KR20060125832A - Calcitonin Gene Related Peptide Receptor Antagonists - Google Patents

Abstract

The present invention provides a compound of formula (I) as a calcitonin gene-related peptide receptor ("CGRP-receptor"), pharmaceutical compositions comprising the same, methods of identifying the same, methods of treatment using the same, and neurovascular vasodilation, neurological inflammation, migraine And airway inflammatory diseases such as other headaches, febrile injuries, cyclic shock, menopause related flushing, asthma and chronic obstructive pulmonary disease (COPD), and other conditions of therapy that may be antagonistic by CGRP receptors. It is about a use.

Description

Calcitonin Gene Related Peptide Receptor Antagonist {CALCITONIN GENE RELATED PEPTIDE RECEPTOR ANTAGONISTS}

The present invention relates to novel small molecule antagonists of calcitonin gene-related peptide receptors (“CGRP-receptors”), pharmaceutical compositions comprising them, methods of identifying them, methods of treatment using them, and neurovascular vasodilation, neurological inflammation, migraine, clustered These in the treatment of headaches and other headaches, febrile injuries, cyclic shock, menopause related flushing, asthma and airway inflammatory diseases such as chronic obstructive pulmonary disease (COPD), and other conditions that may be antagonized by CGRP receptors It relates to the use of.

Calcitonin gene-related peptide (CGRP) is a naturally occurring 37-amino acid peptide, first identified in 1982 (Amara, SG et al, Science 1982, 298, 240-244). Two forms of this peptide (αCGRP and βCGRP) are found, which differ in one and three amino acids respectively in rats and humans. This peptide is widely distributed in both the peripheral nervous system (PNS) and the central nervous system (CNS), and is located mainly in sensory afferent and central neurons, and exhibits many biological actions including vasodilation.

When released from cells, CGRP binds to specific cell surface G protein-coupled receptors and exhibits its biological action mainly by 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, CGRP ₁ and CGRP ₂ , have been proposed based on the antagonist properties of peptide fragment CGRP (8-37) and the ability to activate the CGRP ₂ receptor of linear analogs of CGRP (Juaneda, C. et al.TiPS 2000, 21, 432-438]. However, there is a lack of molecular evidence for the CGRP ₂ receptor (Brain, SD et al, TiPS). 2002, 23, 51-53). The CGRP ₁ receptor has three components: (i) seven transmembrane calcitonin receptor-like receptors (CRLR); (ii) single transmembrane receptor active modified protein type 1 (RAMP1); And (iii) intracellular receptor component protein (RCP) (Evans BN et al., J Biol Chem . 2000, 275, 31438-43).

RAMP1 transports CRLR to the plasma membrane and is required for ligands to bind to CGRP-receptors (McLatchie, LM et al, Nature 1998, 393, 333-339). RCP is required for signal transduction (Evans BN et al., J Biol Chem . 2000, 275, 31438-43). Species-specific differences are known that small molecule antagonists, which are seen in the antagonism of human receptors than in other species, typically bind with a higher affinity in binding to CGRP-receptors (Brain, SD et al, TiPS 2002). , 23, 51-53). The amino acid sequence of RAMP1 determines species selectivity, in particular the amino acid residue Trp74 determines the phenotype of the human receptor (Mallee et al. J Biol) . Chem 2002, 277, 14294-8].

Inhibitors at the receptor level for CGRP are considered useful in pathophysiological conditions in which the CGRP receptor is over activated. Examples of these include neurovascular dilatation, nervous inflammation, migraine, cluster headache and other headaches, febrile injuries, cyclic shock, menopausal flushing and asthma. CGRP receptor activation has been implicated as a pathogenesis of migraine (Edvinsson L. CNS Drugs 2001; 15 (10): 745-53; Williamson, DJ Microsc . Res. Tech . 2001, 53, 167-178; Grant, AD Brit . J. Pharmacol . 2002, 135, 356-362]. Serum levels of CGRP are elevated during migraine (Goadsby PJ, et al. Ann Neurol 1990; 28: 183-7), and treatment with anti-migraine medications restores CGRP to normal levels at the same time as headache relief. Gallai V. et al. Cephalalgia 1995; 15: 384-90]. Migraine patients show elevated baseline CGRP levels compared to controls (Ashina M, et al., Pain. 2000; 86 (1-2): 133-8). Intravenous CGRP injection causes persistent headache in migraine patients (Lassen LH, et al. Cephalalgia . 2002 Feb; 2 ((1): 54-61)). Preclinical studies in dogs and rats show that peptide antagonist CGRP It has been reported that blocking systemic CGRP with (8-37) does not alter resting systemic hemodynamics and local blood flow (Shen, YT. Et al, J Pharmacol Exp Ther 2001, 298, 551-8]. Thus, CGRP-receptor antagonists are novel to treat migraines without the tendency of active vasoconstriction of the cardiovascular system associated with the non-selective 5-HT _{1B / 1D} antagonist 'triptan' (e.g. sumatriptan). Treatment may be provided.

A number of in vivo migraine models are known in the literature (see De Vries, P. et al, Eur J Pharmacol 1999, 375, 61-74). Some documents have electrically stimulated the trigeminal ganglion to measure the expansion of intracranial vessels in which nerves are distributed by the trigeminal ganglion (see, eg, Williamson et al. Cephalalgia 1997 17: 518-24). Reference). Because the facial arteries also distributed nerves by trigeminal ganglia, other model studies have altered facial blood flow induced by electrical trigeminal activation (see, for example, Escott et al. Brain) . Res 1995 669: 93). Alternatively, other peripheral nerves (eg, saphenous nerves) and vascular beds (eg, abdominal blood flow) have also been studied (eg, Escott et al. Br J Pharmacol). 1993 110, 772-6). All models were shown to be blocked upon pretreatment with the peptide antagonist CGPR (8-37), the peptide fragment without the first seven residues, or blocked by the small molecule CGRP-receptor antagonist. In some instances exogenous CGRP was used as a stimulant. However, all of these models are invasive end processes, and none of them show a clinically significant disruptive effect of using post-treatment of CGRP-receptor antagonists to increase blood flow or restore established increases in arterial dilatation. Did. Williamson et al. Cephalalgia 1997 17: 518-24 and Williamson et al. Cephalalgia 1997 17: 525-31, using a terminal 'in vivo' procedure in which the skull is drilled and thinned, especially in anesthetized rats with sodium pentobarb, forming a closed cranial window to view the dural artery. Intravenous CGRP was used as a stimulant to increase intracranial dural artery diameter. This effect was blocked by pretreatment with intravenous CGRP (8-37). Escott et al. Brain Res 1995 669: 93], in particular, drills the skull of rats, electrically stimulates the trigeminal ganglia with brain electrodes, and lasers in the distal process of sodium pentobar anesthesia rats with neuromuscular blockage, tracheal intubation and resuscitation. Doppler facial blood flow was measured. This effect was blocked by pretreatment with CGRP (8-37). Escott et al. Br J Pharmacol 1993 110, 772-6] increased blood flow in the abdominal skin of rats of sodium pentobarb anesthetized animals with cannula in the jugular vein for anesthesia and drug delivery, especially using intradermal (id) CGRP as a stimulant. I was. This effect was blocked by pretreatment with intravenous CGRP (8-37). Chu et al. Neurosci Lett 2001 310, 169-72] used an intradermal CGRP as an irritant in rats, especially in rats, using an anesthetized with sodium pentobarb and a cannula plugged into the trachea for laser Doppler changes in the back blood flow of the dorsal skin. Measurements indicated that sustained CGRP (8-37) release from subcutaneous (sc) implanted osmotic pumps was blocked by pretreatment. Hall et al Br J Pharmacol 1995 114, 592-7 and Hall et al Br J Pharmacol 1999 126, 280-4 use topical CGRP, in particular, to increase hamster ball sac small arterial diameter and to reduce intradermal CGRP. Blood flow was increased in the skin, such as rats of sodium pentobarb anesthetized animals that were cannulated in the jugular vein for anesthesia and drug delivery. This effect was blocked by pretreatment with intravenous CGRP (8-37). Dodds et al. Br J Pharmacol . 2000 Feb; 129 (3): 420-3], in particular, drills the skulls of marmosets (New World monkeys) and uses electrical electrodes to generate electrical stimulation of the trigeminal ganglia, anesthesia of primates anesthetized with sodium pentobarbital. Facial blood flow was measured during the incidence of infiltration with obstruction and resuscitation. Increased blood flow was blocked by pretreatment of small molecule CGRP antagonists. See also WO03 / 272252 (Isolated DNA Molecules Encoding Humanized Calcitonin Gene-Related Peptide Receptor, Related Non-Human Transgenic Animals and Assay Methods). Thus, a non-invasive survival model of primates, particularly measuring exogenous CGRP-induced changes in facial blood flow, pre-treatment and post-treatment of peptides and small molecule CGRP antagonists in spontaneous respiratory marmosets anesthetized with isoflurane The method according to the procedure of the present invention, which demonstrates the treatment effect, provides a significant advantage.

Many non-peptide small molecule CGRP-receptor antagonists are currently reported. WO97 / 09046 and equivalent publications disclose quinine and quinidine related compounds, in particular ligands (particularly antagonists) of CGRP receptors. WO98 / 09630, WO98 / 56779 and equivalent publications particularly disclose various substituted nitrobenzamide compounds as CGRP-receptor antagonists. WO01 / 32649, WO01 / 49676, WO01 / 32648 and equivalent publications disclose a series of 4-oxobutanamides and related cyclopropane derivatives, in particular as CGRP-receptor antagonists. WO00 / 18764, WO98 / 11128, WO00 / 55154 and equivalent publications disclose benzimidazolinyl piperidine, in particular as antagonists for CGRP-receptors. Regardless of CGRP, a series of somatostatin antagonists are disclosed in WO99 / 52875, WO01 / 25228 and equivalents. See also US Pat. Nos. 6,344,449, 6,313,097, 6,521,609, 6,552,043, US20030181462, US20030191068, and WO03 / 076432, and related applications. Thus, novel CGRP-receptor antagonists effective in the treatment of neurological inflammation, migraine and other disorders can have great benefits.

Summary of the Invention

Accordingly, according to a first embodiment of the first aspect of the invention there is provided a compound of formula (I) and pharmaceutically acceptable salts and solvates thereof.

Where

V is —N (R ¹ ) (R ² ) or OR ⁴ ;

R ⁴ is H, C _{1 -} a _{- (4} alkylene C _{1) 0-1} R ^{4 ',} where _{- 6} alkyl, C _{1 4} haloalkyl or

R ^{4 'is} C _{3 - 7} cycloalkyl, phenyl, adamantyl, pyridyl quinuclidine, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydro Hydrothienyl, 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, thiomorpholi and no or a carbonyl dioxide solar, R ^{4 'is} halo, cyano, C _{1 - 4} alkyl, C _1-4 haloalkyl, C _{1 - 4} alkoxy, hydroxy, amino, C _{3 - 7} cycloalkyl, C _{1 - 3} alkylamino, C _{1 - 3} dialkylamino, (C _{1 - 3} alkyl) _0-2 ureido, one or two same or selected from the group consisting of phenyl and benzyl Or optionally substituted with a different substituent, R ^{4 ′} optionally contains one or two carbonyls of which the carbon atom is a member of the ring structure of R ^{4 ′} ,

R ¹ and R ² and L ^1, each independently, L ¹ is H, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _2-6 alkynyl, -C _1-6 alkylene-amino (C _{1 -3} alkyl) _2, C _{3 - 7} cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydro thienyl, pyrrolyl, pyrrolinyl, Pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl And triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl , R ¹ and R ² is halo, cyano, C _{1 - 4} alkyl, C _{1 - 4} haloalkyl, C _{1 - 4} alkoxy, hydroxy, amino, C _{3 - 7} cycloalkyl, C _{1 - 3} alkyl, C _{1 - 3} D. Kill amino, (C _{1 - 3} alkyl) _0-2 ureido, each of which is optionally substituted, and independently, R ¹ and R ² are carbon with 1 or 2 same or different substituents selected from the group consisting of phenyl and benzyl containing 1 that are members of a heterocycle including the atoms R ¹ and R ² or two carbonyl optionally and independently, wherein L ¹ is interposed is a nitrogen that is attached by L ² optionally and independently, L ² independently are C _{1 - 3} alkylene or C _{1 - 3} alkyl, or fluoride, or

R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyra Zolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino, wherein X is optionally substituted with Y, Y is dioxolanyl, C _1-9 alkyl, C _2-9 alkenyl, C _2-9 alkynyl, C _{1 - 4} alkylamino, C _{1- 4} dialkylamino, C _{1 - 4} alkoxy, C _{3 - 7} cycloalkyl, phenyl, azetidinyl, furanyl , Thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl , Azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazoloyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or O-morpholino, where X and Y is Z is optionally interposed, Z is -NHC (O) O-, -NHC ( O) NH-, NC (O) NH 2, -NH-, -C 1 - ₃ alkylene-, -C _{1 - 3} alkylene-, -C _{1 - 3} alkenylene group -NHC (O) OC _1-3 alkylene-a, X and Y is C _{1 - 4} alkyl, amino, C _{1 - 3-amino-alkyl,} -C _{1 - 6} alkylene-amino (C _1-3 alkyl) _2, (C _{1 - 3} alkyl) _0-2 ureido, 1 is selected from the group consisting of phenyl, benzyl or 2 Optionally and independently substituted with the same or different substituents, X and Y optionally and independently containing one or two carbonyls which are members of a heterocycle comprising carbon atoms X and Y, provided that X is Y Substituted and without Z intervening in X and Y, X and Y optionally share one carbon atom and together form a spirocyclic moiety);

Q is Q 'or Q ", where

Q 'is (S ^y ) _s R ³ ;

Q "is NH (S ^y ) _s R ³ , NHC (O) (S ^y ) _s R ³ , NHC (O) O (S ^y ) _s R ³ , NHC (O) NH (S ^y ) _s R ³ , O (S ^y ) _s R ³ , (S ^y ) _s NHR ³ , (S ^y ) _s NHC (O) R ³ , (S ^y ) _s NHC (O) OR ³ , (S ^y ) _s NHC (O) NHR ³ or (S ^y ) _s OR ³ , where

S ^y is C _{1 - 3} alkylene or C _{1 - 3} alkyl vinylidene and s is 0 or 1;

U is CH ₂ or NH, provided that when CH is Q ″ U is CH ₂ ;

R ³ is R ^3a or R ^3b , wherein

R ^3a is

(i) each containing one to five identical or different heteroatoms selected from the group consisting of O, N and S, each optionally containing one or two carbonyls whose carbon atoms are members of the fused ring; A heterocycle having two to seven membered fused rings, or

(ii) contains one to three identical or different heteroatoms selected from the group consisting of O, N and S, and optionally contains one to two carbonyls whose carbon atoms are members of a four to six membered heterocycle; 4 to 6 membered heterocycle

(iii) C _{3 - 7} cycloalkyl, or,

(iv) carbazolyl, fluorenyl, phenyl, -O- phenyl, -OC _{1 - 4} alkylene-phenyl or naphthyl, or is

(v) C _{1 - 8} alkyl, C _{2 - 7} ^{alkenylene, -C (O) R 3 '} , CHC (O) OR 3', CH (CH 3) C (O) OR 3 ', -C (O ) oR ^{3 ',} or C _{2 - 7,} and alkynyl, wherein

R ^3a is benzyl, phenyl, -O- phenyl, -OC _{1 - 3} alkylene-phenyl, -C _{1 - 3} alkylene group -OC (O) - phenyl, cyano, amino, nitro, halo, C _{1 - 6} alkyl , C _{1 - 3} mono- non-tri-haloalkyl, C _{1 - 3} mono- non-tri-halo-alkyloxyalkyl, (C _{1 - 3} alkyl) _1-2 ^{amine, -OR 3 ', -C (O} ) R ^{3 '} , -C (O) OR ^3' , -OC (O) R ^{3 '} , -N (R ^3' ) ₂ , -C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) OR ^{3 '} , -O- C 1 to 1 selected from the group consisting of (O) N (R ^{3 ′} ) ₂ , —N (R ^{3 ′} ) SO ₂ R ^{3 ′} , —SO ₂ N (R ^{3 ′} ) _2, and —SO ₂ R ^{3 ′} . is optionally substituted with three identical or different substituents, R ^{3 'is} H or -C _{1 - 6} alkyl (where, R ^3a is ^{-C (O) R 3',} CHC (O) oR 3 ', CH (CH ₃ ) When C (O) OR ^{3 '} or -C (O) OR ^3' , -C (O) R ^{3 '} , CHC (O) OR ^3' , CH (CH ₃ ) C (O) OR ^{3 '} Or -C (O) OR ^3' is not substituted);

R ^3b is R ^3a but is phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indole -3-yl, 1-formyl-1H-indol-3-yl, 1- (1,1-dimethylethoxycarbonyl) -1H-indol-3-yl, 4-imidazolyl, 1-methyl- 4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo [b] fur-3-yl , Benzo [b] thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; Fluorine, chlorine or bromine atom, or a branched or unbranched alkyl, C _{3 -8} - cycloalkyl group, a phenyl group, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxy Carbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbons Carbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl- or trifluoromethyl Optionally substituted at the mono-, di-, or tri-substituted carbon skeleton with sulfonyl groups, wherein the substituents may be the same or different and are mentioned above One trillion days, benzoylamino-and-benzoyl-methyl-amino group may also additionally can be substituted in the phenyl moiety by fluorine, chlorine or bromine atom, or an alkyl, methyl, amino or acetylamino group trifluoromethyl;

D is O, NCN, or NSO ₂ C _{1 - 3} alkyl;

A is C, N or CH;

m and n are independently 0, 1 or 2, provided that when m and n are 0, A is not N; when m is 2, n is not 2; and when n is 2, m is 2 Not);

E is N, CH or C;

p is 0 or 1,

when p is 1, G, J and E together form A ^X or A ^Y , wherein

A ^X contains 1 to 4 identical or different heteroatoms selected from the group consisting of O, N and S, each optionally containing 1 or 2 carbonyls whose carbon atoms are members of fused heterocycles; Heterocycle having two to seven membered fused rings,

A ^Y contains 1 to 3 heteroatoms selected from the group consisting of O, N and S, and 4 membered optionally containing 1 to 2 carbonyls whose carbon atoms are members of 4 to 6 membered heterocycles To 6 membered heterocycle, wherein

A ^X and A ^Y are C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _{1 - 4} haloalkyl, cyano, C _{3 - 7} cycloalkyl, phenyl, halophenyl, halo, furanyl, pyrrolyl, pyrrolidinyl Optionally with Neyl, Pyrrolidinyl, Imidazolyl, Imidazolinyl, Imidazolidinyl, Pyrazolyl, Pyrazolinyl, Pyrazolidinyl, Pyridyl, Pyrimidinyl, Piperidinyl, Piperazinyl or Morpholino Substituted; or

When p is 0 and G and J are each attached to A, then A is C, and G, J and A together form a spirocyclic ring system containing A, where G, J and A together GJA ' Or GJA ", GJA 'is A ^X or A ^Y and GJA" is A ^X or A ^Y , provided that A ^X is not a 1,3-diaza-fused heterocycle, and A ^Y is 1,3- Not diaza-heterocycle);

In addition, when Q is Q ", R ³ is R ^3a ; when Q is Q ', R ³ is R ^3b ; R ³ is R ^3a , p is 0 and G, J and A together GJA" To form.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q 'and R ³ is R ^3b .

According to another embodiment of the first aspect of the invention the first aspect of the first aspect of the invention wherein Q is Q ', R ³ is R ^3a and p is 0 such that G, J and A together form GJA ". There is provided a compound according to an embodiment.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein Q is Q ', Q' is (S ^y ) _s R ³ and s is 0. to provide.

'Is, Q, Q, Q, according to another embodiment of the first aspect of the present invention is _(S ^y) _s R ³ a, S ^y is C _{1 - 3} alkylene, s is 1, claim 1 of the present invention; There is provided a compound according to the first embodiment.

'It is, Q, Q, Q, according to another embodiment of the first aspect of the present invention is _(S ^y) _s R ³ a, S ^y is C _{1 - 3} alkyl vinylidene and, s is 1, claim 1 of the present invention; There is provided a compound according to the first embodiment.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q 'and U is CH ₂ .

According to another embodiment of the first aspect of the invention, the first embodiment of the first aspect of the invention, wherein Q is Q ', Q' is (S ^y ) _s R ³ , s is 0 and U is CH ₂ It provides a compound according to the embodiment.

'Is, Q, Q, Q, according to another embodiment of the first aspect of the present invention is (S ^y) _s R ³ a, S ^y is C _{1 - 3} alkylene, s is 1, U is CH ₂ There is provided a compound according to the first embodiment of the first aspect of the invention.

'Is, Q, Q, Q, according to another embodiment of the first aspect of the present invention is (S ^y) _s R ^3-a, S ^y is C _{1 -} and vinylidene ₃ alkyl, s is 1, U is CH ₂ There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q 'and U is NH.

According to another embodiment of the first aspect of the invention, the first embodiment of the first aspect of the invention wherein Q is Q ', Q' is (S ^y ) _s R ³ , s is 0 and U is NH It provides a compound according to.

'Is, Q, Q, Q, according to another embodiment of the first aspect of the invention is the (S ^y) _s R ^3, S ^y is C _{1 -} and _3-alkylene, wherein s is 1, and U is NH There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the present invention it is' a, Q, Q, Q is (S ^y) _s R ^3, S ^y is C _{1 -} and _{3-alkylidene,} and s is 1, and U is NH There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q ″.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q ″ and Q ″ is NH (S ^y ) _s R ³ .

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q ″, Q ″ is NH (S ^y ) _s R ³ , and s is 0. to provide.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is NH _(S ^y) _s R ³ a, S ^y is C _{1 - 3} alkylene, s is 1, of the invention There is provided a compound according to one aspect of the first embodiment.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is NH (S ^y) _s R ^3-a, S ^y is C _{1 -} and vinylidene ₃ alkyl, s is 1, of the invention There is provided a compound according to one aspect of the first embodiment.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q ″ and Q ″ is NHC (O) (S ^y ) _s R ³ . .

According to another embodiment of the first aspect of the invention, in the first embodiment of the first aspect of the invention, wherein Q is Q ″, Q ″ is NHC (O) (S ^y ) _s R ³ , and s is 0 To provide a compound according to the invention.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is ^{NHC (O) (S y)} s R 3 a, S ^y is C _{1 - 3} alkylene, s is 1, the There is provided a compound according to the first embodiment of the first aspect of the invention.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is ^{NHC (O) (S y)} s R 3 a, S ^y is C _{1 -} and vinylidene ₃ alkyl, s is 1, the There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q ″ and Q ″ is NHC (O) O (S ^y ) _s R ³ . do.

According to another embodiment of the first aspect of the invention, the first embodiment of the first aspect of the invention wherein Q is Q ″, Q ″ is NHC (O) O (S ^y ) _s R ³ , and s is 0 It provides a compound according to.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is an ^{NHC (O) O (S y} ) s R 3, S y is C _{1 - 3} alkylene, s is 1, There is provided a compound according to the first embodiment of the first aspect of the invention.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is a ^{NHC (O) O (S y} ) s R 3, S y is C _{1 - 3} alkyl vinylidene and, s is 1, There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein Q is Q ″ and Q ″ is NHC (O) NH (S ^y ) _s R ³ . do.

According to another embodiment of the first aspect of the invention, the first embodiment of the first aspect of the invention wherein Q is Q ″, Q ″ is NHC (O) NH (S ^y ) _s R ³ , and s is 0 It provides a compound according to.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is ^{NHC (O) NH (S y} ) s R 3 a, S ^y is C _{1 - 3} alkylene, s is 1, There is provided a compound according to the first embodiment of the first aspect of the invention.

Q is Q, according to another embodiment of the first aspect of the invention ", and, Q" is a ^{NHC (O) NH (S y} ) s R 3, S y is C _{1 - 3} alkyl vinylidene and, s is 1, There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein V is OR ⁴ .

According to another embodiment of the first aspect of the present invention wherein V is OR ^4, R ⁴ is C _{1 -} to provide a compound according to the first embodiment of the first aspect of the present invention ₆ alkyl.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein V is —N (R ¹ ) (R ² ).

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein the substituents are as follows:

V is -N (R ¹ ) (R ² ) or OR ⁴ ,

R ⁴ is H, C _{1 - 6} alkyl, C _{1 - 4} haloalkyl, _- and (C _{1 4} alkylene) _0-1 R ^{4 ',} wherein

R ^{4 'is} C _{3 - 7} cycloalkyl, phenyl, adamantyl, pyridyl quinuclidine, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydro Hydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, oxadizolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholi and no or a carbonyl dioxide solar, R ^{4 'is} halo, cyano, C _{1 - 4} alkyl, C _{1 - 4} haloalkyl, C _{1 - 4} alkoxy, hydroxy, amino, C _{3 - 7} cycloalkyl, C _{1 - 3} alkylamino, C _{1 - 3} dialkylamino amino furnace, (C _{1 - 3} alkyl) _0-2 ureido, one or two same is selected from the group consisting of phenyl and benzyl Or is optionally substituted with different substituents, R ^{4 'is} R ⁴ of the carbonyl carbon ^atom, and containing a member of one or two carbonyl of the ring structure of optionally,

R^One And R²Are each independently L^OneAnd L^OneThis H, C_{One - 6}Alkyl, -C_1-6Alkylene-amino (C_1-3Alkyl)₂, C_3-7Cycloalkyl, phenyl, adamantyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imida Zolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, Selected from the group consisting of pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl, R^One And R²Are halo, cyano and c, respectively_{One - 4}Alkyl, C_{One - 4}Haloalkyl, C_1-4Alkoxy, hydroxy, amino, C_{3 - 7}Cycloalkyl, C_{One - 3}Alkylamino, C_{One - 3}Dialkylamino, (C_{One - 3}Alkyl)_{0- 2}Ureido, phenyl and benzyl, optionally and independently substituted with one or two identical or different substituents selected from the group consisting of R,^One And R²Valence carbon valence R^One And R²Optionally and independently contains one or two carbonyls which are members of a heterocycle comprising^OneL²Nitrogen intervenes optionally by (L²C_{One - 3}Alkylene), or

R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, Oh Jaffe carbonyl, diazepinyl carbonyl, blood is piperazinyl, piperidinyl, morpholino or thio-morpholino, in which X is optionally substituted by Y, Y is dioxolanyl, C _{1 - 4} alkyl, C _{1- 4} alkylamino, C _1-4 dialkylamino, C _1-4 alkoxy, C _{3 - 7} cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidino carbonyl, imidazolyl , Imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azefinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazoloyl , Piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino, wherein Z and Y are optionally Re is, Z is an optionally -NHC (O) O-, -NHC ( O) NH-, NC (O) NH 2, -NH-, -C 1-3 alkylene-, -C _{1 - 3} alkylene- NHC (O) OC _{1 - 3} alkylene -, X and Y is C _{1 - 4} alkyl, amino, C _1-3 alkylamino, -C _{1 - 6} alkylene-amino (C _1-3 alkyl) _2, (C _1-3 alkyl) _0-2 ureido, optionally and independently substituted with one or two identical or different substituents selected from the group consisting of phenyl and benzyl, X and Y comprising carbon atoms X and Y Optionally and independently contain one or two carbonyls that are members of a heterocycle, provided that when X is substituted with Y and Z and Y are not intervened, then X and Y represent one carbon atom. Optionally sharing together to form a spirocyclic moiety).

According to another embodiment of the first aspect of the invention R ⁴ is H, C _{1 - 6} alkyl, C _{1 - 4} haloalkyl or (C _{1 - 4} alkylene) _0-1 R ^{4 'and;} R ^{4 'is} C _{3 - 7} cycloalkyl, phenyl, adamantyl, pyridyl quinuclidine, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydro Hydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, oxadizolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholi No or dioxolanyl; R ^{4 'is} halo, cyano, C _1-4 alkyl, C _{1 - 4} haloalkyl, C _{1 - 4} alkoxy, hydroxy, amino, C _{3 - 7} cycloalkyl, C _{1 - 3} alkylamino, C _{1 - 3} dialkylamino, (C _{1 - 3} alkyl) _0-2 ureido, phenyl, and a first one of the first aspect of the present invention, one or two same or different optionally substituted with substituents selected from the group consisting of benzyl There is provided a compound according to an embodiment.

According to another embodiment of the first aspect of the invention R ⁴ is H, C _{1 - 6} alkyl, C _{1 - 4} haloalkyl or (C _{1 - 4} alkylene) _0-1 R ^{4 'and;} R ^{4 'is} C _{3 - 7} cycloalkyl, phenyl, adamantyl, pyridyl quinuclidine, azabicyclo [2.2.1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydro Hydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, oxadizolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholi Provided is a compound according to the first aspect of the first aspect of the invention, which is furnace or dioxolanyl.

According to another embodiment of the first aspect of the invention R ⁴ is H, C _{1 - 6} alkyl or (C _{1 - 4} alkylene) _0-1 R ^{4 'and;} Provides the compounds according to the first embodiment of the first aspect of the present invention ₇ cycloalkyl _- R ^{4 'is} C _3.

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ),

R ¹ and R ² and L ¹ are each independently, L ¹ is H, C _{1 - 6} alkyl, -C _1-6 alkylene-amino (C _1-3 alkyl) _2, C _{3 - 7} cycloalkyl, phenyl , Azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, already Dazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; or

R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl , Abu Jaffe carbonyl, diazepinyl carbonyl, piperazinyl, piperidinyl, morpholino or thio-morpholino, wherein and X is substituted by Y, Y is dioxolanyl, C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _3-7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidino Neil, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazoloyl, piperazinyl, piperidinyl, morpholino, benzothia Zolyl, benzisothiazolyl or thiomorpholino, wherein X and Y optionally share one carbon atom to form a spirocyclic moiety. Provided are the compounds according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ),

R ¹ and R ² and L ¹ are each independently, L ¹ is H, C _{1 -} or selected from the group consisting of _6-alkyl, or

R ¹ and R ² are to form the X together with the nitrogen to which they are attached, wherein X is piperidinyl or morpholino, wherein X is substituted by Y, Y is dioxolanyl, C _{1 - 4} alkyl or piperazinyl Ridinyl, wherein X and Y optionally share one carbon atom to form a spirocyclic moiety together to provide a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention V is ^{-N (R 1) (R 2} ) , wherein R ¹ and R ² are each independently L ^1, L ¹ is H, C _{1 - 6} alkyl Provided is a compound according to the first aspect of the first aspect of the invention, selected from the group consisting of:

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ) wherein R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is piperidinyl or is morpholino, in which X is substituted by Y, Y is dioxolanyl, C _{1 - 4} alkyl or piperidinyl, in which X and Y are the spirocyclic moieties together to share a single carbon atom optionally Provided are the compounds according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ) wherein R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is piperidinyl , Wherein X is substituted with Y and Y is piperidinyl, providing a compound according to the first aspect of the first aspect of the invention.

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ) wherein R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is morpholino , wherein X is substituted by Y, Y is C _{1 - 4} alkyl, provides, compounds according to the first embodiment of the first aspect of the present invention.

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ) wherein R ¹ and R ² together with the nitrogen to which they are attached form X, wherein X is piperidinyl , wherein X is C _{1 -} to provide a compound according to the first embodiment of the first aspect of the present invention is substituted with an alkyl ₄ Y.

According to another embodiment of the first aspect of the invention V is —N (R ¹ ) (R ² ),

Wherein R ¹ and R ² together with the nitrogen to which they are attached form X,

Wherein X is piperidinyl;

Wherein X is substituted with Y, dioxolanyl;

Wherein X and Y share one carbon atom to form a spirocyclic moiety together to provide a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein X and Y are not interrupted by Z.

According to another embodiment of the first aspect of the invention, Z and X are not interrupted, and X and Y share one carbon atom and together form a spirocyclic moiety. There is provided a compound according to one embodiment.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein R ³ is R ^3a .

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein R ³ is R ^3b .

According to another embodiment of the first aspect of the invention R ^3a is O, N, and containing 1 to 5 identical or different heteroatoms selected from the group consisting of S, respectively, a 5- or fused ring 7 won Provided is a compound according to the first embodiment of the first aspect of the invention, which is a heterocycle having two.

According to another embodiment of the first aspect of the invention one or more of R ^3a contains 1 to 5 identical or different heteroatoms selected from the group consisting of O, N and S and wherein the carbon atoms are members of the fused ring or There is provided a compound according to the first aspect of the first aspect of the invention, which is a heterocycle each having two 5- to 7-membered fused rings, optionally containing two carbonyls.

According to another embodiment of the first aspect of the invention one or more of R ^3a contains 1 to 5 identical or different heteroatoms selected from the group consisting of O, N and S and wherein the carbon atoms are members of the fused ring or Heterocycles having two 5- to 7-membered fused rings, each optionally containing two carbonyls; Wherein R ^3a is benzyl, phenyl, -O- phenyl, -OC _{1 - 3} alkylphenyl, -C _{1 - 3} alkylene group -OC (O) - phenyl, cyano, amino, nitro, halo, C _{1 - 3} Mono - the non-tri-haloalkyl, C _{1 - 3} mono- non-tri-halo-alkyloxyalkyl, C _1-6 alkoxy, (C _{1 - 3} alkyl) _1-2 ^{amine, -OR 3 ', -C (O} ) R ^{3 '} , -C (O) OR ^3' , -0-C (O) R ^{3 '} , -N (R ^3' ) ₂ , -C (O) N (R ^{3 '} ) ₂ , -N (R ^{3 '} ) C (O) (R ^3' ) ₂ , -N (R ^{3 '} ) C (O) N (R ^3' ) ₂ , -N (R ^{3 '} ) C (O) OR ^3' , -OC 1 to 1 selected from the group consisting of (O) N (R ^{3 ′} ) ₂ , —N (R ^{3 ′} ) SO ₂ R ^{3 ′} , —SO ₂ N (R ^{3 ′} ) _2, and —SO ₂ R ^{3 ′} . Optionally substituted with three same or different substituents; R ^{3 'is} H or -C _{1 - 6} alkyl is, there is provided a compound according to the first embodiment of the first aspect of the present invention.

Claim the present invention 1 R ^3a is O, N and S 1 to 3 same or 4-to 6-membered heterocycle containing different heteroatoms selected from the group consisting of In another embodiment of the aspect of the invention A compound according to the first embodiment of the first aspect of the present invention.

According to another embodiment of the first aspect of the invention R ^3a contains 1 to 3 identical or different heteroatoms selected from the group consisting of O, N and S, and the carbon atoms of the 4 to 6 membered heterocycle There is provided a compound according to the first aspect of the first aspect of the invention, which is a 4 to 6 membered heterocycle optionally containing 1 to 2 carbonyl members.

According to another embodiment of the first aspect of the invention R ^3a contains 1 to 3 identical or different heteroatoms selected from the group consisting of O, N and S, and the carbon atoms of the 4 to 6 membered heterocycle 4- to 6-membered heterocycle optionally containing 1 to 2 carbonyl members; Wherein R ^3a is benzyl, phenyl, -O- phenyl, -OC _{1 - 3} alkylphenyl, -C _{1 - 3} alkylene group -OC (O) - phenyl, cyano, amino, nitro, halo, C _{1 - 3} Mono - the non-tri-haloalkyl, C _{1 - 3} mono- non-tri-halo-alkyloxyalkyl, C _{1 - 6} alkoxy, (C _{1 - 3} alkyl) _1-2 ^{amine, -OR 3 ', -C (O} ) R ^{3 '} , -C (O) OR ^3' , -0-C (O) R ^{3 '} , -N (R ^3' ) ₂ , -C (0) N (R ^{3 '} ) ₂ , -N (R ^{3 '} ) C (O) (R ^3' ) ₂ , -N (R ^{3 '} ) C (O) N (R ^3' ) ₂ , -N (R ^{3 '} ) C (O) OR ^3' , -OC 1 to 1 selected from the group consisting of (O) N (R ^{3 ′} ) ₂ , —N (R ^{3 ′} ) SO ₂ R ^{3 ′} , —SO ₂ N (R ^{3 ′} ) _2, and —SO ₂ R ^{3 ′} . Optionally substituted with three same or different substituents; R ^{3 'is} H or -C _{1 - 6} alkyl is, there is provided a compound according to the first embodiment of the first aspect of the present invention.

According to another embodiment of the first aspect of the invention R ^3a is C _{3 -} provides the compounds according to the first embodiment of the first aspect of the present invention ₇ cycloalkyl.

According to another embodiment of the first aspect of the invention R ^3a is C _{3 - 7} cycloalkyl; Wherein R ^3a is benzyl, phenyl, -O- phenyl, -OC _{1 - 3} alkylphenyl, -C _{1 - 3} alkylene group -OC (O) - phenyl, cyano, amino, nitro, halo, C _{1 - 3} Mono - the non-tri-haloalkyl, C _{1 - 3} mono- non-tri-halo-alkyloxyalkyl, C _1-6 alkoxy, (C _{1 - 3} alkyl) _1-2 ^{amine, -OR 3 ', -C (O} ) R ^{3 '} , -C (O) OR ^3' , -OC (O) R ^{3 '} , -N (R ^3' ) ₂ , -C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) OR ^{3 '} , -OC (O ) N (R ^{3 '} ) ₂ , -N (R ^3' ) SO ₂ R ^{3 '} , -SO ₂ N (R ^3' ) ₂ and -SO ₂ R ^{3 '} One to three selected from the group consisting of Optionally substituted with the same or different substituents; R ^{3 'is} H or -C _{1 - 6} alkyl is, there is provided a compound according to the first embodiment of the first aspect of the present invention.

According to another embodiment of the first aspect of the invention R ^3a is carbazolyl, fluorenyl, phenyl, -O- phenyl, -OC _{1 - 4} alkylene-phenyl or naphthyl is, a first aspect of the present invention There is provided a compound according to the first embodiment of.

According to another embodiment of the first aspect of the invention R ^3a is carbazolyl, fluorenyl, phenyl, -O- phenyl, -OC _{1 - 4} alkylene-phenyl or naphthyl; Wherein R ^3a is benzyl, phenyl, -O- phenyl, -OC _{1 - 3} alkylphenyl, -C _{1 - 3} alkylene group -OC (O) - phenyl, cyano, amino, nitro, halo, C _1-3 mono - the non-tri-haloalkyl, C _{1 - 3} mono- non-tri-halo-alkyloxyalkyl, C _{1 - 6} alkoxy, (C _{1 - 3} alkyl) _1-2 ^{amine, -OR 3 ', -C (O} ) R ^{3 '} , -C (O) OR ^3' , -OC (O) R ^{3 '} , -N (R ^3' ) ₂ , -C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) OR ^{3 '} , -OC (O ) N (R ^{3 '} ) ₂ , -N (R ^3' ) SO ₂ R ^{3 '} , -SO ₂ N (R ^3' ) ₂ and -SO ₂ R ^{3 '} One to three selected from the group consisting of Optionally substituted with the same or different substituents; R ^{3 'is} H or -C _{1 - 6} alkyl is, there is provided a compound according to the first embodiment of the first aspect of the present invention.

According to another embodiment of the first aspect of the invention R ^3a is C _{1 - 8} alkyl, C _{2 - 7} ^{alkenylene, -C (O) R 3 '} , -C (O) OR 3' , or C _{2 - 7} There is provided a compound according to the first embodiment of the first aspect of the invention, which is alkynyl.

According to another embodiment of the first aspect of the invention R ^3a is C _{1 - 8} alkyl, C _{2 - 7} ^{alkenylene, -C (O) R 3 '} , -C (O) OR 3' , or C _{2 - 7} Alkynyl; Wherein R ^3a is benzyl, phenyl, -O- phenyl, -OC _1-3 alkyl phenyl, -C _{1 - 3} alkylene group -OC (O) - phenyl, cyano, amino, nitro, halo, C _{1 - 3} Mono - the non-tri-haloalkyl, C _{1 - 3} mono- non-tri-halo-alkyloxyalkyl, C _{1 - 6} alkoxy, (C _{1 - 3} alkyl) _1-2 ^{amine, -OR 3 ', -C (O} ) R ^{3 '} , -C (O) OR ^3' , -OC (O) R ^{3 '} , -N (R ^3' ) ₂ , -C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) N (R ^{3 '} ) ₂ , -N (R ^3' ) C (O) OR ^{3 '} , -OC (O ) N (R ^{3 '} ) ₂ , -N (R ^3' ) SO ₂ R ^{3 '} , -SO ₂ N (R ^3' ) ₂ and -SO ₂ R ^{3 '} One to three selected from the group consisting of Optionally substituted with the same or different substituents; R ^{3 'is} H or -C _{1 - 6} alkyl; However, when R ^3a is —C (O) R ^{3 ′} , CHC (O) OR ^{3 ′} , CH (CH ₃ ) C (O) OR ^{3 ′} or —C (O) OR ^{3 ′} , the above-C ( First embodiment of the first aspect of the invention wherein O) R ^{3 '} , CHC (O) OR ^3' , CH (CH ₃ ) C (O) OR ^{3 ',} or -C (O) OR ^3' are not substituted It provides a compound according to the embodiment.

According to another embodiment of the first aspect of the invention, and R ³ is R ^3a, R ^3a is phenyl, hydroxyphenyl,-azetidinyl, naphthyl, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, dihydro-1,2,3,4 carbonyl, tetrahydro-1,2,3,4 carbonyl, quinolinyl, dihydro-iso-1,2,3,4 carbonyl, tetrahydro-iso-1,2,3,4 carbonyl, isoquinolinyl, dihydro-quinazolinyl nonyl, tetrahydro quinazolinyl nonyl, quinazoline Zolinyl, dihydroquinoxalinoneyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, indazolyl, dihydrobenzimidazoloyl, hydrobenzimidazoloyl, benzimidazolinyl, di Hydrobenzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzoxazolyl, benzotriazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, benzothienyl, dihydrobenzofuranyl, hydro Benzofuranyl, benzofuranyl, benzdioxolanyl, dihydroindolo , Hydroindolinyl, indolyl, indolinyl, isoindoleyl, indolinyl, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, thienyl, pyrrolyl, pyrrolininyl, pyrrolidinyl , Imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, furinyl, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl, piperazinyl or Morpholino; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention R ³ is R ^3a and R ^3a is phenyl, naphthyl, indazolyl, benzimidazolinyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl, Benzdiooxolanyl, dihydroindolonyl, indolyl, furanyl, thienyl, pyridyl, furinyl, carbazolyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention R ³ is R ^3a and R ^3a is dihydrobenzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiope Nonyl, benzothienyl, dihydrobenzofuranyl, hydrobenzofuranyl, benzofuranyl, dihydroindolonyl, hydroindolinyl, indolyl, indolinyl, isoindolyl, indolinyl or indazolyl; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention, and R ³ is R ^3a, R ^3a is dihydro-benzoxazolyl, benzotriazolyl, indolyl, halo-nitro-phenyl, halo-pyrimidine, halo Puri carbonyl, C _{1 - 3} alkyl-nitroaminopyrimidine, triazolopyrimidinyl, pyridyl, indazolyl, phenyl or benzdiooxolanyl; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention R ³ is R ^3a and R ^3a is naphthyl, phenyl-O-phenyl or thienyl; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein R ³ is R ^3b .

According to another embodiment of the first aspect of the invention R ³ is R ^3b and R ^3b is

1H-indole-5-day

;

;

1H-indazol-5-yl

;

;

1H-benzotriazol-5-yl

;

;

1,3-dihydro-indol-2-one-5-yl

;

;

3H-benzooxazol-2-one-6-yl

;

;

1,3-dihydro-benzoimidazol-2-one-5-yl

;

;

1-methyl-1,3-dihydro-benzoimidazol-2-one-6-yl

;

;

3,4-dihydro-1H-quinolin-2-one-6-yl

;

;

1,4-dihydro-benzo [d] [1,3] oxazin-2-one-6-yl

;

;

3,4-dihydro-1H-quinazolin-2-one-6-yl

;

;

3-methyl-3,4-dihydro-1H-quinazolin-2-one-6-yl

; 또는

; or

4H-benzo [1,4] oxazin-3-one-7-yl

이고;

ego;

Wherein, T ^y is H, C _{1 - 4} alkyl to provide a, F, Cl, Br or nitrile of the compound according to the first embodiment of the surface the first station of the present invention.

According to another embodiment of the first aspect of the invention, and R ³ is R ^3b, R ^3b is azetidinyl, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, dihydro-1,2,3,4 Nyl, Hydroquinolinoneyl, Dihydroisoquinolinoneyl, Hydroisoquinolinoneyl, Dihydroquinazolinoneyl, Hydroquinazolinoneyl, Quinazolinyl, Dihydroquinoxalinonyl, Hydroquinoxalinonyl, Quinoxalin Nyl, Benzimidazolyl, 1H-indazol-5-yl, Dihydrobenzimidazoloyl, Hydrobenzimidazoloyl, Benzimidazolinyl, Dihydro-benzithiazolonyl, Hydrobenzthiazolonyl , Benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranyl, hydrobenzofuranyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, Hydroindolinyl, indolinyl, isoindoleyl, indolinyl, pyrazolyl, pyrazoli Neil, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, furinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or mor Polyno; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention R ³ is R ^3b and R ^3b is dihydrobenzimidazoloyl, hydrobenzimidazoloyl, benzimidazolinyl, dihydro-benzthiazolonyl , Hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranyl, hydrobenzofuranyl, 1H-indazol-5-yl, benzdioxolanil, di Hydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroin dolonyl, indolinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolyl Nil, pyrrolidinyl, imidazolinyl, imidazolidinyl, furinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention, and R ³ is R ^3b, R ^3b is azetidinyl, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, dihydro-1,2,3,4 Nyl, Hydroquinolinoneyl, Dihydroisoquinolinoneyl, Hydroisoquinolinoneyl, Dihydroquinazolinoneyl, Hydroquinazolinoneyl, Quinazolinyl, Dihydroquinoxalinonyl, Hydroquinoxalinonyl, Quinoxalin Nyl, Benzimidazolyl, 1H-indazol-5-yl, Dihydrobenzimidazoloyl, Hydrobenzimidazoloyl, Benzimidazolinyl, Dihydro-benzithiazolonyl, Hydrobenzthiazolonyl , Benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobenzofuranyl, hydrobenzofuranyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, furinyl, carbazolyl , Pyrimidinyl, piperidinyl, piperazinyl or morpholino; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention, and R ³ is R ^3b, R ^3b is azetidinyl, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, dihydro-1,2,3,4 Neil, Hydroquinolinoneyl, Dihydroisoquinolinoneyl, Hydroisoquinolinoneyl, Dihydroquinazolinonyl, Hydroquinazolinonyl, Quinazolinyl, Dihydroquinoxalinoneyl, Hydroquinoxalinonyl, Quinoxalin Nil, benzimidazolyl, benzdioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, 1H-indazol-5-yl, indolinyl, isoindolyl, Indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, furinyl, carbazolyl, pyrimidinyl, pipepe Ridinyl, piperazinyl or morpholino; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention R ³ is R ^3b and R ^3b is benzdioxosolil, dihydrobenzoxazolyl, benzotriazolyl, furinyl, carbazolyl; Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted as set forth in the first embodiment of the first aspect.

According to another embodiment of the first aspect of the invention R ³ is R ^3b and R ^3b is dihydrobenzoxazolyl, benzotriazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C _{1 -A} compound according to the first embodiment of the first aspect of the invention, which is ₃ alkyl-nitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, 1H-indazol-5-yl, phenyl or benzdiooxolanyl To provide.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein Q is Q 'and the compound has an absolute configuration of R.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein Q is Q 'and the compound has an absolute configuration of S.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein Q is Q ″ and the compound has an absolute configuration of R.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein Q is Q ″ and the compound has an absolute configuration of S.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein m and n are each one.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein D is O.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein A is C.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein A is CH.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein A is N.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein E is N.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein E is CH.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein E is C.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein the IC ₅₀ for CGRP binding as described herein exhibits less than 10 nM.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein the IC ₅₀ for CGRP binding as described herein exhibits less than 100 nM.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein the IC ₅₀ for CGRP binding as described herein exhibits less than 1000 nM.

According to another embodiment of the first aspect of the invention p is 1; Provided is a compound according to the first embodiment of the first aspect of the invention, wherein G, J and E together form A ^x or A ^y .

According to another embodiment of the first aspect of the invention p is 1; Provided is a compound according to the first embodiment of the first aspect of the invention, wherein G, J and E together form A ^x .

According to another embodiment of the first aspect of the invention p is 1; Provided is a compound according to the first embodiment of the first aspect of the invention, wherein G, J and E together form A ^y .

According to another embodiment of the first aspect of the invention A ^x is a fused heterocycle each having two 5- to 7-membered fused rings, wherein said heterocycle is selected from the group consisting of O, N and S Contains 1 to 4 identical or different heteroatoms; Provided are compounds according to the first aspect of the first aspect of the invention, wherein the carbon atoms optionally contain one or two carbonyls which are members of the fused heterocycle.

According to another embodiment of the first aspect of the invention A ^x is a fused heterocycle each having two 5- to 7-membered fused rings, wherein said heterocycle is selected from the group consisting of O, N and S Provided are compounds according to the first aspect of the first aspect of the invention, containing one to four identical or different heteroatoms.

According to another embodiment of the first aspect of the invention A ^x is a fused heterocycle each having two 5- to 7-membered fused rings, wherein said heterocycle is selected from the group consisting of O, N and S Provided are compounds according to the first embodiment of the first aspect of the invention, containing 1 to 4 identical or different heteroatoms, wherein A ^x is substituted with phenyl.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention wherein A ^x is a fused heterocycle as described herein.

According to another embodiment of the first aspect of the invention 1 wherein A ^y contains 1 to 3 heteroatoms selected from the group consisting of O, N and S, and wherein the carbon atom is a member of a 4 to 6 membered heterocycle There is provided a compound according to the first aspect of the first aspect of the invention, which is a 4-6 membered heterocycle optionally containing two to two carbonyls.

According to another embodiment of the first aspect of the invention A ^y is O, N, and a 4-to 6-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of S, claim 1 of the present invention; There is provided a compound according to the first embodiment.

According to another embodiment of the first aspect of the invention 1 wherein A ^y contains 1 to 3 heteroatoms selected from the group consisting of O, N and S, and wherein the carbon atom is a member of a 4 to 6 membered heterocycle 4- to 6-membered heterocycle optionally containing 2 to 2 carbonyls; There is provided a compound according to the first embodiment of the first aspect of the invention, wherein A ^y is substituted with phenyl.

According to another embodiment of the first aspect of the invention there is provided a compound according to the first embodiment of the first aspect of the invention, wherein A ^y is a 4-6 membered heterocycle described herein.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring containing A, wherein G, J And A together with GJA ′ or GJA ″ provides a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, Provided is a compound according to the first embodiment of the first aspect of the invention, wherein J and A together are GJA '.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, A compound according to the first embodiment of the first aspect of the invention, wherein J and A together are GJA ″.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, Provided is a compound according to the first aspect of the first aspect of the invention, wherein J and A together are GJA 'and GJA' is A ^x .

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, Provided is a compound according to the first embodiment of the first aspect of the invention, wherein J and A together are GJA 'and GJA' is A ^y .

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, A compound according to the first embodiment of the first aspect of the invention, wherein J and A together are GJA ″ and GJA ″ is A ^x .

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, Provided is a compound according to the first aspect of the first aspect of the invention, wherein J and A together are GJA ″ and GJA ″ is A ^y .

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, J and A together are imidazolininyl, imidazolidinonyl, dihydroquinolinone, dihydroisoquinolinone, dihydroquinazolinone, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydroben Dioxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazoloyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofura Group consisting of nonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino To form a heterocycle selected from; Said heterocycle C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _1-4 haloalkyl, cyano, C _{3 - 7} cycloalkyl, phenyl, halophenyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl Bonyl, optionally substituted with diyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, J and A together are imidazolininyl, imidazolidinonyl, dihydroquinolinone, dihydroisoquinolinone, dihydroquinazolinone, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydroben Dioxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazoloyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofura Group consisting of nonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino To form a heterocycle selected from; Said heterocycle C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _1-4 haloalkyl, cyano, C _{3 - 7} cycloalkyl, phenyl, halophenyl, furanyl, pyrazolyl, pyrazolyl Jolly carbonyl, pyrazolyl Jolly Provided is a compound according to the first aspect of the first aspect of the invention, optionally substituted with diyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, or morpholino.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, J and A together are imidazolininyl, imidazolidinonyl, dihydroquinolinone, dihydroisoquinolinone, dihydroquinazolinone, dihydrobenzofuranyl, dihydroindononyl, indolinyl, To form a heterocycle selected from the group consisting of pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; Said heterocycle C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _{1 - 4} haloalkyl, cyano, C _{3 - 7} cycloalkyl, phenyl, halophenyl, piperazinyl or morpholino furnace optionally being substituted, the There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, J and A together are imidazolininyl, imidazolidinonyl, dihydroquinolinone, dihydroisoquinolinone, dihydroquinazolinone, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydroben Dioxazinyl, dihydrobenzoxazinonyl, dihydrobenzimidazoloyl, dihydrobenzimidazolyl, dihydro-benzthiazolonyl, dihydrobenzthiazolyl, dihydrobenzothiophenonyl, dihydrobenzofura Group consisting of nonyl, dihydroindolonyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino To form a heterocycle selected from There is provided a compound according to the first embodiment of the first aspect of the invention.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, J and A together are imidazolininyl, imidazolidinonyl, dihydroquinolinone, dihydroisoquinolinone, dihydroquinazolinone, dihydroquinoxalinonyl, dihydrobenzoxazinyl, hydroben There is provided a compound according to the first aspect of the first aspect of the present invention, which forms a heterocycle selected from the group consisting of oxazinyl and dihydrobenzoxazinonyl.

According to another embodiment of the first aspect of the invention, when p is 0 and G and J are each attached to A, then G, J and A together form a spirocyclic ring system containing A, wherein G, J and A together are imidazolininyl, imidazolidinonyl, dihydroquinolinone, dihydroisoquinolinone, dihydroquinazolinone, dihydroquinoxalinonyl and dihydrobenzoxazinyl There is provided a compound according to the first embodiment of the first aspect of the invention, forming a heterocycle selected from.

According to various embodiments of the second aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein.

According to various embodiments of the third aspect of the present invention, the administration of a pharmaceutical composition comprising a compound of formula (I) as defined herein results in inflammation (particularly neurological inflammation), headache (particularly migraine), pain, recessive injury, circulation How to treat sexual shock, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid / brain bleeding, tumor proliferation, menopause-related flushing, and other conditions that may be effective by antagonism of CGRP receptors to provide.

According to various embodiments of the fourth aspect of the present invention (a) immune regulation in the intestinal mucosa (b) protective effect against cardiac anaphylactic damage (c) interleukin-1b (IL-1b) -stimulation of bone resorption Promoting or preventing There is provided the use of a compound of the invention selected from the group consisting of (d) regulating NK1 receptor expression in spinal cord neurons and (e) airway inflammatory diseases, and chronic obstructive pulmonary diseases including asthma. (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 neurokinin1 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, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi. Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. American Journal of Physiology (2002), 283 (5, Pt. 1), L963-L970]; (f) ["Calcitonin gene-related peptide as inflammatory mediator." Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. Charite Campus-Virchow, 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 Pecs, Pecs, Hung. Current Medicinal Chemistry: Anti-Inflammatory & Anti-Allergy Agents (2003), 2 (2), 191-218.

According to various embodiments of the fifth aspect of the invention, there is provided at least one agent selected from the group consisting of COX-2 inhibitors, NSAIDS, aspirin, acetaminophen, trytans, ergotamine and caffeine to treat migraine headaches; Provided are combinations of the compounds of the invention.

According to a sixth aspect of the invention there is provided a non-terminal method in vivo for identifying anti-migraine compounds.

According to a first embodiment of the sixth aspect of the present invention, in a transgenic mammal with humanized RAMP1 having Trp74 or a mammal endogenously expressing RAMP1 with Trp74, CGRP- in an amount capable of inducing increased blood flow An in vivo non-terminal method of identifying anti-migraine compounds, comprising administering a test compound in an amount capable of reversing CGRP-induced blood flow increase following administration of a receptor agonist.

According to another embodiment of the sixth aspect of the invention, in a transgenic mammal with humanized RAMP1 with Trp74 or with a mammal endogenously expressed with RAMP1 with Trp74, the CGRP-receptor in an amount capable of inducing increased blood flow Prior to administering an agonist, there is provided an in vivo non-terminal method of identifying an anti-migraine compound, comprising administering the test compound in an amount capable of inhibiting CGRP-induced blood flow increase.

According to another embodiment of the sixth aspect of the invention, in a transgenic mammal with humanized RAMP1 with Trp74 or with a mammal endogenously expressing RAMP1 with Trp74, the CGRP-receptor agonist is characterized by an increase in peripheral arterial diameter. An in vivo non-terminal method of identifying anti-migraine compounds, comprising administering in an inducible amount, followed by administering the test compound in an amount that can reverse CGRP-induced increase in peripheral arterial diameter. .

According to another embodiment of the sixth aspect of the invention, in a transgenic mammal with humanized RAMP1 with Trp74 or with a mammal endogenously expressing RAMP1 with Trp74, the CGRP-receptor agonist is characterized by an increase in peripheral arterial diameter. An in vivo non-terminal method of identifying anti-migraine compounds is provided that includes administering the test compound in an amount that can reverse CGRP-induced increase in peripheral arterial diameter prior to administration in an inducible amount.

According to another embodiment of the sixth aspect of the present invention there is provided an in vivo non-terminal method of identifying an anti-migraine compound as described herein, wherein said blood flow is facial blood flow.

According to another embodiment of the sixth aspect of the present invention, an in vivo non-terminal method of identifying an anti-migraine compound as described herein, wherein the mammal endogenously expressing RAMP1 with Trp74 is a primate other than human To provide.

According to another embodiment of the sixth aspect of the present invention there is provided an in vivo non-terminal method of identifying an anti-migraine compound as described herein, wherein the mammal whose endogenous expression of RAMP1 with Trp74 is a human.

According to another embodiment of the sixth aspect of the present invention, the anti-migraine as described herein, wherein the mammal endogenously expressing RAMP1 with Trp74 is a primate other than human, and the primate other than human is marmoset. In vivo non-terminal methods of identifying compounds are provided.

According to another embodiment of the sixth aspect of the present invention there is provided an in vivo non-terminal method of identifying an anti-migraine compound as described herein, wherein the anti-migraine compound is a CGRP-receptor antagonist.

Other embodiments of the invention may include suitable combinations of two or more embodiments and / or aspects disclosed herein.

Still other embodiments of the invention can include suitable subsets of embodiments and / or aspects disclosed herein.

Other embodiments and aspects of the invention will be apparent according to the following description.

Schild analysis.

Dose response of CGRP stimulates cAMP production in the absence (black squares) and presence (all others) of increasing concentrations (left to right) of CGRP antagonists (Example 2). Inset is the shield plot of Log [Dose Ratio-1] (Y-axis) versus Log [Concentration of Antagonist (Example 2)] (X-axis): slope = 0.94, K _b = 0.16 nM.

2. Direct evidence of facial blood flow in place of intracranial artery dilation in rats.

Intravenous delivery of intravenous hαCGRP leads to comparable rates of increase (100-120% of baseline) in rat meninges' median artery diameter and rat facial blood flow (striped bars on the left and right, respectively). Pretreatment with peptide antagonist CGRP (8-37) inhibits 50% of subsequent intravenous hαCGRP administration for both measurements (black bars). Intracranial artery diameter and facial blood flow were measured simultaneously in each animal (n = 5 rats). Data is mean ± sem and * p <0.05, ** p <0.01 for the corresponding hαCGRP alone.

3. Dose-response to hαCGRP in laser Doppler facial blood flow in non-human primates.

Delivery of hαCGRP induces a dose-dependent increase in laser Doppler facial blood flow in primates (eg, marmosets) except humans. Animals (n = 6) were dosed with increasing doses of hαCGRP at 30 minute intervals. The data shows the percent change in peak from baseline ± sem for each animal that itself serves as a control.

Inhibition of CGRP-induced changes in facial blood flow of primates except humans.

A novel CGRP antagonist delivered before hαCGRP (stripe bar) (Example 2) (black bar) dose-dependently inhibits CGRP-induced increase in laser Doppler facial blood flow. Vehicle (white bar) was not valid. Data is mean ± sem (n = 5-6 primates per group). * P <0.05 for CGRP alone.

5. Effect of CGRP antagonist on primate blood pressure excluding humans.

In contrast to dose-dependent inhibition of primate facial blood flow (see FIG. 4), Example 2 showed a minor effect on blood pressure (parallel study in individual animals, n = 6). Animals were repeatedly administered a dose of Example 2 at 20 minute intervals. BP data is the mean value ± sem over 20 minutes, measured by arm cuff.

It is to be understood that the description of the present invention is consistent with the laws and principles of chemical bonding. For example, it may be necessary to remove a hydrogen atom to accept a substituent at any position.

As used herein, “heterocyclic” or “heterocycle” includes cyclic moieties containing one or more heteroatoms (eg, O, N or S), wherein the heterocycle is aromatic unless otherwise defined. And non-aromatic ones, ie, "alicyclic" ones.

The term "fused bicyclic system" as used herein describes, for example, a 5.6-fused bicyclic system containing 1 to 4 nitrogen atoms, for example aromatic and cycloaliphatic systems such as indolizin, indole , Isoindole, 3H-indole, indolin, indazole or benzimidazole.

When substituents are generic, any and all species of that class include aspects of the invention. For example, substituents collectively referred to as "pyrrolonyl" ("pyrrolone" radicals, pyrroles with carbonyl) include pyrrole-2-onyl where carbonyl is adjacent to nitrogen, and pyrrole with methylene interrupted to carbonyl and nitrogen. -3-onyl.

Similarly, the invention includes, unless otherwise defined, a substituent may be attached at any and all points suitable for attachment of the substituent.

However, the compounds included in the present invention are chemically stable, i.e., the hetero-alicyclic substituent of the present invention is such that the heteroatoms of the hetero-alicyclic substituents become alpha with respect to the point of attachment (where the point of attachment is also heteroatom). It should also be understood that it should not be attached.

One embodiment or aspect, which depends on other embodiments or aspects, will only describe variables having values or conditions that differ from the reference embodiment or aspect. For example, even if the dependent embodiment refers only to R ² , variables and conditions not related to R ² should reflect those of the reference embodiment.

If the variable is quantified to a value of zero, the bond attached to the variable no longer exists.

As used herein, "alkylene" refers to a divalent alkan, ie an alkan in which two hydrogen atoms have been removed from the alkan, where hydrogen is removed from two different carbon atoms if the alkan contains one or more carbon atoms), for example- CH ₂ CH ₂ CH _2- .

이 있다.As used herein, "alkylidene" refers to an alkan with two hydrogen atoms removed from one carbon of the alkan, for example

There is this.

The alternating double bond assignments in the 6-membered ring of the 5,6-membered fusion structure shown in formula (I) are relative and should be understood to indicate delocalization of the π orbital electrons of the ring.

As used herein, "aryl" or "ar-" includes phenyl or naphthyl.

As used herein, “heterocyclic” or “heterocyclo” includes both heteroaryl and hetero-cycloaliphatic compounds.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo and iodo, and further means that one or more identical or different halogens may be substituted at each moiety.

Unless defined otherwise, acyclic hydrocarbons such as alkyl, alkoxy, alkenyl and alkynyl may be branched or straight chain.

It is to be understood that the present invention includes any and all possible stereoisomers, geometric isomers, diastereomers, enantiomers, anomers and optical isomers unless otherwise specified.

As used herein, "Trp74" means that the 74th residue of RAMP1 is tryptophan (Mallee et al. J Biol Chem 2002, 277, 14294-8, incorporated herein by reference).

As used herein, an “anti-migraine compound” is any compound, peptide or peptide fragment (modified or unmodified) that can reverse or attenuate CGRP-receptor mediated vasodilation (eg, CGRP-receptor antagonist) It includes.

As used herein, a “test compound” is any compound, peptide or peptide fragment (modified or unmodified) that is tested to determine if it can reverse or attenuate CGRP-receptor mediated vasodilation (eg, CGRP- Presumed to be an receptor antagonist).

As used herein, “CGRP-receptor agonist” includes any compound, peptide or peptide fragment (modified or unmodified) capable of inducing CGRP-receptor mediated vasodilation, in particular for example αCGRP or βCGRP; Other members of the calcitonin class, for example adrenomedullin; N-terminal CGRP fragments such as CGRP (1-12), CGRP (1-15) and CGRP (1-22); C-terminal amide (NH ₂ ) form of CGRP, for example CGRP (1-8 + NH ₂ ), CGRP (1-13 + NH ₂ ) or CGRP (1-14 + NH ₂ ); And non-naturally occurring CGRP analogs, such as [Ala ¹ ψ (CH ₂ NH) Cys ² ] hCGRP, which contain a pseudopeptide bond between Ala ¹ and Cys ² . 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 Dennis T, Fournier A, St Pierre S, Quirion R. Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther. 1989 Nov; 251 (2): 718-25.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. Such salts may include addition salts of inorganic acids (eg hydrochloric acid and sulfuric acid) and organic acids (eg acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid). In addition, when the compound of the present invention contains an acidic group, the acidic group may be an alkali metal salt (eg, potassium salt and sodium salt); Alkaline earth metal salts (eg, magnesium salts and calcium salts); And salts with organic bases (eg, triethylammonium salts and arginine salts). In the case of sublingual preparations, saccharin or malate salts may be particularly advantageous. The compounds of the present invention may or may not be hydrated.

The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (each comprising sustained release or hourly release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of the present invention may also be administered intravenously, intraperitoneally, subcutaneously or intramuscularly using all dosage forms well known to those skilled in the pharmaceutical arts. The compounds may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the route of administration chosen and standard pharmaceutical practice. The compounds of the present invention may also be administered intranasally with topical use of a suitable intranasal vehicle or intradermal using a dermal patch that absorbs into the skin. In the case of intradermal administration of a compound of the present invention, it may be continuously administered by administration.

When 0.01 mg / kg to 30 mg / kg of a compound of the present invention is administered, the dosage and method of administration of the compound of the present invention, and the dosing schedule are determined by the appropriate physician's diagnosis and the age, weight and condition of the recipient, the route of administration, and Careful adjustment should be made in each case, taking into account the nature and extent of the disease state. According to good clinical practice, it is desirable to administer a compound of the present invention at a concentration level that will produce effective efficacy without any harmful or inappropriate side effects.

synthesis

The compounds of the present invention can be synthesized according to the general scheme set forth below. The variables provided in the following schemes are defined according to the description for compounds of the above formula unless otherwise defined. Compounds of the present invention can be prepared according to Scheme 1 or Scheme 2. It is also possible to use the above modifications in the preparation of the compounds of the invention, which modifications are known to those skilled in the art.

Scheme 1. Synthesis of Compound of Formula (I)

The synthesis described in Scheme 1 starts with a compound of Formula II, which is an amino acid with a protected amino terminus. Typical amino protecting groups (PG) include BOC, CBZ and FMOC, the addition and removal of which are well known in the art. The carboxylic acid residue of the compound of formula II is coupled with the amine of formula HNR ¹ R ² using a standard peptide coupling reagent to form the amide of formula III. The amino protecting group is removed to give the compound of formula IV. This compound is then coupled with an amine of formula V (see below) in a mixed urea or urea isostere reaction to produce a compound of formula (I). Mixed ureas are conveniently formed using phosgene, disuccinimidyl carbonate, carbonyl diimidazole or other equivalents. The formation of urea isotopes such as cyanoguanidine and sulfonylguanidine is known in the literature.

Scheme 2. Synthesis of Compound of Formula (I)

The synthesis described in Scheme 2 begins with a compound of Formula V, which is an amino acid with a protected carboxylate terminus. Protection generally uses methyl esters, but other protecting groups such as ethyl, t-butyl and benzyl esters can also be used. Compounds of formula V are coupled with amines of formula VIII (see below) in mixed urea or urea isotope reactions to produce compounds of formula VI as above. The compound of formula VI is converted to the free acid compound of formula VII, which is coupled with an amine of formula HNR ¹ R ² to form a compound of formula I.

Scheme 3. Synthesis of Compound of Formula (I)

The synthesis described in Scheme 3 begins with a compound of Formula VII from Scheme 2. The compound of formula V is coupled with an alcohol R ⁴ -OH. Such ester-forming reactions are well known in the art and can be carried out using, for example, carbodiimide coupling agents (eg, N, N-dicyclohexylcarbodiimide). In addition, it may often be beneficial to include additives that promote acylation (eg 4-dimethylaminopyridine), especially for esters of secondary and tertiary alcohols.

HNR ^One R ²  And chemical formula VIII of Amine  Produce

Amines of formula VIII and HNR ¹ R ² are commercially available or may be prepared by the methods disclosed in the literature or by the methods described herein.

Chemical formula II  And the preparation of amino acids of formula V

Amino acids of Formula (II) and Formula (V) are commercially available or can be prepared as described in Scheme 4.

Scheme 4. Chemical Formula II  And synthesis of compounds of formula V

The synthesis described in Scheme 4 starts with the aldehyde of Formula IX and reacts it with the glycine phosphonate of Formula X in a Wadsworth-Emmons coupling reaction. Compounds of formula (X) are deprotonated with bases (eg, diazabicycloundecene or tetramethylguanidine, or other organic or inorganic bases known in the art). The resulting double bond of the compound of formula XI is reduced to provide a compound of formula XII. The reduction reaction may be carried out to provide racemates or the stereoselective catalyst may be used to provide the enantiomer of Formula (XII). Such reduction may be due to hydrogenation from a hydrogen donor (eg formic acid or cyclohexadiene), or hydrogenation with hydrogen gas, in the presence of a suitable catalyst. Compounds of formula (II) are prepared by acid or base hydrolysis of esters. Compounds of formula V are prepared by removing protecting groups (PG) using methods well known in the art.

Other amino acid derivatives of formula (XII) can be prepared as shown in Scheme 5.

Scheme 5. Chemical Formula XII Synthesis of Compounds

For the purposes of Scheme 5, the compound of formula XIV is an amine or alcohol capable of participating in the Michael reaction with a nucleophilic compound such as the compound of formula XIII shown.

Other compounds of formula I can be prepared according to Scheme 6 or Scheme 7. It may also be possible to prepare the compounds of the present invention using variations of the above schemes known to those skilled in the art.

Scheme 6. Synthesis of Compound of Formula (I)

The synthesis described in Scheme 6 begins with commercially available or synthesized aldehydes. Two carbon homologizations and double-bond reductions (well known in the literature) result in compounds of formula (XV). Some compounds of formula XV are also commercially available and others can be prepared by other methods well known in the art. The preparation of compounds of formulas XVI and XVII is known in the literature as substrates and products of Evans chiral asymmetric synthesis. Hydrolysis results in the compound of formula XVIII. As with the compounds of formula VII in Scheme 2, these carboxylic acids can be obtained by reacting with amines of formula R ¹ R ² NH using well known amide coupling protocols. Hydrolysis of the tert-butyl ester yields a compound of formula XX, which is further coupled with a compound of formula VIII to provide a compound of formula I.

Scheme 7. Synthesis of Compound of Formula (I)

Scheme 7 also begins with a commercially available or synthetic aldehyde. They react with dimethyl succinate in the presence of a base to give a compound of formula XXI. The double bond of the compound of formula XXI is reduced to provide a compound of formula XXII. The reduction reaction may be carried out to provide racemates or the stereoselective catalyst may be used to provide the enantiomer of Formula XXII. Such reactions may result from hydrogenation from a hydrogen donor (eg, formic acid or cyclohexadiene), or hydrogenation with hydrogen gas, in the presence of a suitable catalyst. Amide coupling with amines of formula VIII using well known amide synthesis protocols yields compounds of formula XXIII. The hydrolysis of the methyl esters results in the compound of formula XXIV, which is further coupled with various amines or alcohols to give the amides of formula I and the esters of formula I, respectively.

Compounds of formula (I) can also be prepared according to Scheme 8.

Scheme 8. Synthesis of Compound of Formula (I)

The synthesis described in Scheme 8 begins with commercially available N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester. Differently protected aspartic acid derivatives can also be used for ease of synthesis. Beta carboxyl groups are coupled with amines of formula VIII using standard peptide coupling protocols. The alpha-carboxyl protecting group of the compound of formula XXV is removed by hydrogenolysis to provide the compound of formula XXVI. They are further coupled with amines of formula HNR ¹ R ² to provide compounds of formula XXVII. The amino protecting group is removed by treatment with a strong acid (eg trifluoroacetic acid or hydrogen chloride) in an organic solvent. The resulting compound of formula (XXVIII) is then reacted with various electrophilic reagents to produce the compound of formula (I). For example, they can be heated at various temperatures or coupled with halo-aromatic compounds using known methods including catalysis (stoichiometric amounts or catalytic amounts) using transition metals (eg palladium or copper) as catalysts. do. They can also react with various aldehydes or ketones under reducing alkylation conditions well known in the art. They can also react with isocyanates, acyl chlorides or carbamoyl chlorides to produce urea, amide or carbamate derivatives, respectively. It should be understood that the order of the modifications described above may vary depending on the choice of protecting groups and the order of their removal.

Compounds of formula (I) can also be prepared according to Scheme 9.

Scheme 9. Synthesis of Compound of Formula (I)

The synthesis described in Scheme 9 begins with the imine of formula XXIX prepared by condensation of ethyl glyoxalate with an amine of formula R ³ -NH ₂ . They react with 2-tert-butoxy-2-oxoethylzinc chloride to give compounds of formula XXX. Treatment with strong acid removes the tert-butyl ester protecting group to give a free acid of formula XXXI, which is coupled with an amine of formula VIII to give a compound of formula XXXII. The ethyl ester is hydrolyzed with a metal hydroxide salt or an aqueous base to give the free alpha-acid of formula XXXIII. These are then coupled with an amine of formula HNR ¹ R ² to afford a compound of formula I.

Ureidoamide  Intermediates and Example

General Example. ¹ H- and ¹³ C-NMR spectra were run on a Bruker 500 or 300 MHz instrument and chemical shifts were reported in ppm (δ) relative to tetramethylsilane (δ = 0.0). All evaporations were performed under reduced pressure. Unless stated otherwise, LC / MS analysis was performed on a Shimadzu instrument using a YMC C18 column (3 × 50 mm) for 3 minutes using a 2-minute linear gradient of solvent B 0% to 100% in solvent A. Run by operation. For LC / MS and Shimazu Preparative HPLC system, UV detector was set to 220 nm, solvent A was 10% methanol / 90% water / 0.1% trifluoroacetic acid and solvent B was 90% methanol / 10% water / 0.1% trifluoroacetic acid.

1-benzyl-2 ', 3'-dihydro-2'-oxospyro- [piperidine-4,4' (1'H) -quinazoline

Polyphosphoric acid (113 g) was heated to 100-110 ° C. and stirred with the addition of 1-benzyl-piperidin-4-one (9.27 ml, 50 mmol). Immediately thereafter, phenyl urea (9.55 g, 70 mmol) was added in portions in small amounts to prevent excessive foaming. The mixture was heated to 150-160 ° C. overnight. Water (200 mL) was then slowly added to the mixture and cooled to 100-110 ° C. (at lower temperatures the mixture became too viscous to stir). The resulting solution was neutralized to about pH 8 by addition of 10 N NaOH and then extracted with chloroform. After drying the organic phase with magnesium sulfate, the crude product obtained by concentration was purified by flash column chromatography on silica gel (6: 4 ethyl acetate / hexane) to give the desired product (9.0 g, 58%). Mass spectroscopy: 308.25 (MH) ⁺ .

2 ', 3'-dihydro-2'-oxospyro- [piperidine-4,4' (1'H) -quinazoline

Degassed methanol (50 ml) and 6-N hydrochloric acid (2.0 ml) 1-benzyl-2 ', 3'-dihydro-2'-oxospyro- [piperidine-4,4'(1'H)- To a solution of quinazoline (1.00 g) was added 10% palladium charcoal (150 mg). The mixture was stirred overnight under a hydrogen atmosphere of 60 psi on a Parr apparatus. LC / MS showed incomplete reaction. More 10% palladium charcoal (200 mg) was added and the mixture was further stirred for 2 days. At that point, all starting material was exhausted. The mixture was filtered and the filtrate was concentrated to give 531 mg (64%) of the desired compound. Mass spectroscopy: 218.12 (MH) ⁺ .

4-Amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester

To a well stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (9.0 g, 45.3 mmol) in methanol is added ammonium chloride (2.66 g, 49.8 mmol) at room temperature and for 1 hour. Stirred. Sodium cyanide (2.44 g, 49.8 mmol) was added and stirring continued for an additional 16 hours. The reaction mixture was quenched with 5% aqueous sodium hydrogen carbonate (50 mL) and diluted with water, then methanol was removed by rotary evaporation. Cyanoamine was extracted with methylene chloride (3 x 100 mL), dried over sodium sulfate and the solvent was evaporated to afford the desired compound as an oil in 91% yield.

2-phenyl-1,3,8-triaza-spiro [4.5] deck-1-en-4-one, hydrochloride

To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.44 mmol) in methylene chloride (30 mL) was added triethylamine (1.24 mL, 8.88 mol). And benzoyl chloride (936 mg, 6.66 mmol) was added. After 30 minutes, 4- (dimethylamino) pyridine (40 mg, 0.33 mmol) was added and stirring continued for an additional 12 hours. The reaction mixture was then quenched with 1 M sodium hydroxide (10 mL), diluted with ethyl acetate (100 mL) and isolated. The organic layer was washed sequentially with 1 M sodium hydroxide (40 mL), aqueous sodium hydrogen carbonate (50 mL), and brine (50 mL) and then dried over sodium sulfate. The desired product, 4-benzoylamino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester, was obtained in 90% yield through crystallization with 30% ethyl acetate in hexane as solvent.

To a solution of 4-benzoylamino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.3 g, 4 mmol) in ethanol (10 mL) was added 6 M sodium hydroxide (1.5 mL). Then, 30% hydrogen peroxide was added. The reaction mixture was refluxed for 3 hours. The reaction mixture was then diluted with water (30 mL) and 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. Crystallization of the desired product 4-oxo-2-phenyl-1,3,8-triaza-spiro [4.5] dec-1-ene-8-carboxylic acid tert-butyl ester from 30% ethyl acetate in hexane Obtained with a yield of 80%. The tert-butyl ester was then dissolved in methylene chloride (5 mL) and saturated hydrogen chloride solution in dioxane (25 mL) was added. After 2 hours, the solvent was removed to give 2-phenyl-1,3,8-triaza-spiro [4.5] dec-1-en-4-one, hydrochloride as a white powder, yield 95%.

5-formyl-indazole-1-carboxylic acid tert-butyl ester

A solution of methylene chloride (2 mL) of di-tert-butyldicarbonate (388 mg, 1.78 mmol) was added 1H-indazol-5-carbaldehyde (273 mg, 1.87 mmol), 4 in methylene chloride (10 mL). To a solution of -dimethylaminopyridine (114 mg, 0.94 mmol), and triethylamine (0.26 mL, 1.87 mmol) was added dropwise at room temperature. The resulting light yellow solution was stirred at rt for 16 h. The solvent was removed in vacuo to perform flash chromatography using silica gel (25 g) and ethyl acetate / hexanes (1: 1) containing 1% triethylamine as eluent to afford the title compound as a brownish yellow liquid. Obtained (414 mg, 90%).

5- (2-Benzyloxycarbonylamino-2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester

A solution of N- (benzyloxycarbonyl) -α-phosphonoglycine trimethyl ester (5.50 g, 16.6 mmol) and tetramethylguanidine (1.99 mL, 15.9 mmol) in anhydrous tetrahydrofuran (50 mL) at -78 ° C. Stir 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 through syringe for 10 minutes. The reaction mixture was stirred at -78 ° C for 4 hours and then warmed to room temperature overnight. The solvent was evaporated and the residue was subjected to flash chromatography on silica gel (1: 2 ethyl acetate / hexanes) to afford the title compound (5.77 g, 85%) as a white foam.

(±) -5- (2-amino-2-methoxycarbonyl-ethyl) -indazole-1-carboxylic acid tert-butyl ester

5- (2-benzyloxycarbonylamino-2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester (524 mg, 1.16 mmol) in methanol (20 mL) and 10 on carbon A mixture of% palladium (60 mg) was shaken for 4.5 hours under 50 psi hydrogen gas using a Parr hydrogenator. The reaction mixture was drained and purged with nitrogen. The reaction mixture was then filtered through a pad of celite, and the pad was washed with several aliquots of methanol. The methanol filtrate was evaporated to afford the title compound (351 mg, 95%).

(±) -5- (2-methoxycarbonyl-2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl ] -Amino} -ethyl) -indazole-1-carboxylic acid tert-butyl ester

5- (2-Amino-2-methoxycarbonyl-ethyl) -indazol-1-carboxylic acid tert-butyl ester (307 mg, 0.96 mmol) in methylene chloride, N, N-disuccinimidyl carbo A solution of nate (246 mg, 0.961 mmol) and N, N-diisopropylethylamine (0.67 mL, 3.84 mmol) was stirred at room temperature for 30 minutes. 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (238 mg, 1.03 mmol) was added and the reaction mixture was stirred at rt for 16 h. The solvent was evaporated and the flash chromatography using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent on the residue gave the product (259 mg, 47%).

2-trimethylsilanyl-ethanesulfonyl chloride

Sulfuryl chloride (43 ml, 539 mmol) was added to a clear solution of triphenylphosphine (129 g, 490 mmol) in methylene chloride (200 mL) in a flame-dried 3-neck round bottom flask. Add 3 minutes at &lt; RTI ID = 0.0 &gt; After stirring for 5 minutes at 0 ° C., the ice-water bath is removed and sodium 2-trimethylsilylethanesulfonate (50 g, 245 mmol) is added in portions over 10 minutes. The resulting white suspension was stirred at rt for 16 h and then filtered through a pad of celite. The filtrate was concentrated to about 50 mL and ethyl acetate / hexanes (1: 3, 1000 mL) and celite (40 g) were added. The mixture was stirred at rt for 15 min and filtered through a pad of celite. The solvent was removed in vacuo and the residue was loaded onto a pre-wet column of silica gel (300 mL) using 1: 3 ethyl acetate / hexanes as eluent. The solvent was removed and the title compound (41.9 g, 85%) was obtained as a light pale brown liquid. If not used immediately, the final product should be stored under nitrogen in a freezer or cold room to minimize deterioration.

1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indole-5-carboxylic acid ethyl ester

A solution of 1H-indole-5-carboxylic acid ethyl ester (10.31 g, 58.8 mmol) in dimethylformamide (50 mL) was added to a mixture of sodium hydride (1.83 g, 76.4 mmol) in dimethylformamide (150 mL). It was added dropwise at ℃. 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 added slowly to the mixture at 0 ° C. It was. After 2 h saturated aqueous ammonium chloride (200 mL) was added and the mixture was extracted with ethyl acetate (300 mL). After isolation, 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 solvent was removed in vacuo and flash chromatography on silica gel using 1: 1.5 methylene chloride / hexanes as eluent to the residue gave the title compound (15.8 g, 79%) as a white solid.

Similarly manufactured:

1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-carboxylic acid ethyl ester

[1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -methanol

A solution of diisobutylaluminum hydride (82.9 mL, 1 M in toluene, 82.9 mmol) was added to 1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indole-5-carboxylic acid in toluene (200 mL). To a solution of ethyl ester (8.81 g, 25.9 mmol) was added slowly at 0 ° C. After stirring for 45 min at 0 ° C., the reaction was quenched by addition of methanol (26 mL), triturated sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed to room temperature for 1 hour and filtered through a pad of celite. The solvent was removed in vacuo to yield the title compound as a highly viscous liquid that could be solidified by cooling. White solid (8.08 g, 100% yield).

[1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -methanol

1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazole-5-carboxylic acid ethyl ester in tetrahydrofuran (50 mL) azeotropically dried with toluene (2x), 5.77 g, 16.9 mmol) Was added to a mixture of lithium borohydride (3.68 g, 169 mmol) in tetrahydrofuran (100 mL) at 0 ° C. The mixture was allowed to warm to rt and stirred for 14 h. It was cooled to 0 ° C. and lithium borohydride (3.5 g) was added. The mixture was allowed to warm to rt and stirred for 14 h. It was cooled back 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 solvent was removed and the residue was subjected to flash chromatography with 1% triethylamine and ethyl acetate / hexanes (1: 1.5) to give the title compound as a white solid. Obtained (3.8 g, 72%).

1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indole-5-carbaldehyde

Activation of a solution of [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -methanol (2.1 g, 6.74 mmol) in methylene chloride (30 mL) in a 500 mL round bottom flask To a mixture of manganese dioxide (22 g, azeotropically dried with toluene (2x)) and methylene chloride (70 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and filtered through a pad of celite. The solvent was removed in vacuo to afford the title compound as a white solid (1.8 g, 80%).

Similarly manufactured:

1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-carbaldehyde

Mass spectrometry 311.10 (MH) ⁺ .

2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -acrylic acid methyl ester

1,1,3,3-tetramethylguanidine (0.68 mL, 5.43 mmol) was converted to N- (benzyloxycarbonyl) -α-phosphonoglycine trimethyl ester (1.88 g, 5.69 mmol) in tetrahydrofuran (40 mL). To a solution of was added at room temperature. The mixture was stirred at rt for 15 min and cooled to -78 ° C, then 1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indole-5-carbaldehyde (1.6 in tetrahydrofuran (15 mL) g, 5.17 mmol) was added slowly. The resulting reaction mixture was stirred at −78 ° C. for 2 hours and then warmed to room temperature for 3 hours. The solvent was removed in vacuo and flash chromatography on silica gel using 1% triethylamine and methylene chloride / hexanes (1: 1.5) as eluent to the residue gave the title compound as a 92: 8 Z / E mixture. It was measured (integrated by CO ₂ CH ₃ , 3.79 ppm of Z isomer, 3.65 ppm of E isomer). Z isomer:

Similarly manufactured:

2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -acrylic acid methyl ester

Flash chromatography on silica gel using methylene chloride containing 1% triethylamine as eluent gave the title compound as a 95: 5 Z / E mixture (-CH = C (CO ₂ Me) (NHCBz) Measured by integration of 3.72 g, 92%). Z isomer:

(±) -2-amino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -propionic acid methyl ester

To a flame-dried 500 mL round bottom flask, 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -acrylic acid methyl ester (2.24 g, 4.36 mmol), methanol (100 mL) and 10% palladium on charcoal (0.52 g) were added. The mixture was degassed and purged five times with hydrogen. It was stirred at rt for 1 h and filtered through a pad of celite. The solvent was removed and flash chromatography using ethyl acetate / hexanes (1: 1 and 2: 1) containing 1% triethylamine in the residue gave the title compound as a colorless viscous liquid which solidified on cooling. (1.27 g, 76%).

Similarly manufactured:

(±) -2-amino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester

In a glove bag with three vacuum / nitrogen purge cycles, the AIRFREE® (Schlenk) reaction flask with a stir bar was placed in the (-)-1,2-bis ( Filled with (2R, 5R) -2,5-diethylphospholano) benzene (cyclooctadiene) rhodium (I) trifluoromethylsulfonate (123 mg, 0.17 mmol, 5 mol%), After sealing it was removed from the glove bag. 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -acrylic acid methyl ester (1.75 g, 3.40 mmol) was equipped with a stir bar Was weighed into a second Airfree® (Slenk) reaction flask and sealed with a rubber membrane. After three vacuum / nitrogen purge cycles, it was dissolved in a mixture of anhydrous methanol (75 mL) and anhydrous methylene chloride (15 mL). Both solvents were deoxygenated and then added sparging with nitrogen for at least 1 hour. Once in solution, the mixture was again subjected to three vacuum / nitrogen purge cycles. The dehydroamino acid solution was injected via cannula into an AirFree® (Schillen) flask containing the catalyst. After five vacuum / hydrogen purge cycles were performed on the reaction mixture, the flask was opened to 1 atm of hydrogen (balloon). After 16 hours, the reaction mixture was purged with three vacuum / nitrogen purge cycles. The solvent was evaporated and column chromatography with a residue (gradient from 1: 4 ethyl acetate / hexanes to 1: 2 ethyl acetate / hexanes) gave 1.5 g (85%) of the title compound as a white solid, eluent Purity of the compound as determined by HPLC analysis using a Chirocel OD column using 80% hexanes / 20% ethanol was 98.4% ee (retention time: title compound 13.9 min, S-enantiomer 11.2 min) .

(R) -2-Amino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester in methanol (50 mL) g, 2.40 mmol) and a mixture of 10% palladium (124 mg) on carbon were stirred in a Parr hydrogenator under 50 psi of hydrogen for 2 hours. The reaction mixture was purged with three vacuum / nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was washed with several aliquots of methanol. The methanol filtrate was evaporated to give 879 mg (96%) of the title compound as a sticky gum.

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) is added triethylamine (7.83 mL, 56.2 mL, 3 equiv) followed by pure 2-trimethylsilanyl- Ethanesulfonyl chloride (5.60 g, 28.1 mmol, 1.5 equiv) was added dropwise. The mixture gradually became homogeneous and stirred for 16 hours at room temperature. The solution was concentrated to a minimum amount of methylene chloride and then flash column chromatography on silica gel (1: 4 ethyl acetate / hexanes) to give 4.7 g (77%) of the product as a cloudy yellow solid.

2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -acrylic acid methyl ester

Add tetramethylguanidine (1.78 mL, 1.05 equiv) to a solution of N- (benzyloxycarbonyl) -α-phosphonoglycine trimethyl ester (4.93 g, 14.9 mmol, 1.1 equiv) in anhydrous tetrahydrofuran (75 mL) It was. The mixture was stirred at room temperature under nitrogen for 5 minutes and then cooled to -78 ° C. After 15 min stirring at -78 ° C, a solution of 7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazole-5-carbaldehyde in tetrahydrofuran (25 mL) is added It was. The reaction mixture was slowly warmed to room temperature overnight. Even if the reaction was incomplete, the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and washed with 1 M sulfuric acid. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Flash column chromatography (1: 4 ethyl acetate / hexanes) gave 2.66 g (37%) of the product as a white glass foam.

(R) -2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid methyl ester

In a glove bag with three vacuum / nitrogen purge cycles, the Airfree® (Schlenk) reaction flask with stir bar was charged with (-)-1,2-bis ((2R, 5R) -2,5-di Filled with ethylphospholano) benzene (cyclooctadiene) rhodium (I) trifluoromethylsulfonate (259 mg, 0.36 mmol, 9 mol%), sealed with a rubber membrane and removed from the glove bag. 2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -acrylic acid methyl ester (2.03 g, 3.83 mmol) It was metered into a second AirFree® (Schillen) reaction flask equipped with a stir bar and sealed with a rubber membrane. After three vacuum / nitrogen purge cycles, it was dissolved in dry methanol (80 mL, added by sparging with nitrogen for at least 1 hour after deoxygenation). Once in solution, again three vacuum / nitrogen purge cycles were performed. The dehydroamino acid solution was transported via cannula to an AirFree® (Schenk) reaction flask containing a catalyst. The reaction mixture was purged with five vacuum / hydrogen purge cycles and the flask was opened to a hydrogen balloon (1 atm). After 2.5 hours, the reaction mixture was purged with three vacuum / nitrogen purge cycles. Evaporate the solvent and perform column chromatography with residue (gradient from 1: 4 ethyl acetate / hexanes to 1: 2 ethyl acetate / hexanes) to give 1.4 g (68%; ee = 99.2%) of the title compound as a white solid. Obtained.

(R) -2-amino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] propionic acid methyl ester

2-benzyloxycarbonylamino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid methyl ester in methanol (40 mL) g, 2.54 mmol) and 10% palladium on carbon (135 mg) were stirred under 55 psi of hydrogen using a Parr apparatus for 3.0 hours. The reaction mixture was purged with three vacuum / nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was washed with several aliquots of methanol. The methanol filtrate was evaporated to give the title compound (1.01 g, quantitative yield) as sticky gum.

(R) -3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -2-{[4- (2-oxo-1,4- Dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

2-Amino-3- [7-methyl-2- (2-trimethylsilanyl-ethanesulfonyl) -2H-indazol-5-yl] -propionic acid methyl ester (500 mg, 1.26 mmol), N, N- A mixture of diisopropylethylamine (0.66 mL, 3.77 mmol) and disuccinimidylcarbonate (322 mg, 1.26 mmol) was stirred together in methylene chloride (20 mL) at room temperature for 30 minutes. 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (444 mg, 1.35 mmol) was then added and the reaction mixture was stirred at rt overnight. The solvent was evaporated and flash column chromatography (1: 4 acetone / ethyl acetate) was performed with the residue to give 490 mg (yield 60%) of the title compound as a white solid.

Similarly manufactured:

(±) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -propionic acid methyl ester

(R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester

(R) -2-Amino-3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester in methylene chloride (20 mL) (764 mg, 1.99 mmol), N, N-diisopropylethylamine (1.10 mL, 5.97 mmol) and disuccinimidylcarbonate (509 mg, 1.99 mmol) were stirred at room temperature for 40 minutes. 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (purity 70%, 703 mg, 2.13 mmol) was then added and the reaction mixture was stirred at rt overnight. . The solvent was evaporated in vacuo and flash column chromatography (1: 4 acetone / ethyl acetate) was carried out with the residue to give 1.15 g (90%) of the title compound.

Similarly manufactured:

(±) -2-{[4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- ( 2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -methyl propionate

(±) -2-{[4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- ( 2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester

(±) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -propionic acid methyl ester

(±) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester

Example  One

(±) -3- (1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid

5- (2-methoxycarbonyl-2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} A solution of -ethyl) -indazole-1-carboxylic acid tert-butyl ester (168 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL) in methanol (5 mL) and cooled to 0 ° C. A solution of lithium hydroxide monohydrate (49 mg, 2.04 mmol) in water (5 mL) was added. The reaction mixture was stirred at 0 ° C. for 6 hours and then placed in the freezer for an additional 16 hours. The solvent was removed in vacuo and the residue was dissolved in water (15 mL). 1 N hydrochloric acid was added to the aqueous solution to adjust the pH to about 1. The resulting white precipitated solid was collected by filtration. The solid was dried under vacuum to afford the title compound (108 mg, 80%).

(R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] propionic acid

(R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine- in tetrahydrofuran (9 mL) and methanol (3 mL) A solution of 1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester (775 mg, 1.21 mmol) was added to 0 Cooled to ° C. A solution of lithium hydroxide monohydrate (115 mg, 4.84 mmol) in water (3 mL) was added. The reaction mixture was stirred at 0 ° C. for 2 hours and placed in -15 ° C. freezer for 16 hours. While the reaction mixture was cooled in an ice bath, 1 N hydrochloric acid (3.8 mL) was added to increase the pH to about 7. The organic solvent was removed under vacuum. 1 N hydrochloric acid (0.5 mL) was further added to the resulting aqueous solution, followed by extraction with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and evaporated to give 684 mg (90%) of the title compound as a white solid.

Similarly manufactured:

(±) -2-{[4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- ( 2-Trimethylsilanyl-ethanesulfonyl) -1H-indol-5-yl] -propionic acid

Mass spectroscopy 612.25 (MH) ⁺ .

(±) -2-{[4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl] -amino} -3- [1- ( 2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid

Mass spectrometry 613.26 (MH) ⁺ .

(±) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-Trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide

Similarly manufactured:

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl-1 '-Yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-ylmethyl] -ethyl} -amide

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl-1 '-Yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-ylmethyl] -ethyl} -amide

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide

Purification by silica gel chromatography using methylene chloride: methanol / triethylamine (90: 10: 0.5) as eluent.

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid {2- (4-isobutyl-piperazine-1- Yl) -2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-ylmethyl] -ethyl} -amide

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid {2- (1,4-dioxa-8-aza -Spiro [4.5] deck-8-yl) -2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-ylmethyl] -ethyl} -amide

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid {2- (4-isobutyl-piperazine-1- Yl) -2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid {2- (1,4-dioxa-8-aza -Spiro [4.5] deck-8-yl) -2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide

Example  2

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide (568 mg, 0.73 mmol) and cesium A solution of fluoride (1.11 g, 7.31 mmol) was heated in acetonitrile (50 mL) to 80 ° C. for 4.5 h. The reaction mixture was concentrated and flash column chromatography (methylene chloride / methanol / triethylamine, 94: 5: 1) with the residue gave 280 mg (yield 63%) of the title compound as a white solid, which was eluted. Purity of the compound was 98.2% ee as determined by HPLC analysis using a Chicellel OD column using 20% B (A = ethanol, B = 0.05% diethylamine in hexane) (retention time: 9.51 min. S-enantiomer 15.9 minutes).

Similarly manufactured:

Example  3

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1 '-Yl-1- (1H-indol-5-ylmethyl) -2-oxo-ethyl] -amide

Example  4

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1 '-Yl-1- (1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

Example  5

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (1H-indol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] BP in acetonitrile (5 mL) Ferridinyl-1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indol-5-ylmethyl] -ethyl} -amide (52 mg, 0.067 mmol) , A mixture of cesium fluoride (51 mg, 0.33 mmol) was heated to 80 ° C. for 4 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent to afford the title compound as a white solid (yield 70%).

Example  6

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

Purification by silica gel chromatography using methylene chloride: methanol: triethylamine (93: 5: 2) as eluent gave the title compound as a white solid (90% yield).

A separate synthesis was obtained by the chiral separation of racemates using the (Example 1) (R) -enantiomers described above using the following conditions: Chilacell OD preparative column, 50 × 500 mm, 20 μm; A = EtOH, B = 0.05% diethylamine / hexane; 45 minutes at 20% B at 65 ml / min; Retention time: 20.5 minutes for the R enantiomer and 32.8 minutes for the S enantiomer.

Example  7

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidin-1-carboxylic acid [1- (1H-indol-5-ylmethyl)- 2- (4-isobutyl-piperazin-1-yl) -2-oxo-ethyl] -amide

Example  8

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid [2- (1,4-dioxa-8-aza -Spiro [4.5] deck-8-yl) -1- (1H-indol-5-ylmethyl) -2-oxo-ethyl] -amide

Example  9

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidin-1-carboxylic acid [1- (1H-indazol-5-ylmethyl) -2- (4-isobutyl-piperazin-1-yl) -2-oxo-ethyl] -amide

Example  10

(±) -4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid [2- (1,4-dioxa-8-aza -Spiro [4.5] deck-8-yl) -1- (1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

Example  11

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (1,4-dioxa-8- Aza-spiro [4.5] deck-8-yl) -1- (1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

3- (1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi in dimethylformamide (5 mL) 1,4 in methylene chloride (5 mL) in a solution of ferridine-1-carbonyl] -amino} -propionic acid (95 mg, 0.21 mmol) and N, N-diisopropylethylamine (0.14 mL, 0.82 mmol) A solution of Dioxa-8-azaspiro [4,5] decane (32 mg, 0.23 mmol) and PyBOP® (107 mg, 0.21 mmol) was added. The reaction mixture was stirred at rt for 16 h. All solvents were removed under high vacuum. The residue was subjected to flash column chromatography using methylene chloride / methanol / triethylamine (93: 5: 2) to give the title compound as a white solid (67 mg, yield 56%).

4-Bromo-2,6-dimethylphenyldiazo-t-butyl sulfide

4-Bromo-2,6-dimethylaniline (20.00 g, 100 mmol) was ground to a powder using a mortar and pestle and then suspended in 24% hydrochloric acid (41 mL). The stirred mixture was cooled to -20 ° C, treated with sodium nitrite (7.24 g, 1.05 equiv) in water (16 mL) and added dropwise over 40 minutes while maintaining the temperature below -5 ° C. After an additional 30 minutes at −5 ° C. to −20 ° C., the mixture was buffered to about pH 5 by treatment with solid sodium acetate. This mixture (maintained at about −10 ° C.) was added to a stirred solution of t-butyl thiol (11.3 mL, 1 equiv) in ethanol (100 mL) over portions of about 10 minutes at 0 ° C. After the addition, the mixture was stirred at 0 ° C. for 30 minutes and then crushed ice (about 150 mL) was added. This 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%). This compound appears to be stable as a solid, but has involved significant alterations when attempting to recrystallize from ethanol.

5-bromo-7-methylindazole

To a flame-dried round bottom flask, 4-bromo-2,6-dimethylphenyldiazo-t-butyl sulfide (12.50 g, 41.5 mmol) and potassium t-butoxide (46.56 g, 10 equiv) were combined It was. A stir bar was placed 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 injected into a mixture of crushed ice (400 mL) and 10% hydrochloric acid (200 mL). The resulting suspension was left at 4 ° C. overnight, 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 then evaporated to give the product as a gray solid (7.60 g, 87%).

7-methylindazole-5-carboxaldehyde

5-bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in inorganic oil, 1.27 g, 1.1 equiv) were weighed into a flame-dried round bottom flask containing a magnetic stir bar Put in. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at rt for 15 min and homogenized during this time. The stirred mixture was cooled to −70 ° C. and a sec-butyllithium solution in cyclohexane (1.4 M, 45 mL, 2.2 equiv) was added over several minutes. After 1 hour at -70 ° C, dimethylformamide (10 mL) was added over several minutes. The mixture was warmed to rt and stirred overnight. Then cooled to 0 ° C. and treated carefully with 1 N hydrochloric acid (60 mL). After a few minutes, solid sodium bicarbonate was added to the mixture to basify to pH 9-10. The layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were extracted with 0.8 M sodium hydrogen sulfate (3 x 125 mL). The combined aqueous phases were washed with ethyl acetate (100 mL) and then treated with solid sodium hydroxide to adjust the pH to about 10. 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 afford the product as a light pale brown solid (3.01 g, 65%).

2-benzyloxycarbonylamino-3- (7-methyl-1H-indazol-5-yl) -acrylic acid methyl ester

A solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (5.51 g, 1.2 equiv) in stirred tetrahydrofuran (30 mL) was treated with tetramethylguanidine (1.91 mL, 1.1 equiv). After 10 minutes, 7-methylindazole-5-carboxaldehyde (2.22 g, 13.86 mmol) in tetrahydrofuran (20 mL) was added. The disappearance of starting material was monitored by TLC and LC / MS. After 5 days at room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 2% 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 / hexanes to give the product as a colorless foam (4.93 g, 97%).

(±) -2-amino-3- (7-methyl-1H-indazol-5-yl) -propionic acid methyl ester

Nitrogen bubbling a solution of 2-benzyloxycarbonylamino-3- (7-methyl-1H-indazol-5-yl) -acrylic acid methyl ester (4.93 g, 13.49 mmol) in methanol (125 mL) Degassed for 30 minutes by passing through, and carefully added 10% palladium (0.6 g) on charcoal. The mixture was hydrogenated at 40 psi overnight in a Parr shaker apparatus. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated in vacuo to give the product as a colorless foam (3.62 g, quantitative yield).

Example  12

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid methyl ester

A solution of (±) -2-amino-3- (7-methyl-1H-indazol-5-yl) -propionic acid methyl ester (162.9 mg, 0.698 mmol) in methylene chloride (3 mL) stirred at room temperature Treated with bonyl diimidazole (113.2 mg, 1 equiv). After 1.5 h at rt, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (161.5 mg, 1 equiv) was added. The mixture was stirred at rt overnight. The white precipitate was foamed until the desired product was obtained. The solvent was evaporated and the residue was triturated with methylene chloride. The product was collected by filtration, washed with methylene chloride and dried in vacuo to give a white solid (241.5 mg, 71%). Some product remained in the parent liquid.

Similarly manufactured:

Example  13

3- (7-methyl-1H-indazol-5-yl) -2- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-(1H) -quina Sleepy) carbonyl amino] -propionic acid methyl ester

Example  14

3- (7-methyl-1H-indazol-5-yl) -2- (1,2-dihydro-2-oxosispir-4H-3,1-dihydro-benzoxazine-4'4-py Ferridine-carbonylamino) -propionic acid methyl ester

Mass spectroscopy: 478.15 (MH) ⁺ .

3- (7-methyl-1H-indazol-5-yl) -2 {3 ', 4'-dihydro-2'-oxospyro- (piperidine-4, 4'-(1H) -quinolinecar Carbonyl amino} -propionic acid methyl ester

3- (7-methyl-1H-indazol-5-yl) -2- [2'-phenyl-1 ', 3', 8'-triaza-spiro (4 ', 5') deo-1-ene -8-carbonyl amino] -propionic acid methyl ester

Example  15

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-di in 1: 1 tetrahydrofuran / methanol (20 mL) A suspension of hydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester (240.0 mg, 0.489 mmol) was added to lithium hydroxide in water (10 mL) (140.5). mg, 7 equivalents) at room temperature. Within 1 minute, the mixture was homogenized and placed at 4 ° C. overnight. The solvent was evaporated at about 30 ° C. and treated with 1 N hydrochloric acid to adjust the pH to about 1. The resulting white suspension was stored at 4 ° C. for several hours, the product was collected by filtration, washed with a small amount of water and dried in vacuo (169.0 mg, 73%). Solid sodium chloride was added to the filtrate to further precipitate the product (5.2 mg, 75% total yield).

Similarly manufactured:

3- (7-methyl-1H-indazol-5-yl) -2- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-(1H) -quina Zolinecarbonyl Amino] -propionic acid

3- (7-methyl-1H-indazol-5-yl) -2- (1,2-dihydro-2-oxosispir-4H-3,1-dihydro-benzoxazine-4'4-py Ferridine-carbonylamino) -propionic acid methyl ester

3- (7-Methyl-1H-indazol-5-yl) -2 {3 ', 4'-dihydro-2'-oxospyro- (piperidine-4,4'-(1H) -quinoline- Carbonyl amino} -propionic acid

3- (7-methyl-1H-indazol-5-yl) -2- [2'-phenyl-1 ', 3', 8'-triaza-spiro (4 ', 5') deo-1-ene -8-carbonyl amino] -propionic acid

Example  16

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo in 2: 1 dimethylformamide / methylene chloride (1.5 mL) stirred at 0 ° C A solution of -1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid (65.7 mg, 0.138 mmol) was added to 4- (1-piperidyl ) -Piperidine (46.5 mg, 2 equiv), diisopropylethylamine (0.048 mL, 2 equiv) and PyBOP® (75.5 mg, 1.05 equiv). The ice bath was left to melt and the mixture was stirred at rt overnight. The solvent was removed under high vacuum and the residue was purified by flash chromatography on silica gel eluted with 18: 1 methylene chloride / methanol containing 1% triethylamine to give the product as a pale-yellow solid (80.4 mg, 93%).

Similarly manufactured:

Example  17

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (7-methyl-1H-indazole- 5-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide

Example  18

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1-dimethylcarbamoyl-2- (7- Methyl-1H-indazol-5-yl) -ethyl] -amide

Example  19

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (7-methyl-1H-indazole- 5-ylmethyl) -2- (4-methyl-piperazin-1-yl) -2-oxo-ethyl] -amide

Example  20

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (7-methyl-1H-indazole- 5-ylmethyl) -2-oxo-2-pyrrolidin-1-yl-ethyl] -amide

Example  21

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (7-methyl-1H-indazole- 5-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide

Example  22

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (7-methyl-1H-indazole- 5-ylmethyl) -2-oxo-2- (4-pyridin-2-yl-piperazin-1-yl) -ethyl] -amide

Example  23

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide

Example  24

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- (1-piperidinyl) -2-oxoethyl] -2 ', 3'-dihydro-2'- Oxostrophi- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide

Example  25

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide

Example  26

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- (1-piperidinyl) -2-oxoethyl] -1 ', 2'- dihydro-2'- Oxostroph- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide

Example  27

(±)-[1-dimethylcarbamoyl-2- (7-methyl-1H-indazol-5-yl) -ethyl] -1 ', 2'-dihydro-2'-oxospyro- [4H- 3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide

Example  28

(±)-[1- (2-adamantyl-carbamoyl) -2- (7-methyl-1H-indazol-5-yl) -ethyl] -1 ', 2'-dihydro-2' Oxose-pyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide

Example  29

(±) -1 ', 2'-dihydro-2'-oxospyro- [4H-3', 1-benzoxazine-4,4'-piperidine-1-carboxylic acid [1- (7 -Methyl-1H-indazol-5-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide

Example  30

(±) -1 ', 2'-dihydro-2'-oxospyro- [4H-3', 1-benzoxazine-4,4'-piperidine-1-carboxylic acid {2- (7 -Methyl-1H-indazol-5-yl) -1-[(pyridin-4-ylmethyl) -carbamoyl] -ethyl} -amide

Example  31

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] 3 ', 4'-di Hydro-2'-Oxospyro- [piperidine-4,4 '-(1H) -quinoline] -1-carboxamide

Example  32

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-piperidinyl] -2-oxoethyl] 3 ', 4'-dihydro-2'-oxo Spiro- [piperidine-4,4 '-(1H) -quinoline] -1-carboxamide

Example  33

(±)-[1-Dimethylcarbamoyl-2- (7-methyl-1H-indazol-5-yl) -ethyl] 1-3 ', 4'-dihydro-2'-oxospyro- [pi Ferridine-4,4 '-(1H) -quinoline] -1-carboxamide

Example  34

(±) -4-oxo-2-phenyl-1,3,8-triaza-spiro [4,5] dec-1-ene-8-carboxylic acid {1- (7-methyl-1H-indazole -5-ylmethyl) -2- [1,4] bipiperidinyl-1'-yl-2-oxo-ethyl} -amide

Example  35

(±) -4-oxo-2-phenyl-1,3,8-triaza-spiro [4,5] dec-1-ene-8-carboxylic acid {1- (7-methyl-1H-indazole -5-ylmethyl) -2- [1-piperidinylyl] -2-oxo-ethyl} -amide

Example  36

(±) -4-oxo-2-phenyl-1,3,8-triaza-spiro [4,5] dec-1-ene-8-carboxylic acid [1-dimethylcarbamoyl-2- (7 -Methyl-1H-indazol-5-yl) -ethyl] amide

Example  37

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {1- (1H-indazol-5-ylmethyl) -2- Oxo-2- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -ethyl} -amide

Example 38

4- (3- (1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1- Carbonyl] -amino} -propionyl) -piperazine-1-carboxylic acid benzyl ester

Example  39

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (1H-indazol-5-ylmethyl) -2- Oxo-2-piperazin-1-yl-ethyl] -amide

4- (3- (1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-in methanol (50 ml)- To a degassed solution of piperidine-1-carbonyl] -amino} -propionyl) -piperazine-1-carboxylic acid benzyl ester (280 mg, 0.42 mmol), 10% palladiumated charcoal (50 mg) is added It was. The mixture was stirred in a Parr apparatus under 50 psi of hydrogen atmosphere for 3 hours. The mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the desired product in 91% yield. LC / MS: t _R = 1.22 min, 531 (MH) ⁺ .

Example  40a

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {1- (1H-indazol-5-ylmethyl) -2- [4- (2-Methyl-butyl) -piperazin-1-yl] -2-oxo-ethyl} -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (1H-indazol-5-) in methanol (25 mL) A stirred solution of ylmethyl) -2-oxo-2-piperazin-1-yl-ethyl] -amide (100 mg, 0.188 mmol) was treated with 2-methyl-butyraldehyde (0.03 ml, 0.376 mmol). . After 1 hour at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. This mixture was stirred overnight. The solution was filtered through an SCX cartridge. The cartridge was first eluted with methanol and eluted with ammonia solution (1 M) in methanol. The solvent was removed in vacuo to afford the desired product in 50% yield. LC / MS: t _R = 1.31 min, 601 (MH) ⁺ .

Example  General experimental procedure for the manufacture of 40b-40k

Suitable aldehyde (0.04 mmol) was added to a solution of piperazine (0.02 mmol) in methanol (2.0 mL) of Example 39 and the resulting solution was stirred at rt for 1 h. Sodium triacetoxyborohydride (0.2 mmol) was then added and the solution was stirred at rt overnight. The solution was filtered through an SCX cartridge and the cartridge was washed with methanol and ammonia / methanol solution. The ammonia / methanol solution was concentrated in vacuo and the crude product was purified by preparative HPLC to give the products listed in Table 1.

Example  41a

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester

(±) -2-amino-3- (7-methyl-1H-indazol-5-yl) -propionic acid (20 mg, 0.042 mmol) in methylene chloride (2 mL) and dimethylformamide (1 mL), 4 Cyclohexanol in a stirred solution of-(dimethylamino) pyridine (2.5 mg, 0.02 mmoles), and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) (13.3 μl, 0.126 mmol) was added. The reaction mixture was stirred at 50-55 ° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by preparative TLC on silica gel (9: 1 chloroform / methanol) to give the desired product as a white solid (9.4 mg, 40%).

Similarly manufactured:

Example  41b

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-benzyl-piperidin-4-yl ester

Example  41c

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester

Example  41d

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester

Example  41e

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid (R) -1-pyridin-4-yl-ethyl ester

Example  41f

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine-1- Carbonyl] -amino} -propionic acid (S) -1-pyridin-4-yl-ethyl ester

4-Bromo-2-chloro-6-methylphenyldiazo-t-butyl sulfide

4-bromo-2-chloro-6-methylaniline (4.0 g, 18.3 mmol) was suspended in 24% hydrochloric acid (5 mL). The stirred mixture was cooled to -20 [deg.] C. and treated dropwise with sodium nitrite (1.32 g, 1.05 equiv) in water (2 mL) maintaining the temperature at -5 [deg.] C. for 10 minutes. After an additional 30 minutes at −5 ° C. to −20 ° C., the mixture was buffered to about pH 5 by addition of solid sodium acetate. This mixture (maintained at about −10 ° C.) was added in portions over about 10 minutes to a solution of t-butyl thiol (2.06 mL, 1 equiv) in ethanol (18.5 mL) stirred at 0 ° C. After addition, the mixture was stirred at 0 ° C. for 30 minutes and then crushed ice (about 50 mL) was added. This mixture was stored in the refrigerator overnight. The resulting light-brown solid was collected by filtration, washed with water and dried under high vacuum for several hours (4.60 g, 78%). Mass spectroscopy: 323.03 (MH) ⁺ .

5-bromo-7-chloroindazole

In a flame-dried round bottom flask, 4-bromo-2-chloro-6-methylphenyldiazo-t-butyl sulfide (4.60 g, 14.4 mmol) and potassium t-butoxide (16.1 g, 10 equiv) Combined. A stir bar was placed and the mixture was placed under nitrogen. To this was added dry DMSO (50 mL). The mixture was stirred vigorously for 10 minutes at room temperature. The reaction mixture was then carefully injected into a mixture of crushed ice (150 mL) and 10% hydrochloric acid (74 mL). The resulting suspension was placed at 4 ° C. overnight and the solids were collected by filtration and washed with water. The solid was collected and dried in vacuo to yield 2.86 g (86%) of a beige solid.

7-chloroindazole-5-carboxaldehyde

5-bromo-7-chloroindazole (2.0 g, 8.7 mmol) and sodium hydride (221 mg, 1.1 equiv) were weighed into a flame-dried round bottom flask with a magnetic stir bar. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. This mixture was homogenized by stirring at room temperature for 15 minutes. The stirred mixture was cooled to -78 ° C and a solution of tert-butyllithium in pentane (1.7 M, 10.5 mL, 2.0 equiv) was added over several minutes. After 30 minutes at −78 ° C., the reaction was gradually warmed to −50 ° C., held for 15 minutes, and then cooled to −78 ° C. again. Dimethylformamide (2.8 mL) was added slowly and the mixture was warmed to -50 ° C. The solution was quickly transferred to a separatory funnel containing diethyl ether and water. Aqueous was acidified with the addition of 1 M potassium hydrogen sulphate and neutralized with the addition of sodium bicarbonate. The aqueous was washed with water, then extracted with diethyl ether (3x) washed with brine, dried over magnesium sulfate and concentrated to give 1.7 g (100%) of a nearly pure material. Analytical pure samples were obtained by recrystallization from hot methanol.

2-benzyloxycarbonylamino-3- (7-chloro-1H-indazol-5-yl) -acrylic acid methyl ester

The suspension of potassium tert-butoxide (375 mg, 1.2 equiv) in stirred methylene chloride (20 mL) is cooled to -20 ° C and N-benzyloxycarbonyl-α-phosphonoglycine in methylene chloride (5 mL) Treated with a solution of trimethyl ester (1.11 g, 1.2 equiv). After 10 minutes, 7-chloroindazole-5-carboxaldehyde (0.50 g, 2.79 mmol) in methylene chloride (5 mL) was added. The reaction was gradually warmed to room temperature and stirred for 3 days. The reaction was poured into a separatory funnel containing water and diethyl ether. The aqueous was extracted with diethyl ether (3x) washed with brine, dried over magnesium sulfate and concentrated. Column chromatography gave 0.20 g (40%) of starting material and 0.40 g (37%) of product.

(±) -2-amino-3- (7-chloro-1H-indazol-5-yl) -propionic acid methyl ester

A solution of 2-benzyloxycarbonylamino-3- (7-chloro-1H-indazol-5-yl) -acrylic acid methyl ester (300 mg, 0.78 mmol) in methanol (10 mL) was diluted with trifluoroacetic acid (0.2 mL), flushed with nitrogen, and 10% palladium on charcoal (30 mg). This flask was flushed with hydrogen and stirred under hydrogen atmosphere. After 4 days, all starting material was exhausted. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 78 mg (40%).

Example  42

(±) -3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperi Din-1-carbonyl] -amino} -propionic acid methyl ester

Solution of (±) -2-amino-3- (7-chloro-1H-indazol-5-yl) -propionic acid methyl ester (78 mg, 0.31 mmol) in tetrahydrofuran (2 mL) stirred at 0 ° C Was treated with carbonyl diimidazole (50 mg, 1 equiv). The reaction was stirred for 5 minutes, warmed to room temperature, then stirred for 10 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (78 mg, 1.1 equiv. ). The mixture was stirred at rt overnight. The solvent was evaporated and the residue was purified by column chromatography to give 148 mg (94%) of white powder.

Example  43

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-chloro-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

(±) -3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4 in 1: 1 tetrahydrofuran / methanol (1 mL) at room temperature A suspension of -dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester (15 mg, 0.029 mmol) was added to lithium hydroxide in water (0.25 mL). (3.0 mg, 2.5 equiv) of solution and the resulting solution was stirred for 1.5 h. The solution was cooled to 0 ° C., treated with aqueous 1 M potassium hydrogen sulfate (60 L, 2.0 equiv) and then concentrated to give a crude acid which was used immediately without purification. Crude acid is dissolved in dimethylformamide (0.3 mL), methylene chloride (0.15 mL), 4-piperidyl-piperidine (10.1 mg, 2 equiv), diisopropylethylamine (10 μl, 2 equiv), And PyBOP® (16.5 mg, 1.1 equiv) sequentially. The solution was stirred for 30 minutes and concentrated. The product was purified by column chromatography to give 14.7 mg (77%, 2 steps).

4-bromo-2-ethyl-6-methyl-phenylamine

2-ethyl-6-methyl-phenylamine (14 mL, 100 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and water (220 mL) and cooled to 0 ° C. Bromine (5.1 mL, 1 equiv) was added dropwise. White precipitate formed quickly. The precipitate was filtered off and washed with diethyl ether. The precipitate was suspended in water and neutralized with aqueous potassium carbonate. Extraction with diethyl ether gave an oil. The ether was dried over potassium carbonate, filtered and concentrated to give 7.0 g (33%) of purple oil which was used without purification. Mass spectroscopy: 214.01 (MH) ⁺ .

4-Bromo-2-ethyl-6-methylphenyldiazo-t-butyl sulfide

4-bromo-2-ethyl-6-methylaniline (7.0 g, 33 mmol) was suspended in 7.8 M hydrochloric acid (30 mL). The stirred mixture was cooled to −20 ° C. and treated dropwise with sodium nitrite (2.27 g, 1.05 equiv) in water (5 mL) while maintaining the temperature at −5 ° C. dropwise. After an additional 30 minutes at −5 ° C. to −20 ° C., the mixture was buffered to about pH 5 by treatment with sodium acetate. This mixture (maintained at about −10 ° C.) was added in portions to a solution of t-butyl thiol (3.7 mL, 1 equiv) in ethanol (50 mL) at 0 ° C. for 10 minutes. After addition, the mixture was stirred at 0 ° C. for 30 minutes and crushed ice (about 50 mL) was added. The mixture was stored for 2 hours in the refrigerator. The resulting light-brown solid was collected by filtration, washed with water and dried under high vacuum for several hours (9.47 g, 92%). Mass spectroscopy: 315.05 (MH) ⁺ .

5-bromo-7-ethyl-1H-indazole

A solution of potassium t-butoxide (33.6 g, 10 equiv) in stirred DMSO (200 mL) was added 4-bromo-2-ethyl-6-methylphenyldiazo-t-butyl sulfide (9.4 in DMSO (100 mL)). g, 30 mmol) was added via cannula to the solution. The mixture was stirred vigorously for 1 hour. The reaction mixture was then carefully injected into a mixture of crushed ice (500 mL), concentrated hydrochloric acid (25 mL), and water (100 mL). The resulting precipitate was filtered off, washed with water, dissolved in methanol and concentrated to give 5.7 g (85%) of a light brown solid.

7-ethyl-1H-indazol-5-carbaldehyde

5-bromo-7-ethyl-1H-indazole (2.0 g, 8.9 mmol) and sodium hydride (226 mg, 1.1 equiv) were weighed into a flame-dried round bottom flask containing a magnetic stir bar. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (60 mL) was added. The mixture was stirred at rt for 15 min. The stirred mixture was cooled to −78 ° C. and a tert-butyllithium solution (1.7 M, 10.5 mL, 2.0 equiv) in pentane was added over several minutes. After 15 minutes at -78 ° C, the reaction was gradually warmed to -50 ° C and cooled back to -78 ° C. Dimethylformamide (2.8 mL) was added slowly and the mixture was warmed to -50 ° C. The solution was quickly transferred to a stirred solution of 300 mL of water and 1 M potassium hydrogen sulfate (25 mL). The resulting suspension was extracted with diethyl ether, washed with water and then brine, dried over magnesium sulfate and concentrated. Column chromatography gave 160 mg (10%) as a white solid.

2-benzyloxycarbonylamino-3- (7-ethyl-1 H-indazol-5-yl) -acrylic acid methyl ester

N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (0.61 g, 2.0 equiv) and 7-ethyl-1H-indazol-5-carbaldehyde in tetrahydrofuran (5 mL) stirred at 0 ° C. To a solution of 160 mg, 0.92 mmol) tetramethylguanidine (0.22 mL, 1.9 equiv) was added. The reaction was slowly warmed to room temperature overnight. The reaction was concentrated, dissolved in diethyl ether, washed with water and then brine, dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography to give 333 mg (95%) as an oil.

(±) -2-amino-3- (7-ethyl-1H-indazol-5-yl) -propionic acid methyl ester

In a solution of 2-benzyloxycarbonylamino-3- (7-ethyl-1H-indazol-5-yl) -acrylic acid methyl ester (330 mg, 0.78 mmol) in methanol (5 mL) under nitrogen, palladium on char ( 10%, 33 mg) was added. The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated to yield 210 mg (98%) of the material used without purification.

Example  44

(±) -3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid methyl ester

(±) -2-amino-3- (7-ethyl-1H-indazol-5-yl) -propionic acid methyl ester (100 mg, 0.41 mmol) in tetrahydrofuran (2 mL) stirred at 0 ° C. Treated with bonyl diimidazole (66 mg, 1 equiv). The reaction was stirred for 5 minutes, warmed to room temperature, then stirred for 15 minutes and then 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (103 mg, 1.1 Equivalent weight). The mixture was stirred at rt overnight. The solvent was evaporated and the residue was purified by column chromatography to give 188 mg (92%) of a white solid.

Example  45

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-ethyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

(±) -3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin- in methanol (0.6 mL) To a solution of 3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester (15 mg, 0.03 mmol) lithium hydroxide monohydrate (3.0 mg, 2.5 equivalents) in water (0.1 mL) ) Solution was added and the resulting solution was stirred for 6 hours. The solution was cooled to 0 ° C., treated with aqueous 1 M potassium hydrogen sulfate (60 μl, 2.0 equiv) and then concentrated to give a crude acid which was used immediately without purification. The crude acid is dissolved in dimethylformamide (0.4 mL), cooled to 0 ° C., then methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), diisopropylethylamine (12 μl, 2.3 equiv) and PyBOP® (19 mg, 1.2 equiv) sequentially. The solution was stirred at 0 ° C. for 15 minutes, warmed to room temperature, then stirred for 1.5 hours and concentrated. The product was purified by column chromatography to give 14.5 mg (76%, 2 steps).

(3,4-dinitro-phenyl) -methanol

Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 800 mL, 800 mmol) was added to 3,4-dinitrobenzoic acid (93.5 g, 441 mmol in tetrahydrofuran (300 mL) at -20 ° C. over 45 minutes. ) Solution. The resulting mixture was stirred at −20 ° C. for 1 hour, then warmed to room temperature and stirred overnight. It was quenched with 32 mL of 1: 1 acetic acid / water. The solvent was removed in vacuo and the residue was poured into 1000 mL of ice cold saturated sodium bicarbonate and stirred vigorously for 15 minutes. The mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. After filtration, the solvent was removed to give the title compound as a light yellow solid (100%).

3,4-dinitro-benzaldehyde

A solution of (3,4-dinitro-phenyl) -methanol (95.3 g, 481 mmol) in methylene chloride (500 mL) was added to a suspension of pyridinium chlorochromate (156 g, 722 mmol) in methylene chloride (900 mL). I put it at once. The mixture was stirred at rt for 1.5 h, then ether (1500 mL) was added. The supernatant was decanted from the resulting black gum and the insoluble residue was washed thoroughly with methylene chloride (3 × 250 mL). The combined organic solution was filtered through a florisil pad to give a pale light yellow transparent solution. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using methylene chloride as eluent to afford the title compound as a yellow solid (71%).

2-benzyloxycarbonylamino-3- (3,4-dinitro-phenyl) -acrylic acid methyl ester

1,1,3,3-tetramethylguanidine (41.2 mL, 329 mmol) was added N- (benzyloxycarbonyl) -alpha-phosphonoglycine trimethyl ester (114.1 g, 344) in tetrahydrofuran (800 mL) at room temperature. mmol) solution. The mixture was stirred at rt for 15 min and cooled to -78 ° C. A solution of 3,4-dinitro-benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was added slowly via cannula. The resulting mixture was stirred at −78 ° C. for 2 hours, then warmed to room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of 1 N sulfuric acid, twice with water, brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was crystallized from ethyl acetate (20 g crude product 100 mL / ethyl acetate). Yellow crystals were collected and further purified by chromatography on silica gel using methylene chloride as eluent. The title compound was obtained (77%) as yellow crystals.

Similarly manufactured:

2-benzyloxycarbonylamino-3- (3-hydroxy-4-nitro-phenyl) -acrylic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (3,4-dinitro-phenyl) -propionic acid methyl ester

An oven-dried 500 mL Schlenk flask was placed in a glove-bag filled with nitrogen. After the glove-bag was emptied and filled with nitrogen (3 ×), the flask was sealed and taken out of the glove-bag and weighed. It was put back into the glove bag, emptied and filled with nitrogen (3x), followed by (-)-1,2-bis ((2R, 5R) -2,5-diethylphospholano) benzene (cyclooctadie). Filled with nene) rhodium (I) trifluoromethanesulfonate. The flask was sealed and removed from the glove bag and weighed (784 mg, 1.08 mmol). 2-benzyloxycarbonylamino-3- (3,4-dinitro-phenyl) -acrylic acid methyl ester (8.72 g, 21.7 mmol) was placed in another 500 mL Schlenk flask, emptied and filled with nitrogen (3x). . Methylene chloride (350 mL, degassed with nitrogen for 2 hours) was added and the resulting solution was transferred to the catalyst flask via cannula. After the flask was purged and filled with hydrogen (4x), the mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate / hexanes (1: 1) as eluent to afford the title compound as a light pale brown gum (yield 99%, using the following conditions). Ee 99.2% as determined by HPLC analysis: Chiralpak AD column (4.6 x 250 mm, 10 um; A = ethanol, B = hexane; 40% B at 1.0 mL / min for 14 minutes; retention time: R enantiomer 10.9 min, S enantiomer 6.9 min)

Similarly manufactured:

(R) -2-benzyloxycarbonylamino-3- (3-hydroxy-4-nitro-phenyl) -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid methyl ester

Solid ammonium formate (2.27 g, 36 mmol) to (R) -2-benzyloxycarbonylamino-3- (3,4-dinitro-phenyl) -propionic acid methyl ester (1.45 g, 3.6 mmol) and zinc powder To a suspension of (1.41 g, 21.6 mmol) methanol (50 mL, degassed with nitrogen for 2 hours) was added in small portions at 0 ° C. The resulting mixture was stirred at rt overnight. After the solvent was removed in vacuo, toluene (30 mL, degassed) and ethyl acetate (30 mL, degassed) were added followed by acetic acid (3 mL). The mixture was further diluted until all organic solids dissolved, then washed with water, brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo to yield the title compound containing 1 equivalent of acetic acid as a red gum-like solid (85%). Mass spectroscopy: 344.18 (MH) ⁺ .

(R) -2-benzyloxycarbonylamino-3- (2-methyl-1H-benzoimidazol-5-yl) -propionic acid methyl ester

A solution of (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid methyl ester-acetic acid (640 mg) in acetic acid (8 mL) was heated to 130 ° C. for 4 hours. It was. The mixture was poured into water and cooled to 0 ° C. The pH was adjusted to 8 by gradually adding solid sodium bicarbonate. The mixture was then extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with water, brine and dried over sodium sulfate. After filtration, the solvent was removed to give the title compound as a brown effervescent solid (95%).

(R) -2-benzyloxycarbonylamino-3- [2-methyl-3- (2-trimethylsilanyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -propionic acid methyl ester and (R ) -2-benzyloxycarbonylamino-3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-benzoimidazol-5-yl] -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (2-methyl-1H-benzoimidazol-5-yl) -propionic acid methyl ester (533 mg, 1.96 mmol) in acetonitrile (20 mL), and sodium carbonate Was added to pure 2-trimethylsilanyl-ethanesulfonyl chloride at a time. The mixture was stirred at rt overnight. The solvent was removed and the residue was purified by silica gel chromatography using ethyl acetate / hexanes (1: 2) as eluent to afford the title compound as a flexible solid (1: 1 mixture of isomers of N1 and N3, 66%). ).

(R) -2-Amino-3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-benzoimidazol-5-yl] -propionic acid methyl ester and (R) -2- Amino-3- [2-methyl-3- (2-trimethylsilanyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- [2-methyl-3- (2-trimethylsilanyl-ethanesulfonyl) -3H-benzoimidazol-5-yl] -propionic acid methyl ester and (R ) -2-benzyloxycarbonylamino-3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-benzoimidazol-5-yl] -propionic acid methyl ester (1: 1 mixture , 600 mg) methanol (50 mL) suspension, and 10% palladium (180 mg) on charcoal were stirred in a Parr apparatus under 40 psi of hydrogen overnight at room temperature. After replacing the hydrogen atmosphere with nitrogen, the mixture was filtered through a pad of celite. The solvent was removed in vacuo to afford the title compound as a light brown solid (80%).

(R) -3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-benzoimidazol-5-yl] -2-{[4- (2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester and (R) -3- [2-methyl-3- (2-trimethylsilanyl Ethanesulfonyl) -3H-benzoimidazol-5-yl] -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid methyl ester

(R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- Prepared as described above for (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester. Purification by silica gel chromatography using ethyl acetate with 1% triethylamine as eluent gave the title compound as a gray solid (87%).

(R) -3- (2-methyl-1H-benzoimidazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidine-1-carbonyl] -amino} -propionic acid

(R) -3- [2-methyl-1- (2-trimethylsilanyl-ethanesulfonyl) -1H-benzoimidazol-5-yl] -2-{[4- (2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester and (R) -3- [2-methyl-3- (2-trimethylsilanyl Ethanesulfonyl) -3H-benzoimidazol-5-yl] -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 1: 1 mixture of -carbonyl] -amino} -propionic acid methyl ester (R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Treatment was as described for ferridine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid. The hydrolysis state (lithium hydroxide / methanol-tetrahydrofuran-water (1: 1: 1)) was used overnight at -15 ° C. The title compound was obtained (25%) as a white solid. Mass spectroscopy: 477.24 (MH) ⁺ .

Example  46

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (2-methyl-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- Prepared as described above for 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide . Purification by silica gel chromatography using methylene chloride: methanol: triethylamine (93: 5: 2) as eluent gave a white solid. It was dissolved in ethyl acetate (60 mL), washed twice with 1: 1 saturated sodium bicarbonate / brine and dried over sodium sulfate. After filtration, the solvent was removed to give the title compound as a white solid (yield 11%).

(R) -3- (4-amino-3-hydroxy-phenyl) -2-benzyloxycarbonylamino-propionic acid methyl ester hydrochloride

(R) -2-benzyloxycarbonylamino-3- (3-) in 1: 1 methanol / water (400 mL) degassed with powdered iron (3.7 g, 66.4 mmol) and ammonium chloride (5.9 g, 111 mmol) To a solution of hydroxy-4-nitro-phenyl) -propionic acid methyl ester (2.07 g, 5.53 mmol) was added at 0 ° C. The resulting mixture was stirred at rt for 48 h. Trifluoroacetic acid (7 mL) is added and the mixture is swirled until a clear dark red solution containing an unreacted iron powder suspension. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2 x 150 mL) and the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, hydrochloric acid (4.2 mL, 4 M in dioxane) was added. The solvent was removed in vacuo to afford the title compound as a light brown effervescent solid (80%).

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

A solution of methylene chloride (15 mL) of carbonyl diimidazole (498 mg, 3.07 mmol) was added (R) -3- (4-amino-3-hydroxy-phenyl) -2-benzyloxycarbonylamino-propionate methyl To a solution of ester (1.17 g, 3.07 mmol), diisopropylethylamine (1.60 mL, 9.21 mmol) and methylene chloride (85 mL) was added at 0 ° C. The mixture was stirred at 0 ° C for 4 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate / hexanes as eluent to afford the title compound as a white solid (51%).

(R) -2-Amino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazole-6- of 4.4% formic acid in methanol (20 ml, freshly prepared from degassed methanol) A solution of l) -propionic acid methyl ester (310 mg) was added via cannula to a 10% palladium suspension on charcoal of 4.4% formic acid in methanol (20 ml, freshly prepared in degassed methanol). The resulting mixture was stirred at rt for 4 h. After filtration through a pad of celite, the solvent was removed in vacuo to yield a light brown solid. The solid was dissolved in a mixture of ethyl acetate (50 mL), toluene (10 mL) and ethanol (40 ml) and solid sodium bicarbonate (3.1 g) was added. The mixture was stirred at rt for 2 h and filtered. The solvent was removed in vacuo to afford the title compound.

(R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin- 3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

(R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- Prepared as described above for (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid methyl ester. Purification by silica gel chromatography using methylene chloride: methanol: triethylamine (93: 5: 2) as eluent gave the title compound as a white solid (33%).

(R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin- 3-yl) -piperidine-1-carbonyl] -amino} -propionic acid

(R) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- Prepared as described above for (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid. Hydrolysis conditions (lithium hydroxide / methanol-tetrahydrofuran-water (1: 1: 1) at −15 ° C. overnight) were used. The title compound was obtained (95%) as a white solid. Mass spectroscopy: 480.30 (MH) ⁺ .

Example  47

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] amide

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- Prepared as described above for 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide . The crude product was purified by silica gel chromatography using methylene chloride: methanol: triethylamine (93: 5: 2) as eluent to afford a white solid. It was dissolved in ethyl acetate (60 mL), washed twice with 1: 1 saturated sodium bicarbonate / brine and then dried over sodium sulfate. After filtration, the solvent was removed to afford the title compound as a white solid (70%).

(R) -3- (1H-Benzotriazol-5-yl) -2-benzyloxycarbonylamino-propionic acid methyl ester

Of (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid methyl ester monoacetate (2.68 g, 6.65 mmol) in acetic acid (30 mL) and water (40 mL) To the solution was added dropwise a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL) for several minutes at room temperature. The resulting mixture was stirred at room temperature for 20 minutes, then cooled to 0 ° C., and then the pH was adjusted to 11 by addition of concentrated ammonium hydroxide. The mixture was extracted twice with ethyl acetate in the presence of solid sodium chloride and the organic layer was dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate / hexanes (6: 4) as eluent to afford the title compound as a light brown solid (yield 94%).

(R) -2-Amino-3- (1H-benzotriazol-5-yl) -propionic acid methyl ester

Prepared as described above for (R) -2-amino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester.

Example  48

(R) -3- (1H-Benzotriazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine- 1-carbonyl] -amino} -propionic acid methyl ester

(R) -2-{[4- (2-oxo-1,4-dihydro-2H, except when carbonyl diimidazole is used instead of N, N-disuccinimidyl carbonate (DSC) -Quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-yl] -propionic acid Prepared as described above for methyl ester.

Example  49

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [1- (1H-benzotriazol-5-yl Methyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- Prepared as described above for 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide . Purification by silica gel chromatography using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent.

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-1 H-indol-5-yl) -propionic acid methyl ester

PyHBr ₃ (1.28 g, 4.02 mmol) was added to (R) -2-benzyloxycarbonylamino-3- (1H-indol-5-yl) -propionic acid methyl ester (0.47 g, 1.34) in t-butanol (10 mL). mmol) was added in small portions over 30 minutes while maintaining the reaction temperature at 25-30 ° C. The resulting mixture was stirred at rt for 3.5 h. The solvent was removed in vacuo and the residue was extracted with ethyl acetate (2 ×). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, the solvent was removed and the residue was azeotropically dried over anhydrous ethanol. The residue was dissolved in ice acetic acid (10 mL) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred at rt overnight. After acetic acid was removed in vacuo, the residue was purified by flash chromatography on silica gel using ethyl acetate / hexane [first (1: 3), then (3: 2)] as eluent to afford the title compound as a white solid. (41% for 2 steps).

(R) -2-Amino-3- (2-oxo-2,3-dihydro-1 H-indol-5-yl) -propionic acid methyl ester

Prepared as described above for (R) -2-amino-3- (2-oxo-2,3-dihydrobenzooxazol-6-yl) -propionic acid methyl ester.

(R) -3- (2-oxo-2,3-dihydro-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin- 3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

A solution of phosgene in toluene (2 M, 0.158 mL, 0.30 mmol) was transferred to (R) -2-amino-3- (2-oxo-2,3- in methylene chloride (15 mL) and saturated sodium bicarbonate (7.5 mL). To the mixture of dihydro-1H-indol-5-yl) -propionic acid methyl ester (70 mg, 0.25 mmol) was added and stirred vigorously. The mixture was stirred at rt for 30 min before 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 0.25 mmol) was added. The resulting mixture was stirred at rt for 1.5 h, diluted with ethyl acetate and washed with 0.25 N hydrochloric acid saturated with solid sodium chloride. The organic layer was dried over sodium sulfate. After filtration, the solvent was removed to afford the title compound as a light brown viscous oil.

Example  50

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- (2-oxo-2,3-dihydro-1 H-indol-5-ylmethyl) -ethyl] -amide

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] bipiperidinyl- Prepared as described above for 1'-yl-2-oxo-1- [1- (2-trimethylsilanyl-ethanesulfonyl) -1H-indazol-5-ylmethyl] -ethyl} -amide . Purification by flash chromatography on silica gel using methylene chloride / methanol / triethylamine (93: 5: 2) as eluent.

2- (di-tert-butoxycarbonylamino) -acrylic acid methyl ester

Of 2-tert-butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (10.0 g, 30 mmol) and di-tert-butyl-dicarbonate (21.8 g, 2.6 equiv) in acetonitrile (40 mL) To the solution 4-dimethylaminopyridine (0.48 g, 0.1 equiv) was added at room temperature. The solution was stirred overnight and then concentrated. The residue was dissolved in diethyl ether, washed sequentially with 1 M potassium hydrogen sulfate (2 ×), saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give 15.6 g (quantitative yield) of oil. 1 H NMR examination showed a mixture of the title compound and 2- (di-tert-butoxycarbonylamino) -3-tert-butoxycarbonyloxy-propionic acid methyl ester. The mixture was used without isolation, as later found to both react with the secondary amine to give the same product. 2- (di-tert-butoxycarbonylamino) -acrylic acid methyl ester:

2- (di-tert-butoxycarbonylamino) -3-tert-butoxycarbonyloxy-propionic acid methyl ester:

(±) -3- (4-benzyloxy-2-oxo-2H-pyridin-1-yl) -2- (di-tert-butoxycarbonylamino) -propionic acid methyl ester

2- (di-tert-butoxycarbonylamino) -acrylic acid methyl ester (900 mg, 3.0 mmol) and 4-benzyloxy-1H-pyridin-2-one (630 mg, 1.03 equiv) in acetonitrile (2.5 mL) Cesium carbonate (100 mg, 0.10 equiv) was added to the solution. The resulting suspension was heated to 80 ° C. for 2 hours with microwave. The reaction was concentrated, dissolved in water and extracted with methylene chloride (3 ×). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to yield 1.47 g (97%) of the product used without purification. Mass spectroscopy: 503.56 (MH) ⁺ .

(±) -4-benzyloxy-1- [3- [1,4 '] bipiperidinyl-1'-yl-2- (di-tert-butoxycarbonylamino) -3-oxo-propyl]- 1H-pyridin-2-one

3- (4-benzyloxy-2-oxo-2H-pyridin-1-yl) -2- (di-tert-butoxycarbonylamino) -propionic acid methyl ester (1.47 g, in stirred methanol (17 mL), 2.9 mmol) was added a solution of lithium hydroxide monohydrate (0.50 g, 4 equiv) in water (2.85 mL). The reaction mixture was stirred at rt for 3 h, cooled to 0 ° C., then treated with concentrated hydrochloric acid (0.99 mL) and concentrated to give a crude acid which can be obtained in half step below. The crude acid is dissolved in methylene chloride (6 mL) and cooled to 0 ° C., then 4-piperidyl-piperidine (0.25 g, 1 equiv), triethylamine (0.31 mL, 2.5 equiv) and bis- Treated sequentially with 2-oxo-3-oxazolidinyl) phosphinic chloride (0.38 g, 1 equiv). The reaction was warmed to rt and stirred overnight. The reaction was concentrated and purified by preparative HPLC to give 489 mg (52%, 2 steps). Mass spectroscopy: 639.41 (MH) ⁺ .

Example  51

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-benzyloxy-2-oxo- 2H-pyridin-1-ylmethyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] amide

4-benzyloxy-1- [3- [1,4 '] bipiperidinyl-1'-yl-2- (di-tert-butoxycarbonylamino) -3- in stirred methylene chloride (3 mL) To a solution of oxo-propyl] -1 H-pyridin-2-one, trifluoroacetic acid (1 mL) was added at 0 ° C. After 2 hours, the reaction was concentrated to give crude amine (151 mg, 97%), its trifluoroacetic acid salt [mass spectrometry: 439.61 (MH) +] divided into two parts, one part to the following procedure Used. To a solution of crude amine (75 mg, 0.11 mmol) and diisopropylethylamine (80 μl, 4 equiv) in methylene chloride (3 mL) add carbonyl diimidazole (29 mg, 1.6 equiv, 2 parts) to 0 ° C. Was added. After stirring for 10 minutes, the solution was treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-acetic acid (40 mg, 1.15 equiv). The reaction was warmed to rt and stirred overnight. The reaction was concentrated and purified by preparative TLC to give 40.8 mg (53%).

Example  52

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid in stirred methanol (1 mL) [1- (4-benzyloxy- 2-oxo-2H-pyridin-1-ylmethyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide (29 mg) and 10% palladium on charcoal ( 5 mg) solution was placed under hydrogen atmosphere. After 1 hour at room temperature, the reaction was flushed with nitrogen, filtered through celite and concentrated to afford the product.

(±) -2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidin-1-yl) -propionic acid methyl ester

Add piperidine-4-ol (0.33 g, 1.1 equiv) to a solution of 2- (di-tert-butoxycarbonylamino) -acrylic acid methyl ester (1.0 g, 3.0 mmol) in acetonitrile (10 mL) It was. The reaction was left under a gentle stream of nitrogen with stirring overnight. The resulting crude oil was dissolved in ethyl acetate, washed with water, then washed with brine, dried over magnesium sulfate and concentrated to give 1.38 g (quantitative yield) as an oil used without purification. Mass spectroscopy: 403.42 (MH) ⁺ .

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (di-tert-butoxycarbonylamino) -3- (4-hydroxypiperidin-1-yl) Propane-1-one

To a solution of 2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidin-1-yl) -propionic acid methyl ester (1.0 g, 2.5 mmol) in methanol (6 mL) A solution of lithium hydroxide monohydrate (400 mg, 3.9 equiv) in water (1 mL) was added. The reaction was stirred for 6 hours, cooled to 0 ° C., then neutralized with concentrated hydrochloric acid and concentrated. The crude acid was used without purification. The crude acid was suspended in methylene chloride (25 mL) and treated with a few drops of methanol to help dissolve the acid and cool to 0 ° C. The resulting suspension was purified with 4-piperidyl-piperidine (0.53 g, 1.25 equiv), triethylamine (0.70 mL, 2. equiv) and bis-2-oxo-3-oxazolidinyl) phosphinic chloride (0.80 g, 1.25 equiv) in succession. The reaction was allowed to warm to room temperature overnight. The reaction was concentrated and then purified by preparative HPLC to give 310 mg (23%, 2 steps). Mass spectroscopy: 539.49 (MH) ⁺ .

(±) -2-amino-1- [1,4 '] bipiperidinyl-1'-yl-3- (4-hydroxy-piperidin-1-yl) -propan-1-one

1- [1,4 '] bipiperidinyl-1'-yl-2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidine- in methylene chloride (5 mL) To a solution of 1-yl) -propan-1-one (310 mg, 0.58 mmol) trifluoroacetic acid (2.0 mL) was added at 0 ° C. The ice bath was removed and the reaction stirred for 30 minutes. The reaction was concentrated to give the product whose trifluoroacetic acid salt (400 mg, quantitative yield) was used without purification. Mass spectroscopy: 339.46 (MH) ⁺ .

(±)-[2- [1,4 '] bipiperidinyl-1'-yl-1- (4-hydroxy-piperidin-1-ylmethyl) -2-oxo-ethyl] carbamic acid tert- Butyl ester

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-3- (4-hydroxy-piperidin-1-yl) -propane-1- in tetrahydrofuran (5 mL) To a solution of one (trifluoroacetic acid salt, 300 mg, 0.58 mmol) and diisopropylethylamine (0.30 mL, 4 equiv) was added di-tert-butyl-dicarbonate (128 mg, 1 equiv). The resulting solution was stirred at rt for 1 h and concentrated. The residue was dissolved in ethyl acetate, washed with water then brine, dried over magnesium sulfate and concentrated to give 248 mg (98%) for use without purification. Mass spectroscopy: 439.65 (MH) ⁺ .

(±)-[2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-1- (4-oxo-piperidin-1-ylmethyl) -ethyl] carbamic acid tert-butyl ester

1- [1,4 '] bipiperidinyl-1'-yl-2- (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidine- in methylene chloride (4 mL) To a solution of 1-yl) -propan-1-one (200 mg, 0.37 mmol) was added Dess-Martin periodinane (316 mg, 2 equiv) in two portions. After 1 h, the reaction was quenched by addition of saturated sodium bicarbonate and extracted with methylene chloride (3 ×). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to give 187 mg (94%) of the material used without purification. Mass spectroscopy: 437.63 (MH) ⁺ .

(±) -1- (2-amino-3- [1,4 '] bipiperidinyl-1'-yl-3-oxo-propyl) -piperidin-4-one

[2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-1- (4-oxo-piperidin-1-ylmethyl) -ethyl] -carrethane in methylene chloride (5 mL) To a solution of chest acid tert-butyl ester (100 mg, 0.23 mmol) was added trifluoroacetic acid at 0 ° C. The ice bath was removed and stirring continued for 1 h before the reaction was concentrated to give 150 mg (96%) as its trifluoroacetic acid which was used without purification. Mass spectroscopy: 337.64 (MH) ⁺ .

Example  53

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-hydroxy-piperidin-1-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] BP in methylene chloride (5 mL) Solution of Ferridinyl-1'-yl-1- (4-hydroxy-piperidin-1-ylmethyl) -2-oxo-ethyl] -amide (3 trifluoroacetate, 200 mg, 0.39 mmol) To is added diisopropylethylamine (0.27 mL, 3.9 equiv) and carbonyl diimidazole (63 mg, 1 equiv) at 0 ° C. After stirring for 15 minutes, the solution was treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (acetate, 142 mg, 1.25 equiv). The solution was allowed to warm up to room temperature and stirred overnight. The reaction was concentrated and purified by preparative TLC to give 130 mg (56%) as an oil.

3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10 g, 50 mmol) was dissolved in dimethyl formamide dimethylacetal (50 mL) and heated to reflux for 1.25 h. The solution was cooled, concentrated and purified by flash chromatography to yield 2.55 g (19%). Mass spectroscopy: 255.16 (MH) ⁺ .

1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

To a solution of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). Added. The solution was heated to reflux, immediately cooled to room temperature and concentrated to give 1.4 g (63%) of the material to use without purification. Mass spectroscopy: 224.11 (MH) ⁺ .

4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester (0.70 g, 3.1 mmol) was added to trifluoroacetic acid (10 mL) at 0 ° C. Dissolved in, stirred for 1 h, and concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). Filtration gave bis-hydrochloride salt as white solid which gave 510 mg (83%). The free base was prepared by dissolving the salt in water as needed, which was loaded on an SCX column, then flushed with methanol and then eluted with 2 M ammonia in methanol.

(±) -2- (di-tert-butoxycarbonylamino) -3- (1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5yl) -propionic acid methyl ester

2- (di-tert-butoxycarbonylamino)-in a solution of 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (160 mg) in methanol (2.5 mL) Acrylic acid methyl ester (400 mg) was added. The reaction was concentrated to approximately 1.5 mL under a gentle nitrogen stream. The solution was stirred at rt overnight. The reaction was concentrated, dissolved in ethyl acetate, washed with brine, dried over dried magnesium sulfate and concentrated. The resulting residue is pure and can be used without purification.

(±) -2-amino-3- (1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -propionic acid methyl ester

2- (di-tert-butoxycarbonylamino) -3- (1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5- in methylene chloride (5 mL) at 0 ° C. To a solution of l) -propionic acid methyl ester (0.55 g, 1 equiv) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 hours. The solution was concentrated, dissolved in methanol and then passed through a column of strong cation exchange resins. After flushing with methanol, the product was removed in a column eluted with 2 M ammonia in methanol to give the product as a free base (275 mg, 95%).

3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (16 g, 80 mmol) in tetrahydrofuran (400 mL) was added four portions of sodium hydride (4.1 g, 2.1 equiv) at 0 ° C. And added in portions. Iodomethane (12.5 mL, 2.5 equiv) was added dropwise. The reaction was gradually warmed to room temperature and stirred overnight. The reaction was concentrated, dissolved in diethyl ether, washed with brine, dried over magnesium sulfate and concentrated. The product was crystallized from hot pentane (2X) to give 5.9 g (32%).

5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g, 22 mmol) is dissolved in dimethyl formamide dimethylacetal (25 mL) and heated to reflux for 2 hours. It was. The reaction mixture was heated to 130 ° C. for 1 h with microwave and concentrated to give 6.43 g (quantitative yield) as an oil used without purification.

7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

Hydrazine hydrate (1.2) in a solution of 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.35 g, 22 mmol) in methanol (15 mL) mL, 1.1 equiv) was added. The solution was stirred overnight at room temperature and concentrated to give 5.3 g (94%) of the material to use without purification.

Mass spectroscopy: 252.19 (MH) ⁺ .

7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

To a solution of 7,7-dimethyl-1,4,6,7-tetrahydro-pyra3-c] pyridine-5-carboxylic acid tert-butyl ester (5.3 g, 21 mmol) in methylene chloride (10 mL) Trifluoroacetic acid (5 mL) was added at 0 ° C. The reaction was allowed to warm to rt, stirred for 15 min and then further treated with trifluoroacetic acid (5 mL). After 1 h, the reaction was concentrated, dissolved in ethanol (10 mL), then cooled to 0 ° C., treated with concentrated hydrochloric acid (3 mL) and concentrated. The resulting solid was triturated with ethanol and filtered to give 3.02 g (64%) as its bishydrochloride salt. The free base was prepared by dissolving the salt in water as needed, loaded onto an SCX column, flushed with methanol and then eluted with 2 M ammonia in methanol.

(±) -2- (di-tert-butoxycarbonylamino) -3- (7,7-dimethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5- Yl) -propionic acid methyl ester

2- (di-tert-part in a solution of 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (160 mg) in methanol (3 mL) Toxylcarbonylamino) -acrylic acid methyl ester (331 mg) was added. A gentle nitrogen stream was applied and the reaction stirred overnight. In the morning, the volume was greatly reduced. The remaining traces of solvent were removed under high vacuum to yield 490 mg (quantitative yield) of the material used without purification.

(±) -2-amino-3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -propionic acid methyl ester

2- (di-tert-butoxycarbonylamino) -3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3 in methylene chloride (5 mL, 0 ° C.) To a solution of -c] pyridin-5-yl) -propionic acid methyl ester (0.49 g, 1 equiv) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 hours. The solution was concentrated, dissolved in methanol and loaded onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column eluted with 2 M ammonia in methanol to give the product as its free base (250 mg, 94%).

(±) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- (1, 4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -propionic acid methyl ester

2-Amino-3- (1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -propionic acid methyl ester in methylene chloride (2 mL, 0 ° C.) (260 mg Carbonyl diimidazole (188 mg, 1 equiv) was added to a solution of 1 equiv). After 15 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (295 mg, 1.1 equiv) was added in one portion. The ice bath was removed and stirring continued overnight. The reaction was concentrated and purified by column chromatography to give 118 mg (21%).

Example  54

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- (1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-ylmethyl) -ethyl] -amide

2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -3- (in methanol (0.6 mL) Lithium hydroxide in water (0.1 mL) in a solution of 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -propionic acid methyl ester (16 mg, 1 equiv) Monohydrate (3 mg, 2.2 equiv) was added and stirred at rt for 4 h. The solution was cooled to 0 ° C., treated with aqueous 1 M potassium hydrogen sulfate (60 μl, 1.8 equiv) and then concentrated to give a crude acid which was used immediately without purification. The crude acid is dissolved in dimethylformamide (0.3 mL), methylene chloride (0.15 mL), 4-piperidyl-piperidine (11 mg, 2 equiv), diisopropylethylamine (12 μl, 2 equiv) , And PyBOP® (19 mg, 1.1 equiv) sequentially. The solution was stirred for 30 minutes and concentrated. The product was purified by column chromatography to give 17.6 mg (85%, 2 steps).

Example  55

(±) -3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-{[4- (2-oxo -1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

2-amino-3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) in tetrahydrofuran (4 mL, 0 ° C.) Carbonyl diimidazole (162 mg, 1 equiv) was added to a solution of propionic acid methyl ester (250 mg, 1 equiv). After 5 minutes, the ice bath was removed and the reaction stirred for 30 minutes at room temperature. To this 3-piperidin-4-yl-3, 4-dihydro-1H-quinazolin-2-one (250 mg, 1.1 equiv) was added in one portion and the reaction stirred overnight. The reaction was concentrated and purified by column chromatography to give 228 mg (45%).

Example  56

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-ylmethyl) -2-oxo-ethyl] -amide

3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-{[4- (2 -Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester (20 mg, 1.0 equiv) in a solution of water (0.1 mL ) Lithium hydroxide monohydrate (4 mg, 2.2 equiv) was added and stirred at rt for 4 h. The solution was cooled to 0 ° C., treated with aqueous 1 M potassium hydrogen sulfate (75 μl, 1.8 equiv) and then concentrated to give a crude acid which was used immediately without purification. The crude acid is dissolved in dimethylformamide (0.3 mL), methylene chloride (0.15 mL), 4-piperidyl-piperidine (13 mg, 2 equiv), diisopropylethylamine (14 μl, 2 equiv) , And PyBOP® (22 mg, 1.1 equiv) sequentially. The solution was stirred for 1.5 hours and concentrated. The product was purified by column chromatography to give the product contaminated with HOBT. HOBT was removed by passing the product through a plug of base alumina and eluted with 10% methanol in methylene chloride. Concentration then gave 18.3 mg (72%, 2 steps).

2-benzyloxycarbonylamino-3- (6-methoxy-pyridin-3-yl) -acrylic acid methyl ester

N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester in methylene chloride (15 mL) in a suspension of potassium tert-butoxide (1.23 g, 1.5 equiv) in methylene chloride (70 mL, -20 ° C) (3.63 g) , 1.5 equiv) was added. The resulting solution was stirred for 5 minutes and treated with 6-methoxy-pyridine-3-carbaldehyde (1.0 g, 7.3 mmol) in methylene chloride (15 mL). After stirring for 1.5 hours, the reaction was warmed to 0 ° C. and stirred for 1 hour. The reaction was injected rapidly into a separatory funnel containing ethyl acetate and water. Brine was added to allow the layers to separate. The aqueous layer was extracted with ethyl acetate (3x), washed with brine, dried over brine, magnesium sulfate and concentrated to give 2.63 g (quantitative yield) of the material used without purification. Mass spectroscopy: 343.08 (MH) ⁺ .

(±) -2-amino-3- (6-methoxy-pyridin-3-yl) -propionic acid methyl ester

2-benzyloxycarbonylamino-3- (6-methoxy-pyridin-3-yl) acrylic acid methyl ester (620 mg), palladium on charcoal (10%, 100 mg), ethyl acetate (10 mL) and methanol ( 20 mL) was flushed with nitrogen followed by hydrogen and finally attached a hydrogen balloon. The reaction was stirred overnight. The flask was flushed with nitrogen, filtered through celite and concentrated to give 390 mg (quantitative yield) of the material used without purification. Mass spectroscopy: 211.11 (MH) ⁺ .

(±) -3- (6-methoxy-pyridin-3-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine- 1-carbonyl] -amino} -propionic acid methyl ester

N in a solution of 2-amino-3- (6-methoxy-pyridin-3-yl) -propionic acid methyl ester (130 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, 0 ° C.) , N'-disuccinimidyl carbonate (158 mg) was added. After 30 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (120 mg) in methylene chloride (1 mL) was added via cannula. The reaction was warmed to rt and stirred overnight. The reaction was concentrated and purified by preparative HPLC to give 160 mg (55%). Mass spectroscopy: 468.19 (MH) ⁺ .

Example  57

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (6-methoxy-pyridin-3-ylmethyl) -2-oxo-ethyl] -amide

3- (6-methoxy-pyridin-3-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi in methanol (6 mL) To a solution of ferridine-1-carbonyl] -amino} -propionic acid methyl ester (160 mg) was added a solution of lithium hydroxide monohydrate (29 mg) in water (1 mL). The reaction was stirred at rt for 4 h and cooled to 0 ° C. The reaction was treated with 1 N hydrochloric acid (0.6 mL) and concentrated. The residue is dissolved in methylene chloride (5 mL) and 4-piperidyl-piperidine (75 mg), triethylamine (0.14 mL) and bis-2-oxo-3-oxazolidinyl) phosphinyl chloride (104 mg) was treated sequentially. The reaction was stirred overnight, concentrated and purified by preparative HPLC to give 94 mg (45%). LC / MS: t _R = 1.86 min, 604.51 (MH) ⁺ .

2-benzyloxycarbonylamino-3- (2-methoxy-pyrimidin-5-yl) -acrylic acid methyl ester

A solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (3.63 g) in methylene chloride (15 mL) in a suspension of potassium t-butoxide (1.23 g) in methylene chloride (70 mL, -30 C) Was added. The resulting solution was stirred for 5 minutes and treated with 2-methoxy-pyrimidine-5-carbaldehyde (1.0 g) in methylene chloride (15 mL). After stirring for 1.5 hours, the reaction was warmed to 0 ° C. The reaction was injected rapidly into a separatory funnel containing ethyl acetate and water. Brine was added to allow the layers to separate. The aqueous layer was extracted with ethyl acetate (3X), washed with brine, dried over magnesium sulfate and concentrated. The crude product was recrystallized from hot methanol to give 1.4 g of pure material. Mass spectroscopy: 344.10 (MH) ⁺ .

(±) -2-amino-3- (2-methoxy-pyrimidin-5-yl) -propionic acid methyl ester

The flask containing amino ester (700 mg), palladium on charcoal (10%, 100 mg) and methanol (20 mL) was flushed with nitrogen followed by hydrogen and finally attached a hydrogen balloon. The reaction was stirred overnight. The flask was flushed with nitrogen, filtered through celite and concentrated to give 379 mg (88%) of the material to be used without purification. Mass spectroscopy: 212.08 (MH) ⁺ .

(±) -3- (2-methoxy-pyrimidin-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperi Din-1-carbonyl] -amino} -propionic acid methyl ester

To a solution of 2-amino-3- (2-methoxy-pyrimidin-5-yl) -propionic acid methyl ester (125 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, 0 ° C.) N, N'-disuccinimidyl carbonate (155 mg) was added. After 30 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (120 mg) in methylene chloride (2 mL) was added via cannula. The reaction was warmed to rt and stirred overnight. The reaction was concentrated and purified by preparative HPLC to give 99 mg (36%). Mass spectroscopy: 469.10 (MH) ⁺ .

Example  58

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (2-methoxy-pyrimidin-5-ylmethyl) -2-oxo-ethyl] -amide

3- (2-methoxy-pyrimidin-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-in methanol (6 mL) To a solution of piperidine-1-carbonyl] -amino} -propionic acid methyl ester (99 mg) was added a solution of lithium hydroxide monohydrate (18 mg) in water (1 mL). The reaction was stirred at rt for 4 h and cooled to 0 ° C. The reaction was treated with 1 N hydrochloric acid (0.4 mL) and concentrated. The resulting residue is dissolved in methylene chloride (3 mL) and 4-piperidyl-piperidine (50 mg), triethylamine (88 μl) and bis-2-oxo-3-oxazolidinyl) force Treatment was performed sequentially with hisnic chloride (71 mg). The reaction was stirred overnight, concentrated and purified by preparative HPLC to give 103 mg (45%). LC / MS: t _R = 1.23 min, 605.54 (MH) ⁺ .

2-benzyloxy-5-bromo-pyridine

2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, 0.5 equiv) in toluene (30 mL), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium A suspension of hydroxide (1.1 g, 2.4 equiv) was heated to reflux for 3 h in a device equipped with a Dean-Stark trap. The suspension is cooled, concentrated, then suspended in water and extracted with methylene chloride. The combined organic phases were washed with water followed by brine, dried over magnesium sulfate and concentrated to give 1.9 g (85%) of the material to be used without purification. Mass spectroscopy: 264.25 (MH) ⁺ .

6-benzyloxy-pyridine-3-carbaldehyde

Add n-butyllithium (2.5 M in hexanes, 2.61 mL, 1.05 equiv) to a solution of 2-benzyloxy-5-bromo-pyridine (1.64 g, 6.2 mmol) in tetrahydrofuran (25 mL, -78 ° C.) It was. After 1 hour at -78 ° C, dimethylformamide (0.97 mL, 2 equiv) was added and the mixture was stirred for 30 minutes. The reaction was rapidly injected into a stirred solution of 5% aqueous sodium bicarbonate (50 mL) and extracted with diethyl ether (3 ×). The ether was washed with brine, dried over magnesium sulfate and concentrated to give 1.16 g (quantitative yield) of the material which was used without purification. Mass spectroscopy: 186.34 (MH) ⁺ .

2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -acrylic acid methyl ester

N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester in methylene chloride (5 mL) in a suspension of potassium tert-butoxide (0.440 g, 1.7 equiv) in methylene chloride (25 mL) stirred at -20 ° C 1.3 g, 1.7 equiv) was added. The resulting solution was stirred for 5 minutes and treated with 6-benzyloxypyridine-3-carbaldehyde (0.49 g, 2.28 mmol) in methylene chloride (5 mL). The reaction was stirred at −20 ° C. for 1 hour, gradually warmed to 0 ° C. and then injected into a separatory funnel containing water and diethyl ether. The reaction was extracted with diethyl ether (2 ×), washed with brine, dried over magnesium sulfate and concentrated to give 0.98 g (quantitative yield) as an oil used without purification. Mass spectroscopy: 419.32 (MH) ⁺ .

(±) -2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -propionic acid methyl ester

The flask was prepared with 2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -acrylic acid methyl ester (0.50 g, 1.2 mmol), Wilkinson catalyst (200 mg, 0.2 equiv), methanol (5 mL) and toluene (3 mL). The flask was flushed with nitrogen followed by hydrogen, heated to 35 ° C. and stirred under hydrogen atmosphere for 4 days. The reaction was flushed with nitrogen, diluted with methanol, filtered and concentrated to give 145 mg (29%) of crude product purified by column chromatography.

(±) -2-amino-3- (6-benzyloxy-pyridin-3-yl) -propionic acid methyl ester

Trimethylsilyl in a solution of 2-benzyloxycarbonylamino-3- (6-benzyloxy-pyridin-3-yl) -propionic acid methyl ester (130 mg, 0.31 mmol) in stirred methylene chloride (5 mL, 0 ° C.) Iodide (44 μl, 1.0 equiv) was added. The cold water bath was removed and stirred for 1 hour. The reaction was poured into saturated sodium bicarbonate, extracted with ethyl acetate (3x), washed with brine, dried over magnesium sulfate and concentrated to give 81 mg (91%) of the material to be used without purification. Mass spectroscopy: 287.37 (MH) ⁺ .

(±) -3- (6-benzyloxy-pyridin-3-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine -1-carbonyl] -amino} -propionic acid methyl ester

Carbonyl diimidazole (60 mg, 0.21 mmol) in a solution of 2-amino-3- (6-benzyloxy-pyridin-3-yl) -propionic acid methyl ester (60 mg, 0.21 mmol) in stirred methylene chloride (1 mL, 0 ° C.) 34 mg, 1.0 equiv) was added. After 15 minutes, a solution of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 1.2 equiv) in methylene chloride (0.5 mL) is via cannula Added. The ice bath was removed and stirring continued overnight. The reaction was concentrated and purified by column chromatography to give 59 mg (52%). Mass spectroscopy: 544.49 (MH) ⁺ .

Example  59

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (6-benzyloxy-pyridine-3- Ylmethyl) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide

3- (6-benzyloxy-pyridin-3-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) in stirred methanol (3 mL) To a solution of piperidine-1-carbonyl] -amino} -propionic acid methyl ester (59 mg, 0.11 mmol) was added a solution of lithium hydroxide monohydrate (9.1 mg, 2 equiv) in water (0.5 mL). Added. The reaction was stirred at rt for 2 h, cooled to 0 ° C., then quenched with 1 N hydrochloric acid (0.15 mL) and concentrated. The crude product was used without purification. The crude acid is dissolved in methylene chloride (2 mL, 0 ° C.), 4-piperidino-piperidine (34 mg, 1.8 equiv), triethylamine (35 μl, 2.3 equiv) and bis-2-oxo- Treated sequentially with 3-oxazolidinyl) phosphinic chloride (34 mg, 1.2 equiv). The ice bath was removed and the reaction stirred overnight. The reaction was concentrated and purified by preparative TLC to give 30.3 mg (41%). LC / MS: t _R = 1.49 min, 680.29 (MH) ⁺ .

Example  60

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-2-oxo-1- (6-oxo-1,6-dihydro-pyridin-3-ylmethyl) -ethyl] -amide

Flask was prepared from 4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (6-benzyloxy-pyridin-3-ylmethyl ) -2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl] -amide (27 mg, 0.04 mmol), palladium on charcoal (10%, 4 mg) and methanol (1 mL )). The flask was flushed with nitrogen followed by hydrogen and stirred overnight under hydrogen atmosphere. The flask was flushed with nitrogen and the reaction filtered through celite to give 22.1 mg (94%). LC / MS: t _R = 0.93 min, 590.32 (MH) ⁺ .

Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

A solution of ethyl isonipekotate (5.00 g, 0.032 mol) and triethylamine (4.9 mL, 0.035 mmol) in dichloromethane (25 mL) was di-tert-butyldicarbo in dichloromethane (25 mL) at 0 ° C. To the solution of Nate (7.2 g, 0.033 mol) was added slowly. The reaction mixture was stirred at rt overnight, then washed three times with potassium hydrogen sulfate and then once with brine. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the product (8.23 g, 100%) as the desired colorless oil.

4- (2-Nitro-benzyl) -piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

Sodium bis (trimethylsilyl) amide (44 mL) in a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8.23 g, 0.032 mol) in tetrahydrofuran (85 mL) , 0.044 mol) solution was added slowly. The resulting mixture was stirred at −78 ° C. for 1 h, then a solution of 2-nitrobenzyl bromide (8.21 g, 0.038 mol) was added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. It was then concentrated and the residue partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The final product was purified by column chromatography on silica gel (eluent; hexane-ethyl acetate 4: 1) from the complex reaction mixture to give the desired product (1.61 g, 13%) as a brown oil. Mass spectroscopy: 415.38 (M + Na) ⁺ .

4- (2-Amino-benzyl) -piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

4- (2-nitro-benzyl) -piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.61 g, 4.102 mmol) in ethanol (190 mL) and 10% on charcoal The mixture of palladium (0.10 g) was hydrogenated overnight at 50 psi. The resulting mixture was filtered through a plug of celite and the filtrate was concentrated in vacuo to afford the desired product (1.29 g, 99%) as a colorless oil. Mass spectroscopy: 363.45 (MH) ⁺ .

4- (2-Amino-benzyl) -piperidine-4-carboxylic acid ethyl ester hydrochloride

Dioxane (1.29 g, 4.102 mmol) in a solution of 4- (2-amino-benzyl) -piperidine-1,4-dicarboxylic acid 1-tertbutyl ester 4-ethyl ester (1.29 g, 4.102 mmol) in dichloromethane (15 mL) 5 mL) was added a 4.0 M solution of hydrogen chloride. The resulting solution was stirred overnight at room temperature. The solution was concentrated under vacuum to afford the title compound (1.23 g, 100%) as a white solid which was used in the next step without purification. Mass spectroscopy: 263.40 (MH) ⁺ .

3,4-benzo-2,9-diazaspiro [5.5] undec-1-one

A solution of 4- (2-amino-benzyl) -piperidine-4-carboxylic acid ethyl ester hydrochloride (1.23 g, 4.102 mmol) was dissolved in methanol and the resulting solution was stirred overnight at room temperature. Half of the solution was diluted with water and passed through a short plug in hydroxide form of AG® 1-X2 ion-exchange resin (100-200 mesh) eluted with 50% aqueous methanol. The collected fragments were evaporated to afford the desired product as a white solid (0.89 g, 100%).

(R) -2-amino-3-benzo [b] thiophen-3-yl-1- [1,4 '] bipiperidinyl-1'-yl-propane-1-one, dihydrochloride

To a solution of 3-benzo [b] thiophen-3-yl- (2R) -2-tert-butoxycarbonylamino-propionic acid (1.0 g, 3.1 mmol) in methylene chloride (30 mL) well stirred at room temperature. 4-piperidinopiperidine (573 mg, 3.4 mmol), triethylamine (1.3 mL, 9.3 mmol) were added followed by 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine -4 (3H) -one (1.02 g, 3.4 mmol) was added. After 3 hours, the reaction mixture was treated with aqueous sodium hydrogen carbonate (15 mL), brine (20 mL) and dried (sodium sulfate). The crude mixture was purified by flash chromatography using 5% methanol in methylene chloride to yield (1R) -1-benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl at 82% yield. -1'-yl-2-oxo-ethyl) -carbamic acid tert-butylester was obtained. (1R) -1-benzo [b] thiophen-3-ylmethyl-2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl) carbamic acid in methylene chloride (5 mL) tert-butylester (1.2 g, 2.54 mmol) was added to a saturated solution of hydrogen chloride in dioxane (20 mL) and stirred for 2 hours. Remove solvent to remove (2R) -2-amino-3-benzo [b] thiophen-3-yl-1- [1,4 '] bipiperidinyl-1'-yl-propan-1-one, dihydro Chloride was obtained with a yield of 98%.

Example  61

(R) -1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid (1-benzo [b] thiophen-3-yl Methyl-2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl) -amide

2-amino-3-benzo [b] thiophen-3-yl-1- [1,4 '] bipiperidinyl-1'-yl-propan-1-one in 1,2-dichloroethane (1.5 mL) To a solution of (50.0 mg, 0.135 mmol) was added N, N'-disuccinimidyl carbonate (34.6 mg, 0.135 mmol) and diisopropylethyl amine (0.09 mL, 0.500 mmol). The resulting solution was stirred for 1 h and 3,4-benzo-2,9-diazaspiro [5.5] undec-1-one (30.4 mg, 0.140 mmol) was added. The reaction mixture was stirred at rt overnight and concentrated. Purification by reverse phase preparative HPLC gave the desired product as a brown oil (75.5 mg, 77%).

Example  62

N-[(1R) -1- (benzo [b] thien-3-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -3 ', 4'- Dihydro-2-oxospyro- [piperidine-4,4 '(1H) -quinoline] -1-carboxamide

(R) -1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid (1-benzo [b] thiophen-3-yl 3 ', 4'-dihydro-2-oxospyro- [piperi as described for methyl-2- [1,4'] bipiperidinyl-1'-yl-2-oxo-ethyl) -amide Prepared from Dean-4,4 ′ (1H) -quinoline (see MS Chambers, et al., J. Med. Chem., 1992, 35, 2033-2039; WO-94 / 13696).

Example  63

N-[(1R) -1- (benzo [b] thien-3-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'- Dihydro-1-oxospyro- [piperidine-4,4 '(1H) -isoquinoline] -1-carboxamide

(R) -1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid (1-benzo [b] thiophen-3-yl 2 ', 3'-dihydro-1-oxospyro- [piperi as described for methyl-2- [1,4'] bipiperidinyl-1'-yl-2-oxo-ethyl) -amide Prepared from Dean-4,4 ′ (1H) -isoquinoline (see MS Chambers, et al., J. Med. Chem., 1992,35, 2033-2039; WO-94 / 13696).

Example  64

N-[(1R) -1- (benzo [b] thien-3-ylmethyl) -2- [1,4'-bipiperidin] -1'-yl-2-oxoethyl] -1,2- Dihydro-2-oxospyro- [4H-3,1-benzoxazine-4,4'-piperidine] -1'-carboxamide

(R) -1-oxo-3,4-benzo-2,9-diaza-spiro [5.5] undec-3-ene-9-carboxylic acid (1-benzo [b] thiophen-3-yl 1,2-dihydro-2-oxospyro- [4H-3, as described for methyl-2- [1,4 '] bipiperidinyl-1'-yl-2-oxo-ethyl) -amide Prepared from 1-benzoxazine-4,4'-piperidine (the recipe is described in Takai, et al .; Chem. Pharm. Bull. 1985, 33, 1129-1139) Title compound (76 %) Was obtained. Mass spectroscopy: 616 (MH) ⁺ . Rf = 1.42.

Succinate  Intermediates and Example

3-Benzo [b] thiophen-3-yl-acrylic acid

A suspension of 1-benzothiophen-3-carbaldehyde (4.9 g, 0.03 mol), malonic acid (6.6 g, 0.06 mol) and piperidine (1 mL) in 100 mL anhydrous pyridine was heated to 110 ° C. overnight. . The reaction mixture was cooled to rt and the solvent was removed in vacuo. The residue was dissolved in 100 mL of water and the pH of this solution was adjusted to about 3 by addition of 1 N hydrochloric acid. The suspension was filtered, the yellow solid collected, washed with water (3 x 50 mL) and concentrated in vacuo to yield the presented product of purity 95% (5.65 g, 91%).

3-Benzo [b] thiophen-3-yl-propionic acid

3-benzo [b] thiophen-3-yl-acrylic acid in 1: 1 methanol / ethyl acetate (50 mL): a suspension of (5.6 g, 0.027 mol) and 10% Pd / C (600 mg) in Parz. Hydrogenated to 50 psi overnight. The mixture was filtered and concentrated to give crude product which required no further purification (about 100% conversion). Mass spectroscopy: 205 (MH) ^- .

3- (3-Benzo [b] thiophen-3-yl-propionyl) -4 (R) -benzyl-oxazolidin-2-one

Pivaloyl at 0 ° C. in a solution of 3-benzo [b] thiophen-3-yl-propionic acid (2.1 g, 0.010 mol), triethylamine (4.12 g, 0.040 mol) in tetrahydrofuran anhydride (100 mL). Chloride (1.38 mL, 0.011 mol) was added. After stirring for 1.5 h at 0 ° C., lithium chloride (0.475 g, 0.011 mol) and (R) -4-benzyl-2-oxazolidinone (1.988 g, 0.011 mol) were added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then washed with water (3 x 150 mL). The organic layer was separated, dried and evaporated to afford crude product. The title product was obtained by flash chromatography on silica gel eluting with (90%) 100% methylene chloride as a brown oil. The compound was used immediately in the next procedure.

3 (S) -benzo [b] thiophen-3-ylmethyl-4- (4-benzyl-2-oxo-oxazolidin-3-yl) -4-oxo butyric acid tert-butyl ester

-78 in a solution of 3- (3-benzo [b] thiophen-3-yl-propionyl) -4-benzyl-oxazolidin-2-one (3.35 g, 9.18 mmol) in 100 mL anhydrous tetrahydrofuran. Lithium diisopropyl amide (6.1 mL, 11.01 mmol) in tetrahydrofuran at C was added and the reaction mixture was stirred for 30 minutes. After addition of t-butyl bromoacetate (1.62 mL, 11.01 mmol) at −78 ° C., the mixture was stirred with warming to room temperature overnight. The solvent was evaporated and the residue diluted with ethyl acetate. The organic layer was washed with water (3 x 100 mL), dried, filtered and concentrated to give the crude product. The title product was obtained by filtration through silica pat eluted with methylene chloride (49%).

2 (S) -Benzo [b] thiophen-3-ylmethyl-succinic acid, 4-tert-butyl ester

3-benzo [b] thiophen-3-ylmethyl-4- (4-benzyl-2-oxo-oxazolidine-3- in tetrahydrofuran (50 mL) and water (30 mL) stirred at 0 ° C. To a solution of l) -4-oxobutyric acid tert-butyl ester (2.15 g, 4.49 mmol) was added 30% aqueous hydrogen peroxide (1 mL) followed by lithium hydroxide (0.2155 g, 8.98 mmol). The reaction mixture was stirred overnight. Tetrahydrofuran was removed in vacuo and the resulting solution was acidified with 10% citric acid and then extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with sodium bisulfite solution, dried and concentrated to give the title product.

3 (S) -benzo [b] thiophen-3-ylmethyl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxo-butyric acid tert-butyl ester

2-benzo [b] thiophen-3-ylmethyl-succinic acid 4-tert-butyl ester (1.8420 g, 5.76 mmol), piperidylpiperidine (1.2240 g, 7.28 mmol) and triethylamine in 100 mL methylene chloride A solution of (0.7353 g, 7.28 mmol) was treated with 3- (diethoxyphosphoryloxy) -1,2,3-benzotriin-4 (3H) -one (DEPBT, 1.8953 g, 6.34 mmol). The mixture was stirred overnight and then washed with water (3 x 40 mL). The organic layer was dried, filtered and concentrated in vacuo to afford the crude product. This was further purified by flash chromatography on silica gel eluted with 0-10% 2 M ammonia in methanol / methylene chloride to afford the desired product. This product was used without further purification.

3 (S) -Benzo [b] thiophen-3-ylmethyl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxo-butyric acid

Trifluoride solution of 3-benzo [b] thiophen-3-ylmethyl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxo-butyric acid tert-butyl ester in 15 mL methylene chloride Treated with roacetic acid (3 mL) and the reaction mixture was stirred at rt overnight. Evaporation of the solvent gave the trifluoroacetate salt corresponding to the title product (99%).

Example  65

1- [1,4 '] bipiperidinyl-1'-yl-2- (3 (S) -benzo [b] thiophen-3-ylmethyl) -4- [1', 2'-dihydro- 2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione

3-benzo [b] thiophen-3-ylmethyl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxo-butyric acid (25.0 mg, 0.060 mmol) in 5 mL methylene chloride, 1 , 2-dihydro-2-oxospyro-4H-3,1-dihydro-benzoxazine-4'4-piperidine (15.7 mg, 0.072 mmol) and triethylamine (7.3 mg, 0.072 mmol) The solution was treated with 3- (diethoxyphosphoryloxy) -1,2,3-benzotriin-4 (3H) -one (DEPBT, 21.5 mg, 0.072 mmol) at room temperature. The solution was stirred overnight and then washed with water (3 x 5 mL). After drying and concentration of the organic layer, the crude product was purified by flash chromatography on silica gel eluting with 0-10% 2M ammonia in methanol / methylene chloride to give the desired product at 60% yield. LC / MS: t _R = 1.34 min, 615.45 (MH) ⁺ .

2- (7-Methyl-1H-indazol-5-ylmethylene) -succinic acid 1-methyl ester

Potassium t-butoxide (0.4036) in a mixture of 7-methyl indazole aldehyde (0.2619 g, 1.64 mmol) and DBE-4 dibasic ester (dimethyl succinate) (0.32 mL, 2.45 mmol) in t-butanol (20 mL) g, 3.60 mmol) was added. The reaction mixture was heated to 50 ° C. for 2 hours under nitrogen. After an additional 16 hours at room temperature, the solvent was removed in vacuo and the residue was dissolved in water (100 mL) and then extracted with ethyl acetate (3 x 50 mL). The pH was adjusted to 3-4 by addition of 1 N hydrochloric acid to the aqueous layer and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate solution was dried and concentrated in vacuo to yield the crude product as a yellow solid (99%, cis / trans isomer approximately 40:60). The crude mixture was used in the next step without further purification. Mass spectroscopy: 275 (MH) ⁺ .

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -succinic acid 1-methyl ester

2- (7-methyl-1H-indazol-5-ylmethylene) -succinic acid 1-methyl ester (0.440 g, 1.62 mmol) and 10% Pd / in ethyl acetate (15 mL) and methanol (5 mL) A suspension of C (0.04 g) was hydrogenated at 50 psi overnight in a Parr apparatus. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to afford the desired product as a yellow solid (100%). Mass spectroscopy: 277 (MH) ⁺ .

Example  66

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospyro- [4H-3', 1-Benzoxazine-4,4'-piperidinyl] -butyric acid methyl ester

2- (7-Methyl-1H-indazol-5-ylmethyl) -succinic acid 1-methyl ester (0.2253 g, 0.82 mmol) in methylene chloride (15 mL), 1,2-dihydro-2-oxospyro- A solution of 4H-3,1-dihydro-benzoxazine-4'4-piperidine (0.1938 g, 0.89 mmol) and triethylamine (0.099 g, 0.98 mmol) was added to 3- (diethoxyphosphoryl Treated with oxy) -1,2,3-benzotriin-4 (3H) -one (DEPBT, 0.2685 g, 0.90 mmol). The mixture was stirred overnight and then washed with water (3 x 5 mL). The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluted with 0-10% 2M ammonia in methanol / methylene chloride to give the desired product (53%). LC / MS: t _R = 1.40 min, 477.28 (MH) ⁺ .

Similarly manufactured:

Example  67

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidin-1-yl] -butyric acid methyl ester

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospyro- [4H-3', 1-Benzoxazine-4,4'-piperidinyl] -butyric acid

2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2' in tetrahydrofuran (10 mL) and water (8 mL) A solution of -oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butyric acid methyl ester (0.1911 g, 0.40 mmol) and lithium hydroxide (19.3 mg, 0.80 mmol) Was stirred at rt overnight. 1 N hydrochloric acid was added to the reaction mixture to acidify to about pH 1, concentrated to remove tetrahydrofuran in vacuo and collected by filtration to give a white solid precipitate. The solid was washed twice with a small amount of water and dried in vacuo overnight (100%). Mass spectroscopy: 477 (MH) ⁺ .

Example  68

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro -2'-Oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione

2- (7-Methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [l ', 2'-dihydro-2'-oxospyro- [4H- in methylene chloride (5 mL) 3 ', 1-benzoxazine-4,4'-piperidinyl] -butyric acid (0.020 g, 0.04 mmol), piperidylpiperidine (0.0087 g, 0.05 mmol) and triethylamine (0.09 g, 0.08 mmol ) Was treated with 3- (diethoxyphosphoryloxy) -1,2,3-benzotriin-4 (3H) -one (DEPBT, 0.0155 g, 0.05 mmol) at room temperature. The mixture was stirred overnight and then washed with water (3 x 5 mL). The organic layer was dried and the solvent removed in vacuo. The crude product was purified by preparative TLC on silica gel (10% 2 M ammonium hydroxide / methanol in methylene chloride) to give the desired product (36%). LC / MS: t _R = 1.18 min, 613.47 (MH) ⁺ .

Similarly manufactured:

Example  69

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [4- (2-oxo-1 , 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

Example  70

(±) -1- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4- [ 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

Example  71

(±) -1- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4- [ 1 ', 2'-dihydro-2'-oxospyro- [4H-3', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione

Example  72

(±) -N, N-dimethyl-2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H -Quinazolin-3-yl) -piperidin-1-yl] -butyramide

LC / MS: t _R = 1.36 min, 525.35 (M + Na) ⁺ .

Example  73

(±) -1- (2,6-dimethyl-morpholin-4-yl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4- [4- (2-oxo-1 , 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 1.41 min, 573.39 (MH) ⁺ .

Example  74

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -1- (4-methyl-piperidin-1-yl) -4- [4- (2-oxo-1, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

Example  75

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -1-morpholin-4-yl-4- [4- (2-oxo-1,4-dihydro-2H- Quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 1.32 min, 545.42 (MH) ⁺ .

Example  76

(±) -N, N-Dimethyl-2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxoscopy- [4H-3 ', 1-Benzoxazine-4,4'-piperidinyl] -butyramide

LC / MS: t _R = 1.27 min, 512.30 (M + Na) ⁺ .

Example  77

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -1- (piperidin-1-yl) -4- [1 ', 2'-dihydro-2'-oxo Spiro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione

Example  78

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridin-1-yl] -1-piperidin-1-yl-butane-1,4-dione

Example  79

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro-2'- Oxose-pyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione

Example  80

(±) -1- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (1H-indazol-5-ylmethyl) -4- [1 ', 2 '-Dihydro-2'-oxospyro- [4H-3', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione

LC / MS: t _R = 1.25 min, 574.25 (MH) ⁺ .

Example  81

(±) -1- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -2- (1H-indazol-5-ylmethyl) -4- [4- (2 -Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 1.34 min, 587.38 (MH) ⁺ .

Example  82

(±) -2- (1H-indazol-5-ylmethyl) -N, N-dimethyl-4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin- 3-yl) -piperidin-1-yl] -butyramide

LC / MS: t _R = 1.28 min, 489.33 (MH) ⁺ .

Example  83

(±) -5- {2-([1,4 '] bipiperidinyl-1'-carbonyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H- Quinazolin-3-yl) -piperidin-1-yl] -butyl} -indazol-1-carboxylic acid tert-butyl ester

LC / MS: t _R = 1.47 min, 742.55 (M + Na) ⁺ .

Example  84

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidin-1-yl] -N-prop-2-ynyl-butyramide

LC / MS: t _R = 1.33 min, 535.32 (M + Na) ⁺ .

Aspartate  Intermediates and Example

(L) -2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Yl] -butyric acid benzyl ester

N-tert-butyloxycarbonyl-L-aspartic acid-alpha-benzyl ester (1.4 g, 4.33 mmol) and 3,4-dihydro-3- (4-piperidinyl in stirred methylene chloride (12 mL) 3- (diethoxyphosphoryloxy) -1,2,3-benzotriin-4 (3H) -one (DEPBT, 1.425 g) in a solution of -2 (1H) -quinazolinone (1.26 g, 4.33 mmol) , 4.76 mmol) was added in one portion, and triethylamine (0.724 mL, 5.20 mmol) was added dropwise The resulting suspension was stirred gradually to homogenize and stirred overnight at room temperature (15 h) The mixture was diluted with methylene chloride And washed with sodium hydroxide (0.5 N) and water The layers were separated and the organic layer was dried over sodium sulfate and then concentrated in vacuo to yield a light yellow foam The crude product was subjected to flash column chromatography in methylene chloride 10% methanol) to give a colorless oil .. Mass spectrometry: 559 (M + Na) ⁺ .

(L) -2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Day] -butyric acid

2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quina in ethyl acetate / methanol (16 mL, 1: 1) in a Parr bottle To a solution of zolin-3-yl) -piperidin-1-yl] -butyric acid benzyl ester (1.48 g, 2.76 mmol) was poured 10% palladium charcoal (150 mg) at a time. Hydrogenation was performed at 52 psi for 1 hour in the Farr apparatus. TLC (10% methanol in methylene chloride) showed quantitative conversion. The mixture was filtered and concentrated in vacuo to give a glassy colorless solid (1.14 g, 93%).

Example  85

(L)-{1-([1,4 '] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-1,4-dihydro-2H-quinazolin -3-yl) -piperidin-1-yl] -propyl} -carbamic acid tert-butyl ester

2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-in stirred methylene chloride (20 mL)- 3- (diethoxyphosphoryloxy) -1,2 in a solution of piperidin-1-yl] -butyric acid (1.14 g, 2.55 mmol) and 4-piperidinyl-piperidine (525 mg, 2.81 mmol) , 3-benzotriin-4 (3H) -one (DEPBT, 840 mg, 2.81 mmol) was added in one portion, and triethylamine (0.427 mL, 3.06 mmol) was added dropwise. The resulting mixture was stirred at rt overnight (15 h). The mixture was diluted with methylene chloride and washed with sodium hydroxide (0.5 N) solution and water. The layers were separated and the organic layer was dried over sodium sulfate and then concentrated in vacuo to yield a light yellow foam. The crude product was purified by flash column chromatography (10% in methylene chloride (1M ammonia in methanol)) to give a colorless foam (1.08 g, 71%).

(L) -2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl ) -Piperidin-1-yl] -butane-1,4-dione

1-([1,4 '] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-1,4-dihydro- in stirred methylene chloride (12 mL) To a solution of 2H-quinazolin-3-yl) -piperidin-1-yl] -propyl} -carbamic acid tert-butyl ester (1.05 g, 1.76 mmol) was added trifluoroacetic acid (2 mL). The mixture was stirred at rt until the end of the conversion (monitored by LCMS, about 15 h). The mixture was then diluted with water and sodium hydroxide (1.5 g) was added with slow stirring. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a light yellow foam (860 mg, 98%). Mass spectroscopy: 497 (MH) ⁺ .

Example  86

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (1H-indol-5-ylamino) -4- [4- (2-oxo-1,4-dihydro -2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro in tetrahydrofuran (1 mL) in a 5 mL drum vial -2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (52 mg, 0.105 mmol) and N-tert-BOC-5-bromo-indole (document [ Tetrahedron 2000, pp 8473-8482) (31 mg, 0.105 mmol) in a solution of 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) -biphenyl (4.1 mg, 0.0105 mmol), Pd ₂ (dba) ₃ (4.8 mg, 0.005 mmol) and cesium carbonate (54.6 mg, 0.168 mmol) were added under nitrogen. The vial was sealed with a teflon®-lined cap. The dark orange reaction mixture was heated to 80 ° C. with stirring. The reaction was kept at 80 ° C. overnight. After 17 hours approximately 50% was converted. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and filtered. The desired product was purified by adaptive TLC (10% methanol in methylene chloride) to give tert-butyloxycarbonyl-protected product (11 mg, 15%). Mass spectroscopy: 712 (MH) ⁺ . This intermediate (11 mg) was dissolved in 3 mL methylene chloride and treated with trifluoroacetic acid (1.5 mL). When the colorless solution turned light brown, it was stirred for 1.5 hours at room temperature. The mixture was concentrated in vacuo and dried under high vacuum to give a light brown powder (15 mg, 100%). Mass spectroscopy: 612 (MH) ⁺ .

Example  87

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (5-chloro-2-nitro-phenylamino) -4- [4- (2-oxo-1,4- Dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazoline in stirred ethanol (0.5 mL) -3-yl) -piperidin-1-yl] -butane-1,4-dione (33.7 mg, 0.068 mmol) and 4-chloro-1,2-dinitrobenzene (16.8 mg, 0.075 mmol) To saturated sodium bicarbonate solution (4 drops) was added. The mixture was stirred at room temperature for 70 hours, converting approximately 60%. The product was purified by preparative HPLC to give a yellow solid (17.7 mg, 40%). Mass spectroscopy: 652 (MH) ⁺ .

Example  88

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (6-chloro-pyrimidin-4-ylamino) -4- [4- (2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro in 2-propanol (0.5 mL) in a vial for microwave -2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (22.3 mg, 0.045 mmol) and 4,6-dichloropyrimidine (16 mg, 0.095 mmol) The mixture was heated to 130 ° C. for 40 minutes under microwave spinning. LC / MS showed 90% conversion. The solvent was removed in vacuo and the residue partitioned between methylene chloride and 1 N sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (10% in methylene chloride (1 N ammonia in methanol)) to give a white solid (23 mg, 84%).

Similarly manufactured:

Example  89

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-chloro-9H-purin-6-ylamino) -4- [4- (2-oxo-1, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 1.10 min, 649 (MH) ⁺ .

Example  90

(L) -2- (4-amino-6-methyl-5-nitro-pyrimidin-2-ylamino) -1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 1.12 min, 649 (MH) ⁺ .

Example  91

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (4,5-diamino-6-methyl-pyrimidin-2-ylamino) -4- [4- ( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2- (4-amino-6-methyl-5-nitro-pyrimidin-2-ylamino) -1- [1,4 '] bipiperidinyl in 2: 1 methanol / ethyl acetate (6 mL) in a Parr bottle -1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione To the solution was added 10% palladium charcoal (60 mg). The mixture was stirred for 20 hours under a hydrogen atmosphere of 55 psi. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give a colorless solid (41.2 mg, 49.2% for 2 steps).

LC / MS: t _R = 0.86 min, 619 (MH) ⁺ .

Example  92

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H- [1,2,3] triazolo [4,5-d] pyrimidine-5 -Ylamino) -4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

1- [1,4 '] bipiperidinyl-1'-yl-2- (4,5-diamino-6-methyl-pyrimidin-2-ylamino) -4- in stirred acetic acid (1.5 mL) Solution of [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (10.6 mg, 0.0125 mmol) To sodium nitrite (24 mg) was added followed by a small drop of water. The resulting light yellow solution was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and methanol and purified by preparative HPLC to give a colorless oil / solid (3.0 mg, 28%). LC / MS: t _R = 1.07 min, 630 (MH) ⁺ .

Example  General procedure for the synthesis of 93-95:

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H in 1,2-dichloroethane (3.0 mL) -Quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (0.014 mmol), one of the aldehydes (0.07 mmol, 5 equiv) and solid anhydrous magnesium sulfate (0.031 mmol, 2.2 equivalents) was treated with a catalytic amount of acetic acid and stirred overnight. Sodium cyanoborohydride (0.07 mmol, 5 equiv) was then added in one portion and the suspension was stirred again overnight. Filtered by SCX cartridge or purified by preparative HPLC.

Example  93

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2-((2'-pyridyl) -methyl-amino) -4- [4- (2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 0.87 min, 588 (MH) ⁺ .

Example  94

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2-((5'-indazolyl) -methyl-amino) -4- [4- (2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 0.92 min, 626 (MH) ⁺ .

Example  95

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2-((3'-methyl-phenyl) -methyl-amino) -4- [4- (2-oxo-1, 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

LC / MS: t _R = 1.08 min, 600 (MH) ⁺ .

Example  96

(L) -1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperi Din-1-yl] -2- (pyrimidin-4-ylamino) -butane-1,4-dione

1- [1,4 '] bipiperidinyl-1'-yl-2- (6-chloro-pyrimidin-4-ylamino) -4- [4- (2-oxo-1,4-dihydro- 10% palladiumated charcoal with 4 mL ethyl acetate / methanol (1: 1) in a solution of 2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (21 mg) (10 mg) was dissolved in the added Parr bottle. Hydrogenation was performed overnight at 55 psi in the Farr apparatus. The degassed mixture was then filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give a yellow solid (12.4 mg, 45%). Mass spectroscopy: 575 (MH) ⁺ .

Example  97

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2- (4-hydroxy-cyclohexylamino) -4- [4- (2-oxo-1,4-dihydro -2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazoline in stirred methanol (1.0 mL) -3-yl) -piperidin-1-yl] -butane-1,4-dione (47.9 mg, 0.096 mmol) and 4-hydroxy-cyclohexanone (Synthesis reported in Can. J. Chem. 1994, 72, 1699-1704]) (11 mg, 0.096 mmol) was added excess zinc chloride followed by sodium cyanoborohydride (5 equiv). The suspension was stirred for 6 days at room temperature. Methanol was removed in vacuo and the residue partitioned between methylene chloride and 1 N sodium hydroxide. The aqueous layer was extracted with methylene chloride (3x). The combined methylene chloride solution was passed through a celite cartridge and concentrated in vacuo. The residue was filtered through preparative TLC (10% in methylene chloride (1 N ammonia in methanol)) to give the desired product as a white solid (15.3 mg, 27%). Mass spectroscopy: 595 (MH) ⁺ .

Example  98

(L) -1- [1,4 '] bipiperidinyl-1'-yl-2-[(1H-imidazol-4-ylmethyl) -amino] -4- [4- (2-oxo-1 , 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quina in stirred methylene chloride (1.0 mL) Sodium cyanobo in a solution of zolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (20.6 mg, 0.0415 mmol) and 4-imidazolcarboxyaldehyde (4 mg, 0.0415 mmol) Low hydride (8.8 mg, 0.0415 mmol) was added in one portion. The suspension was stirred for 2 days at room temperature and then partitioned between methylene chloride and 1 N sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (10% in methylene chloride (1 N ammonia in methanol)) to give the desired product as a colorless oil which solidified at the same time (6.1 mg, 26%).

Example  99

(L) -N- {1-([1,4 '] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-1,4-dihydro-2H- Quinazolin-3-yl) -piperidin-1-yl] -propyl} -4-methoxy-benzamide

2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-in stirred methylene chloride Add two drops of triethylamine (35 μl) to a solution of piperidin-1-yl] -butane-1,4-dione (91.5 mg, 0.184 mmol) and p-anisoyl chloride (34.6 mg, 0.203 mmol) It was. The light yellow solution was converted completely by stirring at room temperature for 2.5 hours. The reaction mixture was washed with sodium hydroxide (IN) and the aqueous layer was extracted with methylene chloride. The combined organic layers were passed through a celite cartridge and concentrated in vacuo to yield a glassy solid. The crude product was purified by flash column chromatography (10% in methylene chloride (1 N ammonia in methanol)) to give a glassy solid (92.8 mg, 80%).

Example  100

(L) -N-1-([1,4 '] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-1,4-dihydro-2H-quina Zolin-3-yl) -piperidin-1-yl] -propyl} -4-hydroxy-benzamide

N 1-([1,4 '] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-1,4-dihydro in stirred methylene chloride (69 mg) -2H-quinazolin-3-yl) -piperidin-1-yl] -propyl} -4-methoxy-benzamide solution was added dropwise at room temperature with boron tribromide (1M in methylene chloride, 0.6 mL) Treated. The resulting suspension was stirred at rt for 7 h, then the reaction was quenched with excess triethylamine and then methanol. The solvent was removed in vacuo and the residue was dissolved in methanol and then purified by preparative HPLC. LC / MS: t _R = 1.03 min, 617 (MH) ⁺ .

Example  101

(L) -1H-pyrazole-3-carboxylic acid {1-([1,4 '] bipiperidinyl-1'-carbonyl) -3-oxo-3- [4- (2-oxo-1 , 4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -propyl} -amide

Pyrazole-3-carboxylic acid (4 mg, 0.036 mmol) and 2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4 in stirred methylene chloride (1 mL) In a solution of-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione (13 mg, 0.026 mmol) -(Diethoxyphosphoryloxy) -1,2,3-benzotriin-4 (3H) -one (DEPBT, 8.6 mg, 0.036 mmol) was added in one portion followed by the addition of one drop of triethylamine. The resulting mixture was stirred at rt overnight (15 h). The mixture was then partitioned between sodium hydroxide (0.5 N) and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (3 ×). LCMS showed that the product remained in the aqueous layer. The product was purified by preparative HPLC to give a yellow oil (17.2 mg, 94%). Mass spectroscopy: 591 (MH) ⁺ .

Example  General procedure for the synthesis of 102-134:

Starting amine, 2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -Piperidin-1-yl] -butane-1,4-dione was dispersed in 1 mL dichloroethane in a 96-well mini-reactor (about 10 mg each). To each acyl chloride (about 2 equiv) was added a resin-bound solid phase piperidine base (4 equiv). The block was stirred overnight. Approximately 4 equivalents of tris-amine resin was added to each well and the small-reactor was stirred for an additional 5 hours. The reaction mixture was filtered and purified by preparative HPLC or filtered with an SCX cartridge, or both. HPLC retention times and mass spectral data for each example are listed in Table 2.

Example  General procedure for the synthesis of 135-200:

Starting amine, 2-amino-1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -Piperidin-1-yl] -butane-1,4-dione was dispersed in dichloroethane (1 mL) in a 96-well small-reactor (approximately 10 mg in each well). Individual isocyanates (about 2 equivalents) were added to individual wells. Blocks were shaken for 2 days. Approximately 4 equivalents of tris-amine resin were added to each well and the small-reactor was stirred for an additional 2 days. The reaction mixture was filtered and the individual products were purified by preparative HPLC or filtered through an SCX cartridge, or both. HPLC retention times and mass spectral data for each example are listed in Table 3.

2- (1H-indazol-5-ylamino) -succinic acid 4-tert-butyl ester 1-ethyl ester

To a solution / suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 mL) was added ethyl glyoxylate solution (about 50% in toluene, 1.7 mL, 1.1 equiv) in one portion and magnesium sulfate (4.6 g) was added. The mixture was stirred at rt overnight (23 h), then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was azeotropically dried over anhydrous benzene and further dried under high vacuum. The residue was then dissolved in tetrahydrofuran (20 mL) and cooled to 0 ° C. Then a solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was added slowly. After stirring at 0 ° C. for 1 hour, the mixture was stored at 4 ° C. overnight. The mixture was then diluted with ethyl acetate and quenched with 0.5 N HCl minimum and a half-saturated ammonium chloride solution to dissolve the precipitated solid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluted with 10% methanol in methylene chloride to give the desired product (1.3 g, 65%) as light brown oil.

2- (1H-indazol-5-ylamino) -succinic acid 1-ethyl ester

2- (1H-indazol-5-ylamino) -succinic acid 4-tert-butyl ester 1-ethyl ester (123.6 mg, 0.37 mmol) in stirred methylene chloride (2 mL) and trifluoroacetic acid (0.5 mL) The solution of was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to give a dark green oil. LC / MS: t _R = 0.643 min, 278.19 (MH) ⁺ .

2- (1H-indazol-5-ylamino) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Yl] -butyric acid ethyl ester

To a solution of 2- (1H-indazol-5-ylamino) -succinic acid 1-ethyl ester (84 mg, 0.215 mmol) in stirred methylene chloride (1 mL) was added amine (99 mg, 0.429 mmol, 2 equiv). Then, DEPBT (128 mg, 0.43 mmol, 2 equiv) and triethylamine (70 μl, 0.47 mmol, 2.2 equiv) were added. The mixture was stirred overnight, diluted with ethyl acetate and washed with semi-saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to a light brown oil. The crude product was purified by flash column chromatography on silica gel eluted with 10% methanol in methylene chloride to afford the desired product as a red oil (36.2 mg, 34.5% for 2 steps).

2- (1H-indazol-5-ylamino) -4-oxo-4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Day] -butyric acid

To a solution of ethyl ester (34 mg, 0.069 mmol) in tetrahydrofuran (0.3 mL) was added lithium hydroxide in water (1 M, 280 μl, 4 equiv) and the mixture was stirred at rt for 17 h. The solution was dried under a stream of nitrogen. 0.2 mL tetrahydrofuran and 0.2 mL anhydrous benzene were added to the residue and the suspension was dried again with a stream of nitrogen. LC / MS: t _R = 0.900 min, 463.30 (MH) ⁺ .

Example  201

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (1H-indazol-5-ylamino) -4- [4- (2-oxo-1,4-di Hydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

2- (1H-indazol-5-ylamino) -4-oxo-4- [4- (2-oxo-1,4-dihydro- in dimethylformamide (0.5 mL) in a drum vial with a cap To a solution of 2H-quinazolin-3-yl) -piperidin-1-yl] -butyric acid ethyl ester (0.069 mmol), piperidinylpiperidine (14.3 mg, 0.076 mmol, 1.1 equiv), DEPBT (22.8 mg, 1.1 equiv) and triethylamine (8 drops, about 160 RL) were added. The mixture was stirred at rt overnight. The final product was purified by preparative HPLC to give the desired product (15 mg, 26% for 2 steps) as a light brown solid. LC / MS: t _R = 0.917 min, 613.54 (MH) ⁺ .

Additional Example

(1-benzyl-piperidin-4-yl)-(2-nitro-benzyl) -amine

2-nitrobenzaldehyde (1 g, 6.61 mmol) and 4-amino-1-benzylpiperidine (1.35 mL, 6.61 mmol) were combined with ethanol (20 mL). The resulting suspension was stirred at room temperature for 20 minutes and a solution of sodium borohydride (0. 25 g, 6.61 mmol) in ethanol (5 mL) was added dropwise over 10 minutes. After completion of the dropwise addition, the reaction was stirred for 1 hour, cooled to 0 ° C. and concentrated ammonium chloride was added to the reaction mixture until no foam was observed. The solvent was evaporated in vacuo and the resulting crude mixture was dissolved in water (10 mL) and methylene chloride (10 mL). The layers were separated and the organic layer was washed with water (2 ×) and brine (2 ×), then dried over sodium sulfate, filtered and concentrated to give 1.5 g (70%) of the desired product. LC / MS: t _R = 0.7 min, 326.18 (MH) ⁺ .

(2-Amino-benzyl)-(1-benzyl-piperidin-4-yl) -amine

(1-benzyl-piperidin-4-yl)-(2-nitro-benzyl) -amine (1.2 g, 3.7 mmol) and zinc fine powder (1 g, excess) were combined with 75% aqueous acetic acid (16 mL) And stirred at 60 ° C. for 2 hours. After cooling to room temperature, the solvent was removed in vacuo, the resulting crude product was dissolved in water (10 mL) and ammonium hydroxide was added until the pH reached 3. The solution was extracted with methylene chloride (3x). The organic layers were pooled together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered and concentrated to give 0.8 g (73%) of the desired product.

3- (1-benzyl-piperidin-4-yl) -3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide

A solution of (2-amino-benzyl)-(1-benzyl-piperidin-4-yl) -amine (1.0 g, 3.39 mmol) and sulfamide (0.64 g, 6.78 mmol) in pyridine was refluxed for 14 hours. Heated at. After cooling to room temperature, the solvent was evaporated and the crude product was dissolved in water. After adjusting the pH to 9 with 6 N sodium hydroxide, the resulting mixture was extracted with methylene chloride (2x). The extract was washed with water (2 ×), dried over sodium sulfate, filtered and concentrated to yield an oily residue that was dissolved in ethyl acetate (4 mL). This solution was mixed with 4N HCl in 1,4-dioxane (2 mL) and diethyl ether was added until a precipitate formed. The desired product was filtered to give 0.7 g (53%). LC / MS: t _R = 0.96 min, 358.16 (MH) ⁺ .

3-piperidin-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide

3- (1-benzyl-piperidin-4-yl) -3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide in methanol (10 mL) 0.46 g, 1.29 mmol) was flushed with nitrogen and treated with palladium on charcoal (10%, 46 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 0.26 g (75%) of the desired material.

6-bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one

3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.87 mmol) was dissolved in acetic acid (2 mL). To this solution was added dropwise a bromine (1.8 mL, 35.14 mmol) solution in acetic acid (0.5 mL) over 5 minutes. After stirring for 1 hour at room temperature, the reaction mixture is diluted with methylene chloride, washed with water (2x), brine (2x), dried over sodium sulfate, filtered and concentrated to use directly without further purification. 0.16 g (59%) of material was obtained. LC / MS: t _R = 0.91 min, 310.15 (MH) ⁺ .

2-oxo-3-piperidin-4-yl-1,2,3,4-tetrahydro-quinazolin-6-carbonitrile

6-bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.16 g, 0.52 mmol), zinc cyanide (37 mg, 0.31 mmol) and tetra Keith (triphenylphosphine) palladium (0) (60 mg, 0.05 mmol) was combined with dimethylformamide (4 mL). The reaction flask was connected to high vacuum to degas by the freeze-thawing method (3 ×), heated to 90 ° C. and stirred under nitrogen for 1 hour. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture was purified by preparative HPLC to give 50 mg (38%) of the desired nitrile.

N- (1-benzyl-piperidin-4-yl) -2- (2-nitro-phenyl) -acetamide

(2-nitro-phenyl) -acetic acid (2.0 g, 11.04 mmol), 4-amino-1-benzylpiperidine (2.25 mL, 10.03 mmol), 1-hydroxybenzotriazole (1.49 g, 11.04 mmol) and 1- (3-Dimethylaminopropyl) -3-ethyl carbodiimide (2.3 g, 12.03 mmol) was combined with ethyl acetate (25 mL). Triethylamine (4.2 mL. 30.1 mmol) was added to this solution and the reaction mixture was stirred at 40 ° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate and concentrated to give 3.5 g (98%) of the desired product. It was. LC / MS: t _R = 1.24 min, 354.30 (MH) ⁺ .

[2- (2-Amino-phenyl) -ethyl]-(1-benzyl-piperidin-4-yl) -amine

In a flame-dried flask, N- (1-benzyl-piperidin-4-yl) -2- (2-nitro-phenyl) acetamide (3.2 g, 9.06 mmol) and lithium aluminum hydride (1.0 g, 18.12 mmol) was added. 1,4-dioxane (15 mL) was added and the mixture was slowly heated to reflux for 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0 ° C. and excess lithium aluminum hydride was removed by dropwise addition of methanol and 20% potassium hydroxide was carefully added. The aluminum salt was filtered off, and the filtrate was concentrated to use as the next reaction.

3- (1-benzyl-piperidin-4-yl) 1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one

Solution of [2- (2-amino-phenyl) -ethyl]-(1-benzyl-piperidin-4-yl) amine (0.44 g, 1.42 mmol) in tetrahydrofuran (5 mL) stirred at 0 ° C. Was treated with carbonyl diimidazole (0.23 g, 1.42 mmol). The reaction was stirred at 0 ° C. for 30 minutes and at reflux for 1 hour. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to give 100 mg (21%) of the desired product. LC / MS: t _R = 1.29 min, 336.34 (MH) ⁺ .

3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one

3- (1-benzyl-piperidin-4-yl) 1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one (100 mg in methanol (5 mL)) , 0.3 mmol) was flushed with nitrogen and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 50 mg (68%) of the desired material. LC / MS: t _R = 1.07 min, 246.26 (MH) ⁺ .

3-[(1-benzyl-piperidin-4-yl-amino) -methyl] -4-nitro-phenol

5-hydroxy-2-nitro-benzaldehyde (5 g, 29.9 mmol) and 4-amino-1-benzylpiperidine (5.6 mL, 29.9 mmol) were combined with ethanol (30 mL). The resulting suspension was stirred at room temperature for 20 minutes and a solution of sodium borohydride (1.13 g, 29.9 mmol) in ethanol (10 mL) was added dropwise over 10 minutes. At the end of the dropping, the reaction was stirred at room temperature for 1 hour, cooled to 0 ° C. and then concentrated ammonium chloride was added to the reaction mixture until bubbles disappeared. The solvent was evaporated in vacuo and the resulting crude mixture was dissolved in water (30 mL) and methylene chloride (40 mL). The layers were separated and the organic layer was washed with water (2x), brine (2x), dried over sodium sulfate, filtered and concentrated to give 5.8 g (57%) of the desired product. LC / MS: t _R = 0.95 min, 342.27 (MH) ⁺ .

4-Amino-3-[(1-benzyl-piperidin-4-yl-amino) -methyl] -phenol

(1-benzyl-piperidin-4-yl)-(2-nitro-benzyl) -amine (0.25 g, 0.7 mmol) and zinc fine powder (0.2 g, excess) were combined with 75% aqueous acetic acid (8 mL) And stirred at 60 ° C. for 2 hours. After cooling to room temperature, the solvent is removed in vacuo to dissolve the resulting crude mixture in water (10 mL) and ammonium hydroxide is added to bring the pH to 3. The solution was extracted with methylene chloride (3x). The organic layers were pooled together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered and concentrated to give 0.18 g (79%) of the desired product.

3- (1-benzyl-piperidin-4-yl) -6-hydroxy-3,4-dihydro-1H-quinazolin-2-one

Of 4-amino-3-[(1-benzyl-piperidin-4-yl-amino) -methyl] -phenol (0.16 g, 0.51 mmol) in tetrahydrofuran (3 mL) stirred at 0 ° C. The solution was treated with carbonyl diimidazole (52 mg, 0.51 mmol). The reaction was stirred at 0 ° C. for 30 minutes and at reflux for 1 hour. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to give 100 mg (57%) of the desired product. LC / MS: t _R = 1.09 min, 338.28 (MH) ⁺ .

6-hydroxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one

3- (1-benzyl-piperidin-4-yl) -6-hydroxy-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) Flush with nitrogen and treat with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 60 mg (81%) of the desired material. LC / MS: t _R = 0.75 min, 248.22 (MH) ⁺ .

N- (1-benzyl-piperidin-4-yl) -2-methoxy-6-nitro-benzamide

2-methoxy-6-nitro-benzoic acid (2.0 g, 10.1 mmol), 4-amino-1 benzylpiperidine (1.9 mL, 10.1 mmol), 1-hydroxybenzotriazole (1.43 g, 10.5 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.9 g, 10.1 mmol) was combined with ethyl acetate (25 mL). Triethylamine (4.2 mL, 30.3 mmol) was added to this solution, and the reaction mixture was stirred at 40 ° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate and concentrated to give 3.2 g (86%) of the desired product. It was. LC / MS: t _R = 1.10 min, 370.28 (MH) ⁺ .

(2-Amino-6-methoxy-benzyl)-(1-benzyl-piperidin-4-yl) -amine

In a flame-dried flask, N- (1-benzyl-piperidin-4-yl) -2-methoxy-6-nitrobenzamide (1.0 g, 2.8 mmol) and lithium aluminum hydride (0.31 g, 8.45 mmol) ) Combined. To this mixture was added anhydrous 1,4-dioxane (15 mL). The mixture was slowly heated to reflux for 1 hour and stirred at reflux for 16 hours. The reaction mixture was cooled to 0 ° C. and excess lithium aluminum hydride was removed by dropwise addition of methanol and 20% potassium hydroxide was carefully added. The aluminum salt was filtered off, and the filtrate was concentrated to use as the next reaction.

3- (1-benzyl-piperidin-4-yl) -8-methoxy-3,4-dihydro-1H-quinazolin-2-one

A solution of (2-amino-6-methoxy-benzyl)-(1-benzyl-piperidin-4-yl) -amine (0.2 g, 0.62 mmol) in tetrahydrofuran (3 mL) stirred at 0 ° C. Was treated with carbonyl diimidazole (99 mg, 0.62 mmol). The reaction was stirred at 0 ° C. for 30 minutes and then at reflux temperature for 1 hour. After cooling to rt, the solvent was evaporated and the residue was purified by column to give 150 mg (68%) of the desired product. LC / MS: t _R = 1.41 min, 352.30 (MH) ⁺ .

8-methoxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one

3- (1-benzyl-piperidin-4-yl) -8-methoxy-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.28 mmol) in methanol (5 mL) Flush with nitrogen and treat with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 68 mg (93%) of the desired material. LC / MS: t _R = 1.11 min, 262.23 (MH) ⁺ .

N- (1-benzyl-piperidin-4-yl) -2-chloro-6-nitro-benzamide

2-Chloro-6-nitro-benzoic acid (1.2 g, 5.97 mmol), 4-amino-1 benzylpiperidine (1.1 mL, 5.97 mmol), 1-hydroxybenzotriazole (0.84 g, 1.05 equiv) And 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 g, 1.05 equiv) was combined with ethyl acetate (20 mL). Triethylamine (2.5 mL, 3.0 equiv) was added to this solution and the reaction mixture was stirred at 40 ° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate and concentrated to give 1.9 g (85%) of the desired product. It was.

(2-Amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl) -amine

In a flame-dried flask, N- (1-benzyl-piperidin-4-yl) -2-chloro-6-nitrobenzamide (1.67 g, 4.47 mmol) and lithium aluminum hydride (0.51 g, 13.43 mmol) Added together. To this was added anhydrous 1,4-dioxane (15 mL). The mixture was slowly heated to reflux and stirred for 16 hours. The reaction mixture was cooled to 0 ° C. and excess lithium aluminum hydride was removed by dropwise addition of methanol and 20% potassium hydroxide was carefully added. The aluminum salt was filtered off and the filtrate was concentrated to use as the next reaction.

3- (1-benzyl-piperidin-4-yl) -8-chloro-3,4-dihydro-1H-quinazolin-2-one

Carbonyl (2-amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl) -amine (0.66 g, 2.0 mmol) in tetrahydrofuran (8 mL) stirred at 0 ° C. Treated with diimidazole (0.36 g, 2.05 mmol). The reaction was stirred at 0 ° C. for 30 minutes and at reflux for 1 hour. After cooling to room temperature, the solvent was evaporated and the residue was purified by column to give 0.58 g (82%) of the desired product. LC / MS: t _R = 1.40 min, 356.25 (MH) ⁺ .

2-chloro-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one

3- (1-benzyl-piperidin-4-yl) -8-chloro-3,4-dihydro-1H-quinazolin-2-one (0.17 g, 0.48 mmol) in methanol (10 mL) was purged with nitrogen. Flushed and treated with palladium on charcoal (10%, 17 mg). Trifluoroacetic acid (0.2 mL) was added and the mixture was flushed with nitrogen and then stirred under hydrogen atmosphere overnight. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 100 mg (79%) of the desired material. LC / MS: t _R = 0.99 min, 266.08 (MH) ⁺ .

5-bromo-1H-indole-3-carbonitrile

A mixture of 5-bromo-indole-3-carboxaldehyde (5 g, 22.3 mmol), diammonium hydrogen phosphate (15.6 g, 31.8 mmol) in 1-nitropropane (66 mL) and acetic acid (22 mL) was added 16 Heated to reflux for hours. After cooling to room temperature, the solvent was removed under reduced pressure and water was added to the dark residue. After a while, 5-bromo-1H-indole-3-carbonitrile precipitated rapidly. The solid was filtered off, washed several times with water and dried over several hours to give 4.3 g (86%) of the desired product.

5-formyl-1H-indole-3-carbonitrile

5-Bromo-1H-indole-3-carbonitrile (4.25 g, 19.23 mmol) and sodium hydride (0.51 g, 21.2 mmol) were metered into a flame-dried round bottom flask with magnetic stir bar. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (24 mL) was added. The mixture was allowed to homogenize by stirring at room temperature for 15 minutes. The stirred mixture was cooled to -78 ° C and a sec-butyllithium solution (1.4 M, 30.2 mL, 2.2 equiv) in cyclohexane was added over several minutes. After 1 h at -78 ° C, dimethylformamide (6.0 mL) was added slowly and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C. and carefully treated with 1 N hydrochloric acid (45 mL). After a few minutes, solid sodium bicarbonate was added to bring the pH to 9-10. The two layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulphate and concentrated. Column chromatography gave 2.4 g (72%) of pure material. LC / MS: t _R = 0.99 min, 171.07 (MH) ⁺ .

2-benzyloxycarbonylamino-3- (3-cyano-1H-indol-5-yl) -acrylic acid methyl ester

A solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (1.68 g, 5.1 mmol) in tetrahydrofuran (10 mL) stirred at room temperature was treated with tetramethylguanidine (0.6 mL, 1.1 equiv). After 10 minutes 5-formyl-1H-indole-3-carbonitrile (0.72 g, 4.24 mmol) was added. After stirring for 3 days at room temperature, the solvent is evaporated and the residue is washed with water (2x), brine (2x), dried over sodium sulphate and concentrated. Column chromatography gave 1.3 g (82%) of pure material. LC / MS: t _R = 1.43 min, 376.22 (MH) ⁺ .

(±) -2-amino-3- (3-cyano-1H-indol-5-yl) -propionic acid methyl ester

2-benzyloxycarbonylamino-3- (3-cyano-1H-indol-5-yl) -acrylic acid methyl ester (0.5 g, 1.3 mmol) in methanol (8 mL) was flushed with nitrogen and palladium on charcoal (10%, 50 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 0.3 g (92%) of the desired material. LC / MS: t _R = 0.88 min, 244.20 (MH) ⁺ .

Example  202

(±) -3-H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-car Carbonyl] -amino} -propionic acid methyl ester

A solution of 2-amino-3- (3-cyano-1H-indol-5-yl) -propionic acid methyl ester (25 mg, 0.11 mmol) in tetrahydrofuran (3 mL) stirred at 0 ° C. Treated with imidazole (17.5 mg, 1.1 equiv). The reaction was stirred at 0 ° C. for 5 minutes, warmed to room temperature and stirred for 10 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (25 mg, 1.1 equivalents). The mixture was stirred at rt overnight. The solvent was evaporated and the residue was purified by column chromatography to give 40 mg (75%) as a white powder. LC / MS: t _R = 1.37 min, 501.33 (MH) ⁺ .

Example  203

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (3-cyano-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide

3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3- in methanol (0.6 mL) at room temperature Solution of yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester (15 mg, 0.03 mmol) of lithium hydroxide monohydrate (3.0 mg, 2.5 equiv) in water (0.1 mL) Treated with solution. The solution was stirred at rt for 2 h. The solution was cooled to 0 ° C., treated with aqueous 1 M potassium hydrogen sulphate (60 μl, 2.0 equiv) and the solvent was evaporated to yield a crude acid which was used immediately without purification. The crude acid is dissolved in dimethylformamide (0.4 mL) and cooled to 0 ° C., then methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), N, N-diiso Treated sequentially with propylethylamine (12 μl, 2.3 equiv) and PyBop (19 mg, 1.2 equiv). The solution was stirred at 0 ° C. for 15 minutes, warmed to room temperature, then stirred for 1.5 hours, and concentrated. The product was purified by column chromatography to give 10.1 mg (52%, 2 steps).

3- (4-Bromo-2-methyl-phenylamino) -2-methyl-acrylic acid ethyl ester

Concentrated hydrochloric acid (15 mL), water (40 mL) and sodium nitrite in water (40 mL) in a solution of 4-bromo-2-methyl aniline (7.0 g, 37.8 mmol) in acetonitrile (80 mL) g, 39.7 mmol) was added sequentially under ice cooling to produce a diazonium salt. The solution was transferred dropwise at 0 ° C. to a solution of 50% potassium hydroxide (16 mL) and ethyl-2-methyl acetoacetate (5.38 mL, 38 mmol) in ethanol (50 mL). After the addition was completed, the reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate. The organic layer was washed with brine (2 ×), dried over sodium sulfate, filtered and concentrated to give 7.5 g (66%) of the title compound which was used immediately without purification.

5-Bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester

A solution of p-toluenesulfonic acid monohydrate (4.26 g, 75 mmol) in toluene (80 mL) was heated to reflux for 1.5 h under a dean-stark water separator. To this solution is added a solution of 5-bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester (7.5 g, 25.0 mmol) in toluene (40 mL) and the reaction mixture is brought to reflux for 5 hours. Heated. After cooling to room temperature, the reaction mixture was poured into ice water (120 mL) and extracted twice with ethyl acetate. The organic layers were pooled together, washed with sodium bicarbonate (2x), brine (2x), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel gave 5.5 g (78%) of the title compound.

5-bromo-7-methyl-1H-indole

5-bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester (5.3 g, 18.7 mmol) is added to a potassium hydroxide solution in a 1: 1 water / ethanol mixture (20 mL), 12 Heated to reflux for hours. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue was transferred to 6 N hydrochloric acid solution (20 mL). The white precipitate formed was filtered off, washed several times with water and dried for several hours. The crude solid was dissolved in quinoline (14 mL) and heated to reflux for 4 hours. After cooling to room temperature, the crude mixture was poured into a mixture of ice water (100 mL) and concentrated hydrochloric acid (16 mL), extracted with ethyl acetate (2x), brine (2x), dried over sodium sulfate and concentrated. Recrystallization of the desired product from isopropanol caused significant alteration. Flash chromatography on silica gel gave 1.5 g (38%, 2 steps) of the title compound. LC / MS: t _R = 1.72 min, 210.05 (MH) ⁺ .

5-Bromo-7-methyl-1H-indole-3-carboxaldehyde

5-bromo-7-methyl-1H-indole (1.2 g, 5.71 mmol) is dissolved in acetonitrile (6 mL) and bromomethylene dimethyl ammonium bromide (1.36 g, 6.28 mmol) in acetonitrile (9 mL). The solution was slowly poured at -10 ° C to 0 ° C. The reaction was stirred at 0 ° C. for 2 hours and at room temperature for 30 minutes. The solvent was evaporated and the crude mixture was dissolved in water and stirred at 50 ° C. for 4 hours. After cooling to rt, the crude mixture was extracted with ethyl acetate (2 ×). The organic layers were pooled together, washed with brine (2 ×), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel yielded 0.7 g (52%, 2 steps) of the desired compound.

5-bromo-7-methyl-1H-indole-3-carbonitrile

A mixture of 5-bromo-indole-3-carboxaldehyde (0.7 g, 2.94 mmol), ammonium hydrogen phosphate (2.05 g, 15.5 mmol) in 1-nitropropane (9 mL) and acetic acid (3 mL) was added for 16 hours. Heated to reflux. After cooling to room temperature, the solvent was removed under reduced pressure and water was added to the dark residue. After a while, the rapidly precipitated 5-bromo-1H-indole-3-carbonitrile was filtered off, washed with water and dried several times to give 0.6 g (87%) of the nitrile that is frozen. LC / MS: t _R = 1.71 min, 235.01 (MH) ⁺ .

5-formyl-7-methyl-1H-indole-3-carbonitrile

5-bromo-7-methyl-1H-indole-3-carbonitrile (0.58 g, 2.46 mmol) and sodium hydride (68 mg, 2.7 mmol) were weighed into a flame-dried round bottom flask with a magnetic stir bar. Put in. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (9 mL) was added. The mixture was stirred at room temperature for 15 minutes to allow homogenization. The stirred mixture was cooled to −78 ° C. and a sec-butyllithium solution (1.4 M, 3.8 mL, 2.2 equiv) in cyclohexane was added over several minutes. After 1 h at -78 ° C, dimethylformamide (0.9 mL) was added slowly and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C. and treated carefully with 1 N hydrochloric acid. After a few minutes, solid sodium bicarbonate is added to bring the pH to 9-10. Both layers were isolated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulphate and concentrated. Column chromatography gave 60 mg (14%) of the desired product and 0.4 g of unreacted starting material. LC / MS: t _R = 1.21 min, 185.10 (MH) ⁺ .

2-benzyloxycarbonylamino-3- (3-cyano-7-methyl-1H-indol-5-yl) -acrylic acid methyl ester

A solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (180 mg, 0.54 mmol) in tetrahydrofuran (3 mL) stirred at room temperature was treated with tetramethylguanidine (40 μl, 1.1 equiv). After 10 minutes 5-formyl-7-methyl-1H-indole-3-carbonitrile (50 mg, 0.27 mmol) was added. After stirring for 3 days at room temperature, the solvent is evaporated and the residue is washed with water (2x), brine (2x), dried over sodium sulphate and concentrated. Column chromatography gave 100 mg (95%) of pure material. LC / MS: t _R = 1.59 min, 390.24 (MH) ⁺ .

(±) -2-amino-3- (3-cyano-7-methyl-1H-indol-5-yl) -propionic acid methyl ester

2-benzyloxycarbonylamino-3- (3-cyano-7-methyl-1H-indol-5-yl) -acrylic acid methyl ester (0.1 g, 0.26 mmol) in methanol (2.5 mL) was flushed with nitrogen and Treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 60 mg (90%) of the desired material. LC / MS: t _R = 0.93 min, 258.22 (MH) ⁺ .

Example  204

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (3-cyano-7-methyl-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide

Prepared as described for Example 203 above:

4-Bromo-2-isopropyl-6-methyl-phenylamine

2-isopropyl-6-methyl-phenylamine (5 g, 33.5 mmol) was dissolved in acetic acid (20 mL). To this solution was added dropwise a bromine (1.8 mL, 35.14 mmol) solution in acetic acid (5 mL) over 10 minutes. After stirring for 1 hour at room temperature, the reaction mixture was diluted with methylene chloride and washed with water (2x), saturated sodium thiosulfate (2x), saturated sodium bicarbonate (2x) and brine. The organic phase was dried over sodium sulphate, filtered and concentrated. Flash chromatography on silica gel gave 7.6 g (quantitative yield) of the desired product. LC / MS: t _R = 1.37 min, 230.07 (MH) ⁺ .

4-Bromo-2-isopropyl-6-methyl-phenyldiazo-t-butyl sulfide

4-Bromo-2-isopropyl-6-methyl-phenylamine (7.6 g, 33.5 mmol) was suspended in 24% hydrochloric acid (15 mL). The stirred mixture was cooled to −20 ° C. and treated dropwise over 30 minutes with sodium nitrite (2.4 g, 1.05 equiv) in water (5 mL), maintaining the temperature at −5 ° C. After an additional 30 minutes at −5 ° C. to −20 ° C., solid sodium acetate was added to the mixture and buffered to about pH 5. This mixture (maintained at about −10 ° C.) was added in portions to a solution of t-butyl thiol (3.77 mL, 1.0 equiv) in ethanol (25 mL) at 0 ° C. over about 30 minutes. After addition, the mixture was stirred at 0 ° C. for 30 minutes and then crushed ice (about 50 mL) was added. The resulting light brown solid was collected by filtration, washed with water and then dried under high vacuum for several hours to give 7.9 g (72%) of the desired product.

5-bromo-7-isopropyl-1H-indazole

The flame-dried round bottom flask was charged with 4-bromo-2,6-diethylphenyldiazo-t-butyl sulfide (7.94 g, 24 mmol) and potassium t-butoxide (27 g, 10 equiv) I was. A stir bar was placed and the mixture was placed under nitrogen. To this was added dry dimethyl sulfoxide (70 mL). The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully injected into a mixture of crushed ice (250 mL) and 10% hydrochloric acid (120 mL). The resulting suspension was collected by filtration and washed several times with water. The solid was collected and dried in vacuo to yield 4.2 g (74%) of the desired product. LC / MS: t _R = 1.73 min, 241.06 (MH) ⁺ .

7-isopropyl-1H-indazol-5-carbaldehyde

5-bromo-7-isopropyl-1H-indazole (3.1 g, 12.1 mmol) and sodium hydride (0.34 g, 1.1 equiv) were weighed into a flame-dried round bottom flask with a magnetic stir bar. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (18 mL) was added. The mixture was stirred at room temperature for 15 minutes to allow homogenization. The stirred mixture was cooled to −78 ° C. and a sec-butyllithium solution (1.4 M, 20 mL, 2.2 equiv) in cyclohexane was added over several minutes. After 1 hour at -78 ° C, dimethylformamide (3.0 mL) was added slowly and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C. and carefully added with 1 N hydrochloric acid (35 mL). After a few minutes, solid sodium bicarbonate was added until the pH was 9-10. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulphate and concentrated. Column chromatography gave 2.1 g (92%) of pure material. LC / MS: t _R = 1.15 min, 189.12 (MH) ⁺ .

2-benzyloxycarbonylamino-3- (7-isopropyl-1H-indazol-5-yl) acrylic acid methyl ester

A solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (0.39 g, 1.2 equiv) in stirred tetrahydrofuran (5 mL) was treated with tetramethylguanidine (0.16 mL, 1.1 equiv). After 10 minutes, 7-isopropyl-1H-indazole-5-carbaldehyde (0.2 g, 1.06 mmol) was added. After stirring for 3 days at room temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel to give 0.35 g (84%) of product. LC / MS: t _R = 1.61 min, 394.16 (MH) ⁺ .

(±) -2-amino-3- (7-isopropyl-1H-indazol-5-yl) propionic acid methyl ester

A solution of 2-benzyloxycarbonylamino-3- (7-isopropyl-1H-indazol-5-yl) acrylic acid methyl ester (0.35 g, 0.89 mmol) in methanol (7 mL) was flushed with nitrogen and charcoal Treated with palladium (10%, 35 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 0.21 g (90%) of the desired material.

Example  205

(±) -3- (7-isopropyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) Ferridine-1-carbonyl] -amino} -propionic acid methyl ester

3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 Prepared as described above for -carbonyl] -amino} -propionic acid methyl ester. LC / MS: t _R = 1.49 min, 519.35 (MH) ⁺ .

Example  206

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-isopropyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide

3- (7-isopropyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine- Prepared as described above for Example 203 from 1-carbonyl] -amino} -propionic acid methyl ester:

4-Bromo-2,6-diethylphenyldiazo-t-butyl sulfide

4-bromo-2,6-diethylaniline (6.3 g, 27.6 mmol) was suspended in 24% hydrochloric acid (15 mL). The stirred mixture was cooled to −20 ° C. and treated dropwise over 30 minutes with sodium nitrite (2.0 g, 1.05 equiv) in water (5 mL) while maintaining the temperature at −5 ° C. After an additional 30 minutes at −5 ° C. to −20 ° C., the mixture was buffered to about pH 5 by addition of solid sodium acetate. This mixture (maintained at about −10 ° C.) was added in portions to a solution of t-butyl thiol (3.15 mL, 1.0 equiv) in stirred ethanol (25 mL). After addition, the mixture was stirred for 0 to 30 minutes, followed by crushed ice (about 50 mL). The resulting light brown solid was collected by filtration, washed with water and dried under high vacuum for several hours to give 6.0 g (66%) of the desired product.

5-bromo-7-ethyl-3-methylindazole

The flame-dried round bottom flask was charged with 4-bromo-2,6-diethylphenyldiazo-t-butyl sulfide (4.0 g, 12.1 mmol) and potassium t-butoxide (13.2 g, 10 equiv) I was. A stir bar was placed and the mixture was placed under nitrogen. To this was added dry dimethyl sulfoxide (35 mL). The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully injected into a mixture of crushed ice (130 mL) and 10% hydrochloric acid (60 mL). The resulting suspension was collected by filtration and washed several times with water. The solid was collected and dried in vacuo to yield 2.85 g (98%) of a beige solid.

7-ethyl-3-methylindazole-5-carboxaldehyde

5-bromo-7-ethyl-3-methylindazole (2.85 g, 11.9 mmol) and sodium hydride (0.31 g, 1.1 equiv) were weighed into a flame-dried round bottom flask with a magnetic stir bar. Under nitrogen atmosphere at room temperature, dry tetrahydrofuran (15 mL) was added. The mixture was homogenized by stirring at room temperature for 15 minutes. The stirred mixture was cooled to -78 ° C and a solution of tert-butyllithium (1.4 M, 18.7 mL, 2.0 equiv) in pentane was added over several minutes. After 1 h at -78 ° C, dimethylformamide (2.8 mL) was added slowly and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C. and treated carefully with 1 N hydrochloric acid (30 mL). After a few minutes, solid sodium bicarbonate was added until the pH was 9-10. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulphate and concentrated. Column chromatography gave 1.5 g (67%) of pure material. LC / MS: t _R = 1.15 min, 189.12 (MH) ⁺ .

2-benzyloxycarbonylamino-3- (7-ethyl-3-methyl-1H-indazol-5-yl) -acrylic acid methyl ester

A solution of N-benzyloxycarbonyl-oc-phosphonoglycine trimethyl ester (3.17 g, 9.57 mmol, 1.2 equiv) in tetrahydrofuran (15 mL) stirred at room temperature with tetramethylguanidine (1.1 mL, 1.1 equiv) Treated. After 10 minutes, 7-ethyl-3-methylindazole-5-carboxaldehyde (1.5 g, 7.98 mmol) was added. After stirring for 3 days at room temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel to give 2.5 g (80%) of product. LC / MS: t _R = 1.61 min, 394.16 (MH) ⁺ .

(±) -2-amino-3- (7-ethyl-3 methyl-1H-indazol-5-yl) -propionic acid methyl ester

2-benzyloxycarbonylamino-3- (7-ethyl-3-methyl-1H-indazol-5-yl) -acrylic acid methyl ester (1.0 g, 2.54 mmol) in methanol (15 mL) was flushed with nitrogen and Treated with palladium on charcoal (10%, 100 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated. Column chromatography gave 0.6 g (91%) of the desired material.

Example  207

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-ethyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 203 from (±) -2-amino-3- (7-ethyl-3 methyl-1H-indazol-5-yl) -propionic acid methyl ester.

Example  208

(±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 203 from 3-piperidin-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide. .

Example  209

(±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-ethyl-3-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 203 from 3-piperidin-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide. .

Example  210

(±) -2- [4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] -3 -(7-Methyl-1H-indazol-5-yl) -propionic acid methyl ester

3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 Prepared as described above for -carbonyl] -amino} -propionic acid methyl ester. LC / MS: t _R = 1.34 min, 516.40 (MH) ⁺ .

Example  211

(±) -4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide

Prepared as described above for Example 203 from 2-oxo-3-piperidin-4-yl-1,2,3,4-tetrahydro-quinazolin-6-carbonitrile.

Example  212

(±) -4- (2-oxo-1,2,4,5-tetrahydro-benzo [d] [1,3] diazepin-3-yl-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide

Prepared as described above for Example 203 from 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo [d] [1,3] diazepin-2-one.

Example  213

(±) -4- (6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide

Prepared as described above for Example 203 from 6-hydroxy-3-piperidin-4-yl-3,4dihydro-1H-quinazolin-2-one. LC / MS: t _R = 1.24 min, 643.62 (MH) ⁺ .

Example  214

(±) -4- (8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl} -amide

Prepared as described above for Example 203 from 8-methoxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.

Example  215

(±) -4- (8-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide

Prepared as described above for Example 203 from 2-chloro-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.

Example  216

(±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide

Prepared as described above for Example 203. LC / MS: t _R = 1.51 min, 641.63 (MH) ⁺ .

Example  217

(±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] oxazine) -1 Carboxamide

Prepared as described above for Example 203. LC / MS: t _R = 1.48 min, 642.61 (MH) ⁺ .

tert-butyl 2-fluorophenylcarbamate

To a solution of di-tert-butyldicarbonate (45.2 g, 207 mmol, 1.0 equiv) in tetrahydrofuran (210 mL) was added 2-fluoroaniline (20.0 mL, 207 mmol) at room temperature. The reaction was heated to reflux and continued for 6 hours. It is cooled, concentrated, dissolved in pentane, washed sequentially with 5% citric acid, 1 M potassium bisulfate (2x), water, 20% potassium hydroxide and brine, dried over magnesium sulfate and then concentrated To give 48.0 g (quantitative yield) of amber oil used without purification.

2- (tert-butoxycarbonylamino) -3-fluoro-benzoic acid

To a solution of tert-butyl 2-fluorophenylcarbamate (44.0 g, 208 mmol) in tetrahydrofuran (660 mL) was added tert-butyllithium (1.7 M, 306 mL, 2.5 equiv) in pentane at −78 ° C. Added dropwise. After the addition was completed, the reaction was stirred at -78 ° C for 30 minutes. The solution was gradually brought to -20 ° C, then cooled back to -78 ° C and transferred through a cannula to a slurry of carbon dioxide (excess) and tetrahydrofuran (500 mL). The solution was slowly warmed up to room temperature. The reaction mixture was concentrated to remove most tetrahydrofuran and poured into a separatory funnel containing water and diethyl ether. After separating the layers, the aqueous layer was extracted twice more with diethyl ether. This ether was discarded. The aqueous layer was acidified with 5% citric acid and extracted with diethyl ether (3 ×). This ether was dried over magnesium sulfate and concentrated to yield a light yellow solid, which was recrystallized from hot toluene to give 37.1 g (70%) as a pale yellow solid.

tert-butyl 2- (1-benzylpiperidin-4-ylcarbamoyl) -6-fluorophenylearbamate

2- (tert-butoxycarbonylamino) -3-fluoro-benzoic acid (37.1 g, 145 mmol), 4-amino-1-benzylpiperidine (35.6 mL, 1.20 equiv) in ethyl acetate (450 mL) , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30.7 g) in a solution of 1-hydroxybenzotriazole (21.6 g, 1.1 equiv) and triethylamine (44.1 g, 3.0 equiv) , 1.1 equivalents) at a time. Initially, all went into solution, but precipitate formed very quickly. The reaction was fitted to a reflux condenser and heated to reflux for 5 hours. The reaction was diluted with ethyl acetate, washed with water (2x), 1N sodium hydroxide (2x), then brine, dried over magnesium sulfate and concentrated to give 67.0 g (quantitative yield) as a white solid to use without purification. Obtained.

2-amino-N- (1-benzylpiperidin-4-yl) -3-fluorobenzamide

In a solution of tert-butyl 2- (1-benzylpiperidin-4-ylcarbamoyl) -6-fluorophenylcarbamate (67.0 g, 157 mmol) in dichloromethane (700 mL) at 0 ° C. Fluoroacetic acid (100 mL) was added. The ice bath was removed and the reaction stirred overnight at room temperature. The reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2x), washed with water (3x), then brine, dried over magnesium sulfate and concentrated to give 47.6 g (93%) of a white solid which was used without purification. Mass spectroscopy: 328.33 (MH) ⁺ .

N- (2-amino-3-fluorobenzyl) -1-benzylpiperidin-4-amine

2-amino-N- (1-benzylpiperidin-4-yl in dioxane (250 mL) in a reflux suspension of lithium aluminum hydride (16.1 g, 424 mmol, 3.50 equiv) in dioxane (800 mL) A solution of) -3-fluorobenzamide (39.7 g, 121 mmol) was added at a rate such that gas evolution was limited to a stable flow. At the end of the addition, the resulting suspension was heated to reflux for 4 hours. The reaction was cooled to 0 ° C. and quenched by careful addition of 20% potassium hydroxide. Once a white filterable precipitate formed, the solid was filtered through a course glass sintered funnel and the eluent was concentrated to give 36.3 g (96%) of a light yellow oil which was used without purification. Mass spectroscopy: 314.29 (MH) ⁺ .

3- (1-benzylpiperidin-4-yl) -8-fluoro-3,4-dihydroquinazolin-2 (1H) -one

Carbonyl diimidazole (at room temperature in a solution of N- (2-amino-3-fluorobenzyl) -1-benzylpiperidin-4-amine (36.3 g, 116 mmol) in tetrahydrofuran (600 mL) ( 20.7 g, 1.10 equiv) was added in one portion. The reaction was stirred at rt for 3 h, heated to reflux for 30 min and then concentrated. The resulting solid was dissolved in 1: 1 diethyl ether / ethyl acetate, washed with water (3 ×), then brine, dried over magnesium sulfate and concentrated to yield the crude product as a wet yellow solid. The solid was triturated with diethyl ether and filtered to give 30.0 g (76%) of a white powder.

8-fluoro-3,4-dihydro-3- (piperidin-4-yl) quinazolin-2 (1H) -one

250 mL flask was charged with 3- (1-benzylpiperidin-4-yl) -8-fluoro-3,4-dihydroquinazolin-2 (1H) -one (1.40 g, 4.12 mmol) and methanol (25.0 mL). The suspension was heated to heat to allow dissolution. The flask was flushed with nitrogen, treated with palladium on charcoal (141 mg, 0.032 equiv), flushed with nitrogen followed by hydrogen and stirred vigorously under hydrogen atmosphere overnight. The reaction was flushed with nitrogen, filtered through celite and concentrated to yield 0.99 g (97%) of a white solid that was used without purification.

3- (1-benzylpiperidin-4-yl) -8-fluoroquinazolin-2,4 (1H, 3H) -dione

To a solution of 20 amino-N- (10benzylpiperidin-4-yl) -3-fluorobenzamide (750 mg, 2.29 mmol) in dichloromethane (30.0 mL) in dichloromethane (5 mL) at 0 ° C. Triphosgene (227 mg, 0.33 equiv) was added as a solution. The ice bath was removed and the reaction heated to reflux for 6 hours. The reaction was concentrated, dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate, water, brine, dried over magnesium sulfate and concentrated to yield 700 mg of a white solid. The crude product was purified by flash chromatography to give 205 mg (25%) as a white solid. Mass spectroscopy: 354.13 (MH) ⁺ .

8-fluoro-3- (piperidin-4-yl) quinazolin-2,4 (1H, 3H) -dione

3- (1-benzylpiperidin-4-yl) -8-fluoroquinazolin-2,4 (1H, 3H) -dione (75.0 mg, 0.21 mmol) in methanol (3.00 mL) and palladium on charcoal ( Flask containing 8.00 mg, 0.035 equiv) was flushed with nitrogen followed by hydrogen. The reaction was stirred overnight under hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite and concentrated to give 53 mg (95%) as a white solid which was used without purification. Mass spectroscopy: 264.25 (MH) +

8'-fluoro-2 ', 3'-dihydro-2'-oxospyro- (1-phenylmethylpiperidine) -4,4'-quinazoline

A 500 mL 3-neck flask was charged with polyphosphoric acid (110 mL) and equipped with an overhead stirrer, nitrogen inlet, and bubbler. The flask was flushed with nitrogen and heated to 105 ° C. in an oil bath. To this was added 1-benzyl-4-piperidone (21.0 mL, 115 mmol). To this was added a large portion of N- (2-fluorophenyl) urea (21.3 g, 1.2 equiv) in small amounts over 2 hours. The reaction was heated to 160 ° C. with vigorous stirring. After 2 hours, crushed ice was poured into the reaction and quenched by neutralization with 20% potassium hydroxide. The reaction mixture was extracted with dichloromethane, washed with water followed by brine, dried over magnesium sulfate and concentrated. All of this was purified by preparative HPLC (about 130 injections) to yield a very pure product. The product was purified by flash chromatography and the resulting solid was triturated with diethyl ether and filtered to give 275 mg (0.7%) as a white solid.

8'-fluoro-2 ', 3'-dihydro-2'-oxospyro-piperidine-4,4'-quinazoline

8'-fluoro-2 ', 3'-dihydro-2'-oxospyro- (1-phenylmethylpiperidine) -4,4'-quinazoline (250 in methanol (4 mL) and dichloromethanemethane To a solution of mg, 0.77 mmol) palladium on charcoal (30.0 mg, 0.037 equiv) was added. The reaction was flushed with hydrogen and stirred overnight under hydrogen atmosphere. The balloon was removed, the reaction was flushed with nitrogen, filtered through celite, further washed with methanol and concentrated to give 158 mg (87%) of a white solid that was used without purification.

Example  218

(±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-1H-pyrazolo [4,3-c] pyridine-5 (4H ) -Yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  219

(±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c ] Pyridin-5 (4H) -yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamide

Prepared as described above for Example 203.

Example  220

(±) -methyl-2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3 -(7-methyl-1H-indazol-5-yl) propanoate

3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 Prepared as described above for -carbonyl] -amino} -propionic acid methyl ester.

Example  221

(±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1 H-indazol-5 -Yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  222

(±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  223

(±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  224

(±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  225

(±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  226

(±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide) -3- ( 7-ethyl-3-methyl-1H-indazol-5-yl) propanoate

3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 Prepared as described above for -carbonyl] -amino} -propionic acid methyl ester.

Example  227

(±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

Example  228

(R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1 Carboxamide

Prepared as described above for Example 203:

Example  229

(±) -N- (3- (7-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) Propan-2-yl) -8'-fluoro-2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide

Prepared as described above for Example 203.

Example  230

(±) -4- (8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazole -5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide

Prepared as described above for Example 203.

(R) -Methyl 2-amino-3- (2- (trifluoromethyl) -1H-benzo [diimidazol-5-yl) propanoate

A mixture of (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) -propionic acid methyl ester (500 mg, 1.20 mmol) and trifluoroacetic acid (6 mL) for 16 hours Heated to 80 ° C. The reaction mixture was poured into ice water (75 mL), neutralized to pH 7 by addition of aqueous saturated sodium bicarbonate and extracted with ethyl acetate (2 x 250 mL). The organic extract was dried over sodium sulfate, filtered and evaporated to give the title compound as trifluoroacetic acid salt (459 mg, yield 84%).

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2-trifluoro Rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoate

Amino ester (R) -methyl 2-amino-3- (2-trifluoromethyl) -1H-benzo [d] imidazol-5-yl in a mixture of methylene chloride / dimethylformamide (ratio of 15: 1) A solution of propanoate (230 mg, 0.51 mmol), diisopropylethylamine (262 mg, 2.03 mmol) and disuccinimidyl carbonate (129 mg, 0.51 mmol) was stirred at room temperature for 30 minutes. 4- (2-keto-1-benzimidazolinyl) piperidine was added to this solution and the reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered to remove any solids and then purified by flash column chromatography (95: 3: 2 methylene chloride / methanol / triethylamine) to give the title compound (215 mg, 77% yield) as a light brown solid. It was.

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid

Ester (Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1- in tetrahydrofuran and methanol (1: 1 mixture, 20 mL) In a solution of carboxamido) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate (220 mg, 0.40 mmol) in water (10 lithium hydroxide (36 mg, 1.51 mmol) in mL) The mixture was stirred for 2 h at 0 ° C. and then stored for 16 h at −15 ° C. The organic solvent was evaporated. Extraction with acetate and 1 N HCl (3 mL) was added to adjust the pH to 4. The organic extract was dried over sodium sulfate, filtered and evaporated to afford the title compound (176 mg, yield 82%). / MS: t _R = 2.01 min, 531 (MH) ⁺ .

Example  231

N-((R) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) in stirred methylene chloride (2 mL) Acidic of -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) To the solution was added a solution of PyBOP (33 mg, 0.06 mmol) and 4-piperidinopiperidine (12 mg, 0.07 mmol) in methylene chloride (1 mL). The reaction mixture was stirred at rt for 16 h and purified by preparative thin layer chromatography (2 M ammonia in 1:10 methanol / methylene chloride) to give the title compound (4.6 mg, yield 12%).

Example  232

N-((R) -1- (dimethylcarbamoyl) -2- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) ethyl) -4- (1,2 -Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide

Prepared as described above for Example 231.

Benzyl (R) -1- (methoxycarbonyl) -2- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) ethylcarbamate

Triethylamine in a dilute solution of (R) -2-benzyloxycarbonylamino-3- (3,4-diamino-phenyl) propionic acid methyl ester (600 mg, 1.44 mmol) in tetrahydrofuran (125 mL) 320 mg, 3.17 mmol) followed by 1,1'-carbonyldiimidazole (280 mg, 1.73 mmol). The reaction mixture was stirred at rt for 16 h and then filtered to remove solids. The filtrate was evaporated and flash column chromatography (1:12 methanol / methylene chloride) afforded the title compound (313 mg, yield 59%).

(R) -methyl 2-amino-3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoate

Benzyl (R) -1- (methoxycarbonyl) -2- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) ethylcarba in methanol (15 mL) Mate (265 mg, 0.72 mmol) and 10% palladium on carbon (30 mg) were stirred under 50 psi hydrogen using a Parr apparatus for 1.5 hours. The reaction mixture was purged with three vacuum / nitrogen purge cycles. The reaction mixture was then filtered through a Celite® pad and the pad was washed with several aliquots of methanol. Methanol filtrate was evaporated to afford the title compound (168 mg, quantitative yield).

Example  233

(R) -methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2,3- Dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoate

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate.

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2,3-di Hydro-2-oxo-1H-benzo [d] imidazol-6-yl) -propanoic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid.

Example  234

N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide

Prepared as described above for Example 231.

Example  235

N-((R) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) ethyl) -4- (1 , 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide

Prepared as described above for Example 231. LC / MS: t _R = 1.96 min, 506 (MH) ⁺ .

(R) -Methyl 2- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-(1H) -quinazolin) carbonylamino] -3-2,3 -Dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoate

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate.

(R) -2- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-(1H) -quinazolin) carbonylamino] -3-2,3- Dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid.

Example  236

N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospyro (piperidin-4,4'-(1H) -quinazolin) Carboxamide

Prepared as described above for Example 231. LC / MS: t _R = 1.55 min, 615 (MH) ⁺ .

4-acetamido-3-methylbenzoic acid

To a suspension of 4-amino-3-methylbenzoic acid (60 g, 0.40 mol) in methylene chloride (800 mL) was added triethylamine (121 g, 1.19 mol). The solution became clear. Acetic anhydride (81 g, 0.79 mol) was then added and the reaction mixture was stirred at rt for 60 h. The solvent was evaporated. The residue was diluted with water (400 mL) and extracted with ethyl acetate (3 x 600 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to afford the title compound as a light brown solid (43 g, yield 56%).

4-Acetamido-3-methyl-5-nitrobenzoic acid

To a 60% nitric acid solution in sulfuric acid (410 mL) was added 4-acetamido-3methylbenzoic acid (43 g, 0.22 mol) in small portions over 40 minutes while cooling with an ice bath. After all amide was added, the reaction mixture was stirred at 0 ° C. for 1 hour and poured very slowly into 1500 mL of ice. The yellow solid was collected by filtration and washed with ice cold water to give the title compound (38 g, 72% yield).

4-Amino-3-methyl-5-nitrobenzoic acid

A suspension of 4-acetamido-3-methyl-5-nitrobenzoic acid (38 g, 0.16 mol) in 3 N hydrochloric acid (800 mL) was heated to reflux for 8 hours and stirred at room temperature for 8 hours. The yellow solid was collected by filtration and transferred to a 2 L flask with a mixture of methylene chloride and methanol. The solvent was evaporated under high vacuum to afford the title compound (23 g, yield 74%).

3-Methyl-4,5-dinitrobenzoic acid

Hydrogen peroxide (50 wt.%, 15 mL) was added to a suspension of 4-amino-3-methyl-5-nitrobenzoic acid (5.0 g, 25.5 mmol) in trifluoroacetic acid (200 mL). The reaction mixture was heated at 50 ° C. for 2 hours and the dark orange clear solution was a cloudy yellow clear solution. The reaction mixture was slowly poured into ice water (800 mL). The solid was collected by filtration and dried under vacuum to afford the title compound as a gray solid (4.0 g, yield 70%).

(3-methyl-4,5-dinitrophenyl) methanol

A solution of 3-methyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran (200 mL) was cooled to -70 ° C in a dry ice / acetone bath. To this solution was added borane-tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL). The reaction mixture was slowly warmed to rt and stirred for 16 h. The incomplete reaction was cooled back to −50 ° C. and additional borane-tetrahydrofuran (1 M in tetrahydrofuran, 35.4 mL) was added. Again, the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with a mixture of acetic acid and water (1: 1, 30 mL) while cooling to 0 ° C. After stirring for 30 minutes, all organic solvents were evaporated and the aqueous material was neutralized in small portions infused with ice-cold saturated sodium bicarbonate (350 mL). The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was performed by flash column chromatography (1: 2 hexanes / ethyl acetate) to give the title compound (3.2 g, yield 86%).

3-methyl-4,5-dinitrobenzaldehyde

To the flame-dried flask, manganese oxide (IV) (36.0 g, 414 mmol) was azeotropically dried with toluene. Then a solution of (3-methyl-4,5-dinitrophenyl) methanol (3.2 g, 15 mmol) in chloroform (100 mL) was transferred to a flask with manganese dioxide. The reaction mixture was heated to 50 ° C. with stirring for 3 hours. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite to remove manganese dioxide and the celite was washed several times with chloroform. The filtrate was evaporated to afford the title compound (1.4 g, 44% yield).

Benzyl (Z) -1- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) vinylcarbamate

To a solution of N- (benzyloxycarbonyl) -α-phosphonoglycine trimethyl ester (2.4 g, 7.3 mmol) in tetrahydrofuran (40 mL) at 1,1,3,3-tetramethylguanidine (-78 ° C) 729 mg, 6.33 mmol) was added and the mixture was stirred at -78 ° C for 1 hour. To this mixture was added a solution of 3-methyl-4,5-dinitrobenzaldehyde (1.4 g, 6.7 mmol) in tetrahydrofuran (15 mL). The reaction mixture was slowly warmed to rt and stirred at rt for 16 h. The solvent was evaporated and the residue was performed by flash column chromatography (gradient, 1: 2 to 1: 1 ethyl acetate / hexanes). The product was then recrystallized from ethyl acetate / hexanes (1: 1) to afford the title compound (1.7 g, yield 62%).

Benzyl (R) -1- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) ethylcarbamate

In a glove bag with three vacuum / nitrogen purge cycles, the AIRFREE® (Schlenk) reaction flask with stir bar was charged with (-)-1,2-bis ((2R, 5R) -2 Filled with, 5-diethylphospholano) benzene (cyclooctadiene) rhodium (I) trifluoromethylsulfonate (125 g, 0.173 mmol, 4 mol%), sealed with rubber film and removed from glove bag It was. Benzyl (Z) -1- (methoxycarbonyl) -2- (3-methyl-4,5-dinitrophenyl) vinylcarbamate (1.65 g, 3.97 mmol) was added to a second air free with a stir bar ( Schlenk) The reaction flask was weighed and sealed with a rubber film. After three vacuum / nitrogen purge cycles, it was dissolved in a mixture of anhydrous methylene chloride (40 mL). The solvent was deoxygenated and then added by sparging with nitrogen for at least 1 hour. In solution, the mixture was again subjected to three vacuum / nitrogen purge cycles. The dehydroamino acid solution was injected via cannula into an airfree (schlenk) reaction flask containing a catalyst. The reaction mixture was subjected to five vacuum / hydrogen purge cycles and the flask was opened at 1 atmosphere of hydrogen. After 16 hours, the reaction mixture was purged with three vacuum / nitrogen purge cycles. The solvent was evaporated and column chromatography (1: 1 ethyl acetate / hexanes) with the residue gave the title compound (1.58 g, 95%).

Benzyl (R) -1- (methoxycarbonyl) -2- (3,4-diamino-5-methylphenyl) ethylcarbamate

Solid ammonium formate (755 mg, 11.9 mmol) was benzyl (R) -1- (methoxycarbonyl) -2- (3-methyl-4,5 in methanol (20 mL, degassed with nitrogen for 2 hours) To a suspension of dinitrophenyl) ethylcarbamate (500 mg, 1.20 mmol) and zinc powder (470 mg, 7.19 mmol) was added in small portions at 0 ° C. The resulting mixture was stirred at rt for 60 h. The reaction was incomplete. The reaction mixture was cooled back to 0 ° C. and zinc powder (470 mg, 7.19 mmol) was further added. The reaction was stirred for 4 hours to complete the reaction. The reaction mixture was filtered to remove zinc. The filtrate was evaporated. A mixture of toluene and ethyl acetate (1: 1) was added followed by acetic acid (2 mL). The mixture was further diluted until all organic solids dissolved, then washed with water, brine, dried over sodium sulfate and evaporated. The residue was dissolved in ethyl acetate and 4N hydrogen chloride in dioxane (4 mL) was added. Evaporation of the solvent gave the title compound as a dihydrochloride salt (515 mg, quantitative yield).

Benzyl (R) -1- (methoxycarbonyl) -2- (7-methyl-1H-benzo [d] [1,2,3] triazol-5-yl) ethylcarbamate

Benzyl (R) -1- (methoxycarbonyl) -2- (3,4-diamino-5-methylphenyl) ethylcarbamate (250 mg, 0.58 mmol in acetic acid (6 mL) and water (10 mL) To a solution of) was added dropwise a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL) at room temperature over several minutes. The resulting mixture was stirred at rt for 30 min and then cooled to 0 ° C. The pH was adjusted to 11 by addition of a mixture of ammonium hydroxide and water (1: 1, 15 mL). The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (1: 1 ethyl acetate / hexanes) to give the title compound as a light brown solid (155 mg, 72% yield).

(R) -methyl 2-amino-3- (7-methyl-1H-benzo [d] [1,2,3] triazol-5-yl) propanoate

Benzyl (R) -1- (methoxycarbonyl) -2- (7-methyl-1H-benzo [d] [1,2,3] triazol-5-yl) ethylcarbamate (146 mg, 0.40 mmol) was dissolved in 12 mL of a solution of 4.4% formic acid in methanol. A magnetic stir bar was placed in a reaction flask containing this solution and then flushed with nitrogen over several minutes. Palladium on carbon (10%, 200 mg) was added to this solution and the reaction was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction mixture was filtered through a Celite® pad and the pad was washed several times with methanol. The filtrate was evaporated to afford the title compound (quantitative yield).

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-methyl- 1H-benzo [d] [1,2,3] triazol-5-yl) propanoate

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. LC / MS: t _R = 2.17 min, 492 (MH) ⁺ .

(R) -2- (4- (1,2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7- Methyl-1H-benzo [d] [1,2,3] triazol-5-yl) propanoic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. LC / MS: t _R = 2.11 min, 492 (MH) ⁺ .

Example  237

4- (1,2-Dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N-((R) -3- (7-methyl-1H-benzo [d] [1, 2,3] triazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1- Carboxamide

Prepared as described above for Example 231.

(R) -2-benzyloxycarbonylamino-3- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester (373 mg, 1.01 in dichloroethane (20 mL) mmol), N-chlorosuccinimide (168 mg, 1.26 mmol), silica gel (EM Scientific, 230-400 mesh, 3.73 g) were heated to 90 ° C. for 16 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate / hexanes (1: 2) as eluent to afford the title compound (40 mg, 9.8%) and 2-benzyloxycarbonylamino-3- (5-chloro-2- Oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester (78 mg, 19%) was obtained. Comparison of the structure with 2-benzyloxycarbonylamino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester prepared by the reaction shown below and Confirmed by 2D NMR.

(R) -2-benzyloxycarbonylamino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

N-chlorosuccinimide (315 mg, 2.36 mmol) was dissolved in acetic acid (50 mL) (R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazole- To a solution of 6-yl) -propionic acid methyl ester (700 mg, 1.89 mmol) was added at room temperature. The mixture was heated to 100 ° C. for 16 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate / hexanes (4: 6) as eluent followed by (1: 1) to afford the title compound as a cloudy yellow solid (242 mg, 32%). The structure of the product was confirmed by 2D NMR.

(R) -2-benzyloxycarbonylamino-3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester (418 mg, 1.13 mmol), N-bromo A mixture of succinimide (221 mg, 1.24 mmol), silica gel (EM Scientific, 230-400 mesh, 2.51 g) and methylene chloride (70 mL) was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was subjected to silica gel chromatography using ethyl acetate / hexanes (2: 3) as eluent to afford the title compound.

(R) -2-benzyloxycarbonylamino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester (1.07 g, 2.89 mmol), N-bromo A mixture of succinimide (643 mg, 3.61 mmol), and acetic acid (150 mL) was heated to 105 ° C. for 14 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate / hexanes (2: 3) as eluent followed by (1: 1) to afford the title compound (446 mg, 34%). The structure of the title compound was confirmed by 2D NMR.

(R) -2-benzyloxycarbonylamino-3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

(R) -2-benzyloxycarbonylamino-3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester (324 mg, 0.87 mmol), I (PyH) A mixture of ₂ BF ₄ (409 mg, 1.08 mmol), silica gel (EM Scientific, 230-400 mesh, 3.24 g) and dichloroethane (20 mL) was heated to 90 ° C. for 6 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate / hexanes (1: 2) as eluent to afford the title compound (175 mg, 40%). The structure of the title compound was confirmed by 2D NMR.

(R) -2-Amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

Trimethylsilyl iodide (73 mL, 0.73 mmol) in (R) -2-benzyloxycarbonylamino-3- (5-bromo-2-oxo-2,3 in azeotropically dried acetonitrile (10 mL) To a solution of -dihydro-benzooxazol-6-yl) -propionic acid methyl ester (146 mg, 0.33 mmol) was added at room temperature and the resulting mixture was stirred at room temperature for 2 hours. Triethylamine (0.12 mL) was added and the mixture was stirred at rt for 15 min. The solvent was removed in vacuo and the residue was extracted with ethyl acetate. The combined organics were washed with sodium bicarbonate and brine, dried over sodium sulfate and filtered. Solvent was removed and the residue was used directly in the next step. Mass spectrometry 315.10 (MH) ⁺ .

(R) -2-Amino-3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

Prepared as described above for (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydrobenzooxazol-6-yl) -propionic acid methyl ester. Mass spectroscopy 315.06 (MH) ⁺ .

(R) -2-Amino-3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

Prepared as described above for (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester. Mass spectroscopy 271.10 (MH) ⁺ .

(R) -2-Amino-3- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester

Prepared as described above for (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydrobenzooxazol-6-yl) -propionic acid methyl ester. Mass spectroscopy 271.16 (MH) ⁺ .

(R) -2-Amino-3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester:

Prepared as described above for (R) -2-amino-3- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -propionic acid methyl ester. Mass spectroscopy 363.04 (MH) ⁺ .

(R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[2,4-dihydro-2'-oxospyro- (piperidine-4 , 4'-1H-benzo [d] [1,3] oxazine) -1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectroscopy 481.20 (MH) ⁺ .

(R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[2,4-dihydro-2'-oxospyro- (piperidine-4 , 4'-1H-quinazolin) -1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectrometry 480.24 (MH) ⁺ .

(R) -3- (4-chloro-2-oxo-2,3-dihydrobenzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro-2H- Quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectroscopy 528.16 (MH) ⁺ .

(R) -3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro-2H -Quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectroscopy 528.20 (MH) ⁺ .

(R) -3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectroscopy 572.20 (MH) ⁺ .

(R) -3- (5-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectroscopy 572.15 (MH) ⁺ .

(R) -3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid methyl ester

(R) -Methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (tri Prepared as described above for fluoromethyl) -1H-benzo [d] imidazol-5-yl) propanoate. Mass spectrometry 620.20 (MH) ⁺ .

(R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[2,4-dihydro-2'-oxospyro- (piperidine-4 , 4'-1H-benzo [d] [1,3] oxazine) -1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) yl) piperidine-1-carboxamido) -3- (2- (trifluoro Prepared as described above for methyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrometry 467.18 (MH) ⁺ .

(R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[2,4-dihydro-2'-oxospyro- (piperidine-4 , 4'-1H-quinazolin) -1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) yl) piperidine-1-carboxamido) -3- (2- (trifluoro Prepared as described above for methyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectroscopy 466.20 (MH) ⁺ .

(R) -3- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro-2H -Quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) yl) piperidine-1-carboxamido) -3- (2- (trifluoro Prepared as described above for methyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectroscopy 514.20 (MH) ⁺ .

(R) -3- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro-2H -Quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectroscopy 514.24 (MH) ⁺ .

(R) -3- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro- 2Hquinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectroscopy 558.30 (MH) ⁺ .

(R) -3- (5-Bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectroscopy 558.25 (MH) ⁺ .

(R) -3- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-yl) -2-{[4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino} -propionic acid

(R) -2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4I) -yl) piperidine-1-carboxamido) -3- (2- (trifluor Prepared as described above for rhomethyl) -1H-benzo [d] imidazol-5-yl) propanoic acid. Mass spectrometry 606.10 (MH) ⁺ .

Example  238

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.80 min, 630.37 (MH) ⁺ .

Example  239

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-isopropyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.71 min, 590.34 (MH) ⁺ .

Example  240

(R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3 ] Oxazine) -1-carboxamide

Prepared as described above for Example 231. LC / MS: t _R = 1.64 min, 617.34 (MH) ⁺ .

Example  241

(R) -N-((R) -3- (2-oxo-2, 3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade 1) Carboxamide

Prepared as described above for Example 231. LC / MS: t _R = 1.69 min, 617.35 (MH) ⁺ .

Example  242

(R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4-prop-2-yl) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1Hbenzo [d] [1,3] oxazine) -1-carboxamide

Prepared as described above for Example 231. LC / MS: t _R = 1.57 min, 577.32 (MH) ⁺ .

Example  243

(R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-quinazolin) -1-carbox amides

Prepared as described above for Example 231. LC / MS: t R = 1.74 min, 616.37 (MH) ⁺ .

Example  244

(R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-quinazolin) -1-carboxamide

It was prepared as above. LC / MS: t R = 1.79 min, 616.36 (MH) ⁺ .

Example  245

(R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-quinazolin) -1-carboxamide

Prepared as described above for Example 231. LC / MS: t _R = 1.67 min, 576.34 (MH) ⁺ .

Example  246

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.91 min, 664.35 (MH) ⁺ .

Example  247

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.91 min, 664.34 (MH) ⁺ .

Example  248

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.96 min, 708.31 (MH) ⁺ .

Example  249

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.96 min, 708.31 (MH) ⁺ .

Example  250

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 231. LC / MS: t _R = 1.97 min, 756.36 (MH) ⁺ .

Example  251

(±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butyrylamide

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'piperidinyl] -butane-1,4-dione. LC / MS: t _R = 1. 38 minutes, 596 (MH) ⁺ .

Example  252

(±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo -1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione.

Example  253

(±) -phenyl-acetic acid N '-{2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidin-1-yl] -butyryl} -hydrazide

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'piperidinyl] -butane-1,4-dione. LC / MS: t _R = 1.43 min, 630 (M + Na) ⁺ .

Example  254

(±) -1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidin-1-yl] -2- (7-methyl-1H-indazol-5-ylmethyl) -butane-1,4-dione

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione.

Example  255

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [2', 3'-dihydro -2'-Oxospyro- (piperidine-4,4'-quinazolin] -butane-1,4-dione

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butane-1,4-dione. LC / MS: t _R = 1.09 min, 612 (MH) ⁺ .

2-oxo-2,3-dihydro-benzooxazole-6-carbaldehyde

 A solution of 6-bromo-3H-benzooxazol-2-one (0.9236 g, 4.31 μmol) in anhydrous tetrahydrofuran (25 mL) and dimethylformamide (3 mL) was cooled to -78 ° C under nitrogen and , n-butyllithium (2.5 M in hexane) (3.8 mL, 2.2 equiv) was added. After stirring at −78 ° C. for 10 minutes, 24 mL of sec-butyllithium (1.4 M in cyclohexane, 8 equiv) was added. The reaction was stirred while slowly warming to -40 ° C. Upon reaching −40 ° C., the reaction was quenched by addition of methanol. The reaction mixture was concentrated in vacuo and water was added. The aqueous layer was acidified with 1 N HCl (about pH 5), extracted with ethyl acetate (3 x 50 mL), dried over sodium sulfate, filtered and concentrated to give 0.6402 g (91%) of product.

3- (2-Oxo-2,3-dihydro-benzooxazol-6-ylmethylene) -pentanediic acid monomethyl ester

Prepared as described above for 2- (7-methyl-1H-indazol-5-ylmethylene) -succinic acid 1-methyl ester (1.4 g, 90% yield). MS (ESI) 300 (M + Na) ⁺ .

(±) -3- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -pentanediic acid monomethyl ester

Prepared as described above for (±) -2- (7-methyl-1H-indazol-5-ylmethyl) -succinic acid 1-methyl ester (1.4 g, yield 99%). MS (ESI) 302 (M + Na) ⁺ .

(±) -4-oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H -Quinazolin-3-yl) -piperidin-1-yl] -butyric acid methyl ester

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospyro- [4H-3', Prepared as described above for 1-benzoxazine-4,4'-piperidinyl] -butyric acid methyl ester. MS (ESI) 493 (MH) ⁺ .

(±) -4-oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxoscopy- (Piperidine-4,4'-quinazolin)]-butyric acid methyl ester

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospyro- [4H-3', Prepared as described above for 1-benzoxazine-4,4'-piperidinyl] -butyric acid methyl ester. MS (ESI) 479 (MH) ⁺ .

(±) -4-oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxoscopy- (Piperidine-4,4'-quinazolin)]-butyric acid

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospyro- [4H-3', Prepared as described above for 1-benzoxazine-4,4'-piperidinyl] -butyric acid. MS (ESI) 465 (MH) ⁺ .

(±) -4-oxo-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H -Quinazolin-3-yl) -piperidin-1-yl] -butyric acid

(±) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'-dihydro-2'-oxospyro- [4H-3', Prepared as described above for 1-benzoxazine-4,4'-piperidinyl] -butyric acid. MS (ESI) 479 (MH) ⁺ .

Example  256

(±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- ( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'piperidinyl] -butane-1,4-dione. LC / MS: t _R = 1.10 min, 629 (MH) ⁺ .

Example  257

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'piperidinyl] -butane-1,4-dione.

Example  258

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2' , 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'piperidinyl] -butane-1,4-dione. LC / MS: t _R = 1.02 min, 615 (MH) ⁺ .

Example  259

(±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione

(±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [1', 2'-dihydro Prepared as described above for -2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'piperidinyl] -butane-1,4-dione. LC / MS: t _R = 1.04 min, 615 (MH) ⁺ .

Example  260

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 16.

Example  261

(±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [4- (4-fluoro-phenyl ) -Piperazin-1-yl] -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

Prepared as described above for Example 16. LC / MS: t _R = 2.34 min, 621.42 (MH) ⁺ .

Example  262

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperi Din-1-carbonyl] -amino} -propionic acid tert-butyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3- in dimethylformamide A solution of yl) -piperidine-1-carbonyl] -amino} -propionic acid (50 mg, 0.105 mmol) and dicyclohexylcarbodiimide (25 mg, 0.12 mmol) was stirred at room temperature for 30 minutes, penta Fluorophenol (26 mg, 1.3 mmol) was added. Stirring was continued at room temperature overnight, then the solvent was removed and the residue was dried under high vacuum for 4 hours. Crude pentafluorophenyl ester was used in the next step without further purification. To a solution of tert-butyl alcohol (10 equiv) in tetrahydrofuran was added 1.4 M sec-butyllithium (10 equiv) in cyclohexane at -78 ° C under nitrogen. After 10-15 minutes, a solution of pentafluorophenol ester (1 equiv) in tetrahydrofuran was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford the desired compound.

Example  263

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-methyl cyclohexyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid tert-butyl ester. LC / MS: t _R = 2.47 min, 574.39 (MH) ⁺ .

Example  264

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3- in dimethylformamide Yl) -piperidine-1-carbonyl] -amino} -propionic acid (50 mg, 0.105 mmol), EDCI (100 mg), and 4-dimethylaminopyridine (0.2 equiv) in aza-bicyclo [2.2 .2] oct-3-yl alcohol (0.525 mmol, 5 equiv) was added. The mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate and purified by preparative HPLC to afford the desired compound. LC / MS: t _R = 1.62 min, 586.41 (MH) ⁺ .

Example  265

(+)-3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid piperidin-4-yl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester. LC / MS: t _R = 1.58 min, 560.37 (MH) ⁺ .

Example  266

(±) -4- (3- (7-methyl-1H-indazol-5-yl) -2-1 [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl ) -Piperidine-1-carbonyl] -amino} -propionyloxy) -piperidine-1-carboxylic acid tert-butyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester. LC / MS: t _R = 2.38 min, 660.42 (MH) ⁺ .

Example  267

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester. LC / MS: t _R = 1.67 min, 637.43 (MH) ⁺ .

Example  268

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-diethylamino-1-methyl-ethyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4dihydro-2H-quinazolin-3-yl) -piperi Prepared as described above for the din-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester. LC / MS: t _R = 1.66 min, 590.44 (MH) ⁺ .

Example  269

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-2-phenyl-ethyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid t-butyl ester. LC / MS: t _R = 2.52 min, 609.46 (MH) ⁺ .

Example  270

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-3-phenyl-propyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid t-butyl ester. LC / MS: t _R = 2.61 min, 623.48 (MH) ⁺ .

Example  271

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid ethyl ester

(±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Prepared as described above for ferridine-1-carbonyl] -amino} -propionic acid t-butyl ester. LC / MS: t _R = 1.98 min, 505.32 (MH) ⁺ .

Example  272

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro -2'-Oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide

Prepared as described above for Example 16. LC / MS: t _R = 1.49 min, 553.12 (MH) ⁺ .

Example  273

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide

Prepared as described above for Example 16. LC / MS: t _R = 1.56 min, 608.18 (MH) ⁺ .

Example  274

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-[(2-dimethylamino-ethyl-ethyl carbamoyl) -2-oxoethyl] -2 ', 3' -Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide

Prepared as described above for Example 16. LC / MS: t _R = 1.58 min, 561.20 (MH) ⁺ .

Example  275

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide

Prepared as described above for Example 16. LC / MS: t _R = 1.56 min, 609.14 (MH) ⁺ .

Example  276

(±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide

Prepared as described above for Example 16. LC / MS: t _R = 1.57 min, 609.17 (MH) ⁺ .

Example  277

(R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1d-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] amide

Prepared as described above for Example 16.

Example  278

(R) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide

Prepared as described above for Example 16. LC / MS: t _R = 1.63 min, 613.36 (MH) ⁺ .

Other compounds included in the present invention and those that can be prepared according to the descriptions presented herein or methods known to those skilled in the art include the following examples:

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-bromo-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-methyl-piperazin-1-yl) -2 -Oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1-dimethylcarbamoyl-2- (4-methyl-2- Oxo-2,3-dihydro-benzooxazol-6-yl) -ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-yl) -1-dimethylcarbamoyl-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-Methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-Chloro-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3-Methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide

3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester

3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester

3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester

3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester

3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester

3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester

3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester

3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester

3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester

3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester

3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester

3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester

3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester

CGRP  Binding analysis

Tissue culture. SK-N-MC cells were monolayered in media consisting of MEM containing Earle's salt and L-glutamine (Gibco), supplemented with 10% fetal bovine serum (Gibco) at 37 ° C. under 5% CO _2. Incubated with.

Cell pellets. Cells were washed _twice with phosphate-buffered saline (PBS) (155 mM NaCl, 3.3 mM Na ₂ HPO ₄ , 1.1 mM KH ₂ PO ₄ , pH 7.4) and consisted of 10 mM Tris (pH 7.4) and 5 mM EDTA. Incubate at 4 ° C. for 5-10 minutes in hypotonic lysis buffer. The cells were transferred from plates to polypropylene tubes (16 × 100 mm) and homogenized using polytrons. Homogenates were centrifuged at 32,000 × g for 30 minutes. Pellets were resuspended in cold hypotonic lysis buffer containing 0.1% mammalian protease inhibitor cocktail (Sigma) and analyzed for protein concentration. The SK-N-MC homogenate was then aliquoted and stored at -80 ° C until needed.

Radioligand Binding Assay. Compounds of the invention were solubilized and sequential dilutions were performed using 100% DMSO. Aliquots from sequentially diluted compounds are further diluted 25-fold in assay buffer (50 mM Tris-Cl pH 7.5, 5 mM MgCl ₂ , 0.005% Triton X-100) and 96 well assay plates (50 μl volume) Moved to. [ ¹²⁵ I] -CGRP (Amersham Biosciences) was diluted to 60 pM in assay buffer and 50 μl of volume was added to each well. SK-N-MC pellets were thawed and diluted in assay buffer containing freshly prepared 0.1% mammalian protease inhibitor cocktail (Sigma) and then homogenized again. SK-N-MC homogenate (5 μg / well) was added in a volume of 100 μl. The assay plate was then incubated for 2 hours at room temperature. Immediately after the assay was stopped by addition of excess cold wash buffer (20 mM Tris-Cl pH 7.5, 0.1% BSA), it was filtered through a glass fiber filter (Whatman GF / B) pre-soaked in 0.5% PEI. Non-specific binding was defined as 1 μM Beta-CGRP. Protein binding radioactivity was measured with a gamma or scintillation counter. IC ₅₀ was defined as the concentration of compound of the invention required to remove 50% of the radioligand binding.

In the table below, the results are shown as follows: A ≦ 10 nM; 10 nM < B < 100 nM; 100 nM <C ≦ 1000 nM; D> 1000 nM.

Cyclic AMP Analysis

Functional antagonism. Antagonism of the compounds of the invention was determined by measuring the formation of cyclic AMP (adenosine 3'5'-cyclic monophosphate) in SK-N-MC cells that endogenously express human CGRP receptors. The CGRP receptor complex was coupled with the Gs protein and the CGRP was bound to this complex resulting in cyclic AMP production via Gs-dependent activation of adenylate cyclase (Juaneda C et. al., TiPS, 2000; 21: 432-438). As a result, CGRP receptor antagonists inhibited CGRP-induced cyclic AMP formation in SK-N-MC cells (Doods H et al., Br J Pharmacol, 2000; 129 (3), incorporated herein by name). 420-423). For cyclic AMP measurements, SK-N-MC cells were incubated for 30 minutes at room temperature in the presence of 0.3 nM CGRP only or in the presence of various concentrations of the compound of the invention. Compounds of the invention were incubated with SK-N-MC cells for 15 minutes in advance, and then CGRP was added to bind to the receptors (Edvinsson et al., Eur J Pharmacol, 2001, which is incorporated herein by reference). , 415: 39-44). Cyclic AMP was extracted using lysis reagents and concentrations were determined by radioimmunoassay using RPA559 cAMP SPA Direct Screening Assay Kit (Amersham Pharmacia Biotech). IC ₅₀ values were calculated using Excel fit. The compounds of the invention tested were determined to be antagonists because they showed dose-dependent inhibition of CGRP induced cyclic AMP production. The results are summarized in Table 3.

Shield analysis. Shield assays can be used to characterize the nature of the antagonism of the compounds of the invention. Dose responses of CGRP-promoted cAMP production occurred either in CGRP alone or in the presence of various concentrations of the compound of the invention. Antagonist dose represents the X-axis, Y-axis response, [(as defined by dividing the IC ₅₀ of the agonist in the presence of the compound to the IC ₅₀ of the sole effect) dose ratio - 1] denotes a. Linear regression analysis was then performed to log-transform both the X and Y axes. The slope, which is not significantly different from the number of units (1), indicates competitive antagonism. K _b is the dissociation constant of the antagonist.

See shield analysis.

In vitro  Human Cerebral Artery Analysis

Theory and overview. In vitro assays were designed to provide direct evidence of the ability of the new compounds to reverse CGRP-induced expansion in human cerebral vessels. Briefly, this relaxation is achieved by placing the isolated vascular loops in a tissue bath where the blood vessels are pre-contracted with potassium chloride (KCl), then fully expanded to hCGRP, followed by the addition of cumulative amounts of CGRP receptor antagonists. Inverted (see below for detailed supplemental explanation).

Tissue samples. Autopsy samples of human arteries were obtained from the supplier (ABS Inc. or NDRI). All vessels were transported in ice cold HEPES buffer (composition in mM: NaCl 130, KCl 4, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 1.8, glucose 6, NaHCO ₃ 4, HEPES 10, EDTA 0.025). Thereafter, cold Krebs buffer saturated in carbogen (5% CO ₂ and 95% oxygen) (mM composition: NaCl 118.4, KCl 4.7, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 1.8, glucose 10.1, NaHCO ₃ 25).

Isolated tissue bath. The connective tissue was removed from the vessel and cut into cylindrical sections 4-5 mm long. The vessel was then placed between two stainless steel hooks of the tissue bath, one of which was fixed and the other of which was connected to a force displacement transducer. Vascular tension was recorded continuously using a data acquisition system (Powerlab, AD Instruments, Mountain View, CA) connected to the transducer. Tissue baths containing Krebs buffer and vessels were continuously bubbled with carbogen to control temperature (37 ° C.) and pH (7.4). Artery sections were equilibrated for about 30-45 minutes until stable resting state was achieved. Prior to analysis, blood vessels were primed (conditioned) with 100 mM KCl and then washed. Blood vessels were pre-contracted with 10 mM KCl and fully expanded with 1 nM hCGRP. Concentration-response curves for CGRP-receptor antagonists were constructed by adding cumulative amounts of drug in half log units to fully expanded blood vessels. At each concentration, the effect of the drug was expressed as% reversal of CGRP induced relaxation in each vessel. The actual analysis and data analysis is performed for each vessel individually, the non-linear regression analysis by the concentration of the logistic function of four parameters - by fitting the reaction data, and estimate the EC ₅₀ value. A summary of the results is presented in Table 3.

In mammals Small molecule CGRP Of receptor antagonists In vivo  Non-terminal way to investigate efficacy

survey. Blocking cerebral artery dilation induced by calcitonin gene-related peptide (CGRP) has been proposed for the treatment of migraine headaches, but new small molecule CGRP-receptor antagonists show species-specific differences with relatively poor activity in rodents. (Mallee et al. J Biol Chem 2002 277: 14294), requiring a new model for investigating in vivo efficacy. Non-human primates (eg marmosets) are the only animals known to have human-like CGRP receptor pharmacology conferred by the presence of specific amino acid residues (Trp74) of the RAMP1 sequence responsible for the phenotype of human receptors ( Mallee et al. J Biol Chem 2002 277: 14294). Current migraine models are primarily for rats (Escott et al. Brain Res 1995 669: 93; Williamson et al. Cephalalgia 1997 17: 525) or because they are permeable terminal procedures in primates (Doods et al. Br J Pharmacol 2000 129: 420]), as in the present invention, the new non-invasive survival model of primates other than humans for the in vivo efficacy measurement of CGRP-receptor antagonists is very large. Trigeminal nerve activation is known to increase both cerebral (Goadsby & Edvinsson, 1993) and facial blood flow (Doods et al., 2000), but between facial blood flow and cerebral artery expansion induced in the same animal No direct relationship is known. Therefore, prior to starting the study in non-human primates, laser Doppler measurements of facial blood flow were directly identified in rats as a substitute for cerebral artery dilatation in a terminal study measuring both changes in cerebral artery diameter and facial blood flow in the same animal. (See also direct evidence of facial blood flow replacing cerebral artery expansion in rats.) In both measurements, a comparable increase in i.v. Induced by CGRP and blocked by peptide antagonist hαCGRP (8-37). Next, i.v. The method of CGRP-induced facial blood flow change was identified as a recovery model for isoflurane anesthesia rats using hαCGRP (8-37). The survival method is then constructed in primates other than humans, and i.v. A dose-response study characterizing CGRP activity was completed (see FIG. 3. Dose-response to hαCGRP in primate laser Doppler facial blood flow except humans). Peptide and small molecule CGRP-receptor antagonists were used to confirm the validity of the primate model except for humans. Pre-treatment of small molecule antagonists or hαCGRP (8-37) was performed in i.v. Dose-dependently inhibits CGRP-stimulated increase (see Figure 4. Inhibition of CGRP-induced changes in primate facial blood flow except humans), but does not alter blood pressure (Figure 5. See the effects of CGRP antagonists). Pre-treatment of antagonists also reversed CGRP-induced increases in facial blood flow (not shown). This survival model measures the prophylactic and discontinuous effects of alternative marker CGRP-receptor antagonists on activity in cerebral blood vessel diameter in primates other than humans or in transgenic animals with humanized RAMP1 (Trp74) exhibiting similar CGRP receptor pharmacology. Provide a new non-invasive recovery procedure.

animal. Adult male and female Callithrix jacchus were purchased from Harlan and those weighing 350-550 g were selected as subjects. Other mammals endogenously expressing RAMP1 with Trp 74, or transgenic mammals with humanized RAMP1 with Trp 74, can also be used in the methods described herein.

Anesthesia & Surgery Preparation. Animals were anesthetized with isoflurane inhalation in an induction chamber (4-5% fast induction, maintained at 1-2.5%; Solomon et al., 1999). Anesthesia was maintained by continuously supplying air: oxygen (50:50) and isoflurane through the face mask, or by intubation and ventilation (monitoring blood gas). Body temperature was maintained at 38 ± 0.5 ° C. by placing a thermostatic surface with a rectal probe. Small areas of hair (approximately 1.5 square cm) were removed from the one or both sides of the face by hair loss cream application and / or shaving. The surgical site was dissected and treated with betadine. I.v. to any accessible vein for the administration of the test compound and the CGRP-receptor agonist and for recovery of blood samples (up to 2.5 ml, 10%) for blood gas monitoring and content analysis if necessary. The line was placed. A solution of 5% dextrose was administered i.v. to maintain blood glucose. The level of anesthesia was monitored by measuring blood pressure and heart rate using non-invasive arm cuff methods and pulse oximeter, respectively. If necessary, 5-10 mg / kg (iv) of guanethidine can be supplemented with 5 mg / kg (iv) to stabilize the peak changes in the facial blood flow, which are manifested by repeated stimulus-induced changes in the bloodstream ( Escott et al., 1999, incorporated herein by this name. Microvascular blood flow was monitored by attaching a self-attached laser Doppler flow probe to the facial skin.

Compound administration. The test compound was i.v. (0.01-5 ml / kg), i.m. (0.01-0.5 ml / kg), s.c. (0.01-5 ml / kg) or p.o. (0.1-10 ml / kg) (Diehl et al., 2001) incorporated herein by this name. CGRP-receptor agonists are described in i.v. (0.01-5 ml / kg), i.d. (10-100 μl / site) or s.c. (10-100 μl / site).

Laser Doppler Flow Rate Measurement. By administration of vasodilators such as CGRP (0.05-100 μg / kg iv or 2-20 pmol / site id) or adrenoduline (ADM, 0.05-5 mg / kg iv or 10-100 pmol / site id) Controls for facial blood flow increase were induced. The test compound or vehicle was administered before (pre-treatment) or after (treatment) following subsequent repeated administration of vasodilators to allow investigation of the prophylactic or therapeutic action. Blood pressure was continuously monitored to ensure adequate anesthesia and the anesthesia was adjusted to maintain a stable level consistent with pre-treatment levels. While collecting the laser Doppler flow rate data, the previous electrophysiological studies on the marmoset revealed that the readings were sensitive to isoflurane concentrations, thus reducing isoflurain to 0.25-0.75%. (Solomon, 1999, incorporated herein by this name). To reduce the number of animals used, i.v. The effect of the test compound on vasodilator-induced changes can be repeated up to six times in a single period.

recovery. The animals were returned to the transport cage and placed on a temperature controlled surface to keep the animals warm until they could fully wake up and walk. Animals may be tested again after a 7-14 day rest period and may be tested repeatedly at 7-14 day intervals depending on the health of the animal.

Documents incorporated herein by this name Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol. 2001 Jan-Feb; 21 (1): 15-23; Dodds H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 Feb; 129 (3): 420-3; Edvinsson L. Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs 2001; 15 (10): 745-53; Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1995 Jan 9; 669 (1): 93-9; Godsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993 Jan; 33 (1): 48-56; Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olsen J. CGRP may play a causative role in migraine. Cephalalgia, 2002, 22, 54-61; Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA. RAMP1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem. 2002 Feb 14 (published online before print)]; Solomon SG, White AJ, Martin PR. Temporal contrast sensitivity in the lateral geniculate nucleus of a New World monkey, the marmoset Callithrix jacchus. J Physiol. 1999 Jun 15; 517 (Pt 3): 907-17.

Start from another migraine model. The present invention represents a novel migraine model and is remarkably distinguished from other migraine models. Some distinguishing features of the methods of the invention are (i) the only survival model of migraine in any species; (ii) is the only model demonstrating the effect of discontinuation (post-treatment) of CGRP antagonist on activator-induced increase in blood flow; (iii) the only evidence of a direct relationship between facial blood flow and intracranial artery dilation, performed in the same animal; (iv) is the only model that uses non-invasive surgical techniques and does not require catheter installation, intubation or neuromuscular blockage; (v) the only primate model using exogenous CGRP as a stimulus and demonstrating pre-treatment blocking by CGRP antagonism and post-treatment reversal by CGRP antagonism; (vi) is the only migraine model using isoflurane anesthesia in spontaneously breathing animals. This model is described by Williamson et al., Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat-intravital microscope studies. Cephalalgia. 1997 Jun; 17 (4): 525-31; Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia. 1997 Jun; 17 (4): 518-24; [Escott KJ et al., Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1995 Jan 9; 669 (1): 93-9; Chu DQ et al., The calcitonin gene-related peptide (CGRP) antagonist CGRP (8-37) blocks vasodilatation in inflamed rat skin: involvement of adrenomedullin in addition to CGRP. Neurosci Lett. 2001 Sep 14; 310 (2-3): 169-72; Escott KJ, Brain SD. Effect of a calcitonin gene-related peptide antagonist (CGRP8-37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve. Br J Pharmacol. 1993 Oct; 110 (2): 772-6; Hall JM, Siney L, Lippton H, Hyman A, Kang-Chang J, Brain SD. Interaction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvasculature of the rat and hamster. Br J Pharmacol. 1995 Feb; 114 (3): 592-7; Hall JM, Brain SD. Interaction of amylin with calcitonin gene-related peptide receptors in the microvasculature of the hamster cheek pouch in vivo. Br J Pharmacol. 1999 Jan; 126 (1): 280-4; And Dodds H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 Feb; 129 (3): 420-3, which do not exhibit significantly different properties of the method of the present invention.

In the table below, the results are shown as follows: W ≦ 25%; 25% <X ≦ 50%; 50% <Y ≦ 75%; Z> 75%.

Inhibition of CGRP-induced increase in laser Doppler facial blood flow in non-human primates (eg, conventional marmosets) Increased CGRP-induced (10 μg / kg, iv) of non-human primates (% inhibition) in laser Doppler blood flow Example number 0.01 mg / kg, iv 0.03 mg / kg, iv 0.1 mg / kg, iv 0.3 mg / kg, iv 1 mg / kg, iv 2 W X X Y Z 6 Z 16 Y 69 Y Z hαCGRP (8-37) Z W ≦ 25%; 25% <X ≦ 50%; 50% <Y ≦ 75%; Z> 75%.

See effect of CGRP antagonist on blood pressure of non-human primates.

Claims (6)

(±) -3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid methyl ester; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (3-cyano-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (3-cyano-7-methyl-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -3- (7-isopropyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidine-1-carbonyl] -amino} -propionic acid methyl ester; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-isopropyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-ethyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-ethyl-3-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide ; (±) -2- [4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] -3 -(7-methyl-1H-indazol-5-yl) -propionic acid methyl ester; (±) -4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (2-oxo-1,2,4,5-tetrahydro-benzo [d] [1,3] diazepin-3-yl-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (8-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] oxazine) -1 Carboxamides; (±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-1H-pyrazolo [4,3-c] pyridine-5 (4H ) -Yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c ] Pyridin-5 (4H) -yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamides; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-methyl-1H-indazol-5-yl) propanoate; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carbox amide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-ethyl-3-methyl-1H-indazol-5-yl) propanoate; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamides; (±) -N- (3- (7-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) Propan-2-yl) -8'-fluoro-2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazole -5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; N-((R) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -1- (dimethylcarbamoyl) -2- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) ethyl) -4- (1,2 -Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (R) -methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2,3- Dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoate; N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) ethyl) -4- (1 , 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospyro (piperidin-4,4'-(1H) -quinazolin) Carboxamides; 4- (1,2-Dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N-((R) -3- (7-methyl-1H-benzo [d] [1, 2,3] triazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1- Carboxamides; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-isopropyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3 ] Oxazine) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade Photo) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade Photo) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-quinazolin) -1-carbox amides; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidine-4,4'-1H-quinazolin) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidine-4,4'-1H-quinazolin) -1-carboxamide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butyramide; (±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo -1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide; (±) -phenyl-acetic acid N '-{2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidin-1-yl] -butyryl} -hydrazide; (±) -1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidin-1-yl] -2- (7-methyl-1H-indazol-5-ylmethyl) -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [2', 3'-dihydro -2'-oxospyro- (piperidine-4,4'-quinazolin] -butane-1,4-dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- ( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2' , 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [4- (4-fluoro-phenyl ) -Piperazin-1-yl] -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid tert-butyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-methyl cyclohexyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid piperidin-4-yl ester; (±) -4- (3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidine-1-carbonyl] -amino} -propionyloxy) -piperidine-1-carboxylic acid tert-butyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-diethylamino-1-methyl-ethyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-3-phenyl-propyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid ethyl ester; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro -2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-[(2-dimethylamino-ethyl-ethyl carbamoyl) -2-oxoethyl] -2 ', 3' -Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1d-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] amide; And (R) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide, or a pharmaceutically acceptable salt or solvate thereof . 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-bromo-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-l- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-methyl-piperazin-1-yl) -2 -Oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1-dimethylcarbamoyl-2- (4-methyl-2- Oxo-2,3-dihydro-benzooxazol-6-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-yl) -1-dimethylcarbamoyl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-Methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester; And 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester, or a pharmaceutically acceptable salt or solvate thereof. (±) -3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid methyl ester; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (3-cyano-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (3-cyano-7-methyl-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -3- (7-isopropyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidine-1-carbonyl] -amino} -propionic acid methyl ester; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-isopropyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-ethyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2,2- dioxo-1,4-dihydro -2H-2λ ⁶ - benzo [1,2,6] thiadiazol Jean-3-yl) piperidine-1- Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-ethyl-3-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide ; (±) -2- [4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino]- 3- (7-Methyl-1H-indazol-5-yl) -propionic acid methyl ester; (±) -4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (2-oxo-1,2,4,5-tetrahydro-benzo [d] [1,3] diazepin-3-yl-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (8-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] oxazine) -1 Carboxamides; (±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-1H-pyrazolo [4,3-c] pyridine-5 (4H ) -Yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c ] Pyridin-5 (4H) -yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamides; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-methyl-1H-indazol-5-yl) propanoate; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) pipe Razin-1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-ethyl-3-methyl-1H-indazol-5-yl) propanoate; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamides; (±) -N- (3- (7-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) Propan-2-yl) -8'-fluoro-2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazole -5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; N-((R) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -1- (dimethylcarbamoyl) -2- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) ethyl) -4- (1,2 -Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (R) -methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2,3- Dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoate; N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) ethyl) -4- (1 , 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospyro (piperidin-4,4'-(1H) -quinazolin) Carboxamides; 4- (1,2-Dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N-((R) -3- (7-methyl-1H-benzo [d] [1, 2,3] triazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1- Carboxamides; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-isopropyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3 ] Oxazine) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade Photo) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade Photo) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-quinazolin) -1-carbox amides; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidine-4,4'-1H-quinazolin) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidine-4,4'-1H-quinazolin) -1-carboxamide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butyramide; (±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo -1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide; (±) -phenyl-acetic acid N '-{2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidin-1-yl] -butyryl} -hydrazide; (±) -1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidin-1-yl] -2- (7-methyl-1H-indazol-5-ylmethyl) -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [2', 3'-dihydro -2'-oxospyro- (piperidine-4,4'-quinazolin] -butane-1,4-dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- ( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2' , 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [4- (4-fluoro-phenyl ) -Piperazin-1-yl] -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid tert-butyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-methyl cyclohexyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid piperidin-4-yl ester; (±) -4- (3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl ) -Piperidine-1-carbonyl] -amino} -propionyloxy) -piperidine-1-carboxylic acid tert-butyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-diethylamino-1-methyl-ethyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-3-phenyl-propyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid ethyl ester; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro -2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-[(2-dimethylamino-ethyl-ethyl carbamoyl) -2-oxoethyl] -2 ', 3' -Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxo ethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1d-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] amide; And (R) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide, or a pharmaceutically acceptable salt or solvate thereof Pharmaceutical composition comprising a. 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-bromo-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-methyl-piperazin-1-yl)- 2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1-dimethylcarbamoyl-2- (4-methyl-2- Oxo-2,3-dihydro-benzooxazol-6-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-yl) -1-dimethylcarbamoyl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-Methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3-methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester; And 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 A pharmaceutical composition comprising a compound selected from the group consisting of -carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester, or a pharmaceutically acceptable salt or solvate thereof. (±) -3- (3-cyano-1H-indol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid methyl ester; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (3-cyano-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (3-cyano-7-methyl-1H-indol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -3- (7-isopropyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidine-1-carbonyl] -amino} -propionic acid methyl ester; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-isopropyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1 (7-ethyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide; (±) -4- (2,2-dioxo-1,4-dihydro-2H-2λ ⁶ -benzo [1,2,6] thiadiazin-3-yl) -piperidine-1-car Acid [2- [1,4 '] bipiperidinyl-1'-yl-1 (7-ethyl-3-methyl-1H-indazol-5-yl-methyl) -2-oxo-ethyl] -amide ; (±) -2- [4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino] -3 -(7-methyl-1H-indazol-5-yl) -propionic acid methyl ester; (±) -4- (6-cyano-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (2-oxo-1,2,4,5-tetrahydro-benzo [d] [1,3] diazepin-3-yl-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 ' ] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -4- (8-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid {2- [1,4 '] Bipiperidinyl-1'-yl-1- (7-methyl-1H-indazol-5-yl methyl) -2-oxo-ethyl} -amide; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] oxazine) -1 Carboxamides; (±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-1H-pyrazolo [4,3-c] pyridine-5 (4H ) -Yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1-carboxamide; (±) -N- (3- (7-ethyl-1H-indazol-5-yl) -1- (6,7-dihydro-7,7-dimethyl-1H-pyrazolo [4,3-c ] Pyridin-5 (4H) -yl) -1-oxopropan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamides; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-methyl-1H-indazol-5-yl) propanoate; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-phenylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (4-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (1- (4- (2-fluorophenyl) piperazine -1-yl) -3- (7-methyl-1H-indazol-5-yl) -1-oxopropan-2-yl) piperidine-1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazol-5- Yl) -1-oxo-1- (4-o-tolylpiperazin-1-yl) propan-2-yl) piperidine-1-carboxamide; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (7-ethyl-3-methyl-1H-indazol-5-yl) propanoate; (±) -N- (3- (7-ethyl-3-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidine- 1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidin-1- Carboxamides; (±) -N- (3- (7-methyl-1H-indazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) Propan-2-yl) -8'-fluoro-2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin) -1-carboxamide; (±) -4- (8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N- (3- (7-methyl-1H-indazole -5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1-carboxamide; N-((R) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -1- (dimethylcarbamoyl) -2- (2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) ethyl) -4- (1,2 -Dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; (R) -methyl 2- (4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamido) -3- (2,3- Dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) propanoate; N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (1,2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -1- (dimethylcarbamoyl) -2- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) ethyl) -4- (1 , 2-dihydro-2-oxoquinazolin-3 (4H) -yl) piperidine-1-carboxamide; N-((R) -3- (2,3-dihydro-2-oxo-1H-benzo [d] imidazol-6-yl) -1-oxo-1 (4-piperidin-1-yl ) Piperidin-1-yl) propan-2-yl) -4- (2 ', 3'-dihydro-2'-oxospyro (piperidin-4,4'-(1H) -quinazolin) Carboxamides; 4- (1,2-Dihydro-2,4-dioxoquinazolin-3 (4H) -yl) -N-((R) -3- (7-methyl-1H-benzo [d] [1, 2,3] triazol-5-yl) -1-oxo-1- (4- (piperidin-1-yl) piperidin-1-yl) propan-2-yl) piperidine-1- Carboxamides; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-isopropyl-piperazin-1 -Yl) -2-oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3 ] Oxazine) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade Photo) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-benzo [d] [1,3] jade Photo) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (piperidine-1- Yl) piperidin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidin-4,4'-1H-quinazolin) -1-carbox amides; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (cyclohex-1-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidine-4,4'-1H-quinazolin) -1-carboxamide; (R) -N-((R) -3- (2-oxo-2,3-dihydro-benzooxazol-6-yl) -1-oxo-1- (4- (prop-2-yl ) Piperazin-1-yl) propan-2-yl) -2,4-dihydro-2'-oxospyro- (piperidine-4,4'-1H-quinazolin) -1-carboxamide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (4-iodo-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; (±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidinyl] -butyramide; (±) -N- (1-benzyl-2-hydroxy-ethyl) -2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo -1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butyramide; (±) -phenyl-acetic acid N '-{2- (7-methyl-1H-indazol-5-ylmethyl) -4-oxo-4- [4- (2-oxo-1,4-dihydro- 2H-quinazolin-3-yl) -piperidin-1-yl] -butyryl} -hydrazide; (±) -1- [1,4 '] bipiperidinyl-1'-yl-4- [4- (8-fluoro-2-oxo-1,4-dihydro-2H-quinazolin-3- Yl) -piperidin-1-yl] -2- (7-methyl-1H-indazol-5-ylmethyl) -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (7-methyl-1H-indazol-5-ylmethyl) -4- [2', 3'-dihydro -2'-oxospyro- (piperidine-4,4'-quinazolin] -butane-1,4-dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- ( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl] -butane-1,4-dione; (±) -1- [1,4 '] bipiperidinyl-1'-yl-2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2' , 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione; (±) -1- (4-cyclohexyl-piperazin-1-yl) -2- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -4- [2 ', 3'-dihydro-2'-oxospyro- (piperidine-4,4'-quinazolin)]-butane-1,4-dione; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-cyclohexyl-piperazin-1 -Yl) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; (±) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- [4- (4-fluoro-phenyl ) -Piperazin-1-yl] -1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid tert-butyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-methyl cyclohexyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid piperidin-4-yl ester; (±) -4- (3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl ) -Piperidine-1-carbonyl] -amino} -propionyloxy) -piperidine-1-carboxylic acid tert-butyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 3,4,5,6-tetrahydro-2H- [1,4 '] bipyridinyl-4-yl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1-diethylamino-1-methyl-ethyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid 1,1-dimethyl-3-phenyl-propyl ester; (±) -3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -pi Ferridine-1-carbonyl] -amino} -propionic acid ethyl ester; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-methyl] -2-oxoethyl] -2 ', 3'-dihydro -2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2-[(2-dimethylamino-ethyl-ethyl carbamoyl) -2-oxoethyl] -2 ', 3' -Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-4-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (±) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1-pyridin-2-yl-piperazinyl] -2-oxoethyl] -1 ', 2'- Dihydro-2'-oxospyro- [4H-3 ', 1-benzoxazine-4,4'-piperidine] -1-carboxamide; (R) -4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1d-carboxylic acid [2- [1,4 '] bipiperidinyl- 1'-yl-1- (7-methyl-1H-indazol-5-ylmethyl) -2-oxo-ethyl] amide; And (R) -1- (7-methyl-1H-indazol-5-ylmethyl) -2- [1,4-bipiperidin] -1-yl-2-oxoethyl] -2 ', 3'- Dihydro-2'-oxospyro- [piperidine-4,4 '-(1H) -quinazolin] -1-carboxamide, or a pharmaceutically acceptable salt or solvate thereof Use in the manufacture of a medicament for the treatment or prevention of migraine headaches. 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-bromo-1H-indazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2-oxo-1- (2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-methyl-piperazin-1-yl) -2 -Oxo-1- (2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2-piperidin-1-yl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1-dimethylcarbamoyl-2- (4-methyl-2- Oxo-2,3-dihydro-benzooxazol-6-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [2- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-yl) -1-dimethylcarbamoyl-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-methyl-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro-2-oxo-2,3-di Hydro-benzooxazol-6-ylmethyl) -2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (4-ethyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-Methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3-methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (3,7-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl) -2-oxo-ethyl] -amide; 4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carboxylic acid [2- [1,4 '] bipiperidinyl-1'-yl -1- (7-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-ylmethyl) -2-oxo-ethyl] -amide; 3- (7-methyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid isopropyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid tert-butyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid cyclohexyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-piperidin-4-yl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 1-methyl-cyclohexyl ester; 3- (7-chloro-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 -Carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester; And 3- (7-ethyl-1H-indazol-5-yl) -2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 Use in the manufacture of a medicament for the treatment or prevention of migraine of a compound selected from the group consisting of -carbonyl] -amino} -propionic acid 4-phenyl-cyclohexyl ester, or a pharmaceutically acceptable salt or solvate thereof.

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