MXPA06006070A - Calcitonin gene related peptide receptor antagonists - Google Patents

Abstract

The present invention relates to compounds of Formula (I) as antagonists of calcitonin gene-related peptide receptors ("CGRP-receptor"), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.

Description

ANTIGONISTS OF THE PEPTIDE RECEPTOR RELATED TO THE CALCITONINE GENE Field of the Invention The present invention relates to novel small molecule antagonists of peptide receptors related to the calcitonin gene (CGRP receptor), pharmaceutical compositions comprising them, methods for their identification, methods of treatment using them and their use. in therapy for treatment of neurogenic vasodilatation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, choking associated with menopause, inflammatory airways diseases such as asthma and obstructive pulmonary disease chronic (COPD) and other conditions, the treatment of which can be done by the antagonism of CGRP receptors.

Background of the Invention The peptide related to the calcitonin gene (CGRP) is a naturally occurring peptide of 37 amino acids first identified in 1982 (Amara, S. G. et al, Science 1982, 298, 240-244). Two forms of the peptide are expressed (aCGRP and ßCGRP) that differ by one and three amino acids in REF..173114 rats and humans respectively. The peptide is widely distributed in the peripheral nervous system (PNS) and the central nervous system (CNS), located mainly in the central and sensory afferent neurons, and displays various biological effects including vasodilation. . When released from the cell, CGRP binds to receptors coupled with G protein of specific cell surface, and exerts its biological action predominantly by the activation of intracellular adenylate cyclase (Poyner, D.R. et al, Br J Pharmacol 1992, 105, 441-7; Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8). Two classes of CGRP receptors: CGRPí and CGRP2, have been proposed based on the antagonist properties of the CGRP peptide fragment (8-37) and the ability of linear analogs of CGRP to activate CGRP2 receptors (Juaneda, C. et al. al., TiPS 2000, 21, 432-438. However, there is a lack of molecular evidence for the CGRP2 receptor (Brain, SD et al, TiPS 2002, 23, 51-53) .The CGRPX receptor has three components: ) a receptor of the calcitonin receptor type of transmembrane 7 (CRLR); (ii) the type 1 protein that modifies the activity of the simple transmembrane receptor (RAMP1) and (iii) the intracellular receptor protein (RCP) (Evans B, N, et.al., J. Biol Chem, 2000, 275, 31438-43). RAMPl is required for the 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). PCR is required for signal transduction (Evans B. N. et al., J Biol Chem. 2000, 275, 31438-43). There are known species-specific differences in the small molecule antagonism binding to the CGRP receptor, with a typically higher affinity observed for human receptor antagonism than for other species (Brain, SD et al, TiPS 2000, 23, 51-53 ). The amino acid sequence RAMP1 determines the selectivity of the species, in particular, the amino acid residue Trp74 is responsible for the phenotype of the human receptor (Mallee et al., J Biol Chem 2002, 277, 14294-8). The inhibitors are postulated at the receptor level for CGRP because they are useful under pathophysiological conditions, where excessive activation of the CGRP receptor has occurred. Some of these include neurogenic vasodilatation, neurogenic inflammation, migraine, cluster headaches and other headaches, thermal injuries, circulatory shock, menopause suffocation and asthma. Activation of the CGRP receptor has been implicated in the pathogenesis of migraine headache (Edvinsson L. CNS Drugs 2001; 15 (10): 745-53; Williamson, DJ Microsc. Res. Tech. 2001, 53, 167-178; Grant, AD Brit. J. Pharmacol., 2002, 135, 356-362). Serum levels of CGRP rise during migraine (Goadsby PJ, et al Ann Neurol 1990; 28: 183-7) and the treatment of drugs against migraine returns the CGRP levels to a normal coincident with improvement of the headache (Gallai V. et al., Cephalalgia 1995; 15: 384-90). Those suffering from migraine show high baseline levels of CGRP compared to controls (Ashina M, et al., Pain 2000; 86 (1-2): 133-8.2000). CGRP intravenous infusion produces a lasting headache in migraine sufferers (Lassen LH, et al., Cephalalgia, 2002 Feb; 22 (1): 54-61). Preclinical studies in dogs and rats report that the systemic CGRP blockade with the CGRP peptide antagonist (8-37) does not alter the resting systemic hemodynamics or the regional blood flow (Shen, YT et al, J Pharmacol Exp Ther 2001, 298, 551-8). Thus, CGRP receptor antagonists may present a novel treatment for migraine that avoids the cardiovascular risks of active vasoconstriction associated with non-selective 5-HT? B /? D agonists. "triptans" (for example sumatriptan). There are several models of migraine in vivo known in the literature (see De Vries, P. et al, Eur J Pharmacol 1999, 375, 61-74). Some electrically stimulate the trigeminal ganglion and measure the dilatation of the intracranial vessels that enervate (for example Williamson et al., Cephalalgia 1997 17: 518-24). Since the facial arteries are also enervated by the trigeminal nerve, other models study changes in facial blood flow induced by electrical trigeminal activation (for example Escott et al., Brain Res 1995 669: 93). Alternatively, other peripheral nerves (eg, saphenous) and vascular beds (eg, abdominal blood swelling) are also studied (for example, Escott al. Br J Pharmacol 1993 110, 772-6;). All models have been shown to be blocked by pretreatment with the CGPR peptide antagonist (8-37), a peptide fragment that is absent from the first 7 residues, or by a small molecule CGRP receptor antagonist. In some cases, exogenous CGRP has been used as a stimulus. However, these models are all invasive terminal procedures, and none have demonstrated the clinically important abortive effect of reversing an established increase in arterial dilation or increased blood flow using a subsequent 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 among other intravenous CGRP as a stimulus to increase the diameter of the intracranial dural artery in anesthetized rats with sodium pentobarbital, using an "intravital" terminal procedure, which involves drilling to thin the skull and the creation of a closed cranial window to visualize the dural arteries. The effect is blocked by pretreatment with CGRP (8-37) intravenously. Escott et al, Brain Res 1995 669: 93; among others, they pierce inside the skull of the rat and use electrodes for the brain to electrically stimulate the trigeminal ganglion and measure the Doppler laser blood flow in a terminal procedure in rats anesthetized with sodium pentobarbital that involves a neuromuscular block, intubation of the trachea and artificial ventilation. The effect is blocked by pretreatment with CGRP (8-37). Escott et al. Br J Pharmacol 1993 110, 772-6; inter alia use intradermal CGRP (i.d.) as the stimulus to increase blood flow in the abdominal skin of the rat, of animals anesthetized with sodium pentobarbital, prepared with cannulated jugular veins for administration of the drug and anesthetic. The effect was blocked by pretreatment with i.v. CGRP (8-37). Chu et al. Neurosci Lett 2001 310, 169-72 used inter alia intradermal CGRP as the stimulus in rats and measured the laser Doppler changes in the blood flow in the skin of the back in a terminal method using sodium pentobarbital in cannulated animals in the trachea and anesthetized; and showed a pretreatment block by the continuous release of CGRP (8-37) from osmotic pumps implanted subcutaneously (s.c.). Hall et al Br J Pharmacol 1995 114, 592-7 and Hall et al Br J Pharmacol 1999 126, 280-4 inter alia used topical CGRP to increase the diameter of the hamster cheek pouch artery and intradermal CGRP to increase the blood flow in the dorsal skin of rat of anesthetized animals with sodium pentobarbital, prepared with cannulated jugular veins for the anesthetic administration of drug. The effect is blocked by pretreatment with CGRP i.v. (8-37). Doods et al. Br J Pharmacol, 2000 Feb; 129 (3): 420-3 inter alia drilled into the skull of the marmoset (monkey of the new world) and used electrodes for the brain to produce electrical stimulation of the trigeminal ganglion and facial blood flow measured in an invasive terminal procedure involving the neuromuscular block and artificial ventilation of primates anesthetized with sodium pentobarbital. The increase in flow was blocked by a pretreatment of the small molecule CGRP antagonist. See also WO 03/272252 Isolated DNA Molecules Encoding Humanized Calcitonin Gene-Related Peptide Receptor, Related Non-Human Transgenic Animáis and Assay Methods. Thus, the method of the present invention in its procedure is, inter alia, a non-invasive survival model in primates that measures the exogenous changes induced by CGRP in the facial blood flow, and demonstrates the pre- and post-treatment effects of the Small-molecule CGRP antagonists of peptides in israne-anaesthetized tamarins that breathe spontaneously that recover from the procedure and that offer important advantages. Several small molecule CGRP receptor antagonists that are not peptide have recently been reported. WO 97/09046 and equivalents describe inter alia quinine compounds and quinidine-related compounds that are ligands in particular of the CGRP receptor. WO 98/09630 and WO 98/56779 and equivalents describe, inter alia, various nitrobenzamide compounds as CGRP receptor antagonists. WO 01/32649, WO 01/49676 and WO 01/32648 and equivalents describe inter alia a series of 4-oxobutanamides and derivatives related to cyclopropane as CGRP receptor antagonists. WO 00/18764, WO 98/11128 and WO 00/55154 and equivalents describe inter alia benzimidazolinyl piperidines as CGRP receptor antagonists. Not related to CGRP, a series of somatostatin antagonists have been described in WO 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, U.S. 20030181462, US20030191068 and WO 03/076432 and related applications. Thus, novel antagonists of the CGRP receptor effective for the treatment of neurogenic inflammation, migraine and other disorders would be widely advantageous.

Brief Description of the Invention Thus according to a first embodiment of the first aspect of the invention, compounds of the Formula (I) are provided and pharmaceutically acceptable salts and solvates thereof wherein V is -N R1) (R2) or OR4; R4 is H, C6_6alkyl, C4_4 haloalkyl, or (C4_4alkylene) 0-? R4'R4 'is C3_7 cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl , furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl , triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and R4 'is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C? _4 alkyl, C? _ haloalkyl, alkoxy C? _, Hydroxy, amino, C3_cycloalkyl, C3-alkylamino, dialkylamino C? _3, phenyl and benzyl; and R4 'optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the ring structure of R4'; R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, C6_6 alkyl, C2_6 alkenyl. C2_6 alkynyl, -C6-amino-alkylamino (C3_3alkyl) 2, C3_cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl , pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and R1 and R2 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? _ alkyl, C halo _ haloalkyl, C? _ alkoxy, hydroxy, amino, C3_cycloalkyl, C3_3 alkylamino, C3_3 dialkylamino, C3_3 alkyl or 2ureido, phenyl and benzyl; R1 and R2 optionally and independently contain 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the heterocycles comprising R1 and R2; wherein L1 is optionally and independently interrupted from the nitrogen to which it is linked by L2, wherein L2 is independently C3_3 alkylene or C3_3 alkylidene; or R1 and R2 together with the nitrogen to which they are bonded from X, 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 is dioxolanyl, C ± -9 alkyl, C2-9 alkenyl, C2- alkoxy, C3_7 cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl , imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z is -NHC (0) 0-, -NHC (0) NH-, -NC (0) NH2, -NH-, C ?3 alkylene, C alkylene ? _3, alkenylene-C] _3-NHC (0) 0-alkylene C? _; and optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C? _, amino, C? _3 alkylamino, C? ~ 6 -alkylene, or (C? _) 2 alkyl, (C 1 -C 3 alkyl) 0-halide, phenyl and benzyl; X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the heterocycles comprising X and Y; with the proviso that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share a carbon atom and together they form a spirocyclic portion; Q is Q 'or Q ", where Q' is NH (Sy) sR3; and Q" is NH (Sy) sR3, NHC (O) (Sy) sR3, NHC (0) 0 (Sy) SR3, NHC ( 0) NH (Sy) sR3, 0 (S?) SR3, (Sy) sNHR3, (Sy) SNHC (0) R3, (Sy) sNHC (0) 0R3, (Sy) sNHC (0) NHR3 or (Sy) s0R3; wherein Sy is alkylene C? _3 or alkylidene C; _3 and s is 0 or 1; U is CH2 or NH; with the proviso that if Q is Q ", then U is CH2, R3 is Ra or R3b where R3a is (i) a heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle that it contains one to five of the same or different heteroatoms selected from the group consisting of 0, N and S and the heterocycle optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the fused rings; 4-6 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 carbonyl carbon atom is a member of the heterocycle of 4 up to 6 members; (iii) C3-7 cycloalkyl; (iv) carbazolyl, fluorenyl, phenyl, -0-phenyl, -0-C C-phenyl alkylene or naphthyl; or (v) C 1-8 alkyl, C 2-7 alkenyl. -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 ', -C (0) 0 -R3' or C2-7 alkynyl. and 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, -0-alkenylphenyl C? _3, -3-alkylene-OC (0) -phenyl, cyano, amino, nitro, halo, C? - alkyl,? mono-bi-tri-haloalkyl C? _3, mono-bi-tri-haloalkyloxy C? _3, (C? _3 alkyl)? _2 amin, -OR3 ', -C (0) R3', -C (0) 0 -R3 ', -0-C (0) R3', -N (R3 ') 2, -C (0) N (R3') 2, N (R3 ') C (0) (R3') 2, -N (R3 ') C (0) N (R3') 2, -N (R3 ') C (0) OR3', -0- C ( 0) N (R3 ') 2, -N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R3 'is H or alkyl -C? _6. with the proviso that if R3a is -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 ', or -C (0) 0 -R3', then -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 'or -C (0) 0 -R3' are not substituted; R3b is R3a but is not phenyl, 1-naphthyl, 2-naphthyl, 1, 2, 3, 4-tetrahydro-l-naphthyl, lH-indol-3-yl, 1-methyl-lH-indol-3-yl, 1-formyl-lH-indol-3-yl, dimethylethoxycarbonyl) -lH-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-nyl, 3-nyl, zolyl, 1H-indazo-3 -yl, l-methyl-lH-indazol-3-yl, benzo [b] fur-3-yl, benzo [b] n-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted on the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C3-8 cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy groups, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, zolyl , trifluoromethoxy, trifluoromethyl, trifluoromethylsulfinyl or trifluoromethylsulfonyl; wherein the substituents may be the same or different and the benzoyl groups mentioned above, benzoylamino and benzoylmethylamino may be further substituted in the phenyl portion by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group; D is O, NCN or alkyl NS02CÍ-3, - A is C, N or CH; m and n are independently 0, 1 or 2; with the proviso 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; E is N, CH or C; p is 0 or 1; if p is 1, then G, J and E together form Ax or Ay; Ax is a fused heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle contains one to four of the same or different heteroatoms selected from the group consisting of O, N and S; and optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the fused heterocycle; Ay is a heterocycle of 4 to 6 members containing one to three heteroatoms selected from the group consisting of N and S; and optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 4 to 6 member heterocycle; where Ax and A? they are optionally substituted by C? _alkyl, C? _4alkoxy, C halo _haloalkyl, cyano, C3_7 cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinoyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or if p is 0 such that G and J are linked to A, then A is C, and G, J and A together form a spirocyclic ring system with the rings of the system containing A and where G, J and A together they are GJA 'or GJA ", where GJA' is Ax or Ay, and GJA" is Ax or Ay; with the proviso that Ax is not a 1, 3-diaza-fused heterocycle; already? it is not a 1, 3-diaza-heterocycle; and also with the proviso that if Q is Q ", then R3 is R3a, and if Q is Q ', then R3 is R3b, or R3 is R3a, p is 0 and G, J and A together form GJA". According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and R3 is R3b. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', R3 is R3a and p is 0 such that G, J and Together they form GJA. "In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and Q' is (Sy) sR3 and s is 0. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and Q' is (Sy) sR3, Sy is alkylene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and Q' is (Sy) sR3, Sy is alkylidene C? _3 and s is 1.

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and U is CH2. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', Q' is (Sy) sR3, s is 0 and U is CH2 .

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', Q' is (Sy) sR3, Sy is alkylene C? 3, s is 1 and U is CH2. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', Q' is (Sy) R3, Sy is alkylidene C? _3, s is 1 and U is CH2. According to another embodiment of the first aspect of the present invention, there 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, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', Q' is (Sy) sR3, s is and U is NH. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', Q' is (Sy) sR3, Sy is alkylene C? 3, s is 1 and U is NH. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q ', Q' is (Sy) sR3, R3, S? is alkylidene C! _3, s is 1 and U is NH. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q. According to another embodiment of the first aspect of the present invention, compounds are provided according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NH (SY) SR 3. In accordance with another embodiment of the first aspect of the present invention, there 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) R3 and s is 0.

According to another embodiment of the first aspect of the present invention, there 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) sR3, Sy is alkylene C? 3 and s is 1. According to another embodiment of the first aspect of the present invention, there 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) R3, Sy is alkylidene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention, there are provided conformance compounds to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (O) (SY) SR3. According to another embodiment of the first aspect of the present invention, there 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) SR3 and s is 0. According to another embodiment of the first aspect of the present invention, there 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) SR3, Sy is alkylene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) (Sy) SR3, Sy is alkylidene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) 0 (Sy) SR3. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) 0 (Sy) SR3 and s is 0 According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) 0 (Sy) SR3, Sy is alkylene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0 ) 0 (Sy) SR3, Sy is alkylidene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) NH (Sy) SR3.

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) NH (Sy) SR3 and s is 0 According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0) NH (Sy) SR3, Sy is alkylene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NHC (0 ) NH (Sy)? R3, Sy is alkylidene C? _3 and s is 1. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is OR4. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is OR 4 and R 4 is C x 6 -alkyl. According to another embodiment of the first aspect of The present invention provides compounds according to the first embodiment of the first aspect of the present invention wherein V is -IR1) (R2). According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N (RX) (R2) or OR4; R 4 is H, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkylene, or 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, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and R4 is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C? _4 alkyl, C halo _ haloalkyl, 4 alco alkoxy, hydroxy, iso, C3_7 dialkylamino, alkylamino C ? -3, dialkylamino C? _3, (C? _3 alkyl) or? -ureido, phenyl and benzyl; R4 'optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the ring structure of R4'; R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, C? 6 alkyl, C? _6-amino alkylene (C? _3 alkyl) 2 C3_7 cycloalkyl, phenyl, adamantyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and R1 and R2 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? _4 alkyl, C? _4 haloalkyl, C? _4 alkoxy, hydroxy, amino, C3_7 cycloalkyl, C1-3 alkylamino, C1-3 dialkylamino, (C1-3 alkyl) 0-2 solid, phenyl and benzyl; R1 and R2 optionally and independently contain 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the heterocycles comprising R1 and R2; wherein L1 is optionally interrupted from the nitrogen to which it is linked by L2, wherein L2 is C3_3 alkylene; or R1 and R2 together with the nitrogen to which they are bonded from X, 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 is dioxolanyl, C? _ alkyl, C? _4 alkylamino, C? _4 dialkylamino, C? _ alkoxy, C3_7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z is -NHC (O) O-, -NHC (0) NH-, NC (0) NH2, -NH-, C ?3 alkylene, C3 alkylene. -3, NHC (O) O-alkylene Ca_3, and 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, C 1-6 alkylene amino (alkyl 1-3) 2. (alkyl C? -3) 0-2 ureido, phenyl and benzyl; X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the heterocycles comprising X and Y; with the proviso that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share a carbon atom and together they form a spirocyclic portion.

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention, wherein R 4 is H, C 1 -C 4 alkyl, C 4 4 haloalkyl or C 4 alkylene. ) o-? R4 '; R4 'is C3_cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo [2.2.1] eptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino 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 -4 alkyl, C 1 4 haloalkyl, C 4 alkoxy, hydroxy, amino, C 7 cycloalkyl, phenyl and benzyl. .

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 4 is H, C 4 alkyl, C 4 haloalkyl or C 4 alkylene. 0-? R4 '; R4 'C3_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, piperazinyl, morpholino, thiomorpholino or dioxolanyl. According to another embodiment of the first aspect of the present invention, there 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) or -R 4 '; R4 'is C3-7 cycloalkyl. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -NIR1) (R2) and R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, Cl-6 alkyl, C? -6-amino alkylene (C? _3) alkyl 2, C3_7 cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolidin, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; or R1 and R2 together with the nitrogen to which they are bonded from X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C ?4 alkyl, C ?4 alkoxy, C 3-7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl ,. pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y optionally share a carbon atom and together form a spirocyclic moiety. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -NIR1) (R2) and R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, C? _6 alkyl, or R1 and R2 together with the nitrogen to which they are bound form X, wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C? _4 alkyl or piperidinyl; and wherein X and Y optionally share a carbon atom and together form a spirocyclic moiety. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -NIR1) (R2) and wherein R1 and R2 are each independently L1, wherein L1 selects from the group consisting of H, alkyl C? _6. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -NYR1) (R2) and wherein R1 and R2 together with the nitrogen to which they are linked from X, wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C? _4 alkyl or piperidinyl; and wherein X and Y optionally share a carbon atom and together form a spirocyclic moiety. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -NYR1) (R2) and wherein R1 and R2 together with the nitrogen to which they are linked from 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, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N (Ra) (R2) and wherein R1 and R2 together with the nitrogen to which they are linked from X, where X is morpholino; wherein X is substituted with Y, wherein Y is C4 alkyl.

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -NYR1) (R2) and wherein R1 and R2 together with the nitrogen to which they are linked from X, where X is piperidinyl; in -where X is substituted with Y, where Y is alkyl C? _. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein V is -N (R1) (R2) and wherein R1 and R2 together with the nitrogen to which they are linked from X, wherein X is piperidinyl; wherein X is substituted with Y, wherein Y is dioxolanyl; and where X and Y were divided into a carbon atom and together they form a spirocyclic portion. According to another embodiment of the first aspect of the present invention, there 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, there 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; and X and Y were divided into a carbon atom and together they form a spirocyclic portion. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3a. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3b. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is a heterocycle having two rings fused with 5 to 7 members in each of the rings , the heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of O, N and S. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is a heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of 0, N and S and the heterocycle optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the ani llos merged. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is a heterocycle having two rings fused with 5 to 7 members in each of the rings , the heterocycle containing one to five of the same or different heteroatoms selected from the group consisting of 0, N and S and the heterocycle optionally containing 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the fused rings; 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, -0-C3-3 alkylphenyl, C3_3-0C (0) -phenyl alkylene , cyano, amino, nitro, halo, mono-bi-tri-haloalkyl C? _3, mono-bi-tri-haloalkyloxy C? _ 3, alkoxy C_6, (C? _3 alkyl)? _2 amine, -0R3 ', -C (0) R3 ', C (0) 0 -R3', -0-C (0) R3 ', -N (R3') 2, -C (0) N (R3 ') 2, N (R3') C (0) (R3 ') 2. -N (R3 ') C (0) N (R3') 2, -N (R3 ') C (O) OR3', -0- C (0) N (R3 ') 2, -N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R 3 'is H or C 1-6 alkyl- According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3a is a 4- to 6-membered heterocycle which contains one to three 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 there 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 and S, optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 4 to 6 member heterocycle. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 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 carbonyl carbon atom is a member of the heterocycle of 4 to 6 members; wherein R3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C1-3 alkylphenyl, -C1-3 alkylene-OC (0) - phenyl, cyano, amino, nitro, halo, mono-bi-tri-haloalkyl C1-3, mono-bi-tri-haloalkyloxy C1-3, alkoxy C1-6, (alkyl C__3)? _2amina, -OR3 ', -C (0) R3 ', -C (0) 0 -R3', -0-C (0) R3 ', -N (R3') 2, -C (0) N (R3 ') 2, -N (R3 ') C (0) (R3') 2, -N (R3 ') C (0) N (R3') 2, -N (R3 ') C (0) OR3', -0-C (0) N (R3 ') 2. -N (R3 ') S02R3', -S02N (R3 ') 2 and -S02R3'; R3 'is H or C6_6 alkyl. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is C3_7 cycloalkyl. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3a is C 3-7 cycloalkyl; wherein R3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C1-3 alkylphenyl, -C3-0C alkylene (0) - phenyl, cyano, amino, nitro, halo, mono-bi-tri-haloalkyl C1-.3, mono-bi-tri-haloalkyloxy C1-3, alkoxy C? -6, (C? _3 alkyl)? _2amine, -OR3 ', -C (0) R3', -C (0) 0 -R3 ', -0- C (0) R3', -N (R3 ') 2, -C (0) N (R3') 2, -N (R3 ') C (O) (R3') 2, N (R3 ') C (0) N (R') 2, -N (R3 ') C (0) 0R3', -OC (O) N (R3 ') 2, ~ N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R3 'is H or C6_6 alkyl. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is carbazolyl, fluorenyl, -O-phenyl, -O-C4-4 alkylene-phenyl , or naphthyl. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3a is carbazolyl, fluorenyl, phenyl, -0-phenyl, -O-alkylene C? -phenyl, or naphthyl; wherein R3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-C1-3 alkylphenyl, -C1-3 alkylene-OC (0) - phenyl, cyano, amino, nitro, halo, mono-bi-tri-haloalkyl C? _3, mono-bi-tri-haloalkyloxy C1-3, alkoxy C? -6, (C? _3 alkyl)? _2 amine, -0R3 ' , -C (0) R3 ', -C (0) 0 -R3', -0-C (0) R3 ', -N (R3') 2, -C (0) N (R3 ') 2, N (R3 ') C (0) (R3') 2 r N (R3 ') C (0) N (R3') 2, -N (R3 ') C (0) OR3', -0-C (0) N (R3 ') 2, -N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R3 'is H or -alkyl Ca_6. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention in which R3a is C? _8 alkyl, C2_ alkenyl, C (0) R3 ', -C ( 0) 0-R3 'or C2-7 alkynyl. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3a is C 1 8 alkyl, C 7 alkenyl. C (0) R3 ', -C (0) 0 -R3' or C2-7 alkynyl; wherein R3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -O-alkylphenyl C? _3, -alkylene C? _3-0C (O) - phenyl, cyano, amino, -nitro, halo, mono-bi-tri-haloalkyl C1-3, mono-bi-tri-haloalkoxy C1-3, alkoxy C6-6, (C1-3 alkyl)? _2amine, -OR3 ', C (0) R3', -C (0) 0 -R3 ', -0-C (0) R3', -N (R3 ') 2, -C (0) N (R3') 2. -N (R3 ') C (0) (R3') 2, N (R3 ') C (O) N (R3') 2, -N (R3 ') C (0) OR3', -0-C ( 0) N (R3 ') 2, -N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R3 'is H or C6_6 alkyl; with the proviso that if R3 is -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (O) 0 -R3 ', or -C (0) 0 -R3', then -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 'or -C (0) 0 -R3' are not substituted. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3a and R3a is phenyl, hydroxyphenyl, azetidinyl, naphthyl, C? _6 alkyl, C2-6 alkenyl. C2-6 alkynyl. dihidroquinolinonilo, hidroquinolinonilo, quinolinyl, dihidroisoquinolinonilo, hidroisoquinolinonilo, isoquinolinyl, dihidroquinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, indazolyl, dihidrobenzimidazolonilo, hidrobenzimidazolonilo, benzimidazolinilo, dihydro-benztiazolonilo, hidrobenztiazolonilo, benzthiazolyl, dihydrobenzoxazolyl, benzotriazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, benzothienyl, dihydrobenzofuranonyl, dihydroindolonyl, idroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl, indolyl, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, 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. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is Ra and R3a is phenyl, naphthyl, indazolyl, benzimidazolinyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl, benzdioxolanyl, dihydroindolonyl, indolyl, furanyl, thienyl, pyridyl, purinyl, 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 there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3a and R3a is dihydro-benzthiazolonyl, 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. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3 and R3a is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidine, halopurinyl, C-alkyl ? 3-nitroaminopyrimidine, triazolopyrimidinyl, pyridyl, indazolyl, phenyl or 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 there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is Ra and R 3a is naphthyl, phenyl-O-phenyl, or thienyl; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3b. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3b and R3b is lH-Indazol-5-yl lH-Indazol-5-yl lH-Benzotriazol-5-yl 1,3-Dihydro-indol-2-on-5-yl 3H-Benzooxazol-2-on-6-yl, 3-Dihydro-benzoimidazol-2-on-5-yl -Met il-1, 3-dihydro-benzimidazol-2-on-6-yl 3, 4-Dihydro-lH-quinolin-2-on-6-yl 1, -Dihydro-benzo [d] [1,3] oxazin-2-on-6-yl 3, 4-Dihydro-lH-quinazolin-2-on-6-i lo 3-Methyl-3, 4-dihydro-lH-quinazolin-2-on-6-yl 4H-Benzo [1,4] oxazin-3-on-7-yl wherein Ty is H, alkyl C? _4, F, Cl, Br or nitrile. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3b and R3b is azetidinyl, C6_6 alkyl, C2_6 alkenyl, C2_ alkynyl 6, dihidroquinolinonilo, hidroquinolinonilo, dihidroisoquinolinonilo, hidroisoquinolinonilo, dihidroquinazolínonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, 1H yl-indazol-5-, dihidrobenzimidazolonilo, hidrobenzimidazolonilo, benzimidazolinilo, dihydro-benztiazolonilo, hidrobenztiazolonilo, benzthiazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidini it, 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 there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3b and R 3b is dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro-benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, dihidrobenzofuranonilo, hidrobenzofuranonilo, lH yl-indazol-5-, benzdioxolanilo, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hidroindolonilo, indolizinyl, isoindolyl, indolinyl, pyrazolyl, 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.

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3b and R 3b is azetidinyl, C 1-6 alkyl, C 2-6 alkenyl. C2-6 alkynyl. dihidroquinolinonilo, hidroquinolinonilo, dihidroisoquinolinonilo, hidroisoquinolinonilo, dihidroquinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, 1H yl-indazol-5-, dihidrobenzimidazolonilo, hidrobenzimidazolonilo, benzimidazolinilo, dihydro-benztiazolonilo, hidrobenztiazolonilo, benzthiazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, dihidrobenzofuranonilo, hydrobenzofuranonyl, benzodioxolanyl, 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 there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3b and R3b is azetidinyl, C6_6alkyl, C2_6alkenyl, C2alkynyl -6. dihidroquinolinonilo, hidroquinolinonilo, dihidroisoquinolinonilo, hidroisoquinolinonilo, dihidroquinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, benzdioxolanilo, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hidroindolonilo, lH yl-indazol-5-, indolizinyl, isoindolyl, indolinyl, pyrazolyl, 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. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R 3 is R 3b and R 3b 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 there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is R3b and R3 is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C-alkyl ? 3-nitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, lH-indazol-5-yl, phenyl or benzdioxolanyl.

According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and wherein the compounds have an absolute configuration of R. In accordance with In another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q 'and wherein the compounds have an absolute configuration of S. In accordance with another embodiment of the invention, First aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and wherein the compounds have an absolute configuration of R. In accordance with another embodiment of the first aspect of In the present invention, there are provided compounds according to the first embodiment of the first aspect of the invention. to present invention wherein Q is Q "and wherein the compounds have an absolute configuration of S. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention where yn are each 1.

According to another embodiment of the first aspect of the present invention, there 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, there 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 there are provided compounds according to the first embodiment of the first aspect of the present invention wherein A is CH. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein A is N. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein E is N. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention in where E is CH. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein E is C. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein the compounds exhibit as described herein a CGRP IC50 link of less than 10 nM. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein the compounds exhibit as described herein a CGRP IC50 link of less than 100 nM. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein the compounds exhibit as described herein a CGRP IC50 link of less than 1000 nM. According to another embodiment the first aspect of the present invention, there 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 Ay. According to another embodiment of the first aspect of the present invention, there 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, there 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 Oh. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Ax is a heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle contains one to four identical or different heteroatoms selected from the group consisting of 0, N and S; and optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the fused heterocycle. According to another embodiment of the first aspect of the present invention there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Ax is a heterocycle having two rings fused with 5 to 7 members in each of the rings the heterocycle contains one to four identical 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, there are provided compounds according to the first embodiment of the first aspect of the present invention, wherein Ax is a heterocycle having two rings fused with 5 to 7 members in each of the rings the heterocycle contains one to four identical or different heteroatoms selected from the group consisting of 0, N and S and wherein Ax is substituted with phenyl. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein Ax is a fused heterocycle described herein. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein A y is a 4- to 6-membered heterocycle containing one to three heteroatoms selected from the group consisting of consists of 0, N and S; and optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a 4- to 6-membered heterocycle. According to another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein A? is a 4- to 6-membered heterocycle containing one to three heteroatoms selected from the group consisting of 0, N, and S. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention, wherein A y is a 4- to 6-membered heterocycle containing one to three heteroatoms selected from the group consisting of 0, N and S; and optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of 4 to 6 heterocyclic members; and where A? it is substituted with phenyl. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein A y is a 4- to 6-membered heterocycle described herein. According to another embodiment of the first aspect of the present invention, there 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 placed on A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together are GJA 'or GJA. "In accordance with another embodiment of the first aspect of the present invention, compounds are provided according to the first embodiment of the first aspect of the present invention where p is 0 such that G and J are each placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and where G, J and A together are GJA '. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together are GJA. "In accordance with another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G , J and A together are GJA 'and GJA' is Ax. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention. where p is 0 such that G and J are each placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and where G, J and A together are GJA ' and GJA 'is Ay. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and where G, J and A together are GJA "and GJA" is Ax. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and where G, J and A together are GJA "and GJA" is Ay. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl , dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzyl idazolyl, dihydrobenzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein the heterocycle is optionally substituted with C? _4alkyl, C? _alkoxy, C_4haloalkyl, cyano, C3-7cycloalkyl, 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, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydrobenzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein the heterocycle is optionally substituted with C ?4alkyl, C ?4alkoxy, C ?4haloalkyl, cyano, C3_7cycloalkyl, phenyl, halophenyl, furanyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein the heterocycle is optionally substituted with C? _4alkyl, C? _4alkoxy, C? _4haloalkyl, cyano, C3_7cycloalkyl, phenyl, halophenyl, piperazinyl or morpholino. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl , dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, dihydrobenzimidazolyl, dihydrobenzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino. According to another embodiment of the first aspect of the present invention, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together form a heterocycle selected from 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, there 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 placed at A, then G, J and A together form a spirocyclic ring system with the rings of the system containing A and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolinonyl, imidazolidinonyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl and dihydrobenzoxazinyl. In accordance with various embodiments of a second aspect of the present invention there are provided pharmaceutical compositions comprising compounds of the formula (I) as defined herein.

According to various embodiments of the third aspect of the present invention there are provided methods of inflammatory treatment (particularly neurogenic inflammation), headache (particularly migraine), pain, thermal injury, ciruculatory shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid / cranial hemorrhage, tumor growth, suffocation associated with menopause and other conditions, the treatment of which can be effected by antagonism of the CGRP receptor by the administration of pharmaceutical compositions comprising the compounds of Formula (I) as define in the present. In accordance with various embodiments of a fourth aspect of the present invention with uses of the compounds of the present invention selected from the group consisting of (a) immune regulation in the mucosa of the drop; (b) protective effect against 'anaphylactic cardiac injury; (c) stimulation or prevention of stimulation of interleukin-1 (IL-1b) of bone resorption; (d) modulation of the expression of NK1 receptors in spinal neurons and (e) inflammatory diseases of the airways and chronic obstructive pulmonary disease including asthma. See (a) Calcitonin Receptor-Li e 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 guinea-pig cardiac anaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; So, 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 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, People's Republic of China. Journal of Tongj and Medical University (2001), 21 (4), 304-307, (d) Calcitonin gene-related Peptide regulates expression of neurokinin 1 receptors by rat spinal neurons. Seybold VS, McCarson KE, Mermelstein PG, Groth RD, LG Abrahams. J. Neurosci. 2003 23 (5): 1816-1824. Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, 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. Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. American Journal of Physiology (2002), 283 (5, Pt. 1), L963 L970; (f) Calcitonin gene-related peptide as inflammatory mediator. Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. Charite Virchow Campus, Department of Pediatric Pneumology and Immunology, Division of Allergy 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 Pees, Pees, Hung. Current Medicinal Chemistry: Anti-lnflammatory & Anti-Allergy Agents (2003), 2 (2), 191-218 incorporated by reference herein. In accordance with various embodiments of the fifth aspect of the present invention, combinations of the compounds of the present invention are provided with one or more agents selected from the group consisting of COX-2 inhibitors, NSAIDS, aspirin, acetaminophen, triptans, ergotamine and caffeine. for the treatment of migraine.

In accordance with the sixth aspect of the present invention, non-terminal methods are provided in vivo to identify anti-migraine compounds. In accordance with the first embodiment of the sixth aspect of the present invention, there is provided a non-terminal in vivo method of identification of antimigraine compounds, comprising administering a CGRP agonist receptor to a mammal, in an amount capable of inducing an increase in the flux. blood, followed by the administration of a test compound in an amount that can reverse the CGRP-induced increase in blood flow, wherein the mammal is a transgenic mammal with humanized RAMP1 having Trp 74, or a mammal expressing endogenously RAMP1 having Trp 74. According to another embodiment of the sixth aspect of the present invention, there is provided a non-terminal in vivo method of identifying anti-migraine compounds comprising administering to a mammal, a test compound prior to the administration of an agonist. of the CGRP receptor wherein the CGRP receptor agonist is administered in an amount capable of inducing an increase in blood flow, and wherein the test compound is administered in an amount that can suppress the CGRP-induced increase in blood flow, wherein the mammal is a transgenic mammal with humanized RAMP1 having Trp 74, or a Mammalian expressing endogenously RAMPl having Trp 74. According to another embodiment of the sixth aspect of the present invention there is provided a non-terminal in vivo method of identifying anti-migraine compounds comprising administering to a mammal, a CGRP receptor agonist, into an amount that can induce an increase in the diameter of the peripheral artery, followed by the administration of a test compound in an amount that can reverse the CGRP-induced increase in the diameter of the peripheral artery, where the mammal is a mammal transgenic with humanized RAMP1 having Trp 74, or a mammal expressing endogenously RAMP1 having Trp 74. De con With another embodiment of the sixth aspect of the present invention there is provided a non-terminal in vivo method of identifying anti-migraine compounds comprising administering to a mammal a test compound prior to the administration of a CGRP receptor agonist, wherein the agonist of the CGRP receptor is administered in an amount that can induce an increase in the diameter of the peripheral artery, and wherein the test compound is administered in an amount that can suppress the induced increase of CGRP in the diameter of the peripheral artery, in wherein the mammal is a transgenic mammal with humanized RAMP1 having Trp 74, or a mammal expressing endogenously RAMP1 having Trp 74. In accordance with other embodiments of the sixth aspect of the present invention, non-terminal in vivo methods are provided for identifying compounds anti-migraine as described herein, wherein the blood flow is facial blood flow. In accordance with other embodiments of the sixth aspect of the present invention, non-terminal in vivo methods are provided for identifying antimigraine compounds as described herein wherein the mammal expressing endogenously RAMPl having Trp 74 is a non-human primate. In accordance with other embodiments of the sixth aspect of the present invention non-terminal in vivo methods are provided for identifying antimigraine compounds as described herein wherein the mammal expressing endogenously RAMP1 having Trp 74 is man. In accordance with other embodiments of the sixth aspect of the present invention, non-terminal in vivo methods are provided for identifying anti-migraine compounds as described herein wherein the mammal endogenously expressing R? MP1 having Trp 74 is a primate not human and the non-human primate is a marmoset.

In accordance with other embodiments of the sixth aspect of the present invention non-terminal in vivo methods are provided for identifying anti-migraine compounds as described herein, wherein the anti-migraine compounds are antagonists of the CGRP receptor. Other embodiments of the present invention may comprise a suitable combination of two or more of the embodiments. and / or aspects described herein. Still other embodiments of the present invention may comprise a suitable subset of one embodiment and / or aspect described herein. Still other embodiments and aspects of the invention will be apparent in accordance with the description provided below.

Brief Description of the Figures Figure 1. Analysis Schild. The dose response of cAMP production stimulated by CGRP in the absence (full squares) and presence (all others) of increasing concentrations (from left to right) of Example 2 CGRP antagonist. Inside is a Schild plot of the logarithmic dose ratio minus 1 (Y axis) versus logarithmic concentration of the antagonist of Example 2 (X axis): slope = 0.94, Kb = 0.16 nM.

Figure 2. Direct validation of facial blood flow as a substitute for dilatation of the intracranial artery in the rat. Intravenous administration of i.v. h CGRP induces comparable increases in percentage (100-120% of the baseline) in the median artery diameter of the rat and facial blood flow of the rat (bars with left and right stripes, respectively). Pretreatment with the CGRP peptide antagonist (8-37) results in a 50% inhibition of i.v. posterior intravenous haCGRP for both measurements (full bars). The diameter of the intracranial artery and the facial blood flow were measured concurrently in each animal (n = 5 rats). The data is the measure + se * p < 0.05, ** p < 0.01 against the corresponding haCGRP alone.

Figure 3. Dose response for haCGRP in a non-human primate laser Doppler facial blood flow. Administration of haCGRP induces a dose-dependent increase in Doppler facial blood flow with lasers and non-human primates (e.g., common marmosets). Animals (n = 6) received increasing doses of haCGRP at 30 minute intervals. The data is the percentage of change of peaks from the baseline ± sem, with each animal serving as its own control.

Figure 4. Inhibition of changes induced by CGRP in the facial blood flow of non-human primates. The novel CGRP antagonist Example 2 (filled bars) administered prior to haCGRP (bar in fringes), inhibits the CGRP-induced increase in laser Doppler facial blood flow dependent on the dose. The vehicle (open bar) was without effect. The data are the mean + sem (n = 5-6 primates per group). * p < 0.05 compared to CGRP alone.

Figure 5. Effect of the CGRP antagonist on the blood pressure of the non-human primate. In contrast to the dose-dependent inhibition of primate facial blood flow (see figure 4.). Example 2 has a negligible effect on blood pressure (studies in parallel in animals separately, n = 6). The animals received repeated doses of Example 2 at 20 minute intervals. The BP data is the mean ± sem during a period of 20 minutes measured by a bracelet on the arm.

Detailed Description of the Invention The description of the invention herein must be constructed in congruence with the laws and principles of chemical bonds. For example, it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any given location.

As used herein, "heterocyclic" or "heterocycle" includes cyclic portions containing one or more heteroatoms, (e.g., 0, N, or S) heterocycles include those that are aromatic and those that are not, that is. , "alicyclic", unless otherwise specified. As used herein, the term "bicyclic fused system" when described for example, a bicyclic system fused in 5.6 containing 1 to 4 nitrogen atoms includes aromatic and alicyclic systems, for example, indolizine, indole, isoindol, 3H- indole, indoline, indazole or benzimidazole. If a substituent is generically named, then some and all species of that genus comprise that aspect of the invention. For example, a substituent generically named as "pyrrolonyl" (the "pyrrolone" radical, a pyrrole having a carbonyl) includes pyrrole-2-onyls wherein the carbonyl is adjacent to the nitrogen and pyrrole-3-onyls wherein the carbonyl and nitrogen has an intervening methylene. Similarly, the present invention comprises that a substituent can be placed at any and all suitable places of placement on the substituent unless otherwise specified.

However, it is also understood that the compounds encompassed by the present invention are those that are chemically stable that is, heteroalicyclic substituents of the present invention should not be placed in such a way that a heteroatom in the heteroalicyclic substituent is alpha to a point of placement where the placement point is also a heteroatom. A modality or aspect on which another modality or aspect depends, will only describe the variables that have values or dispositions that differ from the modality or aspect on which they depend. If, for example, a dependent modality only addresses R2, then the variables and dispositions not related to R2 should reflect the modality on which they depend. If a variable is quantified with a value of zero, then a link that is placed to the variable should no longer be represented. As used herein, "alkylene" means a divalent alkane, that is, an alkane having two hydrogen atoms removed from the alkane (the hydrogen removed from two carbon atoms when the alkane contains more than one carbon atom, for example ) -CH2CH2CH2- As used herein, "alkylidene" means an alkane having two hydrogen atoms removed from carbon in the alkane, for example, It should be understood that the alternative double-bond designations in the six-member ring in the fused structure of five to six members represented in the formula 1 are relative and represent the delocalized orbital electrons in p of the ring. As used herein, "aryl" or "ar" includes phenyl or naphthyl. As used herein, "heterocyclic" or "heterocycle" includes heteroaryl and heteroalicyclic. As used herein, "halo" or "halogen" includes fluoro, chloro, bromo and iodo and also means one or more same or different halogens that may be substituted in a respective portion. Unless otherwise specified, acyclic hydrocarbons such as alkyl, alkoxy, alkenyl and alkynyl can be branched or non-linear. It will be understood that the present invention may include some and all possible stereoisomers, geometric isomers, diastereomers, enantiomers, anomers and optical isomers, unless otherwise specified by a particular description. As used herein, "Trp74" means that residue 74 is tryptophan R? MP1 (Mallee et al., J Biol Chem. 2002, 277, 14294-8) incorporated herein by reference. As used herein, "anti-migraine compound" includes any peptide compound or peptide fragment (modified or unmodified) capable of reversing or attenuating vasodilation mediated by the CGRP receptor (eg, CGRP receptor antagonists). As used herein, "test compound" includes any peptide compound or peptide fragment (modified or unmodified) that is tested to determine whether it can reverse or attenuate vasodilation mediated by the CGRP receptor (eg, putative antagonists of the CGRP receptor). As used herein, "CGRP receptor agonist" includes any peptide compound or peptide fragment (modified or unmodified) which can induce vasodilation mediated by the CGRP receptor particularly eg aCGRP or ßCGRP; other members of the calcitonin family for example, adrenomedullin; CGRP fragments, at the N-terminus for example, CGRP (1-12) CGRP (1-15) and CGRP (1- 22); amide in terminal C (NH2) versions of CGRP eg CGRP (1-8 + NH2), CGRP (1-13 + NH2) or CGRP (1-14 + NH2); and CGRP analogs that do not occur naturally, for example [Ala -'-? (CH2NH) Cys2] hCGRP containing a pseudopeptide bond between Ala1 and Cys2. See Maggi C ?, 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 (12): 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; 11 0 (2): 93-9; and Dennis T, Fournier A, St Pierre S, Quirion R. Structure-activity profile of calcitonin gene-related peptide in and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther. 1989 Nov; 251 (2): 718-25 incorporated herein by reference. The compounds of this invention can 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 example, acetic acid, citric acid, methanesulfonic acid, toluene sulfonic acid, tartaric acid, and maleic acid. In addition, in case the compounds of this invention contain an acidic group, the acid group may exist in the form of alkali metal salts such as, for example, a potassium salt, and a sodium salt; ferrous alkali metal salts such as for example a magnesium salt and a calcium salt and salts with organic bases such as a 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 can 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 programmed release formulations), pills, powders, granules, elixirs, dyes, suspensions, syrups and emulsions. . The compounds of this invention can 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 will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of this invention can also be administered in intranasal form by the topical use of suitable intranasal vehicles or by transdermal routes using transdermal skin patches. When the compounds of this invention are transdermally administered, the dose will be continuous through the dose regimen.

Although the dosage is seen from 0.01 mg / kg to 30 mg / kg for the compounds of the present invention, the dose and dose regime and programming of compounds of the present invention must be carefully adjusted in each case, using solid professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and degree of the disease condition. In accordance with good clinical practice, it is preferred to administer the present compounds at the concentration level that produces beneficial beneficial effects without causing any adverse or undesirable side effects.

Synthesis The compounds of the present invention can be synthesized according to the reaction schemes provided below. The variables provided in the schemes below are defined according to the description of the compounds in the above formula unless otherwise specified. The compounds of the present invention can be prepared according to reaction scheme 1 or reaction scheme 2. It may also be possible to use variations of the schemes to prepare compounds of current inventions, known variations for those of ordinary experience in the technique. Scheme of reaction 1. Synthesis of Compounds of Formula I II III 1 IV The synthesis described in Reaction Scheme 1 starts with a compound of Formula II, which is an amino acid with a protected amino terminus. Common amino protecting groups (PO) include BOC, CBZ, and FMOC and their addition and removal are well known in the art. The carboxylic acid moiety of the compound of Formula II is coupled with an amine of the Formula HNRaR2 using standard peptide coupling reagents to form an amide of Formula III. The protective amino group is removed resulting in the compound of Formula IV. This compound is then coupled with an amine of Formula V (see below) in a urea or urea isostere mixing reaction, which generates the compound of Formula I. The formation of mixed urea is conveniently carried out using phosgene, disuccinimidyl, cabonyl diimidazole or other equivalents. The formation of urea isosteres, such as cyanoguanidines and sulfonylguanidines, are known in the literature. Scheme of reaction 2. Synthesis of Compounds of Formula I Saw 1 V11 The synthesis described by Reaction Scheme 2 starts with a compound of Formula V, which is an amino acid with a protected carboxylate termination. The protection is generally a methyl ester, but other protecting groups such as ethyl, t-butyl, and benzyl esters can also be used. The compound of Formula V is coupled with an amine of Formula VIII (see below) in a mixture reaction of urea or urea isostere, as above, to generate a compound of Formula VI. The compound of Formula VI is converted to a free acid compound of Formula VII which is then coupled with an amine of Formula HNR1R2 to generate the compound of Formula I.

Reaction scheme 3. Synthesis of the compounds of Formula I VII I The synthesis described by Reaction Scheme 3 starts with a compound of Formula VII of Reaction Scheme 2. The compound of Formula V 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, with carbodiimide coupling agents such as N, N-dicyclohexylcarbodiimide. Furthermore, it is frequently advantageous, especially for secondary and tertiary alcohol esters, to include additives that accelerate acylations such as 4-dimethylaminopyridine.

Preparation of HNR-Y2 and amines of Formula VIII The amines of Formula VIII and H? R ^ -R2 are commercially available, are made by the methods of the literature or are described herein.

VIII Preparation of amino acids of Formula II and Formula V The amino acids of Formula II and Formula V may be commercially available or made as described in Reaction Scheme 4.

Reaction Scheme 4. Synthesis of Compounds of Formula II and Formula V V The synthesis described in Reaction Scheme 4 starts on an aldehyde of Formula IX, which is reacted with a glycine phosphonate of Formula X in a Wads orth-Emmons coupling reaction. The compound of Formula X is deprotonated with a base such as diazabicycloundecene or tetramethylguanidine or other organic and inorganic bases well known in the art. The double bond of the resulting compound of Formula XI is reduced to give compounds of Formula XII. The reduction can be carried out to give either a racemate or by the use of a stereoselective catalyst to give any enantiomer of Formula XII. Such reductions can result from the hydrogenation of transfer from hydrogen donors such as formic acid or cyclohexadiene, or hydrogenation using hydrogen gas, both in the presence of an appropriate catalyst. The compounds of Formula II are prepared by acid hydrolysis or ester base. The compounds of Formula V are prepared by removal of the protecting group (PG) using methods well known in the art. Other amino acid derivatives of Formula XII can be prepared as shown in Reaction Scheme 5. Reaction Scheme 5. Synthesis of Formula XII XIII XII Where, for the purposes of Reaction Scheme 5, the compounds of Formula XIV are nucleophilic compounds such as amines or alcohols which are capable of participating in a Michael reaction with a compound of Formula XIII as shown. Other compounds of Formula I can be prepared according to Reaction Scheme 6 or Reaction Scheme 7. It is also possible to use variations of the schemes to prepare the compounds of the present inventions, the variations known by those of ordinary skill in the art.

Reaction Scheme 6. Synthesis of Compounds of Formula I XVI I or n XIX XVIII 20 XVII XX I The synthesis described in Reaction Scheme 6 starts with commercially available or synthesized aldehydes. The homologation of two carbons and the double bond reduction are well known in the literature and lead to compounds of Formula XV. Some compounds of Formula XV are also commercially available and others can be prepared by other methods well known in the art. The preparation of the compounds of Formula XVI and XVII is known in the literature as substrates and products of the chiral Evans asymmetric synthesis. Hydrolysis leads to the compounds of Formula XVIII. As with the compounds of Formula VII in Reaction Scheme 2, these carboxylic acids can react with amines of the Formula R 1 R 2 NH to provide compounds of Formula XIX using well-known amide coupling protocols. Hydrolysis of the tert-butyl ester leads to compounds of Formula XX, which can further be coupled with compounds of Formula VIII to provide compounds of Formula I.

Scheme of reaction 7. Synthesis of Compounds of Formula I I I Reaction Scheme 7 also starts with commercially available or synthesized aldehydes. These are reacted with dimethyl succinate in the presence of bases to give compounds of Formula XXI. The double bond of the compound of Formula XXI is reduced to give compounds of Formula XXII. The reduction can be carried out to give either a racemate or by the use of a stereoselective catalyst to give any enantiomer of Formula XXII. Such reductions can result from transfer hydrogenation from hydrogen donors such as formic acid or cyclohexadiene, or hydrogenation using hydrogen gas, both in the presence of an appropriate catalyst. The amide coupling with amines of Formula VIII leads to compounds of Formula XXIII using well-known amide synthesis protocols. Hydrolysis of the methyl ester leads to compounds of Formula XXIV, which are additionally coupled with various amines or alcohols to give amides of Formula I and esters of Formula I, respectively. The compounds of Formula I can also be prepared according to Reaction Scheme 8.

Scheme of reaction 8. Synthesis of Compounds of Formula I xxvip i The synthesis described in Reaction Scheme 8 starts with a commercially available N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester. The differently protected aspartic acid derivatives can 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 compound of Formula XXV is removed by hydrogenolysis to give the compounds of Formula XXVI. These are further coupled with amines of the Formula HNRXR2 to give compounds of the 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 the compounds of Formula I. For example, they can be coupled with halo aromatic compounds using known methods involving heating at various temperatures or by metal catalysis. of transition such as palladium or copper, either in stoichiometric quantities or as a catalyst. They can also be reacted with various aldehydes or ketones under reductive alkylation conditions, well described in the art. They can also react with isocyanates, acyl chlorides, or carbamoyl chlorides to generate urea, amide or carbamate derivatives, respectively. It will be understood that the sequence of the modifications described above can be changed depending on the selection of protective groups and the order of their removal. The compounds of Formula I can also be prepared according to Reaction Scheme 9.

Reaction Scheme 9. Synthesis of Compounds of Formula I The synthesis described in Reaction Scheme 9 starts with an imine of Formula XXIX, prepared by condensation of ethyl glyoxalate and amines of the Formula R3-NH2. These are reacted with 2-tert-butoxy-2-oxoethylzinc chloride to give compounds of Formula XXX. Treatment with strong acids removes the tert-butyl ester protecting group to give free acids of Formula XXXI which are coupled to amines of Formula VIII to provide compounds of Formula XXXII. The ethyl ester is hydrolysed with a metal hydroxide or aqueous base salt to give the free alpha acids of Formula XXXIII. These are again coupled with amines of the Formula HNRlrR > 2 to give compounds of Formula I. Intermediates of ureidoamide and General Examples. The 1H- and 13C-RNM spectra were run on a Bruker instrument of 500 or 300 MHz and the chemical turns were reported in ppm (d) with reference to tetramethylsilane (d = 0.0). All evaporations were carried out under reduced pressure. Unless stated otherwise, the LC / MS analysis was carried out on a Shimadzu instrument using a YMC C18 column (3 x 50 mm) using a linear gradient of 2 min from 0% to 100% of the solvent B in A in a 3 min. For LC / MS and for the Shimadzu preparative HPLC system, Solvent A- was: 10% methanol / 90% trifluoroacetic acid, and Solvent B was 90% methanol / 10% water / 0.1% trifluoroacetic acid with an adjusted UV detector at 220 nm. l-benzyl-2 ', 3'-dihydro-2' -oxoespiro- [piperidin-4, 4 '(l'H) -quinazoline Polyphosphonic acid (113 g) was heated to 100-110 ° C and stirred while l-benzyl-piperidin-4-one (9.27 ml, 50 mmol) was added. Immediately after, phenyl urea (9.55 g, 70. mmol) was added in sufficiently small portions to avoid excessive foam. The mixture was heated overnight. Then water (200 mL) was slowly added to the mixture which was allowed to cool to 100-110 ° C (at lower temperatures the mixture became too viscous to stir). The resulting solution was neutralized with 10 N to ca. pH 8, and then extracted with chloroform. The organic phase was dried with magnesium sulfate and then concentrated to give the crude product which was purified by flash column chromatography on silica gel. (ethyl acetate / hexanes 6: 4) to give the desired product (9.0 g, 58%). Mass spectrum: 308.25 (MH) +. 2 ', 3' -dihydro-2 '-oxoespiro- [piperidin-4, 4' (l'H) -quinazoline To a solution of l-benzyl-2 ', 3'-dihydro-2'-oxospiro- [piperdin-4,4' (l'H) -quinazoline (1.00 g) in degassed methanol (50 ml) and 6N hydrochloric acid (2.0 ml) was added 10% pelletized mineral carbon (150 mg). The mixture was stirred on a Parr apparatus under a hydrogen atmosphere at 60 psi (4,218 kg / cm2) overnight. LC / MS shows an incomplete reaction. More 10% pelletized mineral carbon (200 mg) was added, and the mixture was stirred for 2 more days. To such a point, all the starting material was consumed. The mixture was filtered and the filtrate was concentrated to give 531 mg of the desired compound (64%). Mass spectrum: 218.12 (MH) +. 4-Amino-4-cyano-piperidine-l-carboxylic acid tert-butyl ester To a well-stirred solution of tert-butyl ester of 4-oxo-piperidine-1-carboxylic acid (9.0 g, 45.3 mmol) in methanol was added ammonium chloride (2.66 g, 49.8 mmol) at room temperature and stirred for 1 hour. Sodium cyanide (2.44 g, 49.8 mmol) was added and stirred continuously for an additional 16 h. The reaction mixture was quenched with 5% aqueous sodium hydrogen carbonate (50 mL), diluted with water, and the methanol was removed by rotary evaporation. The cyanoamine was extracted with methylene chloride (3x 100 mL), dried over sodium sulfate, and the solvents were evaporated to give the desired compound as an oil in 91% yield. XH-NMR (300 MHz, CDC13): d 3.95-3.90 (m, 1H), 3.80-3.71 (m, 1H), 3.42-3.06 (m, 2H), 2.04-1.94 (m, 1H), 1.71-1.50 (, 3H). Mass spectrum: 226 (MH) +. 2-Phenyl-1,3,8-triaza-spirohydrochloride [4, 5] dec-1-en-4-one To a solution of 4-amino-4-cyano-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 4.44 mmol) in methylene chloride (30 L) was added triethylamine (1.24 mL, 8.88 mol), followed by benzoyl chloride (936 mg, 6.66 mmol). After 30 min, 4- (dimethylamino) pyridine (40 mg, 0.33 mmol) was added and stirred continuously for an additional 12 h. The reaction mixture was then quenched with 1M sodium hydroxide (10 mL), diluted with ethyl acetate (100 mL), and separated. The organic layer was washed sequentially with 1M sodium hydroxide (40 mL), aqueous sodium hydrogen carbonate (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-l-carboxylic acid tert-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 was 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, 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 of 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 as a white powder in 95% yield. Y-NMR (500 MHz, CD3OD): d 8.23-8.21 (m, 2H), 7.96-7.92 (m, 1H), 7.79-7.76 (m, 2H), 3.68-3.64 (, 3H), 3.31-3.30 ( m, 1H), 2.47-2.44 (m, 4H). Mass spectrum: 230 (MH) +. -formyl-indazole-1-carboxylic acid tert-butyl ester A solution of methylene chloride (2 mL) of di-tert-butyldicarbonate (388 mg1.78 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. The solvents were removed in vacuo and the residue was subjected to flash chromatography with silica gel (25 g) and ethyl acetate / hexanes (1: 1) containing 1% triethylamine as eluent to give the title compound as a liquid yellow coffee (414 mg, 90%). Y-NMR (CDC13, 500 MHz) d 10.08 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H) 8.25 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.8 Hz) , 1H), 1.71 (s, 9H). 13CRMN (CDC13, 125 MHz) d 191.8, 149.0, 142.5, 140.6, 133.0, 128.3, 126.4, 125.8, 115.3, 85.7, 27.8. - (2-Benzyloxycarbonylamino-2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester A solution of N- (benzyloxycarbonyl) -a-phosphonoglycine trimethyl ester (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 by means of a syringe for 10 min. The reaction mixture 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 was subjected to flash column chromatography on silica gel (1: 2 ethyl acetate / hexane) to give the title compound as a white foam (5.77 g, 85%). Y-NMR (CDC13, 500 MHz) d 8.09 (d, J = 9.0 Hz, 1H), 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 spectrum: 452 (MH) +. (±) -5- (2-Amino-2-methoxycarbonyl-ethyl) -indazole-1-carboxylic acid tert-butyl ester 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 L) was stirred for 4.5 h under 50 psi (3.515 kg / cm2) hydrogen gas using a hydrogenated Parr. The reaction mixture was evacuated and purged with nitrogen. Then, the reaction mixture was filtered through a pad of celite and the pad was rinsed with several portions of methanol. The filtered methanol was evaporated to give the title compound (351 mg, 95%). Y-NMR (CDC13, 500 MHz) d 8.12-8.10 (m, 2H), 7.55 (br s, 1H), 7.37 (dd, J = 8.9, 1.5 Hz, 1H), 3.77-3.75 (, 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 spectrum: 320 (MH) +. (±) -5- (2-Methoxycarbonyl-2 { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-tert-butyl ester) carbonyl] -amino.}.-ethyl) -indazole-1-carboxylic acid A solution of 5- (2-amino-2-methoxycarbonyl-ethyl) -indazole-1-carboxylic acid tert-butyl ester (307 mg, 0.96 mmol), N, N-disuccinimidyl carbonate (246 mg, 0.961 mmol) ), and N, N-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-lH-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 was subjected to flash chromatography using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent to give the product (259 mg, 47%). Y-NMR (CDC13, 300 MHz) d 8.13-8.10 (m, 2H), 7.48 (br s, 1H), 7.31 (dd, J = 8.8, 1.6 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H), 6.82 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.98 (d, J = 7.7 Hz, 1H), 4.87-4.81 (m, 4.58-4.49 (m, 1H), 4.26 (s, 2H), 4.05-3.97 (m, 2H), 3.74-3.67 (m, 4H), 3.29- 3.23 (m, 2H), 2.93-2.84 (m, 2H), 1.76-1.62 (m, 1H), 1.70 (s, 9H), 1.48-1.42 (m, 1H) Mass spectrum: 577 (MH) +. 2-trimethylsilane-ethanesulfonyl chloride 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 ° C in a 3-necked round bottom flask. dried to the flame. After stirring at 0 ° C for 5 min, the ice-water bath was stirred and ethyl 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 this 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 filtered through a pad of celite. The solvents were removed in vacuo and the residue was loaded on a column pre-wetted with silica gel (300 mL) using 1: 3 ethyl acetate / hexanes as the eluent. The solvents were removed and the title compound was obtained as a light brown liquid (41.9g., 85%). If not used immediately, the final product should be stored under nitrogen in the freezer or refrigerator to minimize decomposition. Y-NMR (CDC13, 500 MHz) d 3.61-3.57 (m, 2H), 1.32-1.27 (, 2H), 0.10 (s, 9H). 1- (2-Trimethylsilanyl-ethanesulfonyl) -lH-indole-5-carboxylic acid ethyl ester A solution of 1H-indole-5-carboxylic acid ethyl ester (10.31 g, 58.8 mmol) in dimethylformamide (50 mL) was added dropwise at 0 ° C to a mixture of sodium hydride (1.83 g, 76.4 mmol ) in dimethylformamide (150 mL). The resulting mixture was stirred at 0 ° C for 30 min, then a solution of 2-trimethylsilanyl-ethanesulfonyl chloride (17.7 g, 88.2 mmol) in dimethylformamide (100 mL) was slowly added at 0 ° C to the above mixture. After 2 h, saturated aqueous ammonium chloride (200 mL) was 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. The solvents were removed in vacuo and the residue subjected to flash chromatography on silica gel using 1: 1.5 methylene chloride / hexanes as eluent to give the title compound as a white solid (15.8 g, 79%). Y-NMR (CDC13, 500 MHz) d 8.36 (d, J = 1.5 Hz, 1H), 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, 1H), 3.94 (s, 3H), 3.21-3.18 (m, 2H), 0.84-0.80 (m, 2H), -0.06 ( s, 9H). 13 C-NMR (CDC13, 125 MHz) d 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 spectrum 354.12 (MH) +.

Prepared similarly: 1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazole-5-carboxylic acid ethyl ester Y-NMR (CDC13, 500 MHz) d 8.51 (s, 1H), 8.34 (s, 1H), 8.21 (dd, J = 8.9, 1.5 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H), 3.42-3.39 (m, 2H), 0.86-0.82 (, 2H), -0.02 (s, 9H). 13 C-NMR (CDCl 3, 125 MHz) d 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 spectrum 355.13 (MH) +. [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -methanol A solution of diisobutylaluminum hydride (82.9 mL, 1M in toluene, 82.9 mmol) was slowly added at 0 ° C to the solution of 1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indole-5-carboxylic acid ethyl ester (8.81 g, 25.9 mmol) in toluene ( 200 mL). After this was stirred at 0 ° C for 45 min, the reaction was quenched by the addition of methanol (26 mL), sprayed with sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed to room temperature in 1 h and filtered through a pad of celite. The solvents were removed to provide the title compound as a highly viscous liquid, which solidified during cooling. A white solid (8.08 g, 100% yield). XH-NMR (CDC13, 500 MHz) d 7.87 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J = 3.7 Hz, 1H), 7.35 (dd, J = 8.6, 1.5 Hz, 1H), 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 (m, 2H), - 0.06 (s, 9H). Mass spectrum 312.14 (MH) +. [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -methanol A solution of ethyl ester of l- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazole-5-carboxylic acid (dried azeotropically with toluene (2x), 5.1 ul, 16.9 mmol) in tetrahydrofuran (50 mL) was added at 0 ° C to a mixture of lithium borohydride (3.68 g, 169 mmol) in tetrahydrofuran (100 mL). The mixture was warmed to room temperature and stirred for 14 h. This was cooled to 0 ° C and lithium borohydride (3.5 g) was added. The mixture was heated to room temperature and stirred for 14 h. This was re-cooled to 0 ° C and saturated aqueous ammonium chloride (25 mL) was added slowly. The resulting white suspension was filtered through a pad of celite, the solvents were removed and the residue was subjected to flash chromatography using ethyl acetate / hexanes (1: 1.5) with 1% triethylamine to give the title compound as a solid. white (3.8 g, 72%). Y-NMR (CD3OD, 500 MHz) d 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, 1H), 4.76 (s, 2H), 3.49-3.46 (m, 2H), 0.76- 0.72 (m, 2H), -0.03 (s, 9H); 13 C-NMR (CD 3 OD, 125 MHz) d 141.2, 140.9, 138.3, 129.2, 125.8, 119.6, 112.7, 63.8, 50.8, 9.9, -3.2. Mass spectrum 313.12 (MH) +. 1- (2-Trimethylsilanyl-ethanesulfonyl) -lH-indol-5-carbaldehyde A solution of [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -methanol (2.1 g, 6.74 mol) in methylene chloride (30 mL) was added at 0 ° C to a mixture of dioxide activated manganese (22 g, dried azeotropically with toluene (2x)) and methylene chloride (70 mL) in a 500 mL round bottom flask. The reaction mixture was stirred at 0 ° C for 30 min and filtered through a pad of celite. The solvents were removed in vacuo to provide the title compound as a white solid (1.8 g, 80%). 1 H-NMR (CDC13, 500 MHz) d 10.06 (s, 1H), 8.15 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.87 (dd, J = 8.6, 1.5 Hz, 1H), 7.54 (d, J = 3.4 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 3.24-3.20 (m, 2H), 0.86-0.82 (, 2H), -0.06 (s, 9H). 13 C-NMR (CDC13, 125 MHz) d 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 spectrum 310.12 (MH) +.

Prepared similarly: 1- (2-Trimethylsilanyl-ethanesulfonyl) -lH-indazole-5-carbaldehyde Mass spectrum 311.10 (MH) Methyl ester of 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -acrylic acid methyl ester 1, 1, 3, 3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added at room temperature to a solution of trimethyl ester of N- (benzyloxycarbonyl) -a -phonoglycine (1.88 g, 5.69 mmol) in tetrahydrofuran (40 mL ). The mixture was stirred at room temperature for 15 min and cooled to -78 ° C and a solution of 1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indole-5-carbaldehyde (1.6 g, 5.17 mmol) in tetrahydrofuran (15 g). mL) was added slowly. The resulting reaction mixture was stirred at -78 ° C for 2 h and then warmed to room temperature in 3 h. The solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using methylene chloride / hexanes (1: 1.5) with 1% triethylamine as eluent to give the title compound as a 92: 8 mixture Z / E (determined by the integration of C02CH3, for the Z isomer at 3.79 ppm, and E isomer at 3.65 ppm). For the Z: Y-NMR isomer (CD3CN, 500 MHz) d 7.96 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 3.7 Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 5H), 7.67 (d, J = 3.7 Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 3.42-3.38 (m, 2H), 0.87-0.83 (m, 2H), -0.04 (s, 9H). Mass spectrum 515.20 (MH) +.

Prepared similarly: Methyl ester of 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -acrylic acid methyl ester Flash chromatography on silica gel using methylene chloride containing 1% triethylamine as eluent affords the title compound as a 95: 5 Z / E mixture (determined by the integration of -CH = C (C02Me) (NHCBz), 3.72. g, 92%). For the Z: Y isomer: -NRM (CD3CN, 500 MHz) d 8.39 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.8 Hz, 1 H), 7.84 (dd, J = 8.8 , 1.2 Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 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 spectrum 516.18 (MH) +.

Methyl ester of (±) -2-amino-3- [1, (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -propionic acid methyl ester To a flame-dried 500 mL round bottom flask was added 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -acrylic acid methyl ester (2.24 h). , 4.36 mmol), methanol (100 mL) and palladium in 10% charcoal (0.52 g). The mixture was degassed and purged with hydrogen 5 times. This was stirred at room temperature for 1 h and filtered through a pad of celite. The solvents were removed and the residue was subjected to flash chromatography using ethyl acetate / hexanes (1: 1 and 2: 1) containing 1% triethylamine to provide the title compound as a colorless viscous liquid (1.27g)., 76%), which solidified during cooling. Y-NMR (CD3CN, 500 MHz) d 7.82 (d, J = 8.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.22 (dd, J = 8.6, 1.5 Hz, 1H), 6.72 (d, J = 3.7 Hz, 1H), 3.70 (dd, J = 7.3, 6.1 Hz, 1H), 3.65 (s, 3H), 3.38-3.34 (, 2H), 3.08 (dd, J = 13.4, Hz, 1H), 2.95 (dd, J = 13.4, 7.3 Hz, 1H) 0.82- 0.79 (m, 2H) -0.05 (s, 9H) 13 C-NMR (CDC13, 125 MHz) d 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 spectrum 383.16 (MH) +.

Prepared similarly: (±) -2-amino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] propionic acid methyl ester Y-NMR (CD3CN, 500 MHz) d 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 (m, 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 (m, 2H), -0.02 (s, 9H). 13 C-NMR (CDC13, 125 MHz) d 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 spectrum 384.15 (MH) +.

Methyl ester of (R) -2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethansulfonyl) -lH-indazol-5-yl] -propionic acid methyl ester In a glove bag that was subjected to 3 cycles of vacuum / nitrogen purge, an AIRFREE® reaction flask (Schlenk) equipped with a stir bar was charged with trifluoromethylsulfonate (-) - 1, 2-bis ((2R, 5R) -2,5-diethylphosphono) benzene (cyclooctadiene) rhodium (I) (123 mg, 0.17 mmol, mol%), sealed with a rubber septum, and removed from the glove bag. The methyl ester of 2-benzyloxycarbonylamino-3- [l- (2-trimethylsilanyl-ethansulfonyl) -lH-indazol-5-yl] -acrylic acid (1.75 g, 3.0 mmol) was weighed in a second flask of AIRFREE® reaction (Schlenk) equipped with a stirring bar and sealed with a rubber septum. After 3 cycles of vacuum / nitrogen purge, this was dissolved in a mixture of anhydrous methanol (75 mL) and anhydrous methylene chloride (15 mL). Both solvents are deoxygenated before the addition by bubbling with nitrogen for at least 1 h. Once in solution, the mixture was re-subjected to 3 cycles of vacuum / nitrogen purge. The acidic dehydroamine solution was introduced into the AIRFREE reaction flask (Schlenk) containing the catalyst by means of a cannula. The reaction mixture was subjected to 5 cycles of vacuum / hydrogen purge before opening the flask at 1 atm. Hydrogen (balloon). After 16 h, the reaction mixture was purged with 3 cycles of vacuum / nitrogen purge. 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 compound as a white solid with 98.4% ee as determined by the CLAR analysis using a Chirocel OD column with 80% hexane / 20% ethanol as eluent (retention time: 13.9 min for the title compound and 11.2 min for the S-enantiomer). XH-NMR (CDC13, 300 MHz) d 8.17 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.35-7.25 (m, 6H), 5.29-5.24 (m , 1H), 5.08 (dd, J = 19.0, 12.1 Hz, 2H), 4.73-4.67 (m, 1H), 3.73 (s, 3H), 3.38-3.32 (m, 2H), 3.29 (dd, J = 14.2, 5.6 Hz, 1H), 3.19 (dd, J = 13.9, 5.6 Hz, 1H), 0.91-0.85 (m, 2H), -0.02 (s, 9H).

Mass spectrum: 518 (MH) +. Methyl ester of (R) -2-Amino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid methyl ester A mixture of methyl ester of (R) -2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid (1.24 g, 2.40 mmol) and palladium on carbon 10% (124 mg) in methanol (50 mL) were stirred for 2 h under 50 psi (3.51 kg / cm 2) hydrogen using a Parr hydrogenator. The reaction mixture was purged with 3 cycles of vacuum / nitrogen purge. The reaction mixture was then filtered through a pad of celite and the pad rinsed with several portions of methanol. The filtered methanol was evaporated to give 879 mg (96%) of the title compound as a sticky gum. 1 H-NMR (CDC 13, 300 MHz) d 8.21 (s, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 7.59 (s, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 3.72 ( s, 3H), 3.38-3.32 (m, 2H), 3.21 (dd, J = 13.9, 5.1 Hz, 1H), 2.98 (dd, J = 13.9, 7.9 Hz, 1H), 0.91-0.85 (m, 2H) , -0.02 (s, 9H). Mass spectrum: 384 (MH) +. 7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazole-5-carbaldehyde To a suspension of 5-aldehyde of 7-methylindazole (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 2-chloride. Pure trimethylsilyl-ethanesulfonyl (5.60 g, 28.1 mmol, 1.5 equiv). The mixture gradually became homogeneous and 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. Y-NMR (CDC13, 300 MHz) d 9.98 (s, 1 H), 8.77 (s, 1 H), 8.09 (s, 1 H), 7.64 (s, 1 H), 3.64-3.58 (m, 2 H), 2.65 (s) , 3H), 0.88-0.82 (m, 2H), 0.01 (s, 9H).

Methyl ester of 2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -acrylic acid methyl ester To a solution of N- (benzyloxycarbonyl) -a-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 then cooled to -78 ° C. After stirring for 15 min at -78 ° C a solution of 7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazole-5-carbaldehyde in tetrahydrofuran (25 L) was added. The reaction mixture was allowed to warm slowly to room temperature overnight. Although the reaction was incomplete, the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and washed with 1M sulfuric acid. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Flash column chromatography (1: 4 ethyl acetate / hexanes) gives 2.66 g (37%) of the product as a white glass foam. Y-NMR (CDCl 3, 300 MHz) d 8.48 (s, 1 H), 7.62 (s, 1 H), 7.38-7.25 (m, 7 H), 6.48 (bs, 1 H), 5.10 (s, 2 H), 3.83 (s) , 3H), 3.58-3.52 m, 2H), 2.51 (s, 3H), 0.89-0.83 (m, 2H), 0.02 (s, 9H). Mass spectrum: 530 (MH) +.

Methyl ester of (R) -2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid methyl ester In a glove bag that was subjected to 3 vacuum / nitrogen purge cycle, in an AIRFREE® (Schlenk) reaction flask equipped with a stir bar was charged with (-) -1,2-bis ((-) - trifluoromethylsulfonate. 2R, 5R) -2,5-diethylphospholane) benzene (cyclooctadiene) rhodium (I) (259 mg, 0.36 mmol, 9 mol-%), sealed with a rubber septum, and removed from the glove bag. The methyl ester of 2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -acrylic acid (2.03 g, 3.83 mmol) was weighed in a second flask Reaction AIRFREE® (Schlenk) equipped with agitation bar and sealed with a rubber septum. After 3 cycles of vacuum / nitrogen purge, this was dissolved in anhydrous methanol (80 mL, deoxygenated before addition to bubbling with nitrogen for at least 1 h). Once in solution, this was again subjected to 3 vacuum / nitrogen cycles. The acid dehydroamine solution was transferred via a cannula to the AIRFREE® reaction flask (Schlenk) containing the catalyst. The reaction mixture was purged with 5 cycles of vacuum / hydrogen purge before opening the flask to a hydrogen balloon (1 atm). After 2.5 h, the reaction mixture was purged with 3 cycles of vacuum / nitrogen purge. The solvent was evaporated and the residue was subjected to column chromatography (gradient 1: 4 ethyl acetate / hexanes for 1: 2 ethyl acetate / hexanes) to give 1.4 g (68%, ee = 99.2%) of the title compound as a white solid. Y-NMR (CDC13.300 MHz) d 8.43 (s, 1H), 7.34 (s, 5H), 7.19 (s, 1H), 6.87 (s, 1H), 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, 1H), 3.73 (s, 3H), 3.57-3.51 (m, 2H), 3.16 (dd, J = 14. 0, 5.9 Hz, 1H). 3.06 (dd, J = 13.9, 6.6 Hz, 2.55 (s, 3H), 0.89-0.83 (m, 2H), 0.01 (s, 9H). 13C-NMR (CDC13, 75 MHz) d 172.0, 155.7, 151.7, 136.2, 13.2.2, 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 spectrum: 532 (MH) +.

Methyl ester of (R) -2-Amino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid methyl ester Methyl ester of 2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid (1.35 g, 2.54 mmol) and 10% palladium on carbon (135 mg) in methanol (40 mL) were stirred for 3.0 h under 55 psi (3.8665 kg / cm2) hydrogen using a Parr apparatus. The reaction mixture was purged with 3 cycles of vacuum / nitrogen purge. The reaction mixture was then filtered through a pad of celite and the pad rinsed with several portions of methanol. The filtered methanol was evaporated to give the title compound (1.01 g, quantitative yield) as a sticky gum. 1 H-NMR (CDC 13, 300 MHz) d 8.45 (s, 1 H), 7.29 (s, 1 H), 6.97 (s, 1 H), 3.79-3.73 (, 1 H), 3.73 (s, 3 H), 3.56-3.50 ( m, 2H), 5.12 (dd, J = 13.5, 5.12 Hz, 4.85 (dd, 13.5, 8.1 Hz, 1H), 2.58 (s, 3H), 0.87-0.81 (m, 2H), 0.01 (s, 9H) 13C-NMR (CDC13, 75 MHz) d 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 spectrum: 398 (MH) +.

Methyl ester of (R) -3- [7-Methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -2- acid. { [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino and propionic A mixture of methyl ester of 2-amino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid (500 mg, 1.26 mmol) N, N- diisopropylethylamine (0.66 mL, 3.77 mmol) and disuccinimidyl carbonate (322 mg, 1.26 mmol) were stirred together with methylene chloride (20 mL) for 30 min at room temperature. Then, 3-piperidin-4-yl-3,4-dihydro-lH-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 the title compound as a white solid. XH-NMR (CDC13, 300 MHz) d 8.47 (s, 1H), 7.23 (s, 1H), 7.19-7.14 (m, 1H), 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 (m, 1H), 4.27 (s, 2H), 4.10-3.98 (m, 2H), 3.73 (s, 2H), 3.57-3.51 (m, 2H), 3.14-3.11 (m, 2H), 2.95 -2.83 (m, 2H), 2.58 (s, 3H), 1.77-1.65 (m, 4H), 0.92-0.84 (m, 2H), -0.01 (s, 9H). Mass spectrum: 655 (MH) +.

Prepared similarly: Methyl ester of acid (±) -2. { [4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -propionic ^ -RMN (CD3OD, 500 MHz) d 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, 1H), 6.95 (t, J = 6.79 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 3.7 Hz, 1H), 4.44-4.38 (m, 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, 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 spectrum: 640.40 (MH) +.

Methyl ester of the acid (R) -2-. { [4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid A solution of (R) -2-Amino-3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid methyl ester (764 mg, 1.99 mmol), N, N-diisopropylethylamine (1.10 mL, 5.97 mmol) and disuccinimidyl carbonate (509 mg, 1.99 mmol) in methylene chloride (20 mL) was stirred for 40 min at room temperature. Then, 3-piperidin-4-yl-3,4-dihydro-lH-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 was subjected to flash column chromatography (1: 4 acetone / ethyl acetate) to give 1.15 g (90%) of the title of the compound. Y-NMR (CDC13, 300 MHz) d 8.21 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 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 Hz, 1H), 5.01 (d, J = 7.6 Hz, 1H), 4.84 (dd, J = 13.1, 6.0 Hz, 1H), 4.56-4.49 (m, 1H), 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 spectrum: 641 (MH) +.

Prepared similarly: Methyl ester of (±) -2- acid. { [4- (2-Oxo-2, 3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -propionic Y-NMR (CD3CN, 500 MHz) d 9.78 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 3.7 Hz, 7.28 (dd, J = 8.5, 1.5 Hz, 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, 3.68 (s, 3H), 3.36-3.32 (m, 2H), 3.27 (dd, J = 14.0, 5.5 Hz, 3.18 (dd, J = 13.7, 8.5 Hz, 1H), 2.90 -2.84 (m, 2H), 2.55 (br s, 1H), 2.36-2.21 (m, 2H), 1.74-1.70 (m, 2H), 0.82-0.78 (, 2H), -0.09 (s, 9H). Mass spectrum 626.26 (MH) +.

Methyl ester of acid (±) -2-. { [4- (2-Oxo-2, 3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid aH-NMR (CD3CN, 500 MHz) d 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, 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, 1H), 3.20 (dd, J = 13.7, 8.8 Hz, 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 spectrum 627.25 (MH) +.

Methyl ester of (+) -2- acid. { [4- (2-Oxo-l, 4-dihydro-2H-quinolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -propionic Y-NMR (CD3OD, 500 MHz) d 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, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 3. 7 Hz, 1H), 4.44-4.38 (m, 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 (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 spectrum 640. 40 (MH) +.

Methyl ester of acid (±) -2-. { [4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid Y-NMR (CD3OD, 500 MHz) d 8.39 (d, J = 0.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 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, 1H), 6.78 (d, J = 7.5 Hz, 1H), 4.63-4.60 (m, 1H), 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 (m, 2H), 3.37-3.33 (m , 1H), 3.18 (dd, J = 13.5, 10.0 Hz, 1H), 2.87-2.79 (m, 2H), 1.73-1.59 (m, 4H), 0.80-0.75 (m, 2H), -0.05 (s, 9H); 13 (CD3OD, 125 MHz) d 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 spectrum: 641.40 (MH) +.

Example 1 Acid (±) -3- (lH-indazol-5-yl) -2-. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A solution of 5- (2-ethoxycarbonyl-2 { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl tert-butyl ester. ] -amino.}.-ethyl) -indazole-1-carboxylic acid (168 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL) in methanol (5 mL) and cooled to 0 ° C. A solution of monohydrate lithium hydroxide (49 mg, 2.04 mmol) in water (5 mL) was added. The reaction mixture was stirred at 0 ° C for 6 h and then placed in the freezer for an additional 16 h. The solvents were removed in vacuo and the residue was dissolved in water (15 mL). The pH of the aqueous solution was adjusted to ca. 1 with 1N hydrochloric acid. The resulting white solid precipitate was collected by filtration. The solid was dried under vacuum to give the title compound (108 mg, 80%). Y-NMR (DMS0-d6, 300 MHz) d 12.94 (bs, 1H), 9.19 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H ), 7.28 (dd, J = 8.5, 1.5 Hz, 1H), 7.13-7.06 (m, 2H), 6.86 (t, J = 7.0 Hz, 1H), 6.76-6.72 (m, 2H), 4.32-4.24 (m, 2H), 4.09-4.02 (m, 4H), 3.17-2.97 (m, 2H), 2.72-2.59 (m, 2H), 1.57-1.35 (m, 4H). IR (KBr, cm "1) 3424, 2963, 2930, 1660, 1628, 1505, 1474, 1446, 753. Mass spectrum: 463 (MH) +.

Acid (R) -2-. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethansulfonyl) -lH-indazol-5-yl] -propionic acid A solution of methyl ester of (R) -2- acid. { [4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid (775 mg, 1.21 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was cooled to 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 ° C for 2 h and then placed in the freezer at -15 ° C for 16 h. While the reaction mixture was cooled with an ice bath, the pH was increased to ca. 7 by the addition of 1N hydrochloric acid (3.8 mL). The organic solvents were removed under vacuum. The resulting aqueous solution was extracted with ethyl acetate after the addition of more 1N 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. Y-NMR (DMSO-d6, 300 MHz) d 9.21 (s, 1H), 8.58 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.13-7.09 (m, 2H), 6.88-6.83 (m, 1H) 6.76-6.74 (m, 2H), 4.33-4.27 (m, 2H), 4.18 (s, 2H), 4.09 -3.96 (, 3H), 3.57-3.51 (, 2H), 3.25-3.04 (m, 2H), 2.74-2.60 (m, 2H), 1.54-1.43 (m, 4H), 0.70-0.64 (m, 2H) , -0.08 (s, 9H). Mass spectrum: 627 (MH) +.

Prepared similarly: Acid (±) -2-. { [4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethansulfonyl) -lH-indol-5-yl] -propionic Mass spectrum 612.25 (MH) +.

Acid (±) -2-. { [4- (2-Oxo-2, 3-dihydro-benzoimidazol-1-yl) piperidin-1-carbonyl] -amino} -3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic Mass spectrum 613.26 (MH) ' Acid (±) -2-. { [4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid -? - NMR (CD3CN, 500 MHz) d 8.37 (s, 1H), 8.08 (s, 1H), 8 01 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 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, 1H), 6.79 (d , J = 8.0 Hz, 1H), 6.28 (br s, 4.54-4.49 (m, 1H), 4.37-4.32 (m, 1H), 4.30 (s, 2H), 3.98-3.92 (m, 2H), 3.45- 3.41 (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 (m, 4H), 0.79-0.76 (m, 2H), -0.05 (s, 9H), Mass spectrum: 627.30 (MH) +. . { 2- [1, 4 '] bipiperidinyl-l' -yl-2-oxo-l- [1- (2-trimethylsilyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amide of (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of (R) -2- acid. { [4-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid (554 mg, 0.88 mmol) and N, N-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) were added a solution of 4-piperidinopiperidine (164 mg, 0.97 mmol) and PyBOP® (460 mg, 0.88 mmol) in methylene chloride (15 L). The reaction mixture was stirred for 16 h at room temperature. This was then concentrated to about 2 L 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. Y-NMR (CD3CN, 300 MHz) d 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7.96 (m, 1H), 7.74 (s, 0.5H), 7.71 (s, 0.5H) , 7.55-7.46 (, 1H), 7.21-7.12 (m, 2H), 6.97-6.92 (, 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 (m 1H), 4.39-4.29 (m, 1H), 4.29 (s, 2H), 4.10-3.96 (m, 3H), 3.46-3.40 (m, 2H), 2.92-2.70 (m, 8H), 2.58-2.37 (m, 5H), 1.74-1.40 (m, 13H), 0.80-0.74 (m, 2H), -0.04 (s, 9H). Mass spectrum: 778 (MH) +.

Prepared similarly: { 2- [1, 4 '] bipiperidinyl-l' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-ylmethyl] -ethyl} -amide of (±) -4- (2-Oxo-2, 3-dihydro-benzoimidazol-l-yl) -piperidine-1-carboxylic acid Y-NMR (CD3CN, 500 MHz) d 9.42 (br s, 1 H), 7.80 (d, J = 8.5 Hz, 0.6 H), 7.78 (d, J = 8.2 Hz, 0.4 H), 7.50 (s, 1 H) , 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 (m, 3H), 6.69 (s, 0.4 H), 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 (m, 1H), 4.49 (s, 0.4 H), 4.46 (s, 0.6 H), 4.36-4.30 (m, 1H), 4.11-4.07 (m, 1H), 3.97-3.91 (m, 1H), 3.31-3.28 (m, 2H), 3.11-3.05 (m, 6H), 2.87-2.80 (m, 2H), 2.43-2.07 (m, 8H), 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). LCMS: tR = 2.47 min, 762.37 (MH) +. . { 2- [1, 4 '] bipiperidinyl-1' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amide of (±) -4- (2-Oxo-2, 3-dihydro-benzoimidazol-l-yl) -piperidine-1-carboxylic acid Y-NMR (CD3CN, 500 MHz) d 9.67 (s, 1H), 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, 1H), 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, 1H), 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, 1H), 4.35-4.29 (m, 1H), 4.10-4.05 (m, 1H), 4.00-3.93 (, 1H) 3.40-3.36 (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). LCMS: tR = 2.35 min, 763.35 (MH) +. . { 2- [1, 4 '] bipiperidinyl-1-yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-ylmethyl] -ethyl} -amide of (+) - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Y-NMR (CD3CN, 500 MHz) d 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, 8.5) , 1.5 Hz, 0.4 H), 7.18 (t, j = 7.4 Hz, 1H), 7.09-7.06 (m, 1H), 6.93 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 3.6 Hz, 6.09 (d, J = 8.2 Hz, 1H), 5.05-4.99 (m, 4.53-4.50 (m, 1H), 4.40-4.34 (m, 1H), 4.26 ( s, 1.2H) < 4.24 (s, 0.8H), 3.99-3.94 (m, 1H), 3.35-3.30 (m, 2H), 3.15-3.07 (m, 3H), 3.08-3.03 (, 1H), 2.81-2.73 (m, 3H), 2.55-2.37 (m, 6H), 2.21-2.16 (m, 1H), 2.13-2.08 (m, 1H), 1.69-1.57 (m, 4H), 1.51-1.45 (m , 4H), 1.41-1.35 (m, 4H), 0.83-0.74 (m, 2H), -0.06 (s, 9H), Mass spectrum: 776.44 (MH) + { 2- [1, '] Bipiperidinyl-l '-yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl] -amide of (±) -4- (2- Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Purified by chromatography on silica gel using methylene chloride / triethylamine: (90: 10: 0.5) as eluent. XH-NMR (CD3CN, 500 MHz) d 8.36 (s, 1H), 8.04 (s, 1H), 8.01 (d, J = 8.8 Hz, 0.6H), 7.97 (dd, J = 8.8 Hz, 0.4 H), 7.74 (s, 1H), 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, 1H), 7. 11 (t, J = 7.3 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 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), 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 (, 2H), 2.56-2.39 (m, 8H), 2.27-2.24 ( m, 1H), 2.20-2.16 (m, 1H), 1.68-1.57 (m, 4H), 1.52-1.45 (m, 4H), 1.34 (, 4H), 1.06-1.01 (m, 0.80-0.75 (m, 2H), 0.07 (s, 9H) Mass spectrum: 777.40 (MH) +. {2- (4-isobutyl-piperazin-1-yl) -2-oxo-l- [1- (2-trimethylsilanyl (±) -4- (2-Oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid-l-indol-5-ylmethyl] -ethyl.

^ -H-NMR (CD3CN, 500 MHz) d 9.75 (s, 1H), 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, 1H), 7.12-7.09 (m, 1H), 7.04-7.02 (m, 1H), 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, 1H), 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, 1H), 3.36-3.32 (m, 2H), 3.14-3.10 (m, 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 spectrum: 736.40 (MH) +. . { 2- (1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl) -2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-ylmethyl] - ethyl} -amide of (+) -4- (2-Oxo-2,3-dihydro-benzoimidazol-l-yl) -piperidine-1-carboxylic acid Y-NMR (CD3CN, 500 MHz) d 9.27 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 3.6 Hz, 1H), 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), 5.05 (dd, J = 15.0, 7.3 Hz, 1H), 4.41-4.34 (m, 1H), 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 , 1H), 3.05 (dd, J = 13.4, 7.0 Hz, 1H), 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 (, 1H), 1.29-1.26 (m, 1H), 0.84-0.80 (m, 2H), 0.05 (s, 9H). Mass spectrum: 737.37 (MH) +. . { 2- (4-Isobutyl-piperazin-1-yl) -2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amide of (±) -4- (2-Oxo-2, 3-dihydro-benzoimidazol-l-yl) -piperidine-1-carboxylic acid Y-NMR (CD3CN, 500 MHz) d 9.84 (s, 1H), 8.37 (s, 1H), 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, 1H), 7.02-6.98 (m, 2H), 5.97 (d, J = 8.2 Hz, 1H), 5.02 (dd, J = 14.3, 7.3 hz, 1H), 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, 1H), 3.20-3.06 (m, 2.89-2.83 (m, 2H), 2.30-2.27 (m, 4H), 2.21-2.17 (m, 1H), 1.74-1.70 (m, 3H), 0.86 (d , J = 6.7 Hz, 6H), 0.81-0.77 (, 2H), - 0.04 (s, 9H). Mass spectrum: 737.40 (MH) +. . { 2- (1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl) -2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] - ethyl} -amide (±) -4- (2-Oxo-2, 3-dihydro-benzoimidazol-l-yl) piperidine-1-carboxylic acid Y-NMR (CD3CN, 500 MHz) d 9.34 (s, 1H), 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, 1H), 7.11-7.08 (m, 1H), 7.06-7.03 (m, 1H), 7.02-6.98 (m, 2H), 5.98 (d, J = 8.2 Hz, 1H), 5.06 (dd, J = 14.6, 7.3 Hz, 4.39-4.32 (m, 1H), 4.13-4.03 (m, 2H), 3.92-3.88 (m, 2H), 3.71-3.66 (m, 1H), 3.63-3.53 (, 2H) , 3.48-3.45 (m, 1H), 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 (, 2H), 1.67-1.51 (m, 3H), 1.38-1.33 (, 0.81-0.77 (m, 2H), - 0.04 (s, 9H). Mass spectrum: 738.32 (MH) +.

Example 2 [2- [1,4 '] Bipiperidinyl-1' -yl-1- (1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide () of (R) -4- (2) acid -0xo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A solution of. { 2- [1, 4 '] bipiperidinyl-1' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethylsulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amide of (R) -4- (2-0xo-l, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (568 mg, 0.73 mmol) and 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 the analysis HPLC using a Chiracel OD column with 20% B (A = ethanol, B = 0.05% diethylamine in hexanes) as eluent (retention time: 9.51 min for the title compound and 15.9 min for the S-enantiomer). Y-NMR (CD3OD, 500 MHz) d 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, 1H), 5.08-5.05 (m, 1H), 4.60-4.53 (m, 1H), 4.48-4.40 (m, 1H), 4.37 (s, 1.5H), 4.26 (s, 0.5H), 4.24-4.14 (m, 2H), 4.06-3.97 (m, 1H), 3.15 (d, J = 7.9 Hz, 1.5H), 3.12-3.05 (m, 0.5 H), 2.94-2.86 (, 3H), 2.57-2.51 (m, 1.5H), 2.47-2.42 (m, 1H), 2.37-2.33 (m, 0.75H), 2.03-2.02 (m, 1.5H), 1.87-1.75 (m, 3.75H), 1.73-1.68 (m, 2H), 1.67-1.54 (m, 3H), 1.53-1.44 (m, 4H), 1.43-1.34 (m, 2H), 1.30-1.26 (m, m, 1H), 0.83-0.77 (m, 0.75H), 0.16 to -0.24 (m, 0.75H). Mass spectrum: 613 (MH) +. Prepared similarly: Example 3 [2- [1,4 '] Bipiperidinyl-l' -yl-1- (lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-2, 3-dihydro-benzoimidazol-1-yl) ~ piperidin-1-carboxylic acid.

Y-NMR (DMSO-d6, 500 MHz) d 10. 99 (s, 0. 6 H), 10. 96 (s, 0.4 H), 10.85 (s, 1H), 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 (m, 1H), 7.10 (d, J = 7.6 Hz, 0.4 H), 7.02-6.96 (m, 4H), 6.81 (br s, 1H), 6.37-6.35 (m, 1H) , 4.86 (q, J - 8.0 Hz, 0.6H), 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 (, 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 (m, 4H), 2.37-2.33 (m, 2H) , 2.25-2.08 (m, 4H), 2.04-1.90 (m, 2H), 1.47-1.24 (m, 10H), 0.75-0.71 (, 1H). LC / MS: t R = 1.90 min 598.42 (MH) +.

Example 4 [2- [1,4 '] Bipiperidinyl-1'-lyl-1- (lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-Oxo) -2, 3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid Y-NMR (DMSO-de, 500 MHz) d 10.70 (s, 1H), 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 (m, 1H), 7.30-7.26 (m, 1H), 7.14-7.08 (m, 1H), 6.99-6.95 (m, 2H), 6.85 (br s, 1H), 4.89-4.80 (, 1H), 4.45-4.31 (m, 2H), 4.18-4.00 (m, 2H), 3.26-3.16 (m, 1H), 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, 10H), 0.90-0.84 (m, 1H). LCMS: tR = 1.73 min, 599.32 (MH) +. Example 5 [2- [1,4 '] Bipiperidinyl-l' -yl-1- (lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo) -l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A mix of . { 2- [1, 4 '] bipiperidinyl-1' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethylsulfonyl) -lH-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 4 h. The solvents were removed in vacuo and the residue was chromatographed on silica gel using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent to give the title compound as a white solid (70% yield) . Y-NMR (CD3CN, 500 MHz) d 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, 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, 1H), 3.07-3.02 (m, 1.6H), 2.95 (dd, J = 13.7, 7.1 Hz , 0.4 H), 2.85-2.72 (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 [2- [1,4 '] Bipiperidinyl-1' -yl-1- (lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Purified by chromatography on silica gel using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent to give the title compound as a white solid (90% yield). 1 H-NMR (CD 3 OD, 500 MHz) d 8.04 (s, 0.7 H), 8.02 (s, 0.3 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 (m, 1H), 4.59-4.54 (m , 1H), 4.48-4.42 (m, 1H), 4.37 (s, 1H), 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, 2H), 2.51-2.36 (, 2H), 2.07-2.05 (m, 1H), 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 chemical separation of the racemate using the following conditions: column prep. Chiracel OD, 50 x 500 mm, 20 um; A = EtOH, B = 0.05% diethylamine / hexane; 20% B @ 65 ml / min for 45 min; retention time: 20.5 min for R and 32.8 min for enantiomers S.

Example 7 (±) -4- (2-oxo-) (1- (1H-indol-5-ylmethyl) -2- (4-isobutyl-piperazin-1-yl) -2-oxo-ethyl] -amide 2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid LC / MS: t R: - 2.05 min, 572.31 (MH) Example 8 [2- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -1- (lH-indole-5- (±) -4- (2-Oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-l-carboxylic acid (methyl) -2-oxo-ethyl] -amide LC / MS: tR: - 2.35 min, 573.26 (MH) EXAMPLE 9 [1- (1H-Indazol-5-ylmethyl) -2- (4-isobutyl-piperazin-1-yl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo- 2,3-dihydro-benzoimidazol-1-yl) piperidine-1-carboxylic acid LCMS: tR = 1.86 min, 573.28 (MH) +.

Example 10 [2- (1,4-dioxa-8-aza-spiro [.5] dec-8-yl) - (lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2-Oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid LCMS: tR = 2.18 min, 574.23 (MH) +.

Example 11 [2- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -1- (lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid ( ±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of 3- (lH-indazol-5-yl) -2- acid. { [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (95 mg, 0.21 mmol) and N, N-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 methylene chloride / methanol / triethylamine (93: 5: 2) to give the title compound as a white solid (67 mg, 56% yield). Y-NMR (CDC13, 500 MHz) d 10.52 (s, 1H), 7.97 (s, 1H), 7.54 (s, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7. 20 (d, J = 10.7 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J = 8.6 Hz, 1H), 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 (, 1H), 4.25 (s, 2H), 4.11 (br t, J = 15.6 Hz, 2H), 3.92-3.84 ( , 4H), 3.73-3.69 (m, 1H), 3.60-3.56 (m, 1H), 3.48-3.43 (m, 1H), 3.22-3.17 (m, 1H), 3.11 (d, J = 6.7 Hz, 2H ), 2.90-2.85 (m, 2H), 2.68-2.60 (m, 4H), 1.67-1.61 (m, 2H), 1.54-1.49 (m, 2H). Mass spectrum: 588 (MH) +. 4-Bromo-2, 6-dimethylphenyldiazo-t-butyl sulfide 4-Bromo-2,6-dimethylaniline (20.00 g, 100 mmol) is ground to a powder with a mortar 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 equiv) in water (16 L), dropwise for 40 min while the temperature was maintained below -5 ° C. . After an additional 30 min at -5 ° C to -20 ° C, the mixture is quenched to ca. pH 5 with solid sodium acetate. This mixture (maintained at -10 ° C) was added in portions to a stirred solution of t-butyl thiol (11.3 mL, equiv) in ethanol (100 mL) at 0 ° C for ca. 10 minutes. After the addition, the mixture was stirred at 0 ° C for 30 min and then ground ice was added (ca. 150 mL). The mixture is 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 appears to be stable as a solid but significant decomposition was followed when the recrystallization of ethanol was achieved. Y-NMR (CDC 13. 500 MHz) d 1.58 (9H, s), 1.99 (6H, s), 7.21 (2H, s). Mass spectrum: 303.05 (MH) +.

-Bromo-7-methylindazole In 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 was placed under nitrogen. To this was added dry DMSO (120 mL). The mixture was stirred vigorously overnight at rt. The reaction mixture is then carefully poured into a mixture of crushed ice (400 mL) and 10% hydrochloric acid (200 mL). The resulting suspension was left at 4 ° C overnight and the solid was collected by filtration and washed with water. The crude solid was dissolved in 5: 1 and methylene chloride / methanol and the solution was dried over magnesium sulfate and evaporated to give the product as a completely white solid (7.60 g, 87%). Y-NMR (CDC13 / CD30D, 500 MHz) d 2.51 (3H, s), 7.22 (1H, s), 7.69 (1H, s), 7.94 (1H, s). Mass spectrum: 211.03 (MH) +. 7-methylindazole-5-carboxaldehyde -Bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in mineral oil, 1.27 g, 1.1 equiv) were weighed in a flared 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 -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, dimethylformamide (10 mL) was added for several minutes. The mixture was allowed to warm to room temperature and stirred overnight. This was then cooled to 0 ° C and carefully treated with 1N hydrochloric acid (60 mL). After a few minutes, the solid sodium bicarbonate was added to make the mixture basic at pH 9-10. The layers were separated and the aqueous phase was washed 2 times with ethyl acetate. The combined organic phases were extracted with 0.8M sodium acid 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 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 brown solid (3.01 g, 65%). 1 H-NMR (CDC13, MHz) d 2.63 (3H, s), 7.73 (1H, s), 8.12 (1H, s), 8.25 (1H, s), 10.03 (1H, s). Mass spectrum: 161.06 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (7-methyl-lH-indazol-5-yl) -acrylic acid A stirred solution of trimethyl ester of N-benzyloxycarbonyl-a-phosphonoglycine (5.51 g, 1.2 equiv.) In tetrahydrofuran (30 mL) at room temperature was treated 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. The disappearance of the starting material was monitored by TLC and LC / MS. After 5 days at room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 2% phosphonic acid and brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography on silica gel, eluted with 1) 1: 1 and 2) 2: 1 ethyl acetate / hexane, to give the product as a colorless foam (4.93 g, 97%). Y-NMR (CDC13, MHz) d 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 (1H, s). Mass spectrum: 366.16 (MH) +. Methyl ester of (±) -2-amino-3- (7-methyl-lH-indazol-5-yl) -propionic acid 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 by bubbling nitrogen through for 30 min and then 10% palladium in charcoal (0.6 g) was carefully added. The mixture was hydrogenated at 40 psi (2.81 kg / cm2) in a Parr shaker at night. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated in vacuo to give the product as a colorless foam (3.62 g, quant.). Y-NMR (CD30D, 500 MHz) d 2.45 (3H, s), 2.99 (1H, Abq), 3.22 (1H, Abq), 3.74 (3H, s), 3.89 (1H, m), 6.91 (1H, s) ), 7.31 (1H, s), 7.73 (1H, s). Mass spectrum: 234.11 (MH) +.

Example 12 Methyl ester of (±) -3- (7-Methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic A stirred solution of (±) -2-amino-3- (7-methyl-lH-indazol-5-yl) -propionic acid methyl ester (162.9 mg, 0.698 mmol) in methylene chloride (3 mL) was added. Room temperature was treated with carbonyl diimidazole (113.2 mg, 1 equiv). After 1.5 h at room temperature, 3-piperidin-4-yl-3,4-dihydro-lH-guinazolin-2-one (161.5 mg, 1 equiv.). The mixture was stirred at room temperature overnight. A white precipitate has the shape that is shown to be the desired product. The solvent was evaporated and the residue triturated with methylene chloride. The product was collected by filtration, washed with methylene chloride and dried in vacuo to give a white solid (241.5 mg, 71%). Some remaining product mother liquors. ^ H-NMR (dimethylformamide-d-7, 500 MHz) d 1.75 (4H, m), 2.78 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, m), 3.86 (3H, s) ), 4.44 (2H, s), 4.57 (1H, m), 4.72 (1H, m), 7.11 (3H, 7.31 (1H, s), 7.34 (2H, m), 7.72 (1H, s), 9.34 ( 1H, s). Mass spectrum: 491.13 (MH) +.

Prepared similarly: Example 13 Methyl ester of 3- (7-Methyl-lH-indazol-5-yl) -2- [2 ', 3'-dihydro-2'-oxospiro- (piperidin-4, 4' - (1H) -quinazolin) carbonyl amino] -propionic Y-NMR (DMSO-de) d 1.59 (4H, m), 2.46 (3H, s), 3.00-3.08 (4H, m), 3.6 (3H, s), 3.78-3.81 (2H, m), 4.30- 4.32 (1H, m), 6.78-6.88 (4H, m), 7.03 (1H, s), 7.10 (1H, m), 7.13 (1H, s), 7.41 (1H, s), 7.96 (1H, s) , 9.12 (1H, s). Mass spectrum: 477.11 (MH) +. Example 14 Methyl ester of 3- (7-Methyl-lH-indazol-5-yl) -2- (1, 2-dihydro-2-oxospiro-4H-3, l-dihydro-benzoxazin-4'-4- piperidine-carbonylamino) -propionic Mass spectrum: 478. 15 (MH) + Methyl ester of 3- (7-methyl-lH-indazol-5-yl) -2- acid. { 3 ', 4' -dihydro-2 '-oxoespiro- (piperidin-4-4' - (1H) -quinolinecarbonyl Y-NMR (DMSO-de) d 1.42-1.56 (4H, m), 2.47 (3H, s), 2.50-2. 54 (1H, d), 2.60-2.64 (1H, d), 2.98-3.06 4H, m), 3.60 (3H, s) 3.80 (2H, m), 4.30 (1H, m), 6.86 (2H, d) , 6.95 (2H, m), 7.15 (1H, m), 7.40 (1H, s), 7.95 (1H, s), 8.32 (1H, s), 10.14 (1H, s), 13.05 (1H, s). Mass spectrum: 476.17 (MH) +.

Methyl ester of 3- (7-Methyl-lH-indazol-5-yl) -2- [2'-phenyl-1 ', 3', 8'-triaza-spiro (4 ', 5') carbonyl amino ] -propionic XH-NMR (DMSO-de) d 1.50 (2H, m), 1.68 (2H, m), 2.46 (3H, s overlapping with DMSO), 3.05 (2H, m), 3.30 (2H, m), 3.60 (3H, s), 3.86 (2H, m), 4.28 (1H, m), 6.98 (1H, d), 7.04 (1H, s), 7.40 (1H, s), 7.58 (2H, m), 7.65 ( 1H, m), 8.00 (1H, s), 8.04 (2H, m). Mass spectrum: 489.15 (MH) +.

Example 15 Acid (±) -3- (7-methyl-lH-indazol-5-yl) -2-. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A suspension of methyl ester of (+) - 3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (240.0 mg, 0.489 mmol) in 1: 1 tetrahydrofuran / methanoi (20 mL) at room temperature was treated with a lithium hydroxide solution (140.5 mg, 7 equiv) in water (10 mL). Within 1 min, the mixture became homogeneous and this was placed to remain at 4 ° C overnight. The solvents were evaporated at ca. 30 ° C and the pH was adjusted to ca. with 1N 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%). The solid sodium chloride was added to the resulting filtrate in precipitation of more product (5.2 mg, 75% total yield). Y-NMR (CD3OD, 500 MHz) d 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 spectrum: 477.13 (MH) +.

Prepared similarly: 3- (7-Methyl-lH-indazol-5-yl) -2- [2 ', 3'-dihydro-2'-oxospiro- (piperidin-4, 4' - (1H) -quinazolinecarbonyl amino acid ] -propionic XH-NMR (DMSO-dg) d 1.58 (4H,), 2.46 (3H, s), 3.00-3.23 (3H, m), 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, m) 7.18 (1H, s), 7.96 (1H, s), 13.02 (1H, m). Mass spectrum: 463. 09 (MH) +.

Methyl ester of 3- (7-methyl-lH-indazol-5-yl) -2- (1,2-dihydro-2-oxospiro-4H-3, l-dihydro-benzoxazin-4'4-piperidin-) carbonylamino) -propionic Y.-NMR (DMSO-d6) d 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 (1H, m), 6.78 (1H, d), 6.87 (2H, m), 6.96 (1H, m), 7.05 (1H, s), 7.24 (1H, m), 7.41 (1H, s), 7.96 ( 1H, s), 10.22 (1H, s) 12.42 (1H, br.) 13.02 (1H, m). Mass spectrum: 464.07 (MH) +. 3- (7-Methyl-lH-indazol-5-yl) -2 acid. { 3 ', 4' -dihydro-2 '-oxoespiro- (piperidin-4, 4' - (1H) -quinolin-carbonyl amino.}. -propionic 2 H-NMR (DMSO-d 6) d 1.39-1.45 (2H, m), 1.53-1.56 (2H, m), 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 (1H, m), 6.69-6.70 (1H, d), 6.86-6.87 (1H , d), 6.93-6.94 (1H, m) 6.99-7.00 (1H,), 7.05 (1H, m), 7.41 (1H, s), 7.95 (1H, s), 10.13 (1H, s), 12.50 ( 1H, m), 13.03 (1H, m). Mass spectrum: 462 (MH) +. 3- (7-Methyl-lH-indazol-5-yl) -2- [2'-phenyl-l ', 3', 8 'triaza-spiro (4', 5 ') deo-l-ene-8 -crbonyl amino] -propionic Y-NMR (DMSO-de) d 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 (1H, m), 6.69 (1H, m), 7.04 (1H, s), 7. 40 (1H, s), 7.52-7.58 (3H, m), 7.99 (3H, m), 11.55 (1H, m), 13. 00 (1H, m). Mass spectrum: 475.08 (MH) +.

Example 16 [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A stirred solution of (+) - 3 - (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic (65.7 mg, 0.138 mmol) in 2: 1 dimethylformamide / methylene chloride (1.5 mL) at 0 ° C was treated with 4- (1-piperidyl) -piperidine (46.5 mg, 2 equiv), diisopropylethylamine (0.048 L) , 2 equiv) and PyBOP® (75.5 mg, 1.05 equiv). The ice bath is 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, eluted with 18: 1 methylene chloride / methanol containing 1% triethylamine, to give the product as a pale yellow solid (80.4 mg, 93%). %). Y-NMR (CD30D, 500 MHz) d 0.28 (1H, m), 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 m), 6.81 (1H, d), 6.96 (1H, t) , 7.16 (3H, m), 7.49 (1H, s), 8.03 (1H, s). Mass spectrum: 627.29 (MH) +. Prepared similarly: Example 17 (1-) -4- (2-oxo-1- [1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide , 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Y-NMR (CD3OD, 500 MHz) d 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, m), 3.18 (4H, m), 3.40 (2H, m), 3.61 (1H, m), 4.16 (1H, m), 4.28 (1H, Abq), 4.43 (1H, m), 5.02 ( 1H, m), 6.51 (1H, d), 6.79 (1H, d), 6.96 (1H, t), 7.11 (1H, d), 7.15 (1H, t), 7.48 (1H, s), 8.01 (1H, s). Mass spectrum: 544.24 (MH) +.

EXAMPLE 18 (1-) -4- (2-Oxo-1,4-dihydro-2H-quinazolin-) - [l-dimethylcarbamoyl-2- (7-methyl-lH-indazol-5-yl) -ethyl] -amide. 3-yl) -piperidine-1-carboxylic acid Y-NMR (CD3OD, 500 MHz) d 1.12 (2H, d), 1.64 (2H, m), 2. 57 (3H, s), 2.74 (1H, m), 2.87 (3H, s), 2.89 (3H, s), 2.86 (2H, m), 3.07 (2H,), 3.20 (1H, m), 4.17 (1H, m), 4.25 (1H, Abq), 4.43 (1H, 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 (1H , s). Mass spectrum: 504.15 (MH) +.

Example 19 [1- (7-Methyl-lH-indazol-5-ylmethyl) -2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Y-NMR (CD3OD, 500 MHz) d 1.30 (2H,), 1.66 (2H, m), 1. 78 (1H, m), 1.90 (1H, m), 2.00 (3H, s), 2.19 (1H, m), 2.35 (1H, m), 2.58 (3H, s), 2.88 (2H, m), 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, t), 6.80 (1H, d), 6.95 ( 1H, t), 7.11 (2H, m), 7. 16 (1H, t), 7.47 (1H, s), 8.02 (1H, s). Mass spectrum: 559. 23 (MH) +. Example 20 [1- (7-Methyl-lH-indazol-5-ylmethyl) -2-oxo-2-pyrrolidin-1-yl-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Y-NMR (CD3OD, 500 MHz) d 1.40-1.90 (5H, m), 2.02 (3H, brs), 2.57 (3H, s), 2.86 (1H, m), 2.89 (2H, q), 3.09 (2H , m), 3. 16 (1H, m), 3.25 (2H,), 3.40 (1H, m), 3.56 (1H, m), 4.17 (2H, d), 4.27 (2H, s), 4.40 (1H, m), 4.69 (1H, t), 6.80 (1H, s), 6.95 (1H, t), 7.10 (1H, s), 7.16 ( 1H, m), 7.48 (1H, s), 7. 53 (1H, m), 8.01 (1H, s). Mass spectrum: 530.19 (MH) +.

Example 21 [1- (7-Methyl-lH-indazol-5-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide of the acid (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid XH-NMR (CD3OD, 500 MHz) d 1.38 (1H, t), 1.68 (2H, m), 1. 81 (1H, m), 2.30 (1H, m), 2.53 (3H, s), 2.95 (4H, m), 3.13 (2H, d), 3.22 (1H, m), 3.35-3.65 (4H, m), 3.79 (1H, m), 4.18 (2H, d), 4.31 (2H, s), 4.42 (1H, m), 4.99 (1H, t), 6.64 (2H, d), 6.80 (1H, 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), 8.16 (1H, m). Mass spectrum: 622.26 (MH) +.

Example 22 [1- (7-Methyl-lH-indazol-5-ylmethyl) -2-oxo-2- (4-pyridin-2-yl-piperazin-1-yl) -ethyl] -amide of the acid (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid ^ -NMR (CD30D, MHz) d 1.27 (1H, m), 1.38 (1H, m), 1.67 (2H, m), 1.84 (1H, m), 2.54 (3H, s), 2.65 (1H, m) , 2.88 (2H, m), 3.15 (4H,), 3.35 (1H, m), 3.58 (3H, m), 3.77 (1H, m), 4.18 (2H, d), 4.30 (2H, s), 4.42 (1H, m), 5.01 (1H, 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 (1H, s), 8.05 (1H, 7). Mass spectrum: 622.25 (MH) +. Example 23 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'-dihydro-2 '-oxoespiro- [piperidin-4, 4' - (1H) -quinazolin] -1-carboxamide Y-NMR (DMSO-de, 500 MHz) d 1.2-1.73 (14H, m), 2.46 (3H, s), 2.75-3.24 (12H, m), 3.87 (2H, m), 4.45 (1H, m) , 4.78-4.85 (1H, m), 6.80 (1H, m), 6.86 (1H, m), 7.05 (1H, m), 7.12 (1H,), 7.21 (1H, m), 7.27 (2H, m), 7.98 (1H , m), 9.23 (1H, m).

Mass spectrum: 613.25 (MH) +.

Example 24 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- (1-piperidinyl) -2-oxoethyl] -2'-3'-dihydro-2'-oxospiro- [piperidin -4,4 '- (1H) -quinazolin] -1-carboxamide Y-NMR (CD3OD, 500 MHz) d 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 (1H, s), 7.96 (1H, s). Mass spectrum: 530.17 (MH) +.

Example 25 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -1 ', 2'-dihydro-2 '-oxoespiro- [4H-3', 1-benzoxazin-4, 4 '-piperidin] -1-carboxamide Y-ÍDMSO-dg, 500 MHz) d 1.88 (14H, m), 2.64 (3H, s), 2.78 (12H, m), 4.0 (2H, m), 4.4 (1H, m), 4.85 (1H, m), 6.80-6.88 (2H, m), 7.03 (2H, m), 7.11 (1H, m), 7.23 (1H, m), 7.36 (2H,), 7.97 (1H,). Mass spectrum: 614.73 (MH) +.

Example 26 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- (1-piperidinyl) -2-oxoethyl] -1 ', 2'-dihydro-2'-oxospiro- [4H -3 ', l-benzoxazin-4, 4' -piperidine] -1-carboxamide XH-NMR (DMSO-de, 500 MHz) d 1.15-1.91 (10H, 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 (1H, m), 6.99 (1H, m), 7.04 (1H, s), 7.24 (1H, m), 7.37 ( 1H, s), 7.96 (1H, s). Mass spectrum: 531.23 (MH) +.

Example 27 (±) - [l-dimethylcarbamoyl-2- (7-methyl-lH-indazol-5-yl) -ethyl] -1 ', 2'-dihydro-2'-oxoespiro- [4H-3', l -benzoxazin-4, 4 '-piperidine] -1-carboxamide Y-NMR (DMSO-de, 500 MHz) d 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 spectrum: 491.14 (MH) +. Example 28 (±) - [1- (2-adamantyl-carbamoyl) -2- (7-methyl-lH-indazol-5-yl) -ethyl] -1 ', 2'-dihydro-2'-oxoespiro- [ 4H-3 ', l-benzoxazin-4, 4'-piperidine] -1-carboxamide Y-NMR (DMSO-de, 500 MHz) d 1.40-1.95 (15H, m), 2.46 (3H, m), 2.89-3.07 (4H, m), 3.81 (1H, m), 3.90 (2H, m) , 4.48 (1H, m), 6.74 (2H, m), 6.86 (1H, d), 6.97 (1H, m), 7.11 (1H, s), 7.24 (1H, m), 7.36 (1H, s), 7.44 (1H, s), 7.96 (1H, s). Mass spectrum: 597.27 (MH) +. EXAMPLE 29 [1- (7-Methyl-lH-indazol-5-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide of the acid (+) -1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', l-benzoxazin-4, 4'-piperidine-1-carboxylic acid LCMS: tR = 1.56 min, 609.14 (MH) +. Example 30 { 2- (7-Methyl-lH-indazol-5-yl) -1- [(pyridin-4-ylmethyl) -carbamoyl] -ethyl} -amide of (±) -1 ', 2'-dihydro-2'-oxospiro- [4H-3', l-benzoxazin-4, 4'-piperidine-1-carboxylic acid LCMS: tR = 1.49 min, 553.12 (MH) +.

Example 31 (+) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] 3 ', 4'-dihydro-2' -oxoespiro- [piperidin-4, 4 '- (1H) quinolin] -1-carboxamide Y-NMR (DMSO-de, 500 MHz) d 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 (1H, m), 6.82-7.64 (3H, m), 7.13-7.23 (2H, m), 7.36 (3h, m), 7.96 (1H, s). Mass spectrum: 612.32 (MH) +. Example 32 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [1-piperidinyl] -2-oxoethyl] 3 ', 4'-dihydro-2'-oxoespiro- [piperidin- 4, 4 '- (1 H) -quinolin] -1-carboxamide Yi-NMR (DMSO-d6, 500 MHz) d 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,), 6.87 (1H, d), 6.94 (1H, m), 7.03 (1H, s), 7.06 (1H, m) , 7.15 (1H, m), 7.37 (1H, s), 7.40 (1H, s), 7.96 (1H, s). Mass spectrum: 529.25 (MH) +. Example 33 (+) - [l-dimethylcarbmoyl-2- (7-methyl-lH-indazol-5-yl) -ethyl] -1,3 ', 4'-dihydro-2'-oxoespiro-. { piperidin-4, 4 '- (1H) -quinolin] -1-carboxamide ), 1.56 (2H, m), 2.46 (3H, s), 2.56 (2H,), 2.79 (3H, s), 2.90 (5H, m), 3.84 (2H, m), 4.73 1H, m), 6.69 (1H, d), 2.69 (1H, d), 6.94 (1H, m), 7.05 (2H, m), 7.14 (1H, m), 7.37 (1H, s), 7.42 (1H, s), 7.96 ( 1H, s). Mass spectrum: 489.2 (MH) +. Example 34 { l- (7-methyl-lH-indazol-5-ylmethyl) -2- [1,4] bipiperidinyl-1'-yl-2-oxo-ethyl} -Amino acid (±) -4-oxo-2-phenyl-1,3,8-triaza-spiro [4, 5] dec-l-ene-8-carboxylic acid Y-NMR (EMSO-de, 500 MHz) d 1.34-2.00 (14H, m), 2.48 (3H, s overlapped with DMSO), 2.70-3.30 (12H, m), 3.90 (2H, m), 4.40 m) , 4.82 (1H, m), 6.82 (1H, m), 7.04 (1H, s), 7.37 (2H, m), 7.56 (3H, m), 7.98 (3H, m). Mass spectrum: 625.29 (MH) +. Example 35 { 1- (7-methyl-lH-indazol-5-ylmethyl) -2- [1-piperidinyl] -2-oxo-ethyl} -amide of (+) - 4-oxo-2-phenyl-l, 3,8-triaza-spiro [4,5] dec-l-ene-8-carboxylic acid XH-NMR (DMSO-d6, 500 MHz) d 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), 7.37 (2H, m), 7.40 (1H, s), 7.53 (2H, m), 7.98 ( 2H, m). Mass spectrum: 543.26 (MH) +. Example 36 (1-) -4-oxo-2-phenyl-1, 3, 8, triaza-spiro [l-dimethylcarbamoyl-2- (7-methyl-1H-indazol-5-yl) -ethyl] -amide] 4, 5] dec-1-ene-8-carboxylic acid Y-NMR (DMSO-d6, 500 MHz) d 1.28-1.61 (4H, m), 2.78 (4H, m), 2.90 (6H, m), 3.94 (2H, m), 4.74 (1H, m), 6.77. (1H, m), 7.05 (1H, s), 7.37 (4H, s), 7.42 (1H, s), 7.52 (2H, m), 7.98 (2H, m). Mass spectrum: 502.21 (MH) +. Example 37 { 1- (lH-indazol-5-ylmethyl) -2-oxo-2- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -ethyl} -amide LCMS: tR = 1.674 (MH) -. EXAMPLE 38 4- (3- (lH-Indazol-5-yl) -2-. {[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) - benzyl ester piperidin-1-carbonyl] -amino.}. -propionyl) -piperazine-1-carboxylic acid LC / MS: tR = 1.74 min, 665 (MH) ' Example 39: 4- (2-Oxo-1,4-dihydro-2H-quinazolin- 1- [1- (1H-indazol-5-ylmethyl) -2-oxo-2-piperazin-1-yl-ethyl] -amide 3-yl) -piperidine-1-carboxylic acid To a degassed solution of 4- (3- (lH-indazol-5-yl) -2- { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-benzyl ester. -yl) -piperidine-1-carbonyl] -amino.}. -propionyl) -piperazine-1-carboxylic acid (280 mg, 0.42 mmol) in methanol (50 ml) was added 10% pelletized mineral carbon (50 mg).

The mixture was stirred on a Parr apparatus under a hydrogen atmosphere at 50 psi (3.515 kg / cm2) for 3 h. The mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the desired product in 91% yield. LCMS: tR = 1.22 min, 531 (MH) +.

Example 40a. { 1- (lH-indazol-5-ylmethyl) -2- [4- (2-methyl-butyl) -piperazin-1-yl] -2-oxo-ethyl} -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A stirred solution of 4- (2-oxo-l) 4- (2-oxo-1-l-indazol-5-ylmethyl) -2-oxo-2-piperazin-1-yl-ethyl] -amide., 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (100 mg, 0.188 mmol) in methanol (25 mL) was treated with 2-methyl-butyraldehyde (0.03 mL, 0.376 mmol). After 1 h at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was left to stir overnight. The solution was filtered through an SCX cartridge. The cartridge was eluted first with methanol and then with 1M solution of ammonia in methanol. The solvent was removed in vacuo to give the desired product in 50% yield. LCMS: tR = 1.31 min, 601 (MH) +.

Experimental general procedure for the preparation of examples 40b-40k. The appropriate aldehyde (0.04 mmol) was added to a solution of Example 39 piperazine (0.02 mmol) in methanol (2.0 mL) and the resulting solution was stirred at room temperature for 1 h. Then the sodium triacetoxyborohydride (0.2 mmol) was added and the solution was allowed to stir overnight at room temperature. The solution was then filtered through an SCX cartridge and the cartridge was washed with methanol and a solution of ammonia / methanol. The ammonia / methanol solution was concentrated in vacuo and the crude products were purified by preparative HPLC to provide the products listed in Table 1.

Table 1. Examples 40b-40k.

Example 41a Cyclohexyl ester of 3- (7-Methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic To a stirred solution of (±) -2-amino-3- (7-methyl-lH-indazol-5-yl) -propionic acid (20 mg, 0.042 mmol), 4- (dimethylamino) pyridine (2.5 mg, 0.02) mmoles), and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) in methylene chloride (2 mL) and dimethylformamide (1 mL), cyclohexanol (13.3 μL, 0.126) was added. mmoles). The reaction mixture was stirred at 50-55 ° C for 4 h. The solvent was removed under reduced pressure, the residue purified by preparative CCD on silica gel (9: 1 chloroform / methanol) to give the desired product as a white solid (9.4 mg, 40%). XH-R N (CD3OD, 500 MHz) d 1.32-1.87 (14H, m), 2.57 (3H, s), 2.86 (2H, m), 3.11-3.26 (2H, m), 4. 13-4.22 (3H, m), 4.46 (1H, m), 4.55 (1H, m), 4.80 (1H, m), 6. 79 (1H, d), 6.97 (1H, m), 7.08-7.18 (2H, m), 7.35 (1H, s), 7. 47 (1H, s), 8.01-8.02 (1H, m). Mass spectrum: 559.22 (MH) +.

Prepared similarly: Example 41b L-benzyl-piperidin-4-yl ester of 3- (7-Methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 1. 76 min, 650. 30 (MH) +.

Example 41c L-methyl-piperidin-4-yl ester of 3- (7-Methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LC / MS: tR = 1.59 min, 574.27 (MH) +.

Example 4Id 4-Phenyl-cyclohexyl ester of 3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LC / MS: 2.69 min, 635.29 (MH) Example 41e (R) -l-pyridin-4-yl-ethyl ester of 3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LC / MS: t R = 1.66 min, 582.22 (MH) Example 41 f 3- (7-Methyl-lH-indazol-5-yl) -2 (S) -l-pyridin-4-yl-ethyl ester -. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LC / MS: tR = 1.65 min, 582.23 (MH) +. 4-bromo-2-chloro-6-methylphenyldiazo-t-butyl sulfide 4-Bromo-2-chloro-6-methylaniline sulfide (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), drop by drop for 10 min while the temperature is kept below -5 ° C. After an additional 30 min at -5 ° C to -20 ° C, the mixture was quenched at ca. pH 5 with solid sodium acetate. This mixture (maintained 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 ° C for ca. 10 minutes. After the addition, the mixture was stirred at 0 ° C for 30 min and then ground ice (ca 50 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 hours (4.60 g, 78%). Mass spectrum: 323.03 (MH) +.

-Bromo-7-chloroindazole In a round-bottomed flask dried to the flame, 4-bromo-2 sulfide was combined, chloro-6-methylphenyldiazo-t-butyl (4.60 g, 14.4 mmol) and potassium t-butoxide (16.1 g, 10 equiv). A stir bar was added and the mixture was placed under nitrogen. To this was added dry DMSO (50 L). The mixture was vigorously stirred 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 allowed 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. Y-NMR (CDC13, 500 MHz) d 7.52 (d, J = 1.5, 1H), 7.82 (d, J = 1.5, 1H), 8.08 (s, 1H), Mass spectrum: 230.90 (MH) +. 7-chloroindazole-5-carboxaldehyde -bromo-7-chloroindazole (2.0 g, 8.7 mmol) and sodium hydride (221 mg, 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 several minutes. After 30 min at -78 ° C, the reaction was allowed to be gradually at -50 ° C, held for 15 min, and cooled again to -78 ° C. Dimethylformamide (2.8 mL) was slowly added and the mixture was allowed to warm to -50 ° C. The solution is rapidly transferred to a separatory funnel containing diethyl ether and water. The aqueous is made acid by the addition of 1 M potassium acid sulfate and 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 1.7 g (100%) of almost pure material. A pure analytically sample was obtained by recrystallization from hot methanol .1H-NMR (CDC13, 500 MHz) d 7.97 (s, 1H), 8.20 (s, 1H), 8.30 (s, (1H), 10.02 (s, (1H) ) Mass spectrum: 181.09 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (7-chloro-lH-indazol-5-yl) -acrylic acid 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 trimethyl ester of N-benzyloxycarbonyl-a-phosphonoglycine (11 g, 1.2 equiv.) In methylene chloride (5 mL). After 10 min, 7-chloroindazole-5-carboxaldehyde (0.50 g, 2.79 mmol) in methylene chloride (5 mL) was added. The reaction was allowed to warm gradually to room temperature and stirred for 3 days. The reaction was evacuated in 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 gives 0.40 g (37%) of the product together with 0.20 g (40%) of the starting material. 1 H-NMR (CDC 13, 500 MHz) d 3.64 (s, 3 H), 5.11 (s, 2 H), 6.44 (bs, 1 H), 7.30 (bs, 5 H), 7.43 (s, 1 H), 7.62 (s, 1 H) ), 7.80 (s, 1H), 8.07 (s, 1H). Mass spectrum: 386.16 (MH) +.

Methyl ester of (±) -2 ~ Amino-3- (7-chloro-lH-indazol-5-yl) -propionic acid A solution of methyl ester of 2-benzyloxycarbonylamino-3- (7-chloro-lH-indazol-5-yl) -acrylic acid (300 mg, 0.78 mmol) in methanol (10 mL) was treated with trifluoroacetic acid (0.2 mL), wetted with nitrogen, and treated with 10% palladium in mineral carbon (30 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere. After 4 days, all the starting material has been consumed. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gives 78 mg (40%). Y-NMR (CDC13, 500 MHz) d 1.31 (bs, 3H), 2.95 (dd, J = 13.7, 7.9, 1H), 3.18 (dd, J = 13.7, 5.2, 1H), 3.48 (s, 3H), 3.78 (dd, J = 7.9, 5.2, 1H), 7.23 (s, 1H), 7.46 (s, 1H), 8.00 (s, 1H). Mass spectrum: 254.06 (MH) +. Example 42 Methyl ester of (+) - 3 - (7-Chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A stirred solution of (±) -2-amino-3- (7-chloro-lH-indazol-5-yl) -propionic acid methyl ester (78 mg, 0.31 mmol) in tetrahydrofuran (2 mL) at 0 ° C was treated with carbonyl diimidazole (50 mg, 1 equiv). The reaction was stirred for 5 min, warmed to room temperature, and stirred 10 min, and treated with 3-piperidin-4-yl-3,4-dihydro-lH-quinazolin-2-one (78 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography to give 148 mg (94%) as a white powder. Y-NMR (DMSO-d6, 500 MHz) d 1.46 (m, 4H), 2.55-2.80 (m, 2H), 3.05 (dd, J = 13.7, 10.7, 1H), 3.15 (m, 1H), 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, 1H), 7.12 (dd, J = 7.6, 7.6, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.15 (s, 1H), 9.18 (s, 1H), 13.48 (s, 1H). Mass spectrum: 511.18 (MH) +. Example 43 [2- [1,4 '] Bipiperidinyl-l' -yl-1- (7-chloro-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A suspension of methyl ester of (+) - 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (15 mg, 0.029 mmol) in 1: 1 tetrahydrofuran / methanoi (1 mL) at room temperature was treated with a solution of lithium hydroxide (3.0 mg, 2.5 equiv) in water (0.25 mL), and the resulting solution it was stirred for 1.5 h. The solution was cooled to 0 ° C, treated with aqueous 1M potassium acid sulfate (60 μL, 2.0 equiv), and concentrated to give the crude acid which was used immediately without purification. The crude acid was dissolved in (0.3 mL) and treated sequentially with methylene chloride (0.15 mL), 4-piperidyl-piperidine (10.1 mg, 2 equiv), diisopropylethylamine (10 μL, 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). 1 H-NMR (CDC13, 500 MHz) d 1.30-1.60 (m, 8H), 1.65-1.88 (m, 5H), 2.14 (m, 1H), 2.23 (m, 1H), 2.30-2.70 (m, 7H) , 2.80-3.20 (m, 5H), 3.94 (d, J = 13.4, 13.1, 1H), 4.10-4.30 (m, 4H), 4.55 (, 1H), 4.62 (dd, J = 13.1, 12.8, 1H), 5.19 (m, 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 spectrum: 647.37 (MH) +. 4-bromo-2-ethyl-6-methyl-phenylamine 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 ° C. To this was added bromide (5.1 mL, 1 equiv.) Drop by drop. This rapid formation of a white precipitate. The precipitate was filtered and washed with diethyl ether. The precipitate was suspended in water and neutralized with aqueous potassium carbonate. A formed oil which was extracted in diethyl ether. The ethanol was dried over potassium carbonate, filtered, and concentrated to give 7.0 g (33%) as a purple oil which is used without purification. Mass spectrum: 214.01 (MH) +. 4-Bromo-2-ethyl-6-methylphenyldiazo-t-butyl sulfide 4-Bromo-2-ethyl-β-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 nitrate (2.27 g, 1.05 equiv.) In water (5 L), dropwise for 10 min while the temperature was kept below -5 ° C. . After an additional 30 min at -5 ° C to 20 ° C, the mixture was quenched at ca. pH 5 with solid sodium acetate. The mixture was added (maintained at ca. -10 ° C) in portions to a stirred solution of t-butyl thiol (3.7 mL, 1 equiv.) In ethanol (50 mL) at 0 ° C for ca. 10 minutes. After the addition, the mixture was stirred at 0 ° C for 30 min and then ground ice (ca 50 mL) was added. The mixture was 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 spectrum: 315.05 (MH) +. 5-bromo-7-ethyl-lH-indazol 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-butyl sulfide (9.4 g, 30 mmol) in DMSO (100 mL) by means of a cannula. The mixture was stirred vigorously for 1 h. The reaction mixture was then carefully poured into a mixture of ground 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 brown solid. Y-NMR (CDC13, 500 MHz) d 1.39 (t, J = 7.6, 3H), 2.92 (q, J = 7.6, 2H), 7.30 (s, 1H), 7.75 (s, 1H), 8.04 (s, 1 HOUR) . Mass spectrum: 225.00 (MH) +. 7-Ethyl-lH-indazole-5-carbaldehyde -Bromo-7-ethyl-lH-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 magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (60 L) 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 eguiv.) Was added over several minutes. After 15 min at -78 ° C, the reaction was gradually warmed to -50 ° C, and re-cooled to -78 ° C. Dimethylformamide (2.8 L) was added slowly and the mixture was allowed to warm to -50 ° C. The solution is transferred rapidly to a stirred solution of water 300 mL and 1M potassium acid sulfate (25 mL). The resulting suspension was extracted with diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography gives 160 mg (10%) as a white solid. aH-NMR (CD30D, 500 MHz) d 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 spectrum: 175.08 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (7-ethyl-lH-indazol-5-yl) -acrylic acid To a stirred solution of trimethyl ester of N-benzyloxycarbonyl-a-phosphonoglycine (0.61 g, 2.0 equiv.) And 7-ethyl-lH-indazol-5-carbaldehyde (160 mg, 0.92 mmol) in tetrahydrofuran (5 mL) a 0 ° C tetramethylguanidine was added (0.22 mL, 1.9 equiv.). The reaction was allowed to warm slowly 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 13, 500 MHz) d 1.33 (t, J = 7.6, 3H), 2.86 (q, J = 7.3, 2H), 3.83 (s, 3H), 5.11 (s, 2H), 6.39 (bs, 1H), 7.29 (bs, 5H), 7.43 (s, 1H), 7.50 (s, 1H), 7.78 (s, 1H), 8.04 (s, 1H). Mass spectrum: 380.17 (MH) +.

Methyl ester of (±) -2-Amino-3- (7-ethyl-lH-indazol-5-yl) -propionic acid To a solution of methyl ester of 2-benzyloxycarbonylamino-3- (7-ethyl-lH-indazol-5-yl) -acrylic acid (330 mg, 0.78 mmol) in methanol (5 L) under nitrogen was added palladium on carbon mineral (10%, 33 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated to give 210 mg (98%) which was used without purification. Y-NMR (CDC13, 500 MHz) d 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, 7.38 (s, 1H), 7.97 (s, 1H). Mass spectrum: 248.15 (MH) +.

Example 44 Methyl ester of (±) -3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A stirred solution of (+) - 2-amino-3- (7-ethyl-lH-indazol-5-yl) -propionic acid methyl ester (100 mg, 0.41 mmol) in tetrahydrofuran (2 mL) at 0 ° C was treated with carbonyl diimidazole (66 mg, 1 eguiv). 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-lH-quinazolin-2-one (103 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography to give 188 mg (92%) as a white solid. ^? - NMR (CDC13, 500 MHz) d 1.36 (t, J = 7.6, 3H), 1.69 (m, 4H), 2.86 (m, 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 (m, 1H) , 5.02 (m, 1H), 6.70 (d, J = 7.9, 1H), 6.90-7.05 (, 4H), 7.16 (dd, J = 7.6, 7.6, 1H), 7.34 (s, 1H), 8.03 (s) , 1 HOUR) . Mass spectrum: 505.29 (MH) +.

Example 45 [2- [1, 4 '] bipiperidinyl-1-yl-l- (7-ethyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-0xo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of methyl ester of (±) -3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (15 mg, 0.03 mmol) in methanol (0.6 mL) was added a solution of monohydrate lithium hydroxide (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 1M aqueous potassium acid sulfate (60 μL, 2.0 equiv), and concentrated to give the crude acid which was used immediately without purification. The crude acid was dissolved in dimethylformamide (0.4 mL), cooled to 0 ° C, and treated sequentially with methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), diisopropylethylamine (12 μL, 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 14.5 mg (76%, 2 steps). Y-NMR (CDC13, 500 MHz) d 1.28-1.48 (, 10H), 1.52 (m, 2H), 1.60-1.82 (m, 6H), 1. 95 (m, 1.4H), 2.06 (m, 1.6H), 2.20-2.50 (m 5H), 2.77-2.93 (m, 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 (m, 2H), 4.26 ( s, 2H), 4.57 (m, 2H), 5.10-5.24 (m, 1H), 5.67 (d, J = 8.2, 0.6H), 5.74 (d, J = 7.9, 0.4H), 6.67 (d, J = 7.9, 1H), 5.67 (d, J = 8.2, 0. 6H), 5.74 (d, J = 7.9, 0.4H), 6.67 (d, J = 7.9, 1H), 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 (m, 1.6H), 7.15 (d, J = 7.0, 6.7 , 1H), 7.31 (s, 0.4H), 7.38 (s, 0.6H), 7.94 (s, 0.4H), 7.95 (s, 0.6H).

Mass spectrum: 641.50 (MH) +. (3, 4-Dinitro-phenyl) -methanol The borane-tetrahydrofuran complex (1M in tetrahydrofuran, 800 mL, 800 mmol) was added at -20 ° C for 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 h and then warmed to room temperature and stirred overnight. This was quenched by the addition of 32 mL of 1: 1 acetic acid / water. The solvents were removed in vacuo and the residue was vacuum-cooled in ice with 1000 L of saturated sodium bicarbonate with vigorous stirring for 15 min. The mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. After filtration, the solvents were removed to provide the title compound as a light yellow solid (100%). Y-NMR (CDC13, 500 MHz) d 7.91 (d, J = 8.0 Hz, 1H), 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 A solution of (3,4-dinitro-phenyl) -methanol (95.3 g, 481 mmol) in methylene chloride (500 mL) was all added once to a suspension of pyridinium chlorochromate (156 g, 722 mmol) in chloride of methylene (900 mL). The mixture was stirred at room temperature for 1.5 h and then ether was added (1500 mL). The supernatant was decanted from the resulting white gum, and the insoluble residue was washed thoroughly with methylene chloride (3 x 250 L). The combined organic solution was filtered through a florisil pad to provide a light bright yellow light solution. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel using methylene chloride as eluent to give the title compound as a yellow solid. Y-NMR (CDC13, 300 MHz) d 8.45 (d, J = 1.5 Hz, 1H), 8.28 (dd, J = 8.1, 1H), 8. 07 (d, J = 8.1 Hz, 1H). 13CRMN (CD3OD, 125 MHz) d 187.7, 139.2, 134.2, 126.2, 125.7.

Methyl ester of 2-benzyloxycarbonylamino-3- (3,4-dnitro-phenyl) -acrylic acid 1, 1, 3, 3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N- (benzyloxycarbonyl) -alpha-phosphonoglycine trimethyl ester (114.1 g, 344 mmol) in tetrahydrofuran (800 mL). ). The mixture was stirred at room temperature for 15 min and cooled to -78 ° C. A solution of 3,4-dinitro-benzaldehyde was slowly added (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) by means of a cannula. The resulting mixture was stirred at -78 ° C for 2 h and then allowed to warm to room temperature overnight. The 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 1N sulfuric acid, water 2 times, brine and dried over sodium sulfate. After filtration, the solvents were removed in vacuo and the residue was crystallized from ethyl acetate (20 g crude product / 100 mL 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 as yellow crystals (77%). Y-NMR (CDCl 3, 500 MHz) d 7.85 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.5, 1.5 Hz, 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).

Prepared similarly: Methyl ester of 2-benzyloxycarbonylamino-3- (3-hydroxy-4-nitro-phenyl) -acrylic acid Jí A NHGte Y-NMR (CDCI3, 500 MHz) d 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).

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (3,4-dinitrophenyl) -propionic acid Oven-drying in a 500 mL Shlenck flask was placed in a glove bag filled with nitrogen. After the glove bag was evacuated and filled with nitrogen (3x), the flask was sealed and taken from the glove bag and weighed. This was returned to the glove bag and evacuated and filled with nitrogen (3x), then this was charged with (-) - 1, 2-bis ((2R, 5R) -2,5-diethylphospholane) benzene trifluoromethanesulfonate. (cyclooctadienene) rhodium (I). The flask was sealed and taken from the glove bag and weighed (784 mg, 1.08 mmol). Methyl ester of 2-benzyloxycarbonylamino-3- (3,4-dinitrophenyl) -acrylic acid (8.72 g, 21.7 mmol) was added to another 500 mL Schlenck flask and evacuated and filled with nitrogen (3x). Methylene chloride (350 mL, degassed with nitrogen for 2 h) was added and the resulting solution transferred to the catalyst flask or through a 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 chromatography on silica gel using ethyl acetate / hexanes (1: 1) as eluent to give the title compound as a light brown gummy solid (99% yield and 99.2% determined by HPLC analysis using the following conditions: Chiralpak AD column (4.6 x 250 mm, 10 μm, A = ethanol, B = hexane, 40% B @ 1.0 mL / min for 14 min, retention time: 10.9 min for the R enantiomer and 6.9 min for the S-enantiomer). 1 H-NMR (CDC 13.500 MHz) d 7.80 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H ), 7.38-7.31 (m, 5H), 5.37 (d, J = 6.0 Hz, 1H), 5.13-5.05 (m, 2H), 4.68 (d, J = 6.0 Hz, 1H), 3.71 (s, 3H9, 3.36 (dd, J = 13.5, 5.0 Hz, 1H), 3.17 (dd, J = 13.5, 5.6 Hz, 1H).

Prepared similarly: (R) -2-benzyloxycarbonylamino-3- (3-hydroxy-4-nitro-phenyl) -propionic acid methyl ester Y-NMR (CDC13, MHz) d 7.97 (d, J = 9.0 Hz, 1H), 7.36-7.30 (m, 5H), 6.90 (s, 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, 1H), 3.74 (s, 3H), 3.20 (dd, j = 13.5, 5.0 Hz, 1H), 3.05 (dd, J = 13.5, 6.0 Hz, 1H). Methyl ester of (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid Solid ammonium formate (2.27 g, 36 mmol) was added in small portions at 0 ° C to a suspension of methanol (50 mL, degassed with nitrogen for 2 h) of methyl ester of (R) -2-benzyloxycarbonylamino- 3- (3,4-dinitrophenyl) -propionic acid (1.45 g, 3.6 mmol) and zinc powder (1.41 g, 21.6 mmol). The resulting mixture was stirred at room temperature overnight. The solvents were removed in vacuo and then toluene (30 mL, degassed) and ethyl acetate were added. (30 mL, degassed), followed by acetic acid (3 mL). The mixture was further diluted until all the organic solids were dissolved, then this was washed with water, brine and dried over sodium sulfate. After filtration, the solvents were removed in vacuo to provide the title compound containing 1 equivalent of acetic acid as a reddish gummy solid (85%). Mass spectrum: 344.18 (MH) +.

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (2-methyl-lH-benzoimidazol-5-yl) -propionic acid methyl ester A solution of acetic acid methyl ester of acid (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic (640 mg) in acetic acid (8 mL) were heated at 130 ° C for 4 h. The mixture was then poured into water and cooled to 0 ° C. The pH 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, the solvents were removed to provide the title compound as a brown foamy solid (95%). Y-NMR (CDC13, 500 MHz) d 7.39 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.26-7.22 (m, 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 spectrum: 368.19 (MH) +.

Methyl ester of (R) -2-benzyloxycarbonylamino-3- [2-methyl-3- (2-trimethylsilanyl-ethansulfonyl) -3H-benzoimidazol-5-yl] -propionic acid ester and methyl ester of the acid (R) -2-Benzyloxycarbonylamino-3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -lH-benzoimidazol-5-yl] -propionic acid To a suspension of acid methyl ester (R) -2-Benzyloxycarbonylamino-3- (2-methyl-1H-benzoimidazol-5-yl) -propionic acid (533 mg, 1.96 mmol), and sodium carbonate in acetonitrile (20 mL) was added 2-trimethyl chloride pure silanyl-ethanesulfonyl all at once. The mixture was stirred at room temperature overnight. The solvents were removed and the residue purified by chromatography on silica gel using ethyl acetate / hexanes (1: 2) as eluent to give the title compound as a waxy solid (1: 1 mixture of NI and isomers).

N368%). aH-NMR (CDC13, 500 MHz) d 7.68 (d, J = 8.5 hz, 0.5H), 7.55 (d, J = 8.5 Hz, 0.5H), 7.53 (s, 0.5H), 7.41 (s, 0.5H) ), 7.34-7.29 (m, 5H), 7.06-7.04 (m, 1H), 5.22 (d, J = 8.0 Hz, 0.5H), 5.17 (d, J = 7.5 Hz, 0.5H), 5.11-5.07 ( m, 2H), 4.72-4.69 (m, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.24-3.17 (m, 2H), 2.79 (s, 3H), 0.92-0.83 ( m, 2H), -0.02 (s, 4.5H), -0.05 (s, 4.5H). Mass spectrum: 532.26 (MH) +.

Methyl ester of (R) -2-amino-3- [2-methyl-1- (2-trimethyl-silane-ethanesulfonyl) -lH-benzoimidazol-5-yl] -propionic acid ester and methyl ester of (R) acid -2-Amino-3- [2-methyl-3- (2-Trimethyl-sil indyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -propionic acid A suspension of methanol (50 mL) of methyl ester of (R) -2-benzyloxycarbonylamino-3- [2-methyl-3- (2-trimethylsilanyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -propionic acid methyl ester and methyl ester of (R) -2-benzyloxycarbonylamino-3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -lH-benzoimidazol-5-yl] -propionic acid (mixture 1: 1, 600 mg), and 10% palladium in mineral coal (180 mg) was stirred in a Parr apparatus overnight under 40 psi (2812 kg / cm 2) of hydrogen at room temperature. After replacing the hydrogen atmosphere with nitrogen, the mixture was filtered through a pad of celite. The solvents were removed in vacuo to provide the title compound as a brown solid (80%). 1 H-NMR (CD 3 OD, 500 MHz) d 7.81 (d, J = 8.5, 0.5 Hz, 0.5 H), 7.70 (s, 0.5 H), 7.58 (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, 1.5H), 3.72 (s, 1.5H), 3.55-3.51 ( m, 2H), 3.18 (d, J = 6.0 Hz, 1H), 3.22-3.18 (m, 0.5H), 3.14-3.09 (m, 0.5H), 2.81 (s, 1.5H), 2.80 (s, 1.5 H), 0.92-0.88 (m, 2H), 0.02 (s, 4.5H), 0.01 (s, 4.5H); 13CRMN (CD3OD, 125 MHz) d 174.3, 174.1, 153.5, 153.3, 141.7, 140.6, 133.9, 133.82, 133.78, 132.7, 126.5, 126.3, 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 spectrum: 398.20 (MH) +.

Methyl ester of (R) -3- [-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -lH-benzoimidazol-5-yl] -2- acid methyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic and methyl ester of (R) -3- [2-Methyl-3- (2-trimethylsilanyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for methyl ester of (R) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid. Purified by chromatography on silica gel using ethyl acetate with 1% triethylamine as eluent to give the title compound as a completely white solid (87%). Y-NMR (CD3OD, 500 MHz) d 7.82 (d, J = 8.5 Hz, 0.5H), 7.80 (s, 0.5H), 7.59 (d, J = 8.0 Hz, 0.5H), 7.55 (s, 0.5H) ), 7.33-7.30 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.79 (d , J = 7.5 Hz, 1H), 4.60-4.55 1H), 4.45-4.40 (, 1H), 4.29-4.27 (m, 2H), 4.15-4.10 (m, 2H), 3.77 (s, 1.5H), 3.74 (s, 1.5H), 3.56-3.51 (m, 2H), 3.35-3.31 (m, 2H), 3.21-3.15 (m, 1H), 2.91-2.80 (m, 2H), 2.78 (s, 1.5H), 2.77 (s, 1.5H), 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). 13CRMN (CD3OD, 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, 119.6, 118.8, 118.4, 114.0, 113.4, 113.2, 57.3, 56.3, 56.2, 51.2, 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 spectrum: 655.36 (MH) +.

(R) -3- (2-Methyl-lH-benzoimidazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic The 1: 1 mixture of (R) -3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -lH-benzoimidazol-5-yl] -2- methyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic acid and methyl ester of (R) -3- [2-methyl-3- (2-trimethylsilanyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic was treated as described above for (R) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid. Hydrolysis conditions (lithium hydroxide / tetrahydrofuran-methanol-water (1: 1: 1) at -15 ° C overnight were used The title compound was obtained as a white solid (25%). : 477.24 (MH) +.

Example 46 [2- [1,4 '] Bipiperidinyl-l' -yl- (2-methyl-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2 -oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above for. { 2- [1,4 '] bipiperidinyl-l' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amide. Purified by chromatography on silica gel 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 sodium bicarbonate / brine 2 times and dried over sodium sulfate. After filtration, the solvents were removed to provide the title compound as a white solid (11% yield). LCMS: tR = 1.59 min, 627.34 (MH) +.

Methyl ester hydrochloride of (R) -3- (4-amino-3-hydroxy-phenyl) -2-benzyloxycarbonylamino-propionic acid Iron powder (3.7 g, 66.4 mmol) and ammonium chloride (5.9 g, 111 mmol) were added at 0 ° C to a solution of (R) -2-benzyloxycarbonylamino-3- (3-hydroxy) methyl ester. -4-nitro-phenyl) -propionic (2.07 g, 5.53 mmol) in degassed methanol: 1: water (400 mL). The resulting mixture was stirred at room temperature for 48 h. Trifluoroacetic acid (7 L) was added, and the mixture was stirred until a clear dark red solution containing a suspension of unreacted iron powder was obtained. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 x 150 L)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. The solvents were removed in vacuo, and the title compound was obtained as a brown foamy solid (80%). Y-NMR (CD3OD, 500 MHz) d 7.34-7.28 (m, 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 (, 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, 1H), 2.90 (dd, J = 13.5, 9.0 Hz, 1H). 13CRMN (CD3OD, 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 spectrum: 345.20 (MH) +.

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid A solution of methylene chloride (15 mL) of carbonyl diimidazole (498 mg, 3.07 mmol) was added at 0 ° C to a solution of methyl ester of (R) -3- (4-amino-3-hydroxy) acid. phenyl) -2-benzyloxycarbonylamino-propionic acid (1.17 g, 3.07 mmol), diisopropylethylamine (1.60 mL, 9.21 mmol), and methylene chloride (85 mL). The mixture was stirred at 0 ° C for 4 h. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate / hexanes as eluent to give the title compound as a white solid (51%). Y-NMR (CDC13, 500 MHz) d 9.07 (s, 1H), 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 = 12.5 Hz, 1H), 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). 13CRMN (CDC13, 125 MHz) d 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 spectrum: 371.18 (MH) +.

Methyl ester of (R) -2-Amino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester 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 methanol (20 ml, freshly prepared in degassed methanol) was added by means of a cannula to a palladium suspension in 10% 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 1 filtration through a pad of celite, the solvents were removed in vacuo to give a brown solid. The solid was dissolved in a mixture of ethyl acetate (50 mL), toluene (10 L) and ethanol (40 mL), and solid sodium bicarbonate (3.1 g) was added. The mixture was stirred at room temperature for 2 h and filtered. The solvents were removed in vacuo to provide the title compound. XH-NMR (CD3OD, 500 MHz) d 8.41 (br s, 2H), 7.17 (s, 1H), 7.09 (br s, 2H), 4.32 (s, 1H), 3.83 (s, 3H), 3.33 (s) , 1H), 3.30 (s, 1H), 3.22 (s, 1H). Mass spectrum: 237.20 (MH) +.

Methyl ester of (R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- [. { 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} ? ropionic Prepared as described above for methyl ester of (R) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic acid. Purified by chromatography on silica gel using methylene chloride: methanol: triethylamine (93: 5: 2) as eluent to give the title compound as a white solid (33%). "? -NRM (CD3OD, 500 MHz) d 7.17-7.13 (m, 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, 1H), 4.55-4.51 (, 1H), 4.44-4.41 (m, 1H), 4.33 (s, 2H), 4.14-4.10 (, 2H), 3.74 (s, 3H), 3.33 (br s, 2H), 3.23 (dd, j = 13.7, 5.2 Hz, 1H), 3.03 (dd, J = 14.0, 9.7 Hz, 1H), 2.92-2.82 (m, 2H) ), 1.79-1.63 (m, 4H). 13CRMN (CD3OD, 125 MHz) 173.8, 158.2, 156.2, 155.6, 144.4, 137.1, 132.7, 129.3, 128.2, 125.7, 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 spectrum: 494.30 (MH) +.

(R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4 (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for (R) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl} -Not me} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid. Hydrolysis conditions (lithium hydroxide / methanol-tetrahydrofuran-water (1: 1: 1) at -15 ° C overnight were used The title compound was obtained as a white solid (95%). : 480.30 (MH) +.

EXAMPLE 47 [2- [1,4 '] Bipiperidinyl-1'-yl-2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of the acid (R ) -4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above for. { 2- [1,4 '] - bipiperidinyl-1' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid. The crude product was purified by chromatography on silica gel 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 saturated sodium bicarbonate 1: 1 / brine 2 times and dried over sodium sulfate. After filtration, the solvents were removed to provide the title compound as a white solid (70%). Y-NMR (CD3OD, 500 MHz) d 7.20-7.14 (m, 4H), 7.08 (d, J = 9.0 Hz, 1H), 6.96 (td, J = 7.5, 1.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.99-4.94 (m, 1H), 4.61-4.58 (m, 1H), 4.47-4.43 (m, 1H), 4.39 (s, 1H), 4.23-4.16 (m, 2H), 4.08-4.04 (m, 1H), 3.06-2.88 (m, 5H), 2.74-2.69 (m, 2H), 2.59-2.52 (m, 2H), 2.41-2.33 (m, 2H), 1.96-1.89 (m , 1H), 1.88-1.47 (m, 16H). LCMS: tR = 1.86 min, 630.31 (MH) +.

Methyl ester of (R) -3- (lH-benzotriazol-5-yl) -2-benzyloxycarbonylamino-propionic acid To a solution of methyl ester mono-acetate (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid (2.68 g, 6.65 mmol) in acetic acid (30 L) and water ( 40 mL), at room temperature a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL) was added dropwise over several minutes. The resulting mixture was stirred at room temperature for 20 min, then cooled to 0 ° C, concentrated ammonium hydroxide was added to adjust the pH to 11. The mixture was extracted with ethyl acetate 2 times in the presence of solid sodium chloride and the organic layers were dried over sodium sulfate. After filtration, the solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate / hexanes (6: 4) as eluent to give the title compound as a brown solid (94% yield) ). Y-NMR (CD3OD, 500 MHz) d 7.75 (d, J = 8.5 Hz, 1H), 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, 1H), 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), 13CRMN (CD3OD, 125 MHz) d 172.1, 156.0, 136.1, 128.6 , 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spectrum 355.18 (MH) +.

Methyl ester of (R) -2-amino-3- (lH-benzotriazol-5-yl) -propionic acid Prepared as described by the methyl ester of (R) -2-amino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid. Y-NMR (CD3OD, 500 MHz) d 8.38 (br s, 2 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.81 (s, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 4.44 (s, 1H), 3.81 (s, 3H), 3.48-3.45 (m, 1H), 3.40-3.37 (m, 1H), 3.33 (br s, 1H). 13 C NMR (CD3OD, 125 MHz) d 169.8, 139.4, 138.9, 133.0, 127.6, 115.52, 115.47, 54.3, 52.6, 36.7. Mass spectrum 221.15 (MH) +. Example 48 Methyl ester of (R) -3- (lH-Benzotriazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described by the methyl ester of (R) -2- acid. { [4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -pi? Eridin-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -propionic except that the carbonyl diimidazole was used in place of N, N-disuccinimidyl carbonate (DSC). Y-NMR (CD3OD, 300 MHz) d 7.82 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.39 (dd, J = 8.7, 1.2 Hz, 1H), 7.15-7.08 (, 2H) , 6.94 (td, J = 7.5, 0.9 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 4.67-4.60 (, 1H), 4.39-4.31 (, 1H), 4.15 (s, 2H), 4.08-4.03 (, 2H), 3.72 (s, 3H), 3.38 (dd, J = 13.9, 5.5 Hz, 1H), 3.32-3.29 (m, 1H), 3.17 (dd, J = 13.9, 10.3 Hz, 1H ), 2.87-2.71 (m, 2H), 1.64-1.48 (m, 4H). Mass spectrum 478.30 (MH) +.

Example 49 [l- (lH-benzotriazol-5-ylmethyl) -2- [1, 4 '] bipiperidinyl-1-yl-2-oxo-ethyl] -amide of (R) -4- (2-oxo) acid -l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described by. { 2- [1, 4 '] bipiperidinyl-1' -yl-2-oxo-l- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amido of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid. Purified by chromatography on silica gel using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent. "" "H-NMR (CD3OD, 500 MHz) d 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, 2H), 6.96-6.91 (m, 1H), 6.78 (d, J = 8.0 Hz, 0.75H), 6.77 (d , J = 8.0 Hz, 0.25H), 5.07-5.03 (m, 1H), 4.58-4.55 (m, 1H), 4.45-4.40 (, 1H), 4.34 (s, 1.25H), 4.24 (s, 0.75H) ), 4.20-4.05 (m, 2.25H), 4.00-3.96 (m, 0.75H), 3.24-3.09 (m, 2H), 2.91-2.78 (m, 4H), 2.64-2.61 (m, 2H), 2.56 -2.42 (m, 2H), 2.15-2.10 (m, 1.25H), 2.02-1.98 (m, 1.75H), 1.95-1.90 (m, 1H), 1.68-1.60 (m, 8H), 1.54-1.46 ( m, 6H) LC / MS: tR = 1.86 min, 614.28 (MH) +.

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-lH-indazol-5-yl) -propionic acid methyl ester PyHBr3 (1.28 g, 4.02 mmol) was added in small portions over 30 minutes to a solution of (R) -2-benzyloxycarbonylamino-3- (1H-indol-5-yl) -propionic acid methyl ester (0.47 g). , 1.34 mmol) in t-butanol (10 mL) while the reaction temperature was maintained between 25-30 ° C. The resulting mixture was stirred at room temperature 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, the solvents were removed and the residue dried azeotropically with anhydrous ethanol. The residue was dissolved in glacial 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 provide the title compound. title as a white solid (41% during 2 stages). Y-NMR (CDC13, 500 MHz) d 8.03 (s, 1H), 7.36-7.31 (m, 5H), 6.94 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 5.26 (d, J = 8.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.05 (d, j = 12.5 Hz, 1H), 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, 1H), 3.00 (dd, J = 14.0, 6.0 Hz, 1H). 1C NMR (CDC13, 125 MHz) d 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, 36. Mass spectrum 369.20 ( MH) +. Methyl ester of (R) -2-amino-3- (2-oxo-2,3-dihydro-l-indol-5-yl) -propionic acid methyl ester Prepared as described by (R) -2-amino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester. Y-NMR (CD3OD, 500 MHz) d 8.48 (br s, 2H), 7.16 (s, 1H), 7.10 (s, 1H), 6.89 (s, 1H), 4.21 (s, 1H), 3.81 (s, 3H), 3.54 (s, 1H), 3.33 (s, 2H), 3.20 (s, 1H), 3.12 (s, 1H). 13 C NMR (CD3OD, 125 MHz) d 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 spectrum 235.30 (MH) +.

Methyl ester of (R) -3- (2-oxo-2,3-dihydro-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A solution of phosgene in toluene (2M, 0.158 mL, 0.30 mmol) was added to a vigorously stirred mixture of methyl ester of propionic acid (70 mg, 0.25 mmol) in methylene chloride (15 L) and saturated sodium bicarbonate ( 7.5 L). After the mixture was stirred at room temperature for 30 minutes, 3-piperidin-4-yl-3,4-dihydro-lH-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 which was saturated with solid sodium chloride. The organic layer was dried over sodium sulfate. After filtration, the solvents were removed to provide the title compound as a brown, viscous oil. LCMS: tR = 2.01 min, 492.10 (MH) +.

Example 50 [2- [1,4 '] Bipiperidinyl-1'-yl-2-oxo-l- (2-oxo-2,3-dihydro-lH-indol-5-ylmethyl) -ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described by him. { 2- [1,4 '] bipiperidinyl-1' -yl-2-oxo-l- [1- (2-trimethylsilyl-ethanesulfonyl) -lH-indazol-5-ylmethyl] -ethyl} -amido of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid. Purified by flash chromatography on silica gel using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent. 1 H-NMR (CD 3 OD, 500 MHz) d 7.20-7.09 (m, 4 H), 6.97 (t, J = 7.3 Hz, 1 H), 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 (m, 0.65 H), 4.92-4.88 (, 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 (m, 2H), 4.05 -4.02 (m, 1H), 3.65-3.61 (m, 2H), 3.52-3.47 (m, 1H), 3.20-3.16 (, 1H), 3.00-2.88 (m, 2H), 2.70-2.64 (m, 2H) ), 2.53-2.46 (m, 2H), 2.40-2.34 (m, 2H), 1.94-1.46 (m, 15H), 1.39-1.36 (m, 2H). LC / MS: tR = 1.83 min, 628.40 (MH) +.

Methyl ester of 2- (di-tert-butoxycarbonylamino) -acrylic acid 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) were added. added 4-dimethylaminopyridine (0.48 g, 0.1 equiv) at room temperature. The solution was stirred overnight and concentrated. The residue was dissolved in diethyl ether, washed sequentially with 1M potassium hydrogen sulfate (2x), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give 15.6 g (quant.) As a oil. The NMR inspection showed a mixture of the title compound and 2- (di-tert-butoxycarbonylamino) -3-tert-butoxycarbonyloxy-propionic acid methyl ester. As this was found to last that both were reacted with secondary amines to give the same products, the mixture was used without separation. Methyl ester of 2- (di-tert-butoxycarbonylamino) -acrylic acid: aH-NMR (CDC13) d 1.45 (s, 18H), 3.78 (s, 3H), 5.63 (s, 1H), 6.33 (s, 1H) ). Mass spectrum: 324.14 (M + Na) +. 2- (Di-tert-butoxycarbonylamino) -3-tert-butoxycarbonyloxy-propionic acid methyl ester. ^ H-NMR (CDC13, 500 MHz) d 1.46 (s, 9H), 1.49 (s, 18H), 3.72 (s, 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 spectrum: 442.21 (M + Na) +. Methyl ester of (±) -3- (4-benzyloxy-2-oxo-2H-pyridin-1-yl) -2- (di-tert-butoxycarbonylamino) -propionic acid methyl ester To a solution of 2- (di-tert-butoxycarbonylamino) -acrylic acid methyl ester (900 mg, 3.0 mmol), and (630 mg, 1.03 equiv) in acetonitrile (2.5 mL) cesium carbonate (100 mg) was added. , 0.10 equiv). The resulting suspension was heated at 80 ° C in a 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 further purification. Mass spectrum: 503.56 (MH) +. (±) -4-benzyloxy-l- [3- [1,4 '] bipiperidinyl-1' -yl-2- (di-tert-butoxycarbonylamino) -3-oxo-propyl] -IH-pyridine-one To a stirred solution of 3- (4-benzyloxy-2-oxo-2H-pyridin-1-yl) -2- (di-tert-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 eguiv) in water (2.85 mL). The reaction mixture was stirred for 3 h at room temperature, cooled to treat with concentrated hydrochloric acid (0.99 mL), and concentrated to provide the crude acid, half of which was taken in the next step. The crude acid was dissolved in methylene chloride (6 mL), cooled to 0 C and treated sequentially with 4-piperidyl-piperidine (0.25 g, equiv), triethylamine (0.31 mL, 2.5 equiv), and bis-2-chloride. -oxo-3-oxazolidinyl) phosphinic (0.38 g, equiv). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated, and purified by preparative HPLC to give 489 mg (52%, 2 steps). Mass spectrum: 639.41 (MH) +.

Example 51 [1- (4-benzyloxy-2-oxo-2H-pyridin-1-ylmethyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide of the acid (+ ) -4- (2-oxo-l, 4-dihydro-2-H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a stirred solution of 4-benzyloxy-1- [3- [1,4 '] bipiperidinyl-1-yl-2- (di-tert-butoxycarbonylamino) -3-oxo-propyl] -lH-pyridin-2 NaOH in methylene chloride (3 mL) was added trifluoroacetic acid (1 mL) at 0 ° C. After 2 h, the reaction was concentrated to give the crude amine (151 mg, 97%) to this trifluoroacetic acid salt [Mass spectrum: 439.61 (MH) +] which was divided into two portions, using half in The following procedure. To a solution of the crude amine (75 mg, 0.11 mmol) and diisopropylethylamine (80 μl, 4 equiv.) In methylene chloride (3 mL) at 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-lH-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 preparative CDD to give 40.8 mg (53%). Y-NMR (CD3OD, 500 MHz) d 1.25-1.56 (, 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, 4.8, 1H), 6.05 (dd, 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 = 7.6, 1H), 7.12 (dd, J = 7.6, 7.4, 1H) ), 7.28-7.43 (m, 5H), 7.48 (d, J = 7.6, 1H). Mass spectrum: 696.85 (MH) +.

Example 52 [2- [1, 4 '] bipiperidinyl-l' -yl-1- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -2-oxo-ethyl] -amide of the acid (+ ) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A stirred solution of [1- (4-benzyloxy-2-oxo-2H-pyridin-1-ylmethyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide of the acid 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (29 mg) and 10% palladium in mineral carbon (5 mg) in methanol (1 L) was placed under an atmosphere of hydrogen. After 1 h at room temperature, the reaction was wetted with nitrogen, filtered through celite, and concentrated to give the product. Y-NMR (CD30D, 500 MHz) d 1.40-1.85 (m, 12H), 2.04 (dd, 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, 1H), 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 spectrum: 606.32 (MH) +.

Methyl ester of (±) -2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidin-1-yl) -propionic acid To a solution of 2- (di-tert-butoxycarbonylamino) -acrylic acid methyl ester (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 during the reaction while it was 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 further purification. . Mass spectrum: 403.42 (MH) +. (±) -1- [1, '] bipiperidinyl-l' -yl-2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidin-1-yl) -propane-1-one To a solution of 2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidin-1-yl) -propionic acid methyl ester (1.0 g, 2.5 mmol) in methanol (6 mL) was added a solution of monohydrate lithium hydroxide (400 mg, 3.9 equiv.) in water mL). The reaction was stirred 6 h, cooled to neutral 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 methanol to help dissolve the acid, and cooled to 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) phosphinic 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 preparative HPLC to give 310 mg (23%, 2 steps). Mass spectrum: 539.49 (MH) +. (+) -2-amino-1- [1,4 '] bipiperidinyl-1' -yl-3- (4-hydroxy-piperidinyl-1-yl) -propane-1-one 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 chloride (5 mL) at 0 ° C, trifluoroacetic acid (2.0 mL) was added. The ice bath was stirred and the reaction was stirred for 30 min. The reaction was concentrated to provide the product as this trifluoroacetic acid salt (400 mg, quant.) Which was used without further purification. Mass spectrum: 339.46 (MH) +.

Tert-butyl ester of (±) - [2- [1,4 '] bipiperidinyl-1' -yl-1- (4-hydroxy-piperidin-1-ylmethyl) -2-oxo-ethyl] -carbamic acid ester To a solution of 2-amino-l- [1,4 '] bipiperidinyl-1-yl-3- (4-hydroxy-piperidin-1-yl) -propan-1-one (trifluoroacetic acid salt, 300 mg , 0.58 mmol) and diisopropylethylamine (0.30 mL, 4 equiv) in tetrahydrofuran (5 L) was added di-tert-butyl-dicarbonate (128 mg, 1 equiv). The resulting solution was stirred at room temperature for 1 h, and concentrated. The residue was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to give up to 248 mg (98%) which was used without further purification. Mass spectrum: 439.65 (MH) +.

Tert-butyl ester of (±) - [2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-l- (4-oxo-piperidin-l-ylmethyl) -ethyl] -carbamic acid ester To a solution of 1- [1,4 '] bipiperidinyl-1' -yl-2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidin-1-yl) -propan-1-one (200 mg, 0.37 mmol) in methylene chloride (4 L) was added Dess-Martin periodinane (316 mg, 2 equiv) in two portions. After 1 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 further purification. Mass spectrum: 437.63 (MH) +. (±) -1- (2-amino-3- [1,4 '] bipiperidinyl-1' -yl-3-oxo-propyl] piperidin -one To a solution of [2- [1,4 '] bipiperidinyl-l-yl-2-oxo-l- (4-oxo-piperidin-1-methylmethyl) -ethyl] -carbamic acid tert-butyl ester ( 100 mg, 0.23 mmol) in methylene chloride (5 mL) at 0 ° C, trifluoroacetic acid was added. The ice bath was stirred, stirred continuously for 1 h, and the reaction was concentrated to give 150 mg (96%) as this trifluoroacetic acid salt, which was used without further purification. Mass spectrum: 337.64 (MH) +.

Example 53 [2- [1,4 '] Bipiperidinyl-1' -yl-1- (4-hydroxy-piperidin-1-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2) acid -oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of 4- (2-oxo) [2- [1,4 '] bipiperidinyl-1' -yl-1- (4-hydroxy-piperidin-1-ylmethyl) -2-oxo-ethyl] -amide. -l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (trifluoroacetic acid salt, 200 mg, 0.39 mmol) in methylene chloride (5 mL) at 0 ° C, diisopropylethylamine was added (0.27 L, 3.9 equiv), and carbonyl diimidazole (63 mg, equiv). After stirring for 15 min, the solution was treated with 3-piperidin-4-yl-3,4-dihydro-lH-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 preparative CCD to give 130 mg (56%) as an oil. LCMS: tR = 1.17 min, 596.44 (MH) +. 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester The tert-butyl ester of 4-oxo-piperidin-1-carboxylic acid (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 spectrum: 255.16 (MH) +. 1,, 6, 7-tetrahydro-pyrazolo [4, 3-c] pyridine-5-carboxylic acid tert-butyl ester To a solution of tert-butyl ester of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 L, 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 used without further purification. Mass spectrum: 224.11 (MH) +. 4,5,6, 7-Tetrahydro-lH-pyrazolo [4, 3-c] pyridine The 1,4,6,7-Tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester (0.70 g, 3.1 mmol) was dissolved in trifluoroacetic acid (10 mL) at 0 °. C, was stirred for 1 h, and concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-chlorohydrate salt was precipitated as a white solid which was filtered to give 510 mg (83%). The free base was prepared as necessary by dissolving the salt in water, loading onto an SCX column, wetting with methanol, and then eluting with 2M ammonia in methanol.

Methyl ester of (±) -2- (di-tert-butoxycarbonylamino) -3- (1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -propionic acid To a solution of 4, 5, 6, 7-tetrahydro-lH-pyrazolo [4, 3-cjpyridine (160 mg) in 2.5 mL of 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, washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was pure enough to be used without purification. Y. NMR (CDC13, 500 MHz) d 1.44 (s, 9H), 2.73 (m, 3H), 2.91 (m, 1H), 3.06 (dd, J = 13.4, 8.6, 1H), 3.22 (dd, J = 13.4, 8.2, 1H), 3.54 (d, J = 13.4, 1H), 3.63 (d, J = 13.4, 1H), 3.71 (s, 3H), 5.11 (dd, J = 8.5, 5.2, 1H), 7.25 (s, 1H). Mass spectrum: 425.23 (MH) +.

Methyl ester of (±) -2-amino-3- (1, 4, 6, 7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-yl) -propionic acid 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, equiv.) in methylene chloride (5 mL, 0 ° C) was added trifluoroacetic acid (1.5 mL). The ice bath was stirred and stirred continuously for 2 h. The solution was concentrated, redissolved in methanol, and passed on a strong cation exchange resin column. After wetting with methanol, the product was removed from the column by elution with 2 M ammonium in methanol to provide the product as this free base (275 mg, 95%). Y-NMR (CDC13, 500 MHz) d 2.71 (dd, J = 12.8. 8. 6, 1H), 2.74-2.91 (m, 6H), 3.48 (s, 2H), 3.54 (d, J = 13.4, 1H), 3.62 (d, J = 13.4, 1H), 3.69 (dd, J = 8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spectrum: 225.16 (MH) +. 3, 3-dimethyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (16 g, 80 mmol) in tetrahydrofuran (400 mL) a sodium hydride (4.1 g, 2.1 equiv) was added 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 was stirred overnight. The reaction was concentrated, dissolved in diethyl ether, washed with brine, dried over magnesium sulfate, and concentrated. The product was crystallized from hot pentane (2X) to give 5.9 g (32%). Y-NMR (CDC13, 500 MHz) d 1.09 (s, 6H), 1.47 (s, 9H), 2.47 (dd, J = 6.4, 6.4, 2H), 3.41 (, 2H), 3.70 (m, 2H). Mass spectrum: 250.12 (M + Na) +. -dimethylaminomethylene-3, 3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester The tert-butyl ester of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid (5 g, 22 mmol) was dissolved in dimethyl formamide dimethylacetal (25 mL) and heated to reflux for 2 h. The reaction mixture was then heated at 130 ° C for 1 h by means of microwaves, and concentrated to give 6.43 g (quant.) As an oil which was used without purification. Y-NMR (CDC 13. 500 MHz) d 1.07 (s, 6H), 1.45 (s, 9H), 3.06 (s, 6H), 3.37 (m, 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 ester To a solution of tert-butyl ester of 5-dimethylaminomethylene-3, 3d-methyl-4-oxo-piperidine-1-carboxylic acid (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 overnight and concentrated to give 5.3 g (94%) which was used without further purification. Mass spectrum: 252.19 (MH) +. 7, 7-Dimethyl-4, 5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine To a solution of tert-butyl ester of 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridine-5-carboxylic acid (5.3 g, 21 mmol) in sodium chloride. methylene (10 L) at 0 ° C, trifluoroacetic acid (5 mL) was added. The reaction was allowed to warm to room temperature, stirred 15 minutes, and treated with additional trifluoroacetic acid (5 L). After 1 h, the reaction was concentrated, dissolved in ethanol (10 mL), cooled to treat with concentrated hydrochloric acid (3 mL), and concentrated. The resulting solid was triturated with ethanol, and filtered to give 3.02 g (64%) as this bis-chlorohydrate salt. The free base was prepared as necessary by dissolving the salt in water, loading onto an SCX column, wetting with methanol, and then eluting with 2M ammonia in methanol. -H-NMR (D20, 500 MHz) d 1.49 (s, 6H), 3.46 (s, 2H), 4.39 (s, 2H), 7.86 (s, 1H). Mass spectrum: 152.14 (MH) +.

Methyl ester of (±) -2- (di-tert-butoxycarbonylamino) -3- (7,7-dimethyl-l, 4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridine-5-) il) -propionic To a solution of 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (160 mg) in methanol (3 mL) was added methyl ester of 2-acid. (di-tert-butoxycarbonylamino) -acrylic (331 mg). A gentle stream of nitrogen was applied and the reaction was stirred overnight. In the morning, the volume was gradually reduced. The last traces of the solvent were removed under high vacuum to give 490mg (quant.) Which was used without purification. Y-NMR (CDC13, 500 MHz) d 1.24 (s, 3 H), 1.26 (s, 3 H), 1.38 (s, 18 H), 2.33 (d, J = 11.3, 1 H), 2.57 (d, J = 11.3, 1H), 3.09 (dd, J = 13.1, 5.5, 1H), 3.15 (dd, J = 13.4, 9.5, 1H), 3.35 (d, J = 12.8, 1H), 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 spectrum: 453.30 (MH) +.

Methyl ester of (±) -2-amino-3- (7,7-dimethyl-l, 4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-yl) -propionic acid To a solution of methyl ester of 2- (di-tert-butoxycarbonylamino) -3- (7,7-dimethyl-l, 4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-methyl) il) -propionic (0.49 g, equiv.) in methylene chloride (5 mL, 0 ° C) was added trifluoroacetic acid (1.5 mL). The ice bath was stirred and stirred continuously for 2 h. The solution was concentrated, redissolved in methanol, and loaded onto a strong cation exchange resin column. After wetting with methanol, the product was removed from the column by elution with 2M ammonium in methanol to provide the product as this free base (250 mg, 94%). Y-NMR (CDC13, 500 MHz), d 1.27 (s, 3H), 1.28 (s, 3H), 2.41 (d, J = 11.3, 1H), 2.50 (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, 1H). Mass spectrum: 253.16 (MH) +.

Methyl ester of acid (±) -2-. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- (1, 4, 6, 7-tetrahydro-pyrazolo [-4, 3-c] pyridin-5-yl) -propionic To a solution of methyl ester of 2-amino-3- (1,4,6,7-tetrahydro-pyrazolo [4, 3-c] iridin-5-yl) -propionic acid (260 mg, equiv.) In Methylene chloride (2 mL, 0 ° C) was added carbonyl diimidazole (188 mg, equiv).

After 15 minutes, 3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one (295 mg, 1.1 equiv) was added in one portion. The ice bath was stirred and stirred continuously overnight. The reaction was concentrated and purified by column chromatography to give 118 mg (21%). Y-NMR (CDC13, 500 MHz) d 1.60-1.80 (m, 4H), 2.70-3.05 (m, 8H), 3.45 (s, 2H), 3.56 (d, J = 13.4, 1H), 3.62 (d, J = 13.4, 1H ), 3.75 (s, 3H), 4.02 (d, J = 13.1, 1H), 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 spectrum: 482.27 (MH) +.

Example 54 [2- [1, 4 '] bipiperidinyl-1-yl-2-oxo-l- (1,4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-ylmethyl) - ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of 2- methyl ester. { [4- (2-oxo-l, 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 (16 mg, equiv) in methanol (0.6 mL) was added monohydrate lithium hydroxide (3 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 1 M potassium hydrogen sulfate (60 μl, 1.8 equiv), and concentrated to give the crude acid which was used immediately without purification. The crude acid was dissolved in (0.3 L) and treated sequentially with methylene chloride (0.15 mL), 4-piperidyl-piperidine (11 mg, 2 equiv), diisopropylethylamine (12 μl, 2 equiv), and PyBOP® (19 mg, 1.1 equiv). The solution was stirred 30 minutes and concentrated. The product was purified by column chromatography to give 17.6 mg (85%, 2 steps). Y-NMR (CDC1, 500 MHz) d 1.30-1.60 (m, 9H), 1.62-1.78 (m, 5H), 1.81 (bd, J = 11.0, 2H), 2.23-2.49 (m, 6H), 2.55- 3.10 (m, 11H), 3.59 (d, J = 7.3, 2H), 4.00-4.20 (m, 3H), 4.23 (s, 2H), 4.50 (m, 1H), 4.63 (m, 1H), 5.03 ( m, 1H), 5.71 (d, J = 7.3, 1H), 6.67 (d, J = 7.9, 1H), 6.91 (dd, J = 7.6, 7.3, 1H), 7.02 (dd, J = 7.9, 7.3, 1H), 7.14 (dd, J = 7.6, 7.6, 1H), 7.24 (s, 1H), 7.39 (s, 1H), 10.76 (bs, 1H). Mass spectrum: 618.34 (MH) +. EXAMPLE 55 Methyl ester of (+) - 3 - (7,7-Dimethyl-1,4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic To a solution of 2-amino-3- (7,7-dimethyl-l, 4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-yl) -propionic acid methyl ester (250 mg, equiv) in tetrahydrofuran (4 mL, diimidazole carbonyl (162 mg, 1 equiv.) After 5 min, the ice bath was stirred and the reaction was stirred at room temperature for 30 min. He added 3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one (250 mg, 1.1 equiv) in one portion, and the reaction was stirred overnight.The reaction was concentrated and purified by chromatography column to give 228 mg (45%) and NMR (CDC13, 500 MHz) d 1.30 (s, 3H), 1.31 (s, 3H), 1.60-1.80 (m, 4H), 2.43 (d, J = 11.6, 1H), 2.53 (d, JY1.3, 1H), 2.80-2.95 4H), 3.51 (dd, J = 20.4, 13.1, 2H), 3.74 (s, 3H), 4.00 (d, J = 13.7, 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, 1H), 7.24 (s, 1H). Mass spectrum: 510.27 (MH) +.

Example 56 [2- [1, '] Bipiperidinyl-1-yl-l- (7,7-dimethyl-l, 6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-ylmethyl) - (+) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid 2-oxo-ethyl] -amide To a solution of 3- (1,1-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridin-5-yl) -2- methyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (20 mg, 1.0 equiv) in methanol (0.6 L) was added lithium hydroxide monohydrate (4 mg, 2.2 equiv) in water (0.1 L) and stirred for 4 h at room temperature. The solution was cooled to 0 ° C, treated with aqueous 1M potassium hydrogen sulfate (75 μl, 1.8 equiv), and concentrated to give the crude acid which was used immediately without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and treated sequentially with methylene chloride (0.15 mL), 4-piperidyl-piperidine (13 mg, 2 equiv), diisopropylethylamine (14 μL, 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 contaminated with HOBT. The HOBT was removed by passing the product through a plug of basic alumina, eluting with 10% methanol in methylene chloride. The concentration gave 18.3 mg (72%, 2 stages). XH-NMR (CDC13, 500 MHz) d 1.25-1.32 (m, 6H), 1.40 (m, 4H), 1.54 (m, 5H), 1.65 (, 4H), 1.83 (m, 2H), 2.30-2.56 ( , 8H), 2.81 (m, 4H), 3.04 (dt, J = 57.1, 12.2, 1H), 3.43-3.60 (m, 2H), 4.00-4.17 (m, 2H), 4.18-4.26 (m, 3H) , 4.49 (m, 1H), 4.62 (, 1H), 5.03 (m, 1H), 5.80 (dd, J = 16.8, 9.8, 1H), 6.69 (d, J = 7.9, 6.90 (dd, J = 7.3, 7.3, 1H), 6.99 (dd, J = 7.6, 7.3, 1H), 7.13 (dd, J = 7.6, 7.6, 1H), 7.19 (s, 1H), 7.66 (bd, J = 12.8, Mass spectrum: 646.43 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (6-methoxy-pyridin-3-yl) -acrylic acid 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 trimethyl ester of N-benzyloxycarbonyl-a-phosphonoglycine (3.63 g, 1.5 equiv) in methylene chloride (15 mL). The resulting solution was stirred 5 min and treated with 6-methoxy-pyridine-3-carbaldehyde (1.0 g, 7.3 mmol) 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 emptied into a separatory funnel containing ethyl acetate and water. The brine was added to aid in the separation of the layers. The aqueous was extracted with ethyl acetate (3x) which was again washed with brine, dried over magnesium sulfate, and concentrated to give 2.63 g. (quantitative) which was used without purification. Mass spectrum: 343.08 (MH) +.

Methyl ester of (±) -2-amino-3- (6-methoxy-pyridin-3-yl) -propionic acid A flask containing 2-benzyloxycarbonylamino-3- (6-methoxy-pyridin-3-yl) -acrylic acid methyl ester (620 mg), palladium on charcoal (10%, 100 mg), ethyl acetate mL) and methanol (20 mL) was wetted with nitrogen, then hydrogen, before finally fixing a hydrogen balloon. The reaction was allowed to stir overnight. The flask was wetted with nitrogen, filtered through celite, and concentrated to give 390 mg (quantitative) which was used without purification. Mass spectrum: 211.11 (MH) +.

Methyl ester of (±) -3- (6-methoxy-pyridin-3-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic To a solution of methyl ester of 2-amino-3- (6-methoxy-pyridin-3-yl) -propionic acid (130 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, 0 ° C) N, N-disuccinimidyl carbonate (158 mg) was added. After 30 min, 3-piperidin-4-yl-3,4-dihydro-lH-quinazolin-2-one (120 mg) in methylene chloride (1 mL) was added via a cannula. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by preparative HPLC to give 160 mg (55%). Mass spectrum: 468.19 (MH) +.

Example 57 [2- [1, '] Bipiperidinyl-l' -yl-1- (6-methoxy-pyridin-3-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of methyl ester of 3- (6-methoxy-pyridin-3-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (160 mg) in methanol (6 L) 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 ° C. The reaction was treated with 1N 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), and bis-2-oxo-3-oxazolidinyl) phosphinic chloride ( 104 mg). The reaction was stirred overnight, concentrated, and purified by preparative HPLC to give 94 mg (45%). LCMS: Tr = 1.86 min., 604.51 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (2-methoxy-pyrimidin-5-yl) -acrylic acid To a suspension of potassium t-butoxide (1.23 g) in methylene chloride (70 mL, -30 ° C) was added a solution of N-benzyloxycarbonyl trimethyl ester (3.63 g) in methylene chloride (15 mL). ). The resulting solution was stirred 5 min and treated with 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 emptied into a separatory funnel containing ethyl acetate and water. The brine was added to aid in the separation of the layers. The aqueous was extracted with ethyl acetate (3X) which was again washed with brine, dried over magnesium sulfate, and concentrated. The crude product was recrystallized from hot methanol to give 1.4 g of pure material. Mass spectrum: 344.10 (MH) +.

Methyl ester of (±) -2-amino-3- (2-methoxy-pyridin-5-yl) -propionic acid A flask containing amino ester (700 mg), palladium on charcoal (10%, 100 mg) and methanol (20 mL) was wetted with nitrogen, then hydrogen, before finally fixing a hydrogen balloon. The reaction was allowed to stir overnight. The flask was wetted with nitrogen, filtered through celite, and concentrated to give 379 mg (88%) which was used without purification. Mass spectrum: 212.08 (MH) +.

Methyl ester of (+) - 3- (2-methoxy-pyrimidin-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic To a solution of methyl ester of 2-amino-3- (2-methoxy-pyrimidin-5-yl) -propionic acid (125 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 L, 0 ° C) N, N'-disuccinimidyl carbonate (155 mg) was added. After 30 min, 3-piperidin-4-yl-3,4-dihydro-lH-quinazolin-2-one (120 mg) in methylene chloride (2 mL) was added via a cannula. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by preparative HPLC to give 99 mg (36%). Mass spectrum: 469.10 (MH) +.

Example 58 [2- [1,4 '] Bipiperidinyl-1'-yl-1- (2-methoxy-pyrimidin-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2) acid -oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a solution of methyl ester of 3- (2-methoxy-pyrimidin-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (99 mg) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (18 mg) in water (1 L). The reaction was stirred at room temperature for 4 h and cooled to 0 ° C. The reaction was treated with 1N hydrochloric acid (0.4 mL), concentrated. The obtained residue was dissolved in methylene chloride (3 mL), and treated sequentially with 4-piperidyl-piperidine (50 mg), triethylamine (88 μL), and bis-2-oxo-3-oxazolidinyl) phosphinic chloride (71 mg). The reaction was stirred overnight, concentrated, and purified by preparative HPLC to give 103 mg (45%). LC / MS Tr = 1.23 min, 605.54 (MH) +. 2-Benzyloxy-5-bromo-pyridine A suspension of 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-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) was heated to reflux for 3 h in an apparatus equipped with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in 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 spectrum: 264.25 (MH) +. 6-Benzyloxy-pyridine-3-carbaldehyde 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 L, 2 equiv) was added and the mixture was stirred for 30 min. The reaction was rapidly emptied into a stirred solution of 5% aqueous sodium bicarbonate (50 mL) and extracted with diethyl ether (3x). The ether was washed with brine, dried over magnesium sulfate, and concentrated to give 1.16 g (quantitative) which was used without purification. Mass spectrum: 186.34 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -acrylic acid To a stirred suspension of potassium tert-butoxide (0.440 g, 1.7 equiv) in methylene chloride (25 mL) at -20 ° C was added trimethyl ester N-benzyloxycarbonyl-a-phosphonoglycine (1.3 g, 1.7 equiv) in methylene chloride (5 mL). The resulting solution was stirred for 5 min and treated with 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 warm gradually to 0 ° C, and emptied into a separatory funnel containing water and diethyl ether. The reaction was extracted with diethyl ether (2x), washed with brine, dried over magnesium sulfate, and concentrated to give 0.98 g (quantitative) as an oil which was used without purification. Mass spectrum: 419.32 (MH) +.

Methyl ester of (±) -2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -propionic acid A flask was charged with methyl ester of 2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -acrylic acid (0.50 g, 1.2 mmol), Wilkinson catalyst (200 mg, 0.2 equiv), methanol (5 mg). mL), and toluene (3 mL). The flask was wetted with nitrogen, then hydrogen, heated to 35 ° C, and allowed to stir under a hydrogen atmosphere for 4 days. The reaction was wetted with nitrogen, diluted with methanol, filtered, and concentrated to give the crude product which was purified by column chromatography to give 145 mg (29%).

Methyl ester of (±) -2-amino-3- (6-benzyloxy-pyridin-3-yl) -propionic acid 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, trimethylsilyl iodide was added. (44 μL, 1.0 equiv) The ice bath was stirred and stirred continuously for 1 h The reaction was emptied into saturated sodium bicarbonate, extracted with ethyl acetate (3x), washed with brine, dried over magnesium sulfate, and concentrated to give 81 mg (91%) which was used without purification Mass spectrum: 287.37 (MH) +.

Methyl ester of (±) -3- (6-benzyloxy-pyridin-3-yl) -2- acid. { [4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 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. added diimidazole carbonyl (34 mg, 1.0 equiv.). After 15 min, a solution of 3-piperidin-4-yl-3,4-dihydro-lH-quinazolin-2-one (58 mg, 1.2 equiv.) In methylene chloride (0.5 L) was added by a cannula The ice bath was stirred and stirring continued overnight. The reaction was concentrated and purified by column chromatography to give 59 mg (52%). Mass spectrum: 544.49 (MH) +.

Example 59 [1- (4) -4- (2- (6-Benzyloxy-pyridin-3-ylmethyl) -2- [1,4]] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid To a stirred solution of 3- (6-benzyloxy-pyridin-3-yl) -2- methyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic (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 the addition of 1 N hydrochloric acid (0.15 L), and concentrated. The crude product was used without purification. The crude acid was dissolved in methylene chloride (2 mL, 0 ° C) and treated sequentially with 4-piperidino-piperidine (34 mg, 1.8 equiv), triethylamine (35 μL, 2.3 equiv.), And bis-2-oxo-3-oxazolidinyl) phosphinic chloride (34 mg, 1.2 equiv). The ice bath was stirred and the reaction was allowed to stir overnight. The reaction was concentrated and purified by preparative CCD to give 30.3 mg (41%). LCMS: Tr = 1.49 min, 680.29 (MH) +.

Example 60 [2- [1, 4 '] Bipiperidinyl-1'-yl-2-oxo-l- (6-oxo-l, 6-dihydro-pyridin-3-ylmethyl) -ethyl] -amide of the acid (± ) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-l-carboxylic acid A flask was charged with 4- (2- (1- (6-benzyloxy-pyridin-3-ylmethyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide. oxo-1, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (27 mg, 0.04 mmol), palladium on charcoal (10%, 4 mg), and methanol (1 mL). The flask was wetted with nitrogen, then hydrogen, and allowed to stir under a hydrogen atmosphere overnight. The flask was wetted with nitrogen, and the reaction was filtered through celite to give 22.1 mg (94%). LCMS: Tr = 0.93 min, 590.32 (MH) +. 4-ethyl ester of piperidin-1,4-dicarboxylic acid 1-tert-butyl ester 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 ° C was slowly added a solution of di-tert-butyldicarbonate (7.2 g, 0.033 mol) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature overnight, then washed with potassium acid sulfate three times and with brine once. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product (8.23 g, 100%) as a colorless oil. 1 H NMR (C6D6, 500 MHz) d 3.88 (q, J = 7.5 Hz, 2H), 2.52 (, 1H), 1.60-1.48 (m, 8H), 1.42 (s, 9H), 0.92 (t, 3H). Mass spectrum: 280.44 (M + Na) +. 4-ethyl ester of 4- (2-nitro-benzyl) -piperidin-1,4-dicarboxylic acid 1-tert-butyl ester To a 4-ethyl ester solution of 1-tert-butyl ester of piperidin-1,4-dicarboxylic acid (8.23 g, 0.032 mol) in tetrahydrofuran (85 mL) was slowly added a solution of bis (trimethylsilyl) amide. sodium (44 mL, 0.044 mol). After the resulting mixture was 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 to room temperature and stirred overnight. This 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 in vacuo. The final product was purified from the complex reaction mixture by column chromatography on silica gel (eluent-hexanes-ethyl acetate 4: 1) to give the desired product (1.61 g, 13%) as an oil coffee. Mass spectrum: 415.38 (M + Na) +. 4-ethyl ester of 4- (2-amino-benzyl) -piperidin-1,4-dicarboxylic acid 1-tert-butyl ester A 4-ethyl ester mixture of 4- (2-nitro-benzyl) -piperidin-1,4-dicarboxylic acid 1-tert-butyl ester (1.61 g, 4.102 mmol) and palladium in 10% charcoal (0.10 g) in ethanol (190 L) was hydrogenated at 50 psi (3.515 Kg / cm2) overnight. The resulting mixture was filtered through a plug of celite, and the filtrate was concentrated under vacuum to provide the desired product (1.29 g, 99%) as a colorless oil. Mass spectrum: 363.45 (MH) +. 4- (2-Amino-benzyl) -piperidine-4-carboxylic acid ethyl ester hydrochloride To a 4-ethyl ester solution of the 4- (2-amino-benzyl) -piperidin-1,4-dicarboxylic acid 1-tert-butyl ester (1.29 g, 4.102 mmol) in dichloromethane (15 L) was added. added a 4.0 M solution of hydrogen chloride in dioxane (5 L). The resulting solution was stirred at room temperature overnight. Concentration of the solution under vacuum afforded the title compound (1.23 g, 100%) as a white solid, which was used in the next step without purification. Mass spectrum: 263.40 (MH) +. 3, 4-Benzo-2, 9-diazaspiro [5.5] undeca-1-one A solution of 4- (2-amino-benzyl) -piperidine-4-carboxylic acid ethyl ester chlorohydrate (1.23 g, 4.102 mmol) was dissolved in methanol and the resulting solution was stirred at room temperature overnight. The solution was diluted in half with water and passed through a short plug of the ion exchange resin hydroxide form AG® 1-X2 (100-200 mesh), eluting with 50% aqueous methanol. Evaporation of the collected fractions gave the desired product (0.89 g, 100%) as a white solid. Y-NMR (CD3OD, 500 MHz) 7.23 (m, 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 spectrum: 217.46 (MH) +.

(R) -2-Amino-3-benzo [b] thiophen-3-yl-l- [1,4 '] bipiperidinyl-1' -yl-propan-1-one, chlorohydrate 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 temperature was added. added (573 mg, 3.4 mmol), triethylamine (1.3 mL, 9.3 mmol) followed by 3- (diethoxyphosphoryloxy) -1,2, 3-benzotriazin-4 (3 H) -one (1.02 g, 3.4 mmol). After 3 h, the reaction mixture was treated with aqueous sodium hydrogen carbonate (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 (1R) -1-benzo [b] thiophen-3-ylmethyl-2- [1, 4 '] tert-butyl ester. ] bipiperidinyl-1-yl-2-oxo-ethyl) -carbamic acid in 82% yield. (IR) -1-Benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl-l' -yl-2-oxo-ethyl) -carbamic acid tert-butyl ester (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-l- [1,4 '] bipiperidinyl-l' -yl-propan-1-one, dichlorohydrate in 98 Performance% ^ -RMN (500 MHz, CD3OD): d 7.98-7.88 (m, 2 H), 7.55-7.40 (m, 3 H), 4.85-4.83 (m, 1H), 3.66-2.68 (m, 9 H), 1.92-1.44 (m, 12 H). Mass spectrum: 372 (MH) +.

Example 61 (1-Benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl) -amide of (R) -l-0xo-3 acid, 4-benzo-2, 9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid To a solution of 2-amino-3-benzo [b] thiophen-3-yl-l- [1,4 '] bipiperidinyl-1'-yl-propan-1-one (50.0 mg, 0.135 mmol) in 1, 2-dichloroethane (1.5 mL) was added 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-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 carried out by preparative reverse phase HPLC to give the desired product (75.5 mg, 77%) as brown oil. Y-NMR (CD3OD, 500 MHz) d 7.92-7.85 (m, 2H), 7.44-7.34 (m, 3H), 7.21-7.16 (m, 2H), 7.00 (t, J = 7.0 Hz, 1H), 6.86 (t, J = 8.5 Hz, 1H), 5.15-5.02 (m, 1H), 4.72-4.45 (m, 1H), 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 (m, 1H), 2.08-1.64 (m, 8H), 1.58-1.20 (m, 6H). Mass spectrum: 614.37 (MH) +.

EXAMPLE 62 N- [(IR) -1- (Benzo [b] thien-3-ylmethyl) -2- [1 ', 4-bipiperidin] -1-yl-2-oxoethyl] -3', 4'-dihydro -2-oxospiro- [piperidin-4, 4 '(1H) -quinoline] -1-carboxamide Prepared as described by (1-benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl) -amide of the acid (R) -l- oxo-3, 4-benzo-2, 9-diaza-spiro [5.5] undec-3-ene-9-carboxylic from 3 ', 4' -dihydro-2-oxospiro- [piperidin-4, 4 '( 1H) -quinoline (MS Chambers, et al., J. Med. Chem., 1992, 35, 2033-2039; O-94/13696). ^? - NMR (CDC 13. 500 MHz) d -0.35 (1H, m), 0.79 (1H, m), 1.2-2.1 (12H, m), 2.22 (5H, m), 2.38 (2H, m), 2.74 (2H, Abq), 3.19 (3H, m), 3.33 (2H, m), 3.65 (1H, d), 3.80 (1H, m), 3.93 (1H, t), 4.49 (1H, d), 5.31 ( 1H, t), 5.96 (1H, t), 6.89 (1H, d), 7.05 (1H, t), 7.18 (1H, d), 7.26 (1H, m), 7.33 (1H, m), 7.40 (1H , m), 7.78 (1H, m), 7.96 (1H, Abq), 9.01 (1H, brs), 9.17 (1H, brs). Mass spectrum: 614.36 (MH) +.

Example 63 N- [(IR) -1- (Benzo [b] thien-3-ylmethyl) -2- [1,4-bipiperidin] -l-yl-2-oxoethyl] -2 ', 3'-dihydro-1- oxoespiro- [piperidin-4, 4 '(1H) -isoquinoin] -1-carboxamide Prepared as described by (l-benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl-1-yl-2-oxo-ethyl) -amide of the acid (R) -l- oxo-3, 4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid from 2 ', 3'-dihydro-l-oxospiro- [piperidin-4,4'- (1H) -isoquinoline (M.S.

Chambers, et al., J. Med. Chem., 1992, 35, 2033-2039; WO 94/13696). ^ -R (CDC13, 500 MHz) d 0.01 (1H, m), 0.78 (1H, m), 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 (1H, d), 5.29 (1H, m), 5.62 (1H, d), 6.47 (1H, brs), 7.38 (5H, m), 7. 51 (1H, m), 7.77 (1H, m), 7.85 (1H, m), 8.11 (1H, d). Mass spectrum: 614.42 (MH) +.

EXAMPLE 64 N- [(IR) -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] -1 '-carboxamide Prepared as described by (1-benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl-1'-yl-2-oxoethyl) -amide of (R) -l-oxo- 3, 4-benzo-2, 9-diaza-spiro [5.5] undec-3-ene-9-carboxylic from 1,2-dihydro-2-oxospiro- [4H-3, 1-benzoxazine-4, 4 '-piperidine (prepared as described in Takai, et al., Chem. Pharm. Bull. 1985, 33, 1129-1139) to give the title compound (76%). Mass spectrum: 616 (MH) +. Rf = 1.42.

Succinate Intermediates and Examples 3-Benzo [b] thiophen-3-yl-acrylic acid 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 heated at 110 ° C overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken 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 (5.65 g, 91%). 3-Benzo [b] thiophen-3-yl-propionic acid A suspension of 3-benzo [b] thiophen-3-yl-acrylic acid: (5.6 g, 0.027 mol) and 10% Pd / C (600 mg) in 1: 1 methanol / ethyl acetate (50 mL) was hydrogenated in a Parr apparatus at 50 psi (3.515 Kg / cm2) during the night. The mixture was filtered and concentrated to give the crude product without further purification (ca. 100% conversion). Mass spectrum: 205 (MH) ". 3- (3-Benzo [b] thiophen-3-yl-propionyl) -4 (R) -benzyl-oxazolidin-2-one To a solution of 3-benzo [b] thiophen-3-yl-propionic acid (2.1 g, 0.010 mol), triethylamine (4.12 g, 0.040 mol) in anhydrous tetrahydrofuran (100 mL) at 0 ° C was added pivalyl 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-oxazolidinoa (1.988 g, 0.011 mol) were added. The reaction mixture was allowed to warm 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 methylene chloride 100% This compound was used immediately in the following procedure. 3 (S) -Benzo [b] thiophen-3-ylmethyl-4- (4-benzyl-2-oxo-oxazolidin-3-yl) -4-oxobutyric acid tert-butyl ester To a solution of 3- (3-benzo [b] thiophen-3-yl-propionyl) -4-benzyl-oxazolidin-2-one (3.35 g, 9.18 mmol) in anhydrous tetrahydrofuran 100 mL at -78 ° C was added. add lithium diisopropyl amide in tetrahydrofuran (6.1 mL, 11.01 mmol) and the reaction mixture was stirred for 30 min. Following the addition of t-butyl bromoacetate (1.62 mL, 11.01 mmol) at -78 ° C, the mixture was stirred overnight while this was allowed to warm to room temperature. The solvent was evaporated and the residue was 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%) 2 (S) -Benzo [b] thiophen-3-ylmethyl-succinic acid, 4-tert-butyl ester 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 g) mmol) in tetrahydrofuran (50 mL) and water (30 mL) at 0 ° C was added 30% aqueous hydrogen peroxide (1 mL) followed by lithium hydroxide (0.2155 g, 8.98 mmol). The reaction mixture was stirred overnight.

The tetrahydrofuran was removed in vacuo and the resulting solution was made acidic 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. 3 (S) -Benzo [b] thiophen-3-ylmethyl-4- [1,4 '] tert-butyl ester bipiperidinyl-1'-yl-4-oxo-butyric acid tert-butyl ester A solution of 2-benzo [b] thiophen-3-ylmethyl-succinic acid 4-tert-butyl ester (1.8420 g, 5.76 mmol), piperidylpiperidine (1.2240 g, 7.28 mmol) and triethylamine (0.7353 g, 7.28 mmol) in methylene chloride 100 mL 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 product. This was further purified by flash chromatography on silica gel, eluting with ammonia in 0-10% 2 M methanol / methylene chloride, to give the desired product. This product was carried out without further purification. 3 (S) -Benzo [b] thiophen-3-ylmethyl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxo-butyric acid A solution of 3-benzo [b] thiophen-3-ylmethyl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxo-butyric acid tert-butyl ester in methylene chloride 15 mL was treated with trifluoroacetic acid (3 mL) and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated to give the corresponding trifluoroacetate salt of the title product (99%). Example 65 1- [1,4 '] Bipiperidinyl-1' -yl-2- (3 (S) -Benzo [b] thiophen-3-ylmethyl) -4- [1 ', 2'-dihydro-2' - oxospiro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione 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'-piperidine (15.7 mg, 0.072 mmol) and triethylamine (7.3 mg, 0.072 mmol) in methylene chloride 5 mL at room temperature was treated with 3- ( doetoxyphosphoryloxy) -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 ammonium in 2M-10% methanol / methylene chloride, to give the desired product in 60% yield. LCMS: tR = 1.34 min, 615.45 (MH) +. 1-methyl ester of 2- (7-methyl-lH-indazol-5-ylmethylene) -succinic acid To a mixture of 7-methyl indazole aldehyde (0.2619 g, 1. 64 mmol) and dibasic ester DBE-4 (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 2 h under nitrogen. After an additional 16 h at room temperature, the solvent was removed in vacuo and the residue was taken up in water (100 L) and extracted with ethyl acetate (3 x 50 mL). The aqueous layer was made acidic with 1 N hydrochloric acid at 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 brought to the next stage without further purification. Mass spectrum: 275 (MH) +. 1-methyl ester of (±) -2- (7-methyl-lH-indazol-5-ylmethyl) -succinic acid A suspension of 2- (7-methyl-lH-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 ) and methanol (5 mL) was hydrogenated in a Parr apparatus overnight at 50 psi (3.515 Kg / cm2). The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to give the desired product as a yellow solid (100%). Mass spectrum: 277 (MH) +.

EXAMPLE 66 (±) -2- (7-Methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxoespiro- [4H-] methyl ester 3 ', 1-benzoxazine-4, 4'-piperidinyl] -butyric A solution of 2- (7-methyl-lH-indazol-5-ylmethyl) -succinic acid 1-methyl ester (0.2253 g, 0.82 mmol), 1,2-dihydro-2-oxospiro-4H-3, -dihydro-benzoxazine-4 '4-piperidine (0.1938 g, 0.89 mmol) and triethylamine (0.099 g, 0.98 mmol) in 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 ammonia in 0-10% 2M methanol / methylene chloride, to provide the desired product (53%). LCMS: tR = 1.40 min, 477.28 (MH) +.

Prepared similarly: Example 67 Methyl ester of (+) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin) -3-yl) -piperidin-1-yl] -butyric acid Y-NMR (400 MHz, CDC13) d 8.02 (1H, s), 7.98 (1H, m), 7.90 (1H, m), 7.35-6.89 (4H, m), 6.72 (1H, m), 4.71. (1H, m), 4.57 (1H, m), 4.27 (1H, s), 4.22 (1H, m), 3.85 (1H, m), 3.65 (3H, m), 3.30 (1H, m), 3.11 ( 2H, m), 2.83 (2H, m), 2.81-2.54 (4H, m), 2.35 (1H, m), 1.73-1.67 (4H, m). Mass spectrum: 490.32 (MH) +. (+) -2- (7-Methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxoespiro- [4H-3', l-benzoxazine- 4, 4 '-piperidinyl] -butyric A solution of methyl ester of 2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospiro- [4H-3', l-benzoxazine-4,4'-piperidinyl] -butyric acid (0.1911 g, 0.40 mol) and lithium hydroxide (19.3 mg, 0.80 mmol) in tetrahydrofuran (10 mL) and water (8 mL) was stirred overnight at room temperature ambient. The reaction mixture was made acidic with 1N hydrochloric acid at ca. pH 1 and concentrated to remove tetrahydrofuran in vacuo to give a white solid precipitate which was collected by filtration. The solid was washed twice with small amounts of water and dried in vacuo overnight (100%). Mass spectrum: 477 (MH) +.

Example 68 (±) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2'-dihydro-2' -oxoespiro- [4 H -3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione A solution of 2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [l ', 2'-dihydro-2'-oxoes? Iro- [4H-3', 1-benzoxazine - 4, 4 '-piperidinyl] -butyric (0.020 g, 0.04 mmol), piperidylpiperidine (0.0087 g, 0.05 mmol) and triethylamine (0.09 g, 0.08 mmol) in methylene chloride (5 mL) at room temperature was treated with 3- (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 L). The organic layer was dried and the solvents were removed in vacuo.

The crude product was purified by preparative CCD on silica gel (10M 2M ammonium hydroxide / methanol in methylene chloride) to give the desired product (36%). CL / MS: Tr = 1.18 min, 613.47 (MH) +.

Prepared similarly: Example 69 (±) -1- [1,4 '] -Bipiperidinyl-1' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [4- (2-oxo -l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione Y-NMR (400 MHz, CDC13) d 7. 99 (1H, m), 7. 62 (1H, m), 7 31 (1H, m), 7.14 (1H, m), 7.04-6.90 (3H, m), 6.70 (2H, d, J = 8.0 Hz), 4.70-4.58 (3H, m ), 4.24 (2H, m), 4.00 (2H, m), 3.70 (1H, m), 3.18-2.72 (5H, m), 2.64-2.22 (8H, m), 2.18-0.82 '(17H, m) . Mass spectrum: 626.34 (MH) +.

Example 70 (+) -1- (1, 4-Dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4- [4 - (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione XH-NMR (400 MHz, CDC13) d 8.06 (1H, s), 7.75 (1H, m), 7.36 (1H, m), 7.14 (1H, 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 (1H, m), 2.51 (3H, s), 2.35 (1H, m), 2.00 (1H, m), 1.70-1.00 (9H, m). Mass spectrum: 601.38 (MH) +.

Example 71 (±) -1- (1, 4-Dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', 1-benzoxazin-4, 4 '-piperidinyl] -butane-1,4-dione 1 H-NMR (400 MHz, CDC13) d 9.27 (1H, m), 8.00 (1H, s), 7.37 (1H, m), 7.23 (1H, m), 7.10-6.99 (3H, m), 6.87 (1H , m), 4.54 (1H, m), 3.97-3.50 (10H, m), 3.30 (1H, m), 3.16-2.76 (4H,), 2.53 (3H, s), 2.35 (1H, m), 2.20 -1.00 (9H, m). Mass spectrum: 588.36 (MH) +. Example 72 (±) -N, N-Dimethyl-2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H- quinazolin-3-yl) -piperidin-1-yl] -butyramide LCMS: tR = 1.36 min, 525.35 (M + Na) +.

Example 73 (±) -1- (2,6-Dimethyl-morpholin-4-yl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione LC / MS: tR = 1.41 min, 573.39 (MH) +. Example 74 (±) -2- (7-Methyl-lH-indazol-5-ylmethyl) -1- (4-methyl-piperidin-1-yl) -4- [4- (2-oxo-l, 4- diona Y-NMR (400 MHz, CDC13) d 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,), 3.09-2.81 (4H, m), 2.61 (3H, s), 2.41 (2H, m), 1.76-0.51 (15H, m). Mass spectrum: 557.38 (MH) +.

Example 75 (±) -2- (7-Methyl-lH-indazol-5-ylmethyl) -l-morpholin-4-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin -3-yl) -piperidin-1-yl] -butane-1,4-dione LCMS: tR = 1.32 min, 545.42 (MH) +.

Example 76 (±) -N, N-Dimethyl-2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospiro- [4H -3 ', l-benzoxamide-4, 4'-piperidinyl] -butyramide LC / MS: t R = 1.27 min, 512.30 (M + Na) +.

Example 77 (+) -2- (7-Methyl-lH-indazol-5-ylmethyl) -1- (piperidin-1-yl) -4- [1 ', 2'-dihydro-2'-oxoespiro- [4H -3 ', l-benzoxamide-4, 4'-piperidinyl] -butane-1,4-dione XH-NMR (400 MHz, CDC13) d 9.26-9.01 (1H, 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 ( 1H, m), 1.43-0.79 (9H, m). Mass spectrum: 530.34 (MH) +. Example 78 (±) -2- (7-Methyl-lH-indazol-5-ylmethyl) -4- [4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidin-1- il] -1-piperidin-l-yl-butane-1,4-dione ^ -RMN (400 MHz, CDC13) d 8.02 (1H, s), 7.82 (1H, m), 7. 37 (1H, m), 7.14 (1H, 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 (1H, 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, m), 1. 43 (4H, b), 1.26 (2H, b), 0.81 (2H, b). Mass spectrum: 543.40 (MH) +.

Example 79 (±) -1- [1, 4 '] Bipiperidinyl-1' -yl-2- (lH-indazol-5-ylmethyl) -4- [1 ', 2'-dihydro-2' -oxoespiro- [ 4H-3 ', l-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione Y-NMR (400 MHz, CDC13) d 8.86 (1H, m), 7.98 (1H, s), 7.54-6.85 (7H, m), 4.73-4.48 (3H, m), 3.96 -.80 (3H, m ), 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 spectrum: 599.31 (M + Na) +.

Example 80 (±) -1- (1, 4-Dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxospiro- [4H-3', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione LC / MS: RT = 1.25 min, 574.25 (MH) +.

Example 81 (±) -1- (1, 4-Dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (lH-indazol-5-ylmethyl) -4- [4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione LCMS: tR = 1.34 min, 587.38 (MH) +.

Example 82 (±) -2- (lH-Indazol-5-ylmethyl) -N, N-dimethyl-4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3- il) -piperidin-1-yl] -butyramide LCMS: tR = 1.28 min, 489.33 (MH) +. Example 83 Tert-butyl ester of (±) -5- acid. { 2- ([1,4 '] bipiperidinyl-1' -carbonyl) -4-oxo-4- [4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidin-1-yl ] -butil} -indazole-1-carboxylic acid LCMS: t R = 1.47 min, 742.55 (M + Na) + Example 84 (+) -2- (7-Methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -N-prop-2-ynyl-butyramide LC / MS: RT = 33 min, 535.32 (M + Na) Intermediates of aspartate and Examples Benzyl ester of (L) -2-tert-Butoxycarbonylamino-4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine -1-il] -butyric To a stirred solution of N-tert-butyloxycarbonyl-L-aspartic acid alpha-benzyl ester (1.4 g, 4.33 mmol) and 3,4-dihydro-3- (4-piperidinyl-2 (1H) -quinazolinone (1.26 g) , 4.33 mmol) in methylene chloride (12 mL) was added 3- (diethoxyphosphoryloxy) -1, 2, 3-benzotriain-4 (3H) -one (DEPBT, 1425 g, 4.76 mmol) in one portion followed by addition drop by drop of triethylamine (0.724 mL, 5.20 mmol) The resulting suspension gradually became homogeneous with stirring and was stirred at room temperature overnight (15 h) .The mixture was diluted with methylene chloride and washed with hydroxide. Sodium (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 (methanol in sodium chloride). 10% methylene) to give a colorless oil Mass spectrum: 559 (M + Na) and (L) -2-tert-Butoxycarbonylamino-4-oxo- 4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyric acid To a solution of benzyl ester of 2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyric (1.48 g, 2.76 mmol) in ethyl acetate / methanol (16 mL, 1: 1) in a Parr bottle was added 10% pelletized mineral carbon (150 mg) in one portion. Hydrogenation was carried out with a Parr apparatus at 52 psi (3.6556 Kg / cm2) for 1 h. CCD (methanol in 10% methylene chloride) indicated a quantitative conversion. The mixture was filtered and concentrated in vacuo to give a glassy, colorless solid (1.14 g, 93%). Example 85 tert-butyl ester of (L) - acid. { 1- ([1, 4 '] Bipiperidinyl-1' -carbonyl) -3-oxo-3- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1- il] -propyl} -carbamic To a stirred solution of 2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-l, 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 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 resulting mixture was stirred at room temperature overnight (15 h). The mixture was diluted with methylene chloride and washed with sodium hydroxide solution (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% (1M ammonia in methanol) in methylene chloride) to give a colorless foam (1.08 g, 71%). Y-NMR (400 MHz, CDC13) d 8.86-8.55 (1H, br), 7.05 (1H, br), 6.93 (1H, br), 6.82 (1H, br), 6.72 (1H, d, J = 7.6 Hz ), 6.10-5.68 (1H, br), 5.20 (1H, m), 54.70-4.40 (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 spectrum: 597 (MH) +. (L) -2-Amino-l- [1,4 '] bipiperidinyl-1' -yl-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin- 1-yl] -butane-1,4-dione To a stirred solution of tert-butyl ester of the acid. { 1- ([1,4 '] bipiperidinyl-l' -carbonyl) -3-oxo-3- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1- il] -propyl} -carbamic (1.05 g, 1.76 mmol) in methylene chloride (12 L) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature until complete conversion (monitored by LCMS, ca. 15 h). The mixture was then diluted with water and sodium hydroxide (1.5 g) added slowly 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 spectrum: 497 (MH) +.

Example 86 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (lH-indol-5-ylamino) -4- [4- (2-oxo-l, 4-dihydro-2H -quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione To a solution of 2-amino-l- [1,4 '] bipiperidinyl-1' -yl-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin- 1-yl] -butane-1, -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 L) in a 5 mL cylinder vial was added 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) -biphenyl (4.1 mg, 0.0105 mmol), Pd2 (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® line stopper. The dark orange reaction mixture was heated to 80 ° C with stirring. The reaction was continued at 80 ° C overnight. The conversion reached approximately 50% after 17 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and filtered. The desired product was purified by preparative CCD (methanol in 10% methylene chloride) to provide the product protected by tert-butyloxycarbonyl (11 mg, 15%). Mass spectrum: 712 (MH) +. This intermediate (11 mg) was dissolved in methylene chloride 3 mL 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 concentrated in vacuo and dried under high vacuum to give a tan powder (15 mg, 100%). Mass spectrum: 612 (MH) +.

Example 87 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (5-chloro-2-nitro-phenylamino) -4- [4- (2-oxo-l, 4-4 -diona To a stirred solution 2-amino-l- [1,4 '] bipiperidinyl-1' -yl-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin- 1-yl] -butane-1,4-dione (33.7 mg, 0.068 mmol) and 4-chloro-l, 2-dinitrobenzene (16.8 mg, 0.075 mmol) in ethanol (0.5 mL) was added a solution of sodium bicarbonate. saturated sodium (4 drops). The mixture was stirred at room temperature for 70 h until about 60% conversion. The product was purified by preparative HPLC to give a yellow solid (17.7 mg, 40%). Mass spectrum: 652 (MH) +.

Example 88 (L) -1- [1,4 '] Bipiperidinyl-l' -yl-2- (6-chloro-pyrimidin-4-ylamino) -4- [4- (2-oxo-l, 4-dihydro -2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione A mixture of 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 (22.3 mg, 0.045 mmol) and 4,6-dichloropyrimidine (16 mg, 0.095 mmol) in 2-propanol (0.5 mL) in a microwave processable vial was heated to 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% (ammonia in 1N methanol) in methylene chloride) to give a white solid (23 mg, 84%). ^ -RMN (400 MHz, CDC13) d 8.36 (1H, d, J = 12.8 Hz), 8.04-7.81 (1H, 2s), 7.14 (1H, t, J = 7.6 Hz), 7.10-6.80 (2H, m), 6.74 (1H, t, J = 8.2 Hz), 6.52-6.42 (1H, m), 5.90- 5.50 (1H, br), 4.85-4.40 (3H, m), 4.40-4.05 (3H , m), 4.05-3.82 (1H, m), 3.20-3.00 (2H, m), 3.00-2.68 (2H, m), 2.68-2.30 (8H, m), 2.05-1.90 (2H, m), 1.90 -0.70 (12H, m). Mass spectrum: 609 (MH) +. Prepared similarly: Example 89 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (2-chloro-9H-purin-6-ylamino) -4- [4- (2-oxo- 1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione LCMS: tR = 1.10 min, 649 (MH) +. Example 90 (L) -2- (4-i-amino-6-methyl-5-nitro-pyrimidin-2-ylamino) -1- [1,4 '] bipiperidinyl-l' -il-4- [4- (2 -chloro-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione LCMS: tR = 1.12 min, 649 (MH) +.

Example 91 (L) -1- [1,4 '] Bipiperidinyl-1-yl-2- (4,5-diamino-6-methyl-pyrimidin-2-ylamino) -4- [4- (2-oxo -l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione To a solution of 2- (4-amino-6-methyl-5-nitro-pyrimidin-2-ylamino) -1- [1,4 '] bipiperidinyl-1' -yl-4- [4- (2-oxo -l, 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% pelletized mineral coal (60 mg). The mixture was stirred under a hydrogen atmosphere at 55 psi (3.8665 Kg / cm2) for 20 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give a colorless solid (41.2 mg, 49.2% over two steps). LCMS: tR = 0.86 min, 619 (MH) +.

Example 92 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (7-methyl-lH- [1,2,3] triazolo [4,5-d] pyrimidin-5-ylamino ) -4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione 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 was stirred at room temperature for 6 h. The reaction mixture was diluted with water and methanol and purified by preparative HPLC to provide a colorless oil / solid (3.0 mg, 28%). LC / MS: RT = 1.07 min, 630 (MH) +. General procedure for the syntheses of Examples 93-95: A mixture of 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 (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 of acetic acid and stirred overnight. The sodium cyanoborohydride (0.07 mmol, 5 eq) was then added in one portion and the suspension was stirred again overnight. The purification was carried out either by filtration through an SCX cartridge or by preparative CIAR. Example 93 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- ((2'-pyridyl) -methyl-amino) -4- [4- (2-oxo-1, 4- dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione 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-1-yl] -butane-1,4-dione LC / MS: tR = 0. 92 min, Example 95 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- ((3'-methyl-phenyl)) -methyl-amino) -4- [4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione LC / MS: tR = 1. 08 min, 600 (MH) +. Example 96 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1 -yl] -2- (pyrimidin-4-ylamino) -butane-1,4-dione To a solution of 1- [1,4 '] bipiperidinyl-1' -yl-2- (6-chloro-pyrimidin-4-ylamino) -4- [4- (2-oxo-l, 4-dihydro-2H -quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (21 mg) was dissolved in ethyl acetate / methanol 4 mL (1: 1) in a Parr bottle, pelleted mineral carbon was added 10% (10 mg). Hydrogenation was carried out on a Parr apparatus at 55 psi (3.8665 Kg / cm2) overnight. The degassed mixture was then filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give a yellow solid (12.4 mg, 45%). Mass spectrum: 575 (MH) +. Example 97 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- [4-hydroxy-cyclohexylamino) -4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin -3-yl) -piperidin-1-yl] -butane-1,4-dione To a stirred 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 (47.9 mg, 0.096 mmol) and 4-hydroxy-cyclohexanone (Synthesis reported in Can. J. Chem 1994, 72, 1699-1704) (11 mg, 0.096 mmol) in methanol (1.0 mL) was added in 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 residue was partitioned between methylene chloride and 1 N sodium hydroxide. The 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 CCD (10% (ammonia in 1N methanol) in methylene chloride) to provide the desired product as a white solid (15.3 mg, 27%).

Mass spectrum: 595 (MH) +. EXAMPLE 98 (L) -1- [1,4 '] Bipiperidinyl-1' -yl-2- [(1H-imidazol-4-ylmethyl) -amino] -4- [4- (2-oxo-l, 4 -dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione To an agitated solution of 2-amino-l- [1,4 '] bipiperidinyl-1' -yl-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) - piperidin-1-yl] -butane-1, 4-dione (20.6 mg, 0.0415 mmol) and 4-imidazolecarboxyaldehyde (4 mg, 0.0415 methylene chloride (1.0 mL) was added sodium cyanoborohydride (8.8 mg, 0.0415 mmol) The suspension was stirred at room temperature for 2 days and then partitioned between methylene chloride and 1N 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 CCD (10% (ammonia in 1N methanol) in methylene chloride) to provide the desired product as a colorless oil which solidified on standing (6.1 mg, 26%). ^? - NMR (400 MHz, CDC13) d 7.61 (1H, d, J = 4.8 Hz), 7.16 (1H, t, J = 7.6 Hz), 7.10-6.85 (3H, m), 6.67 ( 1H, d, J = 8.0 Hz), 4.85-4.63 (2H, m), 4.63-4.40 (1 H, m), 4.40-3.65 (7H, m), 3.25-2.40 (10H, m), 2.15-0.70 (18H, m). Mass spectrum: 577 (MH) +. Example 99 (L) -N-. { 1- ([1,4 '] Bipiperidinyl-1' -carbonyl) -3-OXO-3- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1- il] -propyl} -4- ethoxy-benzamide To a stirred mixture of 2-amino-1- [1,4 '] bipiperidinyl-1-yl-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin -1-yl] -butane-1,4-dione (91.5 mg, 0.184 mmol) and p-anisoyl chloride (34.6 mg, 0.203 mmol) in methylene chloride was added two drops of triethylamine (35 uL). The light yellow solution was stirred at room temperature for 2.5 h to complete the conversion. The reaction mixture was washed with sodium hydroxide (1N) 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% (ammonia in 1N methanol) in methylene chloride) to give a glassy solid (92.8 mg, 80%). XH-NMR (400 MHz, CDC13) d 8.55-8.47 (1H, d), 8.10-7.78 (3H, m), 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,), 2.70-2.30 (8H,), 2.05-1.19 (14H,). Mass spectrum: 631 (MH) +. 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- il] -propyl} -4-methoxy-benz amide A solution ag ([1,4] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1- il] -propyl} -4-methoxy-benzamide solution in methylene chloride (69 mg) was treated with boron tribromide (in 1M 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: RT = 1.03 min, 617 (MH) +. Example 101 { 1- ([1,4 '] Bipiperidinyl-1' -carbonyl) -3-oxo-3- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1- il] -propyl} - (L) -lH-pyrazole-3-carboxylic acid amide To an agit solution of pyrrazole-3-carboxylic acid (4 mg, 0.036 nmol) and 2-a-rN-1-l- [1, 4 '] bipipericiinil-l'-il-4- [4- (2-oxo -l, 4-dihydro-2H-q? inazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (13 mg, 0.026 mol) in methylene chloride mL) was added 3- (diethoxyphosphoryloxy) -l, 2,3-benzotriain-4 (3H) -one (DEPBT, 8.6 mg, 0. 036 mmol) in one portion followed by a 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 were separated and the aqueous layer was extracted with methylene chloride (3x). CLEM indicated that the product remains in the aqueous layer. The product was purified by preparative HPLC to give a yellow oil (17.2 mg, 94%). Mass spectrum: 591 (MH) +. General procedure for the synthesis of Examples 102- 134: X ™ c, or the starting amine, 2-amino-l- [1,4 '] bipiperidinyl-l' -yl-4- [4- (2-oxo-l, 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 (ca. 2 equiv.) Were added followed by a solid phase piperidine base bound to the resin (4 equiv.). The block was stirred overnight. Approximately 4 equivalents of tris-amine resin was added to each well and the mini-reactor was stirred for another 5 h. The reaction mixtures were filtered, and purified by either preparative HPLC or by filtration through an SCX cartridge or both. The HPLC retention times and mass spectrum data for each example are listed in Table 2.

Table 2. Amides and Carbamates General procedure for the syntheses of Examples 135-200: The starting amine, -amino-l- [1, 4 '] bipiperidinyl-l' -yl-4- [4- (2-oxo-l, 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 stirred for 2 days. Approximately 4 equivalents of tris-amine resin was added to each well and the mini-reactor was stirred for another two days. The reaction mixtures were filtered, and the individual product was purified by either preparative CIAR or filtration through an SCX cartridge or both. HPLC retention times and mass spectrum data for each example are listed in Table 3.

Table 3. Ureas 1-ethyl ester of 2- (lH-indazol-5-ylamino) -succinic acid 4-tert-butyl ester To a solution / suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 mL) was added ethyl glyoxylate solution (ca. 50% in toluene, 1.7 mL, 1.1 equiv) in one portion followed by sulfate. of magnesium (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 azeotropic process with anhydrous benzene and further dried under high vacuum. The residue was then dissolved in tetrahydrofuran (20 mL) and cooled to 0 ° C. A solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was then added slowly. After stirring at 0 ° C for 1 h, the mixture was stored overnight. The mixture was then diluted with ethyl acetate and quenched with half the 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 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 provide the desired product (1.3 g, 65%) as a tan oil (400 MHz, CDC13) d 7.89 (1H, s), 7.40-7.27 (1H, m), 6.98-6.77 (2H, m), 4.42-4.35 (1H, m), 4.30-4.12 (3H, m), 2.80 (2H, d, J = 4.4 Hz), 1.43 (9H, s), 1.27-1.17 (4H, m), Mass spectrum: 356.24 (M + Na) +, 278.23 (M - fcBu) +, tR = 1.287 min. 2- (lH-indazol-5-ylamino) succimic acid 1-ethyl ester A stirred solution of 2- (lH-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 solution, water and brine. The organic layer was dried and concentrated to give a dark green oil: LC / MS: RT = 0.643 min, 278.19 (MH) +.

Ethyl ester of 2- (lH-indazol-5-ylamino) -4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1- acid il] -butyric To a stirred solution of 2- (lH-indazol-5-ylamino) -succinic acid 1-ethyl ester (84 mg, 0.215 mmol) in methylene chloride (1 mL) was added the amine (99 mg, 0.429). mmol, 2 equiv) followed by DEPBT (128 mg, 0.43 mmol, 2 equiv.) and triethylamine (70 μL, 0.47 mmol, 2.2 equiv). The mixture was stirred overnight and then diluted with ethyl acetate and washed with half a saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to a cinnamon 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 (32.2 mg, 34.5% over two steps) as a reddish oil. Y-NMR (400 MHz, CDC13) d 7.90 (2H, d, J = 4.4 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.20-7.14 (1H, m), 7.00-6.80 (4H, m ), 6.70 (1H, 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 (1H, m), 3.20-2.99 (2H, m), 2.99-2.84 (1H, m), 2.70-2.52 (1H, m), 1.80-1.50 (5H,), 1.35-1.12 (5H, m). LCMS: tR = 1130 min, 491.37 (MH) +. 2- (lH-indazol-5-ylamino) -4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyric acid To a solution of the ethyl ester (34 mg, 0.069 mmol) in tetrahydrofuran (0.3 mL) was added lithium hydroxide in water (1M, 280 μL, 4 equiv) and the mixture was stirred at room temperature for 17 h. The solution was dried under a stream of nitrogen. Tettrahydrofuran 0.2 mL and anhydrous benzene 0.2 mL were added to the residue and the suspension was dried by blowing again with a stream of nitrogen. LCMS: tR = 0.900 min, 463.30 (MH) +.

Example 201 (±) -1- [1, 4 '] Bipiperidinyl-1'-yl-2- (lH-indazol-5-ylamino) -4- [4- (2-oxo-1,4-dihydro-2H -quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione To a solution of ethyl ester of 2- (lH-indazol-5-ylamino) -4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) - piperidin-1-yl] -butyric acid (0.069 mmol) in dimethylformamide (0.5 mL) in a capped round 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 μL). The mixture was stirred at room temperature overnight. The final product was purified by preparative HPLC to provide the desired product (15 mg, 26% over two steps) as a tan solid. CL / EM: tR 0. 917 min, 613.54 (MH) +. Additional examples (l-benzyl-piperidin-4-yl) - (2-nitrobenzyl) -amine The 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 stirred at room temperature for 20 min before adding a solution of sodium borohydride (0.25 g, 6.61 mmol) in ethanol (5 mL) dropwise over 10 min. After the addition was complete, the reaction was stirred for 1 h, cooled to 0 ° C and concentrated ammonium chloride was added to the reaction mixture until no bubbling was observed. The solvents were evaporated in vacuo and the resulting crude mixture was dissolved in water (10 mL) and methylene chloride (10 mL). The layers were separated and the organic layer was washed with water (2x) and brine (2x), dried over sodium sulfate, filtered, and concentrated to provide 1.5 g (70%) of the desired product. LCMS: rt = 7 min, 326.18 (MH) +. (2-Amino-benzyl) - (l-benzyl-piperidin-4-yl) -amine The (1-benzyl-piperidin-4-yl) - (2-nitro-benzyl) -amine (1.2 g, 3.7 mmol) and zinc powder (1 g, excess) were combined in 75% aqueous citric acid (16 g). mL) and was stirred at 60 ° C for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resulting crude was dissolved in water (10 mL), followed by the addition of ammonium hydroxide until a pH of 3 was reached. The solution was extracted with methylene chloride (3x) The organic layers are pooled together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to provide 0.8 g (73%) of the desired product. Y-NMR (CD3OD) d 2.50 (m, 2H), 3.20 (m, 2H), 3.49 (dd, J = 7.0, 7.3, 1H), 3.62 (m, 4H), 4.20 (s, 2H), 4.36 (s, 2H), 7.04 (m, 2H), 7.32 (dd, J = 7.3, 7.6, 1H), 7.41 (d, J = 7.9, 1H), 7.50 (m, Mass spectrum: 296.40 (MH) +. 3- (l-Benzyl-piperidin-4-yl) -3, 4-dihydro-lH-benzo [1,2,6] thiadiazin-2, 2-dioxide A solution of (2-amino-benzyl) - (1-benzyl-piperidin-4-yl) -amine (1.0 g, 3.39 mmol) and sulfamide (0.64 g, 6.78 mmol) in pyridine was heated to reflux for 14 h. After cooling to room temperature, the solvent was evaporated and the crude product dissolved in water. After adjusting 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 give 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 the addition of diethyl ether until the precipitation of the product occurs. The desired product was obtained by filtration to provide 0.7 g (53%). LCMS: tr = 0.96 min, 358.16 (MH) +. 3-Piperidin-4-yl-3, 4-dihydro-lH-benzo [1,2,6] thiadiazine-2, 2-dioxide 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 L ) was wetted with nitrogen, and treated with palladium on charcoal (10%, 46 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.26 g (75%) of the desired material. ^ -RMN (CD30D) d 1.53-1.61 (m, 2H), 1.80 (m, 2H), 2.55 (m, 2H), 2.95-3.05 (m, 2H), 3.30 (m, 2H), 3.70 (m, 2H), 4.65 (s, 2H), 6.70 (d, J = 7.9, 1H), 7.40 (dd, J = 8.2, 6.7, 1H), 7.10 (m, 2H). Mass spectrum: 268.10 (MH) +. 6-Bromo-3-piperidin-4-lyl-3, 4-dihydro-lH-quinazolin-2-one The 3-piperidin-4-yl-3,4-dihydro-lH-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 (1.8 mL, 35.14 mmol) in acetic acid (0.5 mL) dropwise during 5 min. After stirring 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 concentrated to provide 0.16. g (59%) that was used immediately without further purification. LC / MS: tR = 0.91 min, 310.15 (MH) +. 2-oxo-3-piperidin-4-yl-l, 2,3, 4-tetrahydro-quinazolin-6-carbonitrile 6-bromo-3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one (0.16 g, 0.52 mmol), zinc cyanide (37 mg, 0.31 mmol) and tetrakis (triphenylphosphine) palladium ( 0) (60 mg, 0.05 mmol) were combined in dimethylformamide (4 mL). The reaction flask was connected under high vacuum and degassed (3x) by a freeze-thaw method, before being heated to 90 ° C with stirring under nitrogen for 1 h. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture was purified by preparative HPLC to provide 50 mg (38%) of the desired nitrile. Y-NMR (CD30D) d 1.99 (m, 2H), 2.08-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, 1H), 4.40 (m, 1H) , 4.47 (s, 2H), 6.93 (d, J = 8.1, 1H), 4.10 (m, 2H). Mass spectrum: 257.13 (MH) +. N- (1-Benzyl-piperidin-4-yl) -2- (2-nitro-phenyl) -acetamide The (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 carbodiimide of 1- ( 3-dimethylaminopropyl) -3-ethyl (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 was 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 give 3.5 g. (98%) of the desired product. LCMS: tR = 1.24 min, 354.30 (MH) +. [2- (2-Amino-phenyl) -ethyl] - (l-benzyl-piperidin-4-yl) -amine In a flame-dried flask, N- (1-benzyl-piperidin-4-yl) -2- (2-nitro-phenyl) -acetamide (3.2 g, 9.06 mmol) and lithium aluminum hydride (1.0 g, 18.12 mmol) were combined. The 1,4-dioxane (15 mL) was added and the mixture was slowly refluxed for 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0 ° C and the excess lithium aluminum hydride was destroyed by the dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate was concentrated and used as in the next reaction. 3- (1-benzyl-piperidin-4-yl) 1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one A stirred solution of [2- (2-amino-phenyl) -ethyl] - (1-benzyl-piperidin-4-yl) -amine (0.44 g, 1.42 mmol) in tetrahydrofuran (5 mL) at 0 ° C was treated with diimidazole carbonyl (0.23 g, 1.42 mmol). The reaction was stirred for 30 min at 0 ° C and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to provide 100 mg (21%) of the desired product. LCMS: tR = 1.29 min, 336.34 (MH) +. 3- Piperidin-4-yl-1,4,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one 3- (L-benzyl-piperidin-4-yl) 1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one (100 mg, 0.3 mmol) in methanol (5 L ) was wetted with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 50 mg (68%) of the desired material. LCMS: tR = 1.07 min, 246.26 (MH) +. 3- [(L-benzyl-piperidin-4-yl-amino) -methyl] -4-nitro-f-enol The 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 adding a solution of sodium borohydride (1.13 g, 29.9 mmol) in ethanol (10 mL) dropwise over 10 min. After the addition was complete, the reaction was stirred at room temperature for 1 h, cooled to 0 ° C and concentrated ammonium chloride was added to the reaction mixture until no bubbling was observed. The solvents were evaporated in vacuo and the resulting crude mixture was dissolved in water (30 mL) and methylene chloride (40 mL). The layers were separated and the organic layer was washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to provide 5.8 g (57%) of the desired product. LCMS: tR = 0.95 min, 342.27 (MH) +. 4-Amino-3- [(l-benzyl-piperidin-4-yl-amino) -methyl] -phenol (L-benzyl-piperidin-4-yl) - (2-nitro-benzyl) -amine (0.25 g, 0.7 mmol) and zinc powder (0.2 g, excess) were combined in 75% aqueous citric acid (8 L) and stirred at 60 ° C for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resulting crude mixture was dissolved in water (10 mL), followed by the addition of ammonium hydroxide until a pH of 3 was reached. The solution was extracted with sodium chloride. methylene (3x). The organic layers are grouped together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to provide 0.18 g (79%) of the desired product. 3- (1-phenyl-piperidin-4-yl) -6-hydroxy-3,4-dihydro-lH-quinazolin-2-one A stirred solution of 4-amino-3- [(1-benzyl-piperidin-4-yl-amino) -methyl] -phenol (0.16 g, 0.51 mmol) in tetrahydrofuran (3 mL) at 0 ° C was treated with diimidazole carbonyl (52 mg, 0.51 mmol). The reaction was stirred for 30 min at 0 ° C and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to provide 100 mg (57%) of the desired product. LCMS: tR = 1.09 min, 338.28 (MH) +. 6-Hydroxy-3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one The 3- (1-benzyl-piperidin-4-yl) -6-hydroxy-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was wetted with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 60 mg (81%) of the desired material. LCMS: tR = 0.75 min, 248.22 (MH) +.

N- (1-Benzyl-piperidin-4-yl) -2-methoxy-6-nitro-benzamide 2-Methoxy-6-nitro-benzoic acid (2.0 g, 10.1 mmol), 4-amino-1-benzylpiperidine (1.9 L, 10.1 mmol), 1-hydroxybenzotriazole (1.43 g, 10.5 mmol) and l- (3- dimethylaminopropyl) -3-ethyl carbodiimide (1.9 g, 10.1 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL, 30.3 mmol) and the reaction mixture was stirred 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 provide 3.2 g. (86%) of the desired product. LCMS: tR = 1.10 min, 370.28 (MH) +. (2-Amino-6-methoxy-benzyl) - (1-benzyl-piperidin-4-yl) -amine Into a flame-dried flask, N- (1-benzyl-piperidin-4-yl) -2-methoxy-6-nitro-benzamide (1.0 g, 2.8 mmol) and lithium aluminum hydride (0.31 g, 8.45 g) were combined. mmol). To the mixture was added anhydrous 1,4-dioxane (15 mL). The mixture was slowly refluxed for 1 h and stirred under reflux for 16 h. The reaction mixture was cooled to 0 ° C and the excess lithium aluminum hydride was destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate was concentrated and used as in the next reaction. 3- (1-benzyl-piperidin-4-yl) -8-methoxy-3,4-dihydro-1H-quinazolin-2-one 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 diimidazole carbonyl (99 mg, 0.62 mmol). The reaction was stirred for 30 min at 0 ° C and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to provide 150 mg (68%) of the desired product. LC / MS: tR = 1.41 (MH) +. 8-Methoxy-3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one The 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 wetted with nitrogen, and it was treated with palladium on charcoal (10%, 10 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 68 mg (93%) of the desired material. LCMS: tR = 1.11 min, 262.23 (MH) +. N- (1-benzyl-piperidin-4-yl) -2-chloro-6-nitro-benzamide 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 l- (3- dimethylaminopropyl) -3-ethyl carbodiimide (1.1 g, 1.05 equiv) were combined in ethyl acetate (20 mL). To this solution was added triethylamine (2.5 L. 3.0 equiv) and the reaction mixture was 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 provide 1.9 g. (85%) of the desired product. (2-Amino-6-chloro-benzyl) - (1-benzyl-piperidin-4-yl) -amine In a flame-dried flask, N- (1-benzyl-piperidin-4-yl) -2-chloro-6-nitro-benzamide (1.67 g, 4.47 mmol) and lithium aluminum hydride (0.51 g, 13.43 mmol ) were combined. To this was added anhydrous 1,4-dioxane (15 L). The mixture was slowly brought to reflux and stirred for 16 h. The reaction mixture was cooled to 0 ° C and the excess lithium aluminum hydride was destroyed by the dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate was concentrated and used as in the next reaction. 3- (l-benzyl-piperidin-4-yl) -8-chloro-3,4-dihydro-lH-quinazolin-2-one A stirred solution of (2-amino-6-chloro-benzyl) - (1-benzyl-piperidin-4-yl) -amine (0.66 g, 2.0 mmol) in tetrahydrofuran (8 L) at 0 ° C was treated with diimidazole carbonyl (0.36 g, 2.05 mmol). The reaction was stirred for 30 min at 0 ° C and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to provide 0.58 g (82%) of the desired product. LCMS: tR = 1.40 min, 356.25 (MH) +. 2-chloro-3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one The 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 wetted with nitrogen, and it was treated with palladium on charcoal (10%, 17 mg). The trifluoroacetic acid (0.2 mL) was added and the mixture was wetted with nitrogen then allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 100 mg (79%) of the desired material. LCMS: tR = 0.99 min, 266.08 (MH) +. 5-bromo-lH-indol-3-carbonitrile A mixture of 5-bromo-indole-3-carboxaldehyde (5 g, 22.3 mmol) diammonium acid phosphate (15.6 g, 31.8 mmol) in 1-nitropropane (66 mL) and acetic acid (22 mL) was heated to reflux for 16 h. After cooling to room temperature, the solvents were removed under reduced pressure and water was added to the dark residue. After a short wait, he rushed quickly. The solid was filtered, washed several times with water and dried for several hours to provide 4.3 g (86%) of the desired product. 1 H NMR (CD 3 OD) d 7.40 (m, 2 H), 7.77 (s, 1 H), 7.97 (s, 1 H). Mass spectrum: 222.95 (MH) +. 5-Formyl-lH-indole-3-carbonitrile The 5-bromo-lH-indole-3-carbonitrile (4.25 g, 19.23 mmol) and sodium hydride (0.51 g, 21.2 mmol) were weighed in 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 becomes homogeneous. The stirred mixture was cooled 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 was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C and treated carefully with 1 N hydrochloric acid (45 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was reached. 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 2.4 g (72%) of pure material. LC / MS: t R = 171.07 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (3-cyano-lH-indol-5-yl) -acrylic acid methyl ester 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-lH-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), dried over sodium sulfate, and concentrated. Column chromatography gave 1.3 g (82%) of pure material. LCMS: tR = 1.43 min, 376.22 (MH) +.

Methyl ester of (±) -2-amino-3- (3-cyano-lH-indol-5-yl) -propionic acid The methyl ester of 2-benzyloxycarbonylamino-3- (3-cyano-lH-indol-5-yl) -acrylic acid (0.5 g, 1.3 mmol) in methanol (8 mL) was wetted with nitrogen, and treated with palladium in charcoal (10%, 50 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.3 g (92%) of the desired material. LCMS: tR = 0.80 min, 244.20 (MH) +. Example 202 Methyl ester of (±) -3- (3-cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A stirred solution of the methyl ester of 2-amino-3- (3-cyano-lH-indol-5-yl) -propionic acid (25 mg, 0.11 mmol) in tetrahydrofuran (3 mL) at 0 ° C was treated with diimidazole carbonyl (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-lH-quinazolin-2-one (25). mg, 1.1 equiv.). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography to give 40 mg (75%) as a white powder. LC / MS: t R = 1.37 min, 501.33 (MH) +. EXAMPLE 203 [2- [1,4 '] Bipiperidinyl-l' -yl-1- (3-cyano-lH-indol-5-yl-methyl) -2-oxo-ethyl] -amide of the acid (±) - 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid A solution of the methyl ester of 3- (3-cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic (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 was stirred at room temperature for 2 h. The solution was cooled to 0 ° C, and treated with aqueous 1M potassium hydrogen sulfate (60 μL, 2.0 equiv.), And the solvents were 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 ° C, and treated sequentially with methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), N, N-diisopropylethylamine ( 12 μL, 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). Y-NMR (CD3OD) d 1.60-2.10 (m, 14H), 2.53 (d, J = 13.0, 1H), 2.58 (d, J = 12.2, 1H), 2.65-3.00 (m, 7H), 3.12 (d) , J = 7.0, 1H), 3.17 (d, J = 7.0, 1H), 3.84 (s, 1H), 3.46 (bs, 1H), 4.08-4.86 (m, 5H), 4.70 (, 1H), 5.02 ( dd, J = 8.2, 6.7.1H), 6.79 (d, J = 7.6, 1H), 6.9 (m, 1H), 7.10 (d, J = 7.3, 7.9, 1H), 9.18 (s, 1H), 7.15 (dd, J = 7.3, 7.6, 1H), 7.30 (m, 1H), 7.50 (, 1H), 8.00 (s, 1H). Mass spectrum: 647.41 (MH) +. 3- (4-Bromo-2-methyl-phenylamino) -2-methyl-acrylic acid methyl ester To a solution of 4-bromo-2-methyl aniline (7.0 g, 37.8 mmol) in acetonitrile (80 L) was added, sequentially, concentrated hydrochloric acid (15 mL), water (40 mL) and a sodium nitrate solution. (2.74 g, 39.7 mmol) in water (40 mL) under cooling on ice 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 ° C. After the addition was complete, the 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. 1 H-NMR (CD30D) d 1.80 (t, J = 7.0, 3H), 2.13 (s, 3H), 2.29 (s, 3H), 4.26 (dd, J = 5.8, 7.0, 1H), 4.30 (dd, J = 5.8, 7.0, 1H), 7.26 (m, 2H), 7.43 (m, 1H). Mass spectrum: 323.07 (MNa) +.

-Bromo-7-methyl-lH-indole-2-carboxylic acid ethyl ester A solution of p-toluenesulfonic acid monohydrate (4.26 g, 75 mmol) in toluene (80 L) was heated to 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 was heated to a reflux for 5 h. After cooling to room temperature, the reaction mixture was poured into ice water (120 mL) and extracted twice with ethyl acetate. The organic layers are pooled together and washed with sodium bicarbonate (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated. Column chromatography on silica gel provides 5.5 g (78%) of the title compound. Y-NMR (CD30D) d 1.35 (t, J = 7.0, 3H), 2.52 (s, 3H), 4.36 (q, J = 7.0, 2H), 7.13 (s, 1H), 7.14 (s, 7.70 (s) , 1H), 11.90 (s, 1H), Mass spectrum: 284.09 (MH) +. 5-Bromo-7-methyl-lH-indole.

The ethyl ester of 5-bromo-7-methyl-1H-indole-2-carboxylic acid (5.3 g, 18.7 mmol) was added to a solution of potassium hydroxide in a water / ethanol 1: 1 mixture (20 mL). and it was heated to reflux for 12 h. After cooling to room temperature, the solvents were removed in vacuo and the resulting residue was transferred to a 6N hydrochloric acid solution (20 mL). The white precipitate formed is filtered, washed several times with water, and it dries for several hours. The crude solid was dissolved in quinoline (14 mL) and heated to 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 isopropanol result in significant decomposition. The title compound was obtained by flash chromatography on silica gel to provide 1.5 g (38%, 2 steps). LC / MS: t R = 1.72 min, 210.05 (MH) +. -bromo-7-methyl-lH-indole-3-carboxaldehyde The 5-bromo-7-methyl-lH-indole (1.2 g, 5.71 mmol) was dissolved in acetonitrile (6 mL) and slowly transferred to a solution of bro-ometilen dimethyl ammonium bromide (1.36 g, 6.28 mmol) in acetonitrile (9 mL) at -10 ° C to 0 ° C. The reaction was stirred at 0 ° C for 2 hours and at room temperature for 30 min. The solvents were evaporated and the crude mixture was 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 are pooled together and washed with brine (2x), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel provides 0.7 g (52%, 2 steps) of the desired compound. Y-NMR (CD30D) d 2.50 (s, 3H), 7.24 (s, 1H), 8.34 (, 1H), 9.93 (s, 1H). Mass spectrum: 238.05 (MH) +. 5-bromo-7-methyl-lH-indole-3-carbonitrile A mixture of 5-bromo-indole-3-carboxaldehyde (0.7 g, 2.94 mmol), ammonium acid phosphate (2.05 g, 5 mmol) in 1-nitropropane (9 mL) and acetic acid (3 L) were heated to reflux for 16 h. After cooling to room temperature, the solvents were removed under reduced pressure and water was added to the dark residue. After a short wait, the 5-bromo-lH-indole-3-carbonitrile was precipitated rapidly, filtered, washed several times with water and dried for several hours to provide 0.6 g (87%) of the desired nitrile. LC / MS: t R = 1.71 min, 235.01 (MH) +. -formyl-7-methyl-lH-indole-3-carbonitrile The 5-bromo-7-methyl-lH-indole-3-carbonitrile (0.58 g, 2.46 mmol) and sodium hydride (68 mg, 2.7 mmol) were weighed in a flared round bottom flask containing a bar magnetic stirrer. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (9 L) was added. The mixture was stirred at room temperature for 15 min, during which time it becomes 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 (0.9 mL) was slowly added and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C and carefully treated with 1N hydrochloric acid. After a few minutes, the solid sodium bicarbonate was added until a pH of 9-10 was reached. 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 60 mg (14%) of the desired product and 0.4 g of the unreacted starting material. LCMS: tR = 1.21 min, 185.10 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (3-cyano-7-methyl-1H-indol-5-yl) -acrylic acid methyl ester A stirred solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (180 mg, 0.54 mmol) in tetrahydrofuran (3 mL) at room temperature was treated with tetramethylguanidine (40 μL, 1.1 equiv). After 10 min, 5-formyl-7-methyl-lH-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. LCMS: tR = 1.59 min, 390.24 (MH) +.

Methyl ester of (+) -2-amino-3- (3-cyano-7-methyl-lH-indol-5-yl) -propionic acid methyl ester The methyl ester of 2-benzyloxycarbonylamino-3- (3-cyano-7-methyl-1H-indol-5-yl) -acrylic acid (0.1 g, 0.26 mmol) in methanol (2.5 mL) was wetted with nitrogen, and it was treated with palladium on charcoal (10%, 10 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted 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) +. EXAMPLE 204 [2- [1,4 '] Bipiperidinyl-1' -yl-1 (3-cyano-7-methyl-lH-indol-5-yl-methyl) -2-oxo-ethyl] -amide of the acid ( +) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203: Y-NMR (CD3OD) d 1.55-2.10 (m, 16H), 2.50 (s, 3H), 2.80-3.20 (m, 9H), 4.10-4.40 (, 7H), 4.90 (m, 3H), 6.72 (d, J = 7.9, 1H), 6.93 (dd, J = 8.5, 8.5, 1H), 7.40 (s, 1H), 7.88 (s, 1H), 7.90 (s, 1H) ), 7.90 (s, 1H), 7.99 (s, 1H). Mass spectrum: 651.57 (MH) +. 4-Bromo-2-isopropyl-6-methyl-phenylamine The 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 1 h at room 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. by flash chromatography on silica gel provides 7.6 g (quantitative) of the desired product LC / MS: t R = 1.37 min, 230.07 (MH) +. 4-Bromo-2-isopropyl-6-methyl-phenyldiazo-t-butyl sulfide The 4-bromo-2-isopropyl-6-methyl-phenylamine (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 nitrate (2.4 g, 1.05 equiv.) In water (5 mL), dropwise for 30 min while the temperature was maintained below -5 ° C. After an additional 30 min at -5 ° C to -20 ° C, the mixture is quenched to ca. pH 5 with solid sodium acetate. This mixture (maintained at ca. -10 ° 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 ° C for ca. 30 min. After the addition, the mixture was stirred at 0 ° C for 30 min and then ground ice (ca 50 mL) was added. The resulting light brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours to provide 7.9 g (72%) of the desired product. Y-NMR (CDC13) d 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, 1 HOUR) . Mass spectrum: 331.08 (MNa) +.

-Bromo-7-isopropyl-lH-indazole 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 was placed under nitrogen. To this was 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 several times with water. The solid was collected and dried in vacuo to give 4.2 g (74%) of the desired product. LCMS: tR = 1.73 min, 241.06 (MH) +. 7-Isopropyl-lH-indazol-5-carbaldehyde The 5-bromo-7-isopropyl-lH-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 15 min, during which time it becomes 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 -78 ° C, dimethylformamide (3.0 mL) was added slowly and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C and treated carefully with 1 N hydrochloric acid (35 L). After a few minutes, the solid sodium bicarbonate was added until a pH of 9-10 was reached. 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. LCMS: tR = 1.15 min, 189.12 (MH) +. Methyl ester of 2-benzyloxycarbonylamino-3- (7-isopropyl-lH-indazol-5-yl) acrylic acid A stirred solution of trimethyl N-benzyloxycarbonyl-a-phosphonoglycine ester (0.39 g, 1.2 equiv) in tetrahydrofuran (5 mL) at room temperature was treated with tetramethylguanidine (0.16 mL, 1.1 equiv.). After 10 min, 7-isopropyl-lH-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 was purified by flash chromatography on silica gel to give 0.35 g (84%) of the product. LCMS: tR = 1.61 min, 394.16 (MH) +. Methyl ester of (±) -2-amino-3- (7-isopropyl-lH-indazol-5-yl) propionic acid A solution of the methyl ester of 2-benzyloxycarbonylamino-3- (7-isopropyl-lH-indazol-5-yl) acrylic acid (0.35 g, 0.89 mmol) in methanol (7 mL) was wetted with nitrogen, and treated with Palladium in charcoal (10%, 35 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.21 g (90%) of the desired material.

EXAMPLE 205 Methyl ester of (±) -3- (7-isopropyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for methyl ester of 3- (3-cyano-lH) -indol-5-yl) -2- acid. { [4- (2-Oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino and propionic. LCMS: tR = 1.49 min, 519.35 (MH) +.

Example 206 [2- [1, 4 '] bipiperidinyl-1-yl-l (7-isopropyl-lH-indazol-5-yl-methyl) -2-oxo-ethyl] -amide of (±) -4 acid - (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from the methyl ester of 3- (7-isopropyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 1 H-NMR (CD3OD) d 1.45 (m, 6H), 1.60-2.05 (m, 14H), 2.20-2.50 (m, 4H), 2.73 (d, J = 13.7, 1H), 2.90 (m, 4H), 4.05 (d, J = 14.0, 1H), 4.20 (m, 2H), 4.35 (s, 1H), 4.65 (d, Y12.2, 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 spectrum: 655.40 (MH) +. 4-Bromo-2,6-diethylphenyldiazo-t-butyl sulfide The 4-bromo-2,6-diethylaniline (6.3 g, 27.6 mmol) was suspended in 24% hydrochloric acid (15 L). The stirred mixture was cooled to -20 ° C and treated with sodium nitrate (2.0 g, 1. 05 equiv.) In water (5 mL), dropwise for 30 min while the temperature was maintained below -5 °. C. After an additional 30 min at -5 ° C to -20 ° C, the mixture is quenched to ca. pH 5 with solid sodium acetate. This mixture (maintained at ca -10 ° C) was added in portions to a stirred solution of t-butyl thiol (3.15 mL, 1.0 equiv.) In ethanol (25 mL) at 0 ° C for ca. 30 min. After the addition, the mixture was stirred at 0 ° C for 30 min and then ground ice (ca 50 mL) was added. The resulting light brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours to provide 6.0 g (66%) of the desired product. Y-NMR (CDC13) d 1.15 (t, JY.6, 6H), 1.50 (s, 9H), 2.27 (m, 4H), 7.21 (s, 2H). Mass spectrum: 331.08 (MH) +.

-Bromo-7-ethyl-3-methylindazole 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 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 L). The resulting suspension was collected by filtration and washed several times with water. The solid was collected and dried in vacuo to give 2.85 g (98%) as a beige solid. Y-NMR (CD3OD) d 1.32 (t, J = 7.6, 3H), 2.50 (s, 3H), 2.88 (m, 2H), 7.25 (s, 1H), 7.68 (s, 1H). Mass spectrum: 239.26 (MH) +. 7-Ethyl-3-methylindazole-5-carboxaldehyde -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 L) was added. The mixture was stirred at room temperature for 15 min, during which time it becomes 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) was added over several minutes. After 1 h at -78 ° C, dimethylformamide (2.8 mL) was added slowly and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C and treated carefully with 1N hydrochloric acid (30 mL). After a few minutes, the solid sodium bicarbonate was added until a pH of 9-10 was reached. 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. LCMS: tR = 1.15 min, 189.12 (MH) +.

Methyl ester of 2-benzyloxycarbonylamino-3- (7-ethyl-3-methyl-lH-indazol-5-yl) -acrylic acid methyl ester A stirred solution of trimethyl N-benzyloxycarbonyl-a-phosphonoglycine ester (3.17 g, 9.57 mmol, 1.2 equiv.) In tetrahydrofuran (15 mL) at room temperature 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 was purified by flash chromatography on silica gel to give 2.5 g (80%) of the product. LCMS: tR = 1.61 min, 394.16 (MH) +.

Methyl ester of (±) -2-amino-3- (7-ethyl-3-methyl-lH-indazol-5-yl) -propionic acid The methyl ester of 2-benzyloxycarbonylamino-3- (7-ethyl-3-methyl-lH-indazol-5-yl) -acrylic acid (1.0 g, 2.54 mmol) in methanol (15 L) was wetted with nitrogen, and it was treated with palladium on charcoal (10%, 100 mg). The flask was wetted with hydrogen and allowed to stir under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.6 g of the desired material. 1 H-NMR (CD30D) d 1.32 (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, 1H), 3.35 (s, 1H), 3.65 (m, 3H), 7.00 (s, 1H), 7.33 (s, 1H) . Mass spectrum: 262.24 (MH) +.

Example 207 [2- [1,4 '] Bipiperidinyl-l' -yl-1 (7-ethyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4 acid - (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from the methyl ester of (±) -2-amino-3- (7-ethyl-3-methyl-lH-indazol-5-yl) -propionic acid. Y-NMR (CD3OD) d 1.35 (m, 3H), 1.85-2.20 (, 4H), 2.50 (s, 1H), 2.70 (, 2H), 2.85 (s, 3H), 2.88-3.25 (m, 7H) , 3.35 (s, 1H), 3.47 (dd, J = 7.3, 7.3, 1H), 4.00-4.40 (m, 7H), 4.70 (m, 1H), 5.00 (m, 3H), 6.79 (d, J = 7.6, 1H), 6.93 (dd, J = 7.3, 7.3, 1H), 7.10 (m, 1H), 7.15 J = 7.3, 7.6, 1H), 7.45 (m, 1H). Mass spectrum: 655.50 (MH) +.

EXAMPLE 208 [2- [1,4 '] Bipiperidinyl-l' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the (±) -4 acid (2, 2-dioxo-l, 4-dihydro-2H-2? 6-benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from 3-piperidin-4-yl-3, 4-dihydro-lH-benzo [l, 2,6] thiadiazine-2,2-dioxide: Y-NMR (CD3OD) d 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, 1H), 6.70 (d, J = 8.1, 1H), 6.79 (dd, J = 7.67, 7.3, 1H), 7.44 (s, 1H), 7.10 (, 1H), 7.13 (m, 3H), 8.03 (s, 1H). Mass spectrum: 663.60 (MH) +.

Example 209 [2- [1,4 '] Bipiperidinyl-l' -yl-1 (7-ethyl-3-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2, 2-dioxo-l, 4-dihydro-2H-2? 6-benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from 3-piperidin-4-yl-3, 4-dihydro-lH-benzo [1,2,6] thiadiazine-2, 2-dioxide: Y-NMR (CD3OD) d 1.35 (m, 3H), 1.42-2.05 (m, 10H), 2.40 (m, 3H), 2.55 (s, 3H), 2.67-3.12 (m, 7H), 3.85 (m, 1H), 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 spectrum: 691.51 (MH) +.

Example 210 Methyl ester of (±) -2- [4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] - 3- (7-methyl-lH-indazol-5-yl) -propionic Prepared as described above by the methyl ester of 3- (3-cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic: LC / MS: tR = 1.34 min, 516.40 (MH) +. Example 211 { 2- [1,4 '] bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-yl-methyl) -2-oxo-ethyl} -amide of (±) -4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from 2-oxo-3-piperidin-4-yl-1, 2, 3, 4-tetrahydro-quinazoline-6-carbonitrile: Y-NMR (CD3OD) d 1.80 (m , 12H), 2.40 (m, 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, 1H), 7.21 (s, 1H), 7.50 (m, 4H), 8.05 (s, 1H). Mass spectrum: 652.64 (MH) +. Example 212 { 2- [1,4 '] bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4-2-oxo-l, 2,4,5,5-tetrahydro-benzo [d] [1, 3] diazepin-3-yl-l-carboxylic acid Prepared as described above by Example 203 from 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one: Y-NMR (CD3OD ) d 1.40-2.00 (, 12H), 2.30-2.60 (, 8H), 2.70-3.20 (m, 10H), 3.70 (, 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, 1H), 8.05 (s, 1H) ). Mass spectrum: 652.64 (MH) +.

Example 213 { 2- [1,4 '] bipiperidinyl-l' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from 6-hydroxy-3-piperidin-4-yl-3,4-dihydro-lH-quinazolin-2-one: LC / MS: tR = 1.24 min, 643.62 (MH ) + Example 214 { 2- [1, 4 '] bipiperidinyl-1-yl-l- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (8-methoxy-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from 8-methoxy-3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one: Y-NMR (CD3OD) d 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 (, 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 spectrum: 657.41 (MH) +. Example 215 { 2- [1,4 '] bipiperidinyl-l' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (8-chloro-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by Example 203 from 2-chloro-3-piperidin-4-yl-3, 4-dihydro-lH-quinazolin-2-one: Y-NMR (CD30D) d 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 (, 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, 7.6, 1H), 7.47 (m, 1H) , 8.04 (s, 1H). Mass spectrum: 661.27 (MH) +.

Example 216 (±) -N- (3- (7-ethyl-3-methyl-lH-indazol-5-yl) -1-oxo- (4- (piperidin-1-yl) iperidin-1-yl) propan -2-il) -2 ', 3' -dihydro-2 'oxoespiro- (piperidin-4,4' -quinazolin) -1-carboxamide Prepared as described above by Example 203 LC / MS: t R = 1.51 min, 641.63 (MH) +.

Example 217 (+) - N - (3- (7-ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl ) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-carboxamide Prepared as described above by Example 203: LC / MS: t R = 1.48 min, 642.61 (MH) +. tert-Butyl 2-fluorophenylcarbamate 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 for 6 h. It was cooled, concentrated, dissolved in pentane, washed with 5% citric acid, then 1 M potassium bisulfate (2x), then water, then 20% potassium hydroxide, then brine, dried over magnesium sulfate , and concentrated to give 48.0 g (quantitative) as an amber oil which was used without purification. Y-NMR (CDC13, 500 MHz) d 1.52 (s, 9H), 6.68 (bs, 6.85-7.20 (m, 3H), 8.07 (dd, J = 8.1, 8.1, 1H). Mass spectrum: 234.18 (MNa ) + 2- (Tert-butoxycarbonylamino) -3-fluoro-benzoic acid 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, 306 mL, 2.5 equivalents) dropwise . After the addition was complete, the reaction was stirred at -78 ° C for 30 min. The solution was allowed to gradually reach -20 ° C before being cooled down to -78 ° C and transferred by means of a cannula to a thick mixture 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 tetrahydrofuran, and it is poured into a separatory funnel containing water and diethyl ether. The layers were separated, and the aqueous was extracted with diethyl ether twice more. The ethereals were discarded. The aqueous was made acidic with 5% citric acid, extracted with diethyl ether (3x). The ether was dried over magnesium sulfate, and concentrated to give a light yellow solid which was recrystallized from hot toluene to give 37.1 g (70%) as a faint yellow solid 1H-R (CDC13, 500 MHz) d 1.50 ( s, 9H), 6.25 (bs, 1H), 7.18 (ddd, J = 7.9, 7.9, 4.9, 1H), 7.33 (d, J = 9.5, 9.2, 1H), 7.79 (d, J = 7.9, 1H) 7.94 (s, 1H). Mass spectrum: 278.21 (MNa) +. 2- (Tert-Butyl-l-benzylpiperidin-4-ylcarbamnoyl) -6-fluorophenylcarbamate 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-hydroxybenzotriazole (21.6 g, 1.1 equiv. .), and triethylamine (44.1 g, 3.0 equiv.) in ethyl acetate (450 mL) was added l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30.7 g, 1.1 equiv.) in one portion. Initially, all within a solution, but a precipitate formed very quickly. The reaction was equipped with a reflux condenser and heated to reflux for 5 h. The reaction was diluted with ethyl acetate, washed with water (2x), then 1N sodium hydroxide (2x), then brine, dried over magnesium sulfate, and concentrated to give 67.0 g (quantitative) as a white solid which was used without purification. Y-NMR (CDC 13. 500 MHz) d 1.48 (s, 9H), 1.55 (m, 2H), 1.99 (bd, J = 11.0, 2H), 2.17 (dd, J = 11.0, 11.0, 2H), 2.84 ( bd, J = 11.3, 2H), 3.51 (s, 2H), 3.94 (m, 1H), 6.13 (bd, J = 7.6, 1H), 7.10-7.28 (m, 4H), 7.31 (m, 4H), 7.59 (s, 1H). Mass spectrum: 428.41 (MH) +. 2-7? Mino-N- (l-benzylpiperidin-4-yl) -3-fluorobenazamide To a solution of tert-butyl 2- (l-benzylpiperidin-4-ylcarbamoyl) -6-fluorophenylcarbamate (67.0 g, 157 mmol) in dichloromethane (700 mL) at 0 ° C was added trifluoroacetic acid (100 mL). The ice bath was stirred and the reaction was 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 was washed with water (3x), then brine, dried over magnesium sulfate, and concentrated to give 47.6 g (93%) as a white solid which was used without purification. Mass spectrum: 328.33 (MH) +.

N- (2-Amino-3-fluorobenzyl) -l-benzylpiperidin-4-amine To a reflux 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- (l-benzylpiperidin-4-yl) -3-fluorobenzamide (39.7 g, 121 mmol) in dioxane (250 mL) at a ratio such that the evolution of the gas is limited to a safe flow. After the addition was complete, the resulting suspension was heated to reflux for 4 h. The reaction was cooled to 0 ° C, and quenched by the careful addition of 20% potassium hydroxide. Once a white, filterable precipitate is formed, the solid is filtered through a sintered thick glass funnel, and the eluent is concentrated to give 36.3 g (96%) as a light yellow oil which was used without purification. Mass spectrum: 314.29 (MH) +. 3- (l-benzylpiperidin-4-yl) -8-fluoro-3,4-dihydroquinazolin-2 (lH) -one 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 diimidazole carbonyl (20.7 g, 10 equiv. ) in one portion. The reaction was stirred at room temperature for 3 h, heated to reflux for 30 min, and concentrated. The resulting solid was dissolved in 1: 1 diethyl ether / ethyl acetate, washed with water (3x), then brine, dried over magnesium sulfate, and concentrated to give the crude product as a yellow, wet solid. The solid was triturated with diethyl ether and filtered to give 30.0 g (76%) as a white powder. Y-NMR (CDC13, 500 MHz) d 1.68 (m, 2H), 1.86 (dddd, J = 11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, J = 11.6, 10.1, 2H), 2.98 (d , J = 11.6, 2H), 3.51 (s, 2H), 4.34-4.44 (m, 3H), 6.71 (bs, 1H), 6.79-6.89 (m, 2H), 6.94 (dd, J = 9.2, 9.2, 1H), 7.21-7.34 (m, 5H). Mass spectrum: 340.30 (MH) +.

-Fluoro-3, 4-dihydro-3- (piperidin-4-yl) quinazolin-2 (1H) -one A 250 mL flask was charged with 3- (l-benzylpiperidin-4-yl) -8-fluoro-3,4-dihydroquinazolin-2 (lH) -one (1.40 g, 4.12 mmol) and methanol (25.0 mL). The suspension was heated with a heat gun to aid in the dissolution. The flask was wetted with nitrogen, treated with palladium on charcoal (141 mg, 0.032 equiv.), It is wetted with nitrogen, then hydrogen, and stirred vigorously under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated to give 0.99g (97%) as a white solid which was used without purification. Y-NMR (CDC13, 500 MHz) d 1.71 (m, 4 H), 2.75 2 H), 3.16 (m, 2 H), 4.38 (s, 2 H), 4.46 (m, 1 H), 6.77 (bs, 1 H), 6.81 -6.89 (m, 2H), 6.95 (, 1H). Mass spectrum: 250.22 (MH) +. 3- (1-benzylpiperidin-4-yl) -8-fluoroquinazoline-2,4 (1H, 3H) -dione 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 ° C, triphosgene was added (227 mg, 0.33 g). equiv.) as a solution in dichloromethane (5 mL). The ice bath was stirred and the reaction was heated to reflux for 6 h. The reaction was concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate, then water, then brine, dried 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 spectrum: 354.13 (MH) +. i-Fluoro-3- (piperidin-4-yl) quinazoline-2,4 (1H, 3H) -dione A flask containing a solution of 3- (l-benzylpiperidin-4-yl) -8-fluoroquinazolin-2,4 (1H, 3H) -dione (75.0 mg, 0.21 mmol) and palladium in charcoal (8.00 mg, 0.035 equiv) in methanol (3.00 mL) was first wetted with nitrogen, then hydrogen. The reaction was stirred under a hydrogen atmosphere overnight. The reaction was wetted with nitrogen, filtered through celite, and concentrated to give 53 mg (95%) as a white solid which was used without purification. Mass spectrum: 264.25 (MH) +. 8 '-Fluoro-2', 3 '-dihydro-2' -oxoespiro- (1-phenylmethylpiperidine) -4,4' -quinazoline A 3-neck flask of 500 mL was charged with polyphosphonic acid (110 L) and equipped with a dome stirrer, a nitrogen inlet, and a bubbler. The flask was wetted with nitrogen and heated to 105 ° C in an oil bath. To this was added l-benzyl-4-piperidone (21.0 mL, 115 mmol). To this was added N- (2-fluorophenyl) urea (21.3 g, 1.2 equiv) in very small portions for 2 h. The reaction was heated to 160 ° C with vigorous stirring. After 2 h, the reaction was quenched by pouring on ground ice and neutralized with 20% potassium hydroxide. The reaction mixture was extracted with dichloromethane, washed with water, then brine, dried over magnesium sulfate, and concentrated. The whole batch was purified by preparative HPLC (~ 130 injections) to give a much purer product. The product was further purified 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. Y-NMR (CDC13, 500 MHz) d 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), 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 spectrum: 326.13 (MH) +. 8 '-Fluoro-2', 3 '-dihydro-2' -oxoespiro-piperidin-4, 4'-quinazoline To a solution of 8'-fluoro-2 ', 3'-dihydro-2'-oxospiro- (1-phenylmethylpiperidin) -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 wetted with hydrogen, and stirred under a hydrogen atmosphere overnight. The balloon was removed, the reaction was wetted with nitrogen, filtered through celite, washed with additional methanol, and concentrated to give 158 mg (87%) as a white solid which was used without purification. 1 H-NMR (CDCl 3 / CD 3 OD, 500 MHz) d 1.87 (d, J = 12.8, 2H), 2.15 (dd, J = 14.0, 14.0, 5.5, 2H), 3.10 (m, 4H), 6.84 (m, 2H ), 6.93 (d, J = 7.0, 1H). Mass spectrum: 236.11 (MH.}. +.

Example 218 (+) - N - (3- (7-ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-lH-pyrazolo [4, 3-c] pyridin-5 (4H) -yl) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide Prepared as described above by Example 203: 1H-NMR (CD3OD, 500 MHz) d 1.24 (m, 2H), 1.55-2.07 (, 5H), 2.57 (m, 1H), 2.82 (m, 4H), 3.08 (m, 2H), 3.30 (m, 3H), 3.35 (m, 5H), 3.48 (m, 3H), 3.65 (m, 1H), 4.14 (m, 2H), 4.27 (m, 2H), 4.33- 4.57 (m, 2H), 5.06 (dd, J = 6.7, 6.7, 1H), 5.22 (d, J = 1.8, 2H), 6.78 (d, J = 7.6, 1H), 6.93 (m, 1H), 7.00 -7.18 (m, 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 spectrum: 596.43 (MH) +.

Example 219 (±) -N- (3- (7-ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-lH-pyrazolo [4, 3-c] pyridin- 5 (4H) -yl) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide Prepared as described above by Example 203 XH-NMR (CD30D, 500 MHz) d 1.11 (, 3H), 1.50-1.80 (m, 4H), 2.87 (, 4H), 3.10 (m, 2H), 3.32 (m , 9H), 3.48 (m, 4H), 4.00-4.45 (m, 6H), 5.05-5.25 (m, 2H), 6.77 (d, J = 6.1, 1H), 6.93 (m, 1H), 7.13 (m, 3H), 7.30-7.60 (m, 2H), 7.95 (m, 1H). Mass spectrum: 624.49 (MH) +. EXAMPLE 220 2- (4- (8-fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (7-methyl-lH-indazol-5-yl) ) (±) -methyl propanoate Prepared as described above for 3- (3-cyano-lH-indol-5-yl) -2- methyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] amino} -propionic: Y-NMR (CDC13, 500 MHz) d 1.53-1.68 (m, 4H), 2.48 (s, 3H), 2.82 (m, 2H), 3.05 (m, 6H), 3.09 (dd, JaB = 13.7 , 6.1, 1H), 3.14 (dd, JAB = 14.0, 6.1, 1H), 3.35 (bs, 1H), 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, 1H), 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 spectrum: 509.25 (MH) +.

Example 221 (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3- (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide Prepared as described above by Example 203 (CD3OD, 500 MHz) d -0.25 (m, 1H), 0.82 (, 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 (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 spectrum: 645.58 (MH) +. Example 222 (+) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) - 1-oxo-l- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide Prepared as described above by Example 203: Y-NMR (CDC13, 500 MHz) d 1.73 (m, 4H), 2.49 (m, 4H), 2.80-3.26 (, 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, 1H), 5.90 ( bs, 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, 1H), 7.26-7.33 (m , 2H), 7.44 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H). Mass spectrum: 639.36 (MH) +.

Example 223 (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazin-1-yl) -3- (7-Methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide Prepared as described above by Example 203: ^? - NMR (CDC13, 500 MHz) d 1.73 (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 (, 1H9, 3.78 (, 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, 1H), 6.70-6.84 (, 3H), 6.85-7.02 (m, 5H), 7.09 ( s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 8.06 (s, 1H), Mass spectrum: 657.35 (MH) +.

Example 224 (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazin-1-yl) -3- (7-Methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide Prepared as described above by Example 203: XH-NMR (CDC13, 500 MHz) d 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, JAB = 13.1, 8.6, 1H), 3.12 (m, 1H), 3.30 (m, 1H) , 3.57 (m, 1H), 3.73 (, 2H), 4.13 (dd, J = 19.8, 15.0, 2H), 4.33 (s, 2H), 4.53 (m, 1H), 5.18 (dd, J = 8.2, 5.8 , 1H), 5.82 (bs, 1H), 6.58 (dd, J = 8.2, 8.2, 1H), 6.81 (d, J = 7.6, 1H), 6.85-7.05 (m, 5H), 7.09 (s, 1H) , 7.44 (s, 1H), 7.58 (s, 1H), 8.05 (s, 1H). Mass spectrum: 657.37 (MH) +.

Example 225 (+) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) - 1-oxo-l- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide Prepared as described above by Example 203: Y-NMR (CDC13, 500 MHz) d 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, 8.5, 1H), 2.65 (m, 1H), 2.81 (, 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, 2H), 4.31 (s, 2H), 4.53 (m, 1H), 5.19 (dd, J = 7.9, 5.8, 1H), 5.84 (bs, 1H), 6.54 (d, J = 7.6, 1H), 6.81 (d, J = 7.6, 1H), 6.89 (ddd, J = 7.6, 7.6, 5.2, 1H), 6.96 (m, 2H), 7.00-7.23 (m, 4H), 7.39 (s, 1H), 7.43 (s, 1H), 8.04 (s, 1H). Mass spectrum: 653.38 (MH) +.

Example 226 2- (4- (8-fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (7-ethyl-3-methyl-lH-indazole -5-yl) (±) -methyl propanoate Prepared as described above by the methyl ester of 3- (3-cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic: Y-NMR (CD3OD, 500 MHz) d 1.33 (, 3H), 1.39-1.72 (m, 4H), 2.70-2.95 (m, 3H), 3.06 (m, 1H), 3.25 (m, 1H) , 3.70 (m, 3H), 3.95-4.30 (m 4H), 4.38 (, 1H9, 4.57 (m, 1H), 6.80-7.05 (m, 3H), 7.08 (s, 1H), 7.38 (s, 1H) Mass spectrum: 537.47 (MH) +.

Example 227 (±) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) ) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide Prepared as described above by Example 203: Y-NMR (CD3OD, 500 MHz) d -0.36 (m, 1H9, 0.70 (m, 1H), 1.21 (bd, J = 11.9, 1H), 1.28-2.00 (m , 19H), 2.31 (dd, J = 11.6, 11.3, 1H), 2.40 (dd, J = 13.1, 11.6, 1H), 2.79-3.16 (m, 7H), 3.72 (m, 1H), 3.85-4.03 ( m, 1H), 4.10-4.48 (m, 5H), 4.53 (bd, J = 11.0, 1H), 5.05 (m, 1H), 6.85-7.03 (m, 3H), 7.08 (s, 0.2H), 7.18 (s, 0.8H), 7.37 (s, 1H), Mass spectrum: 673.42 (MH) +.

Example 228 (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin -l-yl) propan-2-yl) -4- (8-fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide Prepared as described above by Example 203: Y-NMR (CD30D, 500 MHz) d 0.71 (m, 1H), 1.26 (m, 1H), 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 = 11.6, 1H), 4.32-4.45 (m, 3H), 4.68 (bd, J = 13.4, 1H), 4.92 (, 1H), 6.87-7.22 (m, 6H). Mass spectrum: 648.47 (MH) +.

Example 229 (+) - N - (3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- (4-piperidin-1-yl) piperidin-1-yl) propan-2 il) -8 '-fluoro-2', 3 '-dihydro-2' -oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide Prepared as described above by Example 203: Y-NMR (CD3OD, 500 MHz) d -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 (, 4H), 4.55-4.73 (, 2H), 4.96 (dd, J = 7.9, 7.6, 1H), 5.01 (dd, J = 10.4, 5.8, 1H), 6.65-7.15 (m, 5H), 7.21 (s, 1H), 7.47 (s, 1H), 7.96 (m, 1H), 8.04 (s, 1H). Mass spectrum: 631.29 (MH) +.

Example 230 (±) -4- (8-Fluoro-l, 2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl ) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide Prepared as described above by Example 203: Y-NMR (CD3OD, 500 MHz) d -0.26 (m, 1H), 0.81 (m, 1H), 1.20-2.10 (m, 11H), 2.20-2.80 (m, 9H), 2.90 (m, 3H), 3.10 (m, 3H), 3.34 (m, 1H), 3.44 (m, 1H), 4.06 (bd, J = 13.4, 1H), 4.17 (d, JAB = 15.9, 1H), 4.22 (d, JAB = 13.1, 1H), 4.64 (dd, J = 24.4, 13.1, 1H), 4.91-5.13 (m, 2H), 7.00-7.25 (m, 2H), 7.44 (m, 2H ), 7.81 (m, 1H), 7.92-8.08 (m, 1H). Mass spectrum: 659.59 (MH) +. 2-Amino-3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) propanoate of (R) -methyl A mixture of the methyl ester of (R) -benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid (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 7 with saturated aqueous 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). Y-NMR (CDC13, 300 MHz) d 7.37 (bs, 7.35 (bs, 7.17 (d, J = 8.4 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 spectrum: 288 (MH) +. 4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2-trifluoromethyl) -lH-benzo [d] imidazol-5-yl) propanoate of ( R) -methyl 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 mg, 2.03 mmol), and disuccinimidyl carbonate (129 mg, 0.51 mmol) in a mixture of methylene chloride / dimethylformamide (ratio 15: 1) was stirred at room temperature for 30 minutes. min. To the solution was added 4- (2-keto-l-benzimidazolinyl) piperidine and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was filtered to remove any solid and then purified by flash column chromatography (95: 3: 2 methylene chloride / methanol / triethylamine) to give the title compound (215 mg, 77% yield) as a tan solid. Y-NMR (CDC13, 300 MHz) d 7.67 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.21-7.16 (m, 1H), 7.05-6.94 (m, 3H), 6.70-6.68 2H), 5.11 (d, J = 7.3 Hz, 1H), 4.78 (dd, J = 12.1, 5.5 Hz, 1H), 4.42 (d, J = 4.4 Hz, 2H), 4.29 (d, J = 12.1 Hz, 1H9, 3.82-3.72 (m, 2H), 3.74 (s, 3H), 3.44 (dd, J = 13.9, 5.5 Hz, 1H), 3.22 (dd, J = 13.9, 5.5 Hz), 2.95-2.83 (m, 3H), 2.18-2.03 (, 2H), 1.79-1.68 (m, 2H) Mass spectrum: 545 (MH) +. (R) -2- (4- (1,2-dihydro-2-oxoquinazolin) -3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid To a solution of the ester of 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [d ] imidazol-5-yl) propanoate of (R) -methyl (220 mg, 0.40 mmol) in tetrahydrofuran and methanol (mixture 1: 1, 20 mL) at 0 ° C, lithium hydroxide was added (36 mg, 1.51 mmol) in water (10 mL). The mixture was stirred at 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 1N HCl (3 mL). The organic extracts were dried over sodium sulfate, filtered, and evaporated to give the title compound (176 mg, 82% yield). LCMS: tR = 2.01 min, 531 (MH) +. Example 231 N ~ ((R) -3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) -1-oxo-1- (4-piperidin-1-yl) piperidin-1- il) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide To a stirred solution of (R) -2- (4- (1, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -IH) -benzo [d] imidazole-5-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 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 subjected to preparative thin layer chromatography for purification (1:10 2M ammonia in methanol / methylene chloride) to give the title compound (4.6 mg, 12% yield). Y-NMR (CD3OD, 500 MHz) d 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, 1 HOUR) , 6. 81 (d, J = 7.9 Hz, 1H9, 5.06-5.02 (m, 1H), 4.67-4.58 (m, 1H), 4.49-4.40 (m, 1H), 4.38 (s, 1H), 4.33 (bs, 1H), 4.25-4.16 (m, 2H), 4.10-4.03 (m, 1H), 3.22-3.14 (m, 3H), 3.04-2.87 (m, 4H), 2.79-2.71 (m, 1H), 2.58-2.48 (, 1H), 2.44-2.33 (m, 1H), 2.31-2.22 (m, 1H), 2.04-1.92 (m, 1H), 1.86-1.43 (m, 11H), 1.33-1.29 (m, 1H), 0.94-0.84 (, 1H), -0.04- -0.12 (m, 1 HOUR) . LCMS: tR = 1.97 min, 681 (MH) +.

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) piperidin-1-carboxamide Prepared as described above by Example 231. Y-NMR (CD3OD, 300 MHz) d 7.69-7.56 (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, 1H9, 4.46-4.35 (m, 1H), 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) +.

(R) -1- (methoxycarbonyl) -2- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) ethylcarbamate benzyl To a diluted solution of (R) -2-benzyloxycarbonylamino-3- (3, -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 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered to remove the 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). Y-NMR (CD3OD, 300 MHz) d 7.28- 7.21 (m, 5H), 6.94-6.83 (m, 3H), 5.06-4.95 (m, 2H), 4.46-4.41 (m, 1H), 3.68 (s, 3H), 3.17-3.11 (, 1H), 2.95-2.88 (m, 1H).

LCMS: tR = 2.11 min, 370 (MH) +. 2-amino-3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) propanoate of (R) -methyl The (R) -1- (methoxycarbonyl) -2- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) ethylcarbamate benzyl ester (265 mg, 0.72 mmol) and palladium on carbon 10% (30 mg) in methanol (15 mL) were stirred for 1.5 h under 50 psi (3.51 kg / cm2) of hydrogen using a Parr apparatus. The reaction mixture was purged with 3 cycles of vacuum / nitrogen purge. The reaction mixture was then filtered through a pad of Celite® and the pad rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (168 mg, quantitative performance). 1 H-NMR (CD 3 OD, 300 MHz) d 6.97 (d, J = 8.1 Hz, 1 H), 6.87 (s, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 3.71-3.64 (m, 1 H), 3.67 (s, 3H), 3.04-2.89 (m, 2H). LCMS: tR = 0.87 min, 236 (MH) +. EXAMPLE 233 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2,3-dihydro-2-oxo-lH-benzo [d imidazol-6-yl) propanoate of (R) -methyl Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [d ] imidazol-5-yl) propanoate of (R) ~ methyl. Y-NMR (CD3OD, 300 MHz) d 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, 1H9, 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) +.

Acid (R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2,3-dihydro-2-oxo-lH- benzo [d] imidazol-6-yl) -propanoic acid Prepared as described above for (R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) - IH-benzo [d] imidazol-5-yl) propanoic acid. 1H-NMR (CD3OD, 300 MHz) d 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 (, 1H). LCMS: tR = 1.83 min, 479 (MH) +.

Example 234 N- ((R) -3- (2,3-Dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl) piperidin -1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) -piperidine-1-carboxamide Prepared as described above for example 231. Y-NMR (CD3OD, 300 MHz) d 7.17-7.10 (m, 2H), 7.01 (s, 1H), 6.95-6.90 (m, 3H), 6.78 (d, J = 8.1 Hz, 1H), 4.98-4.93 (m, 1H), 4.62-4.55 (m, 1H), 4.41-4.33 (m, 2H), 4.20-4.16 (m, 2H), 4.04-3.96 (m, 1H) ), 3.05-2.85 (m, 7H), 2.71-2.57 (m, 1H), 2.53-2.32 (, 1H), 1.86-1.76 (m, 2H), 1.70-1.61 (m, 8H), 1.50-1.41 ( m, 2H), 1.03-0.89 (m, 1H), 0.10-0.02 (m, 1H). Mass spectrum: 629.22 (MH) +.

Example 235 N- ((R) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-lH-banzo [d] imidazol-6-yl) ethyl) -4- (1, 2- dihydro-2-oxoquinazoline-3 (4H) -yl) piperidine-1-carboxamide Prepared as described above by example 231. LCMS: tR = 1.96 min, 506 (MH) +. 2- [2 ', 3' -dihydro-2 '-oxoespiro- (piperidin-4, 4' - (1H) -quinazoline) carbonylamino] -3-2, 3-dihydro-2-oxo-lH-benzo [d imidazol-6-yl) propanoate of (R) -methyl Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [ d] imidazol-5-yl) propanoate. Y-NMR (DMSO-d6, 500 MHz) d 10.54 (s, 1H), 10.50 (s, 1H), 9.22 (s, 1H), 7.21 (s, 1H), 7.13-7.10 (m, 1H), 6.96 -6.79 (, 7H), 4.29-4.25 (m, 1H), 3.82-3.78 (m, 2H), 3.60 (s, 3H), 3.32-3.23 (m, 1H), 3.16-3.14 (m, 1H), 3.00-2.90 (m, 2H), 2.08 (s, 1H), 1.67-1.55 (m, 4H). LCMS: tR = 1.62 min, 479 (MH) +. Acid (R) -2- [2 ', 3' -dihydro-2 '-oxospiro- (piperidin-4, 4' - (1H) -quinazoline) carbonylamino] -3-2, 3-dihydro-2-oxo- lH-benzo [d] imidazol-6-yl) propanoic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [d] imidazol-5-yl) propanoic acid. Y-NMR (CD30D, 300 MHz) d 7.19-7.14 (, 1H), 7.05-6.95 (m, 5H), 6.81 (d, J = 7.7 Hz, 1H), 5.04-4.90 (m, 1H), 4.57- 4.52 (m, 1H), 3.96-3.84 (m, 2H), 3.24-3.14 (m, 2H), 3.07-2.95 (m, 1H), 1.94-1.73 (m, 4H). LCMS: tR = 1.67 min, 465 (MH) +.

Example 236 N- ((R) -3- (2,3-Dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) -1-oxo-1- (4-piperidin-1-yl) piperidin -1-yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospiro (piperidin-4, 4' - (1H) -quinazoline) carboxamide Prepared as described above by the LC / MS example: tR = 1.55 min, 615 (MH) +. 4-Acetamido-3-methylbenzoic acid 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 was diluted with water (400 mL) and extracted with ethyl acetate (3 x 600 L). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the title compound as a brown solid (43 g, 56% yield). a H-NMR (d 6 -DMSO, 300 MHz) d 9.36 (s, 1 H), 7.77 (s, 1 H), 7.10 (s, 2 H), 2.27 (s, 3 H), 2.10 (s, 3 H). LCMS: tR = 1194 (MH) +. 4-Acetamido-3-methyl-5-nitrobenzoic acid 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 for 40 minutes while cooling with an ice bath. After the addition of all the amide was complete, the reaction mixture was stirred for 1 h at 0 ° C and then slowly emptied onto 1500 mL of ice. The yellow solid was collected by filtration and washed with ice cold with water to give the title compound (38 g, 72% yield). Y-NMR (CD30D, 300 MHz) d 8.29 (s, 1H), 8.18 (s, 1H), 2.39 (s, 3H), 2.-16 (s, 3H). Mass spectrum: 237 (MH) +. 4-Amino-3-methyl-5-nitrobenzoic acid A suspension of 4-acetamido-3-methyl-5-nitrobenzoic acid (38 g, 0.16 mol) in 3N hydrochloric acid (800 L) was heated to 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 evaporated under high vacuum to give the title compound (23 g, 74% yield). Y-NMR (DMSO-d6, 300 MHz) d 12.79 (bs, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.61 (s, 2H), 2.34 (s, 3H). 13C-NMR 75 MHz) d 166.0, 147.0, 135.1, 130.0, 126.4, 125.9, 116.7, 17.9. LCMS: tR = 1.23 min, 195 (MH). " -dinitrobenzoic acid To a suspension of 4-amino-3-methyl-5-nitrobenzoic acid (5.0 g, 25.5 mmol) in trifluoroacetic acid (200 L) was added hydrogen peroxide (50% by weight, 15 L). The reaction mixture was heated at 50 ° C for 2 h and the solution was optionally followed from a dark orange clear solution to a pale yellow pale solution. The reaction mixture was slowly emptied into ice water (800 mL). The solid was collected by filtration and dried under vacuum to give the title compound as an opaque white solid (4.0 g, 70% yield). 1 H NMR (CD 3 OD, 300 MHz) d 8.59 (s, 1 H), 8.40 (s, 1 H), 2.45 (s, 3 H). 13 C-NMR (CD 3 OD, 75 MHz) d 165.8, 147.4, 142.0, 139.3, 134.8, 134.6, 125.4, 17.2. Mass spectrum: 225.14 (MH). "(3-Methyl-4,5-dinitrophenyl) methanol A solution of 3-methyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran (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 mixture was allowed to warm slowly to room temperature and was stirred for 16 h. The reaction was incomplete, re-cooled to -50 ° C and additional borane tetrahydrofuran in tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL) was added. Again, the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction was quenched with a mixture of acetic acid and water (1: 1, 30 mL) while cooling to 0 ° C. After stirring for 30 min, all the organic solvent was evaporated and the aqueous material neutralized by cold ice-bicarbonate saturated sodium (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 evaporated. The residue was subjected to flash column chromatography (1: 2 hexanes / ethyl acetate) to give the title compound (3.2 g, 86% yield). Y-NMR (CDC13, 300 MHz) d 8.00 (s, 1H), 7.62 (s, 1H), 4.82 (s, 2H), 2.41 (s, 3H). 13 C-NMR (CDC13, 75 MHz) d 144.5, 143.3, 140.9, 134.3, 132.9, 120.8, 63.0, 17.4. 3-Methyl-4, 5-dinitrobenzaldehyde In a flame-dried flask, manganese oxide (IV) (36.0 g, 414 mmol) was dried azeotropically 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 manganese dioxide. The reaction mixture was heated to 50 ° C with stirring for 3 h. During the 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 times. The filtrate was evaporated to give the title compound (1.4 g, 44% yield). Y-NMR (CDC13, 300 MHz) d 10.09 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 2.51 (s, 3H). (Z) -1- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) vinylcarbamate benzyl To a solution of N- (benzyloxycarbonyl) -a -phofonoglycine 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 -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 warm slowly to room temperature and then stirred for 16 h at room temperature. The solvent was evaporated and the residue was subjected to flash column chromatography (gradient, 1: 2 to 1: 1 ethyl acetate / hexane). The product was then recrystallized from ethyl acetate / hexanes: to give the title compound (1.7 g, 62% yield). ^? - NMR (CDC13, 300 MHz) d 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). 13 C-NMR (CDC13, 75 MHz) d 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, 68.3, 53.5, 17.4. Mass spectrum: 414.20 (MH) ". (R) -1- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) ethylcarbamate benzyl In a glove bag that was subjected to 3 cycles of vacuum / nitrogen purge, in an AIRFREE® reaction flask (Schlenk) was equipped with a stir bar was charged with (-) -1, 2-bis trifluoromethylsulfonate. (2R, 5R-2, 5-diethylphospholane) benzene (cyclooctadiene) rhodium (I) (125 g, 0.173 mmol, 4 mol%), was sealed with a rubber septum, and removed from the glove bag. Z) -1- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) vinylcarbamate (1.65 g, 3.97 mmol) was weighed in a second AIRFREE® reaction flask (Schlenk) equipped with a stir bar and It was sealed with a rubber septum After 3 cycles of vacuum / nitrogen purge, this was dissolved in an anhydrous methylene chloride mixture (40 mL) .The solvent was deoxygenated prior to the addition by nitrogen sparge for at least 1 Once in the solution, the mixture was re-subjected to 3 vacuum / nitrogen purge cycle.The dehydroamino acid solution is introduced into the reaction flask. ón (Schlenk) containing the catalyst by means of a cannula. The reaction mixture was subjected to vacuum / hydrogen purge cycle before opening the flask at 1 atmosphere of hydrogen. After 16 h, the reaction mixture was purged with 3 cycles of vacuum / nitrogen purge. 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%). Y-NMR (CDC13, 300 MHz) d 7.75 (s, 1H), 7.39-7.33 (m, 6H), 5.37 (d, J = 7.0 Hz, 1H), 5.15-5.04 (m, 2H), 4.70-4.46 (m, 1H), 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). LCMS: tR = 2.71 min, 418 (MH) +. (R) -1- (methoxycarbonyl) -2- (3,4-diamino-5-methylphenyl) ethylcarbamate benzyl Solid ammonium formate (755 mg, 11.9 mmol) was added in small portions at 0 ° C to a suspension of (R) -l- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) ethylcarbamate. Benzyl (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. The reaction was not completed. The reaction mixture was again cooled to 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 mixture of toluene and ethyl acetate (1: 1) were added, followed by acetic acid (2 mL). The mixture was further diluted until all the organic solids were dissolved, then this 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) was added. The solvent was evaporated to give the title compound as the hydrochloride salt (515 mg, quantitative yield). ? -NRM (CD3OD, 300 MHz) d 7.35-7.30 6.94-6.93 (m, 2H), 5.03 (s, 2H), 4.42-4.37 (m, 1H), 3.70 (s, 3H), 3.09- 3.03 (m , 1H), 2.87-2.79 (m, 1H), 2.25 (s, 3H). LC / MS: tR = 1.79 min, 358 (MH) +. (R) -1- (methoxycarbonyl) -2- (7-methyl-lH-benzo [d] [1,2,3] triazol-5-yl) ethylcarbamate To a solution of benzyl (R) -1- (methoxycarbonyl) -2- (3,4-diamino-5-methylphenyl) ethylcarbamate (250 mg, 0.58 mmol) in acetic acid (6 mL) and water (10 mL) it was added to a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL), dropwise for several minutes at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, then cooled to 0 ° C. A mixture of ammonium hydroxide and water (1: 1, 15 mL) was added until the pH was adjusted to 11. The mixture was extracted with ethyl acetate twice. The organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvents were removed in vacuo and the residue was purified by flash column chromatography (1: 1 ethyl acetate / hexanes) on silica gel to give the title compound as a brown solid (155 mg, 72% yield). XH-NMR (CDC13, 300 MHz) d 7.34 (s, 1H), 7.32- 7.28 (m, 6H), 6.93 (s, 1H), 5.40 (d, J = 8.1 Hz, 1H), 5.13-5.02 (m , 2H), 4.76-4.69 (m, 1H), 3.73 (s, 3H), 3.28 (dd, J = 13.9, 5.5 Hz, 1H), 3.16 (dd, J - 13.9, 6.2 Hz, 1H), 2.64 ( s, 3H). LCMS: tR = 2.30 min, 369 (MH) +. 2-amino-3- (7-methyl-lH-benzo [d] [1,2,3] triazol-5-yl) propanoate of (R) -methyl The (R) -1- (methoxycarbonyl) -2- (7-methyl-1H-benzo [d] [1,2,3] triazol-5-yl) ethylcarbamate benzyl ester (146 mg, 0.40 mmol) was dissolved in 12 mL of a 4.4% solution of formic acid in methanol. The reaction flask containing this solution was equipped with a magnetic stir bar and then wetted with nitrogen for several minutes. Palladium on carbon (10%, 200 mg) was added to the solution and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite® several times with methanol. The filtrate was evaporated to give the title compound (quantitative yield). Y-NMR (CDC13, 300 MHz) d 8. 40 (bs, 1H), 7.55 (s, 1H), 7.14 (s, 1H), 4.29-4.24 (m, 1H), 3. 78 (s, 3H), 3.39-3.19 (m, 2H), 2.69 (s, 3H). LC / MS: tR = 1. 18 min, 235 (MH) +. 2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-methyl-lH-benzo [d] [1,2,3] triazol-5-yl) propanoate of (R) -methyl Prepared as previously described by 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [ d] imidazol-5-yl) propanoate. LCMS: tR = 2.17 min, 492 (MH) +. Acid (R) -2- (4- (1,2-dihydro-2,4-dioxoquinazoline-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-methyl-lH-benzo [d] [1,2,3] triazol-5-yl) propanoic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) propanoic acid. LCMS: tR = 2.11 min, 492 (MH) +.

Example 237 4- (1,2-dihydro-2,4-dioxoquinazoline-3- (4H) -yl) -N- ((R) -3- (7-methyl-lH-benzo [d] [1,2 , 3] triazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide Prepared as described above by the example 231. Y-NMR (CD3OD, 300 MHz) d 8.01 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.28-7. 11 (m, 4H), 5.06-5.00 (m, 1H), 4.70-4.60 (m, 1H), 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 spectrum: 642 (MH) +.

Methyl ester of (R) -2-Benzyloxycarbonylamino-3- (< chloro-2-oxo-2, 3-dihydro-benzooxazol-6-yl) -propanoic acid A mixture of (R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propanoic 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 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 give the title compound (40 mg, 9.8%), also methyl ester of 2-benzyloxycarbonylamino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid (78 mg, 19%). The structure was confirmed by 2D NMR and when compared to the methyl ester of 2-benzyloxycarbonylamino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propanoic acid prepared by the reaction shown then. Y-NMR (CD3COCD3, 500 MHz) d 7.37-7.27 (m, 5H), 7.18 (d, J = 1.0 Hz, 1H), 7.16 (s, 1H), 6.76 (d, J = 8. 5 hz, 1H), 5.06 (d, J = 5 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H), 4.55-4.51 (m, 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); 13 C-NMR (CD3COCD3,125 MHz) d 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 spectrum 405 (MH +).

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propanoic acid The N-chlorosuccinimide (315 mg, 2.36 mmol) was added to a solution of methyl ester of (R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) - propionic (700 mg, 1.89 mmol) in acetic acid (50 mL) at room temperature. The mixture was heated at 100 ° C for 16 h. After this it was cooled to room temperature, the 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 give the title compound as an opaque yellow solid (242 mg, 32%). The structure of the product was confirmed by 2D NMR. Y-NMR (CD3COCD3, 500 MHz) d 10.47 (s, 1H), 7.36-7.28 (m, 6H), 7.20 (s, 1H), 6.80 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 12.5 Hz, 1H), 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, 1H), 3.08 (dd, J = 14.0, 10.5 Hz, 1H); 13 C-NMR (CD3COCD3, 125 MHz) d 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 spectrum 405 (MH +).

Methyl ester 'of (R) -2-benzyloxycarbonylamino-3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid A mixture of 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 chloride (70 mL) was stirred at room temperature for 16 h. The solvents were removed in vacuo and the residue was subjected to silica gel chromatography using ethyl acetate / hexanes (2: 3) as eluent to provide the title compound. ^ -NMR (CD3COCD3, 500 MHz) d 10.71 (s, 7.35-7.28 (m, 6H), 7.21 (s, 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.06 (d, 12.5 Hz, 1H ), 5.02 (d, J = 12.5 Hz, 1H), 4.56-4.51 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J = 14.0, 5.0 Hz, 1H), 3.03 (dd, J = 14.0, 10.0 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) d 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 spectrum 448.03 (MH +).

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester 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 L) was heated at 105 ° C for 14 h. After cooling to 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 give the title compound (446 mg, 34%). The structure of the title compound was confirmed by 2D NMR. Y-NMR (CD3COCD3, 500 MHz) d 10.46 (s, 1H), 7.36-7.28 (m, 7H), 6.82 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 12.5 Hz, 1H), 5.00 (d, J = 12.5 Hz, 1H), 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); 13 C-NMR (CD3COCD3, 125 MHz) d 172.2, 156.4, 154.2, 143.7, 137.6, 131.1, 130.6, 128.7, 128.0, 118.2, 113.9, 112.9, 66.2, 54.3, 52.1, 38.3; Mass spectrum 448.03 (MH +).

Methyl ester of (R) -2-benzyloxycarbonylamino-3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester A mixture of (R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester (324 mg, 0.87 mmol), I (PyH) 2BF4 (409 mg1.08 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 eluent to give the title compound (175 mg, 40%). The structure of the title compound was confirmed by 2D NMR. Y-NMR (CD3COCD3, 500 MHz) d 10.47 (s, 1H), 7.46 (s, 1H), 7.37-7.29 (m, 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 (m, 1H), 3.72 (s, 3H), 3.23 (dd, J = 14.0, 5.0 Hz, 1H), 3.01 (dd, J = 14.0, 9.5 Hz, 1H); 13 C-NMR (CD3COCD3, 125 MHz) d 172.2, 156.4, 153.4, 143.3, 137.6, 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 spectrum 496.01 (MH +).

Methyl ester of (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid Trimethylsilyliodide (73 L, 0.73 mmol) was added to a solution of (R) -2-benzyloxycarbonylamino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) methyl ester. ) -propionic azeotropically dried (146 mg, 0.33 irmol) in acetonitrile (10 mL) at room 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. The solvents were removed and the residue was used directly in the next step. Mass spectrum 315.10 (MH) +.

Methyl ester of (R) -2-Amino-3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester Prepared as previously described by the methyl ester of 3-dihydro-benzooxazol-6-yl) -propionic acid. Mass spectrum 315.06 (MH) +.

Methyl ester of (R) -2-amino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid Prepared as described above by the methyl ester of (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester. Mass spectrum 271.10 (MH) +. Methyl ester of (R) -2-Amino-3- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid Prepared as described above by the methyl ester of (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid. Mass spectrum 271. 16 (MH) +. Methyl ester of (R) -2-Amino-3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid: Prepared as described above by the methyl ester of (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester. Mass spectrum 363.04 (MH) +. Methyl ester of (R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazin) -1-carbonyl] -amino} -propionic Prepared as described above for 2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [d ] imidazol-5-yl) propanoate of (R) -methyl. Mass spectrum 481.20 (MH) +. Methyl ester of (R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazoline) -1-carbonyl] -amino} -propionic Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2-trifluoromethyl) -lH-benzo [d ] imidazol-5-yl) propanoate of (R) -methyl. Mass spectrum 480.24 (MH) +.

Methyl ester of (R) -3- (4-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic OR Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [ d] imidazol-5-yl) propanoate of (R) -methyl. Mass spectrum 528.16 (MH) +. Methyl ester of (R) -3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [d ] imidazol-5-yl) propanoate of (R) -methyl. Mass spectrum 528.20 (MH) +.

Methyl ester of (R) -3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [ d] imidazol-5-yl) propanoate. Mass spectrum 572.20 (MH) +. Methyl ester of (R) -3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, -dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [ d] imidazol-5-yl) propanoate of (R) -methyl. Mass spectrum 572.15 (MH) +. Methyl ester of (R) -3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for 2- (4- (1, 2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [ d] imidazol-5-yl) propanoate of (R) -methyl. Mass spectrum 620.20 (MH) +. Acid (R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -2-. { [2,4-dihydro-2'-oxospiro- (piperidin-4,4'-1H-benzo [d] [1,3] oxazine) -1-carbonyl] -amino} -propionic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrum 467.18 (MH) +.

Acid (R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -2-. { [2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazoline) -1-carbonyl] -amino} -propionic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrum 466.20 (MH) +. (R) -3- (4-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) iperidine-1-carboxamido) -3- (2- (trifluoromethyl) -IH-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrum 514.20 (MH) +.

(R) -3- (5-Chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrum 514.24 (MH) +.

(R) -3- (4-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) yl) propanoic acid. Mass spectrum 558.30 (MH) +.

(R) -3- (5-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as previously described by the acid (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3 (4H) -yl) piperidin-1-carboxamido) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrum 558.25 (MH) +. (R) -3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for (R) -2- (4- (1,2-dihydro-2-oxoquinazoline-3- (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluoromethyl) acid. ) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrum 606.10 (MH) +.

Example 238 [2- (4-cyclohexyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of the acid (R ) -4- (2-Oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-l-carboxylic acid Prepared as described above by example 231. LC / MS: t R = 1.80 min, 630.37 (MH) +. Extract 239 [2- (4-isopropyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of (R) acid -4- (2-Oxo-l, 4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carboxylic acid Prepared as described above by example 231. LC / MS: tR = 1.71 min, 590.34 (MH) +. Example 240 (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin -1-yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-carboxamide Prepared as described above by the LC / MS example: tR = 1.64 min, 617.34 (MH) +. Example 241 (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-l- (4- (cyclohex-l-yl) piperazine -l-yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-carboxamide Prepared as described above by example 231. LC / MS: tR = 1.69 min, 617.35 (MH) +. Example 242 (R) -N- ((R) -3- (2-0x0-2, 3-dihydro-benzooxazol-6-yl) -1-oxo-l- (4-prop-2-yl) piperazine- 1-yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-carboxamide Prepared as described above by example 231. LC / MS: t R = 1.57 min, 577.32 (MH) +. Example 243 (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin -1-yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-H-quinazoline) -1-carboxamide Prepared as described above by example 231. LC / MS: t R = 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-l-yl) piperazine -l-yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-quinazoline) -1-carboxamide Prepared as above: LC / MS: tR 1.79 min, 616.36 (MH) +.

Example 245 (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-l- (4- (prop-2-yl) piperazine -l-yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-H-quinazoline) -1-carboxamide Prepared as described above by example 231. LC / MS: tR = 1.67 min, 576.34 (MH) +. Example 246 [2- [1, 4 '] bipiperidinyl-1' -yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2-oxo-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carboxylic acid Prepared as described above by example 231. LC / MS: tR = 91 min, 664.35 (MH) +. Example 247 [2- [1,4 '] bipiperidinyl-1' -yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2-oxo-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1-carboxylic acid Prepared as described above by example 231. LC / MS: tR = 1.91 min, 664.34 (MH) +. Example 248 [2- [1, 4 '] bipiperidinyl-1' -yl-1- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by example 231. LCMS: tR = 1.96 min, 708.31 (MH) +. Example 249 [2- [1, 4 '] bipiperidinyl-l' -yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) piperidin-1-carboxylic acid Prepared as described above by CL / MS: tR = 1.96 min, 708.31 (MH) +. Example 250 [2- [1, 4 '] bipiperidinyl-l' -yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by example 231. LC / MS: t R = 1.97 min, 756.36 (MH) +. Example 251 (±) -N- (l-benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [1 ', 2'-dihydro] -2 '-oxoespiro- [4H-3', 1-benzoxazine-, 4 '-piperidinyl] -butyramide Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', l-benzoxazin-4, 4 '-piperidinyl] -butane-1,4-dione. LCMS: tR = 38 min, 596 (MH) +.

Example 252 (±) -N- (l-benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo- 1, 4-dihydro-2H-quinazoline-3-yl) -piperidin-1-yl] -butyramide Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-yl ethyl) -4- [1 ', 2 '-dihydro- 2' -oxoespiro- [4H-3 ', 1-benzoxazin-4, 4' -piperidinyl] -butane-1, -dione. LCMS: tR = 1.50 min, 609 (MH) +. Y NMR (400 MHz, CD30D) 7.90 (1H, s), 7.64-7.84 (1H, m), 6.71-7.42 m), 4.58 (1H, m), 3.82-4.50 (6H, m), 2.21-3.52 ( 13H,), 1.42-1.87 (4H, m).

Example 253 N '-. { 2- (7-Methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl ] -butyryl} -hydrazide of (±) -phenyl-acetic acid Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1', 2 ' -dihydro-2'-oxospiro- [4H-3 ', l-benzoxanin-4, 4' -piperidinyl] -butane-1,4-dione. LCMS: tR = 43 min, 630 (M + Na) +. Example 254 (±) -1- [1, 4 '] Bipiperidinyl-1' -yl-4- [4- (8-fluoro-2-oxo-l, 4-dihydro-2H-quinazoline-3-yl) - piperidin-1-yl] -2- (7-methyl-lH-indazol-5-ylmethyl) -butane-1,4-dione Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-1' -yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1 ', 2' - dihydro-2'-oxo-spiro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione. LCMS: tR = min, 644 (MH) +. Y NMR (400 MHz, CDC13) d 8.00 (1H, s), 6.82-7.40 (6H,), 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). Example 255 (±) -1- [1,4 '] biperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [2 ', 3'-dihydro-2' -oxoespiro- (piperidin-4, 4'-quinazoline] -butane-1, -dione Prepared as-described above by (±) -1- [1,4 '] bipiperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', l-benzoxazin-4, 4 '-piperidinyl] -butane-1,4-dione. LC / MS: 612 (MH) +. 2-oxo-2, 3-dihydro-benzooxazol-6-carbaldehyde A solution of 6-bromo-3H-benzooxazol-2-one (0.9236g, 4.31 micromoles) in anhydrous tetrahydrofuran (25 mL) and (3 mL) under nitrogen was cooled to -78 ° C before the addition of n-butyllithium. (2.5M in hexane) (3.8 mL, 2.2 equiv). After stirring for 10 minutes at -78 ° C, 24 L of sec-butyllithium (1.4 M in cyclohexane, 8 equiv) was added. The reaction was stirred while heating slowly to -40 ° C. When this temperature was achieved, the reaction was quenched by the addition of methanol. The reaction mixture was concentrated in vacuo and water was added. The aqueous layer was acidified with 1N HCl (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) +. 1 H NMR (400 MHz, DMSO-d 6) d 9.90 (1H, s), 7.79 (1H, d, J = 8.0 Hz), 7.74 (1H, s), 7.28 (1H, d, J = 8.0 Hz). 3- (2-Oxo-2,3-dihydro-benzooxazol-6-ylmethylene) -pentandioic acid monomethyl ester Prepared as previously described by the 2- (7-methyl-lH-indazol-5-ylmethylene) -succinic acid 1-methyl ester (1.4 g, 90% yield). MS (ESI) 300 (M + Na) + Monomethyl ester of (±) -3- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -pentandioic acid Prepared as described above for the (1) -2- (7-methyl-lH-indazol-5-ylmethyl) -succinic acid 1-methyl ester (1.4 g, 99% yield). MS (ESI) 302 (M + Na) +.

Methyl ester of (±) -4-oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-l, 4-dihydro-2H) - quinazoline-3-yl) -piperidin-1-yl] -butyric Prepared as described above by the methyl ester of (±) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2' - oxospiro- [4 H -3 ', l-benzoxazin-4, 4'-piperidinyl] -butyric MS (ESI) 493 (MH) +.

Methyl ester of (±) -4-oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospiro- ( piperidin-4, 4 '-quinazoline)] -butyric Prepared as described above for methyl ester of (+) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxoespiro] - [4 H -3 ', l-benzoxazine-4,4'-piperidinyl] -butyric acid. MS (ESI) 479 (MH) +. (±) -4-Oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxoespiro- (pyridine-4, 4 '-quinazoline)] -butyric Prepared as previously described by the acid (±) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [1 ', 2'-dihydro-2'-oxospiro- [4H -3 ', l-benzoxazin-4, 4'-piperidinyl] -butyric acid, MS (ESI) 465 (MH) +. (±) -4-Oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) 4- [4- (2-oxo-l, 4-dihydro-2H-quinazoline-3-) il) -piperidin-1-yl] -butyric Prepared as previously described by the acid (±) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [1 ', 2'-dihydro-2'-oxoespiro- [4H -3 ', l-benzoxazine-4, 4'-piperidinyl] -butyric acid, MS (ESI) 479 (MH) +.

Example 256 (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo- 1,4-dihydro-2H-quinazoline-3-yl) -piperidin-1-yl] -butane-1,4-dione Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-1' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', l-benzoxazin-4, 4 '-piperidinyl] -butane-1,4-dione. LCMS: tR = 1.10 minutes, 629 (MH) +.

Example 257 (+) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo -l, 4-dihydro-2H-quinazoline-3-yl) -piperidin-1-yl] -butane-1,4-dione Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-1' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', 1-benzoxazin-4, '4-piperidinyl] -butane-1,4-dione. LCMS: tR = 1.08 min, 629 (MH) +. 1 H NMR (400 MHz, CDC13) d 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).

Example 25Í (+) -1- [1,4 '] bipiperidinyl-l' -yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3' - dihydro-2'-oxospiro- (piperidin-4,4' -quinazoline)] -butane-1,4-dione Prepared as described above by (+) -1- [1,4 '] bipiperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 ', 2' -dihydro-2 '-oxoespiro- [4H-3', l-benzoxin-4, 4 '-piperidinyl] -butane-1,4-dione. LCMS: tR = 1.02 min, 615 (MH) +.

Example 259 (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro] -2 '-oxoespiro- (piperidin-4, 4'-quinazoline)] -butane-1,4-dione Prepared as described above by (±) -1- [1,4 '] bipiperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [1 '2' - dihydro-2'-oxospiro- [4H-3 ', l-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione. LCMS: tR = 1.04 min, 615 (MH) +.

Example 260 [2- (4-cyclohexyl-piperazin-1-yl) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above for example 16. 1 H-NMR (CD3OD, 500 MHz) d 0.81 (1H, m), 0.89 (1H, m), 1.02 (1H,), 1.1-2.0 (12H,), 2.23 (1H, d), 2.47 (1H, d), 2.61 (3H, s), 2.90 (4H, t), 3.08 ( 4H, m), 3. 2-3.5 (4H, m), 3.82 (1H, m), 4.14 (2H, d), 4.29 (2H, s), 4.40 (1H, t), 6.80 (1H, d), 6.95 (1H, t) , 7.12 (3H, m), 7.47 (1H, s), 8.01 (1H, s). Mass spectrum: 627.47 (MH) +.

Example 261 [2- [4- (4-Fluoro-phenyl) -piperazin-1-yl] -1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid ( ±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid Prepared as described above by example 16. LC / MS: tR = 2.34 min, 621.42 (MH) +.

Example 262 Tert-butyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic A solution of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic (50 mg, 0.105 mmol) and dicyclohexylcarbodiimide (25 mg, 0.12 mmol) in dimethylformamide was stirred for 30 minutes at room temperature, and then pentafluorophenol (26 mg, 1.3 mmol) was added. The 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 nitrogen was added 1.4M sec-butyllithium in cyclohexane (10 equiv.). After 10-15 minutes, 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. Y-NMR (CD3OD) d 1.40 (s, 9H) 1.56 (m, 4H), 2.54 (s, 3H) 2.85 (m, 2H) 3.05 (m, 1H), 3.19 (m, 1H), 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 (m, 3H), 7.14 (s, 1H), 7.97 ( s, 1H). LCMS: tR = 2.19 minutes, 533.36 (MH) +.

Example 263 1-Methyl cyclohexyl ester of (+) - 3 - (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above by the tert-butyl ester of (+) - 3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 2.47 minutes, 574.39 (MH) +. Example 264 1-Aza-Bicyl [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic To a solution of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic (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, dried over magnesium sulfate, and purified by preparative HPLC to provide the desired compound. LCMS: tR = 1.62 min, 586.41 (MH) +. Example 265 Piperidin-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above by the 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LC / MS: tR = 1.58 minutes, 560.37 (MH) +. Example 266 Tert-butyl ester of (±) -4- (3- (7-methyl-lH-indazol-5-yl) -2- { [4- (2-oxo-l, 4-dihydro) -2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino.}. -propionyloxy) -piperidine-1-carboxylic acid Prepared as described above by the 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 38 minutes, 660.42 (MH) +. Example 267 3, 4, 5,6-Tetrahydro-2H- [1,4'-bipyridinyl-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2 acid -. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 67 min, 637.43 (MH) +.

Example 268 1-Diethylamino-l-methyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above by the 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 66 min, 590.44 (MH) +.

Example 269 1, 1-dimethyl-2-phenyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above by the t-butyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 609.46 (MH) +.

EXAMPLE 270 1,1-Dimethyl-3-phenyl-propyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for the ester Example 271 Ethyl ester of (+) - 3 - (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Prepared as described above for t-butyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic LCMS: tR = 1.98 minutes, 505.32 (MH) +. Example 272 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-ethyl] -2-oxoethyl] -2 ', 3'-dihydro-2 '-oxoespiro- [piperidin-4, 4' - (1H) -quinazoline] -1-carboxamide Prepared as described above by the example 16. LCMS: tR = 49 min, 553.12 (MH) +.

Example 273 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 '3' -dihydro-2 ' -oxoespiro} [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide Prepared as described above by example 16. LC / MS: tR = 56 min, 608.18 (MH) +.

Example 274 (+) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [(2-dimethylamino-ethyl-ethylcarbamoyl) -2-oxoethyl] -2 ', 3'-dihydro-2' -oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide Prepared as described above by example 16. LC / MS: t R = 1.58 min, 561.20 (MH) +.

Example 275 (±) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2 '-oxospiro- [4H-3', 1-benzoxazine-4, 4 '-piperidine] -1-carboxamide Prepared as described above by example 16. LC / MS: tR = 1.56 min, 609.14 (MH) +. Example 276 (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2 '-oxospiro- [4H-3', 1-benzoxazine-4, 4 '-piperidine] -1-carboxamide Prepared as described above by example 16. LC / MS: 1.57 min, 609.17 (MH) +. Example 277 [2- [1,4 '] Bipiperidinyl-l' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-ld-carboxylic acid Prepared as described above for example 16. Y-NMR (CD3OD, 500 MHz) d -0.27 (1H, m), 0.75 (1H, m), 1.1-2.0 (12H, m), 2.10 (2H, m) , 2.4-2.5 (3H, m), 2.57 (3H, s), 2.68 (2H, m), 2.92 (4H, m), 3.10 (4H,), 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). LCMS: tR = 1.68 min, 627.42 (MH) +.

Example 278 (R) -1- (7-methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 '3' -dihydro-2 ' -oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide Prepared as described above by example 16. LC / MS: tR = 1.63 min, 613.36 (MH) +. Other compounds disclosed within the present invention and capable of being made in accordance with the description provided herein or those methods known to those of skill in the art include the following examples. [2- [1,4 '] Bipiperidinyl-1'-lyl-1- (7-bromo-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-l) , 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-Oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl) -ethyl] -amide of 4- (2-oxo-) 1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-Oxo-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide of 4- (2-oxo-l, 4-) dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-Methyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of 4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] Bipiperidinyl-1' -yl-1- (4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 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 of 4- (2-oxo-) 1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid 4- (2-oxo-2-oxo- 1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [l-dimethylcarbamoyl-2- (4-methyl-2-oxo-2, 3-dihydro-benzooxazol-6-yl) -ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-) quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-chloro-2-oxo-2, 3-dihydro-benzooxazol-6-yl) -1-di-ethylcarbamoyl-ethyl] -amide of 4- (2-oxo-l, 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] - 4- (2-Oxo-1, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide [1- (4-Chloro-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] - 4- (2-Oxo-l, 4-dihydro-2H2-quinazolin-3-yl) -piperidine-l-carboxylic acid amide [2- [1, 4 '] bipiperidinyl-l' -yl-1- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1, 4 '] bipiperidinyl-1' -yl-1- (7-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1, 4 '] bipiperidnil-l' -il-1- (7-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1-yl-l- (7-ethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1, 4 '] bipiperidinyl-l' -yl-1- (3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1, 4 '] bipiperidinyl-1-yl-l- (3,7-dimethyl-2-oxo-2, 3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1' -yl-1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 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-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid 3- (7-Methyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Isopropyl ester of acid 3- (7-chloro-lH-indazol-5-yl) -2-. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 3- (7-Ethyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 3- (7-Chloro-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 3- (7-Ethyl-lH-idazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic Cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic L-methyl-piperidin-4-yl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 3-L-methyl-piperidin-4-yl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 1-Methyl-cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 3- (7-ethyl-lH-indazol-5-yl) -2- acid 1-methyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic 3- (7-Chloro-lH-indazol-5-yl) -2- acid 4-phenyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic 3- (7-Ethyl-lH-indazol-5-yl) -2- acid 4-phenyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic CGRP binding test Cul tivo de tejido. The cells were grown SK-N-MC at 37 ° C in 5% C02 as a monolayer in a medium consisting of MEM with Earle and L-glutamine salts (Gibco) completed with 10% fetal bovine serum (Gibco) Cell pellets The cells were rinsed twice with phosphate buffered saline (155 mM NaCl, 3.3 mM Na2HP04, 1.1 mM KH2P04, pH 7.4), and incubated for 5 to 10 minutes at 4 C in a hypotonic lysis buffer consisting of 10 mM Tris (pH 7.4) and 5 mM EDTA. The cells were transferred from the plates to polypropylene tubes (16 X 100 mm) and homogenized using a polytron. The homogenates were centrifuged at 32,000 x g for 30 minutes. The pellets were resuspended in cold hypotonic lysis buffer with a 0.1% mammalian protease inhibitor cocktail.

(Sigma) and tested for protein concentration. The SK-N-MC homogenate then forms aliquots and is stored at -80 ° C until needed. Radiation test. The compounds of the invention were solubilized and carried through serial dilutions using 100% DMSO. The aliquots of the serial dilutions of the compounds were further diluted 25-fold in assay buffer (50 mM Tris-Cl pH 7.5, 5 mM MgCl2, 0.005% Triton X-100) and transferred (volume of 50 μl) in 96-well assay plates. [125 I] -CGRP (Amersham Biosciences) was diluted to 60 pM in assay buffer and a volume of 50 μl was added to each well. SK-N-MC pellets were thawed, diluted in assay buffer with a 0.1% fresh mammalian protease inhibitor cocktail (Sigma) and homogenized again. The homogenate of SK-N-MC (5μg / wells) was added in a volume of 100 μl. The assay plates were then incubated at room temperature for 2 h. The tests were stopped by the addition of excess cold wash buffer (20 mM Tris-Cl pH 7.5, 0.1% BSA) immediately by filtration on a glass fiber filter (hatman GF / B) previously submerged in 0.5% PEI. The non-specific binding was defined with 1 μM beta-CGRP. The radioactivity bound to the protein was determined using a gamma or scintillation counter. The IC50 was defined as the concentration of a compound of the invention required to displace 50% radioligand binding. In the table below, the results were noted as follows: A < 10 nM; 10 nM < B < 100 nM; 100 nM < C < 1000 nM; D < 1000 nM.

Table 4. CGRP link, cAMP function and human brain artery data Ex Vivo AMP cyclic assay Functional antagonism. Antagonism of the compounds of the invention was determined by measuring the formation of the cyclic AMP (3 Y 'cyclic adenosine monophosphate) SK-N-MC cells. that endogenously express the human CGRP receptor. The CGRP receptor complex is coupled to the Gs protein, and the CGRP bond to this complex leads to cyclic AMP through the Gs-dependent activation of an adenylate cyclase (Juaneda C et al., TiPS, 2000; 21: 432- 438, incorporated herein by reference). Consequently, CGRP receptor antagonists inhibit cyclic AMP formation in CGRP-induced SK-N-MC cells (Doods H et al., Br J Pharmacol, 2000; 129 (3); 420-42); incorporated herein by reference). For cyclic measurements of AMP, SK-N-MC cells were incubated with 0.3 nM CGRP alone or in the presence of various concentrations of the compounds of the invention for 30 minutes at room temperature. The compounds of the invention were preincubated with SK-N-MC cells for 15 minutes before the addition of CGRP to allow addition of the receptor (Edvinsson et al., Eur J Pharmacol, 2001, 415: 39-44; incorporated herein by reference). reference). The cyclic AMP was extracted using the lysis reagent and the concentration was determined by an immunoassay using a direct exclusion assay kit cAMP SPA (Amersham Pharmacia Biotech). The IC50 values were calculated using an adjustment in Excel. The tested compounds of the invention were determined by antagonists since they showed a dose-dependent inhibition of cyclic AMP production induced by CGRP. See table 3 for a summary of the results. Schild analysis. The Schild analysis can be used to characterize the antagonism nature of the compounds of the invention. The dose response of cAMP production stimulated by CGRP is generated with CGRP or in the presence of various compositions of the compounds of the invention. The antagonist dose is plotted as X against the dose ratio (defined as IC50 of the agonist with presence of the compounds divided by the IC50 of the agonist alone) minus 1 as Y). Then the linear regression was performed with the X and Y axis transformed into a logarithm. A slope that does not differ significantly from unit 1 indicates a competitive antagonism. Kb is the dissociation constant of the antagonism.

Table 5 Schild analysis.

See figure 1. Analysis Schild.

Human Brain Artery Test Ex Vivo Reasoning and Introduction. To provide direct evidence of the ability of novel compounds to reverse CRPG-induced dilation in human cerebral vessels, an ex vivo assay was designed. Briefly, rings of isolated vessels were mounted in a tissue bath where vessels were previously contracted with potassium chloride (KCl) and fully dilated with hCGRP, then reversed by the cumulative addition of CGRP receptor antagonists (follow the full details). Tissue samples. Autopsy samples were obtained from human samples from vendors (ABS Inc. or NDRI) all vessels were transported on an ice-cold HEPES buffer solution (composition in mM: 130 NaCl, 4 KCl, 1.2 KH2P04, 1.2 MgS04, 1.8 CaC12, Glucose 6, NaHC03 4, HEPES 10, EDTA 0.025). Upon receipt, the vessels were placed in a cold buffer solution of Kreb (composition in mM: NaCl 118.4, KCl 4.7, KH2P04 1.2, MgSO4 1.2, CaC12 1.8, Glucose 10.1 NaHCO3 25) saturated with carbogen (5% C02 and 95% of oxygen) . Isolated woven baths. The connective tissue vessels were cleaned and cut into cylindrical segments 4-5 mm in length. The cups were then mounted in tissue bath between two stainless steel hooks, one of which was fixed and the other of which was connected to a force-displacement transducer. The vessel voltage was recorded continuously using a data acquisition system (Powerlab, AD Instruments, Mountain View, CA) connected to the transducer. Tissue baths containing Krebs buffer and mounted cups were controlled by temperature (37 ° C) and pH (7.4) with a continuous bubbling of carbogen. The arterial segments were allowed to equilibrate for about 30-45 min until a stable resting tone was reached. Prior to the test, the vessels were primed (conditioned), with 100mM KCl and subsequently washed. The vessels were pre-contracted with 10 mM KCl and dilated completely with 1 nM hCGRP. The concentration response curves to the CGRP receptor antagonists were made by the cumulative addition of drugs in logarithmic units in fully dilated vessels. At each concentration, the effects of the drugs were expressed as a percentage of the inversion of relaxation induced by CGRP in each vessel. The data analysis and current assay were performed for each vessel individually, adjusting the response data to the concentration to a logistic function of four parameters by a linear regression analysis to estimate EC50 values. A summary of the result is given in Table 3.

Non-terminal method to evaluate the in vivo efficacy of small molecule CGRP receptor antagonists in mammals Introduction. The blocking of cerebral artery dilation induced by the peptide related to the calcitonin gene (CGRP) has been proposed as a treatment for migraine headache, however, the novel small molecule CGRP receptor antagonists have shown species-specific differences with relatively poor activity in rodents (Mallee et al., J Biol Chem 2002 277: 14294) requiring new models for the evaluation of in vivo efficacy. Non-human primates (eg, marmosets) are the only animals known to have a pharmacology of the CGRP receptor similar to that of humans, given by the presence of a specific amino acid residue (Trp74) in its RAMP1 sequence that is responsible for the phenotype of the human receptor (Mallee et al., J. Biol Chem 2002 277: 14294). Since current models of migraine mainly use rats (Escott et al Brain Res 1995 669: 93; Williamson et al Cephalalgia 1997 17:.. 525). They are invasive, or, terminal procedures in primates (Doods et al Br J Pharmacol 2000, 129: 420), a novel non-invasive survival model in non-human primates for the evaluation of the in vivo efficacy of CGRP receptor antagonists as in the present invention is an important contribution. Although trigeminal activation is known to increase facial and cerebral blood flow (Goadsby & amp; amp;; Edvinsson, 1993) (Doods et al., 2000) the demonstration of the direct relationship between facial blood flow and dilation of the cerebral artery made in the same animals was not known. Therefore, before starting studies in non-human primates, laser Doppler measurement of facial blood flow was validated directly in the rat as a substitute for dilatation of the cerebral artery in terminal studies that measured the diameter of the cerebral artery and changes in facial blood flow in the same animals (see Figure 2. Direct validation of facial blood flow as a substitute for dilation of the cerebral artery in rats). In both measurements, comparable increases were induced by i.v CGRP and blocked by the peptide antagonist haCGRP (8-37). Afterwards, the method of changes induced by i.v CGRP in the facial blood flow was used as a recovery model in rats anesthetized with isoflurane using haCGRP (8-37). The survival method was then established in non-human primates and a dose response study characterizing the activity of iv CGRP was finalized (see figure 3. Response of dose to haCRGP in facial blood flow with Doppler lasers from non-human primates) . Antagonists of the small molecule haCRGP receptor and the peptides were used to validate the non-human primate model. Pretreatment with small or antagonists haCRGP (8-37) depending on the dose molecule inhibited increases CGRP stimulated by intravenous facial blood flow in the primate (Figure 4. Inhibition of CGRP-induced changes in blood flow non-human primate facial), without altering the blood pressure (see figure 5. Effect of the CGRP antagonist on the blood pressure of non-human primates). Subsequent antagonist treatment also reverses the CGRP-induced increases in facial blood flow (not shown). This survival model provides a recovery procedure noninvasive novel to evaluate abortive and prophylactic effects of CGRP antagonists receptor in non-human primates or in transgenic animals with PAMPl (Trp74) having a pharmacology of CGRP receptor as a surrogate marker for the activity of the cerebral vessel diameter. Animals . The common male and female marmosets (Callithrix jacchus) acquired with Harían and that weigh 350-550 g served as subjects. Other mammals endogenously expressing RAMPl having Trp 74 or transgenic mammals with a humanized RAMP1 having Trp74 can also be employed in the method described herein. Anesthesia and surgical preparation. Animals are anesthetized by inhalation with isoflurane in an induction chamber (4-5% 'of rapid induction maintained with 1-2.5% Solomon et al., 1999). Anesthesia is maintained by providing a constant supply of air and oxygen (50:50) and isoflurane by means of a face mask or by intubation and ventilation (with blood gas monitoring). Blood temperature is maintained at 38 ± 0.5 ° C by placement on a controlled surface with automated temperature with a rectal probe. A small area of hair (approximately 1.5 square cm) is removed from one or both sides of the face by application of a depilatory cream and / or shave. The surgical areas were secured and separated with betadine. An intravenous line was placed in any accessible vein for the administration of the test compounds and the agonist sector CGRP and it would be necessary to remove the samples, blood (maximum 2.5 ml, 10%) for a gas monitoring in blood and content analysis. An intravenous 5% dextrose solution was administered in order to maintain blood sugar levels. The depth of anesthesia was observed by measuring blood pressure and heart rate using a non-invasive arm clamping method and a pulse oxygen meter, respectively. Guanethidine 5-10 mg / kg i.v. supplemented with 5 mg / kg iv as needed may be given to stabilize the peak flow in an observed facial blood flow with repeated changes induced by stimulation in the blood flow (Escott et al., 1999, incorporated as reference in the I presented). The microvascular blood flow is observed by placing a self-adhesive laser Doppler flow probe to the facial skin. Administration of the compound. The test compounds can be administered i.v. (0.01-5 ml / kg), i.m. (0.01-0.5 ml / kg), s.c. (0.01-5ml / kg) or p.o. (0. l-10ml / kg) (Diehl et al., 2001, incorporated herein by reference). The CGRP receptor agonists can be delivered i.v. (0.01-5 ml / kg), i.d. (10-100μl / site) or s.c. (10-100 μl / site). Laser Doppler flowmetry. An increase in control in facial blood flow is induced by the administration of a vasodilator such as CGRP (0.05-100 μg / kg iv) or 2-20 pmol / id site) or adrenomedullin (ADM, 0.05-5 mg / kg iv or 10-100 pmol / site id). The test compound or vehicle is administered before (pretreatment) or after (posttreatment) of the repeated administration to the vasodilator agent, providing the ability to evaluate prophylactic or therapeutic actions. Blood pressure is continuously monitored to ensure adequate depth of anesthesia, and the anesthetic is adjusted to maintain stable levels that match the pretreatment values. During the collection of laser Doppler flowmetry data, isoflurane can be reduced to 0.215-0.75% as previous electrophysiological studies in marmosets found that the records were sensitive to the concentration of isoflurane (Solomon, 1999 incorporated herein by reference). . To reduce the number of animals used, the effect of the test compound on the changes induced by the intravenous vasodilator in the blood flow can be repeated three times in a single section. Recovery . The animals were returned to the transport cage which is placed on a temperature controlled surface, to keep the animals warm until they are fully awake and circulating. The animals can be tested after 7 to 14 days of rest, and intervals of 7 to 14 days can be repeatedly tested depending on the health of the animal. See Diehl KH, R, Morton D, Pfister R, Rabemampianin Y, Smith D, Vidal JM, van de Vorstenbosch C. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol. 2001 Jan Feb; 2 (1): 15-23; Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Ebe'rlein W. Pharmacologial profile of 'BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 Feb; 129 (3): 4250-3; 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 mouse: a major role for calcitonin gene- related peptide. Brain Res. 1995 Jan 9; 669 (1): 93-9; Goadsby PJ. Edvinsson L. The trigeminovascular system and migrain: studies characterizing cerebrospinal 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, Roblan KS, Kane SA. RAMP1 determines the species selectivity of non-peptide CGRP receptor antagonists. J. Biol Chem. 2002 Feb 14 [pub. In advance to printing]; Solomon SG, White AJ. Martin PR. Temporal contrast sensitivity in the lateral geniculate nucleus of a New World onkey, the marmoset Callithrix jacchus. J Physiol. 1999 Jun 15; 517 (Pt 3): 907-17; all incorporated as reference in the present. Removal of other migraine models. This invention represents a novel model of migraine and is markedly different from other migraine levels. Some of the features that make a difference from the method of the present invention include (i) unique model of migraine survival in any species; (ii) the only model to demonstrate the abortive (post-treatment) effects of CGRP antagonists in active induced increases in blood flow; (iii) the only demonstration of a direct relationship between a facial blood flow and the dilatation of the intracranial artery made 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 pre-treatment blockade by antagonism of CGRP and an invasion of the post-treatment by antagonism of CGRP (vi) the only migraine model to use isoflurane anesthesia in animals that breathe spontaneously. The models described in Williamson et al., Sumatriptan, inhibit the neurogenic vasodilatation of the dural blood vessels in intravital microscope studies in anesthetized rats. Cephalalgia. 1997 Jun; 17 (4): 525-31; Williamson DJ, Hargreaves RJ, Hill RG Spheard SL. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide in dural vessel diameter in the anaesthetized rat. Cephalalgia. 1997 Jun, 17 (4): 518-24; Escott KJ et al., Trigeminal ganglion sti ulation increases facial skin blood flow in the mouse: 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 antagonist (CGRP 8-37) on skin vasodilation and oedema induced by stimulation of the rat saphenous nerve. Br J Pharmacol. 1993 Oct; 110 (2): 772-6; Hall JM, Simey L, Lippton H, Hyman A, Kang-Chang J. Brain SD. Interaction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvascular of the rat and hamster. Br J Pharmacol. 1995 Feb; 114 (3): 592-7; Hall JM, Brain SD. Interaction of amuylin with calcitonin gene-related peptide receptors in the microvasculature of the hamster cheek pouch in vivo. Br J Pharmacol. 1999 Jan; 126 (1): 280-4; and Doods H. Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the firs selective small molecule CGRP receptor antagonist. Br J Pharmacol. 2000 Feb; 129 (3): 420-3 fail to possess the remarkable features of the method of the present invention. In the table below the results are indicated as follows W < 25%; 25% < X < fifty%; 50% < And < 75%; Z > 75% Table 6. Inhibition of CGRP-induced increase in laser Doppler facial blood flow in a non-human primate (e.g., common Titi).

See Figure 5. Effect of the CGRP Antagonist on the blood pressure of the non-human primate.

It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.

Claims (6)

Claims Having described the invention as above, the content of the following claims is claimed as property.

1. A compound, characterized in that it is selected from the group consisting of methyl ester of (±) -3- (3-Cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (3-cyano-lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of (+) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1 (3-cyano-7-methyl-lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; Methyl ester of (±) -3- (7-isopropyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-isopropyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-ethyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2, 2-dioxo-l, 4-dihydro-2H-2? 6-benzo [1,2,6] thiazin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1-yl-l (7-ethyl-3-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (+) acid -4- (2,2-dioxo-1,4'-dihydro-2H-2? 6-benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid; Methyl ester of (±) -2- [4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] -3- (7-methyl-lH-indazol-5-yl) -propionic; . { 2- [1, 4 '] Bipiperidinyl-1-yl-l- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; . { 2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (2-oxo-l, 2,4,5,5-tetrahydro-benzo [d] [1,3] diazepin-3-yl-l-carboxylic acid; 1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (+) -4- (6-) acid Hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; {.2- [1,4 '] Bipiperidinyl-1-yl-1- (7- (+) -4- (8-methoxy-2-oxo-l, 4-dihydro-2H-quinazolin-3-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide. -yl) -piperidine-1-carboxylic acid; {.2- [1, 4 '] Bipiperidinyl-1-yl-l- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl .) - (±) -4- (8-Chloro-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; (±) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan -2-il) -2 ', 3' -dihydro-2 'oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide; (±) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) iperidin-1-yl) propan -2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-benzo [d] [1,3] oxazine) -1-carboxamide; (±) -N- (3- (7-Ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-lH-pyrazolo [4, 3-c] pyridin-5 (4H) -il) ) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (H) -yl) piperidine-1-carboxamide; (±) -N- (3- (7-Ethyl-lH-indazol-5-yl) -l- (6,7-dihydro-7,7-dimethyl-lH-pyrazolo [4, 3-c] pyridin- 5 (4H) -yl) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; 2- (4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (7-methyl-lH-indazol-5-yl) propanoate of (+) - methyl; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazin-1-yl) -3 - (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazin-1-yl) -3 - (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinnazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; 2- (4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-l-carboxamido) -3- (7-ethyl-3-methyl-lH-indazol-5 -yl) (±) -methyl propanoate; (±) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan -2-yl) -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) -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-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-l-yl) piperidin-l-yl) propan-2-yl ) -8 '-fluoro-2', 3 '-dihydro-2' -oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) - 1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; N- ((R) -3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) ) propan-2-yl) -4- (1, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamide; 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; 2- (4- (1, 2-Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazole -6-yl) propanoate of (R) -methyl; N- ((R) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-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) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-lH-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-lH-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl) piperidin-1 -yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospiro (piperidin-4, 4' - (1H) -quinazoline) carboxamide; 4- (1,2-dihydro- 2,4-dioxoquinazolin-3 (4H) -yl) -N- ((R) -3- (7-methyl-lH-benzo [d] [1, 2, 3] triazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; [2- (4-Cyclohexyl-piperazin-1-yl) -2-oxo (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide. il) -piperidine-1-carboxylic acid; [2- (4-Isopropyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (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- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-carboxamide; (R) -N- ((R) -3- (2-O xo-2, 3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl) piperazin-1-yl) propan-2-yl) -2,4-dihydro- 2'-oxospiro- (piperidin-4,4'-lH-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-1) -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-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) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazoline) -1-carboxamide; (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl) piperazine-1 -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazoline) -1-carboxamide; (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl) piperazin-1 -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazoline) -1-carboxamide; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-l' -yl-1- (4-bromo-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1'-ylY- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R ) -4- (2-oxo-l, -dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1-yl-l- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (±) -N- (l-Benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2 '-oxoespiro- [4H-3', 1-benzoxazin-4, 4 '-piperidinyl] -butyramide; (±) -N- (l-Benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide; N '-. { 2- (7-Methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl ] -butyryl} -hydrazide of (+) - phenylacetic acid; (+) -1- [1,4 '] Bipiperidinyl-1' -yl-4- [4- (8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine- 1-yl] -2- (7-methyl-lH-indazol-5-ylmethyl) -butane-1,4-dione; (±) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [2 ', 3'-dihydro-2' -oxoespiro - (piperidin-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-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (+ ) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-l, 4 -dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (+) -1- [1,4 '] Bipiperidinyl-1' -il-2- (2 -oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospiro- (piperidin-4,4' -quinazoline)] -butane-1, 4- dione; (±) -1- (4-Cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3' -dihydro -2 '-oxoespiro- (piperidin-4,4' -quinazoline)] -butane-1,4-dione; [2- (4-Cyclohexyl-piperazin-1-yl) -1- (7-methyl-1H- indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -pi peridin-1-carboxylic acid; [2- [4- (4-Fluoro-phenyl) -piperazin-1-yl] -1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (+) acid -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (±) -3- (7-Methyl-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-methyl cyclohexyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Piperidin-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Tert-butyl ester of (±) -4- (3- (7-methyl-lH-indazol-5-yl) -2- { [4- (2-oxo-l, 4-dihydro-2H) -quinazolin-3-yl) -piperidine-1-carbonyl] -amino.}.-propionyloxy) -piperidine-1-carboxylic acid; 3, 4, 5,6-Tetrahydro-2H- [1, 4 '] bipyridinyl-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Diethylamino-l-methyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1, 1-dimethyl-2-phenyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1, 1-dimethyl-3-phenyl-propyl ester of (+) - 3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Ethyl ester of (+) - 3 - (7-Methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [(2-dimethylamino-ethyl-ethyl carbamoyl) -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2' - oxospiro- [4 H -3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- (l-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2' - oxospiro- (4H-3 ', 1-benzoxazine-4, 4'-piperidine] -1-carboxamide; [2- (1,4'] Bipiperidinyl-1 '-yl-1- (7-methyl-lH-indazole (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-l-carboxylic acid-5-oxo-ethyl] -amide; ) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -l-yl-2-oxoethyl] -2 ', 3'-dihydro-2'-oxospiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

2. A compound, characterized in that it is selected from the group consisting of [2- [1,4 '] bipiperidinyl-1' -yl-1- (7-bromo-lH-indazol-5-ylmethyl) -2-oxo-ethyl] 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2-Oxo-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide of 4-acid - (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2-Oxo-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide of 4- (2-oxo-l, 4-) dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- (4-Methyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of 4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1-yl-l- (4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 4- (2-oxo-l, 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 of 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 of 4- (2-oxo-) 1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [l-Dimethylcarbamoyl-2- (4-methyl-2-oxo-2, 3-dihydro-benzooxazol-6-yl) -ethyl] -amide of 4- (2-oxo-l, 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 of 4- (2-oxo-l, 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] - 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [1- (4-Chloro-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2- [1,4 '] Bipiperidinyl-1-yl-l- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of acid 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-ethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (3,7-dimethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 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-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; 3- (7-Methyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Ethyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Ethyl-lH-indazol-5-yl) -2- tert-butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; L-methyl-piperidin-4-yl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-ethyl-lH-indazol-5-yl) -2- l-methyl-piperidin-4-yl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Methyl-cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-ethyl-lH-indazol-5-yl) -2- acid 1-methyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- acid 4-phenyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; and 4-phenyl-cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic or a pharmaceutically acceptable salt or solvate thereof.

3. A pharmaceutical composition characterized in that it comprises a compound selected from the group consisting of methyl ester of (±) -3- (3-cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (3-cyano-lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1 (3-cyano-7-methyl-lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; Methyl ester of (+) - 3 - (7-isopropyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-isopropyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1 (7-ethyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -pipe idin-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1-yl-l (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2, 2-dioxo-l, 4-dihydro-2H-2? 6-benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1-yl-l (7-ethyl-3-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2,2-dioxo-1,4-dihydro-2H-2? 6-benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid; Methyl ester of (±) -2- [4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] -3- (7-methyl-lH-indazol-5-yl) -propionic; . { 2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; . { 2- [1,4 '] Bipiperidinyl-l' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (2-oxo-l, 2,4,5,5-tetrahydro-benzo (d] [1, 3] diazepin-3-yl-l-carboxylic acid; 1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (6-) acid hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; {. 2- [1, '] Bipiperidinyl-1' -yl-1- (7-methyl) -lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (+) -4- (8-methoxy-2-oxo-l, 4-dihydro-2H-quinazolin-3-) il) -piperidine-1-carboxylic acid; {. 2- [1, 4 '] Bipiperidinyl-1-yl-l- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} - (+) -4- (8-chloro-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide: (±) -N- (3) - (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) -2 ' , 3'-dihydro-2 '-oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide; (±) -N- (3- (7-Ethyl-3-methyl-lH-indazole ~ 5- il) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxoespi ro- (piperidin-4,4'-lH-benzo [d] [1, 3] oxazine) -1-carboxamide; (±) -N- (3- (7-Ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-lH-pyrazolo [4, 3-c] pyridin-5 (4H) -il) ) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (±) -N- (3- (7-Ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-lH-pyrazolo [4, 3-c] pyridin- 5 (4H) -yl) -l-oxopropan-2-yl) -4- (1, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamide; 2- (4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (7-methyl-lH-indazol-5-yl) propanoate of (±) -methyl; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazin-1-yl) -3 - (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazin-1-yl) -3 - (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; 2- (4- (8-fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (7-ethyl-3-methyl-lH-indazol-5 -yl) (±) -methyl propanoate; (+) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan -2-yl) -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) -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-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl ) -8 '-fluoro-2', 3 '-dihydro-2' -oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) - 1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; N- ((R) -3- (2- (trifluoromethyl) -lH-benzo [d] imidazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) ) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -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 (4H) -yl) piperidin-1-carboxamide; 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazole) -6-yl) propanoate of (R) -methyl; N- ((R) -3- (2,3-Dihydro-2-oxo-lH-benzo [d] imidazol-6-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) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) ethyl) -4- (1, 2-dihydro- 2-oxoquinazolin-3- (4H) -yl) piperidin-1-carboxamide; N- ((R) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl) piperidin-1 -yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospiro (piperidin-4, 4' - (1H) -quinazoline) carboxamide; 4- (1,2-Dihydro- 2,4-dioxoquinazolin-3 (4H) -yl) -N- ((R) -3- (7-methyl-lH-benzo [d] [1, 2, 3] triazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; [2- (4-Cyclohexyl-piperazin-1-yl) -2-oxo (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide. il) -piperidine-1-carboxylic acid; [2- (4-Isopropyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (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- (piperidin-4,4'-lH-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-yl) piperazin-1-yl) propan-2-yl) -2, 4 -dihydro-2 '-oxoespiro- (piperidin-4,4'-lH-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-1) -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-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) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-quinazoline) -1-carboxamide; (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl) piperazine-1 -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-quinazoline) -1-carboxamide; (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl) piperazin-1) -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazoline) -1-carboxamide; [2- [1,4 '] Bipiperidinyl-1-yl-l- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1-yl-l- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1-yl-l- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-l' -yl-1- (5-bromo-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1-yl-l- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (+) -N- (l-Benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2 '-oxoespiro- [4H-3', 1-benzoxazin-4, 4 '-piperidinyl] -butyramide; (+) -N- (l-Benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide; N'-. { 2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl} ] -butyryl} -hydrazide of (±) -phenyl-acetic acid; (±) -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-lH-indazol-5-ylmethyl) -butane-1,4-dione; (±) -1- [1, 4 '] Bipiperidinyl-l' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [2 ', 3'-dihydro-2' -oxoespiro - (piperidin-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-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; ) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-l, 4 -dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (+) -1- [1,4 '] Bipiperidinyl-1' -il-2- (2 -oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospiro- (piperidin-4,4' -quinazoline)] -butane-1, 4- dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3' -dihydro -2 '-oxoespiro- (piperidin-4,' -quinazoline)] -butane-1,4-dione; [2- (4-Cyclohexyl-piperazin-1-yl) -1- (7-methyl-1H-indazole (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -amide-2-oxo-ethyl] -amide) -piperidine-1-carboxylic acid; [2- [4- (4-Fluoro-phenyl) -piperazin-1-yl] -1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (±) -3- (7-Methyl-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Methyl cyclohexyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; (+) - 3 - (7-Methyl-lH-indazol-5-yl) -2- piperidin-4-yl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Tert-butyl ester of (±) -4- (3- (7-methyl-lH-indazol-5-yl) -2- { [4- (2-oxo-l, 4-dihydro-2H) -quinazolin-3-yl) -piperidine-1-carbonyl] -amino.}.-propionyloxy) -piperidine-1-carboxylic acid; 3, 4, 5,6-Tetrahydro-2H- [1, 4 '] bipyridinyl-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Diethylamino-l-methyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1, 1-dimethyl-2-phenyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1, 1-dimethyl-3-phenyl-propyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [(2-dimethylamino-ethyl-ethyl carbamoyl) -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (+) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2' - oxospiro- [4 H -3 ', 1-benzoxazine-4, 4' -piperidine] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2' - oxospiro- [4 H -3 ', 1-benzoxazine-4, 4' -piperidine] -1-carboxamide; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-l-carboxylic acid; and (R) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -l-yl-2-oxoethyl] -2 ', 3'-dihydro-2' -oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition characterized in that it comprises a compound selected from the group consisting of [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-bromo-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of 4- (2-oxo-l) , 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2-Oxo-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide of 4-acid - (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2-Oxo-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide of 4- (2-oxo-l, 4-) dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- (4-Methyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of 4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (4-methyl-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 4- (2-oxo-l, 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 of 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 of 4- (2-oxo-) 1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [l-Dimethylcarbamoyl-2- (4-methyl-2-oxo-2, 3-dihydro-benzooxazol-6-yl) -ethyl] -amide of 4- (2-oxo-l, 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 of 4- (2-oxo-l, 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] - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [1- (4-Chloro-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2- [1, 4 '] Bipiperidinyl-l' -yl-1- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-l' -yl-1- (7-ethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1-yl-l- (3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (3,7-dimethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 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-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; 3- (7-Methyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic; 3- (7-Ethyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Ethyl-lH-indazol-5-yl) -2- tert-butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; L-methyl-piperidin-4-yl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-ethyl-lH-indazol-5-yl) -2- l-methyl-piperidin-4-yl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Methyl-cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Methyl-cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- acid 4-phenyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; and 4-phenyl-cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic or a pharmaceutically acceptable salt or solvate thereof.

5. The use of a compound selected from the group consisting of methyl ester of (±) -3- (3-cyano-lH-indol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (3-cyano-lH-indol-5-yl-methyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1-yl-l (3-cyano-7-methyl-lH-indol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; Methyl ester of (±) -3- (7-isopropyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-isopropyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, '] Bipiperidinyl-1' -yl-1- (7-ethyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2 -oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1'-lyl-1 (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- ( 2, 2-dioxo-l, 4-dihydro-2H-2? 6-benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1 (7-ethyl-3-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (±) -4- (2,2-dioxo-1,4-dihydro-2H-2? D -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-carboxylic acid; Methyl ester of (±) -2- [4- (6-Cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] -3- (7-methyl-lH-indazol-5-yl) -propionic; . { 2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (6-cyano-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; . { 2- (1, 4 ') Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (+) -4- (2-oxo-l, 2,4,4,5-tetrahydro-benzo (d) (1,3) diazepin-3-yl-l-carboxylic acid;. {2- (l, 4 ') Bipiperidinyl-l- IL-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of (±) -4- (6-hydroxy-2-oxo-1, 4-) dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; {2- (1, 4 ') Bipiperidinyl-1-yl-1- (7-methyl-1H-indazol-5-ylmethyl) ) -2-Oxo-ethyl.} - (+) -4- (8-methoxy-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; {Β 2- [1, 4 '] Bipiperidinyl-l' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl} -amide of the acid (±) -4- (8-chloro-2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (±) -N- (3- (7-Ethyl-3-methyl) -lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) -2 ', 3' -dihydro-2 '- oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide; (±) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l-(4- (piperidin-1-yl) piperidin-1-yl) ropan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-benzo [d] [1 , 3] oxazine) -1-carboxamide; (±) -N- (3- (7-Ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-lH-pyrazolo [4, 3-c] pyridin-5 (4H) -il) ) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (±) -N- (3- (7-Ethyl-lH-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-lH-pyrazolo [4, 3-c] pyridin- 5 (4H) -yl) -l-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; 2- (4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (7-methyl-lH-indazol-5-yl) propanoate of (±) -methyl; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazin-1-yl) -3 - (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide; (+) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazin-1-yl) -3 - (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-Fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; 2- (4- (8-Fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-ethyl-3-methyl-lH-indazol-5 -yl) (+) - methyl propanoate; (+) -N- (3- (7-Ethyl-3-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan -2-yl) -4- (8-fluoro-l, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamide; (R) -N- ((R) 3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1- il) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) pipefidin-1-carboxamide; (±) -N- (3- (7-Methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl ) -8 '-fluoro-2', 3 '-dihydro-2' -oxoespiro- (piperidin-4,4' -quinazoline) -1-carboxamide; (±) -4- (8-Fluoro-l, '2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; N- ((R) -3- (2- (trifluoromethyl) -IH-benzo [d] imidazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) ) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -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 (4H) -yl) piperidin-1-carboxamide; 2- (4- (1, 2-Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamido) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazole -6-yl) propanoate of (R) -methyl; N- ((R) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-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) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) ethyl) -4- (1,2-dihydro- 2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamide; N- ((R) -3- (2,3-dihydro-2-oxo-lH-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl) piperidin-1 -yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospiro (piperidin-4, 4' - (1H) -quinazoline) carboxamide; 4- (1,2-dihydro- 2,4-dioxoquinazolin-3 (4H) -yl) -N- ((R) -3- (7-methyl-lH-benzo [d] [1, 2, 3] triazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; [2- (4-Cyclohexyl-piperazin-1-yl) -2-oxo (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-l- (2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide. il) -piperidine-1-carboxylic acid; [2- (4-Isopropyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of (R) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid (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- (piperidin-4,4'-lH-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-yl) piperazin-1-yl) propan-2-yl) - 2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-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-1) -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-benzo [d] [1,3] oxazine) -1-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) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-lH-quinazolin) -1-carboxamide; (R) -N- ((R) -3- (2-0x0-2, 3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl) piperazine-1 -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-iH-quinazoline) -1-carboxamide; (R) -N- ((R) -3- (2-Oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl) piperazine) -yl) propan-2-yl) -2,4-dihydro-2'-oxospiro- (piperidin-4,4'-IH-quinazoline) -1-carboxamide; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid (R) -4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (+) -N- (l-Benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2 '-oxoespiro- [4H-3', 1-benzoxazin-4, 4 '-piperidinyl] -butyramide; (±) -N- (l-Benzyl-2-hydroxy-ethyl) -2- (7-methyl-lH-indazol-5-ylmethyl) -4-OXO-4- [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide; N '-. { 2- (7-Methyl-lH-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl) ] -butyryl} -hydrazide of (±) -phenyl-acetic acid; (+) -1- [1,4 '] Bipiperidinyl-1' -yl-4- [4- (8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine- 1-yl] -2- (7-methyl-lH-indazol-5-ylmethyl) -butane-1,4-dione; (±) -1- [1,4 '] Bipiperidinyl-1' -yl-2- (7-methyl-lH-indazol-5-ylmethyl) -4- [2 ', 3'-dihydro-2' -oxoespiro - (piperidin-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-l, 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- (2-oxo-l, 4 -dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (+) -1- [1,4 '] Bipiperidinyl-1' -il-2- (2 -oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospiro- (piperidin-4,4' -quinazoline)] -butane-1, 4- dione; (±) -1- (4-Cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3' -dihydro -2 '-oxoespiro- (piperidin-4,4' -quinazoline)] -butane-1,4-dione; [2- (4-Cyclohexyl-piperazin-1-yl) -1- (7-methyl-1H- indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (±) -4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-i) l) -piperidine-1-carboxylic acid; [2- [4- (4-Fluoro-phenyl) -? Iperazin-1-yl] -1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of the acid (± ) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; (±) -3- (7-Methyl-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Methyl cyclohexyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-aza-bicyclo [2.2.2] oct-3-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Piperidin-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic; (+) -4- (3- (7-Methyl-lH-indazol-5-yl) -2- { [4- (2-oxo-l, 4-dihydro-2H) tert-butyl ester -quinazolin-3-yl) -piperidine-1-carbonyl] -amino.}.-propionyloxy) -piperidine-1-carboxylic acid; 3, 4, 5, 6-Tetrahydro-2H- [1,4 '] bipyridinyl-4-yl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Diethylamino-l-methyl-ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1, 1-Dimethyl-2-phenyl-ethyl of (+) - 3 - (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1, 1-Dimethyl-3-phenyl-propyl of (+) - 3 - (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Ethyl ester of (±) -3- (7-methyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'-dihydro-2' - oxospiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2 - [(2-dimethylaminoethyl-ethyl-carbamoyl) -2-oxoethyl] -2 ', 3'-dihydro-2' - oxoespiro- [piperidin-4, 4 '- (1H) -quinazolína] -1-carboxamide; (±) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2' - oxospiro- [4 H -3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (+) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [l-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'-dihydro-2' - oxospiro- [4 H -3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (7-methyl-lH-indazol-5-ylmethyl) -2-oxo-ethyl] -amide of (R) -4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-l-carboxylic acid; and (R) -1- (7-Methyl-lH-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -l-yl-2-oxoethyl] -2 ', 3'-dihydro-2' -oxoespiro- [piperidin-4, 4 '- (1H) -quinazoline] -1-carboxamide or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of migraine.

6. The use of a compound selected from the group consisting of [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-bromo-lH-indazol-5-ylmethyl) -2-oxo-ethyl] - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2-Oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide of 4 - (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2-Oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide of 4- (2-oxo-l, 4-) dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- (4-Methyl-piperazin-1-yl) -2-oxo-l- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide of 4- (2- oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (4-methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 4- (2-oxo-l, 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 of 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 of 4- (2-oxo-) 1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [l-Dimethylcarbamoyl-2- (4-methyl-2-oxo-2, 3-dihydro-benzooxazol-6-yl) -ethyl] -amide of 4- (2-oxo-l, 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 of 4- (2-oxo-l, 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] - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [1- (4-Chloro-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] - 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (4-ethyl-2-oxo-2, 3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide of the acid 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-chloro-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-ethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1,4 '] Bipiperidinyl-l' -yl-1- (3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1' -yl-1- (3,7-dimethyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] 4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid amide; [2- [1,4 '] Bipiperidinyl-1' -yl-1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; [2- [1, 4 '] Bipiperidinyl-1-yl-l- (7-ethyl-3-methyl-2-oxo-2,3-dihydro-lH-benzoimidazol-5-ylmethyl) -2-oxo- ethyl] -amide of 4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid; 3- (7-Methyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Ethyl-lH-indazol-5-yl) -2- isopropyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- tert -butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Ethyl-lH-indazol-5-yl) -2- tert-butyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl] -amino} -propionic; Cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; Cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; L-methyl-piperidin-4-yl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-ethyl-lH-indazol-5-yl) -2- l-methyl-piperidin-4-yl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 1-Methyl-cyclohexyl ester of 3- (7-chloro-lH-indazol-5-yl) -2- acid. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-ethyl-lH-indazol-5-yl) -2- acid 1-methyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; 3- (7-Chloro-lH-indazol-5-yl) -2- acid 4-phenyl-cyclohexyl ester. { [4- (2-oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic; and 4-phenyl-cyclohexyl ester of 3- (7-ethyl-lH-indazol-5-yl) -2- acid. { - [4- (2-Oxo-l, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of migraine.