septum. After 3 vacuum/nitrogen purge cycles, it was dissolved in a mixture of 5 anhydrous methylene chloride (40 mL). The solvent was deoxygenated prior to addition by sparging with nitrogen for at least 1 h. Once in solution, the mixture was again subjected to 3 vacuum/nitrogen purge cycles. The dehydroamino acid solution was introduced into the AIRFREE* (Schlenk) reaction flask containing the catalyst via cannula. The reaction mixture was subjected to 5 vacuum/hyrogen purge cycles 10 before opening the flask to 1 atmosphere of hydrogen. After 16 h, the reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The solvent was evaporated and the residue was subjected to column chromatography (1:1 ethyl acetate/hexanes) to give the title compound (1.58 g, 95%). 'H-NMR (CDCl 3 , 300 MHz) 6 7.75 (s, 1H), 7.39-7.33 (in, 6H), 5.37 (d, J= 7.0 Hz, 1H), 5.15-5.04 (in, 2H), 15 4.70-4.46 (in, IH), 3.77 (s, 3H), 3.30 (dd, J = 13.9, 5.5 Hz, 1H), 3.12 (dd, J = 13.9, 6.2 Hz, 1H), 2.33 (s, 3H). LC/MS: tR = 2.71 min, 418 (MH)*. Benzyl (R)-1-(methoxycarbonyl)-2-(3,4-diamino-5-methylphenyl)ethylcarbamate "1 0
H
2 N r. 0 HN
H
2 N 20 Solid ammonium formate (755 mg, 11.9 mmol) was added in small portions at 04C to suspension of benzyl (R)-1-(methoxycarbonyl)-2-(3-methyl-4,5 dinitrophenyl)ethylcarbamate (500 mg, 1.20 mmol) and zinc powder (470 mg, 7.19 mmol) in methanol (20 mL, degassed with nitrogen for 2 h). The resulting mixture was stirred at room temperature for 60 h. Reaction was incomplete. The reaction 25 mixture was again cooled to 0 0 C and additional zinc powder (470 mg, 7.19 mmol) was added. The reaction was stirred for 4 h at which time the reaction was complete. The reaction mixture was filtered to remove zinc. The filtrate was evaporated. A WO 2005/065779 PCT/US2003/038799 288 mixture of toluene and ethyl acetate (1:1) were added, followed by acetic acid (2 mL). The mixture was further diluted until all organic solids dissolved, then it was washed with water, brine, dried over sodium sulfate, and evaporated. The residue was then redissolved in ethyl acetate and 4N hydrogen chloride in dioxane (4 mL) 5 was added. The solvent was evaporated to give the title compound as the dihydrochloride salt (515 mg, quantitative yield). 'H-NMR (CD 3 0D, 300 MHz) 8 7.35-7.30 (in, 5H), 6.94-6.93 (in, 2H), 5.03 (s, 2H), 4.42-4.37 (in, 1H), 3.70 (s, 3H), 3.09-3.03 (in, 1H), 2.87-2.79 (in, 1H), 2.25 (s, 3H). LC/MS:-tR = 1.79 min, 358 (MH)*. 10 Benzyl (R)-1-(methoxycarbonyl)-2-(7-methyl-IH-benzo[d][1,2,3]triazol-5 yl)ethylcarbamate N' N N H HN To a solution of benzyl (R)-1-(methoxycarbonyl)-2-(3,4-diamino-5 15 methylphenyl)ethylcarbamate (250 mg, 0.58 mmol) in acetic acid (6 mL) and water (10 mL) was added a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL), dropwise over several minutes at room temperature. The resulting mixture was stirred at room temperature for 30 min, then cooled to 0 0 C. A mixture of ammonium hydroxide and water (1:1, 15 mL) was added to adjust pH to 11. The 20 mixture was extracted with ethyl acetate twice. The organic layers washed with brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by flash column chromatography (1:1 ethyl acetate/hexanes) on silica gel to afford the title compound as a tan solid (155 mg, 72% yield). 'H NMR (CDCl 3 , 300 MHz) 8 7.34 (s, 1H), 7.32-7.28 (in, 6H), 6.93 (s, 1H), 5.40 (d, J 25 8.1 Hz, 1H), 5.13-5.02 (in, 2H), 4.76-4.69 (in, 1H), 3.73 (s, 3H), 3.28 (dd, J = 13.9, 5.5 Hz, I H), 3.16 (dd, J= 13.9, 6.2 Hz, IH), 2.64 (s, 3H). LC/MS: tR 2.30 min, 369 (MH)*.
WO 2005/065779 PCT/US2003/038799 289 (R)-Methyl 2-amino-3-(7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate NN N' NH H Benzyl (R)-1-(methoxycarbonyl)-2-(7-methyl-1H-benzo[d][1,2,3]triazol-5 5 yl)ethylcarbamate (146 mg, 0.40 mmol) was dissolved in 12 mL of a solution of 4.4% formic acid in methanol. The reaction flask containing this solution was equipped with a magnetic stirbar and then flushed with nitrogen over several minutes. To the solution was added palladium on carbon (10%, 200 mg) and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction 10 mixture was filtered through a pad of Celite® washing the pad several times with methanol. The filtrate was evaporated to give the title compound (quantitative yield). IH-NMR (CDCl 3 , 300 MHz) 8 8.40 (bs, lH), 7.55 (s, 1H), 7.14 (s, 1H), 4.29-4.24 (m, 1H), 3.78 (s, 3H), 3.39-3.19 (in, 2H), 2.69 (s, 3H). LC/MS: tR= 1.18 min, 235 (MH)*. 15 (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido) 3-(7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate
N
0 NN N 0 N0 aN JNH Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 20 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoate. LC/MS: tR = 2.17 min, 492 (MH)*.
WO 2005/065779 PCT/US2003/038799 290 (R)-2-(4-(1,2-dihydro-2,4-dioxoquinazolin-3 (4H)-yl)piperidine- 1 -carboxamido)-3-(7 methyl-iH-benzo[d][1,2,3]triazol-5-yl)propanoic acid OH N 0 NH 0 ONa N NH 0 Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) 5 yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoic acid. LC/MS: tR 2.11 min, 492 (MH)+. Example 237 4-(1,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-((R)-3-(7-methyl-1H 10 benzo[d][1,2,3]triazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2 yl)piperidine- 1 -carboxamide N N N N NH O Na N Prepared as described above for Example 231. 'H-NMR (CD 3 0D, 300 MHz) 8 8.01 (d, J= 8.1 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1 H), 7.28-7.11 (m, 4H), 5.06-5.00 (m, 1 H), 15 4.70-4.60 (m, I H), 4.31-4.17 (m, 2H), 3.50-3.44 (m, 1H), 3.20-2.82 (m, 7H), 2.75 2.47 (m, 6H), 2.12-2.02 (m, 2H), 1.93-1.67 (m, 11H), 1.37-1.28 (m, 2H, 0.97-0.79 (m, 2H), 0.23-0.09 (m, 1H). Mass spec.: 642 (MH)*.
WO 2005/065779 PCT/US2003/038799 291 (R)-2-Benzyloxycarbonylamino-3-(4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) propionic acid methyl ester O : CO 2
CH
3 O N NHCbz H CI A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6 5 yl)-propionic acid methyl ester (373 mg, 1.01 mmol), N-chlorosuccinimide (168 mg, 1.26 mmol), silica gel (EM Scientific, 230 - 400 mesh, 3.73 g) in dichloroethane (20 mL) was heated at 90'C for 16 h. After cooling down to room temperature, the solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (1:2) as eluent to afford the title 10 compound (40 mg, 9.8%), also 2-benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3 dihydro-benzooxazol-6-yl)-propionic acid methyl ester (78 mg, 19%). The structure was confirmed by 2D NMR and by comparison with that of 2 benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) propionic acid methyl ester prepared by the reaction shown below. IH-NMR 15 (CD 3
COCD
3 , 500 MHz) 5 7.37 - 7.27 (in, 5H), 7.18 (d, J= 1.0 Hz, I H), 7.16 (s, 1H), 6.76 (d, J = 8.5 hz, 1H), 5.06 (d, J= 12.5 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H), 4.55 4.51 (in, 1H), 3.72 (s, 3H), 3.26 (dd, J= 14.0, 5.0 Hz, 1H), 3.04 (dd, J = 14.0, 9.5 Hz, 1H); "C-NMR (CD 3
COCD
3 , 125 MHz) 6 172.2, 156.4, 154.0, 144.8, 137.6, 133.3, 128.7, 128.2, 128.0, 127.9, 125.0, 66.3, 55.9, 52.0, 37.3; Mass spec. 405 (MH*). 20 (R)-2-Benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) propionic acid methyl ester O N H CO 2
CH
3 O=< NHCbz H N-Chlorosuccinimide (315 mg, 2.36 mmol) was added to a solution of (R)-2 25 benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (700 mg, 1.89 mmol) in acetic acid (50 mL) at room temperature. The mixture was heated at 100'C for 16h. After it was cooled down to room temperature, solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (4:6) then (1:1) as eluent to afford the WO 2005/065779 PCT/US2003/038799 292 title compound as an off-yellow solid (242 mg, 32%). The structure of the product was confirmed by 2D NMR. 'H-NMR (CD 3
COCD
3 , 500 MHz) 8 10.47 (s, 1H), 7.36 - 7.28 (m, 6H), 7.20 (s, IH), 6.80 (d, J= 8.5 Hz, IH), 5.05 (d, J= 12.5 Hz, lH), 5.00 (d, J= 12.5 Hz, 1H), 4.65 - 4.60 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J= 14.0, 5.0 Hz, 5 1H), 3.08 (dd, J= 14.0, 10.5 Hz, IH); 1 3 C-NMR (CD 3
COCD
3 , 125 MHz) 6 172.2, 156.5, 154.5, 143.1, 137.5,130.8,129.0, 128.9, 128.7, 128.2, 128.0, 112.8, 110.9, 66.3, 54.3, 52.1, 35.8; Mass spec. 405 (MH+). (R)-2-Benzyloxycarbonylamino-3-(4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) 10 propionic acid methyl ester 0
CO
2
CH
3 N = NHCbz H Br A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6 yl)-propionic acid methyl ester (418 mg, 1.13 mmol), N-bromosuccinimide (221 mg, 1.24 mmol), silica gel (EM Scientific, 230 - 400 mesh, 2.51 g) and methylene 15 chloride (70 mL) was stirred at room temperature for 16 h. Solvents were removed in vacuo and the residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3) as eluent to afford the title compound. 'H-NMR (CD 3
COCD
3 , 500 MHz) 6 10.71 (s, 1H), 7.35 - 7.28 (in, 6H), 7.21 (s, 1H), 6.75 (d, J= 7.5 Hz, 1 H), 5.06 (d, 12.5 Hz, IH), 5.02 (d, J= 12.5 Hz, I H), 4.56 - 4.51 (m, IH), 3.73 (s, 3H), 20 3.26 (dd, J= 14.0, 5.0 Hz, IH), 3.03 (dd, J= 14.0, 10.0 Hz, 1H); 13 C-NMR
(CD
3
COCD
3 , 125 MHz) 6 172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128.7, 128.2, 128.0, 127.8, 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; Mass spec. 448.03 (MH*).
(R)-
2 -Benzyloxycarbonylamino-3-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) 25 propionic acid methyl ester [n CO 2
CH
3 .. NHCbz N Br H A mixture of (R)- 2 -benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6 yl)-propionic acid methyl ester (1.07 g, 2.89 mmol), N-bromosuccinimide (643 mg, 3.61 mmol), and acetic acid (150 mL) was heated at 105'C for 14 h. After cooling to WO 2005/065779 PCT/US2003/038799 293 room temperature, the solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3), then (1:1) as eluent to afford the title compound (446 mg, 34%). The structure of the title compound was confirmed by 2D NMR. 'H-NMR (CD 3
COCD
3 , 500 MHz) 8 10.46 (s, IH), 7.36 5 7.28 (in, 7H), 6.82 (d, J= 8.5 Hz, 1H), 5.05 (d, J= 12.5 Hz, IH), 5.00 (d, J = 12.5 Hz, IH), 4.67-4.62 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J= 14.0, 5.0 Hz, 1H), 3.10 (dd, J= 14.0, 10.5 Hz, 1H); "C-NMR (CD 3
COCD
3 , 125 MHz) 6 172.2,156.4, 154.2, 143.7, 137.6, 131.1, 130.6, 128.7, 128.2, 128.0, 118.2, 113.9, 112.9, 66.2, 54.3, 52.1, 38.3; Mass spec. 448.03 (MH*). 10 (R)-2-Benzyloxycarbonylamino-3-(4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) propionic acid methyl ester 0 I CO 2
CH
3 O N HCbz H A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6 15 yl)-propionic acid methyl ester (324 mg, 0.87 mmol), I(PyH) 2
BF
4 (409 mg, 1.08 mmol), silica gel (EM Scientific, 230 - 400 mesh, 3.24 g) and dichloroethane (20 mL) was heated at 90'C for 6 h. After cooling to room temperature the solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (1:2) as fluent to afford the title compound (175 mg, 40%). 20 The structure of the title compound was confirmed by 2D NMR. 'H-NMR
(CD
3
COCD
3 , 500 MHz) 8 10.47 (s, 1H), 7.46 (s, 1H), 7.37 - 7.29 (in, 5H), 7.22 (s, 1H), 6.74 (d, J = 8.5 Hz, 1H), 5.07 (d, J= 12.5 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H), 4.54 - 4.49 (in, 1H), 3.72 (s, 3H), 3,23 (dd, J= 14.0, 5.0 Hz, lH), 3.01 (dd, J= 14.0, 9.5 Hz, IH); "C-NMR (CD 3
COCD
3 , 125 MHz) 8 172.2, 156.4, 153.4, 143.3, 137.6, 25 134.1, 133.64, 133.60, 128.7, 128.2, 128.0, 110.7, 71.1, 66.3, 56.0, 52.0, 37.1; Mass spec. 496.01 (MH+). (R)-2-Amino-3-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 294 O [ CO 2
CH
3 N Br H 2 H Trimethylsilyliodide (73 mL, 0.73 mmol) was added to a solution of azotropically dried (R)-2-benzyloxycarbonylamino-3-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6 yl)-propionic acid methyl ester (146 mg, 0.33 mmol) in acetonitrile (10 mL) at room 5 temperature, and the resulting mixture was stirred at room temperature for 2 h. Triethylamine (0.12 mL) was added and the mixture was stirred at room temperature for 15 min. The solvents were removed in vacuo, and the residue was extracted with ethyl acetate. The combined organics were washed with sodium bicarbonate and brine, dried over sodium sulfate and filtered. Solvents were removed and the residue 10 was used directly in the next step. Mass spec. 315.10 (MH)*. (R)-2-Amino-3-(4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester O . CO 2 Me N N
H
2 H Br 15 Prepared as described above for (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro benzooxazol-6-yl)-propionic acid methyl ester. Mass spec. 315.06 (MH)+. (R)-2-Amino-3-(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester O N H C0 2
CH
3 O=< N ) ClNH 2 20 H Prepared as described above for (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro benzooxazol-6-yl)-propionic acid methyl ester. Mass spec. 271.10 (MH)+. 25 (R)-2-Amino-3-(4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 295 0 CO 2
CH
3 O N NH 2 H Cl Prepared as described above for (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro benzooxazol-6-yl)-propionic acid methyl ester. Mass spec. 271.16 (MH)*. 5 (R)-2-Amino-3-(4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester: O CO 2
CH
3 N NH 2 H Prepared as described above for (R)-2-Amino-3-(5-bromo-2-oxo-2,3-dihydro benzooxazol-6-yl)-propionic acid methyl ester. Mass spec. 363.04 (MH)*. 10 (R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[2,4-dihydro-2'-oxospiro (piperidine-4,4'- 1 H-benzo[d] [1,3] oxazine)- 1 -carbonyl] -amino} -propionic acid methyl ester S O\\C0 2 Me N= CH 0 H N ~ ~ 0 N - O H 15 Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoate. Mass spec. 481.20 (MH)*. (R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yI)-2- { [2,4-dihydro-2'-oxospiro 20 (piperidine-4,4'- 1 H-quinazoline)- 1 -carbonyl]-amino } -propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 296 o ON \\O 2 Me N)Cr N NH N H H Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 3(4H)-yl)piperidime-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoate. Mass spec. 480.24 (MH)*. 5 (R)-3-(4-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester H o
CO
2 Me O I H N O H Cl N o N HN Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 10 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoate. Mass spec. 528.16 (MH)*. (R)-3-(5-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino}-propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 297 H
CO
2 Me N D( HN 0 H CI N o N HN Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 3(4H)-yl)piperidine- 1 -carboxamido)-3-(2-(trifluoromethyl)-IH-benzofd]imidazol-5 yl)propanoate. Mass spec. 528.20 (MH)*. 5 (R)-3-(4-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2- {[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino } -propionic acid methyl ester H O
CO
2 Me BrN O HN H Sr o N Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 10 3(4H)-yl)piperidine- 1 -carboxamido)-3-(2-(trifluoromethyl)- 1H-benzo[d] imidazol-5 yl)propanoate. Mass spec. 572.20 (MH)+. (R)-3-(5-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino } -propionic acid methyl ester WO 2005/065779 PCT/US2003/038799 298 H 0 NCO 2 Me N 'HN 0 H Br~f N O N HN Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[djimidazol-5 yl)propanoate. Mass spec. 572.15 (MH) . 5 (R)-3-(4-Iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester H
CO
2 Me N OHNO H HN Prepared as described above for (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin 10 3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-IH-benzo[d]imidazol-5 yl)propanoate. Mass spec. 620.20 (MH)*. (R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[2,4-dihydro-2'-oxospiro (piperidine-4,4'- 1 H-benzo[d] [1,3]oxazine)- 1 -carbonyl]-amino } -propionic acid WO 2005/065779 PCT/US2003/038799 299 N. \\\C0 2 H N .
H HN 0 H N N N -- O H Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-H-benzo[d]imidazol-5 yl)propanoic acid. Mass spec. 467.18 (MH)*. 5 (R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[2,4-dihydro-2'-oxospiro (piperidine-4,4'- I H-quinazoline)- 1 -carbonyl] -amino} -propionic acid o N 0 N HN H N O H Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) 10 yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-IH-benzo[d]imidazol-5 yl)propanoic acid. Mass spec. 466.20 (MH)*. (R)-3-(4-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid H 0 N C0 2 H CI N 0 N H5 N 15 WO 2005/065779 PCT/US2003/038799 300 Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoic acid. Mass spec. 514.20 (MH)*. 5 (R)-3-(5-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid H o ~ C0 2 H N HH o N Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 10 yl)propanoic acid. Mass spec. 514.24 (MH)*. (R)-3-(4-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -propionic acid H o C0 2 H O=<KN H N 0 H Br N 0 N H N 15 Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoic acid. Mass spec. 558.30 (MH)*.
WO 2005/065779 PCT/US2003/038799 301 (R)-3-(5-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2- { [4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -propionic acid H o ~ C0 2 H 0 N HN 0 H B N 0 N H N Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) 5 yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoic acid. Mass spec. 558.25 (MH)*. (R)-3-(4-Iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-{[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -propionic acid H o ~ C0 2 H 0#I< N H HN 0 O N H N 10 Prepared as described above for (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine-I-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5 yl)propanoic acid. Mass spec. 606.10 (MH)*. 15 Example 238 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 cyclohexyl-piperazin-1-yI)-2-oxo-1-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) ethyl]-amide WO 2005/065779 PCT/US2003/038799 302 0 N0 N N / HN O H N N 0 NH Prepared as described above for Example 231. LC/MS: tR 1.80 min, 630.37 (MH)+. Example 239 5 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 isopropyl-piperazin-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) ethyl]-amide 0N NO HN 0 N N 0 NH Prepared as described above for Example 231. LC/MS: tR 1.71 min, 590.34 10 (MH)*. Example 240 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1-oxo-1 -(4-(piperidin-1 yl)piperidin- 1 -yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1 H 15 benzo[d] [1,3]oxazine)- 1 -carboxamide WO 2005/065779 PCT/US2003/038799 303 O0N N O N
O
N NO N ~ N 0 H Prepared as described above for Example 231. LC/MS: tR 1.64 min, 617.34 (MH)*. 5 Example 241 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1-oxo-1-(4-(cyclohex-1 yl)piperazin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1 H benzo[d][1,3]oxazine)-1-carboxamide 0 N NN 0 HH N N - O H 10 Prepared as described above for Example 231. LC/MS: tR 1.69 min, 617.35 (MH)+. Example 242 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1-oxo-1 -(4-(prop-2 15 yl)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'- I H benzo[d][1,3]oxazine)-1 -carboxamide WO 2005/065779 PCT/US2003/038799 304 0 N N | HN 0 H N 0 N O H Prepared as described above for Example 231. LC/MS: tR 1.57 min, 577.32 (MH)*. 5 Example 243 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- I -(4-(piperidin- 1 yl)piperidin- 1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1
H
quinazoline)- 1 -carboxamide 0 N 0 NHN 0 N NH N HO H 10 Prepared as described above for Example 231. LC/MS: tR 1.74 min, 616.37 (MH)*. Example 244 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1-oxo-1-(4-(cyclohex-1 yl)piperazin- 1-yl)propan-2-yI)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-I
H
15 quinazoline)- 1 -carboxamide WO 2005/065779 PCT/US2003/038799 305 0N NHN 0 H N NH N - O H Prepared as above., LC/MS: tR 1.79 min, 616.36 (MH)*. Example 245 5 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1-oxo-1-(4-(prop-2 yl)piperazin-I -yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H quinazoline)- I -carboxamide 0 N NN H N N NO H Prepared as described above for Example 231. LC/MS: t R 1.67 min, 576.34 10 (MH)*. Example 246 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1-(4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 15 oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 306 O N N N O H NH Prepared as described above for Example 231. LC/MS: tR 1.91 min, 664.35 (MH)*. 5 Example 247 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide 0 N N N CN O H I NH 10 Prepared as described above for Example 231. LC/MS: tR = 1.91 min, 664.34 (MH)*. Example 248 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 15 [1,4']bipiperidinyl-l'-yl-l-(4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 307 O N NO HN O H Br N 0 NH Prepared as described above for Example 231. LC/MS: tR 1.96 min, 708.31 (MH)+. 5 Example 249 (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide oO N N O NNBr N N 0 NH 10 Prepared as described above for Example 231. LC/MS: tR = 1.96 min, 708.31 (MH)*. Example 250 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 15 [1,4']bipiperidinyl- l'-yl-1 -(4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 308 O \.---N N OHN O N H N 0 NH Prepared as described above for Example 231. LC/MS: tR 1.97 min, 756.36 (MH+). 5 Example 251 (+)-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4 [1',2'-dihydro-2'-oxospiro-[4H-3', 1-benzoxazine-4,4'-piperidinyl]-butyramide 0 O NH NN NI 0 N 0 NH H S OH Prepared as described above for ( )-1-[1,4']bipiperidinyl- 1'-yl-2-(7-methyl- 1 H 10 indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1.
3 8 min, 596 (MH)+. Example 252 (±)-N-(] -Benzyl-2-hydroxy-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4 15 (2-oxo-1,4-dihydro-2 H-quinazolin-3-yl)-piperidin-1-yl]-butyramide WO 2005/065779 PCT/US2003/038799 309 H 0 N N N 'N ~ 0 bOH Prepared as described above for (±)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-1H indazol-5-ylmethyl)-4-[ l',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1.50 min, 609 (MH)'. 'H NMR (400 MHz, 5 CD 3 0D) 5 7.90 (1H, s), 7.64-7.84 (1H, in), 6.71-7.42 (11H, in), 4.58 (1 H, in), 3.82 4.50 (6H, in), 2.21-3.52 (13H, m), 1.42-1.87 (4H, in). Example 253 (t)-Phenyl-acetic acid N'-{2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo 10 1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-hydrazide H O N N N N "5 N 0 NH H .I o HN Prepared as described above for (±)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-1H indazol-5-ylmethyl)-4-[l',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1.
4 3 min, 630 (M+Na)+. 15 Example 254 WO 2005/065779 PCT/US2003/038799 310 (+)-1-[1,4']Bipiperidinyl- 1'-yl-4-[4-(8-fluoro-2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidin- 1 -yl]-2-(7-methyl-1 H-indazol-5-ylmethyl)-butane- 1,4-dione H F N N N Ox N H N N Prepared as described above for (+)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-1H 5 indazol-5-ylmethyl)-4-[l',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1-.1 8 min, 644 (MH)+. 'H NMR (400 MHz, CDC1 3 ) 5 8.00 (1H, s), 6.82-7.40 (6H, m), 4.48-4.70 (3H, m), 4.31 (2H, s), 3.85-4.11 (2H, m), 3.65 (1H, m), 2.70-3.16 (5H, m), 2.53 (3H, s), 0.72-2.52 (23H, m). 10 Example 255 (±)-1-[1,4']Bipiperidinyl-l'-yl-2-(7-methyl-IH-indazol-5-ylmethyl)-4-[2',3'-dihydro 2'-oxospiro-(piperidine-4,4'-quinazoline]-butane- 1,4-dione 0 HN 'NH N N 0 0 H N N 15 Prepared as described above for (±)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-1H indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=l .09 min, 612 (MH)*.
WO 2005/065779 PCT/US2003/038799 311 2 -Oxo- 2
,
3 -dihydro-benzooxazole-6-carbaldehyde 0 O HN CHO A solution of 6-bromo-3H-benzooxazol-2-one (0.
9 2 3 6 g, 4.31 micromoles) in 5 anhydrous tetrahydrofuran (25 mL) and dimethylformamide (3 mL) under nitrogen was cooled to -78'C before addition of n-butyllithium (2.5M in hexane) (3.8 mL, 2.2 equiv). After stirring for 10 min at -78'C, 24 mL of sec-butyllithium (1.4 M in cyclohexane, 8 equiv) was added. The reaction was stirred while slowly warming to -40'C. When this temperature was reached, the reaction was quenched by addition 10 of methanol. The reaction mixture was concentrated in vacuo and water was added. The aqueous layer was acidified with IN HC (ca. pH 5) and extracted with ethyl acetate (3 x 50 mL), dried over sodium sulfate, filtered and concentrated to give the product, 0.6402 g (91%). MS (ESI) 164 (MH)'. 'H NMR (400 MHz, DMSO-d6) 6 9.90 (1H, s), 7.79 (1H, d, J=8.0 Hz), 7.74 (lH, s), 7.28 (1H, d, J=8.0 Hz). 15 3-(2-Oxo-2,3-dihydro-benzooxazol-6-ylmethylene)-pentanedioic acid monomethyl ester 0 O 0 HN O 0 OH Prepared as described above for 2-(7-methyl- 1 H-indazol-5-ylmethylene)-succinic 20 acid 1-methyl ester (1.4 g, 90% yield). MS (ESI) 300 (M+Na)*.
(±)-
3
-(
2 -Oxo- 2 ,3-dihydro-benzooxazol-6-ylmethyl)-pentanedioic acid monomethyl ester WO 2005/065779 PCT/US2003/038799 312 0 O0 HN 0 0 OH Prepared as described above for (d)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-succinic acid 1-methyl ester (1.4 g, 99% yield). MS (ESI) 302 (M+Na)*. 5 ()-4-Oxo-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[4-(2-oxo- 1,4-dihydro 2 H-quinazolin-3-yl)-piperidin-1-yi]-butyric acid methyl ester H 0 Y N Ng N 0 0 N N H I Prepared as described above for (&)- 2 -(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4 [1',2'-dihydro-2'-oxospiro-[4H-3',1 -benzoxazine-4,4'-piperidinyl]-butyric acid methyl 10 ester. MS (ESI) 493 (MH)*. ( )-4-Oxo-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[2',3'-dihydro-2' oxospiro-(piperidine-4,4'-quinazoline)]-butyric acid methyl ester 0 H N NH O N H 15 Prepared as described above for (±)- 2 -(7-methyl- I H-indazol-5-ylmethyl)-4-oxo-4 [1',2'-dihydro-2'-oxospiro-[4H-3',I-benzoxazine-4,4'-piperidinyl]-butyric acid methyl ester. MS (ESI) 479 (MH)*.
(+)-
4 -Oxo-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[2',3'-dihydro-2' 20 oxospiro-(piperidine-4,4'-quinazoline)]-butyric acid WO 2005/065779 PCT/US2003/038799 313 0 HN 'kNH O N 0: C~0 N0 :)0rHo H Prepared as described above for (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4 [1',2'-dihydro-2'-oxospiro-[4H-3', I -benzoxazine-4,4'-piperidinyl]-butyric acid. MS (ESI) 465 (MH)+. 5 (±)-4-Oxo-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[4-(2-oxo-1,4-dihydro 2H-quinazolin-3-yl)-piperidin- l-yl] -butyric acid H N O N H Prepared as described above for ( )-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4 10 [l',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidinyl]-butyric acid. MS (ESI) 479 (MH)*. Example 256 (±)-1-(4-Cyclohexyl-piperazin-1-yI)-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 15 4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl] -butane-1,4-dione H O N N 0 H N
NN
WO 2005/065779 PCT/US2003/038799 314 Prepared as described above for (±)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-1H indazol-5-ylmethyl)-4-[ 1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1.10 min, 629 (MH)+. 5 Example 257 (±)-1-[1,4']Bipiperidinyl-l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[4 (2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- l-yl] -butane-1,4-dione H O N O ~ N N 0 H N N Prepared as described above for (±)-1-[1,4']bipiperidinyl-1'-yl-2-(7-methyl-1H 10 indazol-5-ylmethyl)-4-[ 1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1.08 min, 629 (MH)+. 'H NMR (400 MHz, CDCl 3 ) 5 9.89 (1H, s), 8.28 (1H, d, J=11.2 Hz),6.90-7.25 (5H, m), 6.75 (1H, d, J=8.0 Hz), 4.40-4.79 (3H, m), 4.35 (2H, s), 2.27-3.98 (19H ,m), 1.46-2.10 (9H, m), 1.36 (1H, m), 1.08 (1H, m), 0.12 (1H, m). 15 Example 258 (+)-1-[1,4']Bipiperidinyl-l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4 [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane- 1,4-dione WO 2005/065779 PCT/US2003/038799 315 0 HN NH -N 0=10 N N N H Q Prepared as described above for (±)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-1H indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4' piperidinyl]-butane-1,4-dione. LC/MS: tR=1.0 2 mmi, 615 (MH)f. 5 Example 259 (d)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 4-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)] -butane-1,4-dione 0 H N N H o 0 liC__ N 0 N N H N 10 Prepared as described above for (+)-1-[1,4']bipiperidinyl-l'-yl-2-(7-methyl-lH indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxospiro-[4H-3',I-benzoxazine-4,4' piperidinyl]-butane- 1,4-dione. LC/MS: tR=1.04 min, 615 (MH)*. Example 260 15 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 cyclohexyl-piperazin-1-yl)-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 316 HN-N H 0 N H N N 0 N 0 N Prepared as described above for Example 16. 'H-NMR (CD 3 0D, 500 MHz) 8 0.81 (1H, in), 0.89 (1 H, in), 1.02 (1H, in), 1.1-2.0 (12H, in), 2.23 (1H, d), 2.47 (1H, d), 2.61 (3H, s), 2.90 (4H, t), 3.08 (4H, in), 3.2-3.5 (4H, in), 3.82 (1 H, m), 4.14 (2H, d), 5 4.29 (2H, s), 4.40 (LH, t), 6.80 (LH, d), 6.95 (1H, t), 7.12 (3H, in), 7.47 (1H, s), 8.01 (1H, s). Mass spec.: 627.47 (MH)*. Example 261 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[4-(4 10 fluoro-phenyl)-piperazin-1-yl]-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl] amide HN-N H 0 N H N N 0 N 0 N F Prepared as described above for Example 16. LC/MS: tR= 2
.
3 4 min, 621.42 (MH)+. 15 Example 262 (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1 -carbonyl]-amino}-propionic acid tert-butyl ester WO 2005/065779 PCT/US2003/038799 317 N-NH H NyN 0 0 A solution of (±)-3-(7-methyl-IH-indazol-5-yl)- 2-{[4-(2-oxo-1,4-dihydro-2H quinazolin-3-yl)-piperidine-1-carbonyl]- amino}-propionic acid (50 mg, 0.105 mmol) and dicyclohexylcarbodiimide (25 mg, 0.12 mmol) in dimethylformamide was stirred 5 for 30 min at room temperature, and then pentafluorophenol (26 mg, 1.3 mmol) was added. Stirring was continued at room temperature overnight, and then the solvent was removed, the residue was dried under high vacuum for 4 h. The crude pentafluorophenyl ester was used without further purification in the next step. To a solution of tert-butyl alcohol (10 equiv.) in tetrahydrofuran at -78'C under 10 nitrogen was added 1.4M sec-butyllithium in cyclohexane (10 equiv.). After 10-15 min, a solution of pentafluorophenol ester (1 equiv.) in tetrahydrofuran was added. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo, and the residue was purified by preparative-HPLC to give the desired compound. 'H-NMR(CD 3 0D) 6 1.40 (s, 9H) 1.56 (m, 4H), 2.54 (s, 3H) 15 2.85 (m, 2H) 3.05 (m, IH) 3.19 (in, IH ) 4.14 (m, 4H ) 4.44 (m, 2H ) 6.76 (d, J=7.68 Hz, 1H ) 6.93 ( t, J=7.5 Hz, 1H ) 7.10 (in, 3H) 7.14 (s, 1H ) 7.97 (s, I H ). LC/MS: tR= 2 .1 9 min, 533.36 (MH)*. Example 263 20 (+)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1 -carbonyl]-amino} -propionic acid 1-methyl cyclohexyl ester N-NH H Y N NN 0 0 0 WO 2005/065779 PCT/US2003/038799 318 Prepared as described above for ( )-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidine-I-carbonyl]-amino} -propionic acid tert-butyl ester. LC/MS: tR=2.47 min, 574.39 (MH)*. 5 Example 264 ( )-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester N NH H /N N H N N o 0 N To a solution of (±)-3-(7-methyl-1H-indazol-5-yl)- 2- {[4-(2-oxo-1,4-dihydro-2H 10 quinazolin-3-yl)-piperidine-1-carbonyl]- amino}-propionic acid (50 mg, 0.105 mmol), EDCI (100 mg), and 4-dimethylaminopyridine (0.2 equiv.) in dimethylformamide was added aza-bicyclo[2.2.2]oct-3-yl alcohol (0.525 mmol, 5 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with brine, 15 dried over magnesium sulfate, and purified by preparative HPLC to yield the desired compound. LC/MS: tR=1.62 min, 586.41 (MH)*. Example 265 (+)-3-(7-Methyl-iH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 20 piperidine- I -carbonyl]-amino} -propionic acid piperidin-4-yl ester N-NH H 0 N N H HNN Na 0 0 0 WO 2005/065779 PCT/US2003/038799 319 Prepared as described above for (±)-3-(7-methyl-1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino } -propionic acid 1-aza bicyclo[2.2.2]oct-3-yl ester. LC/MS: tR=1.5 8 min, 560.37 (MH)*. 5 Example 266 (±)-4-(3-(7-Methyl-iH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionyloxy)-piperidine- 1 -carboxylic acid tert-butyl ester N-NH H N N 0 H N >O' t Na N yNC 0 0 10 Prepared as described above for (+)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino} -propionic acid I-aza bicyclo[2.2.2]oct-3-yl ester. LC/MS: tR= 2
.
3 8 min, 660.42 (MH)+. Example 267 15 (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl] -amino} -propionic acid 3,4,5,6-tetrahydro-2H [1,4']bipyridinyl-4-yl ester N-NH H 0 N N- N H Na N N 0 0 0 Prepared as described above for (±)-3-(7-methyl-IH-indazol-5-yl)-2-{[4-(2-oxo-1,4 20 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl]-amino } -propionic acid 1-aza bicyclo[2.2.2]oct-3-yl ester. LC/MS: tR-.
6 7 min, 637.43 (MH)*. Example 268 WO 2005/065779 PCT/US2003/038799 320 (±)-3-(7-Methyl-1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester N-NH H 0 N N H N N 0 00 Prepared as described above for (±)-3-(7-methyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4 5 dihydro-2H-quinazolin-3-yl)-piperidine-l -carbonyl]-amino}-propionic acid 1-aza bicyclo[2.2.2]oct-3-yl ester. LC/MS: tRl .66 min, 590.44 (MH)+. Example 269 (*)-3-(7-Methyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 10 piperidine- 1 -carbonyl]-amino }-propionic acid 1,1-dimethyl-2-phenyl-ethyl ester N-NH / H 0 N N H N N 0 0 0 Prepared as described above for (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carbonyl] -amino} -propionic acid t-butyl ester. LC/MS: tR= 2 .5 2 min, 609.46 (MH)*. 15 Example 270 (+)-3-(7-Methyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1,1-dimethyl-3-phenyl- propyl ester N-NH 0 N N H N N 0 0 WO 2005/065779 PCT/US2003/038799 321 Prepared as described above for (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4 dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carbonyl]-amino} -propionic acid t-butyl ester. LC/MS: tR= 2
.
6 1 min, 623.48 (MH)+. 5 Example 271 ( )-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino } -propionic acid ethyl ester N-NH H 0 N N H N N r 0 Prepared as described above for (±)-3-(7-methyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo-1,4 10 dihydro-2H-quinazolin-3-yl)-piperidine- I -carbonyl] -amino} -propionic acid t-butyl ester. LC/MS: tR 1.
9 8 min, 505.32 (MH)*. Example 272 (±)-1-(7-Methyl-IH-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-2-oxoethyl]-2',3' 15 dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide N-NH / 0 HN NH H N N 0 N 0 X
-
H N Prepared as described above for Example 16. LC/MS: tR=1.
4 9 min, 553.12 (MH)'. 20 Example 273 (±)-1 -(7-Methyl-iH-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl] 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1 H)-quinazoline]- 1 -carboxamide WO 2005/065779 PCT/US2003/038799 322 N -NH 0 HN NH H N N O 0 N 0 N Prepared as described above for Example 16. LC/MS: tR1.5 6 mmi, 608.18 (MH)*. Example 274 5 (i)-1-(7-Methyl-iH-indazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethyl carbamoyl)-2-oxoethyl]-2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline] 1 -carboxamide N-NH 0 HN NH H N N N 0 N N O Prepared as described above for Example 16. LC/MS: tR=1.58 min, 561.20 (MH)*. 10 Example 275 (+)-1-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl] 1',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide N-NH 0 O NH N yNI NJ N 0
N
WO 2005/065779 PCT/US2003/038799 323 Prepared as described above for Example 16. LC/MS: tR=1.56 min, 609.14 (MH)*. Example 276 (±)-1-(7-Methyl-i H-indazol-5-ylmethyl)-2-[1-pyridin-2-yl-piperazinyl]-2-oxoethyl] 5 1',2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1 -carboxamide N-NH 0 O NH H N N 0 N 0 N N Prepared as described above for Example 16. LC/MS: tR=1.57 min, 609.17 (MH)*. Example 277 10 (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 yl)-piperidine- 1 d-carboxylic acid [2 [1,4'jbipiperidinyl-l'-yl-1-(7-methyl-IH-indazol-5-ylmethyl)-2-oxo-ethyl]amide HN-N H 0 N N H N N N O0 Prepared as described above for Example 16. 'H-NMR (CD 3 0D, 500 MHz) S -0.27 (IH, m), 0.75 (lH, m), 1.1-2.0 (12H, m), 2.10 (2H, m), 2.4-2.5 (3H, m), 2.57 (3H, s), 15 2.68 (2H, m), 2.92 (4H, m), 3.10 (4H, m), 3.9-5.1 (4H, several m), 6.82 (1H, d), 6.96 (1H, t), 7.18 (3H, m), 7.50 (1H, s), 8.05 (1H, s). LC/MS: tR=1.
6 8 min, 627.42 (MH)*. Example 278 WO 2005/065779 PCT/US2003/038799 324 (R)- 1 -(7-Methyl-i H-indazol-5-ylmethyl)-2-[1,4-bipiperidin]-1 -yl-2-oxoethyl]-2',3' dihydro-2'-oxospiro-[piperidine-4,4'-(I H)-quinazoline]- 1 -carboxamide N-NH / 0 HN NH H N N 0 N 0 NN Prepared as descr ibed above for Example 16. LC/MS: ta=1.63 min, 613.36 (MH)*. 5 Among other compounds envisaged within the present invention and capable of being made according to the description provided herein or those methods known to those skilled in the art include the following prophetic examples: 10 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl- 1'-yl-l -(7-bromo-1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide H N H Br 0 N N N N 0 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2 15 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl] amide WO 2005/065779 PCT/US2003/038799 325 O HN H 0 0 N N H N N N 0 N N 4-(2-Oxo-l,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-piperidin-1-yl-ethyl]-amide 0 HN -H N N H N N 5 N OO 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 methyl-piperazin-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-ethyl] amide 0 HN 4H N N N N 0 10 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 326 0 HN H 0 0 N N H N N 0 N 0 5 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [1-(4 methyl-2-oxo-2,3-dihydro-benzooxazol-6-ymethyl)-2-oxo-2-piperidin-1 -yl-ethyl] amide 0 H N 4H O 0 N N H N yN N 0 10 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide 0 H N 4H H HK 0 N N 0 WO 2005/065779 PCT/US20031038799 327 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [1 dimethylcarbamnoyl-2-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-ethyl] -amide 0 HNK y N~N N 0 N 5 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-l1-carboxylic acid [2-(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-yl)-l1-dimethylcarbamoyl-ethyl]-amide 0 HN 4K N 0 H 'H N rN N 0 N NN ..
H
WO 2005/065779 PCT/US2003/038799 328 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yI)-piperidine-lI-carboxylic acid [1 -(4-chioro 2 -oxo- 2 ,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazin- I-yl) ethyl]-amide 0 HN 4 H Ci 0 0 N H N rN r 0 N 0 N 5 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-lI-carboxylic acid [2 [ 1,4?]bipiperidiny- l'-yl-lI -(4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide H N 4K H 0N H N yNa N 0 10 4-(2-Oxo- 1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-lI -(7-methyl-2-oxo-2,3-dihydro- 1 H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 329 0 HNK H NH 0 N N H N N N 0 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yI)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl- 1'-yl-1-(7-chloro-2-oxo-2,3-dihydro- 1 H-benzoimidazol-5 5 ylmethyl)-2-oxo-ethyl]-amide 0 HN H cl NH 0 N N H N N N 0N 0 N 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl- '-yl-1 -(7-ethyl-2-oxo-2,3 -dihydro- I H-benzoimidazol-5 10 ylmethyl)-2-oxo-ethyl]-amide 0 HN4 H NH 0 N H N N O O N 0 N0 WO 2005/065779 PCT/US20031038799 330 4-(2-Oxo- 1 ,4-diliydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-l -(3-methyl-2-oxo-2,3-dihydro- 1 H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl] -amide HN4 H N- 0 N NN 5 4-(2-Oxo- 1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-l -(3 ,7-dimethyl-2-oxo-2,3-dihydro- 1 H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl] -amide 0 HN4 H N0 N H N Ng N' 0 10 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yI)-piperidine-1 -carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-lI -(7-chloro-3-methyl-2-oxo-2,3-dihydro- 1 H-benzoimidazol 5-ylmethyl)-2-oxo-ethyl]-amide WO 2005/065779 PCT/US2003/038799 331 0 HN H cl N O N N H N 0 N N: O 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl- 1'-yl-1 -(7-ethyl-3-methyl-2-oxo-2,3-dihydro- 1 H-benzoimidazol-5 5 ylmethyl)-2-oxo-ethyl]-amide 0 HN4 H N 0 N N H N N N 0 N 3-(7-Methyl- 1 H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino} -propionic acid isopropyl ester HN-4O \ / NH 10 N NO 3-(7-Chloro- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl] -amino} -propionic acid isopropyl ester WO 2005/065779 PCT/US2003/038799 332 CI O \ /NH HN HN -NN N N 0 O N 3-(7-Ethyl- I H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid isopropyl ester HN \ / NH HN HNH NN N N 0 0 0 5 - 3-(7-Chloro- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) 10 piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester CI
HN-
4 HN NH N 0 3 -(7-Ethyl-i H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid tert-butyl ester O \ /NH HN-4 HN 5 N N 0 15 3-(7-Chloro- I H-indazol-5 -yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino } -propionic acid cyclohexyl ester WO 2005/065779 PCT/US2003/038799 333 Cl \/ NH HN H N NH HNN N -N 0 0 0 3-(7-Ethyl-1 H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yI) piperidine-1 -carbonyl]-amino} -propionic acid cyclohexyl ester \ / NH H N H N 5N N 0 0 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-methyl-piperidin-4-yl ester CI OH \ / NH HN HN N N N-O 0 N C: _C 00 b 10 3-(7-Ethyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino} -propionic acid 1-methyl-piperidin-4-yl ester Oy / NH HN- H N N N-s 0 150 N 15 WO 2005/065779 PCT/US2003/038799 334 3-(7-Chloro- I H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester Cl HN- HN \/ NH N N 0 N 5 3-(7-Ethyl-iH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-methyl-cyclohexyl ester HN HN \ / NH N N 0 N
-
0 10 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 4-phenyl-cyclohexyl ester 0 O N N MN / 0 N NH NH HN0 Cl 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 15 piperidine- 1 -carbonyl]-amino} -propionic acid 4-phenyl-cyclohexyl ester WO 2005/065779 PCT/US20031038799 335 0 N H NH NH HN 0 WO 2005/065779 PCT/US2003/038799 336 CGRP Binding Assay Tissue Culture. SK-N-MC cells were grown at 37 'C in 5% CO 2 as a monolayer in medium consisting of MEM with Earle's salts and L-glutamine (Gibco) 5 supplemented with 10% fetal bovine serum (Gibco). Cell Pellets. The cells were rinsed twice with phosphate-buffered saline (155 mM NaCl, 3.3 mM Na 2
HPO
4 , 1.1 mM KH 2
PO
4 , pH 7.4), and incubated for 5-10 min. at 4 0 C in hypotonic lysis buffer consisting of 10 mM Tris (pH 7.4) and 5 mM EDTA. 10 The cells were transferred from plates to polypropylene tubes (16 x 100 mm) and homogenized using a polytron. Homogenates were centrifuged at 32,000 x g for 30 min. The pellets were resuspended in cold hypotonic lysis buffer with 0.1% mammalian protease inhibitor cocktail (Sigma) and assayed for protein concentration. The SK-N-MC homogenate was then aliquoted and stored at -80 'C until needed. 15 Radioligand Binding Assay. The compounds of invention were solubilized and carried through serial dilutions using 100% DMSO. Aliquots from the compound serial dilutions were further diluted 25 fold into assay buffer (50 mM Tris-Cl pH 7.5, 5 mM MgCl 2 , 0.005% Triton X- 100) and transferred (volume 50 pl) into 96 well 20 assay plates. [I 2 5 ]-CGRP (Amersham Biosciences) was diluted to 60 pM in assay buffer and a volume of 50 1I was added to each well. SK-N-MC pellets were thawed, diluted in assay buffer with fresh 0.1% mammalian protease inhibitor cocktail (Sigma), and homogenized again. SK-N-MC homogenate (5 Rg/well) was added in a volume of 100 pl. The assay plates were then incubated at room 25 temperature for 2 h. Assays were stopped by addition of excess cold wash buffer (20 mM Tris-Cl pH 7.5, 0.1% BSA) immediately followed by filtration over glass fiber filters (Whatman GF/B) previously soaked in 0. 5% PEI. Non-specific binding was defined with I gM beta-CGRP. Protein bound radioactivity was determined using a gamma or scintillation counter. The IC 5 o was defined as the concentration of a 30 compound of invention required to displace 50% of radioligand binding.
WO 2005/065779 PCT/US2003/038799 337 In the table below, results are denoted as follows: A I 1OnM; 1OnM < B s 100 nM; 100 nM < C:5 1000 nM; D > 1000 nM. Table 4. CGRP Binding, cAMP Function and Ex Vivo Human Cerebral Artery Data 5 Example CGRP binding cAMP Function 2 Cerebral Artery 3
IC
50 (nM) IC 50 (nM) ECso (nM) 1 C * * 2 A A A 3 B B B 4 B B * 5 A A * 6 A A A 7 C C * 8 C C * 9 B B * 10 C B * 11 B B * 12 B C * 13 C * * 14 D * * 15 C C * 16 A A A 17 A A A 18 A B A 19 A A A 20 A A A 21 A A A 22 A A * 23 A A A 24 B B * 25 A A A WO 2005/065779 PCT/US2003/038799 338 CGRP binding cAMP Functionr Cerebral Artery' Example #
IC
50 (nM) IC 50 (nim) EC 50 (nM) 26 B B * 27 B C * 28 C * * 29 A * * 30 B * * 31 A A * 32 C * * 33 C * * 34 A A * 35 B B * 36 B B * 37 A B * 38 B B * 39 C C * 40a A A * 40b B * * 40c D * * 40d C * * 40e D * * 40f D * 40g D * * 40h D * * 40i B * * 40j D * * 40k D * * 41a B * * 41b A * * 41c A * * 41d B * * 41e A * * WO 2005/065779 PCT/US2003/038799 339 CGRP binding cAMP Function' Cerebral Artery 3 Example #
IC
5 o (nM) IC 50 (nM) EC 50 (nM) 41f B * * 42 C * * 43 A A A 44 C * * 45 A * * 46 B B * 47 A A A 48 D * * 49 A * * 50 A * * 51 D * * 52 D * * 53 D * * 54 B C A 55 C * * 56 A A * 57 C * * 58 D * * 59 C * * 60 C * * 61 C C * 62 B B * 63 C C * 64 B * B 65 A B B 66 C * * 67 B C B 68 A A A 69 A A A 70 A A A WO 2005/065779 PCT/US2003/038799 340 CGRP binding' cAMP Function' Cerebral Artery Example #
IC
50 (nM) IC 50 (nM) EC 50 (nM) 71 A A A 72 A A A 73 B B * 74 A A A 75 A B * 76 B B A 77 B B * 78 A A * 79 B C * 80 C * * 81 B C * 82 B C * 83 B C * 84 B B * 85 C * * 86 C B C 87 B B * 88 C B * 89 C B * 90 B * * 91 C * * 92 B C * 93 C * * 94 C C * 95 C * * 96 D * * 97 D * * 98 D * * 99 D D * 100 C * * WO 2005/065779 PCT/US2003/038799 341 CGRP binding' cAMP Function 2 Cerebral Artery 3 Example #
IC
50 (nM) IC 50 (nM) EC 50 (nM) 101 D * * 102 C * * 103 C * * 104 C * * 105 C * * 106 C * * 107 C * * 108 C * 109 C * * 110 C * * 111 C * * 112 C * * 113 C * * 114 C * * 115 C * * 116 C * * 117 C * * 118 C * * 119 C * 120 C * 121 C * * 122 C * * 123 B * * 124 C * * 125 C * * 126 C * * 127 C * * 128 C * * 129 C * * 130 C * * WO 2005/065779 PCT/US2003/038799 342 CGRP binding cAMP Function 2 Cerebral Artery 3 Example #
IC
50 (nM) IC 50 (ni) EC 50 (nM) 131 C * * 132 C * * 133 C * * 134 C * * 135 C * * 136 C * * 137 C * 138 C * * 139 C * * 140 B * * 141 C * * 142 C * * 143 C * * 144 C * * 145 C * * 146 B * * 147 C * * 148 B * * 149 B * * 150 B * * 151 C * 152 C * * 153 C * * 154 C * * 155 C * * 156 C * * 157 C * * 158 B * * 159 B * * 160 C * * WO 2005/065779 PCT/US2003/038799 343 CGRP binding cAMP Function Cerebral Artery 3 Example # CR idn A PFnto
IC
50 (nM)
IC
50 (nM)
EC
50 (nM) 161 B * * 162 C * * 163 C * * 164 C * * 165 C * * 166 C * * 167 C * * 168 C * * 169 C * * 170 C * * 171 B * * 172 B * * 173 C * * 174 C * * 175 C * * 176 B * * 177 B * * 178 B * * 179 C * * 180 C * * 181 C * * 182 C * * 183 C * * 184 B * * 185 C * * 186 C * * 187 C * * 188 C * * 189 C * * 190 C * * WO 2005/065779 PCT/US2003/038799 344 CGRP binding' cAMP Function 2 Cerebral Artery3 Example #
IC
50 (nM) IC 50 (nM) EC 50 (nM) 191 C * * 192 C * * 193 B * * 194 C * * 195 C * * 196 B * * 197 C * * 198 C * * 199 B * * 200 B * * 201 C * * Cyclic AMP Assay Functional Antagonism. Antagonism of the compounds of invention was determined by measuring the formation of cyclic AMP (adenosine 3'5'-cyclic monophosphate) in 5 SK-N-MC cells that endogenously express the human CGRP receptor. CGRP receptor complex is coupled with Gs protein and CGRP binding to this complex leads to the cyclic AMP production via Gs - dependent activation of an adenylate cyclase (Juaneda C et al., TiPS, 2000; 21:432-438; incorporated by reference herein). Consequently, CGRP receptor antagonists inhibit CGRP - induced cyclic AMP 10 formation in SK-N-MC cells (Doods H et al., Br J Pharmacol,2000; 129(3):420-423) ; incorporated by reference herein). For cyclic AMP measurements SK-N-MC cells were incubated with 0.3 nM CGRP alone or in the presence of various concentrations of the compounds of invention for 30 min at room temperature. Compounds of invention were pre-incubated with SK-N-MC cells for 15 min before the addition of 15 CGRP to allow receptor occupancy (Edvinsson et al., Eur J Pharmacol, 2001, 415:39 44; incorporated by reference herein). Cyclic AMP was extracted using the lysis reagent and its concentration was determined by radioimmunoassay using RPA559 cAMP SPA Direct Screening Assay Kit (Amersham Pharmacia Biotech). IC50 values were calculated using Excel fit. The tested compounds of invention were determined WO 2005/065779 PCT/US2003/038799 345 to be antagonists as they exhibited a dose - dependent inhibition of the CGRP induced cyclic AMP production. See Table 3 for summary of results. Schild Analysis. Schild analysis can be used to characterize the nature of antagonism 5 of the compounds of invention. The dose response of CGRP stimulated cAMP production was generated either with CGRP alone, or in the presence of various concentrations of compounds of invention. The antagonist dose is plotted as X against the dose ratio (defined as IC50 of agonist with the presence of the compounds divided by the IC50 of the agonist alone) minus 1 as Y. Linear regression was then 10 performed with both X and Y axis log-transformed. A slope that does not differ significantly from unity (1) indicates competitive antagonism. Kb is the dissociation constant of the antagonist. Table 5. Schild Analysis Example # KO(nM) slope 2 0.16 0.94 3 55 0.96 5 3 0.92 6 0.36 0.93 16 1.3 17 1.1 0.92 18 1 0.8 21 0.018 0.89 43 0.018 1.2 45 1.4 47 0.1 0.93 69 0.016 1 70 0.71 71 2 0.87 15 See Figure 1. Schild Analysis.
WO 2005/065779 PCT/US2003/038799 346 Ex Vivo Human Cerebral Artery Assay Rationale and Overview. To provided direct evidence of the ability for novel compounds to reverse CGRP-induced dilation in human cerebral vessels, an ex vivo assay was designed. Briefly, isolated vessel rings were mounted in a tissue bath 5 where vessels were pre-contracted with potassium chloride (KCl ) and fully dilated with hCGRP, then this relaxation was reversed by the cumulative addition of CGRP receptor antagonists (complete details follow). Tissue Samples. Autopsy samples of human arteries were obtained from vendors 10 (ABS Inc. or NDRI). All vessels were transported on ice-cold HEPES buffer (composition in mM: NaCl 130, KCl 4, KH2PO4 1.2, MgSO4 1.2, CaCl2 1.8, Glucose 6, NaHCO3 4, HEPES 10, EDTA 0.025). Upon receipt, the vessels were placed in cold Kreb's buffer (composition in mM: NaCl 118.4, KCl 4.7, KH2PO4 1.2, MgSO4 1.2, CaCl2 1.8, Glucose 10.1, NaHCO3 25) saturated with carbogen (5% 15 C02 and 95 % oxygen). Isolated Tissue Baths. The vessels were cleaned of connective tissues and cut into cylindrical segments of 4-5mm in length. The vessels were then mounted in tissue baths between two stainless steel hooks; one of which is fixed and the other of which 20 was connected to a force displacement transducer. The vessel tension was continuously recorded using a data acquisition system (Powerlab, ADInstruments, Mountain View, CA) connected to the transducer. The tissue baths containing Krebs buffer and mounted vessels were temperature (37 C) and pH (7.4) controlled with continuous bubbling of carbogen. The artery segments were allowed to equilibrate for 25 about 30-45 min until a stable resting tone was achieved. Prior to the assay, vessels were primed (conditioned) with 100 mM KCl and subsequently washed. The vessels were pre-contracted with 10 mM KCI and fully dilated with I nM hCGRP. Concentration-response curves to CGRP-receptor antagonists were performed by the cumulative addition of drugs in half log units in fully dilated vessels. At each 30 concentration, the effects of the drugs were expressed as % reversal of CGRP induced relaxation in each vessel. The actual assay and data analysis were performed for each vessel individually, fitting the concentration-response data to a four WO 2005/065779 PCT/US2003/038799 347 parameter logistic function by non-linear regression analysis, to estimate the EC50 values. A summary of results is provided in Table 3. Non-Terminal Method for Assessing In Vivo Efficacy of Small Molecule CGRP 5 receptor antagonists in Mammals Overview. Blocking cerebral artery dilation induced by calcitonin gene-related peptide (CGRP) has been proposed as a treatment for migraine headache, however, novel small molecule CGRP-receptor antagonists have shown species-specific differences with relatively poor activity in rodents (Mallee et al. J Biol Chem 2002 10 277:14294) requiring new models for assessment of in vivo efficacy. Non-human primates (e.g., marmosets) are the only animals known to have human-like CGRP receptor pharmacology conferred by the presence of the specific amino acid residue (Trp74) in their RAMP 1 sequence which is responsible for the phenotype of the human receptor (Mallee et al. J Biol Chem 2002 277:14294). Since current migraine 15 models primarily use rats (Escott et al. Brain Res 1995 669:93; Williamson et al. Cephalalgia 1997 17:525), or are invasive, terminal procedures in primates (Doods et al. Br J Pharmacol 2000 129:420), a novel non-invasive, survival model in non human primates for in vivo efficacy assessment of CGRP-receptor antagonists as in the present invention is a significant contribution. While it is known that trigeminal 20 activation increases both cerebral (Goadsby & Edvinsson, 1993) and facial blood flow (Doods et al., 2000), demonstration of a direct relationship between facial blood flow and cerebral artery dilation conducted in the same animals was not known. Therefore, before initiating studies in non-human primates, laser Doppler measurement of facial blood flow was directly validated in the rat as a surrogate for 25 cerebral artery dilation in terminal studies that measured both cerebral artery diameter and changes in facial blood flow in the same animals (see Figure 2. Direct Validation of Facial Blood Flow as Surrogate for Cerebral Artery Dilation in the Rat). In both measures, comparable increases were induced by i.v. CGRP and blocked by the peptide antagonist haCGRP(8-37). Next, the method of i.v. CGRP 30 induced changes in facial blood flow was validated as a recovery model in isoflurane anesthetized rats using haCGRP(8-37). The survival method was then established in non-human primates and a dose-response study characterizing i.v. CGRP activity was WO 2005/065779 PCT/US2003/038799 348 completed (see Figure 3. Dose-Response for haCGRP in Non-Human-Primate Laser Doppler Facial Blood Flow). Peptide and small-molecule CGRP-receptor antagonists were used to validate the non-human primate model. Pre-treatment with small molecule antagonists or haxCGRP(8-37) dose-dependently inhibited i.v. CGRP 5 stimulated increases in primate facial blood flow (see Figure 4. Inhibitition of CGRP Induced Changes in Non-Human Primate Facial Blood Flow), without altering blood pressure (see Figure 5. Effect of CGRP Antagonist on Non-Human Primate Blood Pressure). Post-treatment of antagonists also reversed CGRP-induced increases in facial blood flow (not shown). This survival model provides a novel, non-invasive 10 recovery procedure for evaluating prophylactic and abortive effects of CGRP receptor antagonists in non-human primates, or in transgenic animals with humanized RAMP 1 (Trp74) which have similar CGRP receptor pharmacology, as a surrogate marker for activity in cerebral vessel diameter. 15 Animals. Adult male and female common marmosets (Callithrix jacchus) purchased from Harlan and weighing 350-550 g served as subjects. Other mammals endogenously expressing RAMP 1 having Trp 74 or transgenic mammals with humanized RAMP 1 having Trp 74 can also be employed in the method described herein. 20 Anesthesia & Surgical Preparation. Animals are anesthetized by isoflurane inhalation in an induction chamber (4-5% rapid induction, maintained with 1-2.5%; Solomon et al., 1999). Anesthesia is maintained by delivering a constant supply of air:oxygen (50:50) and isoflurane via face mask, or by intubation and ventilation 25 (with blood gas monitoring). Body temperature is maintained at 38 ± 0.5 *C by placement on an automated temperature controlled surface with rectal probe. A small area of fur (approx. 1.5 cm square) is removed from one or both sides of the face by application of a depilatory cream and/or shaving. Surgical areas are clipped and prepared with betadine. An i.v. line is placed in any accessible vein for the 30 administration of test compounds and CGRP-receptor agonist and, if needed, withdrawal of blood samples (max 2.5 ml, 10%) for blood gas monitoring and content analysis. A solution of 5% dextrose is administered i.v. in order to maintain blood sugar levels. Anesthesia depth is monitored by measuring blood pressure and WO 2005/065779 PCT/US2003/038799 349 heart rate using a non-invasive arm cuff method and a pulse oximeter, respectively. Guanethidine 5-10 mg/kg i.v., supplemented with 5 mg/kg i.v. as needed, may be given to stabilize the peak flux in facial blood flow seen with repeated stimulation induced changes in blood flow (Escott et al., 1999; incorporated by reference herein). 5 Microvascular blood flow is monitored by attaching a self adhesive laser Doppler flow probe to the facial skin. Compound Administration Test compounds may be administered i.v. (0.01-5 ml/kg), i.m. (0.01-0.5 ml/kg), s.c. (0.01-5 ml/kg) or p.o. (0.1-10 mlkg) (Diehl et al., 2001; 10 incorporated by reference herein). CGRP-receptor agonists may be delivered i.v. (0.01-5 ml/kg), i.d. (10-100 pl/site) or s.c. (10-100 pt/site). Laser Doppler Flowmetry A control increase in facial blood flow is induced by administration of a vasodilator, such as CGRP (0.05-100 pg/kg i.v.) or 2-20 15 pmol/site i.d) or adrenomedullin (ADM, 0.05-5 mg/kg i.v. or 10-100 pmol/site i.d.). Test compound or vehicle is administered either before (pre-treatment) or after (post treatment) subsequent repeat administration of the vasodilating agent, providing the ability to assess prophylactic or therapeutic actions. Blood pressure is monitored continuously to ensure adequate depth of anesthesia, and anesthetic is adjusted to 20 maintain stable levels that match pre-treatment values. During collection of laser Doppler flowmetry data, isoflurane may be reduced to 0.25-0.75% as previous electrophysiologic studies in marmosets found that recordings were sensitive to isoflurane concentration (Solomon, 1999; incorporated by reference herein). To reduce the number of animals used, the effect of test compound on i.v. vasodilator 25 induced changes in blood flow may be repeated up to 6 times in a single session. Recovery Animals are returned to the transport cage which is placed on a temperature controlled surface to keep the animals warm until fully awake and ambulatory. Animals may be tested again after 7-14 days rest, and may be tested 30 repeatedly at 7-14 day intervals depending on the health of the animal. See Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C. A good practice guide to the administration of substances WO 2005/065779 PCT/US2003/038799 350 and removal of blood, including routes and volumes. J Appl Toxicol. 2001 Jan Feb;21(1):15-23; Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 Feb;129(3):420-3; 5 Edvinsson L. Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs 2001;15(10):745-53; Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1995 Jan 9;669(l):93-9; Goadsby PJ, Edvinsson L. The trigeminovascular 10 system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993 Jan;33(1):48-56; Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olsen J. CGRP may play a causative role in migraine. Cephalalgia, 2002, 22, 54-61; Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA. RAMP I determines 15 the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem. 2002 Feb 14 [epub ahead of print]; Solomon SG, White AJ, Martin PR. Temporal contrast sensitivity in the lateral geniculate nucleus of a New World monkey, the marmoset Callithrix jacchus. J Physiol. 1999 Jun 15;517 ( Pt 3):907-17; all incorporated by reference herein. 20 Departuresfrom Other Migraine Models. This invention represents a novel migraine model and is remarkably distinct from other migraine models. Some of the distinguishing characteristics of the method of the present invention include: (i) the only survival model of migraine in any species; (ii) the only model to demonstrate the abortive (post-treatment) effects of CGRP antagonists on active induced increases 25 in blood flow; (iii) the only demonstration of a direct relationship between facial blood flow and intracranial artery dilation carried out in the same animals; (iv) the only model to use non-invasive surgical techniques, and does not require catheter placement, intubation, or neuromuscular blockade; (v) the only primate model to use exogenous CGRP as the stimulus and demonstrate pretreatment blockade by CGRP 30 antagonism and post-treatment reversal by CGRP antagonism; (vi) the only migraine model to use isoflurane anesthesia in spontaneously breathing animals. The models described in Williamson et al., Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat-intravital microscope studies. Cephalalgia.
WO 2005/065779 PCT/US2003/038799 351 1997 Jun;17(4):525-31; Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia. 1997 Jun;17(4):518-24; Escott KJ et al., Trigeminal ganglion stimulation increases 5 facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1995 Jan 9;669(1):93-9; Chu DQ et al., The calcitonin gene-related peptide (CGRP) antagonist CGRP(8-37) blocks vasodilatation in inflamed rat skin: involvement of adrenomedullin in addition to CGRP. Neurosci Lett. 2001 Sep 14;310(2-3):169-72; Escott KJ, Brain SD. Effect of a calcitonin gene-related peptide 10 antagonist (CGRP8-37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve. Br J Pharmacol. 1993 Oct; 110(2):772-6; Hall JM, Siney L, Lippton H, Hyman A, Kang-Chang J, Brain SD. Interaction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvasculature of the rat and hamster. Br J Pharmacol. 1995 Feb; 114(3):592-7; 15 Hall JM, Brain SD. Interaction of amylin with calcitonin gene-related peptide receptors in the microvasculature of the hamster cheek pouch in vivo. Br J Pharmacol. 1999 Jan;126(l):280-4; and Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 20 Feb;129(3):420-3 fail to possess the remarkable features of the method of the present invention. In the table below, results are denoted as follows: W 25%; 25% < X 50%; 50% < Y ! 75%; Z > 75%. 25 Table 6. Inhibition of CGRP-Induced Increase in Laser Doppler Facial Blood Flow in the Non-Human Primate (e.g., Common Marmoset) WO 2005/065779 PCT/US2003/038799 352 Non-Human Primate (% Inhibition) of CGRP-induced (10 pg/kg, iv) increase in laser Doppler facial blood flow Example # 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, iv iv iv iv iv 2 W X X Y Z 6 Z 16 Y 69 Y Z haCGRP Z (8-37) W < 25%; 25% < X < 50%; 50% < Y : 75%; Z > 75%. See Figure 5. Effect of CGRP Antagonist on Non-Human Primate Blood Pressure.

Claims (3)

1. A compound selected from the group consisting of (±)-3-(3-Cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino } -propionic acid methyl ester; 5 (+)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-l-(3-cyano-1H-indol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(3-cyano-7-methyl-1H-indol-5-yl-methyl)-2-oxo-ethyl] amide; 10 (±)-3-(7-Isopropyl-IH-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl- I'-yl-1 (7-isopropyl- 1 H-indazol-5-yl-methyl)-2-oxo-ethyl] -amide; (d)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipcridine-1-carboxylic acid [2 15 [1,4']bipiperidinyl-l'-yl-1(7-ethyl-iH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; (L)-4-(2,2-Dioxo-1,4-dihydro-2H-2X 6 -benzo[1,2,6]thiadiazin-3-yl)-piperidine-1 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-1(7-methyl-I H-indazol-5-yl-methyl)-2 oxo-ethyl]-amide; (+)-4-(2,2-Dioxo-1,4-dihydro-2H-2X 6 -benzo[1,2,6]thiadiazin-3-yl)-piperidine-1 20 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-1(7-ethyl-3-methyl-1H-indazol-5-yl methyl)-2-oxo-ethyl]-amide; (±)-2-[4-(6-Cyano-2-oxo-l,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carbonyl] amino] -3 -(7-methyl-i H-indazol-5-yi)-propi onic acid methyl ester; (±)-4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid 25 {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide; (+)-4-(2-Oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl-1-carboxylic acid {2 [1,4']bipiperidinyl-l'-yl-I-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl}-amide; (A)-4-(6-Hydroxy-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid 30 {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide; WO 2005/065779 PCT/US2003/038799 354 (±)-4-(8-Methoxy-2-oxo- 1,4-dihydro-2H-qinazolin-3-yl)-piperidine- I -carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-l-(7-methyl-I H-indazol-5-yl methyl)-2-oxo-ethyl} amide; (±)-4-(8-Chloro-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid 5 {2-[1,4']bipiperidinyl-l'-yl-l-(7-methyl-IH-indazol-5-yl methyl)-2-oxo-ethyl} amide; (±)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-I-(4-(piperidin-1-yl)piperidin-1 yl)propan-2-yl)-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)- 1 carboxamide; 10 (d)-N-(3-(7-Ethyl-3-methyll H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1 H-benzo[d] [1,3 ]oxazine) 1 -carboxamide; (±)-N-(3-(7-Ethyl- 1 H-indazol-5-yl)- I -(6,7-dihydro- 1 H-pyrazolo[4,3-c]pyridin-5(4H) yl)-I -oxopropan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 15 carboxamide; (±)-N-(3 -(7-Ethyl-1 H-indazol-5-yl)- 1 -(6,7-dihydro-7,7-dimethyl- 1 H-pyrazolo[4,3 c]pyridin-5(4H)-yl)- 1 -oxopropan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamide; (+)-Methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-I 20 carboxamido)-3-(7-methyl- 1 H-indazol-5-yl)propanoate; (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3 (4H)-yl)-N-(3-(7-methyl- I H-indazol
5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 carboxamide; (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl- I H-indazol 25 5-yl)- 1 -oxo- I -(4-phenylpiperazin- 1 -yl)propan-2-yl)piperidine- I -carboxamide; (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3 (4H)-yl)-N-(1 -(4-(4 fluorophenyl)piperazin- 1 -yl)-3-(7-methyl- 1 H-indazol-5-yl)- 1 -oxopropan-2 yl)piperidine- 1 -carboxamide; (+)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(4-(2 30 fluorophenyl)piperazin- 1 -yl)-3-(7-methyl- 1 H-indazol-5-yl)- I -oxopropan-2 yl)piperidine- 1 -carboxamide; (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3 (4H)-yl)-N-(3 -(7-methyl-i H-indazol 5-yl)- 1 -oxo- 1 -(4-o-tolylpiperazin- 1 -yl)propan-2-yl)piperidine- I -carboxamide; WO 2005/065779 PCT/US2003/038799 355 (±)-Methyl 2-(4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 carboxamido)-3-(7-ethyl-3-methyl- 1 H-indazol-5-yl)propanoate; (±)-N-(3-(7-Ethyl-3-methyl-i H-indazol-5-yl)- 1 -oxo-I -(4-(piperidin- 1 -yl)piperidin- 1 yl)propan-2-yl)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 5 carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(piperidin- 1 yl)piperidin- 1 -yl)propan-2-yl)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamide; (±)-N-(3 -(7-Methyl-i H-indazol-5-yl)- I -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 10 yl)propan-2-yl)-8'-fluoro-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)- 1 carboxamide; (±)-4-(8-Fluoro- 1,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-methyl- I H indazol-5 -yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 carboxamide; 15 N-((R)-3 -(2-(trifluoromethyl)- 1H-benzo[d] imidazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 yl)piperidin- 1 -yl)propan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine 1 -carboxamide; N-((R)- I -(dimethylcarbamoyl)-2-(2-(trifluoromethyl)- 1 H-benzo[d] imidazol-5 yl)ethyl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 -carboxamide; 20 (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido) 3-(2,3-dihydro-2-oxo-IH-benzo[d]imidazol-6-yl)propanoate; N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-y1)-1-oxo-1(4-piperidin-1 yl)piperidine- 1 -yl)propan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine 1 -carboxamide; 25 N-((R)- I -(dimethylcarbamoyl)-2-(2,3-dihydro-2-oxo- 1 H-benzo[d] imidazol-6 yl)ethyl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 -carboxamide; N-((R)-3-(2,3-dihydro-2-oxo- I H-benzo[d] imidazol-6-yl)- 1 -oxo- 1 (4-piperidin- 1 yl)piperidine- 1 -yl)propan-2-yl)-4-(2',3'-dihydro-2'-oxospiro(piperidine-4,4'-(1H) quinazoline)carboxamide; 30 4-(1,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-((R)-3 -(7-methyl-I H benzo[d] [1,2,3]triazol-5-yl)- I -oxo- 1 -(4-(piperidin- I -yl)piperidin- 1 -yl)propan-2 yl)piperidine- I -carboxamide; WO 2005/065779 PCT/US20031038799 356 (R)-4-(2-Oxo- I , 4 -dihydro-2H-quinazoin-3 -yl)-piperi dine-. 1 -carboxylic acid [2-(4 cyclohexyl-piperazin- 1 -yl)-2-oxo- 1 -( 2 -oxo- 2 ,3-dihydro-benzooxazol-6-ylmethyl) ethyl]-amide; (R)-4-(2-Oxo- 1, 4 -dihydro-2H-quinazolin-3-yl)-piperidine 1 -carboxylic acid [2-(4 5 isopropyl-piperazin- 1 -yl)-2-oxo- 1 -( 2 -oxo- 2 ,3-dihydro-benzooxazol-6-ylmethyl) ethyl]-amide; (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(piperidin- 1 yl)piperidin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I11 benzo[d] [ 1,3]oxazine)- 1 -carboxamide; 10 (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yi)- 1 -oxo- 1 -(4-(cyclohex- 1 yl)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I H benzo[d] [ 1,3]oxazine)- 1 -carboxamide; (R)-N-((R)-3 -( 2 -Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(prop-2 yl)piperazin- I -y])propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I H 15 benzo[d] [ 1,3] oxazine)- I -carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol6yl). 1 -oxo- 1 -(4-(piperidin- 1 yl)piperidin- 1 -yl)propan-2-yI)-2,4-dihydra-2 '-oxospiro-(piperidine-4,4'- 1 H quinazoline)- I -carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazo-6y)- 1 -oxo- 1 -(4-(cyclohex- 1 20 yl)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4'- 1 H quinazoline)-1I -carboxamide; (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yI)- I -oxo- 1 -(4-(prop-2 yl)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4'- 1 H quinazoline)- 1 -carboxamide; 25 (R)-4-(2-Oxo- 1, 4 -dihydro-2H-quinazolin-3-yl)-piperine-l1-carboxylic acid [2 [1,4' ]bipiperidinyl- l'-yl-l -( 4 -chloro- 2 -oxo-2,3-dihydro-benzooxazol-6&ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo-1I, 4 -dihydro-2H-quinazolin-3-yi)-piperidine-1I-carboxylic acid [2 [1,4' Ibipiperidinyl- l'-yl-l -(5-chloro-2-oxo-2,3-dihydro-benzooxazol6ylmethyl)-2 30 oxo-ethyl]-amide; (R)-4-(2-Oxo-1I, 4 -dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-l -( 4 -bromo- 2 -oxo-2,3-dihydro-benooxazolh6ylmethyl)-2 oxo-ethyl]-amide; WO 2005/065779 PCT/US2003/038799 357 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 5 [1,4']bipiperidinyl- 1'-yl-1 -(4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (±)-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4 [1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4'-piperidinyl]-butyramide; (±)-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4-[4 10 (2-oxo-1,4-dihydro-2 H-quinazolim-3-yl)-piperidin-1-yl]-butyramide; (1)-Phenyl-acetic acid N'-{2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo 1,4-dihydro-2H-quinazolin-3-yl)-piperidm-1-yl]-butyryl}-hydrazide; (d)-1-[1,4']Bipiperidinyl-l'-yl-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3 yl)-piperidin-1-yl]-2-(7-methyl-1H-indazol-5-ylmethyl)-butane-1,4-dione; 15 (i)-1-[1,4']Bipiperidinyl-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[2',3' dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline] -butane-1,4-dione; (t)-1-(4-Cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl] -butane-1,4-dione; (±)-1-[1,4']Bipiperidinyl-l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[4 20 (2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1 -yl]-butane- 1,4-dione; (i)-1-[1,4']Bipiperidinyl-1'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4 [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane- 1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzooxazdl-6-ylmethyl) 4-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)] -butane- 1,4-dione; 25 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 cyclohexyl-piperazin-1-yl)-l-(7-methyl-I H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l-carboxylic acid [2-[4-(4 fluoro-phenyl)-piperazin-1-yl]-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl] amide; 30 ( )-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid tert-butyl ester; (+)-3-(7-Methyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-methyl cyclohexyl ester; WO 2005/065779 PCT/US2003/038799 358 (+)-3-(7-Methyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino } -propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester; (+)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid piperidin-4-yl ester; 5 (+)-4-(3-(7-Methyl-IH-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionyloxy)-piperidine- 1 -carboxylic acid tert-butyl ester; (±)-3-(7-Methyl-1IH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 3,4,5,6-tetrahydro-2H 10 [1,4']bipyridinyl-4-yl ester; (±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid I -diethylamino- 1-methyl-ethyl ester; (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2-{[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1,1 -dimethyl-2-phenyl-ethyl ester; 15 (+)-3-(7-Methyl- 1 H-indazol-5 -yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yI) piperidine- 1 -carbonyl]-amino } -propionic acid 1,1 -dimethyl-3-phenyl- propyl ester; (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl) piperidine-1-carbonyl]-amino} -propionic acid ethyl ester; (±)- 1 -(7-Methyl-1 H-indazol-5-ylmethyl)-2-[ 1 -pyridin-4-yl-methyl] -2-oxoethyl] 20 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1 H)-quinazoline]- 1 -carboxamide; (*)-1 -(7-Methyl-i H-indazol-5-ylmethyl)-2-[1 -pyridin-4-yl-piperazinyl]-2-oxoethyl] 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1 H)-quinazoline]- 1 -carboxamide; (+)- 1 -(7-Methyl-1 H-indazol-5 -ylmethyl)-2-[(2-dimethylamino-ethyl-ethyl carbamoyl)-2-oxoethyl]-2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1 H) 25 quinazoline]-1 -carboxamide; (±)-1 -(7-Methyl-I H-indazol-5-ylmethyl)-2-[1 -pyridin-4-yl-piperazinyl]-2-oxoethyl] 1',2'-dihydro-2'-oxospiro-[4H-3',I -benzoxazine-4,4'-piperidine]- 1 -carboxamide; (±)- 1 -(7-Methyl-I H-indazol-5-ylmethyl)-2-[1 -pyridin-2-yl-piperazinyl]-2-oxoethyl] 1',2'-dihydro-2'-oxospiro-[4H-3', I -benzoxazine-4,4'-piperidine]- I -carboxamide; 30 (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3yl)-piperidine-1d-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl]amide; and (R)-1-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1,4-bipiperidin] -1-yl-2-oxoethyl]-2',3'- WO 2005/065779 PCT/US2003/038799 359 dihydro-2'-oxospiro-[piperidine-4,4'-(1 H)-quinazoline]- 1 -carboxamide or a pharmaceutically acceptable salt or solvate thereof. 2. A compound selected from the group consisting of 5 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl- l'-yl-l-(7-bromo-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2-oxo-1-(2 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-l -yl)-ethyl] amide; 10 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-piperidin- I -yl-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 methyl-piperazin-1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-ethyl] amide; 15 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4 methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl] 20 amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [1 -(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin- 1 -yl-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [1 dimethylcarbamoyl-2-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-ethyl]-amide; 25 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yI)-piperidine-1-carboxylic acid [2-(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -dimethylcarbamoyl-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [1 -(4 methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl piperazin- 1 -yl)-ethyl]-amide; 30 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [I -(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazin- 1-yl) ethyl]-amide; WO 2005/065779 PCT/US2003/038799 360 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 5 [1,4']bipiperidinyl-l'-yl-l-(7-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl- '-yl-1 -(7-chloro-2-oxo-2,3-dihydro- 1 H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 10 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1-(7-ethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [2 [1,4'jbipiperidinyl- l'-yl-1 -(3-methyl-2-oxo-2,3-dihydro- I H-benzoimidazol-5 15 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(3,7-dimethyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 20 [1,4']bipiperidinyl-l'-yl-l-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol 5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-IH-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 25 3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid isopropyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino} -propionic acid isopropyl ester; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 30 piperidine- I -carbonyl] -amino} -propionic acid isopropyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-I -carbonyl]-amino}-propionic acid tert-butyl ester; WO 2005/065779 PCT/US2003/038799 361 3-(7-Ethyl- I H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid tert-butyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid cyclohexyl ester; 5 3-(7-Ethyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid cyclohexyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-methyl-piperidin-4-yl ester; 3-(7-Ethyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 1.0 piperidine- 1 -carbonyl]-amino} -propionic acid 1 -methyl-piperidin-4-yl ester; 3-(7-Chloro- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1-methyl-cyclohexyl ester; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 15 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester; and 3-(7-Ethyl- I H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl) piperidine-1-carbonyl]-amino} -propionic acid 4-phenyl-cyclohexyl ester or a pharmaceutically acceptable salt or solvate thereof. 20 3. A pharmaceutical composition comprising a compound selected from the group consisting of (±)-3-(3-Cyano-1 H-indol-5-yl)-2- {[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester; 25 (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1-(3-cyano-1H-indol-5-yl-methyl)-2-oxo-ethyl]-amide; (+)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yI)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(3-cyano-7-methyl-1H-indol-5-yl-methyl)-2-oxo-ethyl] amide; 30 (±)-3-(7-Isopropyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(7-isopropyl-IH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; WO 2005/065779 PCT/US2003/038799 362 (±)-4-(2-Oxo-1, 4 -dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(7-ethyl-iH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2,2-Dioxo- 1,4-dihydro-2H-2k 6 -benzo[ 1, 2 , 6 ]thiadiazin-3-yl)-piperidine- 1 carboxylic acid [2-[1, 4 ']bipiperidinyl-l'-yl-1(7-methyl-iH-indazol-5-yl-methyl)-2 5 oxo-ethyl]-amide; ( )-4-(2,2-Dioxo-1,4-dihydro-2H-2X 6 -benzo[1,2,6]thiadiazin-3-yl)-piperidine-1 carboxylic acid [2-[1, 4 ']bipiperidinyl- I'-yl- I (7-ethyl-3-methyl- 1 H-indazol-5-yl methyl)-2-oxo-ethyl]-amide; (±)-2-[4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine- 1 -carbonyl] 10 amino]-3-(7-methyl-IH-indazol-5-yl)-propionic acid methyl ester; (±)-4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-I H-indazol-5-yl methyl)-2-oxo-ethyl} amide; (±)-4-(2-Oxo-1,2,4,5-tetrahydro-bcnzo[d][1,3]diazepin-3-yl-1-carboxylic acid {2 15 [1,4']bipiperidinyl-l'-yl-1-(7-methyl-iH-indazol-5-yI methyl)-2-oxo-ethyl}-amide; (±)-4-(6-Hydroxy-2-oxo- 1, 4 -dihydro-2H-qinazolin-3-yl)-piperidine- I -carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-I H-indazol-5-yl methyl)-2-oxo-ethyl} amide; (±)-4-(8-Methoxy-2-oxo-1, 4 -dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic 20 acid {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-i H-indazol-5-yI methyl)-2-oxo-ethyl} amide; (±)-4-(8-Chloro-2-oxo-1, 4 -dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide; 25 (t)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1 yl)propan-2-yl)-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)- 1 carboxamide; (±)-N-(3-(7-Ethyl-3-methyl I H-indazol-5-yl)- I -oxo- 1 -(4-(piperidin-1 -yl)piperidin- I yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1 H-benzo[d][1,3]oxazine) 30 1 -carboxamide; (±)-N-(3-(7-Ethyl- 1 H-indazol-5-yl)- I -(6,7-dihydro- 1 H-pyrazolo[4,3-c]pyridin-5(4H) yl)- 1 -oxopropan-2-yl)-4-(1,2-dihydro- 2 -oxoquinazolin-3(4H)-yl)piperidine I carboxamide; WO 2005/065779 PCT/US2003/038799 363 (±)-N-(3-(7-Ethyl- 1 H-indazol-5-yl)- 1 -(6,7-dihydro-7,7-dimtethyl- 1 H-pyrazolo[4,3 clpyridin-5(4H)-yl)- 1 -oxopropan-2-yl)-4-(l ,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamide; (±)-Methyl 2-(4-(8-fluoro-1I,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 5 carboxamido)-3-(7-methyl- 1 H-indazol-5 -yl)propanoate; (+)-4-(8-Fluoro- I ,2-dihydro-2-oxoquinazolin-3 (4H)-yl)-N-(3-(7-methyl- 1 H-indazol 5-yl)-l1 -oxo- 1 -(4-(piperidin- I -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 carboxamide; (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-rnethyl- I H-indazol 10 5-yl)-l1 -oxo- 1 -(4-phenylpiperazin- 1 -yl)propan-2-yl)piperidine- 1 -carboxamide; (±)-4-(8-Fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N{1 -(4-(4 fluorophenyl)piperazin- 1 -yl)-3-(7-methyl- I H-indazol-5-yl)- 1 -oxopropan-2 yl)piperidine- I -carboxamide; (±)-4-(8-Fluoro- I ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-( 1 -(4-(2 15 fluorophenyl)piperazin- 1 -yl)-3-(7-methyl- 1 H-indazol-5 -yl)-lI -oxopropan-2 yl)piperidine- 1 -carboxamide; (±)-4-(8-Fluoro- 1,2-dihydro-2-oxoquinazoin-3 (4H)-y)-N-(3-(7-methy-I H-indazol 5-yl)- I -oxo- 1 -(4-o-tolylpiperazin- I -yl)propan-2-yl)piperidine- 1 -carboxamide; (±)-Methyl 2-(4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 20 carboxamido)-3-(7-ethyl-3-methyl- 1 H-indazol-5-yl)propanoate; (±)-N-(3-(7-Ethyl-3-rnethyl- I H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 yl)propan-2-yI)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-l1-oxo-l1-(4-(piperidin- 1 25 yl)piperidin- 1-yl)propan-2-yl)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3 (4H) yl)piperidine- 1 -carboxamide; (IL)-N-(3-(7-Methyl- I H-indazol-5-yl)- 1 -oxo- I -(4-(piperidin- I -yl)piperidin- 1 yl)propan-2-yl)-8 '-flhoro-2' ,3 '-dihydro-2 '-oxospiro-(piperidine-4,4 '-quinazoline)- 1 carboxamide; 30 (±)-4-(8-Fluoro- 1 ,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-methyl- 1 H indazol-5 -yl)-1I -oxo- I -(4-(piperidin- I -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 carboxamide; WO 2005/065779 PCT/US20031038799 364 N-((R)-3-(2-(trifluoromethyl)- 1H-benzo[d] imidazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 yl)piperidin- 1 -yI)propan-2-yl)-4-(1I,2-dihydro-2-oxoquinazolin-3(41f)-yl)piperdine 1 -carboxamide; N-((R)- 1 -(dimethylcarbamoyl)-2-(2-(trifluoromethyl)- 1 H-benzo[d] imidazol-5 5 yl)ethyl)-4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1I-carboxamide; (R)-methyl 2-(4-( 1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1-carboxamido) 3-(2,3-dihydro-2-oxo- I1H-benzo[d] imidazol-6-yl)propanoate; N-((,R)-3 -(2,3-dihydro-2-oxo- 1H-benzo[d] imidazol-6-yl)- 1 -oxo- 1 (4-piperidin- 1 yl)piperidine- 1 -yl)propan-2-yl)-4-( 1,2-dihydro-2-oxoquinazolin-3(411)-yl)piperidine 10 1 -carboxamide; N-((R)- 1 -(dimethylcarbamoyl)-2-(2,3-dihydro-2 -oxo- I1H-benzo [d] imidazol-6 yl)ethyl)-4-( 1,2 -dihydro-2-oxoquinazolin-3 (4H)-yI)piperidine- 1 -carboxamide; N-((R)-3 -(2,3-dihydro-2-oxo- I1H-benzo [d] imidazol-6-yl)- 1 -oxo- 1 (4-piperidin- 1 yl)piperidine- I -yl)propan-2-yl)-4-(2' ,3 '-dihydro-2 '-oxospiro(piperidine-4,4'-( 1 H) 15 quinazoline)carboxamide; 4-( 1,2-dihydro-2,4-dioxoquinazolin-3 (4H)-yl)-N-((R)-3 -(7-methyl- 1 H benzo [d] [ 1,2,3 ]triazol-5 -yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 -yI)propan-2 yl)piperidine- 1 -carboxamide; (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-l1-carboxylic acid [2-(4 20 cyclohexyl-piperazin- 1-yl)-2-oxo-lI-(2-oxo-2,3 -dihydro-benzooxazol-6-ylmethyl) ethyl]-amide; (R)-4-(2-Oxo- 1 ,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [2-(4 isopropyl-piperazin- 1 -yl)-2-oxo- 1 -(2-oxo-2,3 -dihydro-benzooxazol-6-ylmethyl) ethyl]-amide; 25 (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yl)- I -oxo- 1 -(4-(Piperidin- 1 yl)piperidin- 1 -yl)propan-2 -yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4'- 1 H benzo[d] [ 1, 3] oxazine)- 1 -carboxamide; (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(cyclohex- 1 yI)piperazin- I -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I H 30 benzo[d][1, ,3 ]oxazine)-1I-carboxamide; (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yl)- 1 -oxo- I -(4-(prop-2 yl)piperazin-1I-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1I H benzoid] [ 1,3] oxazine)- 1 -carboxamide; WO 2005/065779 PCT/US20031038799 365 (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo-l1-(4-(Piperidin- 1 yl)piperidin- I -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I H quinazoline)-1I -carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(cyclohex- 1 5 yl)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4'- 1 H quinazoline)- 1 -carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- I -(4-(prop-2 yl)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(Piperidine-4,4' -1 H quinazoline)- 1 -carboxamide; 10 (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1-carboxylic acid [2 [ 1,4' ]bipiperidinyl- l'-yl-lI -(4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperime- I-carboxylic acid [2 [1,4 ']bipiperidinyl- l'-yl-l -(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 15 oxo-ethyl]-amide; (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I -carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 20 [1 ,4'lbipiperidinyl- l'-yl-l -(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [1,4' Ibipiperidinyl- l'-yl-l -(4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl] -amide; 25 (±)-N-( I -Benzyl-2-hydroxy-ethyl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4 [1 ',2 '-dihydro-2 '-oxospiro-[4H-3 ',1 -benzoxazine-4,4' -piperidinyl] -butyramide; (±)-N-(lI-Benzyl-2-hydroxy-ethyl)-2-(7-rnethyl-l1H-indazol-5-ylmethyl)-4-oxo-4-[4 (2-oxo-t1,4-dihydro-2 H-quinazolin-3-yl)-piperidin- 1-yl]-butyramide; (4)-Phenyl-acetic acid N'- {2-(7-methyl- 1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo 30 1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin- l-yI] -butyryl} -hydrazide; (±)-l1-[1,4 ']Bipiperidinyl-1' -yl-4-[4-(8-fluoro-2-oxo-1I,4-dihydro-2H-quinazolin-3 yI)-piperidin- l-yl] -2-(7-methyl- 1H-indazol-5-ylmethyl)-butane- 1,4-diane; WO 2005/065779 PCT/US2003/038799 366 (I)-1-[1,4']Bipiperidinyl- 1'-yl-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-[2',3' dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline]-butane- 1,4-dione; (+)- 1 -(4-Cyclohexyl-piperazin- 1 -yl)-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl] -butane- 1,4-dione; 5 ()-1-[1,4']Bipiperidinyl- l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[4 (2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butane- 1,4-dione; (±)- 1-[1,4']Bipiperidinyl- l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4 [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane- 1,4-dione; (±)- 1 -(4-cyclohexyl-piperazin- I -yl)-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 10 4-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane- 1,4-dione; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l-carboxylic acid [2-(4 cyclohexyl-piperazin-1-yl)-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; (+)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[4-(4 fluoro-phenyl)-piperazin-1-yl]-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl] 15 amide; ( )-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid tert-butyl ester; (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1-methyl cyclohexyl ester; 20 (±)-3 -(7-Methyl-i H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl) piperidine- 1 -carbonyl] -amino} -propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester; (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid piperidin-4-yl ester; (±)-4-(3 -(7-Methyl-i H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3 -yl) 25 piperidine- 1 -carbonyl]-amino} -propionyloxy)-piperidine- 1 -carboxylic acid tert-butyl ester; (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo- l,4-dihydro-2H-quinazol in-3 -yl) piperidine- 1 -carbonyl]-amino} -propionic acid 3,4,5,6-tetrahydro-2H [1,4']bipyridinyl-4-yl ester; 30 ( )-3-(7-Methyl-iH-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester; (±)-3-(7-Methyl-iH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino} -propionic acid 1,1 -dimethyl-2-phenyl-ethyl ester; WO 2005/065779 PCT/US2003/038799 367 (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-3-phenyl- propyl ester; (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid ethyl ester; 5 (+)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-2-oxoethyl] 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (+)-1-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl] 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-Methyl-IH-indazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethyl 10 carbamoyl)-2-oxoethyl]-2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1 H) quinazoline]-1 -carboxamide; (±)-1 -(7-Methyl-i H-indazol-5-ylmethyl)-2-[1 -pyridin-4-yl-piperazinyl]-2-oxoethyl] 1',2'-dihydro-2'-oxospiro-[4H-3',1 -benzoxazine-4,4'-piperidine]- 1 -carboxamide; (+)-1 -(7-Methyl-I H-indazol-5-ylmethyl)-2-[1 -pyridin-2-yl-piperazinyl]-2-oxoethyl] 15 1',2'-dihydro-2'-oxospiro- [4H-3',1 -benzoxazine-4,4'-piperidine]- I -carboxamide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3yl)-piperidine-ld-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-1-(7-methyl-iH-indazol-5-ylmethyl)-2-oxo-ethyl]amide; and (R)-I-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1,4-bipiperidin]-1-yl-2-oxoethyl]-2',3' 20 dihydro-2'-oxospiro-[piperidine-4,4'-(1 H)-quinazoline]- 1 -carboxamide or a pharmaceutically acceptable salt or solvate thereof. 4. A pharmaceutical composition comprising a compound selected from the group consisting of 25 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(7-bromo-IH-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl] amide; 30 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-piperidin- I -yl-ethyl]-amide; WO 2005/065779 PCT/US2003/038799 368 4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-l-carboxylic acid [2-(4 methyl-piperazin- 1 -yl)-2-oxo- I -(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-ethyl] amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-l1-carboxylic acid [2 5 [1 ,4 t ]bipiperidinyl- l'-yl-l -(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [1 -(4 methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin-1 -yl-ethyl] amide; 10 4-(2-Oxo-1I,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [1 -(4-chioro 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin- 1 -yl-ethyl]-amnide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-l1-carboxylic acid [1 dimethylcarbamoyl-2-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-ethyl]-amide; 4-(2-Oxo-1I,4-dihydro-211-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2-(4-chloro 15 2-oxo-2,3-dihydro-benzooxazol-6-yl)-l1-dimnethylcarbamoyl-ethyl]-amide; 4-(2-Oxo- 1 ,4-dihydro-2H-quinazolin-3 -yl)-piperi dine- 1 -carboxylic acid [1 -(4 methyl-2-oxo-2,3 -dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl piperazin- 1-yl)-ethyll-amide; 4-(2-Oxo- I ,4-dihydro-21--quinazolin-3 -yl)-piperidine- I -carboxylic acid [ 1 -(4-chioro 20 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazin- Il-yI) cthyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperldine-l1-carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-lI -(4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl] -amide; 25 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(7-methyl-2-oxo-2,3-dihydro- IH-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1-carboxylic acid [2 [1 ,4']bipiperidinyl-l'-yl-l -(7-chloro-2-oxo-2,3-dihydro- 1H-benzoimidazol-5 30 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- I-carboxylic acid [2 [1 ,4']bipiperidinyl- l t -yl-l -(7-ethyl-2-oxo-2,3-dihydro- 1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; WO 2005/065779 PCT/US2003/038799 369 4 -(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-1'-yl-1-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl] -amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 5 [1,4']bipiperidinyl-l'-yl-l-(3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol 5-ylmethyl)-2-oxo-ethyl]-amide; 10 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid isopropyl ester; 15 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid isopropyl ester; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid isopropyl ester; 3-(7-Chloro-IH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 20 piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1 -carbonyl]-amino}-propionic acid tert-butyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid cyclohexyl ester; 25 3-(7-Ethyl-IH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid cyclohexyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 1 -methyl-piperidin-4-yl ester; 3 -(7-Ethyl-I H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) 30 piperidine- 1 -carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; WO 2005/065779 PCT/US2003/038799 370 3-(7-Ethyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino} -propionic acid 4-phenyl-cyclohexyl ester; and 5 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1-carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester or a pharmaceutically acceptable salt or solvate thereof. 5. Use of a compound selected from the group consisting of 10 (±)-3-(3 -Cyano- 1 H-indol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid methyl ester; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1-(3-cyano- IH-indol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2 15 [1,4']bipiperidinyl-1'-yl-1(3-cyano-7-methyl-1H-indol-5-yl-methyl)-2-oxo-ethyl] amide; (±)-3-(7-Isopropyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino } -propionic acid methyl ester; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 20 [1,4']bipiperidinyl-1'-yl-1(7-isopropyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; ( )-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1(7-ethyl-iH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2,2-Dioxo- 1,4-dihydro-2H-2X 6 -benzo[ 1,2,6]thiadiazin-3-yl)-piperidine- 1 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-1(7-methyl-iH-indazol-5-yl-methyl)-2 25 oxo-ethyl]-amide; (±)-4-(2,2-Dioxo- 1,4-dihydro-2H-2X 6 -benzo[1,2,6]thiadiazin-3-yl)-piperidine- 1 carboxylic acid [2-[1,4']bipiperidinyl-l'-yl-1(7-ethyl-3-methyl-1H-indazol-5-yl methyl)-2-oxo-ethyl]-amide; (±)-2-[4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carbonyl] 30 amino]-3-(7-methyl-1H-indazol-5-yl)-propionic acid methyl ester; (±)-4-(6-Cyano-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-1H-indazol-5-yl methyl)-2-oxo-ethyl} amide; WO 2005/065779 PCT/US2003/038799 371 (±)-4-(2-Oxo-1, 2 ,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl-1-carboxylic acid {2 [1,4']bipiperidinyl-l'-yl-1-(7-methyl-IH-indazol-5-yl methyl)-2-oxo-ethyl)-amide; (±)-4-(6-Hydroxy-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidme-1-carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} 5 amide; (±)-4-(8-Methoxy-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-l'-yl-1-(7-methyl-I H-indazol-5-yl methyl)-2-oxo-ethyl} amide; (+)-4-(8-Chloro-2-oxo-1,4-dihydro-2H-qinazolin-3-yl)-piperidine-I-carboxylic acid 10 {2-[1,4']bipiperidinyl-1'-yl-l-(7-methyl-iH-indazol-5-yl methyl)-2-oxo-ethyl} amide; (±)-N-(3-(7-Ethyl-3-methyl-I H-indazol-5-yl)-I-oxo-1-(4-(piperidin-1-yl)piperidin-I yl)propan-2-yl)-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)- 1 carboxamide; 15 (±)-N-(3-(7-Ethyl-3-methyl 1 H-indazol-5-yl)-1 -oxo-1 -(4-(piperidin-1 -yl)piperidin- 1 yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4' -1 H-benzo[d] [1,3]oxazine) 1 -carboxamide; (i)-N-(3-(7-Ethyl- 1 H-indazol-5-yl)- 1 -(6,7-dihydro- 1 H-pyrazolo[4,3-c]pyridin-5(4H) yl)-1 -oxopropan-2-yl)-4-(1, 2 -dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 20 carboxamide; (±)-N-(3-(7-Ethyl- 1 H-indazol-5-yl)- 1 -(6,7-dihydro-7,7-dimethyl-1 H-pyrazolo[4,3 c]pyridin-5(4H)-yl)- 1 -oxopropan-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamide; (±)-Methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 25 carboxamido)-3-(7-methyl-1H-indazol-5-yl)propanoate; (±)-4-(8-Fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-IH-indazol 5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1 carboxamide; (±)-4-(8-Fluoro-1, 2 -dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol 30 5-yl)-1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl)piperidine-1-carboxamide; (+)-4-(8-Fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(4 fluorophenyl)piperazin- I -yl)-3-(7-methyl- I H-indazol-5-yl)- 1 -oxopropan-2 yl)piperidine- 1 -carboxamide; WO 2005/065779 PCT/US20031038799 372 (±)-4-(8-Fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(4-(2 fluorophenyl)piperazin- I -yl)-3-(7-methyl- 1 H-indazol-5-yl)- 1 -oxopropan-2 yl)piperidine-1I -carboxamide; (±)-4-(8-Fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3 -(7-methyl- I H-indazol 5 5-yl)-lI -oxo- I -(4-o-tolylpiperazin- I -yl)propan-2-yl)piperidine- I -carboxamide; (±)-Methyl 2-(4-(8-fluoro-1I,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 carboxamido)-3-(7-ethyl-3-methyl- 1H-indazol-5-yl)propanoate; (+)-N-(3-(7-Ethyl-3-methyl- 1H-indazol-5-yl)-l1-oxo-lI-(4-(piperidin- 1-yl)piperidin- 1 yl)propan-2-yl)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H)-yI)piperidine- I1 10 carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-lI-oxo-l1-(4-(piperidin- 1 yl)piperidin- 1-yl)propan-2-yl)-4-(8-fluoro- 1,2-dihydro-2-oxoquinazolin-3(4H) yl)piperidine- 1 -carboxamide; (+)-N-(3-(7-Methyl- 1 H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- I -yl)piperidin- 1 15 yl)propan-2-yl)-8 '-fluoro-2' ,3 '-dihydro-2 '-oxospiro-(piperidine-4,4' -qumnazoline)- 1 carboxamide; (+L)-4-(8-Fluoro- 1 ,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-methyl- 1 H indazol-5-yl)- 1 -oxo- I -(4-(piperidin- 1 -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 carboxamide; 20 N-((R)-3 -(2-(trifluoromethyl)- 1 H-benzo[d]imidazol-5 -yl)-lI -oxo- 1 -(4-(piperidin- I1 yl)piperidin- 1 -yl)propan-2-yl)-4-( 1,2-dihydro-2-oxoquinazolin-3(4TH-yl)piperidine 1 -carboxamide; N-((R)- 1 -(dimethylcarbamoyl)-2-(2-(trifluoromethyl)- 1H-benzo[d] imidazol-5 yl)ethyl)-4-( 1,2-dihydro-2-oxoquinazolin-3(4-)-yI)piperidine-l1-carboxamide; 25 (R)-methyl 2-(4-(1I,2-dihydro-2-oxoquinazolin-3 (4H-yl)piperidine- 1-carboxamido) 3-(2,3-dihydro-2-oxo- 1H-benzo[djimnidazol-6-yl)propanoate; N-((R)-3-(2,3 -dihydro-2-oxo- 1H-benzo[dlimidazol-6-yl)- 1 -oxo- 1 (4-piperidin- 1 yl)piperidine- I -yl)propan-2-yl)-4-( 1,2-dihydro-2-oxoquinazolin-3(4R)-yl)piperidine I -carboxamide; 30 N-((R)- 1 -(dimethylcarbamoyl)-2-(2,3 -dihydro-2-oxo- I H-benzo[d]imidazol-6 yl)ethyl)-4-( 1,2-dihydro-2-oxoquinazolin-3 (4TH-yI)piperidine- 1 -carboxamide; WO 2005/065779 PCT/US20031038799 373 N-((R)-3 -(2,3-dihydro-2-oxo- 1H-be nzo[dl midazol-6-yl)- 1 -oxo- 1 (4-piperidin- 1 yl)piperidine- 1 -yl)propan-2-yl)-4-(2 ',3 '-dihydro-2 '-oxospiro(piperidine-4,4' -(1 I) quinazoline)carboxamide; 4-(1 ,2-dihydro-2,4-dioxoquinazolin-3 (41f)-yI)-N-((R)-3-(7-methyl- 1H 5 benzo[d] [ 1,2,3]triazol-5 -yl)-l -oxo- I -(4-(piperidin- I -yI)piperidin- 1 -yl)propan-2 yl)piperidine- 1 -carboxamide; (R)-4-(2-Oxo-1I,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2-(4 cyclohexyl-piperazin- I -yl)-2-oxo- 1 -(2-oxo-2,3-diliydro-benzooxazol-6-ylmethyl) ethyl] -amide; 10 (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2-(4 isopropyl-piperazin- 1-yl)-2-oxo-lI-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) ethyl]-amide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yI)-l1-oxo-l1-(4-(piperidin- 1 yl)piperidin- 1-yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1H 15 benzo[d] [1 ,3]oxazine)- I-carboxamide; (R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-l1-oxo-l1-(4-(cyclohex- 1 yl)piperazin- 1-yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4'- 1H benzo[d] [1 ,3]oxazine)-l1-carboxamide; (R)-N-((R)-3-(2-Oxo-2,3 -dihydro-benzooxazol-6-yl)-lI-oxo-l1-(4-(prop-2 20 y1)piperazin- 1 -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4' -1 H benzo[d] [ 1,3]oxazine)-1I -carboxamide; (R)-N-((R)-3 -(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(piperidin- 1 yl)piperidin-1I-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'- 1 H quinazoline)- I -carboxamide; 25 (R)-N-((R)-3 -(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- I -oxo- I -(4-(cyclohex- 1 yl)piperazin- I -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I H quinazoline)- 1 -carboxamide; (R)-N-((R)-3 -(2-Oxo-2,3 -dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(Prop-2 yl)piperazin- I -yl)propan-2-yl)-2,4-dihydro-2 '-oxospiro-(piperidine-4,4 '-1I1H 30 quinazo line)- 1 -carboxamide; (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [ 1,4']bipiperidinyl- l'-yl-lI -(4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; WO 2005/065779 PCT/US2003/038799 374 (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- I -carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-1 -(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 5 [1,4']bipiperidinyl- l'-yl-1 -(4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl- l'-yl-1 -(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; 10 (R)-4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine- 1 -carboxylic acid [2 [1,4']bipiperidinyl- l'-yl-1 -(4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; (±)-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4 [1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4'-piperidinyl] -butyramide; 15 ( )-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl- 1 H-indazol-5-ylmethyl)-4-oxo-4-[4 (2-oxo-1,4-dihydro-2 H-quinazolin-3-yl)-piperidin-1-yl]-butyramide; (+)-Phenyl-acetic acid N'- {2-(7-methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo 1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-hydrazide; (+)-1-[1,4']Bipiperidinyl-l'-yl-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3 20 yI)-piperidin-1-yl]-2-(7-methyl-1H-indazol-5-ylmethyl)-butane-1,4-dione; (±)-1-[1,4']Bipiperidinyl-l'-yl-2-(7-methyl-IH-indazol-5-ylmethyl)-4-[2',3' dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline]-butane- 1,4-dione; (±)- I -(4-Cyclohexyl-piperazin- 1 -yl)-2-(2-oxo-2,3 -dihydro-benzooxazol-6-ylmethyl) 4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl] -butane- 1,4-dione; 25 (±)- 1-[1,4']Bipiperidinyl- l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4-[4 (2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin- l-yl] -butane- 1,4-dione; (:)- 1-[1,4']Bipiperidinyl- l'-yl-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-4 [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)] -butane- 1,4-dione; (±)- I -(4-cyclohexyl-piperazin- I -yl)-2-(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 30 4-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)] -butane-1,4-dione; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 cyclohexyl-piperazin-1-yl)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; (*)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[4-(4- WO 2005/065779 PCT/US2003/038799 375 fluoro-phenyl)-piperazin- 1-yl] -1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-ethyl] amide; (±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid tert-butyl ester; 5 (±)-3-(7-Methyl- 1 H-indazol-5-yl)-2-{[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino } -propionic acid 1-methyl cyclohexyl ester; (+)-3-(7-Methyl-IH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl] -amino} -propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester; (+)-3-(7-Methyl- 1 H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) 10 piperidine- 1 -carbonyl]-amino} -propionic acid piperidin-4-yl ester; (±)-4-(3-(7-Methyl-IH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionyloxy)-piperidine-1 -carboxylic acid tert-butyl ester; (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 15 piperidine- 1 -carbonyl]-amino} -propionic acid 3,4,5,6-tetrahydro-2H [1,4']bipyridinyl-4-yl ester; (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester; (+)-3-(7-Methyl-iH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 20 piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino } -propionic acid 1,1-dimethyl-3-phenyl- propyl ester; (±)-3-(7-Methyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino} -propionic acid ethyl ester; 25 (±)-1-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-2-oxoethyl] 2 ',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (1)-i-(7-Methyl-iH-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl] 2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (1)-i-(7-Methyl-1H-imdazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethy 30 carbamoyl)-2-oxoethyl]-2',3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H) quinazoline]- I -carboxamide; (±)- 1 -(7-Methyl-i H-indazol-5-ylmethyl)-2-[ I-pyridin-4-yl-piperazinyl]-2-oxoethyl] 1',2'-dihydro-2'-oxospiro- [4H-3',1 -benzoxazine-4,4'-piperidine] -1 -carboxamide; WO 2005/065779 PCT/US2003/038799 376 ()-1 -(7-Methyl-i H-indazol-5-ylmethyl)-2- [1 -pyridin-2-yl-piperazinyl]-2-oxoethyl] 1',2'-dihydro-2'-oxospiro-[4H-3', 1 -benzoxazine-4,4'-piperidine] -1 -carboxamide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3yl)-piperidine- 1 d-carboxylic acid [2 [1,4']bipiperidinyl- i'-yl-1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-ethyl]amide; 5 and (R)- 1 -(7-Methyl-i H-indazol-5-ylmethyl)-2-[1,4-bipiperidin]- 1 -yl-2-oxoethyl]-2',3' dihydro-2'-oxospiro-[piperidine-4,4'-(1 H)-quinazoline] -1 -carboxamide or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of migraine. 10
6. Use of a compound selected from the group consisting of 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl-l'-yl-l-(7-bromo-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2 15 oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl] amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2-oxo- 1-(2 oxo-2,3 -dihydro-benzooxazol-6-ylmethyl)-2-piperidin- 1 -yl-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4 20 methyl-piperazin- 1 -yl)-2-oxo- 1 -(2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-ethyl] amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2 [1,4']bipiperidinyl- l'-yl-1-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; 25 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4 methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl] amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-piperidin-I -yl-ethyl] -amide; 30 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1 dimethylcarbamoyl-2-(4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-ethyl]-amide; 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-chloro 2-oxo-2,3-dihydro-benzooxazol-6-yl)-1-dimethylcarbamoyl-ethyl]-amide; WO 2005/065779 PCT/US20031038799 377 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [1 -(4 methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl piperazin-1 -yl)-ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [1 -(4-chioro 5 2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-piperazin- -yl) ethyl]-amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [ 1,4']bipiperidinyl- I'-yl-lI -(4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2 oxo-ethyl]-amide; 10 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-l1-carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(7-methyl-2-oxo-2,3-dihydro-l1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amidc; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-l1-carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(7-chloro-2-oxo-2,3 -dihydro- IH-benzoimidazol-5 15 ylmethyl)-2-oxo-ethyl]-aniide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(7-ethyl-2-oxo-2,3-dihydro- 1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1I,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 20 [1 ,4']bipiperidinyl- l'-yl-l -(3-methyl-2-oxo-2,3-dihydro- IH-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 4-(2-Oxo-1I,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [1 ,4']bipiperidinyl- l t -yl-l -(3 ,7-dimethyl-2-oxo-2,3-dihydro- 1H-benzoimidazol-5 ylmethyl)-2-oxo-ethyl]-amide; 25 4-(2-Oxo-1I,4-dihydro-2H-quinazolin-3-yl)-piperidine-lI-carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(7-chloro-3-methyl-2-oxo-2,3 -dihydro- 1H-benzoimidazol 5-ylmethyl)-2-oxo-ethyl] -amide; 4-(2-Oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidine-l1-carboxylic acid [2 [1 ,4']bipiperidinyl- l'-yl-l -(7-ethyl-3-methyl-2-oxo-2,3-dihydro- 1H-benzoimidazol-5 30 ylmethyl)-2-oxo-cthyl]-amide; 3-(7-Methyl- 1H-indazol-5-yl)-2- {[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yI) piperldin- 1 -carbonyl] -amino I -propionic acid isopropyl ester; WO 2005/065779 PCT/US2003/038799 378 3-(7-Chloro-1 H-indazol-5-yl)-2- { [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- I -carbonyl]-amino } -propionic acid isopropyl ester; 3-(7-Ethyl-IH-indazol-5-yI)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid isopropyl ester; 5 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1 -carbonyl]-amino} -propionic acid tert-butyl ester; 3-(7-Ethyl-IH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) 10 piperidine-1-carbonyl]-amino}-propionic acid cyclohexyl ester; 3-(7-Ethyl-iH-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid cyclohexyl ester; 3-(7-Chloro- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino}-propionic acid 1-methyl-piperidin-4-yl ester; 15 3-(7-Ethyl-1H-indazol-5-yl)-2-{ [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid I -methyl-piperidin-4-yl ester; 3-(7-Chloro- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid I -methyl-cyclohexyl ester; 3-(7-Ethyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) 20 piperidine-1-carbonyl]-amino}-propionic acid 1-methyl-cyclohexyl ester; 3-(7-Chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1-carbonyl]-amino} -propionic acid 4-phenyl-cyclohexyl ester; and 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1 -carbonyl]-amino} -propionic acid 4-phenyl-cyclohexyl ester or a 25 pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of migraine.
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IS8482A (en) 2006-05-26
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WO2005065779A1 (en) 2005-07-21
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EP1689493A4 (en) 2008-04-23
RS20060382A (en) 2008-09-29
CA2549330A1 (en) 2005-07-21
CN100558428C (en) 2009-11-11
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AR046788A1 (en) 2005-12-21

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