MXPA06011025A

MXPA06011025A - Heterocyclic cgrp antagonists for the treatment of migraine

Info

Publication number: MXPA06011025A
Application number: MXPA/A/2006/011025A
Authority: MX
Inventors: E Macor John; M Dubowchik Gene; P Degnan Andrew; Han Xiaojun
Original assignee: Bristolmyers Squibb Company; P Degnan Andrew; M Dubowchik Gene; Han Xiaojun; E Macor John
Priority date: 2004-03-29
Filing date: 2006-09-26
Publication date: 2007-04-20

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

ANTAGONISTS OF PEPTIDE RECEPTORS RELATED TO THE CALCITONIN GENE (CGRP) HETEROCICLICOS FOR TREATMENT D? MIGRAINE FIELD OF THE INVENTION The present invention relates to novel small molecule antagonists of the peptide receptors related to the calcitonin gene ("CGRP receptor"), pharmaceutical compositions comprising them, methods for their identification, methods of treatment that use them and its use in therapy for the treatment of vasodilatation, neurogenic, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, suffocations associated with menopause, inflammatory airway diseases such as asthma and Chronic obstructive pulmonary disease (COPD), and other conditions, treatment of which can be effected by 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 (aCGRP and ßCGRP) are expressed which differ by one and three amino acids in rats and humans respectively. The peptide is distributed REF. : 175832 extensively in the peripheral nervous system (PNS) and 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 specific cell surface G protein, and exerts its biological action predominantly by the activation of intracellular adenylate cyclase (Poyner, DR 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, S. D. et al, TiPS 2002, 23, 51-53). The CGRPi receptor has three components: (i) a transmembrane-type calcitonin receptor-type receptor 7 (CRLR); (ii) the type 1 protein that modifies the activity of the single 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, S. D. et al, TiPS 2002, 23, 51-53). The RAMPl amino acid sequence 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). Inhibitors at the receptor level for CGRP are postulated to be useful under pathophysiological conditions, where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilatation, neurogenic inflammation, migraine, zone headache and other headaches, thermal injuries, circulatory shock, menopausal flushing, 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, D. J. Microsc.

Res. Tech. 2001, 53, 167-178; Grant, A. D. Brit. J.

Pharmacol. 2002, 135, 356-362). CGRP serum levels rise during migraine (Goadsby PJ, et al Ann Neurol 1990; 28: 183-7) and treatment of migraine drugs returns CGRP levels to a normal coincident with improvement of 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 nor the regional blood flow.

(Shen, Y-T et al, J Pharmacol Exp Ther 2001, 298, 551-8).

Thus, CGRP receptor antagonists can present a novel treatment for migraine that avoids the cardiovascular risks of active vasoconstriction associated with non-selective agonists 5-HT? B /? D / "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 they 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 (eg, Escott et al., Brain Res 1995 669: 93). Alternatively, other peripheral nerves (eg, saphenous) and vascular beds (e.g., abdominal blood flow) are also studied (e.g. Escott et al., Br J Pharmacol 1993 110, 772-6;). All models have been shown to be blocked by pretreatment with the peptide antagonist CGPR (8-37), a peptide fragment that is absent 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; They use among other intravenous CGRP as a stimulus to increase the diameter of the intracranial dural artery in rats anesthetized with sodium pentobarbital, using an "intravital" terminal procedure, which involves drilling to thin the skull and creating 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 is measured by Doppler laser effect, the facial blood flow in a terminal procedure in anesthetized rats with sodium pentobarbital that involves a neuromuscular block , tracheal intubation 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 CGRP (8-37) i.v. Chu et al. Neurosci Lett 2001 310, 169-72 used, inter alia, intradermal CGRP as the stimulus in rats and measured laser Doppler changes in the blood flow in the skin of the back with 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 blogged 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 of the flow was blocked by a pretreatment of the CGRP antagonist of the molecule pegueña. 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 effects previous and subsequent to the treatment of the antagonists. CGRP of small molecule of peptides in marmosets anesthetized with isoflurane that breathe spontaneously that recover from the procedure and that offers 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 which are ligands in particular CGRP receptor antagonists. 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 E.U.A. 6,344,449, E.U.A. 6,313,097, E.U.A. 6,521,609, E.U.A. 6,552,043, E.U.A. 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 the first embodiment of the first aspect of the present invention, compounds of the formula (I) are provided and pharmaceutically acceptable salts and solvates thereof wherein V is -N (RX) (R2) or OR4; R4 is H, C6-6alkyl, C1-4haloal u.ilo or (C4-4alkylene) 0-1R4 'R4' is C3-7cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl , dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl , piperidinyl, piperazinyl, morpholino, thio orfolino or dioxolanyl; and R4 'is optionally substituted with 1 or 2 of the same or different substitutes selected from the group consisting of halo, cyano, C? _4alkyl, C? -4haloalkyl, C? _4alkoxy, hydroxyl, amino, C3_7cycloalkyl, C? _3alkylamino, C 1-3 -alkylamino, (C? _3alkyl) or-2-ureido, phenyl and benzyl; and R4 'optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the ring structure R4'; R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, Ci-ßalkyl, C2_6alfJ-enyl, C2-6alkynyl, -Ci-ealkylene-amino (C? -3alkyl) 2, C3_7cycloalkyl , 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 substitutes selected from the group consisting of halo, cyano, C? _ alkyl, C? -4 haloalkyl, C? -alkoxy, hydroxyl, amino, C3_7-cycloalkyl, C? _3alkylamino, C? _3-dialkylamino, (C? _3alkyl) or-2-ureido, 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 attached by L2, wherein L is independently C3 ~ alkylene or C3 ~ 3 alkylidene; or R1 and R2 together with the nitrogen to which they bind form 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? _9alkyl, C_9alkenyl, C2-9alkynyl, C? 4alkylamino, C? _dialkylamino, 'C? _4alkoxy, C3_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, benzothiazolyl 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-, -CX-3alkylene-, -C? ~ 3-alkylene-, -C? ~ 3alkenylene-NHC (0) 0-C? _ 3-alkylene-; and optionally and independently substituted with 1 or 2 of the same or different substitutes selected from the group consisting of halo, C? _alkyl, amino, C? _3alkylamino, -Ci-ealkylene-amino (C? _3alkyl) 2, (C? 3alkyl) or-2u.reido, 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 carry a carbon atom and together they form a spirocyclic portion; Q is Q 'or Q ", where Q' is (SY) SR3; and Q" is NH (SY) SRA NHC (O) (Sy) sR3, NHC (O) O (S?) BR3, NHC (0) ) NH (S?) SR3, 0 (S?) SR3, (Sy) sNHR3, (S?) SNHC (O) R3, (S?) SNHC (0) OR3, (Sy) sNHC (0) NHR3 or ( S?) SOR3; wherein Sy is C? _alguylene or C? _3 alkylidene and s is 0 or 1; R3 is R3a or R3 wherein R3a is (i) a heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle contains from one to five of the same or different heteroatoms selected from the group consisting of O, N and S and the heterocycle optionally contain 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the fused rings;(ii) a 4- to 6-membered heterocycle containing one to three identical 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; (iii) C3-7cycloalkyl; (iv) carbazolyl, fluorenyl, phenyl, -0-phenyl, -0-C? 4-alkylene-phenyl, or naphthyl; or (v) Ci-salkyl, C2-alkenyl, -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 ', -C (0) 0-R3 'or C2_7alkynyl; and wherein R3a is optionally substituted with 1 to 3 of the same or different substitutes selected from the group consisting of benzyl, phenyl, -O-phenyl, -0-C? _ 3-alkylene-phenyl, -C? _3-alkylene-0C (0) - phenyl, cyano, amino, nitro, halo, C? -6alkyl, C? _3mono-bi-tri-haloalkyl, C? _3mono-bi-tri-haloalkyloxy, (C1_3alkyl)? -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 - S02RJ R3 'is H or -C? _6alkyl; with the proviso that if R is, -C (0) R, CHC (0) 0AFr, CH (CH3) C (0) 0 -R3 'or -C (0) 0 -R3', then the -C ( 0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) OR3 'or -C (0) 0 -R3' is unsubstituted; 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, l-formyl-lH-indol-3-yl, 1- (1,1-dimethylethoxycarbonyl) -lH-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, lH-indazol-3-yl, l-methyl-lH-indazol-3-yl, benzo [b] fur-3-yl, benzo [b] thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted on the carbon skeleton with mono-, di or trisubstituted by fluorine, chlorine or bromine atoms or branched or unbranched alkyl groups, C3_s-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy groups , trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxyl, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxyl, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulfonyloxy, aminocarboyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; wherein the substitutes may be the same or different and the groups mentioned above benzoyl, benzoylamino and benzoylmethylamino can be further substituted again in the phenyl portion by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino; D is 0, NCN or NS02C? _3alkyl ?; A is C, N, CH or COH; 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 an Ax or A ?; Ax is a fused heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle contains from 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; TO? 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 the 4 to 6 membered heterocycle; where Ax and A? they are optionally substituted with C? _4alkyl, C? -4alkoxy, C? -4haloalkyl, cyano, C3_ cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or if p is 0 such that G and J join each with 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 are GJA 'or GJA "; where GJA 'is Ax or A ?; and GJA "is Ax or A ?, with the proviso that Ax is not a 1,3-diaza fused heterocycle ring, and Ay 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. "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 R3 is R3b 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', R3 is R3 and p is 0 such that G, J and A together form GJA. " According to another embodiment of the first aspect of the present invention, 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 C? _ 3 alkylene 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, S ? is methylene and s is 1. 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, S? is C? _ 3-alkylidene 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 '. 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 (S?) S 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 ', Q' is (SY)? R3, S? is C? _3 alkylene 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 ', Q' is (S?) s R3, S? is C? _3 alkylidene and s is 1.

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. In accordance with another embodiment of the first aspect of the present invention, provide compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q "and Q" is NH (Sy) R3 In accordance with another embodiment of the first aspect of the present invention, there are provided with 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, S? is Alkylene 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) sR3 , S? is C? _ 3-alkylidene and s is 1. According to another embodiment of the first aspect, 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. 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)? R3, S ? is C? _3 alkylene 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 (O ) (Sy) sR3, S? is C3-alkylidene 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 (O ) 0 (S?) SR3. 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 wherein Q is Q "and Q" is NHC (O) O (SY) SR3 and s is O. According to another embodiment of the first aspect of 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) O (S?) SR3, S? is C? _3 alkylene 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 (O ) 0 (S?) SR3, S? is C? _3 alkylidene 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 (S?)? R3. 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 (S?) SR3 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 Q is Q "and Q" is NHC (0) NH (S? ) sR3, Sy is C? _3 alkylene 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 (O) NH (Sy)? R3, S? is C3-alkylidene 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 OR4 and R4 is C6_6alkyl. 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). 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; R4 is H, C6alkyl, C4-haloalkyl, (C4-4alkylene) or R4'R4 'is C3_7cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl , tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl , morpholino, thiomorpholino or dioxolanil; and R4 'is optionally substituted with 1 or 2 of the same or different substitutes selected from the group consisting of halo, cyano, C? _4alkyl, C? -haloalkyl, C? _4alkoxy, hydroxyl, amino, C3_7cycloalkyl, C? _3alkylamino, C-dyalkylamino, (C? _3 alkyl) or-2-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? _6alkyl, -C? 6alkyleneamino (C? Alkyl) 2, C3_7cycloalkyl, 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 substitutes selected from the group consisting of halo, cyano, C? 4alkyl, C? _4haloalkyl, C? -4alkoxy, hydroxyl, amino, C3_ 7-cycloalkyl, C? _3-alkylamino, Ci-3d-alkylamino, (C? _3 alkyl) 0-2-ureido, 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 attached by L2, wherein L2 is C3_3alkylene; or R1 and R2 together with the nitrogen to which they bind form 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? _4 alkyl, C? _ alkylamino, C? _ dialkyl amino, 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 (0) 0-, -NHC (0) NH-, NC (0) NH2, -NH-, -C? _ 3alkylene-, C ? -3-alkylene-NHC (O) 0-C? _3-alkylene-; and optionally and independently substituted with 1 or 2 identical or different substitutes selected from the group consisting of halo, C? -alkyl, amino, C? _3alkylamino, -C? 6-alkylene-amino (C3_3alkyl) 2, (C3_3alkyl) 0-2U-ary, 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 carry 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 R4 is H, C6-6alkyl, C4-4alpha.alkyl, or ? _alkylene) 0-1R4 '; R4 'is C3_7cycloalkyl, phenyl, adamantyl, quinuplidyl, 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 substitutes selected from the group consisting of halo, cyano, C? _alkyl, C? -4haloalkyl, C? -4alkoxy, hydroxyl, amino, C3_7cycloalkyl, C? _3alkylamino, C? ~ 3dyalkylamino, (C? _ 3alkyl) or-2U.reido, 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? _6 alkyl, C? Haloalkyl or (C? -4 alkylene) 0-? R4 '; R4 'is QA-cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo [2.2.l] 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 R4 is H, Ci-ealkyl or (C? 4alkylene) or -R4 '; R4 'is C3_7cycloalkyl. 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, where L1 is selected from the group consisting of H, C? _6alkyl, -C? _? alkyleneamino (C? _3alkyl) 2, C3_7cycloalkyl, phenyl, azetidinyl, adamantyl, 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 dioxolane; or R1 and R2 together with the nitrogen to which they bind form 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 1-4alkyl, C 4 -alkoxy, C 3 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, i idazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y optionally carry 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 -N (RX) (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 which joins to form X, wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C? _4alkyl or piperidinyl; and wherein X and Y optionally carry 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 is selected from the group consisting of H, C? _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 V is -N (RX) (R2) and wherein R1 and R2 together with the nitrogen to which it joins to form X, wherein X is piperidinyl, piperazinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, phenyl, pyridyl, piperazinyl, piperidinyl or C? _4alkyl; and wherein X and Y optionally carry a carbon atom and together form a spirocyclic moiety. 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 V is -NIR1) (R2) and wherein R1 and R2 together with the nitrogen to which they join form 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 -NYR1) (R2) and wherein R1 and R2 together with the nitrogen at which they join form X, where X is morpholino; wherein X is substituted with Y, wherein Y is Ci- 4alkyl. 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 at which they join form X, where X is piperidinyl; wherein X is substituted with Y, wherein Y is C? _ 4 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 at which they join form X, where X is piperidinyl, - wherein X is substituted with Y, where Y is dioxolanyl; and where X and Y carry 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 carry 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 R3. 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 contains one to five identical or different heteroatoms selected from the group consisting of O, 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 R3a is a heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle contains one to five identical or different heteroatoms selected from the group consisting of 0, N and S and the heterocycle optionally contains 1 or 2 carbonyls in which the carbonyl carbon atom is a member of the fused rings. 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 contains one to five identical or different heteroatoms selected from the group consisting of 0, N and S and the heterocycle optionally contains 1 or 2 carbonyls wherein the carbon atom of the carbonyl is a member of the fused rings; wherein R3a is optionally substituted with 1 to 3 of the same or different substitutes selected from the group consisting of benzyl, phenyl, -O-phenyl, -0-C? _3 alkylphenyl, C? _3alkylene-OC (O) -phenyl, cyano , amino, nitro, halo, C? _3mono-bi-tri-haloalkyl, C? _3mono-bi-tri-haloalkyloxy, C? _alkoxy, (C? -3alkyl)? 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 (R3 ') 2, -N (R3') C (0) OR3 ', -0-C (O) N (R3') 2, -N (R3 ') S02R3', -S02N (R3 ') 2 and -S02R3'; R3 'is H or -C? _6alkyl.

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 from one to three 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 is 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 containing one to three identical or different heteroatoms selected from the group consisting of group consisting of 0, N and S, optionally containing 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 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 R3a is a 4- to 6-membered heterocycle containing from one to three identical or different heteroatoms selected of the group consisting of O, N and S, optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 4- to 6-membered heterocycle; wherein R3a is optionally substituted with 1 to 3 identical or different substitutes selected from the group consisting of benzyl, phenyl, -O-phenyl, -0-C? _3 alkylphenyl, -C? -3alkylene-0C (0) -phenyl, cyano , amino, nitro, halo, C? _3mono-bi-tri-haloalkyl, C? _3mono-bi-tri-haloalkyloxy, C? 6alkoxy, (C? _3alkyl)? 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 (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 C? _6 alkyl. According to another embodiment of the first aspect of the present invention 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. 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_7cycloalkyl; wherein R3a is optionally substituted with 1 to 3 of the same or different substitutes selected from the group consisting of benzyl, phenyl, -O-phenyl, -0-C? _3 alkylphenyl, C? _3 alkylene-OC (0) -phenyl, cyano , amino, nitro, halo, C_3mono-bi-tri-haloalkyl, C? _3mono-bi-tri-haloalkyloxy, C? _6 alkoxy, (C? _ 3 alkyl)? _2 amine, -0R3 ', -C (0) R3', -C (0) 0 -R 3 ', -0-C (0) R 3', N (R 3 ') 2, -C (0) N (R 3') 2, -N (R 3 ') 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 C? _6 alkyl.

According to another embodiment of the first aspect of the present invention 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, -O-phenyl, -0- C 1-4 alkylene-phenyl, or naphthyl. According to another embodiment of the first aspect of the present invention 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, -0- C 1-4 alkylene-phenyl, or naphthyl; wherein R3 is optionally substituted with 1 to 3 of the same or different substitutes selected from the group consisting of benzyl, phenyl, -0-phenyl, -0-C? _3 alkylphenyl, -C? _ alkylene-0C (0) -phenyl, cyano, amino, nitro, halo, C_3mono-bi-tri-haloalkyl, C? -3mono-bi-tri-haloalkyloxy, C? _6alkoxy, (C? _3alkyl)? _2amine, -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 (0) OR3 ', -0-C (0) N (R3') 2, -N (R3 ') S02R3', -S02N (R3 ') 2 and -S02R3'; R3 'is H or C? _6alkyl. According to another embodiment of the first aspect of the present invention of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein R3 is C? -galkyl, C2-alkenyl, -C (0) R3 ', -C (0) 0 -R3' or C2_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 R3 is C? _8alkyl, C2_alkenyl, -C (0) R3 ', -C (0) ) 0-R3 'or C2_7alkyl ilo; wherein R3a is optionally substituted with 1 to 3 of the same or different substitutes selected from the group consisting of benzyl, phenyl, -0-phenyl, -O-C1_3alkylphenyl, -C? _3alkylene-0C (O) -phenyl, cyano, amino, nitro, halo, C? _3mono-bi-tri-haloalkyl, C? _ 3 mono-bi-tri-haloalkyloxy, C? _6 alkoxy, (C? ~ 3 alkyl)? _ 2 amine, -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) 0R3 ', -0-C (0) N (R3 ') 2, -N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R3 'is H or Ci-ealkyl; with the proviso that if R3a is -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) O-R3 'or -C (0) 0 -R3', then the -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 'or -C (0) 0 -R3' are unsubstituted. 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, Ci-galquílo, C2_ ßalkenyl, C_6alkynyl, dihydroquinolinonyl, hydroquinolinonyl, quinolinyl, dihydroisoquinolinonyl, hydroquinonequinolinyl, Esoquinolinilo, dihidroquinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, indazolyl, dihidrobencimidazolonilo, hidrobencimidazolonilo, benzimidazolinyl, dihydro- benzothiazolonyl, hidrobenzotiazolonilo, benzothiazolyl, dihydrobenzoxazolyl, benzotriazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, benzothienyl, dihidrobenzofuranonilo, hidrobenzofuranonilo, benzofuranyl, benzdioxolanilo , dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl , piperazinyl or morpholino; optionally substituted is 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 phenyl, naphthyl, indazolyl, benzimidazolinyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl. , benzdioxolanyl, dihydroindolonyl, indolyl, furanyl, thienyl, pyridyl, purinyl, carbazolyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl; optionally substituted is 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 dihydrobenzthiazolonyl, hydrobenzothiazolonyl, benzothiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, benzothienyl. , dihydrobenzofuranonyl, hydrobenzofuranonyl, benzofuranyl, dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl or indazolyl; optionally substituted is 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 R3 is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidine, halopurinyl, C ? -3-alkyl-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 R3 is R3a and R3a is naphthyl, phenyl-0-phenyl, or thienyl; optionally substituted is 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. In accordance with another embodiment of the first aspect of the present invention is provided in the first embodiment of the first aspect of the present invention wherein R3 is R3b and R3b is lH-indol-5-yl lH-indazol-5-yl lH-benzotriazol-5-yl , 3-Dihydro-indol-2-on-5-yl H-benzooxazol-2-on-6-yl , 3-dihydro-benzoimidazol-2-on-5-yl -Methyl-l, 3-dihydro-benzoimidazol-2-on-6-yl, 4-Dihydro-lH-quinolin-2-on-6-yl , 4-Dihydro-benzo [d] [1,3] oxazin-2-on-6-yl , 4-Dihydro-lH-quinazolin-2-on-6-yl -Methyl-3, 4-dihydro-lH-quinazolin-2-on-6-yl H-benzo [1,4] oxazin-3-on-7-yl where T? is H, C? alkyl, 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, C? _alkyl, C2-6alkenyl, C2_6alkynyl, dihidroquinolinonilo, hidroquinolinonilo, dihidroisoquinolinonilo, hidroisoquinolinonilo, dihidroguinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, 1H-indazol-5-yl, dihidrobencimidazolonilo, idrobencimidazolonilo, benzimidazolinyl, dihydro- benzothiazolonyl, hidrobenzotiazolonilo, benzothiazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, dihidrobenzofuranonilo, hydrobenzofuranonyl, benzodioxole ilo, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazole idinyl, 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 as provided in the first embodiment of the first aspect of the present invention wherein R 3 is R 3b and R 3 is dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydrobenzothiazolonyl, hydrobenzothiazolonyl, benzothiazolyl, Dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, lH-indazol-5-yl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or 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, C2_6alkynyl, dihydroquinolinonyl, idroquinolinonilo, dihidroisoquinolinonilo, hidroisoquinolinonilo, dihidroquinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, 1H yl-indazol-5-, dihidrobencimidazolonilo, hidrobencimidazolonilo, benzimidazolinyl, dihydro-benzothiazolonyl, hidrobenzotiazolonilo, benzothiazolyl, dihidrobenzotiofenonilo, hidrobenzotiofenonilo, dihi robenzofuranonilo, hidrobenzofuranonilo , benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; optionally substituted as provided in the first embodiment of the first aspect. According to another embodiment of the first aspect of the present invention, there is provided a compound according to the first embodiment of the first aspect of the present invention wherein R3 is R3 and R3b is azetidinyl, C6-6alkyl, C2_6alkenyl, C2-6alkynyl, 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 R3 is R3b and R3b 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 R3b is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C ? 3-alkyl-nitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, 1H-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. 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 First aspect of the present invention, there are provided compounds according to the first embodiment of the first aspect of the present invention wherein m and m are each 1. In accordance with another embodiment of the first aspect of the present invention, there are provided compounds in accordance with the first embodiment of the first aspect of the present invention wherein D is 0. According to 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 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. In accordance with another embodiment of the first aspect of the present invention as provided in 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, compounds are provided 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. invention where E 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 E is C. In accordance with another embodiment of the first aspect of the present invention as provided in 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. 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 wherein the compounds exhibit as described herein a CGRP IC50 bond 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 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 an Ax or A ?. 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 an 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 TO?. 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 having two fused rings 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 fused heterocycle having two fused rings 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. 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 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 same 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 as 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? is a 4- to 6-membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 4- to 6-membered heterocycle. In accordance with another embodiment of the first aspect of the present invention as provided in 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 O, N, and S. In accordance with another embodiment of the first aspect of the present invention of the present invention, there are provided compounds according to 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 O, N and S; and optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 4 to 6 membered heterocycle; and wherein A y 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 A? is a 4- to 6-membered heterocycle as 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 bound to 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 'or GJA. "In accordance with another embodiment of the first aspect of the present invention, 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 bound to A, then G, J and A together form a spirocyclic ring system with the rings of the system that contains A and where G, J and A together are GJA '. According to another embodiment of the first aspect of the present invention, there is provided a compound according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each bound to 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 is provided with the first embodiment of the first aspect of the present invention where p is 0 such that G and J are each joined to 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. 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 prese nte invention where p is 0 such that G and J join each with 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 they are GJA 'and GJA' is Ay. According to another embodiment of the first aspect of the present invention, there is provided a compound according to the first embodiment of the first aspect of the present invention wherein p is 0 such that G and J are each bound to 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 bound to 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 bound to 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, dihydrobenzothiazoyl, dihydrobenzothiophenonyl, dihydrobenzofuranonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinogo. ; wherein the heterocycle is optionally substituted with C? -4alkyl, C? 4alkoxy, C? _4haloalkyl, cyano, C3_7cycloalkyl, phenyl, halophenyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolydinyl, 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 bound to 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, dihydroisoguinolinonyl, dihydroquinazolinonyl, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazolonyl, -dihydrobenzimidazolyl, dihydro-benzothiazolonyl, dihydrobenzothiazolyl, 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? haloalkyl, cyano, C3_cycloalkyl, phenyl, halophenyl, furanyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino. According to another embodiment of the first aspect of the present invention, 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 bound to 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 bound to 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, dihydrobenzothiazolyl, 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 bound to 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 bound to 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 . According to 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 methods of the treatment of inflammation (particularly neurogenic inflammation), headache (particularly migraine), pain, thermal injury, circulatory shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency are provided. , subarachnoid / cranial hemorrhage, tumor growth, flow associated with menopause and other conditions for the treatment of which may be effected by antagonism of the CGRP receptor by administration of pharmaceutical compositions comprising compounds of Formula (I) as defined at the moment. According to several embodiments of a fourth aspect of the present invention are the uses of the compounds of the present invention selected from the group consisting of (a) immune regulation in the mucosa of the intestines (b) protective effect against cardiac anaphylactic injury ( c) stimulation or prevention of stimulation of interleukin-lb (IL-lb) of bone resorption (d) modulated expression of NK1 receptors in spinal neurons and (e) inflammatory diseases of the respiratory tract and chronic obstructive pulmonary disease includes asthma. See (a) Calcitonin Receptor Like Receptor Is Expressed on Gastrointestinal Immune Cells. Hagner, Stefanie; Knauer, Jens; Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick. Institute of Physiology, Philipps University, Marburg, Germany. Digestion (2002), 66 (4), 197-203; (b) Protective effects of calcitonin gene-related peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan, Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian. School of Pharmaceutical Sciences, Department of Pharmacology, Central South University, Xiang-Ya Road 88, Changsha, Hunan, Naunyn-Schmiedeberg's Archives of Pharmacology (2003), 367 (3), 306-311; (c) The experimental study on the effect calcitonin gene-related peptide on bone resorption mediated by interleukin-1. Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican. Department of Orthopedics, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Peop. Rep. China. Journal of Tongji Medical University (2001), 21 (4), 304-307, (d) Calcitonin gene-related Peptide regulates expression of neurokinin 1 receptors by rat spinal neurons. Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG. 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, Tetsu i; 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 Chemestry: Anti-Inflammatory & Anti-Allergy Agents (2003), 2 (2), 191-218 all incorporated as reference herein. According to various embodiments of the guinto 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 Migraine treatment. 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 an appropriate subset of an embodiment and / or an aspect described herein or combinations thereof.

Still other embodiments and aspect of the invention will be apparent in accordance with the description given below. 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., O, 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-for example, described, a bicyclic system fused at 5.6 containing 1 to 4 nitrogen atoms includes aromatic and alicyclic systems, eg, 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 designated 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 a methylene that intervenes. 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 substitutes of the present invention should not be placed in such a way that a heteroatom in the heteroalicyclic substituent is alpha up 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 which 'has two hydrogen atoms removed from a carbon atom 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 formula (I) 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 RAMPl tryptophan (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 the 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) that 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 naturally occur for example [Ala1 ^ (CH2NH) Cys2] hCGRP that contains a pseudopeptide bond between Ala1 and Cys2. See Maggi CA, Rovero P, Giuliani S, Evangelista S, Regoli D, Meli A. Biological activity of N-terminal fragments of calcitonin gene-related peptide. Eur J Pharmacol. 1990 Apr 10; 179 (1-2): 217-9; Qing X, Wimalawansa SJ, Keith IM. Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonary hypertension in rats. Regul Pept. 2003 Jan 31; 110 (2): 93-9; and Dermis 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.; alkaline earth 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 art. 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 conventional 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. 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 the 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 a concentration level that produces effective beneficial effects without causing any deleterious or undesirable side effects.

SYNTHESIS The compounds of the present invention can be synthesized according to the general schemes given 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 may be prepared in accordance with reaction 1 or reaction 2. It may also be possible to use variations of the schemes to prepare compounds of the current inventions, variations known to those of ordinary skill in the art.

Diagram of Reaction 1. Synthesis of Compounds of Formula I IV The synthesis described in Reaction Scheme 1 starts with the compound of formula II, which is an α-hydroxycarboxylic acid with an appropriate protected hydroxyl termination. Common hydroxy protecting groups (PG) include benzyl group and trialkylsilyl group and their addition and removal are well known in the art. The carboxylic acid moiety of the compound of the formula II is coupled with an amine of the formula HNR -'- R2 using conventional peptide coupling reagents to form an amide of the formula III. The hydroxy protecting group is removed resulting in a compound of the formula IV. This compound is then coupled with an amine of formula VIII (see below) in a reaction forming a carbamate, generating the compound of formula I. The formation of the carbamate is conveniently carried out using phosgene, disuccinimidyl carbonate, carbonyl diimidazole or other equivalents.

Reaction Scheme 2. Synthesis of Compounds of Formula I v VI The synthesis described by Reaction Ester 2 starts with a compound of Formula V, which is a -hydroxycarboxylic 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 carbamate reaction mixture, 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 The synthesis described by Reaction Scheme 3 starts with a compound of Formula VII in Reaction Scheme 2. The compound of Formula VII 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-dicyclohexylcarbodii ida. Furthermore, it is frequently advantageous, especially for secondary and tertiary alcohol esters, to include additives that accelerate acylations such as 4-dimethylaminopyridine.

Preparation of HNR1R2 and amines of Formula VIII The amines of Formula VIII and HNR1R2 are commercially available, are made by the methods of the literature or are described herein.

Preparation of α-hydroxycarboxylic acid of Formula II and Formula V The α-hydroxycarboxylic acid ester of Formula II and Formula V can be made by methods known to one of ordinary skill in the art or made as described in Reaction Scheme 4.

Reaction Scheme 4. Synthesis of Compounds of Formula II xp xm p The synthesis of the compounds of formula II and formula V are described in Reaction Scheme 4. A 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. An aldehyde of Formula IX, which is reacted with a glycine phosphonate of Formula X in a Wadsworth-Emmons coupling reaction to provide an olefin of formula XI. The compound of formula XI is converted to an α-ketoester of Formula XII by removing the protective amino group (PG) followed by hydrolysis using water either on its own or in conjunction with an acid such as hydrochloric acid, trifluoroacetic acid, and other organic or inorganic acids. The a-ketoester of formula XII can be reduced to give the compound of formula V by an appropriate reducing agent such as sodium borohydride, sodium cyanoborohydride, hydrogen in the presence of an appropriate catalyst such as palladium on carbon, or other reducing agents well known in the art. The hydroxyl of the compound of formula V can be protected to give an appropriate hydroxyl-protected termination of formula XIII. Common hydroxyl protecting groups (PG) include methoxymethyl ether, benzyloxymethylether, substituted benzyl groups and trialkylsilyl group and their addition and removal are well known in the art. The compound of formula XIII can be converted to the compound of formula II by treatment with lithium chloride, lithium hydroxide, sodium hydroxide, or other organic or inorganic base using water or other suitable solvents using the methodology well known in the art. . The compounds of formula II and formula V can also be prepared as described below in Reaction Scheme 5.

Reaction Scheme 5. Synthesis of compounds of the formula XIII II The compound of formula XIV is deprotonated with a base such as diazabicycloundecene or tetramethylguanidine or other organic or inorganic bases well known in the art. An aldehyde of the formula IX is reacted with the lactate phosphonate of the formula X in a Wadsworth-Emmons coupling reaction yielding an olefin of the formula XV. The compound of formula XV is reduced to a lactate ester of formula V by hydrogenation of the double bond. The reduction can result in either a racemic compound, using, for example, hydrogenation on charcoal with palladium, or a chiral compound using a chiral catalyst such as (-) - 1,2-bis- ((2R, 5R) tetrafluoroborate. ) -2, 5- diethylphospholane) benzene (cycloctadiene) rhodium (I). The hydroxyl of the compound of formula V can be protected to give an appropriate hydroxyl-protected termination of formula XIII. Common hydroxyl protecting groups (PG) include methoxymethyl ester, benzyloxymethylether, substituted benzyl group and trialkylsilyl group and their addition and removal are well known in the art. The compound of formula XIII can be converted to the compound of formula II by treatment with lithium chloride, lithium hydroxide, sodium hydroxide, or other organic bases or sodium hydroxide, or other organic or inorganic bases using water or other solvents appropriate - using the methodology well known in the art. The compounds of the formula XI where R3 is an aromatic ring, can also be prepared as shown in Reaction Scheme 6.

Reaction Scheme 6. Synthesis of compounds of the formula XVII XVI XI Reaction 6 starts with an amino acrylate protected by N of formula XVI which can be coupled to a compound of formula XVII comprising an aromatic ring to which it is linked to a starting group (X) such as iodine or bromine in the presence of a transition metal catalyst such as sodium acetate. palladium (II) in a non-reactive solvent with or without heating. The synthesis of α-hydroxy carboxylic acids of formula II and esters of α-hydroxy carboxylic acid is well established in the literature and its synthesis should be known to those of ordinary skill in the art.

INTERMEDIARIES AND EXAMPLES General. The - '• H-NMR and 13C-NMR spectra are run on a Bruker instrument at 500 or 300 MHz and the chemical changes are presented in ppm (d) with reference to tetramethylsilane (d = 0.0). All evaporations are carried out at reduced pressure. Unless stated otherwise, the LC / MS analyzes are carried out on a Shimadzu instrument using a YMC C18 column (3 x 50 mm) that employs a linear gradient at 2 minutes from 0% to 100% solvent B in A in a 3 minute run. For LC / MS and for the Shimadzu Preparative HPLC system, solvent A was: 10% methanol / 90% water / 0.1% trifluoroacetic acid, and solvent B was 90% methanol / 10% water / 0.1% trifluoroacetic acid with a detector UV set at 220 nm. l-benzyl-2 ', 3'-dihydro-2'-oxospiro- [piperidin-, 4' (l'H) -quinazoline Polyphosphoric acid (113 g) was heated to 100-110 ° C and stirred while adding l-benzyl-piperidin-4-one (9.27 ml, 50 mmol). Immediately after, phenyl urea was added (9.55 g, 70. mmol) in portions small enough to avoid frothing. The mixture was heated at 150-160 ° C overnight. Water (200 ml) was then added slowly to the mixture which was allowed to cool to 100-110 ° C (at lower temperatures the mixture becomes very viscous to stir). The resulting solution was neutralized with ION NaOH to ca. pH 8, and then extracted with chloroform. The organic phase was dried over magnesium sulfate and then concentrated to give the crude product which was purified by flash column chromatography on silica gel (6: 4 ethyl acetate / hexanes) to give the desired product (9.0 g, 58%). Mass spectrum: 308.25 (MH) A 2 ', 3' -dihydro-2 '-oxoespiro- [piperidin-4, 4' (l'H) -quinazoline To a solution of l-benzyl-2 ', 3'-dihydro-2'-oxospiro- [piperidin-4, 4' (l'H) -quinazoline (1.00 g) in degassed methanol (50 ml) and 6N hydrochloric acid (2.0 ml) charcoal was added with 10% palladium (150 mg). The mixture was stirred on a Parr apparatus in a hydrogen atmosphere at 4.21 Kg / cm2 (60 psi) overnight. CL / MS showed an incomplete reaction. More charcoal with 10% palladium (200 mg) was added, and the mixture was stirred for 2 more days. At this 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) A 4-amino-4-cyano-piperidine-l-carboxylic acid tert-butyl ester To a well stirred solution of the tert-butyl ester of 4-oxo-piperidin-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 stirring was continued for an additional 16 hours. 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. 1 H-NMR (300 MHz, CDC13): d 3.95-3.90 (, 1H), 3.80-3.71 (m, 1H), 3.42-3.06 (m, 2 H), 2.04-1.94 (m, lH), 1.71-1.50 (m, 3 H). Mass spectrum: 226 (MH) A 2-phenyl-1,3,8-triaza-spiro [4,5] dec-l-en-4-one hydrochloride To a solution of the 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.44 mmol) in methylene chloride (30 ml), triethylamine (1.24 ml, 8.88 mol) was added. ), followed by benzoyl chloride (936 mg, 6.66 mmol). After 30 minutes, 4- (dimethylamino) pyridine (40 mg, 0.33 mmol) was added and stirring was continued for an additional 12 hours. The reaction mixture was then quenched with IM sodium hydroxide (10 ml), diluted with ethyl acetate (100 ml), and separated. The organic layer was washed sequentially with sodium hydroxide. (40 ml), aqueous sodium hydrogen carbonate (50 ml), and brine (50 ml) then dried over sodium sulfate. The desired product, tert-butyl ester of 4-benzoylamino-4-cyano-piperidine-1-carboxylic acid is obtained in 90% yield through crystallization using 30% ethyl acetate in hexane as the 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 hours. 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, tert-butyl ester of 4-oxo-2-phenyl-1,3,8-triaza-spiro [4.5] dec-1-en-8-carboxylic acid is obtained in 80% yield through crystallization from 30% ethyl acetate in hexane. The tert-butyl ester was then dissolved in methylene chloride (5 ml) and a saturated solution of hydrogen chloride in dioxane (25 ml) was added. After 2 hours, the solvent was removed to give the 2-phenyl-1,3,8-triaza-spiro [4.5] dec-1-en-4-one hydrochloride as a white powder in 95% yield. 1 H-NMR (500 MHz, CD 3 OD): d 8.23-8.21 (m, 2 H), 7.96-7.92 (m, 1 H), 7.79-7.76 (m, 2 H), 3.68-3.64 (, 3 H), 3.31-3.30 (, 1 H), 2.47-2.44 (m, 4 H). Mass spectrum: 230 (MH) A 5-formyl-indazole-l-carboxylic acid tert-butyl ester A solution of methylene chloride (2 ml) of di-tert-butyldicarbonate (388 mg, 1.78 mmol) was added dropwise at room temperature to a solution of lH-indazole-5-carbaldehyde (273 mg)., 1.87 mmol), 4-dimethylaminopyridine (114 mg, 0.94 mmol), and triethylamine (0.26 mL, 1.87 mmol) in methylene chloride (10 mL). The resulting bright yellow solution was stirred at room temperature for 16 hours, the solvents were removed in vacuo and the ree was subjected to flash chromatography with silica gel (25 g) and ethyl acetate / hexanes (1: 1) containing triethylamine. to 1% as eluent to provide the title compound as a brown solid (414 mg, 90%). XH-NMR (CDC13, 500 mhz) d 10.08 (s, 1H), 8.38 (s, lH), 8.34 (s, ÍH), 8.25 (d, j = 8.5 hz, ÍH), 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. 5- (2-Benzyloxycarbonylamino-2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester A solution of trimethyl ester N- (benzyloxycarbonyl) -a -phosphonoglycine (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 minutes. 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 syringe for 10 minutes. The reaction mixture was stirred at -78 ° C for 4 hours 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%). ^ -RN (CDC1, 500 MHz) d 8.09 (d, j = 9.0 Hz, 1H), 8.08 (s, 1H), 7.84 (s, ÍH), 7.67 (d, j = 9.0 Hz, lH), 7.47 ( s, ÍH), 7.30 (br s, 5H), 6.43 (br s, ÍH), 5.09 (s, 2H), 3.84 (s, 3H), 1.72 (s, 9H). Mass spectrum: 452 (MH) A 2-Trimethylsilanyl-ethanesulfonyl chloride so2c? Sulfuryl chloride (43 ml, 539 mmol) was added in 3 minutes to a clear solution of triphenylphosphine (129 g, 490 mmol) in methylene chloride (200 ml) at 0 ° C in a three-necked round bottom flask. necks dried to the flame. After stirring at 0 ° C for 5 minutes, the ice water bath was removed and sodium 2-trimethylsilyletanesulfonate (50 g, 245 mmol) was added in portions over 10 minutes. The resulting white suspension was stirred at room temperature for 16 hours, then 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 during minutes and filtered through a pad of celite. The solvents were removed in vacuo and the residue was loaded onto a column pre-moistened with silica gel (300 ml) using 1: 3 ethyl acetate / hexanes as the eluent. The solvents were removed and the title compound 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 dissolution. ^? - NMR (CDC13, 500 MHz) d 3.61-3.57 (m, 2H), 1.32-1.27 (m, 2H), 0.10 (s, 9H). 1- (2-Trimethylsilanyl-ethanesulfonyl) -lH-indole-5-carboxylic acid ethyl ester carboxylic acid (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 minutes, 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 hours, the 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 was 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%). ^ -RN (CDC13, 500 MHz) d 8.36 (d, J = 1.5 Hz, 1H), 8.03 (dd, J = 9.0, 2.0 Hz, ÍH), 7.92 (d, J = 8.5 Hz, ÍH), 7.50 ( d, J = 3.5 Hz, 1H), 6.75 (d, J = 3.5 Hz, lH), 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) -lH-indazole-5-carboxylic acid ethyl ester ^? - NMR (CDC13, 500 MHz) d 8.51 (s, ÍH), 8.34 (s, ÍH), 8.21 (dd, J = 8.9, 1.5 Hz, 1H), 8.12 (d, J = 9.2 Hz, ÍH) , 3.96 (s, 3H), 3.42 - 3.39 (m, 2H), 0.86 - 0.82 (, 2H), -0.02 (s, 9H). 13 C-NMR (CDC13, 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) A [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. (8.81g, 25.9 mmol) in toluene (200ml). After stirring at 0 ° C for 45 minutes, the reaction was quenched by the addition of methanol (26ml), powdered sodium sulfate decahydrate (194 g) and celite (26 ml). The mixture was warmed to room temperature in 1 hour and filtered through a pad of celite. The solvents were removed in vacuo to provide the title compound as a highly viscous liquid, which solidified upon cooling. A white solid (8.08 g, 100% yield). ^ - MN (CDC13, 500 MHz) d 7.87 (d, J = 8.5 Hz, 1H), 7.62 (s, ÍH), 7.44 (d, J = 3.7 Hz, lH), 7.35 (dd, J = 8.6, 1.5 Hz, 1H), 6.66 (d, J = 3.7 Hz, lH), 4.79 (s, 2H), 3.18 - 3.14 (m, 2H), 1.73 (s, lH), 0.85 - 0.82 (m, 2H), - 0.06 (s, 9H). Mass spectrum. 312.14 (MH) A [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazol-5-yl] -methanol A solution of 1- (2-trimethylsilane-ethanesulfonyl) -lH-indazole-5-carboxylic acid ethyl ester (azeotropically dried with toluene (2x), 5.77g, 16.9 mmol) in tetrahydrofuran (50 ml) was added at 0 °. C to a mixture of lithium borohydride (3.68g, 169 mmol) in tetrahydrofuran (100 ml). The mixture was warmed to room temperature and stirred for 14 hours. It was cooled to 0 ° C and lithium borohydride (3.5g) was added. The mixture was warmed to room temperature and stirred for 14 hours. It was again 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 provide the title compound as a solid white (3.8g, 72%). ^ - MN (CD3OD, 500 MHz) d 8.41 (s, ÍH), 8.04 (d, J = 8.5 Hz, ÍH), 7.85 (s, ÍH), 7.61 (dd, J = 8.5, 1.2 Hz, 1H), 4.76 (s, 2H), 3.49 - 3.46 (, 2H), 0.76 - 0.72 (m, 2H), -0.03 (s, 9H); 13 C-NMR (CD3OD, 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) A 1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-carbaldehyde A solution of [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -methanol (2.1g, 6.74 mmol) in methylene chloride (30 ml) was added at 0 ° C to a mixture of dioxide of activated manganese (22 g, azeotropically dried 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 minutes and filtered through a pad of celite. The solvents were removed in vacuo to provide the title compound as a white solid (1.8g, 80%). Al-NMR (CDC13, 500 MHz) d 10.06 (s, HH), 8.15 (s, HH), 8.01 (d, J = 8.6 Hz, HH), 7.87 (dd, J = 8.6, 1.5 Hz, HH), 7.54 (d, J = 3.4 Hz, 1H), 6.80 (d, J = 3.6 Hz, ÍH), 3.24 - 3.20 (, 2H), 0.86 - 0.82 (m, 2H), -0.06 (s, 9H). 13 C-NMR (CDCl 3, 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) A Similarly prepared: 1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indazole-5-carbaldehyde Mass spectrum. 311.10 (MH) A Methyl ester of 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indol-5-yl] -acrylic acid 1, 1, 3, 3-tetramethylguanidine (0.68 ml, 5.43 mmol) was added at room temperature to a solution of N- (benzyloxycarbonyl) -a -phofonoglycine trimethyl ester (1.88g)., 5.69 mmol) in tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 15 minutes and cooled to -78 ° C, and a solution of 1- (2-trimethylsilanyl-ethanesulfonyl) -lH-indole-5-carbaldehyde (1.6g, 5.17 mmol) in tetrahydrofuran ( 15 ml) was added slowly. The resulting reaction mixture was stirred at -78 ° C for 2 hours and then warmed to room temperature in 3 hours. 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 Z / E 92 mixture: 8 (determined by the integration of C02CH3, for Z isomer at 3.79 ppm, and E isomer at 3.65 ppm). For the Z isomer: aH-NMR (CD3CN, 500 MHz) d 7.96 (s, ÍH), 7.91 (d, J = 8.5 Hz, ÍH), 7.66 (d, J = 8.5 Hz, ÍH), 7.56 (d, J = 3.7 Hz, ÍH), 7.51 (s, ÍH), 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) A Prepared similarly: 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 afforded the title compound as a Z / E 95: 5 mixture (determined by the integration of CH = C (C0Me) (NHCBz), 3.72. g, 92%). for the Z isomer: ^ -R (CD3CN, 500 MHz) d 8.39 (s, ÍH), 8.12 (s, ÍH), 8.03 (d, J = 8.8 Hz, ÍH), 7.84 (dd, J = 8.8, 1.2 Hz, ÍH), 7.51 (s, lH), 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) To 7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazole-5-carbaldehyde To a suspension of 7-methylindazole-5-aldehyde (3.0 g, 18.7 mmol) in methylene chloride (150 ml) was added triethylamine (7.83 ml, 56.2 ml, 3 equivalents) followed by dropwise addition of sodium chloride. pure trimethylsilyl-ethanesulfonyl (5.60 g, 28.1 mmol, 1. 5 equivalent). The mixture gradually became homogeneous and allowed to stir at room temperature for 16 hours. 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 yellow solid. pale. 1 H NMR (CDC 13, 300 MHz) d 9.98 (s, 1 H), 8.77 (s, 1 H), 8.09 (s, ÍH), 7.64 (s, 1H), 3.64-3.58 (m, 2H), 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 equivalent) in anhydrous tetrahydrofuran (75 mL) was added tetramethylguanidine (1.78 mL, 1.05 equivalent). The mixture was stirred at room temperature under nitrogen for 5 minutes and then cooled to -78 ° C. After stirring for 15 minutes at -78 ° C, a solution of 7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazole-5-carbaldehyde in tetrahydrofuran (25 ml) was added. The reaction mixture was allowed to warm slowly to room temperature overnight. Although the reaction was incomplete, the solvent evaporated. The resulting residue was dissolved in ethyl acetate and washed with sulfuric acid. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Flash column chromatography (1: 4 ethyl acetate / hexanes) gave 2.66 g (37%) of the product as a white glassy foam. 1 H-NMR (CDC13, 300 MHz) d 8.48 (s, lH), 7.62 (s, 1H), 7.38-7.25 (m, 7H), 6.48 (bs, ÍH), 5.10 (s, 2H), 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) A 4-bromo-2,6-dimethylphenyldiazo-t-butyl sulfide 4-Bromo-2,6-dimethylaniline (20.00 g, 100 mmol) was ground to a powder with a set of mortar and then suspended in 24% hydrochloric acid (41 ml). The stirred mixture was cooled to -20 ° C and treated with sodium nitrate (7.24 g, 1.05 equivalent) in water (16 ml), dropwise over 40 minutes while the temperature was maintained below -5 ° C. After an additional 30 minutes at -5 ° C to -20 ° C, the mixture was 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 (11.3 ml, 1 equivalent) in ethanol (100 ml) at 0 ° C for ca. 10 minutes. After the addition, the mixture was stirred at 0 ° C for 30 minutes and then ground ice (ca. 150 ml) was added. The mixture was stored in the refrigerator overnight. The resulting light brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours. (26.90 g, 89%). The compound appears to be stable as a solid but undergoes significant dissolution when ethanol recrystallization was tested. - "" H-NMR (CDC13, 500 MHz) d 1.58 (9H, s), 1.99 (6H, s), 7.21 (2H, s). Mass spectrum: 303.05 (MH) A 5-Bromo-7-methylindazole Within 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 equivalent) 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 room temperature. The reaction mixture was then carefully poured into a mixture of crushed ice (400 ml) and 10% hydrochloric acid (200 ml). The resulting suspension was allowed to stand at 4 ° C overnight and the solid was collected by filtration and washed with water. The crude solid was dissolved in 5: 1 methylene chloride / methanol and the solution was dried over magnesium sulfate and evaporated to give the product as an opaque white solid (7.60 g, 87%). ^ -RM (CDCl3 / CD3OD, 500 MHz) d 2.51 (3H, s), 7.22 (1H, s), 7.69 (H, s), 7.94 (1H, s). Mass spectrum: 211.03 (MH) A 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 equivalent) were weighed in a flame-dried round bottom flask containing a magnetic stirring bar. . In a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 ml) was added. The mixture was stirred at room temperature for 15 minutes, during which time it became homogeneous. The stirred mixture was cooled to -70 ° C and a solution of sec-butyllithium in cyclohexane (14M, 45 mL, 2.2 equivalent) was added over several minutes. After 1 hour at * -70 ° C, dimethylformamide (10 ml) was added for several minutes. The mixture was warmed to room temperature and stirred overnight. It was then cooled to 0 ° C and carefully treated with IN hydrochloric acid (60 ml). After a few minutes, the solid sodium bicarbonate was added to make the mixture basic until pH 9-10. The layers were separated and the aqueous phase was washed twice 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 (CDC 13, 500 MHz) d 2.63 (3H, s), 7.73 (H, s), 8.12 (lH, s), 8.25 (H, s), 10.03 (H, s). Mass spectrum: 161.06 (MH) A 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 equivalents) in tetrahydrofuran (30 ml) at room temperature was treated with tetramethylguanidine (1.91 ml, 1.1 equivalent). After 10 minutes, 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 CCD 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% phosphoric acid and brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 1) 1: 1 and 2) 2: 1 ethyl acetate / hexane, to give the product as a colorless foam (4.93 g, 97%). ^? - NMR (CDC13, 500 MHz) d 2.43 (3H, s), 3.80 (3H, s), 5.12 (2H, s), 6.66 (lH, s), 7.28 (5H, brs), 7.33 (1H, s), 7.47 (lH, s), 7.74 (ÍH, s), 7.96 (ÍH, s). Mass spectrum: 366.16 (MH) A Ter-Butyl (Z) -1- (methoxycarbonyl) -2- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl vinylcarbamate To a solution of 2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazole-5-carbaldehyde (4.46 g, 15.4 mmol) and N- (tert-butoxycarbonyl) -methyl-2- ( dimethylphosphono) glycinate (4.80 g, 1.0 equivalent) in tetrahydrofuran (40 ml) at room temperature was added N, N, N ', N' -tetramethylguanidine (3.29 ml, 1.7 equivalent). The reaction was allowed to stir at room temperature for 3 days. The reaction was diluted with ethyl acetate and water. It was emptied into diethyl ether, and washed with water (2X), then brine, dried over magnesium sulfate and concentrated. Column chromatography (30% ethyl acetate / hexanes - >40% ethyl acetate / hexanes) gave 5.90 g (83%) as a foam. Mass spectrum: 462.40 (MH) A Methyl 3- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl) -2-hydroxypropanoate To a solution of tert -butyl (Z) -1- (methoxycarbonyl) -2- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl) vinylcarbamate (200 mg , 0.43 mmol) in dichloromethane (2 ml) at 0 ° C was added trifluoroacetic acid (1 ml). The ice bath was removed. After 30 minutes, the reaction was evacuated in a separatory funnel containing ethyl acetate and water, neutralized with solid sodium bicarbonate, and the layers were separated. The organics were washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The yellow residue was treated with sodium cyanoborohydride (200 mg, 7.4 equivalent) and tetrahydrofuran (2 ml). The reaction was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2X), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% ethyl acetate / hexanes) gave 20.4 mg (13%) as a light yellow oil. Mass spectrum: 365.40 (MH) A 4-Nitrophenyl-1- (methoxycarbonyl) -2- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl) ethyl carbonate To a solution of methyl 3- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl) -2-hydroxypropanoate (20 mg, 55 μmol) in pyridine (1 ml) was added 4-nitrophenylchloroformate (55 mg, 5 equivalent). The reaction was stirred at room temperature overnight. The reaction was treated with an additional portion of 4-nitrophenylchloroformate (30 mg, 2.7 eqivalent) and stirred at room temperature for 8 hours. The reaction was emptied into diethyl ether, washed with IM potassium bisulfate until it became acidic, then saturated bicarbonate, then sodium hydroxide, until most of the nitrophenol was removed, then brine, dried over sodium sulfate, and concentrated to give 50 mg (quantitative) of a pale yellow solid which was used immediately in the next reaction. Mass spectrum: 530.30 (MH) A 4- (1,2-Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxylic acid 1- (methoxycarbonyl) -2- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl) ethyl A flask was charged with 4-nitrophenyl 1- (methoxycarbonyl) -2- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7-methyl-2H-indazol-5-yl) ethyl carbonate (27 mg , 51 μmol) and 3, -dihydro-3- (piperidin-4-yl) -quinazolin-2 (1 H) -one (34 mg, 2.8 equivalent). The solids were dissolved in dimethylformamide (1 ml) and treated with diisopropylethylamine (0.1 ml, 11 equivalent). The reaction was stirred at room temperature for 2 days. The reaction was concentrated, dissolved in ethyl acetate, washed with 20% potassium hydroxide (3X), then brine, dried over magnesium sulfate, and concentrated. The chromatographic column (100% ethyl acetate) was removed with petrolatum material to give 50 mg (quantitative). Mass Spectrum: 622.50 (MH) A 4- (1,2-Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxylic acid 1- (methoxycarbonyl) -2- (7-methyl-1H- indazol-5-yl) ethyl 4- (1,2-Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxylic acid 1- (methoxycarbonyl) -2- (2- ((2- (trimethylsilyl) ethoxy) methyl) -7 -methyl-2H-indazol-5-yl) ethyl (50 mg, 40 μmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 5 ml). After 2 hours at room temperature, the reaction was concentrated. The chromatographic column (50% ethyl acetate / hexanes -> 100% ethyl acetate) gave 14.5 mg (37%). Mass spectrum: 492.15 (MH) +.

Example 1 4- (1, 2-dL dro-2-? 2 { O? P ____ azolin-3 (4H) -yl) piperidin-1-carbaxylate of 3- (7-Methyl-lH-in azole-5 il) -1-c? ol- (4- (piperidin-l-yl) piperidin-l-yl) prcpan-2-yl To a solution of 1- (1, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxylic acid 1- (methoxycarbonyl) -2- (7-methyl-lH-indazol-5-yl) ethyl) (14.5 mg, 30 μmol) in methanol (1 ml). a solution of lithium hydroxide monohydrate (6.2 mg, 5 equiv.) in water (1 ml) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated, it was dissolved in water, treated with 0.1 ml of hydrochloric acid ÍM. A precipitate was formed and the reaction was concentrated to give the crude carboxylic acid which was taken to the next step without purification. Mass spectrum: 478.17 (MH) AA a solution of the crude acid, 4-piperidinpiperidine (9.9 mg, 2 eguivalents), and diisopropylethylamine (10 μL, -2 equivalents) in dimethylformamide (1 ml) and dichloromethane (1 ml). 0 ° C was added PyBOP® (16 mg, 1.05 eguivalents). The ice bath was removed and stirring continued for 1 hour. The reaction was concentrated and purified by preparative HPLC to give the title compound (16 mg, 73%) as this trifluoroacetic acid salt. ^? - NMR (CD30D) d 0.10 (m, 0.5), 1.11 (m, 0.5H), 1.50-2.35 (m, 13H), 2.45-3.30 (m, 10H), 3.38 (m, 2H), 3.55 ( m, 2H), 4.15-4.70 (m, 6H), 4.85 (m, 1H), 5.76 (, 1H), 6.98 (d, J = 7.6, 1H), 7.14 (dd, J = 7.6, 7.3, lH) , 7.20-7.55 (m, 3H), 7.71 (m, ÍH), 8.25 (m, ÍH). Mass spectrum: 628.29 (MH) A 7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2-H-indazole-5-carbaldehyde To a solution of 7-methyl-lH-indazole-5- carbaldehyde (5.0 g, 31.25 mmol) and N-methyl-dicyclohexylamine (13.5 mL, 62.35 mmol) in dry tetrahydrofuran (120 mL) at 0 ° C, was added 2- (trimethylsilyl) ethoxymethyl chloride (6.65 mL, 39.5 mmol ). The ice bath was removed and stirring continued for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with water (2X), brine (2X), dried over sodium sulfate, and concentrated in vacuo. The chromatographic column gave 8.5 g (93%). ^? - NMR (CD3OD, 300 MHz) d -0.04 (s, 9H), 0.83-1.01 (m, 2H), 2.60 (s, 3H), 3.22-3.34 (m, 2H), 3.60-3.76 (m, 2H), 5.58 (s, 2H), 7.54 (s, 1H), 8.23 (s, lH), 8.64 (s, 1H), 9.91 (s, 1H). Mass spectrum: 291.33 (MH) A 2-Acetoxy-2- (diethoxyphosphoryl) acetic acid The glyoxylic acid monohydrate (4.0 g, 43.45 mmol) was suspended in diethyl phosphite (5.59 ml, 1.0 equivalent), warmed to 60 ° C, and kept so for 5 hours. The reaction was cooled, diluted with dichloromethane (40 ml), and treated with pyridine (3.51 ml, 1.0 equivalent) and acetyl chloride (3.09 ml, 1.0 equivalent). An important exotherm was noted. The reaction was stirred at room temperature for 2 hours. The reaction was washed with 1 M hydrochloric acid (2 X 20 ml), then saturated sodium bicarbonate. The organics were dried over magnesium sulfate, and concentrated to give < 2 g as an oil. The aqueous washings were combined and extracted with dichloromethane (4X). The organics were dried over magnesium sulfate and concentrated to give 5.85 g (53%) as an oil which solidified during rest. ^ -RN (CDC13, 500 MHz) d 1.36 (t, J = 7.0, 6H), 2.21 (s, 3H), 4.28 (m, 4H), 5.54 (d, J = 17.7, 1H), 8.90 (bs, ÍH). Mass spectrum: 255.10 (MH) To methyl 2-Acetoxy-2- (diethylphosphoryl) cetate To the heterogeneous mixture of 5 M sodium hydroxide (50 ml) and diethyl ether (100 ml) in an Erlenmeyer flask, fired at 0 ° C, was added N-methyl-N '-nitro-N-nitrosoguanidine (6.37 g). , 43.3 mmol) in small portions with stirring movement (without stirring bar). After the addition was complete, the mixture was allowed to maintain at 0 ° C for 15 minutes with occasional stirring movement. The ether was transferred in portions to a suspension of 2- acetoxy-2- (diethoxyphosphoryl) acetic acid (5.50 g, 21.6 mmol) in ether (ca. 50 ml) until all the solid dissolved and a yellow color was maintained. The reaction was allowed to hold at 0 ° C for 15 minutes before bubbling nitrogen through the solution to remove the non-reactive diazomethane. The reaction was concentrated to give 5.90 g (quantitative) as a faint yellow oil. XH-NMR (CDC13, 500 MHz) d 1.36 (td, J = 7.0, 2.4, 6H), 2.21 (s, 3H), 3.82 (s, 3H), 4.23 (m, 4H), 5.43 (d, J = 16.8, 1H). Mass Spectrum: 269.17 (MH) To 2-Acetoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) methyl acrylate To a solution of methyl 2-acetoxy-2- (diethylphosphoryl) acetate (923 mg, 3.44 mmol) in tetrahydrofuran (7 ml) was added lithium chloride (146 mg, 3.44 mmol). The reaction was stirred until the solution was complete. The reaction was cooled to -78 ° C, and treated with N, N, N ', N' -tetramethylguanidine (0.43 ml, 3.44 mmol) to give a white suspension which was stirred for 10 minutes. To this was added 7-methyl-2- ((2- (trimethylsilyl) ethoxy) ethyl) -2-H-indazole-5-carbaldehyde (1.00 g, 3.44 mmol) in one portion. The reaction was stirred for 1 hour at -78 ° C, and then allowed to slowly warm to room temperature in the cool. It was allowed to stir overnight at room temperature. The reaction was poured into water / ether. The mixture was extracted with diethyl ether (2X), which was washed with water, then brine, dried over magnesium sulfate, and concentrated. The chromatographic column (12% to 25% ethyl acetate / hexanes) gave 825 mg (59%) as a mixture of Z- and E- isomers as a colorless oil. Major (Z-isomer): 1 H-NMR (CDC13, 500 MHz) d -0.02 (s, 9H), 0.95 (t, J = 8.5, 2H), 2.25 (s, 3H), 2.62 (s, 3H), 3.66 (m, 2H), 3.71 (s, 3H), 5.75 (s, 2H), 6.88 (s, ÍH), 7.09 (s, ÍH), 7.73 (s, lH), 8.11 (s, 1H). Mass spectrum: 405.17 (MH) +. Minor (E-isomer): ^ H-NMR (CDC13, 500 MHz) d -0.02 (s, 9H), 0.95 (t, J = 8.5, 2H), 2.36 (s, 3H), 2.62 (s, 3H), 3.66 (m, 2H), 3.85 (s, 3H), 5.74 (s, 2H), 7.32 (s, ÍH), 7.38 (s, lH), 7.78 (s, 1H), 8.14 (s, ÍH). Mass spectrum: 405.17 (MH) +. 2-Acetoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoate of (R) -methyl To a solution of methyl 2-acetoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) acrylate (825 mg, 2.04 mmol) in dichloromethane ( passing nitrogen bubbles) degassing (20.00 ml) under nitrogen was added (-) -1, 2-bis- ((2R, 5R) -2,5-diethylphospholane) benzene- (cyclooctadiene) rhodium (I) solid tetrafluoroborate (100.00 mg), all at once. The reaction was placed in a hydrogen atmosphere (55 psi (3.86 Kg / cm2)), and stirred for 6 hours. The reaction was concentrated and purified by column chromatography (25% ethyl acetate / hexanes) to give 700 mg (84%) as a colorless oil. ^? - RN (CDC13, 500 MHz) d -0.03 (s, 9H), 0.94 (t, J = 8.2, 2H), 2.07 (s, 3H), 2.61 (s, 3H), 3.11 (dd, J = 14.3, 8.9, 1H), 3.20 (dd, J = 14.3, 4.6, ÍH), 3.64 (t, J = 8.5, 2H), 3.72 (s, 3H), 5.26 (dd, J = 8.5, 4.6, ÍH) , 5.72 (s, 2H), 6.93 (s, 1H), 7.33 (s, ÍH), 8.02 (s, 1H). Acid (R) -2-hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propane To a solution of (R) -methyl 2-acetoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoate (700 mg, 1.72 mmol ) in tetrahydrofuran (6 ml) and methanol (6 ml) at 0 ° C was added a solution of lithium hydroxide monohydrate (289 mg, 6.89 mmol) in water (6 ml). The reaction was stirred at 0 ° C for 1 hour. The reaction was concentrated, dissolved in 5 ml of water, cooled to 0 ° C, and treated with 1 M hydrochloric acid to a mild acidity. A non-solid ppt was formed. The suspension was extracted with ethyl acetate (2x), which was washed with brine, dried over magnesium sulfate, and concentrated to give 620 mg (quantitative) which was pure by LC / MS and used without purification. Mass spectrum: 351.13 (MH) A 2- (Methoxymethyl) -7-methyl-2H-indazole-5-carbaldehyde To a solution of 7-methylindazole-5-carboxaldehyde (8.80 g, 54.9 mmol) and N-methyl-dicyclohexylamine (23.6 ml, 110 mmol) in tetrahydrofuran (200 ml) at 0 ° C was added chloromethyl methyl ether (7.50 ml). , 1.8 equivalent). The reaction was gradually warmed to room temperature overnight. The reaction was concentrated, dissolved in diethyl ether, washed with water, then 1 M hydrochloric acid, then water, then brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was dissolved in ethyl acetate and treated with hexanes while cloudy. The suspension was heated until a clear solution was obtained and the flask was placed in the freezer. The resulting crystalline solid was ground with a spatula to break it, reheated to dissolve some of the solids, and placed in the freezer. The solids were filtered, washed with very cold diethyl ether (-78 ° C), and dried in air to give 5.43 g. The mother liquor was concentrated, redissolved in diethyl ether (ca. 20 ml), cooled to -78 ° C, and treated with a seed crystal of the product. After 1 hour, the resulting solids were filtered, washed with cold diethyl ether (-78 ° C), and air-dried to give an additional 1.05 g (total yield = 58%). ^? - NMR (CDC13, 500 MHz) d 2.66 (s, 3H), 3.44 (s, 3H), 5.73 (s, 2H), 7.59 (s, 1H), 8.09 (s, 1H), 8.32 (s, ÍH), 9.97 (s, 1H). Mass spectrum: 205.19 (MH) To methyl 2-Acetoxy-3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) acrylate To a solution of methyl 2-acetoxy-2- (diethylphosphoryl) acetate (4.89 g, 18.2 mmol) in tetrahydrofuran (25 mL) was added lithium chloride (0.74 g, 17.5 mmol). The reaction was stirred until the dissolution was complete. The reaction was cooled to -78 ° C, and treated with tetramethylguanidine (2.20 ml, 17.5 mmol) to give a white suspension which was stirred for 10 minutes. To this was added 2- (methoxymethyl) -7-methyl-2H-indazole-5-carbaldehyde (3.10 g, 15.2 mmol) in one portion. After 10 minutes, the ice bath was concentrated and the reaction was stirred overnight. The reaction was poured into water / diethyl ether, and the layers separated. The ether was washed with water, then brine, dried over magnesium sulfate, and concentrated. The chromatographic column gave 2- (methoxymethyl) -7-methyl-2H-indazole-5-carbaldehyde recovered (0.57 g, 18%) and the title compound (2.86 g, 59%) as a mixture of Z- and E isomers - as a colorless oil. Major (Z-isomer): "^ I-NMR (CDC13, 500 MHz) d 2.25 (s, 3H), 2.62 (s, 3H), 3.40 (s, 3H), 3.71 (s, 3H), 5.69 (s, 2H), 6.88 (s, 1H), 7.09 (s, lH), 7.72 (s, 1H), 8.10 (s, 1H) Mass Spec: 319.18 (MH) A Minor (E isomer): ^ - MN ( CDC13, 500 MHz) d 2.35 (s, 3H), 2.62 (s, 3H), 3.40 (s, 3H), 3.85 (s, 3H), 5.69 (s, 2H), 7.32 (s, ÍH), 7.38 ( s, 1H), 7.78 (s, ÍH), 8.14 (s, ÍH) Mass spectrum: 319.18 (MH) A 2-Acetoxy-3- (2- (methoxymethyl) -7-methyl-2H-indazole-5 -il) (R) -Methyl propanoate A solution of methyl 2-acetoxy-3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) acrylate (2.80 g, 8.8 mmol) in dichloromethane (20 ml) was degassed by passing a stream of nitrogen through the solution. To this solution was quickly added (-) -1, 2-bis ((2R, 5R) -2,5-diethylphospholane) benzene (cyclooctadiene) rhodium (I) trifluoromethylsulfonate (100 mg, 0.016 equivalent) as a solid. The reaction was placed under a hydrogen atmosphere (55 psi, (3.86 kg / cm2)) and stirred overnight. The reaction was concentrated and purified by column chromatography (50% ethyl acetate / hexanes) to give 2.74 g (97%) as a colorless oil. ^ -RMN (CDC13, 500 MHz) d 2.08 (s, 3H), 2.61 (s, 3H), 3.11 (dd, J = 14.3, 8.9, 1H), 3.20 (dd, J = 14.3, 4.6, ÍH), 3.39 (s, 3H), 3.72 (s, 3H), 5.26 (dd, J = 8.9, 4.6, ÍH), . 68 (s, 2H), 6.93 (s, ÍH), 7.33 (s, lH), 8.02 (s, 1H). (R) -2-Hydroxy-3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) propane To a solution of (R) -methyl 2-acetoxy-3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) propanoate (2.70 g, 8.4 mmol) in tetrahydrofuran (20 ml) and methanol (20 ml) at 0 ° C was added a solution of lithium hydroxide monohydrate (1.41 g, 4.0 equivalent) in water (20 ml). The reaction was stirred at 0 ° C for 1 hour. The reaction was concentrated, dissolved in water (5 ml), cooled to 0 ° C, and treated with 1 M hydrochloric acid to a mild acidity. The solution was extracted extensively with ethyl acetate and then dichloromethane. The organics were combined, dried over magnesium sulfate, and concentrated to give 1.40 g (63%) as an oil which solidified to a crystalline solid during rest. ^? - NMR (CDC13, 500 MHz) d 2.40 (s, 3H), 2.78 (dd, J = 14.0, 7.9, ÍH), 3.00 (dd, J = 14.0, 4.0, ÍH), 3.18 (s, 3H) , 4.24 (dd, J = 7.9, 4.3, lH), 5.47 (s, 2H), 6.85 (s, ÍH), 7.22 (s, ÍH), 7.90 (s, 1H). Mass Spectrum: 265.08 (MH) To 2-Hydroxy-3- (2- (methoxymethyl) ~ 7-methyl-2H-indazol-5-yl) propanoate of (R) -Methyl To the heterogeneous mixture of 5 M sodium hydroxide (20 ml) and diethyl ether (60 ml) in an Erlenmeyer flask fire-fired at 0 ° C was added N-methyl-N '-nitro-N-nitrosoguanidine (1.17 g). , 7.95 mmol) in small portions with stirring movement (without stirring bar). After the addition was complete, the mixture was allowed to maintain at 0 ° C for 15 minutes with occasional stirring movement. The ether was transferred in portions to a suspension of (R) -2-hydroxy-3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) propane (1.40 g, 5.30 mmol) in dichloromethane. (20 ml) until all the solid dissolved and a yellow color was maintained. The reaction was allowed to subtract at room temperature during ca. 5 minutes, before bubbling nitrogen through the solution to remove non-reactive diazomethane. The reaction was concentrated and purified by column chromatography (50% to 75% ethyl acetate / hexanes) to give 1.47 g (100%) as a colorless oil. XH-NMR (CDC13, 500 MHz) d 1.60 (bs, 1H), 2.58 (s, 3H), 2.95 (dd, J = 13.9, 7.0, ÍH), 3.14 (dd, J = 13.9, 4.0, 1H), 3.36 (s, 3H), 3.76 (s, 3H), 4.46 (bm, ÍH), 5.65 (s, 2H), 6.90 (s, ÍH), 7.31 (s, ÍH), 7.99 (s, ÍH). Mass spectrum: 279.11 (MH) A 2- (Benzoyloxy) -2- (diethoxyphosphoryl) acetic acid Glyoxylic acid monohydrate (20.10 g, 218 mmol) was suspended in diethyl phosphite (28.1 ml, 1.0 equivalent) and warmed to 60 ° C, and kept so for 5 hours. The reaction was cooled to 0 ° C, diluted with dichloromethane (200 ml), and treated with pyridine (17.7 ml, 1.0 equivalent) and benzoyl chloride (25.3 ml, 1.0 equivalent). The ice bath was removed and continued to stir overnight. The reaction was concentrated, diluted with ethyl acetate, washed with water, then 1M potassium bisulfate, then brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was triturated with ether to give a white powder which was filtered, washed with diethyl ether, and air dried to give 29.0 g (42%). XH-NMR (CDC13, 500 MHz) d 1.35 (m, 6H), 4.31 (m, 4H), 5.82 (d, J = 17.7, 1H), 7.46 (m, 2H), 7.60 (m, ÍH), 7.94 (bs, 1H), 8.12 (m, 2H). 1- (diethoxyphosphoryl) -2-methoxy-2-oxoethyl benzoate Diazomethane was generated in 3 Erlenmeyer flasks polished on fire using 1/3 of each N-methyl-N'-nitro-N-nitrosoguanidine (17.1 g 116. mmol), 5 M sodium hydroxide (200 ml), and diethyl ether (450 ml) at 0 ° C by adding the guanidine in small portions with stirring movement for the other two.

After the addition was completed, the mixture was allowed to maintain at 0 ° C for 10 minutes with occasional stirring movement. The ether was transferred in portions to a suspension of 2- (benzoyloxy) -2- (diethoxyphosphoryl) acetic acid. (21.0 g, 66.4 mmol) in dichloromethane (ca. 20 ml) until all the solid dissolved and a yellow color was maintained. The reaction was allowed to subtract at 0 ° C for 15 minutes, before bubbling nitrogen through the solution to remove most of the non-reactive diazomethane (the reaction became almost colorless). The reaction was concentrated to give 22.0 g (quantitative) as a faint yellow oil which was used without purification. ^? - NMR (CDCl3, 500 MHz) d 1.37 (m, 6H), 3.85 (s, 3H), 4.28 (m, 4H), 5.71 (d, J = 16.8, 1H), 7.47 (m, 2H), 7.61 (m, ÍH), 8.11 (m, 2H). Benzoate of l-methoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -l-oxoprop-2-en-2-yl To a solution of 1- (diethoxyphosphoryl) -2-methoxy-2-oxoethyl benzoate (13.7 g, 41.3 mmol) in tetrahydrofuran (70 mL) was added lithium chloride (1.75 g, 41.3 mmol). The reaction was stirred until the solution was complete. The reaction was cooled to -78 ° C, and treated with N, N, N ', N'-tetramethylguanidine (5.20 mL, 41.3 mmol) to give a white suspension which was stirred for 10 minutes. To this was added 7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2-H-indazole-5-carbaldehyde (10.0 g, 34.4 mmol) in one portion. The reaction was stirred for 10 minutes at -78 ° C, placed in a 0 ° C bath, and allowed to warm slowly to room temperature overnight. The reaction was diluted with ethyl acetate, washed with water, then 1 M potassium bisulfate, then saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The chromatographic column (25% ethyl acetate / hexanes) gave 15.10 g (94%) as a mixture of Z- and E- isomers as a colorless viscous oil. Major (Z-isomer): 1 H-NMR (CDC13, 500 MHz) d 0.02 (s, 9H), 0.95 (m, 2H), 2.63 (s, 3H), 3.66 (m, 2H), 3.73 (s, 3H) , 5.74 (s, 2H), 7.02 (s, lH), 7.15 (s, ÍH), 7.51 (, 2H), 7.64 (m, ÍH), 7.80 (s, ÍH), 8.12 (s, 1H), 8.17 (m, 2H). Mass spectrum: 467.18 (MH) A Minor (E-isomer): ^ H-NMR (CDC13, 500 MHz) d 0.04 (s, 9H), 0.92 (m, 2H), 2.50 (s, 3H), 3.62 (m , 2H), 3.85 (s, 3H), 5.69 (s, 2H), 7.37 (s, 1H), 7.49 (s, 1H), 7.54 (m, 2H), 7.67 (m, ÍH), 7.82 (s, lH), 8.07 (s, 1H), 8.25 (m, 2H). Mass spectrum: 467.18 (MH) A Benzoate of (R) -l-methoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -l -oxopropan-2-ilo A Parr shaker was purged with nitrogen. A flask containing l-methoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -l-oxoprop-2-en-2- benzoate il (15.7 g, 33.7 mmol) was purged with nitrogen. The substrate was dissolved in dichloromethane (100 ml). The solution was transferred by means of a cannula in a Parr shaker and was degassed by passing a Nitrogen stream into the solution for 30 minutes (Cyclooctadiene) rhodium (I) tetrafluoroborate of (-) - 1, 2-bis- ((2R, 5R) -2,5-diethylphosphoenas) benzene (300 mg) was rapidly emptied into the flask which was resealed and purged for an additional 5 minutes. The Parr agitator was pressurized to 60 psi (4.21 Kg / cm2) of hydrogen and stirred overnight. The reaction was concentrated and purified by column chromatography to give 15.5 g (98%) as a colorless oil. Mass Spectrum: 469.24 (MH) To (2-Hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoate (R) -Methyl To a solution of (R) -l-methoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -l-oxopropan-2-benzoate μl (14.2 g, 30.3 mmol) in tetrahydrofuran (80 ml) and methanol (80 ml) at 0 ° C was added a solution of lithium hydroxide monohydrate (5.09 g, 121 mmol) in water (80 ml). The reaction was stirred at 0 ° C for 1 hour. The ice bath was removed and continued stirring at room temperature for 2 hours. the reaction was concentrated, dissolved in water (5 ml), cooled to 0 ° C, and treated with 1 M hydrochloric acid to a mild acidity. A non-solid ppt was formed. The suspension was extracted with ethyl acetate (3X), which was washed with brine, dried over magnesium sulfate, and concentrated to give the crude hydroxy acid as an oil with white solid formed therein (probably residual benzoic acid) which was used without purification. Mass spectrum: 349.34 (M-H) To a heterogeneous solution of 5 M sodium hydroxide (150 ml) and diethyl ether (450 ml) in an Erlenmeyer flask, burnished at 0 ° C, was added N-methyl-N'-nitro-N-nitrosoguanidine (13.4 g, 90.9 mmol) in small portions with movement of stirring (without stirring bar). After the addition was completed, the mixture was allowed to maintain at 0 ° C for 15 minutes with occasional stirring movement. The ether was transferred in portions to a solution of crude hydroxy acid prepared above in a minimum of diethyl ether until a yellow color was maintained. The reaction was allowed to subtract at room temperature for 5 minutes, before bubbling nitrogen through the solution to almost remove the non-reactive diazomethane (the reaction became almost colorless). The reaction was concentrated and purified by column chromatography (25 to 50% ethyl acetate / hexanes) to give 10.5 g (95%) of the title compound as a colorless oil. 1 H-NMR (CDC13, 500 MHz) d -0.03 (s, 9H), 0.94 (m, 2H), 2.60 (s, 3H), 2.69 (d, J = 6.1, 1H), 2.98 (dd, J = 14.0 , 7.0, ÍH), 3.16 (dd, J = 13.7, 4.3, 1H), 3.63 (, 2H), 3.78 (s, 3H), 4.49 (m, 1H), 5.71 (s, 2H), 6.92 (s, ÍH), 7.33 (s, 1H), 8.01 (s, ÍH). Mass spectrum: 365.02 (MH) A (R) -2-hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-1-one To a solution of (R) -2-hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propane (610 mg, 1.74 mmol) , diisopropylethylamine (0.61 ml, 3.48 mmol), and 4-piperidinopiperidine (585.76 mg, 2.0 eguivalent) in dimethylformamide (20 ml) and dichloromethane (20 ml) at 0 ° C was added PyBOP® (951 mg, 1.83 mmol). The reaction was stirred at 0 ° C for 2 hours, the reaction was concentrated, diluted with ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (4: 96: 1 methanol / dichloromethane / triethylamine) to give 795 mg (91%). Mass spectrum: 501.40 (MH) A 4-Nitrophenylcarbonate of (R) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1- oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of (R) -2-hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1- (4- (piperidin- 1-yl) piperidin-1-yl) propan-l-one (795 mg, 1.59 mmol) and diisopropylethylamine (0.55 ml, 3.18 mmol) in dichloromethane (10 ml) at 0 ° C was added 4-nitrophenyl-chloroformate ( 352 mg, 1.10 eguivalent) followed by dimethylaminopyridine (10 mg). The ice bath was removed and stirring continued for 7 hours. the reaction was treated with an additional portion of diisopropylethylamine (0.25 ml, 1.45 mmol), 4-nitrophenyl-chloroformate (352 mg, 1.10 equivalent), and dimethylaminopyridine (10 mg) and stirred overnight at room temperature. The reaction was concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate (3x), then brine, dried over magnesium sulfate, and concentrated to give 1.06 g (quantitative) as a bright brown oil which it was used without purification. Mass spectrum: 666.31 (MH) A 4- (2-Oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-methyl-2- (( 2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of 4-nitrophenyl carbonate of (R) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-1- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (150 mg, 0.23 mmol) and 3- (piperidin-4-yl) -3,4-dihydroquinazolin-2 (1 H) -one (78.2 mg, 1.50 eguivalent) in dimethylformamide (1 ml) was added diisopropylethylamine (79 μL). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 90 mg (53%) as a colorless film. Mass spectrum: 758.56 (MH) A Example 2 4- (2-Oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidi-α-l-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1 -oxo-l- (4- (piperidin-1-yl) piperidin-l-yl) propan-2-yl 4- (2-Oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (90 mg, 0.12 mmol) was dissolved in trifluoroacetic acid ( 50% in dichloromethane, 6 ml) and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5: 95: 1 methane / dichloromethane / triethylamine). The compound was then dissolved in 10% methane / dichloromethane and passed through a plug of basic alumina to give 23 mg (31%) as a white solid. XH-NMR (CD3OD, 500 MHz) d -0.21 (m, 0.7H), 0.74 (m, HH), 1.10-2.05 (m, 17H), 2.15- 2.60 (m, 7H), 2.83 (m, 3H) , 3.07 (m, 1.5 H), 3.16 (dd, J = 12.8, 5.8, 0.7H), 3.70-4.55 (m, 7H), 5.42 (m, 0.3H), 5.50 (dd, J = 9.5, 6.1, 0.7 H), 6.70 (m, ÍH), 6.85 (m, 1H), 6.90-7.15 (m, 3H), 7.40 (bs, 1H), 7.93 (bs, 1H). Mass spectrum: 628.34 (MH) A 4- (8-Fluoro-2-oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-Methyl- 2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of 4-nitrophenyl carbonate of (R) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (150 mg, 0.23 mmol) and 8-fluoro-3- (piperidin-4-yl) -3,4-dihydroquinazolin-2 ( 1 H) -one (84.2 mg, 1.50 equivalent) in dimethylformamide (1 ml) was added diisopropylethylamine (79 μL, 0.45 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 78 mg (45%) as a colorless film. Mass Spectrum: 776.58 (MH) A Example 3 4- (8-Fluoro-2-oxo-l, 2-dihydroqtxinazolin-3 (4H) ~ il) piperidin-1-carboxylate of (R) -3- (7- Methyl-lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-l-yl) piperidin-1-yl) propan-2-yl 4- (8-Fluoro-2-oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (78 mg, 0.10 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 ml) and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5: 95: 1 methanol / dichloromethane / triethylamine). The residue was dissolved in 10% methanol / dichloromethane and passed through a plug of basic alumina to give 40.1 mg (62%) as a white solid. XH-NMR (CD3OD, 500 MHz) d -0.20-0.30 (m, 0.6H), 0.80-1.20 (m, 0.7H), 1.40-2.35 (m, 16H), 2.45-2.83 (m, 6H), 2.90 -3.48 (m, 5H), 4.00- 4.83 (m, 7H), 5.71 (m, 0.3 H), 5.79 (dd, J = 9.5, 6.1, 0.7H), 7.00-7.25 (m, 3H), 7.25- 7.41 (m, 1H), 7.69 (bs, lH), 8.22 (bs, 1H). Mass spectrum: 646.50 (MH) A 4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carboxylate of (R) -3- (7-Methyl-2- ((2- ( trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of 4-nitrophenyl carbonate of (R) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-1- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (150 mg, 0.23 mmol) and 3- (piperidin-4-yl) quinoline-2 (1 H) -one hydrochloride (89.5 mg, 1.50 equivalent) in dimethylformamide (1 ml) was added diisopropylethylamine (0.16 ml, 0.90 mmol), and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 102 mg (60%) as a colorless film. Mass spectrum: 755.53 (MH) A Example 4 4- (2-Oxo-l / 2-dihydroqt? Inolin-3-yl) piperidin-l-carboxylate of (R) -3- (7-Methyl-lH-indazole -5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidine-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H- indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (102 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 ml), and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5: 95: 1 methanol / dichloro ethane / triethylamine). The residue was dissolved in 10% methanol / dichloromethane and passed through a plug of basic alumina to give 56.4 mg (67%) as a white solid. 1 H-NMR (CD30D, 500 MHz) d-0.50-0.01 (m, 0.7H), 0.50-0.85 (m, 0.8H), 1.00-2.05 (m, 16H), 2.05-2.55 (m, 7H), 2.55-3.00 (m, 4H), 3.00-3.15 (m, 2H), 3.70-4.50 (m, 4H), 5.41 (m, 0.3H), 5.48 (dd) , J = 9.5, 6.1, 0.6H), 7.01 (m, 1H), 7.11 (m, 1H), 7.21 (m, ÍH), 7.36 (m, 2H), 7.44-7.65 (m, 2H), 7.90 (m, lH). Mass spectrum: 625. 33 (MH) A 4- (2-Oxo-4-phenyl-2,3-dihydroimidazol-1-yl) piperidine-1-carboxylate of (R) -3 A7-Methyl-2- ((2- (trimethylsilyl ) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of 4-nitrophenyl carbonate of (R) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-1- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (150 mg, 0.23 mmol) and 4-phenyl-1- (piperidin-4-yl) -lH-imidazole-2 (3H) -one (PCT Sol. Int. 1998, WO 9811128 Al) (82.2 mg, 1.50 equivalent) in dimethylformamide (1 ml) was added diisopropylethylamine (79 μL, 0.45 mmol) and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 74 mg (43%) as a colorless film. Mass spectrum: 770.57 (MH) A Example 5 4- (2-Oxo-4-phenyl-2,3-di-idroimidazol-1-yl) piperidine-1-carboxylate of (R) -3- (7-Methyl) lH-indazol-5-yl) -l-oxo-l- (4- (piperidin-l-yl) piperidin-l-yl) propan-2-yl 4- (2-Oxo-4-phenyl-2,3-dihydroimidazol-1-yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) ) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (74 mg, 96.1 μmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 ml), and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5: 95: 1 methanol / dichloromethane / triethylamine). The residue was dissolved in 10% methanol / dichloromethane and passed through a plug of basic alumina to give 31.7 (52%) as a white solid. ^ -NMR (CD3OD, 500 MHz) d -0.50-0.10 (m, 0.7H), 0.50-0.90 (m, 1H), 1.05-1.55 (m, 12H), 1.55-2.60 (m, 16H), 2.73 ( , 0.8H), 2.85-3.19 (m, 2.6H), 3.30-3.60 (m, lH), 3.65-4.18 (m, 3.4H), 4.26 (m, ÍH), 4.40 (m, ÍH), 5.25- 5.57 (m, ÍH), 6.90-7.10 (m, ÍH), 7.10-7.60 (m, 7H), 7.84-7.97 (bs, 1H) Mass spectrum: 638.46 (MH) ter-Butyl 4-hydroxy-4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidine-1-carboxylate One flask was charged with 3-bromoquinolin-2 (1H) -one (Sol. Pat. From US Publ 2002, US 2002099208 Al; Payack, JF et al., J. Org. Chem. 2005, 70, 1, 175. ) (1.0 g, 4.46 mmol) and sodium hydride (118 mg, 4.91 mmol). The solids were dissolved in tetrahydrofuran (30 ml), stirred for 15 minutes, and cooled to -78 ° C. The solution was treated with tert-butylithium (1.7 M in pentane, 5.25 ml, 8.93 mmol) and stirred for 1 hour. To this was added N-tert-butoxycarbonyl-4-piperidone (889 mg, 1.0 equivalent). The ice bath was removed and stirring continued for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride. The reaction was diluted with diethyl ether, washed with water (2X), then brine, dried over magnesium sulfate, and concentrated. The resulting oil was triturated with diethyl ether to give a white solid which was filtered, washed with diethyl ether, and air dried to give 430 mg (28%) as a white powder. XH-NMR (CDC13, 500 MHz) d 1.48 (s, 9H), 1.57 (bs, 2H), 1.87 (m, 2H), 2.13 (m, 2H), 3.37 (m, 2H), 4.06 (m, 2H) ), 7.28 (m, 2H), 7.53 (m, 2H), 7.60 (m, lH), 7.69 (s, 1H). Mass spectrum: 367.35 (MNa) A 3- (4-Hydroxypiperidin-4-yl) quinolin-2 (IH) -one tert-Butyl 4-hydroxy-4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate (300 mg, 0.87 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 ml) . The reaction was stirred 30 minutes and concentrated. The residue was dissolved in water, extracted with dichloromethane (2X) which was discarded. The aqueous was made basic with solid potassium carbonate. The resulting solid was filtered to give 145 mg (68%) as a white powder. Mass spectrum: 245.35 (MH) To 4-hydroxy-4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ( (2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of (R) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin- 1-yl) piperidin-1-yl) propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 3- (4-hydroxypiperidin-4-yl) quinolin-2 (1H) -one (55 mg, 1.0 equivalent) in dimethylformamide (1 ml) was added diisopropylethylamine (79 μL, 0.45 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (3: 97: 1 methanol / dichloromethane / triethylamine) to give 90 mg (52%) as a foamy solid. Mass Spectrum: 771.48 (MH) A Example 6 4-Hydroxy-4- (2-oxo-l 2-dihydro-ketainolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-lH- indazol-5-yl) -l-oxo-l- (4- (piperidin-l-yl) piperidin-l-xl) propan-2-yl 4-Hydroxy-4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) ) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (90 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 ml) and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5: 95: 1 to 10: 90: 1 methanol / dichloromethane / triethylamine). The residue was dissolved in 10% methanol / dichloromethane and passed through a plug of basic alumina to give 41 mg (55%) as a white solid. 2H-NMR (CD3OD, 500 MHz) d -0.40-0.00 (m, 0.6H), 0.50-0.95 (m, 0.7H), 1.10-2.75 (m, 21H), 2.83 (m, 0.7H), 3.02- 3.65 (m, 6H), 3.68-4.35 (m, 3H), 4.37-4.57 (m, 1H), 5.40-5.65 (m, ÍH), 7.00-7.15 (m, lH), 7.15-7.25 (m, ÍH) ), 7.25-7.35 (m, lH), 7.40-7.52 (m, 2H), 7.57-7.70 (m, ÍH), 7.87-8.03 (m, lH). Mass spectrum: 641.61 (MH) A 4- (7-Fluoro-2-oxo-l, 2-dihydroguinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-Methyl- 2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of 4-nitrophenyl carbonate of (R) -3- (7- methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-1- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (150 mg, 0.23 mmol) and 7-fluoro-3- (piperidin-4-yl) -3,4-dihydroquinazolin-2 ( H H) -one (56.2 mg, 1.0 eguivalent) in dimethylformamide (1 ml) was added diisopropylethylamine (79 μL, 0.45 mmol) and the reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (3: 97: 1 methanol / dichloromethane / triethylamine) to give 93 mg (53%) as a brown foamy solid. Mass Spectrum: 776.48 (MH) A Example 7 4- (7-Fluoro-2-oxo-l 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-Methyl) -lH-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidi-l-xl) propan-2-yl 4- (7-Fluoro-2-oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl)) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (93 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 ml) and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5: 95: 1 to 10: 90: 1 methanol / dichloromethane / triethylamine). The residue was dissolved in 10% methanol / dichloromethane and passed through a plug of basic alumina to give 41 mg (53%) as a white powder. ^? - NMR (CD30D, 500 MHz) d -0.38-0.15 (m, 0.7H), 0.60- 0.95 (m, ÍH), 1.18-2.18 (m, 17H), 2.29 (m, 0.7H), 2.35- 2.50 (m, 3H), 2.58-3.01 (m, 3.4H), 3.01-3.25 (m, 2.4H), 3.65-4.60 (m, 7H), 5.47 (m, 0.4H), 5.55 (dd, J = 9.5, 6.1, 0.7 H), 6.51 (m, 0.8H), 6.62 (m, 0.8H), 6.90-7.20 (m, 2.2H), 7.45 (bs, 1.1H), 7.98 (bs, 1H). Mass spectrum: 648.64 (MH) A 3- (2- (Methoxymethyl) -7-methyl-2H-indazol-5-yl) -2- ((R-methyl) -propanoate (R) -Methyl To a solution of (R) -methyl 2-hydroxy-3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) propanoate (1.45 g, . 21 mmol) and diisopropylethylamine (2.73 ml, 3.0 equivalent) in dichloromethane (27 ml) at 0 ° C was added 4-nitrophenyl-chloroformate (1.58 g, 1.5 equivalent) and N, N-dimethylaminopyridine (10 mg). The ice bath was removed and stirring continued for 7 hours. The reaction was treated with an additional portion of diisopropylethylamine (1.5 ml, 1.65 equivalent), 4-nitrophenyl-chloroformate (1.6 g, 1.5 equivalent), and N, N-dimethylaminopyridine (10 mg) and stirred overnight. The reaction was concentrated, dissolved in ethyl acetate, washed with water, then 1 M potassium bisulfate, then saturated sodium bicarbonate (5X), then brine, dried over magnesium sulfate, and concentrated to give 6.0 g ( quantitative) as a light brown oil, which was used immediately without purification. Mass spectrum: 444.10 (MH) A 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -l-Methoxy-3- (2- (methoxymethyl) -7 -methyl-2H-indazol-5-yl) -1-oxopropan-2-yl A flask was charged with (R) -methyl 3- (2- (methoxymethyl) -7-methyl-2H-indazol-5-yl) -2- ((4-nitrophenoxy) carbonyloxy) propanoate (2.31 g, 5.20 mmol) , 3- (piperidin-4-yl) quinolin-2 (lH) -one (1.78 g, 1.5 equivalent), diisopropylethylamine (1.82 ml, 2.0 equivalent), and dimethylformamide (20 ml). The reaction was stirred at room temperature for 8 hours and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with water to give a suspension which was exhaustively extracted with ethyl acetate then dichloromethane. The organics were dried over magnesium sulfate and concentrated. The chromatographic column (25% ethyl acetate / hexanes to 10% methanol / ethyl acetate) gave 2.40 g (86%) as a bright yellow foamy solid. Mass spectrum: 533.30 (MH) A 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carboxylate of (R) -l-methoxy-3- (7-methyl-lH-indazol-5-yl) -l-oxopropan -2-ilo To a solution of 4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carboxylate of (R) -l-methoxy-3- (2- (methoxymethyl) -7-methyl-2H- indazol-5-yl) -l-oxopropan-2-yl (1.20 g, 2.25 mmol) in methanol (20 ml) was added acetyl chloride (0.40 ml, 5.62 mmol). The reaction was refluxed and held for 1 hour. The reaction was concentrated by rotary evaporation under high vacuum and purified by column chromatography (5% methanol / dichloromethane) to give 1.09 g (99%) as a white foamy solid. Mass spectrum: 489.29 (MH) A (R) -3- (7-Methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) acid) piperidin-1-carbonyloxy) propanic To a solution of 4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carboxylate of (R) -l-methoxy-3- (7-methyl-lH-indazol-5-yl) -l-oxopropan-2-yl (1.20 g, 2.46 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) at 0 ° C was added a pre-cooled solution of lithium hydroxide monohydrate (309 mg, 3.0 eguivalent) in water (10 ml). After 2 hours, the reaction was concentrated under high vacuum (< 25 ° C). The resulting residue was dissolved in water (20 ml), cooled to 0 ° C, and acidified to ca. pH 2 with 1 N hydrochloric acid. The suspension was kept at 0 ° C for 1 hour, filtered, and the solid was washed with cold water. The resulting white solid was air dried and then dried under high vacuum overnight to give 1.04 g (89%) as a white solid. Mass spectrum: 475.30 (MH) A Example 4 4- (2-Oxo-l 2-dihydroquinolin-3-yl) piperidin-l-carboxylate of (R) -3- (7-methyl-lH-indazole-5- il) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carbonyloxy] ) Propanoic acid (500 mg, 1.05 mmol), diisopropylethylamine (0.37 ml, 2.11 mmol), and 4-piperidinopiperidine (355 mg, 2.0 equivalent) in dimethylformamide (4 ml) and dichloromethane (4 ml) at 0 ° C were added. BOE ^ (576 mg, 1.11 mmol). The reaction was stirred at 0 ° C for 4 h, concentrated, and purified by column chromatography (95: 5: 1 to 93: 7: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 600 mg (88%) as a white powder. Mass spectrum: 625.56 (MH) +. ter-Butyl 4- (5,6-dihydropyridin-l (2H) -yl) piperidine-1-carboxylate 4-Oxo-piperidine-l-carboxylic acid tert-butyl ester (797 mg, 4 mmol), 1, 2, 3, 6-tetrahydropyridine (349 mg, 4.2 mmol), sodium cyanoborohydride (126 mg, 2 mmol) , zinc chloride (410 mg, 3.2 mmol), and anhydrous methanol (20 ml) were mixed together and the mixture was stirred overnight at room temperature. The solvent was evaporated from the mixture and the residue divided between 1 N sodium hydroxide and dichloromethane. The phases were separated and the aqueous layer was extracted with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by flash column chromatography (1: 1 hexanes / ethyl acetate to ethyl acetate to 1: 3 methanol / ethyl acetate) to give 800 mg (75%) as a colorless oil. ^ -RN (CDC13, 400 MHz) d 5.75-5.70 (m, ÍH), 5.68-5.64 (m, lH), 4.13-4.07 (m, 2H), 3.08 (m, 2H), 2.71-2.60 (m, 4H), 2.48-2.41 (m, 1H), 2.15 (m, 2H), 1.82-1.79 (m, 2H), 1.49-1.38 (m, HI). 1- (Piperidin-4-yl) -1,2,3,6-tetrahydropyridine ter-Butyl 4- (5,6-dihydropyridin-1 (2H) -yl) piperidine-1-carboxylate (800 mg, 3 mmol) was dissolved in dichloromethane (54 ml). To this was added trifluoroacetic acid (7.9 ml) and triethylsilane (1.2 ml). The mixture was stirred at room temperature for 3 hours. The solvent was removed from the mixture in vacuo. The residue was dissolved in saturated sodium bicarbonate (50 ml) and stirred for 30 minutes. Sodium hydroxide (50 ml, 50% in water) was added to the solution which was then extracted with dichloromethane (3 x 100 ml). The organic extract was dried over sodium sulfate and the solvent was evaporated to give 370 mg (74%) as a colorless oil. 1 H-NMR (CDC13, 400 MHz) d 5.74-5.70 (m, lH), 5.68-5.64 (m, 1H), 3.14-3.07 (m, 4H), 2.64-2.53 (m, 4H), 2.43-2.37 ( m, HH), 2.15 (m, 2H), 1.85-1.82 (m, 2H), 1.73 (s, HH), 1.47-1.38 (m, 2H).

Example 8 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -1- (4- (5,6-dihydropyridin-1 (2H) -yl) piperidin- l-il) -3- (7-methyl-lH-indazol-5-yl) -l-Qxo? ropan-2-yl To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carbonyloxy) ) propanoic (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1- (piperidin-4-yl) -1, 2, 3, 6-tetrahydropyridine (75.7 mg, 2.0 equivalent) in dimethylformamide (0.50) ml) and dichloromethane (0.50 ml) at 0 ° C was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0 ° C for 4 h. The reaction was concentrated and purified by column chromatography (95: 5: 1 to 90: 10: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 35.9 mg (53%) as a white powder. ^ -RMN (CD3OD, 500 MHz) d -0.35-0.15 (m, 0.7H), 0.60-0.93 (m, 1H), 1.15-2.20 (m, 11H), 2.30-3.25 (m, HI), 3.75- 4.58 (m, 4H), 5.35-5.75 (m, 3H), 7.01-7.14 (, 1H), 7..18 (m, 1H), 7.28 (m, ÍH), 7.36-7.50 (m, 2H), 7.53-7.73 (m, 2H), 7.90-8.01 (m, 1H). Mass spectrum: 623.33 (MH) A 3-Methyl-3,9-diaza-spiro [5.5] undecane dichlorohydrate KC! HCl 3-Benzyl-9-methyl-3,9-diaza-spiro [5.5] undecane (Rice, LM et al J. Heterocyclic Chem. 1964, 1.3, 125.) (1.2 g, 4.65 mmol) was dissolved in ethanol (20 ml). To this solution was added hydrochloric acid (4 N in dioxane, 3 ml) and palladium (10% in charcoal, 500 mg). The reaction was stirred on Parr shaker overnight under 60 psi (42.18 kg / cm2) of hydrogen. The reaction mixture was filtered through a pad of celite, concentrated and the residue was treated with a mixture of ethyl acetate and hexanes, yielding 670 mg (60%) as a white powder. ^ H-NMR (CD3OD) d 1.68-1.72 (m, 4H), 2.88 (s, 3H), 3.16-3.22 (m, 6H), 3.38 (m, 2H). Mass spectrum: 169. 12 (MH) A Example 9 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carboxylate of (R) -3- (7-Methyl-lH-indazol-5-yl) -1-oxo-l - (9-methyl-3, 9-diaza-spiro [5.5] undecane-3-yl) propan-2-yl To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carbonyloxy) ) propanoic (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 3-methyl-3,9-diaza-spiro [5.5] undecane (65.2 mg, 2.0 eguivalent) dichlorohydrate in dimethylformamide (0.50 mL) and dichloromethane (0.50 ml) at 0 ° C was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0 ° C for 4 h. The reaction was concentrated and purified by column chromatography (95: 5: 1 to 90: 10: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 52 mg (77%) as a white powder. 1H-NMR (CD3OD, 500 MHz) d 0.12- 0.55 (m, HH), 0.85-1.70 (m, lIH), 1.85 (m, 2H), 2.05-2.42 (, 8H), 2.50 (s, 3H), 2.73-3.30 (m, 8H), 3.65 (bs, 1H), 4.00-4.43 (m, 2H), 5.46 (dd, J = 7.6, 7.6, ÍH), 7.07 (s, 1H), 7.17 (m, ÍH) ), 7.27 (m, lH), 7.38-7.46 (m, 2H), 7.50 (bs, 0.5 H), 7.58 (m, ÍH), 7.65 (bs, 0.5 H), 7.96 (s, lH). Mass spectrum: 625.33 (MH) A Example 10 4- (2-Oxo-l, 2-Dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo-l - (piperidin-1-yl) propan-2-yl To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carbonyloxy) ) propanoic (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and piperidine (21 μL, 2.0 equivalent) in dimethylformamide (0.5 mL) and dichloromethane (0.5 mL) at 0 ° C was added PyBOP® ( 57.6 mg, 0.11 mmol). The reaction was stirred at 0 ° C for 4 h. The reaction was concentrated and purified by column chromatography (95: 5: 1 to 90: 10: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 55 mg (93%) as a white powder. ^ -NMR (CD3OD, 500 MHz) d 0.75-1.70 (m, 9H), 1.70-1.95 (m, 4H), 2.51 (s, 3H), 2.72-3.04 (m, 3H), 3.11 (m, 4H) , 3.19-3.58 (m, 4H), 3.98-4.49 (m, 2H), 5.47 (dd, J = 7.3, 7.3, ÍH), 7.07 (s, 1H), 7.17 (m, lH), 7.27 (m, 1H), 7.43 (, 2.5H), 7.58 (d, J = 7.3, 1H) , 7.65 (bs, 0.5H), 7.96 (s, ÍH). Mass spectrum: 542.29 (MH) A Example 11 4- (2-Oxo-l-2-di-idroquinolin-3-yl) piperidin-1-carboxylate of (R) -1- (4-cyclohexylpiperazin-1-yl) -3- (7-methyl-1H -indazol-5-yl) - To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carbonyloxy) ) propanoic (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-cyclohexylpiperazine (35.5 mg, 2.0 equivalent) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0 ° C was added PyBOP ® (57.6 mg, 0.11 mmol). The reaction was stirred at 0 ° C for 4 h. The reaction was concentrated and purified by column chromatography (95: 5: 1 to 90: 10: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 62.3 mg (92%) as a white powder. -? - NMR (CD3OD, 500 MHz) d 0.75-2.10 (m, 20H), 2.29 (m, 1H), 2.47 (m, 1H), 2.56 (s, 3H), 2.77-3.41 (m, 9H), 3.73 (m, lH), 4.04-4.49 (m, 2H), 5.52 (dd, J = 8.2, 7.3, ÍH), 7.11 (s, lH), 7.22 (dd, J = 7.0, 7.0, ÍH), 7.33 (d, J = 7.9, 1H), 7.42-7.53 (m, 2H), 7.53-7.76 (m, 2H), 8.01 (s, ÍH). Mass spectrum: 625.33 (MH) A Example 12 4- (2-Oxo-l # 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -1- (4- (4-Fluorophenyl) piperazin-1-yl) -3- (7 -methyl-lH-indazol-5-yl) -l-oxopropan-2-yl To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboryl-lioxy acid ) propanoic (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and N- (4-fluorophenyl) piperazine (38.0 mg, 2.0 equivalent) in dimethyl formamide (0.50 mL) and dichloromethane (0.50 mL) at 0 ° C was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0 ° C for 4 h. The reaction was concentrated and purified by column chromatography (95: 5: 1 to 90: 10: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 71.2 mg (quant.) As a white powder. 1 H-NMR (CD 3 OD, 500 MHz) d 1.25-1.75 (m, 2 H), 1.75-2.25 (m, 9 H), 2.51 (s, 3 H), 2.75 (m, H H), 2.75-3.30 (m, 13 H) , 3.48 (m, 3H), 3.80 (m, 1H), 4.05-4.50 (m, 2H), 5.55 (dd, J = 7.6, 7.3, ÍH), 6.68 (m, 2H), 6.91 (m, ÍH) , 7.11 (s, 1H), 7.21 (dd, J = 7.9, 7.3, ÍH), 7.32 (d, J = 8.2, ÍH), 7.47 (dd, J = 7.9, 7.3, ÍH), 7.51 (m, 1.5 H), 7.61 (d, J = 7.6, ÍH), 7.67 (bs, 0.5H), 8.00 (s, ÍH). Mass spectrum: 637.28 (MH) +.

Ejepplo 13 4- (2-Oxo-l, 2-dü idroqui-olxn-3-yl) piperidin-l-carboylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-o? Ol- (4- (pyridin-4-yl) piperazin-1-yl) propan-2-yl To a solution of (R) -3- (7-methyl-lH-indazol-5-yl) -2- (4- (2-oxo-l, 2-diMdrc uinolin-3-yl) piperidin-1- carboxynyloxy) propanoic (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and l- (4-pyridyl) piperazine (34.4 mg, 2.0 equivalent) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0 ° C was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0 ° C for 4 h, concentrated, and purified by column chromatography (95: 5: 1 to 90: 10: 1 dichloromethane / methanol / triethylamine). The resulting residue was dissolved in 5% methanol / dichloromethane and passed through a column of basic alumina to give 53.8 mg (80%) as a white powder. ^ H-NMR (CD3OD, 500 MHz) d 1.25-2.00 (m, 4H), 2.51 (s, 3H), 2.67 (bs, ÍH), 2.80-3.31 (m, 7H), 3.35-3.83 (m, 5H) ), 4.05-4.49 (m, 2H), 5.52 (dd, J = 7.6, 7.3, ÍH), 6.64 (bs, 2H), 7.12 (s, 1H), 7.22 (dd, J = 7.0, 7.0, ÍH) , 7.32 (d, J = 8.2, ÍH), 7.47 (m, ÍH), 7.52 (m, 1.5H), 7.62 (d, J = 7.0, ÍH), 7.69 (bs, 0.5H), 7.99 (s, ÍH), 8.10 (m, 2H). Mass spectrum: 620.28 (MH) A (+) 2-Hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoic acid A Parr bottle was charged with l-methoxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -l-oxoprop-2-en benzoate. 2-yl (1.0 g, 2.14 mmol), methanol (15 ml), and palladium (10% in charcoal, 100 mg). The Parr agitator was pressurized to 60 psi (42.48 kg / cm2) of hydrogen and stirred for 6 hours. The reaction was filtered through celite and concentrated. The resulting residue was dissolved in tetrahydrofuran (8 ml) and methanol (8 ml) and cooled to 0 ° C. To this was added a solution of lithium hydroxide monohydrate (358 mg, 8.54 mmol) in water (8 ml). The reaction was stirred at 0 ° C for 1 hour, then at room temperature for 2 hours. The reaction was concentrated, dissolved in water, cooled to 0 ° C, and acidified with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2X). The organics were washed with a minimum of brine, dried over magnesium sulfate, and concentrated. Column chromatography (5% to 10% methanol / dichloromethane) gave 340 mg (45%) as a colorless oil. XH-NMR (CDC13, 500 MHz) d -0.04 (s, 9H), 0.93 (m, 2H), 2.53 (s, 3H), 2.92 (m, ÍH), 3.19 (m, ÍH), 3.61 (m, 2H), 4.46 (bs, 1H), 5.68 (s, 2H), 6.93 (s, ÍH), 7.31 (bs, ÍH), 7.94 (bs, 1H). Mass spectrum: 351.36 (MH) A (+) -2-Hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) ethyl) -2H-indazol-5-yl) -1- ( 4- (piperidin-1-yl) piperidin-1-yl) propan-1-one To a solution of (+) -2-hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoic acid (100 mg, 0.29 mmol) , 4-piperidinopiperidine (96.0 mg, 2.0 equivalent), and .diisopropylethylamine (0.10 ml, 0.57 mmol) in dichloromethane (3.6 ml) at 0 ° C was added PyBOP® (156 mg, 0.30 mmol) in 2 portions. The reaction was stirred at 0 ° C for 15 minutes and at room temperature overnight. The reaction was diluted with ethyl acetate, washed with water (2X), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (4% to 10% methanol / dichloromethane) gave 130 mg (91%) as an oil. Mass spectrum: 501.36 (MH) +. 4- (2-Oxo-l, 2-oi-droquinolin-3-yl) piperidin-1-carboxylate of (+) - 3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H -indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl To a solution of (+) - 2-hydroxy-3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1- (4- (piperidin- 1-yl) piperidin-1-yl) propan-l-one (130 mg, 0.26 mmol) and diisopropylethylamine (91 μL, 0.52 mmol) in dichloromethane (1 ml) at 0 ° C was added 4-nitrophenyl-chloroformate ( 57.6 mg, 1.10 equivalent). The ice bath was removed and stirring continued for 4 hours. The reaction was treated with a solution of 3- (piperidin-4-yl) quinolin-2 (1H) -one (88.9 mg, 1.50 eguivalent) and diisopropylethylamine (91 μL, 0.52 mmol) in dimethylformamide (1 ml). The reaction was stirred at room temperature overnight. The reaction was poured into water / dichloromethane. The mixture was extracted with dichloromethane (2X) which was washed with saturated sodium bicarbonate, then water (2X), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (5% to 20% methanol / dichloromethane) gave 112 mg (57%) as an oil.

EXAMPLE 14 4- (2-Oxo-l, 2-dihxdroc [Uiolin-3-yl) piperidin-l-carboxylate of (+) - 3- (7-Methyl-lH-ipdazol-5-yl) -1-oxo -l- (4- (piperidin-l-yl) piperidin-l-xl) propan-2-yl 4- (2 ~ Oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (• +) -3- (7-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H -indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (112 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (50%). in dichloromethane, 6 ml) and stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (5% methanol / dichloromethane to 7: 93: 1 methanol / dichloromethane / 33% trimethylamine in ethanol) gave 89.6 mg (97%) as a white solid. Mass spectrum: 755.37 (MH) A 4- (8-fluoro-2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -l-Methoxy-3- (7-methyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -l-oxopropan-2-yl 3- (4-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-6-yl) -2- ((4-nitrophenoxy) carbonyloxy) propanoate of (R) -methyl (75 mg, 0.24 mmol) was dissolved in N, N-dimethylformamide (6 ml). N, N-Diisopropylethylamine (1.5 ml, 8.6 mmol) was added to the mixture followed by 8-fluoro-3- (piperidin-4-yl) uinolin-2 (1H) -one hydrochloride (75 mg, 0.27 mmol) . The reaction was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate (20 ml), washed successively with water (2X), 1 N hydrochloric acid, and brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound is obtained as a white solid in 82% yield and used without further purification. Mass spectrum: 637.2 (MH) A (R) -2- (4- (8-Fluoro-2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carbonyloxy) -3- (7-methyl-2- ((2- ( trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoic acid 4- (8-fluoro-2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -l-methoxy-3- (4-methyl-2- ((2- (trimethylsilyl ) ethoxy) methyl) -2H-indazol-6-yl) -1-oxopropan-2-yl (120 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 ml). Water (2 ml) was added to the mixture followed by lithium hydroxide monohydrate (25 mg, 0.60 mmol). The reaction was stirred at room temperature for 3 hours and quenched by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (2X). The combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound is obtained without further purification as a white solid in 95% yield. Mass Spectrum: 621.1 (MH) ". 4- (8-Fluoro-2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (R) -2- (4- (8-Fluoro-2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-l-carbonyloxy) -3- (7-methyl-2- ((2)) was dissolved. - (trimethylsilyl) ethoxy) methyl) -2H-indazol-5-yl) propanoic acid (105 mg, 0.17 mmol) in N, N-dimethylformamide (3 ml). N, N-diisopropylethylamine (100 μL, 0.57 mmol) was added to the mixture followed by o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (65 mg, 0.20 mmol). The reaction was stirred at room temperature for 5 minutes. 4-piperidinpiperidine (41 mg, 0.22 mmol) was added to the mixture. The reaction was stirred a. room temperature for 2 hours. The mixture was diluted with ethyl acetate (25 ml), washed successively with water (3X), and brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound is obtained without further purification as a white solid in 96% yield. Mass spectrum: 773.3 (MH) A Example 15 4- (8-Fluoro-2-oxo-1,2-dihydroquinolin-3-l) piperidine-1-carboxylate of (R) -3- (7-Methyl-lH-indazol-5-yl) -l -oxo-l- (4- (piperxdin-l-il) pxperidxn-1-yl) propan-2-yl 4- (8-Fluoro-2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-Methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) ) -2H-indazol-5-yl) -1-oxo-l- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl (122 mg, 0.16 mmol) was dissolved in ethyl acetate. ethyl (2 ml). Hydrochloric acid (4 N in dioxane, 3.0 ml) was added to the mixture. The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. The organic solvents were removed from the product fractions. The remaining solution was made basic with aqueous sodium bicarbonate and extracted with ethyl acetate (2X). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound is obtained as an off white solid with 59% yield. 1 H NMR (500 MHz, DMSO-d 6): d 13.03 (s, 1H), 11.78 (s, ÍH), 7.99 (s, ÍH), 7.70 (m, ÍH), 7.46 (m, 3H), 7.34 (dd) , J = 10.81, 8.09, IH), 7.15 (m, 1H), 7.06 (s, ÍH), 5.43 (, ÍH), 4.34 (m, lH), 4.17 (m, ÍH), 3.88 (m, 1H), 3.06 (, 2H), 2.97 (m, 2H), 2.83 (m, 3H), 2.50 (m, 3H), 2.36 (m, 2H), 2.27 (m, 1H), 2.05 (m, 2H), 1. 82 (d, J = 12.51, 2H), 1.68 (m, ÍH), 1.39 (, 10H), 0.78- 0.26 (, ÍH). Mass spectrum: 643.3425 (MH) A ter-Butyl 2-fluorophenylcarbamate To a solution of di-tert-butyldicarbonate (90.4 g, 414 mmol) in tetrahydrofuran (414 mL) was added 2-fluorobenzenamine (40.0 mL, 414 mmol). The reaction was heated to reflux overnight. The reaction was cooled, concentrated, dissolved in pentane, washed, in order, with 1 N potassium bisulfate (2X), water, 20% potassium hydroxide, and brine, and then dried over magnesium sulfate and concentrated to give a light brown oil which was dried under high vacuum to give 83.7 g (96%) as a light brown oil which was used without further purification. 1 H-NMR (CDC 13, 500 MHz) d 1.52 (s, 9H), 6.68 (bs, ÍH), 6.85-7.20 (m, 3H), 8.07 (dd, J = 8.1, 8.1 Hz, lH). Mass spectrum: 234.18 (MNa) A tert- Butyl 2-fluoro-6-formylphenylcarbamate Concentrate tert-Butyl 2-fluorophenylcarbamate (42.7 g, 202 mmol) from toluene under vacuum (3X) to remove any traces of water. The resulting residue was dissolved in tetrahydrofuran (600 ml), and cooled to -78 ° C. To this was added tert-butylithium dropwise (1.7 M in pentane, 285 mL, 485 mmol). After the addition was complete, the reaction was stirred at -78 ° C for 30 minutes. The solution was gradually warmed to -20 ° C before re-cooling to -78 ° C. To this was added dimethylformamide (46.9 ml, 606 mmol). The reaction was gradually warmed to room temperature overnight. The reaction was emptied into a separatory funnel containing diethyl ether and water. The organics were washed with water (3X) and concentrated. The combined aqueous washes were neutralized with 1 M potassium bisulfate and extracted with diethyl ether. The ether layers were combined with the other organic layers, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification. 1 H-NMR (CDC13, 500 MHz) d 1.50 (s, 9H), 7.27 (m, lH), 7.35 (m, ÍH), 7.56 (d, J = 7.6 Hz, 1H), 7.85 (bs, 1H), 9.99 (d, J = l .2 Hz, lH).

Mass spectrum: 262.16 (MNa) A ter-Butyl 2- ((l-benzylpiperidin-4-ylamino) methyl) -6-fluorophenylcarbamate To a solution of tert-butyl 2-fluoro-6-formylphenylcarbamate (48.0 g, 201 mmol) in ethanol (100 ml) was added 4-amino-1-benzylpiperidine (41.0 ml, 201 mmol). The solution was concentrated in vacuo, and then water was removed by dissolving the residue 2 times in toluene and concentrating the solution in vacuo. The resulting oil was dissolved in tetrahydrofuran (250 ml), cooled to 0 ° C, and treated with sodium borohydride (3.80 g, 100 mmol). The ice bath was removed and stirred continuously overnight. The reaction was treated with ethanol (250 ml), an additional portion of sodium borohydride (2.00 g, 53 mmol), and an additional portion of 4-amino-1-benzylpiperidine (2.0 ml, 9.8 mmol). The resulting solution was stirred for 4 hours at room temperature. The reaction was cooled to 0 ° C, quenched by the addition of saturated ammonium chloride, filtered to remove solids, and concentrated to remove most (but not all) of the tetrahydrofuran. The reaction was extracted with diethyl ether (2X). The ether layer was washed with water (3X), then brine, dried over magnesium sulfate, and concentrated to give 83 g (100%) as a yellow viscous oil that is pure enough to be used in the next step. Mass spectrum: 414.51 (MH) A 3- (l-Benzylpiperidin-4-yl) -8-fluoro-3,4-dihydroguinazolin-2 (lH) -one ? AsN tert-Butyl 2- ((1-benzylpiperidin-4-ylamino) methyl) -6-fluorophenylcarbamate (83.0 g, 201 mmol) was dissolved in pyridine (600 ml) and heated to reflux for 12 hours. The reaction was concentrated, triturated with warm diethyl ether and placed in a freezer overnight. The resulting solid was filtered to give 68.1 g (64%) as a white solid. ^? - RN (CDC13, 500 MHz) d 1.68 (m, 2H), 1.86 (dddd, J = 11.9, 11.9, 11.9, 3.4 Hz, 2H), 2.14 (dd, J = I1.6, 10.1 Hz, 2H ), 2.98 (d, J = 11.6 Hz, 2H), 3.51 (s, 2H), 4.34-4.44 (m, 3H), 6.71 (bs, ÍH), 6.79-6.89 (m, 2H), 6.94 (dd, J = 9.2, 9.2 Hz, ÍH), 7.21-7.34 (m, 5H). Mass spectrum: 340.30 (MH) A 8-Fluoro-3- (piperidin-4-yl) -3,4-dihydroguinazolin-2 (1H) -one To a solution of 3- (1-benzylpiperidin-4-yl) -8-fluoro-3,4-dihydroquinazolin-2 (1H) -one (2.50 g, 7.37 mmol) in acetic acid (50 ml) under nitrogen, he added palladium (10% in charcoal, 300 mg). The Parr agitator was pressurized to 50 psi (35.15 kg / cm2) and stirred for 2 days. The flask was filled with nitrogen, filtered and concentrated. The residue was dissolved in methanol and re-concentrated to give a light brown oil which solidified during rest. The residue was dissolved in 1 N hydrochloric acid, and concentrated in vacuo, maintaining the temperature at 40 ° C. The resulting oil was dissolved in methanol, concentrated and dried under high vacuum to give 2.19 g (quantitative) of the hydrochloride salt as an off-white solid. Generation of the free base: the hydrochloride salt (15.1 g, 52.8 mmol) was suspended in 2 N sodium hydroxide (40 ml) and stirred at room temperature for 2.5 hours. The remaining solid was filtered, washed with water (0 ° C, 2X 50 ml), then with anhydrous diethyl ether (100 ml). The resulting solid was dried under high vacuum overnight to give 12.5 g (95%). ^ -NMR (CDC13, 500 MHz) d 1.71 (m, 4H), 2.75 (m, 2H), 3.16 (m, 2H), 4.38 (s, 2H), 4.46 (m, lH), 6.77 (bs, lH ), 6.81-6.89 (m, 2H), 6.95 (m, 1H). Mass spectrum: 250.22 (MH) A Methyl 2- (l-benzylpiperidin-4-yl) acetate OX UL Sodium hydride (60% in mineral oil, 10.55 g, 264 mmol) was washed with hexanes then suspended in N, N-dimethylformamide (200 ml). The mixture was cooled to 0 ° C. Trimethyl phosphonoacetate (38.0 ml, 249 mmol) was added to the mixture dropwise. The reaction was stirred at 0 ° C for 30 minutes. The l-Benzyl-4-piperidone (40.0 ml, 220 mmol) was added to the reaction mixture dropwise. The reaction was warmed to room temperature and kept under stirring for 1 hour. The reaction mixture was diluted with diethyl ether (500 ml), washed with water (2X), then brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was dissolved in methanol (220 ml). The platinum (IV) oxide (600 mg, 2.64 mmol) was added to the mixture. The reaction vessel was placed in a Parr apparatus, charged with 40 psi (28.12 kg / cm2) of hydrogen gas, and stirred at room temperature for 5 hours. The reaction mixture was removed from the apparatus, filtered through celite, and concentrated. The residue was passed through a short column of silica gel eluted with ethyl acetate. The fractions were concentrated in vacuo. The title compound was obtained as an amber oil in 90% yield. XH NMR (300 MHz, CDC13): d 7.31-7.16 (m, 5H), 3.62 (s, 3H), 3.45 (s, 2H), 2.83 (d, J = 11.71, 2H), 2.20 (d, J = 6.95, 2H), 2.00-1.88 (m, lH), 1.82-1.69 (m, lH), 1.69-1.59 (m, 2H), 1.38-1.25 (, 2H). Mass spectrum: 249.3 (MH) A Methyl 2- (l-benzylpiperidin-4-yl) -3-hydroxy-3- (2-nitrophenyl) ropanoate Diisopropylamine (3.50 ml, 24.9 mmol) was dissolved in tetrahydrofuran (30 ml). The mixture was cooled to -78 ° C. Butylithium (2.5 M in pentane, 9.8 ml, 24.5 mmol) was added dropwise to the mixture, and the reaction was stirred at -78 ° C for 15 minutes. A solution of methyl 2- (1-benzylpiperidin-4-yl) acetate (5.50 g, 22.2 mmol) in THF (8 mL) was then added to the mixture dropwise over 20 minutes. The reaction was stirred at -78 ° C for 45 minutes. A solution of 2-nitrobenzaldehyde (3.70 g, 24.5 mmol) in THF (5 ml) was then added to the mixture dropwise over 15 minutes. The reaction was stirred at -78 ° C for 30 minutes and quenched by the addition of aqueous saturated ammonium chloride. The resulting mixture was warmed to room temperature, extracted with ethyl acetate (2X). The combined organics were dried (magnesium sulfate), filtered and concentrated. Chromatography on silica gel gave the desired product in 89% yield as a yellow foam. Mass spectrum: 399.3 (MH) A 3- (l-Benzylpiperidin-4-yl) -4-hydroxy-3,4-dihydroquiolin- 2 (lH) -one Methyl 2- (l-benzylpiperidin-4-yl) -3-hydroxy-3- (2-nitrophenyl) propanoate (950 mg, 2.4 mmol) was dissolved in acetic acid (20 ml). Iron (O) (1.0 g, 17.7 mmol) was added to the mixture. The reaction was heated to 85 ° C and maintained with stirring for 1.5 hour. The mixture was cooled to room temperature and diluted with water (30 ml). The liguid was decanted again from the solids. The aqueous solution was concentrated in vacuo. The residue was treated with ethyl acetate (50 ml). The mixture was made basic with aqueous sodium hydroxide. Celite was added to the resulting suspension to create a thick mixture which was refiltered. The filtered layers were seped. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound is obtained without further purification as a yellow oil in 69% yield. Mass spectrum: 335.3 (MH) A 3- (l-Benzylpi eridin-4-yl) quinolin-2 (lH) -one 3- (1-Benzylpiperidin-4-yl) -4-hydroxy-3,4-dihydroquinoline-2 (1H) -one (550 mg, 1.6 mmol) was suspended in benzene (10 ml). P-Toluenesulfonic acid monohydrate (370 mg, 1.9 mmol) was added to the mixture. The reaction was heated to reflux and kept so for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in 10% ethanol / dichloromethane (50 ml) and washed with aqueous sodium bicarbonate (2X). The organic layer was dried (Magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give a solid which was filtered, washed with diethyl ether, and dried in vacuo. The title compound is obtained as a completely white solid in 63% yield. 1 H NMR (300 MHz, DMSO-d 6): d 11.72 (s, 1H), 7.72 (s, ÍH), 7.62 (d, J = 6.95, 1H), 7.47-7.38 (m, ÍH), 7.35-7.30 ( m, 4H), 7.29-7.20 (m, 2H), 7.14 (t, J = 7.50, ÍH), 3.49 (s, 3H), 2.92 (d, J = 11.34, 2H), 2.83-2.69 (m, 1H ), 2.04 (t, J = 10.61, 2H), 1.78 (d, J = 12.08, 2H), 1.71-1.47 (, 2H). Mass spectrum: 319.3 (MH) +. 3- (piperidin-4-yl) quinolin-2 (lH) -one 3- (1-Benzylpiperidin-4-yl) quinolin-2 (1 H) -one (1.72 g, 5.40 mmol) was suspended in methanol (70 ml). A catalytic amount of palladium hydroxide (20% in carbon) was added to the mixture. The reaction vessel was placed in a Parr appus and charged with 55 psi (38,665 Kg / cm 2) of hydrogen. The reaction was stirred at room temperature for 5 hours. The mixture was removed from the appus and filtered. The filtrate was concentrated to give the title compound as a white solid in 90% yield. 2 H NMR (300 MHz, EMSO-ds): d 7.65 (s, HH), 7.64 (d, J = 10.61, 1H), 7.41 (t, J = 7.50, HH), 7.26 (d, J = 8.05, HH) ), 7.13 (t, J = 7.32, ÍH), 3.02 (d, J = 11.71, 2H), 2.82 (t, J = 11.89, 2H), 2.58 (t, J = 11.71, 2H), 1.73 (t, J = 11.71, 2H), 1.42 (m, 2H). Mass spectrum: 229.4 (MH) A N- (2-Bromo-6-f luorofenil) pivalami da 2-Bromo-6-fluoroaniline (8.2 g, 43.2 mmol) was dissolved in pyridine (10 ml) and treated with pivaloyl chloride (7.0 ml, 57.2 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and treated with ethyl acetate (50 ml). The mixture was washed 1 N hydrochloric acid (2X), then brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated with hexanes to give a solid which was filtered, washed with hexanes, and dried in vacuo. The title compound was obtained as a white solid in 76% yield. XE NMR (300 MHz, CDC13): d 7.39-7.31 (m, ÍH), 7.14-7.03 (m, 2H), 6.98 (bs, lH), 1.34 (s, 9H). Mass spectrum: 274.1 (MH), 276.1 (MNa) A N- (2-Fluoro-6-formylphenyl) pivalamide N- (2-Bromo-6-fluorophenyl) pivalamide (7.0 g, 25.5 mmol) was dissolved in tetrahydrofuran (200 ml). The mixture was cooled to -78 ° C, and treated with butyllithium (2 M in cyclohexane, 31.0 ml, 62.0 mmol) dropwise. The reaction mixture was maintained at -78 ° C for 30 minutes. A solution of N, N-dimethylformamide (10.0 ml, 129 mmol) in tetrahydrofuran (30 ml) was added to the reaction mixture dropwise. The reaction was maintained at -78 ° C for 30 minutes and quenched by the addition of aqueous ammonium chloride. The mixture was warmed to room temperature and extracted with ethyl acetate (2X). The combined organic layers were dried (magnesium sulfate), filtered and concentrated. Chromatography on silica gel gave the desired product as a white solid in 80% yield. 1H NMR (300 MHz, CDC13): d 9.93 (d, J = l .83, ÍH), 9.14 (bs, lH), 7.56-7.50 (m, ÍH), 7.42-7.25 (m, 2H), 1.34 (s, 9H). Mass spectrum: 224.2 (MH) A ter-Butyl 4- (2-methoxy-2-oxoethyl) piperidine-l-carboxylate Sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) was washed with hexanes and then suspended in N, N-dimethylformamide (100 ml). The mixture was cooled to 0 ° C. Trimethyl phosphonoacetate (17.0 ml, 111 mmol) was added to the mixture dropwise. The reaction was maintained at 0 ° C for 45 minutes. A solution of N-tert-butoxycarbonyl-4-piperidone (18.5 g, 92.6 mmol) in N, -dimethylformamide (25 ml) was added dropwise to the reaction mixture.

The mixture was kept at 0 ° C for 1 hour and then warmed to room temperature where it was kept for 1 hour. The reaction was quenched with 1 N hydrochloric acid. The mixture was extracted with diethyl ether (2X). The combined organic layers were washed with water (2X), then brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was dissolved in 1: 1 ethyl acetate / methanol (60 ml). A catalytic amount of palladium (10% in charcoal) was added to the mixture. The reaction vessel was placed in a Parr apparatus, charged with 55 psi (38,665 kg / cm 2) of hydrogen, and stirred at room temperature for 18 hours. The reaction mixture was removed from the Parr apparatus and filtered. The filtrate was concentrated in vacuo to give the title compound as a slightly colored oil in 94% yield. XH NMR (300 MHz, CDC13): d 4.04 (d, J = 10.25, 2H), 3.64 (s, 3H), 2.68 (t, J = 14.44, 2H), 2.21 (d, J = 6.95, 2H), 1.99-1.80 (m, ÍH), 1.64 (d, J = 13.54, 2H), 1.41 (s, 9H), 1.25-1.03 (m, 2H). 4- (1- (3-fluoro-2-pivalamidophenyl) -l-hydroxy-3-methoxy-3-oxopropan-2-yl) piperidin-1-tert-butyl carboxylate Diisopropylamine (3.40 ml, 24.2 mmol) was dissolved in tetrahydrofuran (70 ml). The mixture was cooled to -78 ° C.

Butyllithium (2 M in cyclohexane, 12.2 ml, 24.4 mmol) was added dropwise to the reaction. The mixture was kept at -78 ° C with stirring and kept for 20 minutes. A solution of tert-butyl 4- (2-methoxy-2-oxoethyl) piperidine-l-carboxylate (5.20 g, 20.2 mmol) in tetrahydrofuran (15 ml) was added to the mixture dropwise. The mixture was maintained at -78 ° C with stirring and maintained for 45 minutes. In a separating flask, sodium hydride (60% in mineral oil, 970 mg, 24.3 mmol) was washed with hexanes then suspended in tetrahydrofuran (50 ml). The mixture was cooled to 0 ° C. A solution of N- (2-Fluoro-6-formylphenyl) pivalamide (4.50 g, 20.2 mmol) in tetrahydrofuran (20 ml) was added to the mixture dropwise. The mixture was kept at 0 ° C with stirring and kept for 1 hour. The aldehyde mixture prepared above was added to the ester mixture dropwise for 1.25 hour. The mixture was kept at -78 ° C with stirring and kept for 1 hour. The reaction was quenched with aqueous ammonium chloride, warmed to room temperature, and diluted with water. The mixture was extracted with ethyl acetate (2X) and the aqueous phase was discarded. The material dried (Magnesium sulfate), filtered and concentrated to dry. Chromatography on silica gel gave the title compound as a white foam in 81% yield. Mass spectrum: 381.2 (M-C4H802 + H) + 8-Fluoro-3- (piperidin-4-yl) quinolin-2 (1H) -one hydrochloride The tert-Butyl 4- (1- (3-fluoro-2-pivalamidophenyl) -1- hydroxy-3-methoxy-3-oxopropan-2-yl) piperidine-1-carboxylate (7.86 g, 16.4 mmol) was dissolved in methanol (20 ml). Water (45 ml) was added to the mixture followed by concentrated hydrochloric acid (15 ml, 183 mmol). The reaction was heated to reflux and maintained for 2.5 hours. The reaction mixture was concentrated in vacuo, redissolved in ethanol (50 ml), and concentrated in vacuo. The residue was crystallized from ethanol. The resulting solids were filtered, washed with cold ethanol, and dried in vacuo. The title compound was obtained as a white solid in 83% yield. 1 H NMR (500 MHz, DMSO ~ d 6): d 11.85 (s, ÍH), 8.98 (m, lH), 8.85 (m, ÍH), 7.75 (s, ÍH), 7.54 (d, J = '7.63, 1H ), 7.36 (dd, J = 10.22, 8.09, 1H), 7.21-7.11 (m, ÍH), 3.41-3.29 (m, 2H), 3.14-2.94 (, 3H), 2.02 (d, J = 13.43, 2H) ), 1.88-1.71 (m, 2H). Mass spectrum: 247.2 (MH) A N- (l-Benzylpiperiin-4-yl) -4-fluoro-2-nor trobenzamide In a furnace the flask charged with 4-fluoro-2-nitrobenzoic acid (7.87 g, 42.5 mmol), 1-hydroxybenzotriazole (6.32 g, '46.8 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (8.96 g) was dried. g, 46.7 mmol) and ethyl acetate (150 ml), followed by the rapid dropwise addition of triethylamine (11.8 ml, 84.7 mmol) at room temperature. The resulting white suspension was stirred for 3 hours. The reaction was evacuated in 1: 1 water / ethyl acetate (400 ml). After separation, the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layer was washed with brine (50 ml), dried over magnesium sulfate, and concentrated in vacuo to give a solid during standing overnight. The. Trituration and washing with ethyl acetate (2 x 6 mL) provided the title compound as a light yellow solid (9.87 g, 71% yield). ^? - NMR (CDC13, 400 MHz) d 7.74 (dd, J = 6.4, 2.0, 1H), 7.50 (dd, J = 6.8, 4.0, ÍH), 7.43-7.22 (m, 6H), 5.71 (d, J = 6.4, ÍH), 4.05-3.93 (m, ÍH), 3.50 (s, 2H), 2.85- 2.79 (m, 2H), 2.20-2.14 (m, 2H), 2.05-2.02 (m, 2H), 1. 58-1.49 (m, 2H). Mass spectrum: 358.49 (MH +). N- (2-amino-4-fluorobenzyl) -1-benzylpiperidin-4-amine To a solution of lithium aluminum hydride (4.01 g, 105.7 mmol) in anhydrous 1,4-dioxane (40 mL) at reflux • •; N- (1-benzylpiperidin-4-yl) -4-f-luoro-2- • nitrobenzamide (9.87 g, 30.2 mmol) in anhydrous 1,4-dioxane (125 mL) was added dropwise under nitrogen for 30 minutes. minutes The resulting mixture was refluxed for 3 hours under nitrogen. After cooling to room temperature, the reaction was carefully quenched with ice water (10 ml), sodium hydroxide A i (50% in water, 50 ml), and extracted with diethyl ether (2 x 500 ml). The combined organic layers were washed with brine (100 ml), dried over magnesium sulfate, and concentrated in vacuo to provide the title compound (8.64 g, 100% yield) as a yellow oil, which was sufficiently pure to be used in the next stage. XH-NMR (CD3OD, 400 MHz) d 7.52-7.40 (m, 5H), 7.28-7.18 (m, 1H), 6.53 (dd, J = 11.2, 2.4, lH), 6.48-6.38 (, 1H), 4.33 (s, 2H), 4.18 (s, 2H), 3.68-3.46 (m, 3H), 3.25-3.10 (m, 2H), • 2.50-2.42 (m, 2H), 2.16-1.93 (m, 2H). Spectrum 'of mass: ..., 314.21 (MH +). - 3- (l-Benzylpiperidin-4-yl) -7-f luoro-3,4-dihydroquinazolin- The 1,1 '-carbonyldiimidazole (6.92 g, 42.7 mmol) was added to a solution of N- (2-amino-4-fluorobenzyl) -l-benzylpiperidin-4-amine (8.64 g, 30.2 mmol) in dry tetrahydrofuran. (150 ml) at 0 ° C in one portion. After 5 minutes, the mixture was warmed to room temperature and stirred for 3 hours. The reaction was partitioned between water / diethyl ether (200 ml / 200 ml). After separation, the aqueous solution was extracted with diethyl ether (200 ml). The combined organic solution was washed with brine (100 ml), dried over magnesium sulfate, and concentrated in vacuo to give a light yellow solid which was triturated with diethyl ether (3 x 10 ml) to give the title compound as a white solid (3.41g, 36% yield). ""? -RMN (CDC13, 400 MHz) d 7.40-7.18 (, 5H), 6.92-6.82 (m, ÍH), 6.75 (dd, J = 8.2, 2.6, ÍH), 6.66 (dd, J = 8.8, 4.8, 1H), 4.48-4.34 (m, 1H), 4.03 (s, 2H), 3.53 (s, 2H), 2.98 (d, J = 11.2, 2H), 2.37-2.12 (m, 2H), 1.99-1.82 ( m, 2H), 1.67 (d, J = 11.2, 2H); Mass spectrum: 340.03 (MH +). 7 -. 7-Fluoro-3 - (piperidin-4-yl) -3,4-dihydroquinazolin-2 (1H) -one 3- (1-Benzylpiperidin-4-yl) -7-fluoro-3,4-dihydroquinazolin-2 (1H) -one (1.32 g, 3.89 mmol) was dissolved in ethanol (100 ml) at room temperature. Palladium (10% in charcoal, 130 mg) was added to this. The resulting mixture was stirred under a hydrogen balloon for 4 days. The reaction was filtered through a pad of celite, eluted with ethanol (50 ml), and concentrated in vacuo to provide a yellow residue. During the addition of diethyl ether (20 ml), a solid precipitated from the solution. Trituration and filtration with diethyl ether (2 x 5 ml) gave the title compound as a yellow solid (0.842 g, 87% yield). 1 H-NMR (CD 3 OD, 400 MHz) d 6.94-6.88 (m, 2 H), 6.78 (dd, J = 6.2, 4.0, H), 4.42 (s, 2 H), 4.41-4.35 (m, H), 3.53- 3.47 (m, 2H), 3.21-3.13 (m, 2H), 2.25-2.14 (m, 2H), 1.98-1.92 (m, 2H). Mass spectrum: 250.10 (MH +). Additionally, the following was also envisioned as compounds of the present invention (replanting) by the CGRP LINK TEST Cul tive of Tissue, SK-N-MC cells are grown at 372C in 5% C02 as a monolayer in a medium consisting of MEM with Earle salts and L-glutamine (Gibco) supplemented with bovine serum. fetal at 10% (Gibco). Cellular sediments Cells are rinsed 2 times with buffered saline phosphate solution (155 mM NaCl, 3.3 mM Na2HP0, 1.1 mM KH2P0, pH 7.4), and incubated for 5-10 minutes at 4fiC in proton and lysis buffer consisting of Tris. 10 mM (pH 7.4) and EDTA. 5 mM. The cells are transferred from the plates to polypropylene tubes (16 x 100 mm) and homogenized using a polytron. The homogenates are centrifuged at 32,000 x g for 30 minutes. The pellets are resuspended in cold hypotonic lysis buffer with a 0.1% mammalian protease inhibitor mixture (Sigma) and evaluated for protein concentration. The SK-N-MC homogenate is then processed in proportion to the stock and stored at -80 ° C until needed. Radioligand binding assays. The compounds of the invention are solubilized and carried through serial solutions using 100% DMSO. Serial aliquots of the compound are 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 50 μl) into 96-well assay plates. wells. [125I] -CGRP (Amersham Biosciences) is diluted to 60 pM in assay buffer and a volume of 50μl is added to each well. SK-N-MC sediments are thawed, diluted in assay buffer with fresh 0.1% mammalian protease inhibitor cocktail (Sigma) and re-homogenized. The homogenate SK-N-MC (5μg / well) is added in a volume of lOOμl. The test plates are then incubated at room temperature for 2 hours. The tests are stopped by the addition of buffer solution by excess cold washing (20 mM Tris-Cl pH 7.5, 0.1% BSA) immediately followed by filtration on glass fiber filters (Whatman GF / B) previously wetted in PEI 0.5% The non-specific binding is defined with 1 UM beta-CGRP. The radioactivity bound to the protein is determined using a gamma or scintillation counter. The IC 50 is defined as the concentration of the compound of the invention required to displace 50% of the bound radioligand. The human CGRP receptor links affinities for examples 1-15 where each is less than InM. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound according to the formula (I) or a pharmaceutically acceptable salt or solvate thereof characterized in that V is -NYR1) (R2) or OR4; R4 is H, C? _6 alkyl, C? _4 haloalkyl or (C? -4 alkylene) or -IR4 'R4' is C3_7 cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo [2.2.l] 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 substitutes selected from the group consisting of halo, cyano, C? _4alkyl, C? _4haloalkyl, C? _4alkoxy, hydroxyl, amino, C3_7cycloalkyl, C? _3alkylamino, C ? -3-alkylamino, (C? _3 alkyl) 0-halide, phenyl and benzyl; and R4 'optionally contains 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the ring structure R4'; R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, C6-6alkyl, C6alkenyl, C2_6alkynyl, Ci-b-alkylene-amino (C3-alkyl) 2, C3-7cycloalkyl, 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 substitutes selected from the group consisting of halo, cyano, C4-4alkyl, C? _haloalkyl, C? _alkoxy, hydroxyl, amino, C3_7cycloalkyl C3-alkylamino, C3-dialkylamino, (C3-3alkyl) 0-ureido, 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 La is optionally and independently interrupted from the nitrogen to which it is attached by L2, wherein L2 is independently C3_3alkylene or C3_3 alkylidene; or R1 and R2 together with the nitrogen to which they bind, form 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? _9alkyl, C2-o.alkenyl, C2-9alkynyl, C? _ alkylamino, C? _dialkylamino, C? _4alcoxy, C3_7cycloalkyl, phenyl, azetidinyl, furanyl , thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolidyl, 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? _ 3alkylene-, - C?-Alkylene-, -C? _3alkenylene-NHC (0) OC-3alkylene-; and optionally and independently substituted with 1 or 2 of the same or different substitutes selected from the group consisting of halo, C? -alkyl, amino, C? _3alkylamino, -C? -6alkylene-amino (C? _3alkyl) 2, ( C? _ 3 alkyl) or-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 carry a carbon atom and together they form a spirocyclic portion; Q is Q 'or Q ", where Q' is (Sy) sR3; and Q" is NH (SY) SR3, NHC (O) (S?) SRA NHC (O) O (S?) SR3, NHC ( 0) NH (S?) SR3, 0 (S?) SR3, (SY) SNHR3, (S?) SNHC (O) R3, (S?) SNHC (0) OR3, (S?) SNHC (0) NHR3 or (S?) sOR3; where S? is C? _3-alkylene or C? -3-alkylidene and s is 0 or 1; R3 is R3a or R3b wherein R3a is (vi) a heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle containing from one to five of the same or different heteroatoms selected from the group consisting of of 0, N and S and the heterocycle optionally contain 1 or 2 carbonyls wherein the carbonyl carbon atom is a member of the fused rings; (vii) a 4 to 6 member heterocycle containing 1 to 3 identical 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 4 to 6 heterocycle members; (viii) C3_7cycloalkyl; (ix) carbazolyl, fluorenyl, phenyl, -0-phenyl, -0-C? 4-alkylene-phenyl, or naphthyl; or (x) C? -8alkyl, C2_7alkenyl, -C (0) R3 ', CHC (0) 0 -R3', CH (CH3) C (0) 0 -R3 ', -C (0) 0 -R3' or C2_7alquinil ?; and wherein R3 is optionally substituted with 1 to 3 of the same or different substitutes selected from the group consisting of benzyl, phenyl, -O-phenyl, -0-C? _ 3-alkylene phenyl, -C? _3 alkylene-0C (0) - phenyl, cyano, amino, nitro, halo, C? _6alkyl, C? _3mono-bi-tri-haloalkyl, C? _3mono-bi-tri-haloalkyloxy, (C? -alkyl)? _2amine, -OR3 ', -C ( 0) R3 ', -C (0) 0 -R3', -0-C (0) R3 ', -N (R3') 2, -C (O) N (R3 ') 2, -N (R3' ) C (0) (R3 ') 2, AN (R3') C (0) N (R3 ') 2, -N (R3') C (0) OR3 ', -0-C (O) N (R3 ') 2, -N (R3') S02R3 ', -S02N (R3') 2 and -S02R3 '; R3 'is H or -C? _6alkyl; 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) OR3 'or -C (0) 0 -R3' are unsubstituted; R3 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, l-formyl-lH-indol-3-yl, 1- (1,1-dimethylethoxycarbonyl) -lH-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, lH-indazol-3-yl, l-methyl-lH-indazol-3-yl, benzo [b] fur-3-yl, benzo [b] thien-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, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl groups , carboxyalkyl, alkoxycarbonyl, carboxyl, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxyl, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, ethylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy , trifluoromethylthio, trifluoromethylsulfinyl trifluoromethylsulfonyl; wherein the substitutes may be the same or different and the groups mentioned above benzoyl, benzoylamino and benzoylmethylamino can be further substituted again in the phenyl portion by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino; D is 0, NCN or NS02C? -3alkyl ?; A is C, N, CH or COH; 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 A ?; Ax is a fused heterocycle having two rings fused with 5 to 7 members in each of the rings, the heterocycle contains from 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; TO? is a 4- to 6-membered heterocycle containing one to three heteroatoms selected from the group consisting of O, N and S; and optionally contains 1 to 2 carbonyls, wherein the carbonyl carbon atom is a member of the 4 to 6 membered heterocycle; where Ax and A? they are optionally substituted with C? _alkyl, C? _4alkoxy, C? _4haloalkyl, cyano, C3_7cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or if p is 0 such that G and J are each 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 are GJA 'or GJA'1; where GJA 'is Ax or A ?; and GJA "is A or A ?, with the proviso that A is not a 1,3-diaza- fused heterocycle, and Ay is not a 1,3-diaza- heterocycle, and also with the proviso that if Q is Q ", then R3 is R3; and if Q is Q ', then R3 is R3b; or R3 is R3a, p is O and G, J and A together form GJA. "2. The compound according to claim 1, characterized in that Q is Q 'and R3 is R3b 3. The compound according to claim 1, characterized in that Q is Q ', R3 is R3a and p is 0 such that G, J and together form GJA ". 4. The compound according to claim 1, characterized in that Q is Q 'and Q' is (SY) SR3 and s is 0. 5. The compound according to claim 1, characterized in that Q is Q 'and Q' is (SY) SR3, S? is C3-alkylene and s is 1. The compound according to claim 1, characterized in that Q is Q 'and Q' is (Sy) sR3, Sy is methylene and s is 1. 7. The compound according to claim 1, characterized in that V is N (R1) (R2) and wherein R1 and R2 together with the nitrogen to which they bind form X, wherein X is piperidinyl, piperazinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, phenyl, pyridyl, piperazinyl, piperidinyl or C? _4alkyl; and wherein X and Y optionally share a carbon atom and together form a spirocyclic moiety. 8. The compound according to claim 1, characterized in that V is -NIR1) (R2) and wherein R1 and R2 together with the nitrogen to which they bind form X, wherein X is piperidinyl, piperazinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, phenyl, pyridyl, piperazinyl, piperidinyl or C? _4alkyl. 9. The compound according to claim 1, characterized in that X and Y are not interrupted with Z. The compound according to claim 1, characterized in that R3 is R3a and R3a is phenyl, hydroxyphenyl-o, azetidinyl, naphthyl. , Cl-6alquilo, C2- 6alquenilo, C2-6alkynyl, dihidroquinolinonilo, hidroquinolinonilo, quinolinyl, dihidroisoquinolinonilo, hidroisoquinolinonilo, isoquinolinyl, dihidroquinazolinonilo, hidroquinazolinonilo, quinazolinyl, dihidroquinoxalinonilo, hidroquinoxalinonilo, quinoxalinyl, benzimidazolyl, indazolyl, dihidrobencimidazolonilo, hidrobencimidazolonilo, benzimidazolinyl, dihydro-benzothiazolonyl , hydrobenzothiazolonyl, benzothiazolyl, dihydrobenzoxazolyl, benzotriazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, benzothienyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzofuranyl, benzodioxolanyl, dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, pyrazolyl, pyrazole inyl, 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. The compound according to claim 1, characterized in that R3 is R3 and R3b is dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydrobenzothiazolonyl, hydrobenzothiazolonyl, benzothiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, lH-indazol-5-yl, benzodioxolanyl, dihydrobenzoxazolyl , benzotriazolyl, dihydroindolonyl, hydroindolonyl, 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. 12. The compound according to claim 1, characterized in that m and n are each 1. The compound according to claim 1, characterized in that D is O. 14. The compound according to claim 1, characterized in that p is 0 such that G and J are each linked to 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 attached form selected from the group heterocycle consisting imidazolinonilo, imidazolidinonyl, dihidroisoquinolinonilo, dihidroquinolinonilo, dihidroquinoxalinonilo, dihidrobenzoxazonilo, hidrobenzoxazinilo, dihidrobenzoxazinonilo, dihidrobencimidazolonilo, dihydrobenzimidazolyl, dihydro-benzothiazolonyl, dihydrobenzothiazolyl, dihidrobenzotiofenonilo, dihidrobenzofuranonilo, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl , imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl. 15. 4- (1, 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxylate of 3- (7-methyl-lH-indazol-5-yl) -loxo-1- (4 -piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4- (2-Oxo-l, 2-dihydroquinazolin-3 (4H) -yl) piperidin-1-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo- 1- (4-piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4- (8-fluoro-2-oxo-l, 2-dihydroquinazolin-3 (4H) -piperidin-1-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1- oxo-l- (4-piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4- (2-Oxo-l, 2-dihydroquinazolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- ( 4-piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4- (2-Oxo-4-phenyl-2,3-dihydroimidazol-1-yl) piperidine-1-carboxylate of (R) -3- (7-methyl-1H-indazol-5-yl) -1-oxo -l- (4-piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4-hydroxy-4- (2-oxo-1,2-dihydroquinazolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-methyl-1 H -indazol-5-yl) -1-oxo -l- (4-piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4- (7-Fluoro-2-oxo-l, 2-dihydroquinolin-3 (4-H) -yl) piperidin-1-carboxylate of (R) -3- (7-methyl-1H-indazol-5-yl) ) -1-oxo-l- (4-piperidin-1-yl) piperidin-1-yl) propan-2-yl; 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) -piperidine-1-carboxylate of (R) -1- (4- (5,6-Dihydropyridinyl (2H) -yl) piperidin-1 -yl) -3- (7-methyl-lH-indazol-5-yl) -1-oxopropan-2-yl; 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- ( 9-methyl-3, 9-diaza-spiro [55] undecan-3-yl) propan-2-yl; 4- (2-Oxo-1,2-dihydroquinolin-3-yl) piperidine-l-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- ( piperidin-1-yl) propan-2-yl; 4- (2-oxo-l, 2-dihydroquinoline-3-yl) piperidine-l-carboxylate (R) -1- (4-Cyclohexylpiperazin-l-yl) -3- (7-methyl-lH-indazole 5-yl) -l-oxopropan-2-yl; 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (R) -l- (4- (4-Fluorophenyl) piperazin-1-yl) 3- (7-methyl- lH-indazol-5-yl) -1-oxopropan-2-yl; 4- (2-Oxo-l, 2-dihydroquinolin-3-yl) piperidine-1-carboxylate of (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- ( 4-piperidin-4-yl) piperazin-1-yl) propan-2-yl; 4- (2-oxo-l, 2-dihydroquinolin-3-yl) piperidin-1-carboxylate of (+) - 3- (7-methyl-lH-indazol-5-yl) l-oxo-l- (4 - (piperidin-l-yl) piperidin-l-yl) propan-2-yl or 4- (8-fluoro-2-oxo-l, 2-dihydroquinoline-3-yl) piperidine-l-carboxylate (R) -3- (7-methyl-lH-indazol-5-yl) -1-oxo-l- (4-piperidin-1-yl) piperidin-1-yl) propan-2-yl or salts or solvates characterized in that they are pharmaceutically acceptable thereof. 16. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1. 17. A method for the treatment of migraine, characterized in that it comprises the administration to a mammal in need thereof of an effective amount of anti-migraine. a pharmaceutical composition according to claim 16.