CN1917921A - Calcitonin gene related peptide receptor antagonists - Google Patents

Abstract

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

Description

Calcitonin gene-related peptide receptor antagonist

field of invention

The present invention relates to novel small molecule antagonists of the calcitonin gene-related peptide receptor ("CGRP-receptor"), pharmaceutical compositions containing them, methods of identifying them, methods of using them in therapy, and their use in therapy Neurogenic vasodilation, neurogenic inflammation, migraine, cluster and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory disease (eg, asthma and chronic obstructive pulmonary disease (COPD)) and other conditions that can be treated by CGRP-receptor antagonism.

Background of the invention

Calcitonin gene-related peptide (CGRP) is a naturally occurring 37-amino acid peptide first identified in 1982 (Amara, S.G. et al., Science 1982, 298, 240-244). The peptide is expressed in two forms (αCGRP and βCGRP), which differ by 1 and 3 amino acids in rat and human, respectively. The peptide is widely distributed in both the peripheral nervous system (PNS) and the central nervous system (CNS), is mainly concentrated in sensory afferents and central neurons, and exhibits various biological effects, including vasodilation.

When CGRP is released from cells, CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological effects mainly by activating intracellular adenylyl cyclase (Poyner, DR, etc., Br J Pharmacol 1992 , 105, 441-7; Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8.). Based on the antagonistic properties of the peptide fragment CGRP(8-37) and the ability of linear analogues of CGRP to activate the CGRP ₂ receptor, two classes of CGRP receptors, CGRP ₁ and CGRP ₂ , have been proposed (Juaneda, C. et al., TiPS 2000 , 21, 432-438). However, molecular evidence for the CGRP ₂ receptor is lacking (Brain, SD et al., TiPS 2002, 23, 51-53). The CGRP ₁ receptor has three components: (i) 7 transmembrane calcitonin receptor-like receptors (CRLR); (ii) a single transmembrane receptor activity-modifying protein type 1 (RAMP1); and ( iii) Intracellular receptor component protein (RCP) (Evans BN et al., J Biol Chem. 2000, 275, 31438-43). RAMP1 is required for trafficking of CRLRs to the plasma membrane and for ligand binding 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 in the binding of small molecule antagonists to CGRP-receptors are known, and antagonism with greater affinity for human receptors than for other species is generally observed (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 is responsible for the phenotype of the human receptor (Mallee et al., J Biol Chem 2002, 277, 14294-8).

Inhibitors at the level of the CGRP receptor are speculated to be beneficial in pathophysiological diseases in which excessive activation of the CGRP receptor occurs. Some of these symptoms include neurogenic vasodilation, neurogenic inflammation, migraine, cluster and other headaches, thermal injury, circulatory shock, menopausal flush, and asthma. CGRP receptor activation is related to the pathogenesis of migraine (Edvinsson L.CNS Drugs2001; 15(10):745-53; Williamson, DJMicrosc.Res.Tech.2001, 53, 167-178.; Grant, ADBrit.J. Pharmacol. 2002, 135, 356-362). Serum levels of CGPR are elevated during migraine (Goadsby PJ et al., Ann Neurol 1990;28:183-7), and treatment with anti-migraine drugs restores CGRP levels to normal levels consistent with headache relief (Gallai V . et al., Cephalalgia 1995;15:384-90). Migraine patients exhibit elevated basal CGRP levels compared to controls (Ashina M. et al., Pain. 2000; 86(1-2): 133-8.2000). In migraine patients, intravenous infusion of CGRP caused persistent headache (Lassen LH et al., Cephalalgia. 2002 Feb;22(1):54-61). Preclinical studies in dogs and rats reported that blockade of systemic CGRP (systemic CGRP blockade) with the peptide antagonist CGRP(8-37) did not alter resting systemic hemodynamics, nor did it alter local Blood flow (Shen, YT. et al., J Pharmacol Exp Ther2001, 298, 551-8). Therefore, CGRP-receptor antagonists may represent a new therapeutic approach for migraine that avoids the interaction with non-selective 5-HT _1B/1D agonists "triptans" (such as suma Cardiovascular susceptibility associated with active vasoconstriction.

Various in vivo models of migraine are known in the literature (see De Vries, P et al., Eur J Pharmacol 1999, 375, 61-74). Some models employ electrical stimulation of the trigeminal ganglion followed by measurement of dilation of innervated intracranial vessels (eg, Williamson et al. Cephalalgia 1997 17:518-24). Since facial arteries are also innervated by the trigeminal nerve, other models have studied facial blood flow changes induced by electrical stimulation of the trigeminal nerve (eg, Escott et al. Brain Res 1995 669:93). In addition, other peripheral nerves (eg, saphenous) and vascular beds (eg, abdominal blood flow) have also been studied (eg, Escott et al. Br J Pharmacol 1993 110, 772-6;). It has been shown that all models can be performed with the peptide antagonist CGRP(8-37), a peptide fragment lacking in the first 7 residues, or with a small molecule CGRP-receptor antagonist blocked by pretreatment. In some cases, exogenous CGRP has been used as a stimulant. However, these models are invasive terminal procedures and none have been shown to reverse well-documented arterial dilation or clinically important interruptions in increased blood flow upon post-treatment with CGRP-receptor antagonists sexual influence. Williamson et al. Cephalalgia 1997 17: 518-24, and Williamson et al. Cephalalgia. 1997 17: 525-31: This method involves drilling a thin hole in the skull and creating a closed cranial window to observe the Arterial, intracranial dural artery diameter was increased using extreme 'in vivo' procedures, specifically intravenous CGRP, as a stimulus in pentobarbital-anesthetized rats. Its effect was blocked by pretreatment with i.v. CGRP(8-37). Escott et al. Brain Res 1995 669:93; in particular, holes were drilled in the skull of rats and electrical stimulation of the trigeminal ganglion was performed using brain electrodes, followed by the extreme method ( Including neuromuscular blockade, endotracheal intubation, and artificial ventilation), measuring laser Doppler chamber facial blood flow. This effect was blocked by pretreatment with CGRP(8-37). Escott et al., Br J Pharmacol 1993110, 772-6: Specifically using intradermal (i.d.) CGRP as a stimulant, increasing sodium pentobarb anesthetized animals (equipped with a cannula inserted into the jugular vein for anesthesia) and administration) of rat abdominal skin blood flow. This effect was blocked by pretreatment with i.v. CGRP(8-37). Chu et al., Neurosci Lett 2001 310, 169-72, using especially i.d.CGRP as a stimulus, using the limit method, using sodium pentobarbital anesthetized and intubated animals, measuring laser Doppler chambers in the dorsal skin of rats changes in blood flow; and showed pretreatment blockade by continuous release of CGRP(8-37) from a subcutaneously (s.c.) implanted osmotic pump. Hall et al. Br J Pharmacol 1995 114, 592-7 and Hall et al. Br J Pharmacol 1999 126, 280-4 specifically used CGRP topically to increase the diameter of arterioles in the buccal pouch of hamsters and i.d. CGRP to increase pentobar ratio Blood flow in the dorsal skin of rats in a sodium anesthetized animal equipped with a cannula inserted into the jugular vein for anesthesia and drug administration. This effect was blocked by pretreatment with i.v. CGRP(8-37). Doods et al. Br J Pharmacol. 2000 Feb; 129(3): 420-3 In particular, drilling holes in the skull of marmosets (new world monkeys), and then using brain electrodes to generate electrical stimulation to the trigeminal ganglion, Facial blood flow was measured in pentobarbital-anesthetized primates using minimally invasive methods including neuromuscular blockade and artificial ventilation. The increase in blood flow was blocked by pretreatment with a small molecule CGRP antagonist. See also WO 03/272252 Isolated DNA Molecules Encoding Humanized Calcitonin Gene-Related Peptide Receptor, Related Non-Human Transgenis Animals and Assay Methods (DNA molecules encoding human calcitonin gene-related peptide receptors isolated, related non-human transgenic animals and Analytical method). Thus, the method of the present invention measures exogenous CGRP-induced changes in facial blood flow and demonstrates the effect of peptide and small molecule CGRP antagonists on spontaneous Preconditioning and postconditioning in marmosets anesthetized by inhalational isoflurane, which provides an important advantage in recovering from the procedure.

A number of non-peptide, small molecule CGRP-receptor antagonists have recently been reported. WO 97/09046 and its equivalents disclose inter alia quinine and quinidine-related compounds which are ligands, in particular antagonists, of CGRP-receptors. WO 98/09630 and WO 98/56779 and equivalents disclose inter alia various substituted nitrobenzamide compounds as CGRP-receptor antagonists. WO 01/32649, WO 01/49676 and WO 01/32648 and equivalents disclose in particular a series of 4-oxobutanamides and related cyclopropane derivatives as CGRP-receptor antagonists. WO 00/18764, WO 98/11128 and WO 00/55154 and equivalents disclose inter alia benzimidazolinylpiperidines as CGRP-receptor antagonists. WO 99/52875 and WO 01/25228 and equivalents have disclosed a series of somatostatin antagonists independent of CGRP. Reference is also made to US 6,344,449, US 6,313,097, US 6,521,609, US 6,552,043, US 20030181462, US 20030191068 and WO 03/076432 and equivalents. Therefore, novel CGRP-receptor antagonists that are effective in the treatment of neurogenic inflammation, migraine, and other conditions would be highly beneficial.

Contents of the invention

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

in

V is -N(R ¹ )(R ² ) or OR ⁴ ;

R ⁴ is H, C _1-6 alkyl, C _1-4 haloalkyl or (C _1-4 alkylene) _0-1 R ^4′ .

R ^4' is C _3-7 cycloalkyl, phenyl, adamantly, quinuclidyl, azabicyclo[2.2.1]heptyl, azetidine base, tetrahydrofuryl, furanyl (furanyl), dioxolanyl (dioxolanyl), thienyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, Pyrazolyl, pyrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl , pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and

R ^4' is optionally substituted by 1 or 2 identical or different substituents selected from the following: halogen, 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 benzyl; and

R ^4' optionally contains 1 or 2 carbonyl groups, wherein the carbon atoms of said carbonyl groups are members of the ring structure of R ^4' ;

R ¹ and R ² are each independently L ¹ , wherein L ¹ is selected from: 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, tetrahydrofuryl, furyl, dioxolanyl, thienyl, tetrahydro Thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl , isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, meth olino, thiomorpholino and dioxolanyl; and

R ¹ and R ² are each optionally and independently substituted by 1 or 2 identical or different substituents selected from the following: halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _{1 -4} alkoxy, hydroxyl, amino, C _3-7 cycloalkyl, C _1-3 alkylamino, C _1-3 dialkylamino, (C _1-3 alkyl) _0-2 ureido, benzene base and benzyl;

R ¹ and R ² optionally and independently contain 1 or 2 carbonyl groups, wherein the carbon atoms of the carbonyl groups are members of a heterocyclic ring comprising R ¹ and R ² ;

wherein ^L is optionally and independently interrupted by the nitrogen to which ^L is attached, wherein ^L is independently _C1-3 alkylene or _C1-3 alkylidene; or

^R1 and ^R2 together with the nitrogen to which they are attached form X,

Wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl (azepinyl), diazepine yl, piperazinyl, piperidinyl, morpholino or thiomorpholino;

wherein X is optionally substituted by Y, wherein 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, furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, Pyrrolidinyl (pyrrolidinonyl), imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinyl (imidazolidinonyl), pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, benzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino;

And X and Y are optionally interrupted by Z, where Z is -NHC(O)O-, -NHC(O)NH-, NC(O) _NH2 , -NH-, -C _1-3 alkylene-, - C _1-3 alkylene-, -C _1-3 alkylene (alkenylene)-NHC(O)OC _1-3 alkylene-; and

X and Y are optionally and independently substituted by 1 or 2 identical or different substituents selected from the following: 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, phenyl and benzyl;

X and Y optionally and independently contain 1 or 2 carbonyls, wherein the carbon atoms of said carbonyls are members of a heterocyclic ring containing X and Y;

with the proviso that if X is substituted by Y, and if X and Y are not interrupted by Z, then X and Y optionally share a carbon atom and together form a spiro moiety;

Q is Q' or Q";

where Q' is (S ^y ) _s R ³ ; and

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 ;

Wherein S ^y is C _1-3 alkylene or C _1-3 alkylidene, and s is 0 or 1;

U is _CH2 or NH;

The condition is that if Q is Q", then U is _CH2 ;

R ³ is R ^3a or R ^3b

where R ^3a is

(i) a heterocyclic ring having two fused rings each containing 5-7 members, said heterocyclic ring containing 1-5 identical or different heteroatoms selected from O, N, and S, and the said heterocyclic ring optionally contains 1 or 2 carbonyl groups, wherein the carbon atoms of said carbonyl groups are members of said fused ring;

(ii) a 4-6 membered heterocyclic ring containing 1-3 identical or different heteroatoms selected from O, N and S, said heterocyclic ring optionally containing 1-2 carbonyl groups, wherein the carbon atom of said carbonyl group is a member of said 4-6 membered heterocycle;

(iii) C _3-7 cycloalkyl;

(iv) carbazolyl, fluorenyl, phenyl, -O-phenyl, -OC _1-4 alkylene-phenyl or naphthyl; or

(v) C _1-8 alkyl, C _2-7 alkenyl, -C(O)R ^3' , CHC(O)OR ^3' , CH(CH ₃ )C(O)OR ^3' , -C (O) OR ^3' or C _2-7 alkynyl; and

Wherein R ^3a is optionally substituted by 1-3 identical or different substituents selected from the following: benzyl, phenyl, -O-phenyl, -OC _1-3 alkylene phenyl, -C _1-3 Alkylene-OC(O)-phenyl, cyano, amino, nitro, halogen, C _1-6 alkyl, C _1-3 mono-di-tri-haloalkyl, C _1-3 mono-di-tri -Haloalkoxy, (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' ;

R ^3' is H or -C _1-6 alkyl;

with the proviso that if R ^3a is -C(O)R ^3' , CHC(O)OR ^3' , CH(CH ₃ )C(O)OR ^3' or -C(O)OR ^3' , then said -C (O)R ^3' , CHC(O)OR ^3' , CH(CH ₃ )C(O)OR ^3' or -C(O)OR ^3' are unsubstituted;

R ^3b is R ^3a , but not phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl -1H-indol-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]furan-3-yl, benzo[b]thiophen-3-yl, pyridyl, quinolinyl or isoquinolyl; optionally fluorine, chlorine or bromine atoms on the carbon skeleton or selected Mono-, di- or trisubstituted from the following groups: branched or linear alkyl, C _3-8 -cycloalkyl, phenylalkyl, alkenyl, alkoxy, phenyl, phenylalkane Oxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxyl, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetyl Amino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazole Base, phenyl, pyridyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl- or trifluoromethanesulfonyl;

The substituents described therein can be the same or different, and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups can be further substituted by fluorine, chlorine or bromine atoms in the phenyl part, or by alkyl, Further substitution with trifluoromethyl, amino or acetylamino;

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;

requirement is

If m and n are 0, then A is not N;

if m is 2, then n is not 2; or

if n is 2, then m is not 2;

E is N, CH or C;

p is 0 or 1;

If p is 1, then G, J and E together form A ^x or A ^y ;

^Ax is a fused heterocyclic ring having two fused rings each containing 5-7 members, said heterocyclic ring containing 1-4 same or different heteroatoms selected from O, N and S; And optionally contain 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is a member of the fused heterocycle;

A ^y is a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from O, N and S; and the heterocyclic ring optionally contains 1-2 carbonyl groups, wherein the carbon atom of the carbonyl group is the A member of a 4-6 membered heterocycle;

Wherein A ^x and A ^y are optionally substituted by a group selected from the following groups: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, cyano, C _3-7 cycloalkyl , phenyl, halophenyl, halogen, furyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; or

If p is 0 such that G and J are each attached to A, then A is C and G, J and A together form a spirocyclic ring system having said ring containing A, wherein G, J and A together are GJA' or GJA";

in

GJA′ is A ^x or A ^y ; and

GJA″ is A ^x or A ^y ;

requirement is

A ^x is not a 1,3-diaza-fused heterocycle; and

A ^y is not a 1,3-diaza-heterocycle;

and the further condition is

If Q is Q", ^R3 is ^R3a ; and

If Q is Q' then

R ³ is R ^3b ; or

R ³ is R ^3a , p is 0 and G, J and A together form GJA″.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q' and R ³ is R ^3b .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', R is ^R and ^p is 0, such that G , J and A together form GJA".

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q' and Q' is (S ^y ) _s R ³ and s is 0.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q' and Q' is (S ^y ) _s R ³ , S ^y is C _1-3 alkylene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q' and Q' is (S ^y ) _s R ³ , S ^y is C _1-3 alkylidene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q' and U is _CH2 .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', Q' is (S ^y ) _s R ³ , s is 0 and U is _CH2 .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', Q' is (S ^y ) _s R ³ , S ^y is C _1-3 alkylene, s is 1 and U is CH ₂ .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', Q' is (S ^y ) _s R ³ , S ^y is C _1-3 alkylidene, s is 1 and U is CH ₂ .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q' and U is NH.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', Q' is (S ^y ) _s R ³ , s is 0 and U is NH.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', Q' is (S ^y ) _s R ³ , S ^y is C _1-3 alkylene, s is 1 and U is NH.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', Q' is (S ^y ) _s R ³ , S ^y is C _1-3 alkylidene, s is 1 and U is NH.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention wherein Q is Q".

Another embodiment according to the first aspect of ^the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NH( ^Sy ) _sR3 .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NH(S ^y ) _s R ³ and s is 0.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NH(S ^y ) _s R ³ , ^Sy is C _1-3 alkylene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NH(S ^y ) _s R ³ , ^Sy is C _1-3 alkylidene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)(S ^y ) _s R ³ .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)(S ^y ) _s R ³ and s is 0.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)(S ^y ) _s R ³ , ^Sy is C _1-3 alkylene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)(S ^y ) _s R ³ , ^Sy is C _1-3 alkylidene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)O(S ^y ) _s R ³ .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)O(S ^y ) _s R ³ and s is 0.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)O(S ^y ) _s R ³ , ^Sy is C _1-3 alkylene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)O(S ^y ) _s R ³ , S ^y is C _1-3 alkylidene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)NH(S ^y ) _s R ³ .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)NH(S ^y ) _s R ³ and s is 0.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)NH(S ^y ) _s R ³ , ^Sy is C _1-3 alkylene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q" and Q" is NHC(O)NH(S ^y ) _s R ³ , S ^y is C _1-3 alkylidene and s is 1.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is ^OR4 .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is OR ⁴ and R ⁴ is C _1-6 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ).

Another embodiment according to the first aspect of the present invention provides a compound according to the first embodiment of the first aspect of the present invention, wherein

V is -N(R ¹ )(R ² ) or OR ⁴ ;

R ⁴ is H, C _1-6 alkyl, C _1-4 haloalkyl, (C _1-4 alkylene) _0-1 R ^4'

R ^4' is C _3-7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo[2.2.1]heptyl, azetidinyl, tetrahydrofuryl, furyl, di Oxylanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,  Azolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl , piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and

R ^4' is optionally substituted by 1 or 2 identical or different substituents selected from the following: halogen, 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 benzyl;

R ^4' optionally contains 1 or 2 carbonyl groups, wherein the carbon atoms of said carbonyl groups are members of the R ^4' ring structure;

R ¹ and R ² are each independently L ¹ , wherein L ¹ is selected from: H, C _1-6 alkyl, -C _1-6 alkylene-amino (C _1-3 alkyl) ₂ , C _3-7 Cycloalkyl, phenyl, adamantyl, azetidinyl, tetrahydrofuryl, furyl, dioxolanyl, thienyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazole base, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, Triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; and

R ¹ and R ² are each optionally and independently substituted by 1 or 2 identical or different substituents selected from the following: halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _{1 -4} alkoxy, hydroxyl, amino, C _3-7 cycloalkyl, C _1-3 alkylamino, C _1-3 dialkylamino, (C _1-3 alkyl) _0-2 ureido, benzene base and benzyl;

R ¹ and R ² optionally and independently contain 1 or 2 carbonyl groups, wherein the carbon atoms of the carbonyl groups are members of a heterocyclic ring comprising R ¹ and R ² ;

wherein L is ^optionally interrupted by the nitrogen to which ^L is attached, wherein ^L is C _1-3 alkylene; or

R ^{and R} together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, Azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino;

Wherein X is optionally substituted by Y, wherein 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, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinyl, pyrazole Base, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolinone, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino;

and where X and Y

optionally interrupted by Z, where Z is -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-; and

Optionally and independently substituted by 1 or 2 identical or different substituents selected from the following: 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, phenyl and benzyl;

X and Y optionally and independently contain 1 or 2 carbonyls, wherein the carbon atoms of said carbonyls are members of a heterocyclic ring comprising X and Y;

Provided that if X is substituted by Y, and if X and Y are not interrupted by Z, then X and Y optionally share a carbon atom and together form a spiro moiety.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ⁴ is H, C _1-6 alkyl, C _1-4 haloalkane or (C _1-4 alkylene) _0-1 R ^4' ; R ^4' is C _3-7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo[2.2.1] Heptyl, azetidinyl, tetrahydrofuranyl, furyl, dioxolanyl, thienyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidine Base, pyrazolyl, pyrazolyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and R ^4' is optionally selected from Substituted by 1 or 2 of the following substituents that are the same or different: halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, hydroxyl, amino, C _3-7 Cycloalkyl, C _1-3 alkylamino, C _1-3 dialkylamino, (C _1-3 alkyl) _0-2 ureido, phenyl and benzyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ⁴ is H, C _1-6 alkyl, C _1-4 haloalkane or (C _1-4 alkylene) _0-1 R ^4' ; R ^4' is C _3-7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo[2.2.1] Heptyl, azetidinyl, tetrahydrofuranyl, furyl, dioxolanyl, thienyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidine Base, pyrazolyl, pyrazolyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ⁴ is H, C _1-6 alkyl or (C _1-4 Alkylene) _0-1 R ^4' ; R ^4' is C _3-7 cycloalkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and

R ¹ and R ² are each independently L ¹ , wherein L ¹ is selected from: H, C _1-6 alkyl, -C _1-6 alkylene-amino (C _1-3 alkyl) ₂ , C _3-7 Cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuryl, furyl, dioxolanyl, thienyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazole base, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, Triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolanyl; or

R ^{and R} together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, Azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is substituted by Y, wherein Y is dioxolanyl, C _1-4 alkyl , C _1-4 alkoxy, C _3-7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidonyl, imidazolyl, imidazolinyl, imidazolidine Base, imidazolidinone group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, azepinyl group, diazepinyl group, pyridyl group, pyrimidinyl group, dihydrobenzimidazolinone group, piperazinyl group , piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino;

and wherein X and Y optionally share a carbon atom and together form a spiro moiety.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and

R ¹ and R ² are each independently L ¹ , wherein L ¹ is selected from: H, C _1-6 alkyl, or

^R1 and ^R2 together with the nitrogen to which they are attached form X,

Wherein X is piperidinyl or morpholino;

Wherein X is substituted by Y, wherein Y is dioxolanyl, C _1-4 alkyl or piperidinyl;

and wherein X and Y optionally share a carbon atom and together form a spiro moiety.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and wherein R ¹ and R ² are each independently L ¹ , wherein L ¹ is selected from: H, C _1-6 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and wherein R ¹ and R ² form X together with their attached nitrogen, wherein X is piperidinyl or morpholino; wherein X is substituted by Y, wherein Y is dioxolanyl, C _1-4 alkyl or piperidinyl; and wherein X and Y optionally share a carbon atom and together form a spiro moiety.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and wherein R ¹ and ^R together with the nitrogen to which they are attached form X, where X is piperidinyl; where X is substituted by Y, where Y is piperidinyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and wherein R ¹ and ^R together with the nitrogen to which they are attached form X, wherein X is morpholino; wherein X is substituted by Y, wherein Y is C _1-4 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and 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 by Y, wherein Y is C _1-4 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein V is -N(R ¹ )(R ² ), and wherein R ¹ and ^R together with the nitrogen to which they are attached form X, where X is piperidinyl; where X is substituted by Y, where Y is dioxolanyl; and where X and Y share a carbon atom and together form a spirocycle part.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein X and Y are not interrupted by Z.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein X and Y are not interrupted by Z; and X and Y share a carbon atom, and together form a spiro moiety.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3a .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a has two fused rings and each of said rings contains 5- A 7-membered heterocycle containing 1 to 5 identical or different heteroatoms selected from O, N and S.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a has two fused rings and each of said rings contains 5- A 7-member heterocycle containing 1 to 5 identical or different heteroatoms selected from O, N and S, and optionally containing 1 or 2 carbonyls, wherein the carbonyl Carbon atoms are members of the fused rings.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a has two fused rings and each of said rings contains 5- A 7-member heterocycle containing 1 to 5 identical or different heteroatoms selected from O, N and S, and optionally containing 1 or 2 carbonyls, wherein the carbonyl The carbon atom is a member of the fused ring; wherein R ^3a is optionally substituted by 1-3 identical or different substituents selected from the group consisting of benzyl, phenyl, -O-phenyl, -OC _{1- 3} Alkylphenyl, -C _1-3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halogen, C _1-3 mono-di-tri-haloalkyl, C _1-3 mono -Di-tri-haloalkoxy, 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' ; R ^3' is H or -C _1-6 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is the same group consisting of 1-3 selected from O, N and S or 4-6 membered heterocyclic rings with different heteroatoms.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is the same group consisting of 1-3 selected from O, N and S Or a 4-6 membered heterocyclic ring with different heteroatoms, and optionally containing 1-2 carbonyl groups, wherein the carbon atom of the carbonyl group is a member of the 4-6 membered heterocyclic ring.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is the same group consisting of 1-3 selected from O, N and S Or a 4-6 membered heterocyclic ring of different heteroatoms, and optionally containing 1-2 carbonyls, wherein the carbon atom of said carbonyl group is a member of said 4-6 membered heterocyclic ring; wherein R ^3a is optionally selected from The following 1-3 same or different substituents are substituted: benzyl, phenyl, -O-phenyl, -OC _1-3 alkylphenyl, -C _1-3 alkylene-OC(O)- Phenyl, cyano, amino, nitro, halogen, C _1-3 mono-two-tri-haloalkyl, C _1-3 mono-two-tri-haloalkoxy, 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' ; R ^3' is H or -C _1-6 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is C _3-7 cycloalkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is C _3-7 cycloalkyl; wherein R ^3a is optionally Substituted by 1-3 identical or different substituents selected from the following: benzyl, phenyl, -O-phenyl, -OC _1-3 alkylphenyl, -C _1-3 alkylene-OC(O )-phenyl, cyano, amino, nitro, halogen, C _1-3 mono-di-tri-haloalkyl, C _1-3 mono-di-tri-haloalkoxy, 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' ; R ^3' is H or -C _1-6 alkyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is carbazolyl, fluorenyl, phenyl, -O-benzene -OC _1-4 alkylene-phenyl or naphthyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is carbazolyl, fluorenyl, phenyl, -O-benzene Base, -OC _1-4 alkylene (alklylene)-phenyl or naphthyl; wherein R ^3a is optionally substituted by 1-3 identical or different substituents selected from the following: benzyl, phenyl, -O -Phenyl, -OC _1-3 alkylphenyl, -C _1-3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halogen, C _1-3 mono-di-tri- Haloalkyl, C _1-3 mono-di-tri-haloalkoxy, 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' ; R ^3' is H or -C _1-6 alkane base.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is C _1-8 alkyl, C _2-7 alkenyl , -C(O)R ^3' , -C(O)OR ^3' or C _2-7 alkynyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ^3a is C _1-8 alkyl, C _2-7 alkenyl , -C(O)R ^3' , -C(O)OR ^3' or C _2-7 alkynyl; wherein R ^3a is optionally substituted by 1-3 identical or different substituents selected from the following: benzyl Base, phenyl, -O-phenyl, -OC _1-3 alkylphenyl, -C _1-3 alkylene-OC(O)-phenyl, cyano, amino, nitro, halogen, C _{1- 3} mono-di-tri-haloalkyl, C _1-3 mono-di-tri-haloalkoxy, 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' ; R ^3' is H or -C _1-6 alkyl; provided that if R ^3a is -C(O)R ^3' , CHC(O)OR ^3' , CH(CH ₃ )C(O)OR ^3' or -C(O) OR ^3' , then the -C(O)R ^3' , CHC(O)OR ^3' , CH(CH ₃ )C(O)OR ^3' or -C(O)OR ^3' are unsubstituted of.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3a and R ^3a is phenyl, hydroxyphenyl, Azetidinyl, naphthyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, dihydroquinolinonyl (quinolinonyl), hydrogenated quinolinonyl, quinoline Base, dihydroisoquinolinone, hydrogenated isoquinolinone, isoquinolinyl, dihydroquinazolinonyl (quinazolinonyl), hydrogenated quinazolinone, quinazolinyl, dihydroquinoxaline Keto group (quinoxalinonyl), hydrogenated quinoxalinone group, quinoxalinyl group, benzimidazolyl group, indazolyl group, dihydrobenzimidazolinone group, hydrogenated benzimidazolone group (hydrobenzimidazolonyl), benzimidazoline Base, dihydro-benzothiazolonyl (benzthiazolonyl), hydrogenated benzothiazolonyl, benzothiazolyl, dihydrobenzoxazolyl, benzotriazolyl, dihydrobenzothiophenone (benzothiophenonyl) , Hydrogenated benzothiophenone group, benzothiophenyl group, dihydrobenzofuranone group, hydrogenated benzofuranone group, benzofuryl group, benzodioxolanyl group, indolinone group, indolinyl group Indolyl, indolyl, indolyl, isoindolyl, indolinyl, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, thienyl, pyrrolyl , pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridinyl , piperazinyl or morpholino; which is optionally substituted as specified in the first embodiment of the first aspect.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3a and R ^3a is phenyl, naphthyl, indazole base, benzimidazolyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl, benzodioxolanyl, indolinyl, indolyl, furyl, thiophene Base, pyridyl, purinyl, carbazolyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridyl; which are optionally substituted as specified in the first embodiment of the first aspect .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3a and R ^3a is dihydro-benzothiazolone group, hydrogenated benzothiazolone group, benzothiazolyl group, dihydrobenzothiophene group, hydrogenated benzothiophene group, benzothiophenyl group, dihydrobenzofuranone group, hydrogenated benzofuranone group, benzene Furanyl, indolinyl, indolinyl, indolyl, indolizyl, isoindolyl, indolinyl or indazolyl; it is optionally as in the first aspect What is specified in the first embodiment is substituted.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3a , and R ^3a is dihydrobenzoxazolyl , benzotriazolyl, indolyl, halonitrophenyl, halopyrimidine, halopurinyl, C _1-3 alkyl-nitroaminopyrimidine, triazolopyrimidinyl, pyridyl, indazole radical, phenyl or benzodioxolanyl; which is optionally substituted as specified in the first embodiment of the first aspect.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3a and R ^3a is naphthyl, phenyl-O - phenyl or thienyl; which is optionally substituted as specified in the first embodiment of the first aspect.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b , and R ^3b is

1H-indol-5-yl

1H-Indazol-5-yl

1H-Benzotriazol-5-yl

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

3H-Benzoxazol-2-on-6-yl

1,3-Dihydro-benzimidazol-2-one-5-yl

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

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

1,4-Dihydro-benzo[d][1,3]oxazin-2-on-6-yl

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

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

or

4H-Benzo[1,4]oxazin-3-on-7-yl

Wherein Ty ^is H, C _1-4 alkyl, F, Cl, Br or nitrile.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b and R ^3b is azetidinyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, dihydroquinolinone, hydrogenated quinolinone, dihydroisoquinolinone, hydrogenated isoquinolinone, Dihydroquinazolinone, hydrogenated quinazolinone, quinazolinyl, dihydroquinoxalinone, hydrogenated quinoxalinone, quinoxalinyl, benzimidazole, 1H-indazole- 5-yl, dihydrobenzimidazolinone, hydrogenated benzimidazolone, benzimidazolinyl, dihydro-benzothiazolone, hydrogenated benzothiazolone, benzothiazolyl, dihydrobenzene Buthiphenone, hydrogenated benzothiophenone, dihydrobenzofuranone, hydrogenated benzofuranone, benzodioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, dihydrobenzofuranone Hydroindolinyl, Hydroindolinyl, Indolizyl, Isoindolyl, Indolinyl, Pyrazolyl, Pyrazolinyl, Pyrazolidinyl, Furanyl, Pyrrolyl, Pyrroline Base, pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; it is optionally as in the first embodiment of the first aspect is superseded as specified in .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b , and R ^3b is dihydrobenzimidazolinone group, hydrogenated benzimidazolone group, benzimidazolone group, dihydro-benzothiazolone group, hydrogenated benzothiazolone group, benzothiazolyl group, dihydrobenzothiophene group, hydrogenated benzothiophene group , Dihydrobenzofuranone, hydrogenated benzofuranone, 1H-indazol-5-yl, benzodioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, indoline Indolinyl, indolinyl, indolyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, pyrrolyl, pyrrolinyl, Pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; it is optionally as described in the first embodiment of the first aspect specified is superseded.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b and R ^3b is azetidinyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, dihydroquinolinone, hydrogenated quinolinone, dihydroisoquinolinone, hydrogenated isoquinolinone, Dihydroquinazolinone, hydrogenated quinazolinone, quinazolinyl, dihydroquinoxalinone, hydrogenated quinoxalinone, quinoxalinyl, benzimidazole, 1H-indazole- 5-yl, dihydrobenzimidazolinone, hydrogenated benzimidazolone, benzimidazolinyl, dihydro-benzothiazolone, hydrogenated benzothiazolone, benzothiazolyl, dihydrobenzene Buthiphenone, hydrogenated benzothiophenone, dihydrobenzofuranone, hydrogenated benzofuranone, benzodioxolanyl, dihydrobenzoxazolyl, benzotriazolyl, purine Carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino; which is optionally substituted as specified in the first embodiment of the first aspect.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b and R ^3b is azetidinyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, dihydroquinolinone, hydrogenated quinolinone, dihydroisoquinolinone, hydrogenated isoquinolinone, Dihydroquinazolinone, hydrogenated quinazolinone, quinazolinyl, dihydroquinoxalinone, hydrogenated quinoxalinone, quinoxalinyl, benzimidazolyl, benzodioxolyl Cyclic, dihydrobenzoxazolyl, benzotriazolyl, indolinyl, indolinyl, 1H-indazol-5-yl, indolizyl, isoindolyl, di Indolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl , piperidinyl, piperazinyl or morpholino; which is optionally substituted as specified in the first embodiment of the first aspect.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b and R ^3b is benzodioxolanyl , dihydrobenzoxazolyl, benzotriazolyl, purinyl, carbazolyl; which are optionally substituted as specified in the first embodiment of the first aspect.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein R ³ is R ^3b , and R ^3b is dihydrobenzoxazolyl , benzotriazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C _1-3 alkyl-nitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, 1H-indazol-5-yl, phenyl or benzodioxolanyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', and wherein said compound has the absolute configuration of R.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q', and wherein said compound has the absolute configuration of S.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q", and wherein said compound has the absolute configuration of R.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein Q is Q", and wherein said compound has the absolute configuration of S.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein m and n are each 1 .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein D is O.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein A is C.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein A is CH.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein A is N.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein E is N.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein E is CH.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein E is C.

Another embodiment according to the first aspect of the present invention provides a compound according to the first embodiment of the first aspect of the present invention, wherein said compound exhibits a CGRP binding of less than 10 nM as described herein ( Binding) _IC50 .

Another embodiment according to the first aspect of the present invention provides a compound according to the first embodiment of the first aspect of the present invention, wherein said compound exhibits a CGRP binding of less than 100 nM as described herein ( Binding) _IC50 .

Another embodiment according to the first aspect of the present invention provides a compound according to the first embodiment of the first aspect of the present invention, wherein said compound wherein said compound exhibits a CGRP binding (Binding) IC ₅₀ .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 1; and G, J and E together form ^Ax or ^Ay .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention wherein p is 1; and G, J and E together form ^Ax .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention wherein p is 1; and G, J and E are taken together to form ^Ay .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein ^Ax has two fused rings and each of said rings contains 5- 7-membered fused heterocyclic rings containing 1 to 4 identical or different heteroatoms selected from O, N and S; and optionally containing 1 or 2 carbonyl groups, wherein the carbon atoms of the carbonyl groups are is a member of said fused heterocycle.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein ^Ax has two fused rings and each of said rings contains 5- A 7-membered fused heterocyclic ring containing 1 to 4 identical or different heteroatoms selected from O, N and S.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein ^Ax has two fused rings and each of said rings contains 5- A 7-membered fused heterocyclic ring containing 1 to 4 identical or different heteroatoms selected from O, N and S, and wherein A ^x is substituted by phenyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein ^Ax is a fused heterocycle as described herein.

Another embodiment according to the first aspect of the present invention provides the compound according to the first embodiment of the first aspect of the present invention, wherein A ^y is a hetero containing 1-3 selected from O, N and S atoms; and optionally contain 1-2 carbonyl groups, wherein the carbon atoms of the carbonyl groups are members of the 4-6 membered heterocycle.

Another embodiment according to the first aspect of the present invention provides the compound according to the first embodiment of the first aspect of the present invention, wherein A ^y is a hetero containing 1-3 selected from O, N and S 4-6 membered heterocyclic rings of atoms.

Another embodiment according to the first aspect of the present invention provides the compound according to the first embodiment of the first aspect of the present invention, wherein A ^y is a hetero containing 1-3 selected from O, N and S and optionally containing 1-2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4-6 membered heterocycle; and wherein A ^y is substituted by phenyl.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein ^Ay is a 4-6 membered heterocycle as described herein.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together are GJA' or GJA".

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together are GJA'.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together are GJA".

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J A spirocyclic ring system which together with A forms said ring of said system containing A, and wherein G, J and A together are GJA' and GJA' is ^Ax .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J A spirocyclic ring system which together with A forms said ring of said system containing A, and wherein G, J and A together are GJA', and GJA' is ^Ay .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J A spirocyclic ring system which together with A forms said ring of said system containing A, and wherein G, J and A together are GJA", and GJA" is ^Ax .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together are GJA", and GJA" is ^Ay .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolidinonyl, imidazolidinonyl, dihydroquinoline Keto group, dihydroisoquinolinone group, dihydroquinazolinone group, dihydroquinoxalinone group, dihydrobenzoxazinyl group, hydrogenated benzoxazinyl group, dihydrobenzoxazinone group , Dihydrobenzimidazolinone, dihydrobenzimidazolyl, dihydro-benzothiazolone, dihydrobenzothiazolyl, dihydrobenzothiophenone, dihydrobenzofuranone, two Indolinyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; Wherein the heterocycle is optionally substituted by a group selected from the following groups: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, cyano, C _3-7 cycloalkyl, Phenyl, halogenated phenyl, furyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolidinonyl, imidazolidinonyl, dihydroquinoline Keto group, dihydroisoquinolinone group, dihydroquinazolinone group, dihydroquinoxalinone group, dihydrobenzoxazinyl group, hydrogenated benzoxazinyl group, dihydrobenzoxazinone group , Dihydrobenzimidazolinone, dihydrobenzimidazolyl, dihydro-benzothiazolone, dihydrobenzothiazolyl, dihydrobenzothiophenone, dihydrobenzofuranone, two Indolinyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; Wherein the heterocycle is optionally substituted by a group selected from the following groups: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, cyano, C _3-7 cycloalkyl, Phenyl, halophenyl, furyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolidinonyl, imidazolidinonyl, dihydroquinoline Keto, dihydroisoquinolinone, dihydroquinazolinone, dihydrobenzofuranone, indolinone, indolinyl, pyrazolinyl, pyrazolidinyl, Pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino; wherein the heterocyclic ring is optionally substituted by a group selected from the group consisting of: C _1-4 alkane C _1-4 alkoxy, C _1-4 haloalkyl, cyano, C _3-7 cycloalkyl, phenyl, halophenyl, piperazinyl or morpholino.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolidinonyl, imidazolidinonyl, dihydroquinoline Keto group, dihydroisoquinolinone group, dihydroquinazolinone group, dihydroquinoxalinone group, dihydrobenzoxazinyl group, hydrogenated benzoxazinyl group, dihydrobenzoxazinone group , Dihydrobenzimidazolinone, dihydrobenzimidazolyl, dihydro-benzothiazolone, dihydrobenzothiazolyl, dihydrobenzothiophenone, dihydrobenzofuranone, two Indolinyl, indolinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholino.

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolidinonyl, imidazolidinonyl, dihydroquinoline Keto, Dihydroisoquinolinone, Dihydroquinazolinone, Dihydroquinoxalinone, Dihydrobenzoxazinyl, Hydrogenated benzoxazinyl and Dihydrobenzoxazinonyl .

Another embodiment according to the first aspect of the present invention provides compounds according to the first embodiment of the first aspect of the present invention, wherein p is 0, such that G and J are each linked to A, then G, J and A together form a spirocyclic ring system of said ring of said system containing A, and wherein G, J and A together form a heterocycle selected from the group consisting of imidazolidinonyl, imidazolidinonyl, dihydroquinoline Keto group, dihydroisoquinolinone group, dihydroquinazolinone group, dihydroquinoxalinone group and dihydrobenzoxazinyl group.

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, there is provided the treatment of inflammation (especially neurogenic inflammation), headache (especially migraine) by administering a pharmaceutical composition comprising a compound of formula (I) as defined herein , pain, thermal injury, circulatory shock, diabetes mellitus, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid/cranial hemorrhage, tumor growth, flushing associated with menopause (flushing), and other methods of treating other symptoms that can be achieved through the antagonism of CGRP receptors.

According to various embodiments of the fourth aspect of the present invention, there is provided the use of a compound of the present invention selected from the group consisting of: (a) immunomodulation in the intestinal mucosa, (b) inhibition of protective cardiac hypersensitivity damage effects, (c) stimulation or prevention of interleukin-1b (IL-1b)-stimulated bone resorption, (d) modulation of NK1 receptor expression in spinal cord neurons and (e) airway inflammatory disease and chronic obstructive Lung disease, including asthma. Reference (a) Calcitonin Receptor-Like Receptor Is Expressed on GastrointestinalImmune Cells (calcitonin receptor-like receptor expressed in 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 calcitoningene-related peptide-mediated evodiamine on guinea-pig cardio Anaphylaxis (calcitonin gene-related peptide-mediated protective effect of halonitrogen compounds on cardiac hypersensitivity in guinea pigs). 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 (calcitonin gene-related peptide on interleukin-1-mediated bone resorption Experimental Research). 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) Calcitoningene-related Peptide regulates expression of neurokininl receptors by rat spinalneurons (calcitonin gene-related peptide regulates the expression of neurokinin 1 receptor in rat spinal neurons) .Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG, J.Neurosci.200323(5):1816-1824. epartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and Department of Pharmacology, Toxicology, and , University of Kansas Medical Center, Kansas City, Kansas 66160 (e) Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice (CGRP-deficient mice antigen-induced airway hyperresponsive attenuation). Aoki-Nagase, Tomoko; Nagase , Takahide; Oh-Hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; 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 (as inflammatory mediator Calcitonin gene-related peptide). 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 (drug targeting agents that inhibit neurogenic inflammation). Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolcsauyi, Janos. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung. Current Medicinal Chemistry: Anti-Inflammatory & Anti-Allergy Agents, 2(2003Agents) ( 2), 191-218, incorporated herein by reference in their entirety.

According to various embodiments of the fifth aspect of the present invention, there are provided combinations of compounds of the present invention and one or more drugs selected from the group consisting of COX-2 inhibitors, NSAIDS, aspirin for the treatment of migraine , acetaminophen, triptans, ergotamine, and caffeine.

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

According to a first embodiment of the sixth aspect of the present invention there is provided an in vivo non-limiting method for identifying anti-migraine compounds, said method comprising administering a CGRP-receptor agonist in an amount capable of inducing an increase in blood flow In mammals, the test compound is then administered in an amount capable of reversing the CGRP-induced increase in blood flow, wherein the mammal is a transgenic mammal containing human RAMP1 of Trp74 or an endogenous expression of Trp74. RAMP1 in mammals.

Another embodiment according to the sixth aspect of the present invention provides an in vivo non-limiting method of identifying an anti-migraine compound comprising administering a test compound to a mammal prior to administering a CGRP-receptor agonist , wherein the CGRP-receptor agonist is administered in an amount that induces an increase in blood flow, and wherein the test compound is administered in an amount that inhibits the CGRP-induced increase in blood flow, wherein the lactating Animals are transgenic mammals containing human RAMP1 at Trp74 or mammals endogenously expressing RAMP1 containing Trp74.

Another embodiment according to the sixth aspect of the present invention provides an in vivo non-limiting method of identifying anti-migraine compounds comprising administering a CGRP-receptor agonist in an amount capable of inducing an increase in peripheral arterial diameter In mammals, the test compound is subsequently administered in an amount capable of reversing the CGRP-induced increase in peripheral arterial diameter, wherein the mammal is a transgenic mammal containing human RAMP1 containing Trp74 or endogenous RAMP1 containing Trp74. Mammals expressing RAMP1.

Another embodiment according to the sixth aspect of the present invention provides an in vivo non-limiting method of identifying an anti-migraine compound comprising administering a test compound to a mammal prior to administering a CGRP-receptor agonist , wherein the CGRP-receptor agonist is administered in an amount that induces an increase in peripheral arterial diameter, and wherein the test compound is administered in an amount that inhibits the CGRP-induced increase in peripheral arterial diameter, wherein the Said mammal is a transgenic mammal containing Trp74 human RAMP1 or a mammal containing Trp74 endogenously expressing RAMP1.

Further embodiments according to the sixth aspect of the present invention provide in vivo non-limiting methods of identifying anti-migraine compounds as described herein, wherein said blood flow is facial blood flow.

Further embodiments according to the sixth aspect of the present invention provide in vivo non-limiting methods of identifying anti-migraine compounds described herein, wherein the Trp74-containing mammal endogenously expressing RAMP1 is a non-human primate class animals.

Further embodiments according to the sixth aspect of the present invention provide in vivo non-limiting methods of identifying anti-migraine compounds as described herein, wherein said Trp74-containing mammal endogenously expressing RAMP1 is a human.

Further embodiments according to the sixth aspect of the present invention provide in vivo non-limiting methods of identifying anti-migraine compounds described herein, wherein the Trp74-containing mammal endogenously expressing RAMP1 is a non-human primate and the non-human primate is a marmoset.

Further embodiments according to the sixth aspect of the present invention provide in vivo non-limiting methods of identifying anti-migraine compounds as described herein, wherein said anti-migraine compounds are CGRP-receptor antagonists.

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

Other embodiments of the invention may also include a suitable subclass of the embodiments and/or aspects disclosed herein.

Other embodiments and aspects of the invention will also be apparent from the following description.

Description of drawings

Figure 1. Schild analysis

Dose response of CGRP-stimulated cAMP production in the absence (solid squares) and presence (all other graphs) of increasing concentrations (left to right) of the CGRP antagonist Example 2. Inset is a Schild plot of log dose ratio minus 1 (Y-axis) versus log concentration of antagonist Example 2 (X-axis): slope = 0.94, _Kb = 0.16 nM.

Figure 2. Direct validation of facial blood flow as a surrogate for dilated intracranial arteries in rats.

Intravenous delivery of (iv) hαCGRP induces comparable percentage increases (100-120% of baseline) in rat middle meningeal artery diameter and in rat facial blood flow (striped bars on left and right, respectively. )). Pretreatment with the peptide antagonist CGRP(8-37), followed by iv administration of h[alpha]CGRP, produced 50% inhibition for both measurements (solid bars). Intracranial artery diameter and facial blood flow were measured simultaneously in each animal (n=5 rats). Data are means±sem ^* p<0.05, ^** P<0.01, comparable to the corresponding hαCGRP alone.

Figure 3. Dose-response of 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 non-human primates (eg, common marmosets). Animals (n=6) received increasing doses of hαCGRP at 30 min intervals. Data are peak % change from baseline ± sem, with each animal serving as its own control.

Figure 4. Inhibition of CGRP-induced alterations in facial blood flow in non-human primates.

Administration of hαCGRP (striped bar graph) following delivery of the novel CGRP antagonist Example 2 (solid bar graph) dose-dependently inhibited the CGRP-induced increase in Laser Doppler facial blood flow. The medium (open bar graph) is not valid. Data are mean±sem (n=5-6 primates per group). ^* p<0.05, compared with CGRP administered alone.

Figure 5. Effect of CGRP antagonists on blood pressure in non-human primates.

Compared with the dose-dependent inhibition of primate facial blood flow (see Figure 4.), Example 2 had a negligible effect on blood pressure (mean studies (parallelstudies) were carried out in separate animals, n = 6). Animals received repeated doses of Example 2 at 20 minute intervals. BP data are mean±sem measured by arm cuff over 20 minutes.

Detailed description of the invention

The specification of the invention should be interpreted herein in accordance with the laws and principles of chemical bonding. For example, it is not necessary to remove a hydrogen atom in order to provide a substituent at any given position.

As used herein, "heterocyclic" or "heterocycle" includes cyclic moieties that contain one or more heteroatoms (eg, O, N, or S). Unless otherwise indicated, the heterocycle includes those that are aromatic as well as those that are not aromatic (ie, "cycloaliphatic").

As used herein, when referring to, for example, 5.6-fused bicyclic ring systems containing 1 to 4 nitrogen atoms, the term "fused bicyclic ring system" includes aromatic and alicyclic systems, such as the nitrogen Indene, indole, isoindole, 3H-indole, indoline, indazole or benzimidazole.

If a substituent is named generically, aspects of the invention include any and all species within that genus. For example, a substituent with the generic designation "pyrrolidone" (a group of "pyrrolone", i.e., a pyrrole having a carbonyl group) includes pyrrol-2-onyl (wherein the carbonyl group is adjacent to the nitrogen) and pyrrole-3- Keto (wherein the carbonyl and nitrogen have a methylene group inserted therebetween).

Similarly, unless otherwise indicated, the invention includes substituents which may be attached to any and all suitable points of attachment thereon.

However, it should also be understood that the compounds encompassed by the present invention are those chemically stable compounds, that is, the aliphatic heterocyclic substituents of the present invention should not have the heteroatoms on the aliphatic heterocyclic substituents as the point of attachment. is attached in a manner wherein the point of attachment is also a heteroatom.

An embodiment or aspect dependent on another embodiment or aspect will only describe variables having various numerical values or conditions different from those of the embodiment or aspect to which it depends. For example, if the dependent embodiment describes only ^R2 , then variables and limitations not related to ^R2 should reflect those of the dependent embodiment.

If a variable is represented by the value 0, the key connecting said variable will no longer exist.

As used herein, "alkylene" refers to a divalent alkane, that is, an alkane from which two hydrogen atoms have been removed (or from two different carbon atoms when the alkane contains more than one carbon atom). atom to remove the hydrogen), for example -CH ₂ CH ₂ CH ₂ -.

As used herein, "alkylidene" refers to an alkane having two hydrogen atoms removed from one carbon atom in the alkane, e.g.

It should be understood that the designations of the alternating double bonds on the 6-membered rings in the 5,6-membered fused structures represented in formula (I) are relative and represent the separation of the rings. Domain π orbital electrons.

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

As used herein, "heterocyclic" or "heterocyclyl" includes both heteroaryl and aliphatic heterocyclyl.

As used herein, "halo" or "halogen" includes fluorine, chlorine, bromine and iodine, and also refers to one or more same or different halogens that may be substituted on the respective moieties.

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

It should be understood that, unless otherwise specifically stated in the specification, the present invention may include any and all possible stereoisomers, geometric isomers, diastereomers, enantiomers, anomers and optically active isomer.

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

"Anti-migraine compound" as used herein includes any compound, peptide or peptide fragment (modified or unmodified) capable of reversing or alleviating CGRP-receptor-mediated vasodilation (e.g., CGRP-receptor body antagonists).

"Test compound" as used herein includes any compound, peptide or peptide fragment (modified or unmodified) that is tested to determine whether it is capable of reversing or alleviating CGRP-receptor mediated vasodilation (such as a putative CGRP - receptor antagonists).

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 such as αCGRP or CGRP ; other members of the calcitonin family, such as adrenomedullin; N-terminal CGRP fragments, such as CGRP(1-12) CGRP(1-15) and CGRP(1-22); C-terminal amides of CGRP (NH2 ) variants such as CGRP(1-8+NH2), CGRP(1-13+NH2) or CGRP(1-14+NH2); and non-naturally occurring CGRP analogs such as [Ala ¹ ψ(CH2NH) Cys ² ] hCGRP, which contains a pseudo-peptide bond between Ala ¹ and Cys ² . See Maggi CA, Rovero P, Giuliani S, Evangelista S, Regoli D, Meli A. Biological activity of N-terminal fragments of calcitoningene-related peptide. Eur JPharmacol.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 (specific N-terminal CGRP fragments mitigate rat chronic hypoxic pulmonary hypertension). 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 peripheral and brain tissues (calcitonin gene-related peptide Structure-activity patterns in the peripheral nervous system and brain tissue). Evidence for receptor multiplicity. J Pharmacol Exp Ther. 1989 Nov;251(2):718-25, incorporated herein by reference.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. These salts may include addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, and with organic acids such as acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid. In addition, in the case where the compound of the present invention contains an acidic group, the acidic group may be an alkali metal salt (such as potassium salt and sodium salt); an alkaline earth metal salt (such as magnesium salt and calcium salt); and a compound formed with an organic base. It exists in the form of salts (such as triethylammonium salt and arginine salt). In the case of sublingual formulations, salts of saccharin or maleate may be particularly advantageous. The compounds of the present invention may be hydrated or non-hydrated.

The compounds of the invention can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed 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, all using dosage forms well known to those skilled in the art of pharmacy. The compounds can be administered alone, but will generally be administered with a pharmaceutical carrier selected with regard to the chosen route of administration and standard pharmaceutical practice. The compounds of the invention may also be administered in intranasal form by topical use of suitable intranasal vehicles, or by the transdermal route using transdermal patches. When the compounds of the invention are administered transdermally, the dose is delivered continuously throughout the dosing regimen.

When planning to administer a compound of the invention at 0.01 mg/kg to 30 mg/kg, sound professional judgment must be used in each case and consideration should be given to the recipient's age, weight and symptoms, route of administration, and disease The dose and dosage regimen and administration schedule of the compounds of the invention are carefully adjusted according to the nature and severity of the symptoms. In accordance with good clinical practice, the compounds of the present invention are preferably administered at concentrations that produce an effective beneficial effect without causing any deleterious or undesired side effects.

synthesis

Compounds of the invention can be synthesized according to the general schemes provided below. The definitions of variables provided in the schemes below are as described for the compounds of the above formulas unless otherwise indicated. Compounds of the invention can also be prepared according to Scheme 1 or Scheme 2. It is also possible to prepare compounds of the invention using variations of the described schemes, which variations are well known to those skilled in the art.

Scheme 1. Synthesis of Compounds of Formula I

The synthesis described in Scheme 1 begins with a compound of formula II, which is an amino acid with a protected amino terminus. Common amino protecting groups (PG) include BOC, CBZ, and FMOC, and their addition and removal methods are well known in the art. The carboxylic acid moiety of the compound of formula II is coupled with an amine of formula HNR ¹ R ² using standard peptide coupling reagents to form an amide of formula III. Removal of the amino protecting group affords compounds 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 yield a compound of formula I. Mixed ureas are conveniently formed using phosgene, disuccinimidyl carbonate, carbonyldiimidazole or other equivalents. The formation of isosteres of urea, such as cyanoguanidine and sulfonylguanidine, is known in the literature.

Scheme 2. Synthesis of Compounds 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 end. The protecting group is usually the methyl ester, but other protecting groups such as ethyl, tert-butyl and benzyl esters may also be used. Coupling of a compound of formula V with an amine of formula VIII (see below) in mixed urea or urea isostere reactants yields a compound of formula VI as above. The compound of formula VI is converted to the free acid compound of formula VII, and the acid is then coupled with an amine of formula HNR ¹ R ² to form a compound of formula I.

Scheme 3. Synthesis of Compounds of Formula I

The synthesis described in scheme 3 starts from the compound of formula VII in scheme 2. The compound of formula V is coupled with the alcohol ^R4 -OH. Such ester forming reactions are well known in the art and can be carried out using, for example, a carbodiimide coupling reagent such as N,N-dicyclohexylcarbodiimide. In addition, it is often advantageous, especially for esters of secondary and tertiary alcohols, to include additives which accelerate the acylation reaction, such as 4-dimethylaminopyridine.

Preparation of HNR ¹ R ² and amine of formula VIII

Amines of formula VIII and HNR ¹ R ² are commercially available or can be prepared by literature methods or methods described therein.

Preparation of Amino Acids of Formula II and V

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

Scheme 4. Synthesis of Formula II and Formula V Compounds

The synthesis described in Scheme 4 begins with an aldehyde of formula IX which is reacted with a glycine phosphonate of formula X via Wadsworth-Emmons coupling. Compounds of formula X are deprotonated with a base such as diazabicycloundecene or tetramethylguanidine or other organic or inorganic bases well known in the art. Reduction of the double bond of the resulting compound of formula XI affords the compound of formula XII. This reduction is carried out to give the racemate, or by using a stereoselective catalyst, the enantiomer of formula XII. This reduction can be carried out by transfer hydrogenation with a hydrogen donor such as formic acid or cyclohexadiene, or by hydrogenation with gaseous hydrogen, both in the presence of a suitable catalyst. Compounds of formula II are prepared by acid or base hydrolysis of said esters. Compounds of formula V may be prepared by removal of the protecting group (PG) using methods known in the art.

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

Scheme 5. Synthesis of Formula XII

To achieve Scheme 5, compounds of formula XIV are nucleophilic compounds, such as amines or alcohols, which are capable of participating in the Michael addition reaction shown with compounds of formula XIII.

Other compounds of formula I can be prepared according to Scheme 6 or Scheme 7. It is also possible to prepare compounds of the invention using variations of the described schemes, which variations are well known to those of ordinary skill in the art.

Scheme 6. Synthesis of Compounds of Formula I

The synthesis described in Scheme 6 starts with commercially available or synthesized aldehydes. Homologation of the two carbons and reduction of the double bond are known in the literature to give compounds of formula XV. Some compounds of formula XV are also commercially available, while others can be prepared by other methods well known in the art. The preparation of compounds of formula XVI and XVII as substrates and products of the Evans chiral asymmetric synthesis is known in the literature. Hydrolysis affords compounds of formula XVIII. These carboxylic acids can be reacted with amines of formula ^R1R2NH to provide compounds of formula XIX using well-known amide coupling protocols as ^described for compounds of formula VII in Scheme 2. Hydrolysis of the tert-butyl ester yields a compound of formula XX, which can be further coupled with a compound of formula VIII to yield a compound of formula I.

Scheme 7. Synthesis of Compounds of Formula I

Scheme 7 also starts with commercially available or synthetic aldehydes. Reaction of these aldehydes with dimethyl succinate in the presence of a base affords compounds of formula XXI. Reduction of the double bond of the compound of formula XXI affords the compound of formula XXII. Reduction can be carried out to give the racemate, or by using a stereoselective catalyst to give the enantiomer of formula XXII. This reduction can be carried out by transfer hydrogenation of a hydrogen donor such as formic acid or cyclohexadiene, or by hydrogenation using gaseous hydrogen, both in the presence of a suitable catalyst. Coupling of amides with amines of formula VIII using well known amide synthesis protocols affords compounds of formula XXIII. Hydrolysis of the methyl esters affords compounds of formula XXIV, which are further coupled with various amines or alcohols to afford amides and esters of formula I, respectively.

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

Scheme 8. Synthesis of Compounds of Formula I

The synthesis described in Scheme 8 starts from commercially available benzyl N-tert-butoxycarbonyl-L-aspartate. It can also be conveniently synthesized using various differently protected aspartic acid derivatives. The beta carboxyl group is coupled to the amine of formula VIII using standard peptide coupling protocols. Removal of the α-carboxy protecting group of the compound of formula XXV by hydrogenolysis affords the compound of formula XXVI. Further coupling of these compounds with amines of formula HNR ¹ R ² affords compounds of formula XXVII. The amino protecting group is removed by treatment with a strong acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent. The resulting compound of formula XXVIII is then reacted with various electrophiles to produce compounds of formula I. They can also be coupled with halo-aromatic compounds, for example, using known methods including heating at various temperatures or by catalysis with transition metals such as palladium or copper, either in stoichiometric amounts or as catalysts. They can also be reacted with various aldehydes or ketones under reductive alkylation conditions well described in the art. They can also be reacted with isocyanates, acid chlorides or carbamoyl chlorides to give 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 Compounds of Formula I

The synthesis described in Scheme 9 starts with imines of formula XXIX. The imine is prepared by condensation of ethyl glyoxylate with an amine of formula ^R3 - _NH2 . Reaction of the imine with 2-tert-butoxy-2-oxoethylzinc chloride provides compounds of formula XXX. Removal of the tert-butyl ester protecting group by treatment with a strong acid affords the free acid of formula XXXI, which is coupled with an amine of formula VIII to yield a compound of formula XXXII. Hydrolysis of the ethyl ester with a metal hydroxide salt or an aqueous base provides the α-free acid of formula XXXIII. These free acids are then coupled with amines of formula HNR ¹ R ² to give compounds of formula I.

Urea group intermediates and examples

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

1-Benzyl-2′,3′-dihydro-2′-oxospiro-[piperidine-4,4′(1′H)-quinazoline

Polyphosphoric acid (113g) was heated to 100-110°C and stirred while 1-benzyl-piperidin-4-one (9.27ml, 50mmol) was added. Immediately thereafter, phenylurea (9.55 g, 70. mmol) was added in small portions sufficient to avoid excessive foaming. The mixture was heated at 150-160°C overnight. Water (200 mL) was then slowly added to the mixture and allowed to cool to 100-110 °C (at low temperatures, the mixture became too viscous to stir). The resulting solution was neutralized to pH about 8 with 10N NaOH, and then extracted with chloroform. The organic phase was dried over magnesium sulfate and then concentrated to give the crude product which was purified by flash column chromatography on silica gel (6:4 ethyl acetate/hexanes) to give the desired product (9.0 g, 58%). Mass spectrum: 308.25(MH) ⁺ .

2′,3′-Dihydro-2′-oxospiro-[piperidine-4,4′(1′H)-quinazoline

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

tert-butyl 4-amino-4-cyano-piperidine-1-carboxylate

To a well stirred methanolic solution of tert-butyl 4-oxo-piperidine-1-carboxylate (9.0 g, 45.3 mmol) was added ammonium chloride (2.66 g, 49.8 mmol) at room temperature and stirred for 1 hour . Sodium cyanide (2.44 g, 49.8 mmol) was added and stirring was continued for an additional 16 hours. The reaction mixture was quenched with 5% aqueous sodium bicarbonate (50 mL), diluted with water, and the methanol was removed by rotary evaporation. The cyanoamine was extracted with dichloromethane (3 x 100 mL), dried over sodium sulfate, and the solvent was evaporated to give the desired oily compound in 91% yield.

¹ H-NMR (300MHz, CDCl ₃ ): δ3.95-3.90(m, 1H), 3.80-3.71(m, 1H), 3.42-3.06(m, 2H), 2.04-1.94(m, 1H), 1.71 -1.50 (m, 3H). Mass spectrum: 226 (MH) ⁺ .

2-Phenyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, hydrochloride

To a solution of tert-butyl 4-amino-4-cyano-piperidine-1-carboxylate (1.0 g, 4.44 mmol) in dichloromethane (30 mL) was added triethylamine (1.24 mL, 8.88 mol), followed by Benzoyl chloride (936 mg, 6.66 mmol). After 30 minutes, 4-(dimethylamino)pyridine (40 mg, 0.33 mmol) was added and stirring was continued for a further 12 hours. The reaction mixture was then quenched with 1M sodium hydroxide (10 mL), diluted with ethyl acetate (100 mL), and separated. The organic layer was washed sequentially with 1M sodium hydroxide (40 mL), aqueous sodium bicarbonate (50 mL) and brine (50 mL), then dried over sodium sulfate. Crystallization by using 30% ethyl acetate in hexane as solvent afforded the desired product, tert-butyl 4-benzoylamino-4-cyano-piperidine-1-carboxylate, in 90% yield.

To a solution of tert-butyl 4-benzoylamino-4-cyano-piperidine-1-carboxylate (1.3 g, 4 mmol) in ethanol (10 mL) was added 6M sodium hydroxide (1.5 mL) followed by 30% hydrogen peroxide. The reaction mixture was then refluxed for 3 hours. The reaction mixture was then diluted with water (30 mL), and 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 from 30% ethyl acetate in hexane gave the desired product, 4-oxo-2-phenyl-1,3,8-triaza-spiro[4.5]dec-1- tert-butylene-8-carboxylate. The tert-butyl ester was then dissolved in dichloromethane (5 mL) and saturated hydrogen chloride 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 salt in 95% yield as a white powder.

¹ H-NMR (500MHz, CD ₃ OD): δ8.23-8.21 (m, 2H), 7.96-7.92 (m, 1H), 7.79-7.76 (m, 2H), 3.68-3.64 (m, 3H), 3.31-3.30 (m, 1H), 2.47-2.44 (m, 4H). Mass spectrum: 230 (MH) ⁺ .

tert-Butyl 5-formyl-indazole-1-carboxylate

At room temperature, a solution of di-tert-butyl dicarbonate (388 mg, 1.78 mmol) in dichloromethane (2 mL) was added dropwise to 1H-indazole-5-carbaldehyde (273 mg, 1.87 mmol), 4-dimethylamino Pyridine (114 mg, 0.94 mmol) and triethylamine (0.26 mL, 1.87 mmol) in dichloromethane (10 mL). The resulting bright yellow solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was subjected to silica gel flash chromatography (25 g) using 1% triethylamine in ethyl acetate/hexanes (1:1) as eluent to give the title compound as a tan liquid ( 414 mg, 90%).

¹ H-NMR (CDCl ₃ , 500MHz) δ10.08(s, 1H), 8.38(s, 1H), 8.34(s, 1H), 8.25(d, J=8.5Hz, 1H), 8.04(d, J =8.8Hz, 1H), 1.71(s, 9H). ¹³ CNMR (CDCl ₃ , 125 MHz) δ191.8, 149.0, 142.5, 140.6, 133.0, 128.3, 126.4, 125.8, 115.3, 85.7, 27.8.

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

N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.50 g, 16.6 mmol) and tetramethylguanidine (1.99 mL, 15.9 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL) at -78°C The solution was stirred for 20 minutes. To this solution was slowly added via syringe a solution of tert-butyl 5-formyl-indazole-1-carboxylate (3.72 g, 15.1 mmol) in tetrahydrofuran (25 mL) over a period of 10 minutes. The reaction mixture was stirred at -78°C for 4 hours and then allowed to warm to room temperature overnight. The solvent was evaporated and the resulting residue was subjected to silica gel flash column chromatography (1:2 ethyl acetate/hexane) to give the title compound (5.77 g, 85%) as a white foam.

¹ H-NMR (CDCl ₃ , 500MHz) δ8.09(d, J=9.0Hz, 1H), 8.08(s, 1H), 7.84(s, 1H), 7.67(d, J=9.0Hz, 1H), 7.47 (s, 1H), 7.30 (br s, 5H), 6.43 (br s, 1H), 5.09 (s, 2H), 3.84 (s, 3H), 1.72 (s, 9H). Mass spectrum: 452 (MH) ⁺ .

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

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

¹ H-NMR (CDCl ₃ , 500MHz) δ8.12-8.10 (m, 2H), 7.55 (br s, 1H), 7.37 (dd, J=8.9, 1.5Hz, 1H), 3.77-3.75 (m, 1H ), 3.70 (s, 3H), 3.19 (dd, J=13.7, 5.5Hz, 1H), 2.99 (dd, J=13.7, 8.0Hz, 1H), 1.72 (s, 9H). Mass spectrum: 320 (MH) ⁺ .

(±)-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

At room temperature, tert-butyl 5-(2-amino-2-methoxycarbonyl-ethyl)-indazole-1-carboxylate (307 mg, 0.96 mmol), N, N-disuccinimidyl A solution of carbonate (246 mg, 0.961 mmol) and N,N-diisopropylethylamine (0.67 mL, 3.84 mmol) in dichloromethane was stirred 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 room temperature for 16 hours. The solvent was evaporated and the residue was subjected to flash chromatography using dichloromethane/methanol/triethylamine (93:5:2) as eluent to give the product (259 mg, 47%).

¹ H-NMR (CDCl ₃ , 300MHz) δ8.13-8.10(m, 2H), 7.48(br s, 1H), 7.31(dd, J=8.8, 1.6Hz, 1H), 7.16(t, J=8.0 Hz, 1H), 7.05(d, J=7.0Hz, 1H), 6.94(t, J=7.7Hz, 1H), 6.82(s, 1H), 6.66(d, J=8.0Hz, 1H), 4.98( d, J=7.7Hz, 1H), 4.87-4.81(m, 1H), 4.58-4.49(m, 1H), 4.26(s, 2H), 4.05-3.97(m, 2H), 3.74-3.67(m, 4H), 3.29-3.23 (m, 2H), 2.93-2.84 (m, 2H), 1.76-1.62 (m, 1H), 1.70 (s, 9H), 1.48-1.42 (m, 1H). Mass spectrum: 577 (MH) ⁺ .

2-Trimethylsilyl-ethanesulfonyl chloride

Sulfonyl chloride (43ml, 539mmol) was added to triphenylphosphine (129g, 490mmol) in dichloromethane (200mL) in a flame-dried three-neck round bottom flask over 3 minutes at 0°C in a clear solution. After stirring at 0°C for 5 minutes, the ice-water bath was removed and sodium 2-trimethylsilylethanesulfonate (50 g, 245 mmol) was added portionwise over 10 minutes. The resulting white suspension was stirred at room temperature for 16 hours, then it was filtered through a pad of celite. The filtrate was concentrated to about 50 mL, and ethyl acetate/hexane (1:3, 1000 mL) and celite (40 g) were added. The mixture was stirred at room temperature for 15 minutes and filtered through a pad of celite. The solvent was removed in vacuo and the residue was packed 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 pale brown liquid. If not used immediately, the final product should be stored in a freezer or refrigerator under nitrogen to minimize decomposition.

¹ H-NMR (CDCl ₃ , 500 MHz) δ 3.61-3.57 (m, 2H), 1.32-1.27 (m, 2H), 0.10 (s, 9H).

1-(2-Trimethylsilyl-ethylsulfonyl)-1H-indole-5-carboxylic acid ethyl ester

At 0°C, a solution of ethyl 1H-indole-5-carboxylate (10.31 g, 58.8 mmol) in dimethylformamide (50 mL) was added dropwise to sodium hydride (1.83 g, 76.4 mmol) in dimethyl in formamide (150 mL). The resulting mixture was stirred at 0°C for 30 minutes, then a solution of 2-trimethylsilyl-ethanesulfonyl chloride (17.7 g, 88.2 mmol) in dimethylformamide (100 mL) was slowly added to in the above mixture. After 2 hours, saturated aqueous ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). After separation, the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed on silica gel using 1:1.5 dichloromethane/hexanes as eluent to afford the title compound (15.8 g, 79%) as a white solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ8.36 (d, J=1.5Hz, 1H), 8.03 (dd, J=9.0, 2.0Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 7.50(d, J=3.5Hz, 1H), 6.75(d, J=3.5Hz, 1H), 3.94(s, 3H), 3.21-3.18(m, 2H), 0.84-0.80(m, 2H), - 0.06(s, 9H). ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 167.3, 137.7, 130.3, 128.3, 125.9, 125.5, 124.0, 112.8, 108.3, 52.2, 51.2, 10.1, -2.1. Mass spectrum 354.12 (MH) ⁺ .

Prepare similarly:

1-(2-Trimethylsilyl-ethanesulfonyl)-1H-indazole-5-carboxylic acid ethyl ester

¹ H-NMR (CDCl ₃ , 500MHz) δ8.51(s, 1H), 8.34(s, 1H), 8.21(dd, J=8.9, 1.5Hz, 1H), 8.12(d, J=9.2Hz, 1H ), 3.96(s, 3H), 3.42-3.39(m, 2H), 0.86-0.82(m, 2H), -0.02(s, 9H). ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 166.4, 143.1, 141.2, 130.1, 126.5, 125.0, 124.2, 112.9, 52.5, 51.3, 9.8, -2.1. Mass spectrum 355.13 (MH) ⁺ .

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

A solution of diisobutylaluminum hydride (82.9 mL, 1M in toluene, 82.9 mmol) was slowly added to 1-(2-trimethylsilyl-ethanesulfonyl)-1H-indole-5 at 0°C - in a solution of ethyl carboxylate (8.81 g, 25.9 mmol) in toluene (200 mL). After stirring at 0°C for 45 minutes, the reaction was quenched by the addition of methanol (26 mL), powdered sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed to room temperature over 1 hour and filtered through a pad of celite. The solvent was removed in vacuo to give the title compound as a very viscous liquid which solidified as a white solid on cooling (8.08 g, 100% yield).

¹ H-NMR (CDCl ₃ , 500MHz) δ7.87(d, J=8.5Hz, 1H), 7.62(s, 1H), 7.44(d, J=3.7Hz, 1H), 7.35(dd, J=8.6 , 1.5Hz, 1H), 6.66(d, J=3.7Hz, 1H), 4.79(s, 2H), 3.18-3.14(m, 2H), 1.73(s, 1H), 0.85-0.82(m, 2H) , -0.06(s, 9H). Mass spectrum 312.14 (MH) ⁺ .

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

At 0 °C, ethyl 1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazole-5-carboxylate (dried azeotropically with toluene (2x), 5.77 g, 16.9 mmol) A solution in tetrahydrofuran (50 mL) was added to a mixture of lithium borohydride (3.68 g, 169 mmol) in tetrahydrofuran (100 mL). The mixture was warmed to room temperature and stirred for 14 hours. It was cooled to 0°C and lithium borohydride (3.5 g) was added. The mixture was warmed to room temperature and stirred for 14 hours. It was cooled to 0°C again, 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 eluting with 1% triethylamine in ethyl acetate/hexane (1:1.5) to afford a white The title compound as a solid (3.8 g, 72%).

¹ H-NMR (CD ₃ OD, 500MHz) δ8.41(s, 1H), 8.04(d, J=8.5Hz, 1H), 7.85(s, 1H), 7.61(dd, J=8.5, 1.2Hz, 1H), 4.76(s, 2H), 3.49-3.46(m, 2H), 0.76-0.72(m, 2H), -0.03(s, 9H); ¹³ C-NMR(CD ₃ OD, 125MHz) δ141.2 , 140.9, 138.3, 129.2, 125.8, 119.6, 112.7, 63.8, 50.8, 9.9, -3.2. Mass spectrum 313.12 (MH) ⁺ .

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

[1-(2-Trimethylsilyl-ethanesulfonyl)-1H-indol-5-yl]-methanol (2.1 g, 6.74 mmol) di A solution in methyl chloride (30 mL) was added to a mixture of activated manganese dioxide (22 g, azeotropically dried with toluene (2x)) and dichloromethane (70 mL). The reaction mixture was stirred at 0 °C for 30 min and filtered through a pad of celite. The solvent was removed in vacuo to give the title compound (1.8 g, 80%) as a white solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ10.06(s, 1H), 8.15(s, 1H), 8.01(d, J=8.6Hz, 1H), 7.87(dd, J=8.6, 1.5Hz, 1H ), 7.54(d, J=3.4Hz, 1H), 6.80(d, J=3.6Hz, 1H), 3.24-3.20(m, 2H), 0.86-0.82(m, 2H), -0.06(s, 9H ). ¹³ C-NMR (CDCl ₃ , 125 MHz) δ191.9, 138.5, 132.3, 130.7, 128.8, 125.3, 125.1, 1134.6, 108.4, 51.4, 10.2, -2.1. Mass spectrum 310.12 (MH) ⁺ .

Prepare similarly:

1-(2-Trimethylsilyl-ethanesulfonyl)-1H-indazole-5-carbaldehyde

Mass spectrum 311.10(MH) ⁺ .

2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indol-5-yl]-methyl acrylate

1,1,3,3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added to N-(benzyloxycarbonyl)-α-phosphono (phophono) glycine trimethyl ester (1.88 g, 5.69mmol) in tetrahydrofuran (40mL) solution. The mixture was stirred at room temperature for 15min, and cooled to -78°C, and 1-(2-trimethylsilyl-ethanesulfonyl)-1H-indole-5-carbaldehyde (1.6g, 5.17mmol) was added slowly solution in tetrahydrofuran (15 mL). The resulting reaction mixture was stirred at -78°C for 2 hours and then allowed to warm to room temperature over 3 hours. The solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel using dichloromethane/hexane (1:1.5) containing 1% triethylamine as eluent to give the title compound as 92:8 Z/E Mixture (Z isomer at 3.79 ppm and E isomer _at 3.65 ppm determined by integration of _CO2CH3 ). For the Z isomer: ¹ H-NMR (CD ₃ CN, 500MHz) δ 7.96 (s, 1H), 7.91 (d, J=8.5Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.56(d, J=3.7Hz, 1H), 7.51(s, 1H), 7.43-7.35(m, 5H), 7.67(d, J=3.7Hz, 1H), 5.16(s, 2H), 3.79(s , 3H), 3.42-3.38 (m, 2H), 0.87-0.83 (m, 2H), -0.04 (s, 9H). Mass spectrum 515.20 (MH) ⁺ .

Prepare similarly:

2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-methyl acrylate

Flash chromatography on silica gel using 1% triethylamine in dichloromethane as eluent afforded the title compound as a 95:5 Z/E mixture via -CH=C(CO ₂ Me)(NHCBz) Integration confirmed, 3.72 g, 92%). For the Z isomer: ¹ H-NMR (CD ₃ CN, 500MHz) δ8.39(s, 1H), 8.12(s, 1H), 8.03(d, J=8.8Hz, 1H), 7.84(dd, J =8.8, 1.2Hz, 1H), 7.51(s, 1H), 7.43-7.35(m, 5H), 5.14(s, 2H), 3.81(s, 3H), 3.51-3.47(m, 2H), 0.83- 0.79 (m, 2H), -0.02 (s, 9H). Mass spectrum 516.18 (MH) ⁺ .

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

To a flame-dried 500 mL round bottom flask was added 2-benzyloxycarbonylamino-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indol-5-yl]-methacrylate Ester (2.24 hours, 4.36 mmol), methanol (100 mL) and 10% palladium on charcoal (0.52 g). The mixture was degassed and purged five times with hydrogen. It was stirred at room temperature for 1 hour and filtered through a pad of celite. The solvent was removed and the residue was treated by flash chromatography using 1% triethylamine in ethyl acetate/hexanes (1:1 and 2:1) to give the title compound as a colorless viscous liquid (1.27 g, 76%), which solidified after cooling.

¹ H-NMR (CD ₃ CN, 500MHz) δ7.82(d, J=8.2Hz, 1H), 7.51-7.49(m, 2H), 7.22(dd, J=8.6, 1.5Hz, 1H), 6.72( d, J=3.7Hz, 1H), 3.70(dd, J=7.3, 6.1Hz, 1H), 3.65(s, 3H), 3.38-3.34(m, 2H), 3.08(dd, J=13.4, 5.8Hz , 1H), 2.95 (dd, J = 13.4, 7.3 Hz, 1H), 0.82-0.79 (m, 2H), -0.05 (s, 9H). ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 176.0, 134.4, 133.4, 131.1, 127.9, 126.4, 122.4, 113.1, 107.7, 56.6, 51.7, 50.8, 41.3, 10.1, -2.7. Mass spectrum 383.16 (MH) ⁺ .

Prepare similarly:

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

¹ H-NMR (CD ₃ CN, 500MHz) δ8.34(s, 1H), 7.98(d, J=8.6Hz, 1H), 7.69(s, 1H), 7.46(dd, J=8.6, 1.5Hz, 1H), 3.71(dd, J=7.3, 5.8Hz, 1H), 3.65(s, 3H), 3.48-3.44(m, 2H), 3.12(dd, J=13.7, 5.8Hz, 1H), 2.97(dd , J=13.7, 7.6Hz, 1H), 0.83-0.79(m, 2H), -0.02(s, 9H). ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 175.9, 141.1, 140.5, 134.6, 131.5, 126.0, 122.2, 112.7, 56.4, 51.8, 51.1, 40.9, 9.8, -2.6. Mass spectrum 384.15 (MH) ⁺ .

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

A ^AIRFREE (R) (Schlenk) reaction flask equipped with a stirrer, sealed with a rubber septum, was charged with (- )-1,2-bis((2R,5R)-2,5-diethylphospholanoyl (phospholano))benzene(cyclooctadiene)rhodium(I) triflate (123 mg, 0.17mmol, 5mol%), and removed from the glove bag. 2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-methyl acrylate (1.75 g, 3.40 mmol) was weighed , into a second AIRFREE ^(R) (Schlenk) reaction flask equipped with a stir bar and sealed with a rubber septum. After 3 vacuum/nitrogen purge cycles, it was dissolved in a mixture of anhydrous methanol (75 mL) and anhydrous dichloromethane (15 mL). Both solvents were deoxygenated, then nitrogen was added by sparging for at least 1 hour. In this solution, the mixture was again subjected to 3 vacuum/nitrogen purge cycles. The dehydroamino acid solution was introduced through a canula into an AIRFREE( ^R ) (Schlenk) reaction flask containing the catalyst. The reaction mixture was subjected to 5 vacuum/hydrogen purge cycles, then the flask was opened to dock with 1 atmosphere of hydrogen (balloon). After 16 hours, the reaction mixture was subjected to 3 vacuum/nitrogen purge cycles. The solvent was evaporated and the residue was subjected to column chromatography (gradient 1:4 ethyl acetate/hexanes to 1:2 ethyl acetate/hexanes) to afford 1.5 g (85%) of the title compound as a white solid which was washed by 98.4% enantiomer determined by HPLC analysis using a Chirocel OD column with 80% hexane/20% ethanol as eluent (retention time: 13.9 min for the title compound, 11.2 min for the S-enantiomer) Excess (ee).

¹ H-NMR (CDCl ₃ , 300MHz) δ8.17(s, 1H), 7.98(d, J=8.8Hz, 1H), 7.47(s, 1H), 7.35-7.25(m, 6H), 5.29-5.24 (m, 1H), 5.08(dd, J=19.0, 12.1Hz, 2H), 4.73-4.67(m, 1H), 3.73(s, 3H), 3.38-3.32(m, 2H), 3.29(dd, J =14.2, 5.6Hz, 1H), 3.19(dd, J=13.9, 5.6Hz, 1H), 0.91-0.85(m, 2H), -0.02(s, 9H). Mass spectrum: 518 (MH) ⁺ .

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

(R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl A mixture of ]-methyl propionate (1.24 g, 2.40 mmol) and 10% palladium on carbon (124 mg) in methanol (50 mL) was vigorously stirred for 2 hours. The reaction mixture was purged through 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. Evaporation of the methanol filtrate gave 879 mg (96%) of the title compound as a sticky gum.

¹ H-NMR (CDCl ₃ , 300MHz) δ8.21(s, 1H), 8.02(d, J=8.8Hz, 1H), 7.59(s, 1H), 7.38(d, J=8.8Hz, 1H), 3.72(s, 3H), 3.38-3.32(m, 2H), 3.21(dd, J=13.9, 5.1Hz, 1H), 2.98(dd, J=13.9, 7.9Hz, 1H), 0.91-0.85(m, 2H), -0.02(s, 9H). Mass spectrum: 384 (MH) ⁺ .

7-Methyl-2-(2-trimethylsilyl-ethanesulfonyl)-2H-indazole-5-carbaldehyde

To a suspension of 7-methylindazole 5-carbaldehyde (3.0 g, 18.7 mmol) in dichloromethane (150 mL) was added triethylamine (7.83 mL, 56.2 mL, 3 equivalents), followed by dropwise addition of Pure 2-trimethylsilyl-ethanesulfonyl chloride (5.60 g, 28.1 mmol, 1.5 equiv). The mixture gradually became homogeneous and was stirred at room temperature for 16 hours. The solution was concentrated to a minimum of dichloromethane and then subjected to flash column chromatography on silica gel (1 :4 ethyl acetate/hexanes) to give the product 4.7 g (77%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 300MHz) δ9.98(s, 1H), 8.77(s, 1H), 8.09(s, 1H), 7.64(s, 1H), 3.64-3.58(m, 2H), 2.65 (s, 3H), 0.88-0.82 (m, 2H), 0.01 (s, 9H).

2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilyl-ethanesulfonyl)-2H-indazol-5-yl]-methyl acrylate

To a solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (4.93 g, 14.9 mmol, 1.1 equiv) in dry tetrahydrofuran (75 mL) was added tetramethylguanidine (1.78 mL, 1.05 equiv). The mixture was stirred at room temperature under nitrogen for 5 min, and then cooled to -78 °C. After stirring at -78°C for 15 min, a solution of 7-methyl-2-(2-trimethylsilyl-ethanesulfonyl)-2H-indazole-5-carbaldehyde in tetrahydrofuran (25 mL) was added. The reaction mixture was allowed to warm slowly to room temperature overnight. Even if the reaction was not complete, the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and washed with 1M sulfuric acid. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Flash column chromatography (1:4 ethyl acetate/hexanes) afforded 2.66 g (37%) of product as a white foam glass.

¹ H-NMR (CDCl ₃ , 300MHz) δ8.48(s, 1H), 7.62(s, 1H), 7.38-7.25(m, 7H), 6.48(bs, 1H), 5.10(s, 2H), 3.83 (s, 3H), 3.58-3.52 (m, 2H), 2.51 (s, 3H), 0.89-0.83 (m, 2H), 0.02 (s, 9H). Mass spectrum: 530 (MH) ⁺ .

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

A ^AIRFREE (R) (Schlenk) reaction flask equipped with a stir bar, sealed with a rubber septum, was charged with (-)-1 in a glove bag subjected to 3 vacuum/nitrogen purge cycles. , 2-bis((2R,5R)-2,5-diethylphosphorolyl)benzene(cyclooctadiene)rhodium(I) triflate (259mg, 0.36mmol, 9mol-% ), and remove from the glove bag. 2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilyl-ethanesulfonyl)-2H-indazol-5-yl]-acrylate methyl ester (2.03g, 3.83 mmol) was weighed and added to a second AIRFREE( ^R ) (Schlenk) reaction flask equipped with a stir bar and sealed with a rubber septum. After 3 vacuum/nitrogen purge cycles, it was dissolved in anhydrous methanol (80 mL, deoxygenated, then nitrogen was added by sparging for at least 1 h). In this solution, the mixture was again subjected to 3 vacuum/nitrogen purge cycles. The dehydroamino acid solution was transferred via cannula to an AIRFREE( ^R ) (Schlenk) reaction flask containing the catalyst. The reaction mixture was subjected to 5 vacuum/hydrogen purge cycles before the flask was opened to dock a balloon of hydrogen (1 atm). After 2.5 hours, the reaction mixture was subjected to 3 vacuum/nitrogen purge cycles. The solvent was evaporated and the residue was subjected to column chromatography (gradient 1:4 ethyl acetate/hexane to 1:2 ethyl acetate/hexane) to afford 1.4 g (68%; ee=99.2%) of a white solid the title compound.

¹ H-NMR (CDCl ₃ , 300MHz) δ8.43(s, 1H), 7.34(s, 5H), 7.19(s, 1H), 6.87(s, 1H), 5.24(d, J=8.1Hz, 1H ), 5.08(dd, J=18.3, 12.1Hz, 2H), 4.67(dd, J=13.9, 6.2Hz, 1H), 3.73(s, 3H), 3.57-3.51(m, 2H), 3.16(dd, J = 14.0, 5.9 Hz, 1H). 3.06 (dd, J = 13.9, 6.6 Hz, 1H), 2.55 (s, 3H), 0.89-0.83 (m, 2H), 0.01 (s, 9H). ¹³ C-NMR (CDCl ₃ , 75MHz) δ172.0, 155.7, 151.7, 136.2, 132.2, 129.8, 129.5, 128.6, 128.4, 128.2, 125.1, 121.1, 118.1, 67.1, 54.7, 52.5, 51.1, 38.6, 17.1, 9.7, -2.0. Mass spectrum: 532 (MH) ⁺ .

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

Using a Parr apparatus, 2-benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilyl-ethanesulfonyl)-2H-indazol-5-yl] under 55 psi hydrogen - Methyl propionate (1.35 g, 2.54 mmol) and 10% palladium on carbon (135 mg) were shaken in methanol (40 mL) for 3.0 hours. The reaction mixture was purged through 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. Evaporation of the methanol filtrate gave the title compound (1.01 g, quantitative yield) as a sticky gum.

¹ H-NMR (CDCl ₃ , 300MHz) δ8.45(s, 1H), 7.29(s, 1H), 6.97(s, 1H), 3.79-3.73(m, 1H), 3.73(s, 3H), 3.56 -3.50(m, 2H), 5.12(dd, J=13.5, 5.12Hz, 1H), 4.85(dd, J=13.5, 8.1Hz, 1H), 2.58(s, 3H), 0.87-0.81(m, 2H ), 0.01(s, 9H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ175.5, 151.8, 133.7, 129.9, 129.4, 125.0, 121.3, 117.9, 55.5, 52.1, 51.1, 41.4, 17.1, 9.8, -2.1. Mass spectrum: 398 (MH) ⁺ .

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

At room temperature, 2-amino-3-[7-methyl-2-(2-trimethylsilyl-ethanesulfonyl)-2H-indazol-5-yl]-propionic acid methyl ester (500 mg, A mixture of 1.26 mmol), N,N-diisopropylethylamine (0.66 mL, 3.77 mmol) and disuccinimidyl carbonate (322 mg, 1.26 mmol) was stirred together in dichloromethane (20 mL) for 30 min. Then, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (444 mg, 1.35 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was subjected to flash column chromatography (1:4 acetone/ethyl acetate) to afford 490 mg (60% yield) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300MHz) δ8.47(s, 1H), 7.23(s, 1H), 7.19-7.14(m, 1H), 7.04(d, J=7.3Hz, 1H), 6.97-6.93 (m, 2H), 6.77(s, 1H), 6.65(d, J=7.7Hz, 1H), 4.99(d, J=7.3Hz, 1H), 4.81(dd, J=13.5, 6.2Hz, 1H) , 4.58-4.46(m, 1H), 4.27(s, 2H), 4.10-3.98(m, 2H), 3.73(s, 2H), 3.57-3.51(m, 2H), 3.14-3.11(m, 2H) , 2.95-2.83 (m, 2H), 2.58 (s, 3H), 1.77-1.65 (m, 4H), 0.92-0.84 (m, 2H), -0.01 (s, 9H). Mass spectrum: 655 (MH) ⁺ .

Prepare similarly:

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

¹ H-NMR (CD ₃ OD, 500MHz) δ7.85(d, J=8.2Hz, 1H), 7.55(s, 1H), 7.51(d, J=3.7Hz, 1H), 7.27(dd, J= 8.6, 1.5Hz, 1H), 7.16(t, J=7.6Hz, 1H), 7.10(d, J=7.6Hz, 1H), 6.95(t, J=7.6Hz, 1H), 6.79(d, J= 8.0Hz, 1H), 6.73(d, J=3.7Hz, 1H), 4.44-4.38(m, 1H), 4.26(s, 2H), 4.13-4.08(m, 2H), 3.73(s, 3H), 3.34-3.29(m, 4H), 3.13(dd, J=13.5, 9.4Hz, 1H), 2.89-2.79(m, 2H), 1.76-1.70(m, 1H), 1.63-1.59(m, 3H), 0.76-0.72 (m, 2H), -0.07 (s, 9H); mass spectrum: 640.40 (MH) ⁺ .

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

(R)-2-Amino-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester (764mg, 1.99 mmol), N,N-diisopropylethylamine (1.10 mL, 5.97 mmol) and disuccinimidyl carbonate (509 mg, 1.99 mmol) in dichloromethane (20 mL) was stirred for 40 min. 3-Piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (70% purity, 703 mg, 2.13 mmol) was then added at room temperature and the reaction mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was subjected to flash column chromatography (1:4 acetone/ethyl acetate) to afford 1.15 g (90%) of the title compound.

¹ H-NMR (CDCl ₃ , 300MHz) δ8.21(s, 1H), 8.01(d, J=8.5Hz, 1H), 7.53(s, 1H), 7.32(d, J=8.5Hz, 1H), 7.16(t, J=7.8Hz, 1H), 7.06(d, J=7.6Hz, 1H), 6.95(d, J=7.6Hz, 1H)1, 6.76(s, 1H), 6.65(d, J= 7.9Hz, 1H), 5.01(d, J=7.6Hz, 1H), 4.84(dd, J=13.1, 6.0Hz, 1H), 4.56-4.49(m, 1H), 4.28(s, 2H), 4.13- 3.98(m, 2H), 3.73(s, 3H), 3.39-3.35(m, 2H), 3.28(dd, J=14.0, 6.1Hz, 1H), 3.24(dd, J=13.7, 5.8Hz, 1H) , 2.94-2.87 (m, 2H), 1.75-1.67 (m, 4H), 0.91-0.87 (m, 2H), -0.02 (s, 9H). Mass spectrum: 641 (MH) ⁺ .

Prepare similarly:

(±)-2-{[4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2 -Trimethylsilyl-ethylsulfonyl)-1H-indol-5-yl]-propionic acid methyl ester

¹ H-NMR (CD ₃ CN, 500MHz) δ9.78(s, 1H), 7.86(d, J=8.5Hz, 1H), 7.56(s, 1H), 7.49(d, J=3.7Hz, 1H) , 7.28(dd, J=8.5, 1.5Hz, 1H), 7.10-7.08(m, 1H), 7.05-7.03(m, 1H), 6.99-6.97(m, 2H), 6.70(d, J=3.7Hz , 1H), 5.91(d J=7.9Hz, 1H), 4.66(q, J=8.2Hz, 1H), 4.45-4.39(m, 1H), 4.14(br s, 1h), 3.68(s, 3H) , 3.36-3.32(m, 2H), 3.27(dd, J=14.0, 5.5Hz, 1H), 3.18(dd, J=13.7, 8.5Hz, 1H), 2.90-2.84(m, 2H), 2.55(br s, 1H), 2.36-2.21 (m, 2H), 1.74-1.70 (m, 2H), 0.82-0.78 (m, 2H), -0.09 (s, 9H). Mass spectrum 626.26 (MH) ⁺ .

(±)-2-{[4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2 -Trimethylsilyl-ethylsulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester

¹ H-NMR (CD ₃ CN, 500MHz) δ9.61(br s, 1H), 8.35(s, 1H), 8.00(d, J=8.5Hz, 1H), 7.74(s, 1H), 7.51(dd , J=8.8, 1.5Hz, 1H), 7.10-7.06(m, 1H), 7.05-7.02(m, 1H), 7.00-6.97(m, 2H), 5.90n(d, J=7.9Hz, 1H) , 4.674.62(m, 1H), 4.42-4.36(m, 1H), 4.13-4.07(br s, 1H), 3.68(s, 3H), 3.45-3.42(m, 2H), 3.30(dd, J =14.0, 5.8Hz, 1H), 3.20(dd, J=13.7, 8.8Hz, 1H), 2.89-2.84(m, 2H), 2.52(br s, 1H), 2.33-2.23(m, 2H), 1.72 -1.69 (m, 2H), 0.80-0.76 (m, 2H), -0.07 (s, 9H). Mass spectrum 627.25 (MH) ⁺ .

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

¹ H-NMR (CD ₃ OD, 500MHz) δ7.85(d, J=8.2Hz, 1H), 7.55(s, 1H), 7.51(d, J=3.7Hz, 1H), 7.27(dd, J= 8.6, 1.5Hz, 1H), 7.16(t, J=7.6Hz, 1H), 7.10(d, J=7.6Hz, 1H), 6.95(t, J=7.6Hz, 1H), 6.79(d, J= 8.0Hz, 1H), 6.73(d, J=3.7Hz, 1H), 4.44-4.38(m, 1H), 4.26(s, 2H), 4.13-4.08(m, 2H), 3.73(s, 3H), 3.34-3.29(m, 4H), 3.13(dd, J=13.5, 9.4Hz, 1H), 2.89-2.79(m, 2H), 1.76-1.70(m, 1H), 1.63-1.59(m, 3H), 0.76-0.72 (m, 2H), -0.07 (s, 9H). Mass spectrum 640.40 (MH) ⁺ .

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

¹ H-NMR (CD ₃ OD, 500MHz) δ8.39(d, J=0.5Hz, 1H), 8.02(d, J=8.5Hz, 1H), 7.75(s, 1H), 7.52(dd, J= 8.5, 1.5Hz, 1H), 7.14-7.10(m, 2H), 6.94(t, J=7.5Hz, 1H), 6.78(d, J=7.5Hz, 1H), 4.63-4.60(m, 1h), 4.43-4.37(m, 1H), 4.27(s, 2H), 4.11(br s, 1H), 4.08(br s, 1H), 3.71(s, 3H), 3.47-3.43(m, 2H), 3.37- 3.33(m, 1H), 3.18(dd, j=13.5, 10.0Hz, 1H), 2.87-2.79(m, 2H), 1.73-1.59(m, 4H), 0.80-0.75(m, 2H), -0.05 (s, 9H); ¹³ C-NMR (CD ₃ OD, 125MHz) δ173.7, 155.5, 158.1, 141.0, 140.6, 137.2, 134.4, 131.3, 128.2, 126.1, 125.8, 122.2, 121.9, 118.3, 113.4, 112.6 , 55.9, 52.1, 51.7, 50.8, 48.9, 48.6, 48.4, 48.2, 48.0, 47.9, 47.7, 47.5, 43.8, 43.7, 43.1, 37.2, 28.5, 9.8, -3.2. Mass spectrum: 641.40 (MH) ⁺ .

Example 1

(±)-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)-piper A solution of pyridine-1-carbonyl]-amino}-ethyl)-indazole-1-carboxylic acid tert-butyl ester (168 mg, 0.29 mmol) was cooled to 0 °C in methanol (5 mL). An aqueous solution (5 mL) of lithium hydroxide monohydrate (49 mg, 2.04 mmol) 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). The pH of the aqueous solution was adjusted to about 1 with 1N hydrochloric acid. The precipitated white solid was collected by filtration. The solid was dried in vacuo to give the title compound (108 mg, 80%).

¹ H-NMR (DMSO-d ₆ , 300MHz) δ12.94(bs, 1H), 9.19(s, 1H), 8.01(s, 1H), 7.61(s, 1H), 7.46(d, J=8.4Hz , 1H), 7.28(dd, J=8.5, 1.5Hz, 1H), 7.13-7.06(m, 2H), 6.86(t, J=7.0Hz, 1H), 6.76-6.72(m, 2H), 4.32- 4.24 (m, 2H), 4.09-4.02 (m, 4H), 3.17-2.97 (m, 2H), 2.72-2.59 (m, 2H), 1.57-1.35 (m, 4H). IR (KBr, cm-1) 3424, 2963, 2930, 1660, 1628, 1505, 1474, 1446, 753. Mass spectrum: 463 (MH) ⁺ .

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

(R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1 A solution of -(2-trimethylsilyl-ethylsulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester (775 mg, 1.21 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was cooled to 0°C. An aqueous solution (3 mL) of lithium hydroxide monohydrate (115 mg, 4.84 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours and then placed in a -15°C freezer for 16 hours. While cooling the reaction mixture with an ice bath, the pH was increased to about 7 by adding 1N hydrochloric acid (3.8 mL). The organic solvent was removed in vacuo. After adding more 1N hydrochloric acid (0.5 mL), the resulting aqueous solution was extracted 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.

¹ H-NMR (DMSO-d ₆ , 300MHz) δ9.21(s, 1H), 8.58(s, 1H), 7.90(d, J=8.4Hz, 1H), 7.78(s, 1H), 7.56(d , J=8.1Hz, 1H), 7.13-7.09(m, 2H), 6.88-6.83(m, 1H), 6.76-6.74(m, 2H), 4.33-4.27(m, 2H), 4.18(s, 2H ), 4.09-3.96(m, 3H), 3.57-3.51(m, 2H), 3.25-3.04(m, 2H), 2.74-2.60(m, 2H), 1.54-1.43(m, 4H), 0.70-0.64 (m, 2H), -0.08 (s, 9H). Mass spectrum: 627 (MH) ⁺ .

Prepare similarly:

(±)-2-{[4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2 -Trimethylsilyl-ethylsulfonyl)-1H-indol-5-yl]-propionic acid

Mass spectrum 612.25 (MH) ⁺ .

(±)-2-{[4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2 -Trimethylsilyl-ethylsulfonyl)-1H-indazol-5-yl]-propionic acid

Mass spectrum 613.26 (MH) ⁺ .

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

¹ H-NMR (CD ₃ CN, 500MHz) δ8.37(s, 1H), 8.08(s, 1H), 8.01(d, J=8.5Hz, 1H), 7.77(s, 1H), 7.53(dd, J=8.5, 1.5Hz, 1H), 7.19(t, J=7.3Hz, 1H), 7.14(d, J=7.3Hz, 1H), 6.98(td, j=7.6, 1.2Hz, 1H), 6.79( d, j=8.0Hz, 1H), 6.28(br s, 3H), 4.54-4.49(m, 1H), 4.37-4.32(m, 1H), 4.30(s, 2H), 3.98-3.92(m, 2H ), 3.45-3.41(m, 2H), 3.37(dd, j=14.0, 4.9Hz, 1H), 3.20(dd, J=14.0, 9.7Hz, 1H), 2.84-2.77(m, 2H), 1.65- 1.57 (m, 4H), 0.79-0.76 (m, 2H), -0.05 (s, 9H). Mass spectrum: 627.30 (MH) ⁺ .

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

To (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1 -(2-Trimethylsilyl-ethylsulfonyl)-1H-indazol-5-yl]-propionic acid (554mg, 0.88mmol) and N,N-diisopropylethylamine (0.62mL, 3.54mmol ) in dichloromethane (20 mL) was added 4-piperidino piperidine (164 mg, 0.97 mmol) and PyBOP ^(R) (460 mg, 0.88 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 16 hours. It was then concentrated to about 2 mL and subjected to flash column chromatography using dichloromethane/methanol/triethylamine (94:5:1 ) as eluent to afford 599 mg (87%) of the title compound as a white solid.

¹ H-NMR (CD ₃ CN, 300MHz) δ8.37(s, 0.5H), 8.36(s, 0.5H), 8.02-7.96(m, 1H), 7.74(s, 0.5H), 7.71(s, 0.5H), 7.55-7.46(m, 1H), 7.21-7.12(m, 2H), 6.97-6.92(m, 1H), 6.79(d, J=8.1Hz, 1H), 5.71(t, J=8.1 Hz, 1H), 5.00(dd, J=15.0, 8.1Hz, 1H), 4.63-4.51(m, 1H), 4.39-4.29(m, 1H), 4.29(s, 2H), 4.10-3.96(m, 3H), 3.46-3.40(m, 2H), 2.92-2.70(m, 8H), 2.58-2.37(m, 5H), 1.74-1.40(m, 13H), 0.80-0.74(m, 2H), -0.04 (s, 9H). Mass spectrum: 778 (MH) ⁺ .

Prepare similarly:

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid (carboxylic acid){2-[1,4′]bipiperidine (bipiperidinyl)-1′-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indol-5-ylmethyl]-ethyl}-amide

¹ H-NMR (CD ₃ CN, 500MHz) δ9.42(br s, 1H), 7.80(d, J=8.5Hz, 0.6H), 7.78(d, J=8.2Hz, 0.4H), 7.50(s , 1H), 7.43(t, J=3.0Hz, 1H), 7.27(d, J=8.5Hz, 0.6H), 7.23(d, J=8.5Hz, 0.4H), 7.10-7.07(m, 1H) , 7.02-6.95(m, 3H), 6.69(s, 0.4H), 6.68(s, 0.6H), 5.88(d, J=8.5Hz, 0.6H), 5.85(d, J=8.4Hz, 0.4H ), 5.04-4.98(m, 1H), 4.49(s, 0.4H), 4.46(s, 0.6H), 4.36-4.30(m, 1H), 4.11-4.07(m, 1H), 3.97-3.91(m , 1H), 3.31-3.28(m, 2H), 3.11-3.05(m, 6H), 2.87-2.80(m, 2H), 2.43-2.07(m, 8H), 1.78-1.74(m, 4H), 1.71 -1.65 (m, 2H), 1.46-1.40 (m, 2H), 1.37-1.31 (m, 2H), 0.80-74 (m, 2H), -0.10 (s, 9H). LC/MS: _tR = 2.47 min, 762.37 (MH) ⁺ .

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid {2-[1,4′]bipiperidine-1′ -yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide

¹ H-NMR (CD ₃ CN, 500MHz) δ9.67(s, 1H), 8.32(s, 1H), 7.96(d, J=8.7Hz, 0.55H), 7.93(d, J=8.6Hz, 0.45 H), 7.70(s, 1H), 7.51(d, J=8.6Hz, 0.55H), 7.47(d, J=8.8Hz, 0.45H), 7.08-7.05(m, 1H), 7.03-6.99(m , 1H), 6.98-6.94(m, 2H), 6.01(d, J=7.9Hz, 0.45H), 5.96(d, J=7.9Hz, 0.55h), 5.05-5.00(m, 1H), 4.49- 4.46(m, 1H), 4.35-4.29(m, 1H), 4.10-4.05(m, 1H), 4.00-3.93(m, 1H), 3.40-3.36(m, 2H), 3.17-3.30(m, 6H ), 2.91-2.71(m, 2H), 2.52-2.13(m, 8H), 1.769br s, 4H), 1.69-1.65(m, 2H), 1.44-1.41(m, 2H), 1.34-1.30(m , 2H), 0.77-0.71 (m, 2H), -0.08 (s, 9H). LC/MS: _tR = 2.35 min, 763.35 (MH) ⁺ .

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

¹ H-NMR (CD ₃ CN, 500MHz) δ8.17(s, 0.6H), 8.16(s, 0.4H), 7.84(d, J=8.5Hz, 0.6H), 7.81(d, J=8.5Hz , 0.4H), 7.54(s, 0.4H), 7.53(s, 0.6H), 7.48(t, J=4.1Hz, 1H), 7.31(dd, J=8.5, 1.5Hz, 0.6H), 7.28( dd, J=8.5, 1.5Hz, 0.4H), 7.18(t, j=7.4Hz, 1H), 7.09-7.06(m, 1H), 6.93(t, J=7.3Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.72(d, J=3.6Hz, 1H), 6.09(d, J=8.2Hz, 1H), 5.05-4.99(m, 1H), 4.53-4.50(m, 1H), 4.40-4.34(m, 1H), 4.26(s, 1.2H)<4.24(s, 0.8H), 3.99-3.94(m, 1H), 3.35-3.30(m, 2H), 3.15-3.07(m, 3H ), 3.08-3.03(m, 1H), 2.81-2.73(m, 3H), 2.55-2.37(m, 6H), 2.21-2.16(m, 1H), 2.13-2.08(m, 1H), 1.69-1.57 (m, 4H), 1.51-1.45 (m, 4H), 1.41-1.35 (m, 4H), 0.83-0.74 (m, 2H), -0.06 (s, 9H). Mass spectrum: 776.44 (MH) ⁺ .

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

Purification was performed by silica gel chromatography using dichloromethane:methanol/triethylamine (90:10:0.5) as eluent. ¹ H-NMR (CD ₃ CN, 500MHz) δ8.36(s, 1H), 8.04(s, 1H), 8.01(d, J=8.8Hz, 0.6H), 7.97(dd, J=8.8Hz, 0.4 H), 7.74(s, 1H), 7.54(dd, J=8.5, 1.5Hz, 0.6H), 7.51(dd, J=8.5, 1.5Hz, 0.4H), 7.18(t, J=7.4Hz, 1H ), 7.11(t, J=7.3Hz, 1H), 6.94(t, J=7.3Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.05(d, J=8.5Hz, 0.4H) , 6.02(d, J=8.5Hz, 0.6H), 5.06-5.01(m, 1H), 4.52-4.50(m, 1H), 4.39-4.34(m, 1H), 4.27(s, 1.2H), 4.25 (s, 0.8H), 4.00-3.97(m, 2H), 3.45-3.40(m, 2H), 3.20-3.08(m, 2H), 2.81-2.74(m, 2H), 2.56-2.39(m, 8H ), 2.27-2.24(m, 1H), 2.20-2.16(m, 1H), 1.68-1.57(m, 4H), 1.52-1.45(m, 4H), 1.41-1.34(m, 4H), 1.06-1.01 (m, 1H), 0.80-0.75 (m, 2H), -0.07 (s, 9H). Mass spectrum: 777.40 (MH) ⁺ .

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

¹ H-NMR (CD ₃ CN, 500MHz) δ9.75(s, 1H), 7.82(d, J=8.2Hz, 1H), 7.54(s, 1H), 7.48(d, J=3.6Hz, 1H) , 7.28(d, J=8.5Hz, 1H), 7.12-7.09(m, 1H), 7.04-7.02(m, 1H), 7.00-6.97(m, 2H), 6.72(d, J=3.7Hz, 1H ), 5.97(d, J=8.2Hz, 1H), 5.01(dd, J=14.6, 7.2Hz, 1H), 4.40-4.34(m, 1H), 4.15-4.08(m, 2H), 3.58-3.54( m, 1H), 3.50-3.45(m, 2H), 3.39-3.35(m, 1H), 3.36-3.32(m, 2H), 3.14-3.10(m, 8H), 2.89-2.83(m, 2H), 2.34-2.23 (m, 4H), 2.17-2.13 (m, 1H), 0.85 (d, J=6.7Hz, 6H), 0.83-0.80 (m, 2H), -0.06 (s, 9H). Mass spectrum: 736.40 (MH) ⁺ .

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid {2-(1,4-dioxa-8-nitrogen Hetero-spiro[4.5]dec-8-yl)-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indol-5-ylmethyl]-ethyl base}-amide

¹ H-NMR (CD ₃ CN, 500MHz) δ9.27(s, 1H), 7.82(d, J=8.5Hz, 1H), 7.55(s, 1H), 7.48(d, J=3.6Hz, 1H) , 7.28(dd, J=8.5, 1.5Hz, 1H), 7.13-7.10(m, 1H), 7.06-7.03(m, 1H), 7.01-6.98(m, 2H), 6.72(d, J=3.6Hz , 1H), 5.95(d, J=8.0Hz, 1H), 5.05(dd, J=15.0, 7.3Hz, 1H), 4.41-4.34(m, 1H), 4.14-4.08(m, 2H), 3.90- 3.86(m, 3H), 3.68-3.64(m, 1H), 3.60-3.56(m, 2H), 3.45-3.40(m, 1H), 3.35-3.31(m, 2H), 3.15(dd, J=13.4 , 7.1Hz, 1H), 3.05(dd, J=13.4, 7.0Hz, 1H), 2.89-2.83(m, 2H), 2.34-2.19(m, 3H), 1.73-1.70(m, 2H), 1.64- 1.56 (m, 2H), 1.53-1.49 (m, 1H), 1.29-1.26 (m, 1H), 0.84-0.80 (m, 2H), -0.05 (s, 9H). Mass spectrum: 737.37 (MH) ⁺ .

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

¹ H-NMR (CD ₃ CN, 500MHz) δ9.84(s, 1H), 8.37(s, 1H), 7.98(d, J=8.5Hz, 1H), 7.74(s, 1H), 7.52(dd, J=8.8, 1.5Hz, 1H), 7.11-7.09(m, 1H), 7.06-7.03(m, 1H), 7.02-6.98(m, 2H), 5.97(d, J=8.2Hz, 1H), 5.02 (dd, J=14.3, 7.3hz, 1H), 4.39-4.33(m, 1H), 4.14-4.07(m, 2H), 3.53-3.50(m, 3H), 3.46-3.42(m, 2H), 3.45 -3.39(m, 1H), 3.20-3.06(m, 5H), 2.89-2.83(m, 2H), 2.30-2.27(m, 4H), 2.21-2.17(m, 1H), 1.74-1.70(m, 3H), 0.86 (d, J=6.7Hz, 6H), 0.81-0.77 (m, 2H), -0.04 (s, 9H). Mass spectrum: 737.40 (MH) ⁺ .

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid {2-(1,4-dioxa-8-nitrogen Hetero-spiro[4.5]dec-8-yl)-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl base}-amide

¹ H-NMR (CD ₃ CN, 500MHz) δ9.34(s, 1H), 8.36(s, 1H), 7.97(d, J=8.5Hz, 1H), 7.74(s, 1H), 7.52(dd, J=8.5, 1.5Hz, 1H), 7.11-7.08(m, 1H), 7.06-7.03(m, 1H), 7.02-6.98(m, 2H), 5.98(d, J=8.2Hz, 1H), 5.06 (dd, J=14.6, 7.3Hz, 1H), 4.39-4.32(m, 1H), 4.13-4.03(m, 2H), 3.92-3.88(m, 2H), 3.71-3.66(m, 1H), 3.63 -3.53(m, 2H), 3.48-3.45(m, 1H), 3.44-3.40(m, 2H), 3.19(dd, j=13.4, 6.5Hz, 1H), 3.08(dd, J=13.7, 7.3Hz , 1H), 2.85(t, J=12.8Hz, 2H), 2.32-2.20(m, 4H), 1.73-1.70(m, 2H), 1.67-1.51(m, 3H), 1.38-1.33(m, 1H ), 0.81-0.77 (m, 2H), -0.04 (s, 9H). Mass spectrum: 738.32 (MH) ⁺ .

Example 2

(R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine- 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′]bipiperidine -1'-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide (568 mg, 0.73 mmol) and cesium fluoride (1.11 g, 7.31 mmol) in acetonitrile (50 mL) was heated at 80°C for 4.5 hours. The reaction mixture was concentrated, and the residue was subjected to flash column chromatography (dichloromethane/methanol/triethylamine, 94:5:1) to afford 280 mg (63% yield) of the title compound as a white solid, which was recovered by using Chirocel HPLC analysis of the OD column determined to have 98.2% ee with 20% B (A = ethanol, B = 0.05% diethylamine in hexane) as eluent (retention time: 9.51 min for the title compound, and 9.51 min for the S- Enantiomer 15.9 minutes). ¹ H-NMR (CD ₃ OD, 500MHz) δ8.04(s, 0.75H), 8.03(s, 0.25H), 7.67(s, 0.75H), 7.65(s, 0.25H), 7.56(d, J =8.5Hz, 0.75H), 7.51(d, J=8.5Hz, 0.25H), 7.41(d, J=8.5Hz, 0.75H), 7.31(d, J=8.5Hz, 0.25H), 7.19-7.12 (m, 2H), 6.97-6.94(m, 1H), 6.80(d, J=7.9Hz, 1H), 5.08-5.05(m, 1H), 4.60-4.53(m, 1H), 4.48-4.40(m , 1H), 4.37(s, 1.5H), 4.26(s, 0.5H), 4.24-4.14(m, 2H), 4.06-3.97(m, 1H), 3.15(d, J=7.9Hz, 1.5H) , 3.12-3.05(m, 0.5H), 2.94-2.86(m, 3H), 2.57-2.51(m, 1.5H), 2.47-2.42(m, 1H), 2.37-2.33(m, 0.75H), 2.03 -2.02(m, 1.5H), 1.87-1.75(m, 3.75H), 1.73-1.68(m, 2H), 1.67-1.54(m, 3H), 1.53-1.44(m, 4H), 1.43-1.34( m, 2H), 1.30-1.26 (m, 1H), 0.83-0.77 (m, 0.75H), -0.16 to -0.24 (m, 0.75H). Mass spectrum: 613 (MH) ⁺ .

Prepare similarly:

Example 3

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine-1′ -yl-1-(1H-indol-5-ylmethyl)-2-oxo-ethyl]-amide

¹ H-NMR (DMSO-d ₆ , 500MHz) δ10.99(s, 0.6H), 10.96(s, 0.4H), 10.85(s, 1H), 7.41(s, 0.4H), 7.36(s, 0.6 H), 7.33(d, J=8.0Hz, 0.6H), 7.29-7.26(m, 1H), 7.16-7.14(m, 1H), 7.10(d, J=7.6Hz, 0.4H), 7.02-6.96 (m, 4H), 6.81 (br s, 1H), 6.37-6.35 (m, 1H), 4.86 (q, J=8.0Hz, 0.6H), 4.80 (q, J=7.5Hz, 0.4H), 4.45 (br s, 1H), 4.38-4.32(m, 1H), 4.21-4.16(m, 1H), 3.98(br s, 1H), 3.18(d, J=5.2Hz, 0.6H), 3.04-2.92( m, 2.4H), 2.82-2.74(m, 4H), 2.37-2.33(m, 2H), 2.25-2.08(m, 4H), 2.04-1.90(m, 2H), 1.47-1.24(m, 10H) , 0.75-0.71 (m, 1H). LC/MS: _tR = 1.90 min, 598.42 (MH) ⁺ .

Example 4

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine-1′ -yl-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide

¹ H-NMR (DMSO-d ₆ , 500MHz) δ10.70(s, 1H), 8.22(d, J=8.2Hz, 0.6H), 8.11(s, 0.4H), 8.00(s, 0.6H), 7.89(d, J=9.1Hz, 0.4H), 7.62-7.57(m, 1H), 7.50-7.43(m, 1H), 7.30-7.26(m, 1H), 7.14-7.08(m, 1H), 6.99 -6.95(m, 2H), 6.85(br s, 1H), 4.89-4.80(m, 1H), 4.45-4.31(m, 2H), 4.18-4.00(m, 2H), 3.26-3.16(m, 1H ), 3.09-2.96(m, 2H), 2.82-2.73(m, 4H), 2.38-2.34(m, 2H), 2.24-2.08(m, 4H), 2.03-1.88(m, 2H), 1.47-1.22 (m, 10H), 0.90-0.84 (m, 1H). LC/MS: _tR = 1.73 min, 599.32 (MH) ⁺ .

Example 5

(±)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine- 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′]bipiperidine-1′- yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indol-5-ylmethyl]-ethyl}-amide (52mg, 0.067mmol), A mixture of cesium fluoride (51 mg, 0.33 mmol) in acetonitrile (5 mL) was heated at 80 °C for 4 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel using dichloromethane/methanol/triethylamine (93:5:2) as eluent to afford the title compound as a white solid (70% yield). ¹ H-NMR (CD ₃ CN, 500MHz) δ9.30(s, 1H), 7.48(s, 1H), 7.42(s, 1H), 7.39(d, J=8.2Hz, 0.6H), 7.36(d , J=8.2Hz, 0.4H), 7.24-7.21(m, 1H), 7.19(t, J=7.9Hz, 1H), 7.12-7.09(m, 1H), 7.06(d, J=8.2Hz, 0.6 H), 7.02(d, J=8.2Hz, 0.4H), 6.95(t, J=7.4Hz, 1, 4.04-3.93(m, 1H), 3.07-3.02(m, 1.6H), 2.95(dd, J=13.7, 7.1Hz, 0.4H), 2.85-2.72(m, 3H), 2.56-2.37(m, 3H), 2.42-2.37(m, 1H), 1.99-1.95(m, 7H), 1.76-1.51 (m, 8H), 1.45-1.40 (m, 3H).LC/MS: _tR = 1.91 min, 612.44 (MH) ⁺ .

Example 6

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

Purification by silica gel chromatography using dichloromethane:methanol:triethylamine (93:5:2) as eluent afforded the title compound as a white solid (90% yield). ¹ H-NMR (CD ₃ OD, 500MHz) δ8.04(s, 0.7H), 8.02(s, 0.3H), 7.67(s, 0.7H), 7.65(s, 0.3H), 7.56(d, J =8.5Hz, 0.7H), 7.51(d, J=8.5Hz, 0.3H), 7.40(d, J=8.5Hz, 0.7H), 7.33(d, J=8.5Hz, 0.3H), 7.19-7.12 (m, 2H), 6.97-6.94(m, 1H), 6.80(d, J=8.0Hz, 1H), 5.08-5.05(m, 1H), 4.59-4.54(m, 1H), 4.48-4.42(m , 1H), 4.37(s, 1H), 4.27-4.20(m, 2H), 4.04(d, J=13.4Hz, 0.3H), 3.99(d, J=13.4Hz, 0.7H), 3.19-3.08( m, 2H), 2.94-2.86 (m, 3H), 2.57 (br s, 2H), 2.51-2.36 (m, 2H), 2.07-2.05 (m 1H), 1.90-1.31 (m, 16H). LC/MS: _tR = 1.85 min, 613.44 (MH) ⁺ . The following conditions are used: Chiracel OD prep column, 50×500mm, 20um; A=EtOH, B=0.05% diethylamine/hexane; 20% B@65ml/min for 45 minutes; retention time: (R)-enanti 20.5 min for the isomer and 32.8 min for the S enantiomer. The (R)-enantiomer was obtained by chiral separation of the racemates, whose discrete synthesis was described above (Example 1 ).

Example 7

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid [1-(1H-indol-5-ylmethyl) -2-(4-Isobutyl-piperazin-1-yl)-2-oxo-ethyl]-amide

LC/MS: _tR = 2.05 min, 572.31 (MH) ⁺ .

Example 8

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid [2-(1,4-dioxa-8-nitrogen Hetero-spiro[4.5]dec-8-yl)-1-(1H-indol-5-ylmethyl)-2-oxo-ethyl]-amide

LC/MS: _tR = 2.35 min, 573.26 (MH) ⁺ .

Example 9

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid [1-(1H-indazol-5-ylmethyl) -2-(4-Isobutyl-piperazin-1-yl)-2-oxo-ethyl]-amide

LC/MS: _tR = 1.86 min, 573.28 (MH) ⁺ .

Example 10

(±)-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid [2-(1,4-dioxa-8-nitrogen Hetero-spiro[4.5]dec-8-yl)-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide

LC/MS: _tR = 2.18 min, 574.23 (MH) ⁺ .

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]dec-8-yl)-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide

To 3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl ]-Amino}-propionic acid (95 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) in dimethylformamide (5 mL) was added 1,4-dioxa - A solution of 8-azaspiro[4,5]decane (32 mg, 0.23 mmol) and PyBOP( ^R) (107 mg, 0.21 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 16 hours. All solvents were removed using high vacuum. The residue was subjected to flash column chromatography eluting with dichloromethane/methanol/triethylamine (93:5:2) to afford the title compound (67 mg, 56% yield) as a white solid. ¹ H-NMR (CDCl ₃ , 500MHz) δ10.52(s, 1H), 7.97(s, 1H), 7.54(s, 1H), 7.37(d, J=8.6Hz, 1H), 7.20(d, J =10.7Hz, 1H), 7.16(t, J=7.2Hz, 1H), 7.04(d, J=7.6Hz, 1H), 7.01(s, 1H), 6.94(t, J=8.6Hz, 1H), 6.67(d, J=7.6Hz, 1H), 5.64(d, J=7.9Hz, 1H), 5.16(dd, J=15.0, 6.7Hz, 1H), 4.56-4.49(m, 1H), 4.25(s , 2H), 4.11(br t, J=15.6Hz, 2H), 3.92-3.84(m, 4H), 3.73-3.69(m, 1H), 3.60-3.56(m, 1H), 3.48-3.43(m, 1H), 3.22-3.17(m, 1H), 3.11(d, J=6.7Hz, 2H), 2.90-2.85(m, 2H), 2.68-2.60(m, 4H), 1.67-1.61(m, 2H) , 1.54-1.49 (m, 2H). Mass spectrum: 588 (MH) ⁺ .

4-bromo-2,6-dimethylphenyldiazo-tert-butyl sulfide (sulfide)

4-Bromo-2,6-dimethylaniline (20.00 g, 100 mmol) was ground into a powder with a mortar and pestle, and then suspended in 24% hydrochloric acid (41 mL). The stirred mixture was cooled to -20°C and treated dropwise with a solution of sodium nitrite (7.24 g, 1.05 equiv) in water (16 mL) over 40 minutes while keeping the temperature below -5°C. After an additional 30 minutes at -5°C to -20°C, the mixture was buffered to about pH 5 with solid sodium acetate. This mixture (kept at about -10°C) was added portionwise to a stirred solution of tert-butylmercaptan (11.3 mL, 1 equiv) in ethanol (100 mL) at 0°C over a period of about 10 minutes . After the addition, the mixture was stirred at 0° C. for 30 minutes, and then crushed ice (ca. 150 mL) was added. Store this mixture in the freezer overnight. The resulting beige solid was collected by filtration, washed with water, and dried under high vacuum for several hours (26.90 g, 89%). The compound was stable as a solid, but when attempting to recrystallize it from ethanol, significant decomposition occurred.

¹ H-NMR (CDCl ₃ , 500 MHz) δ 1.58 (9H, s), 1.99 (6H, s), 7.21 (2H, s). Mass spectrum: 303.05 (MH) ⁺ .

5-bromo-7-methylindazole

4-Bromo-2,6-dimethylphenyldiazo-tert-butyl sulfide (12.50 g, 41.5 mmol) and potassium tert-butoxide (46.56 g, 10 equivalents) were flame-dried ) in a round bottom flask. A stirring bar was added and the mixture was placed under nitrogen. Dry DMSO (120 mL) was added thereto. The mixture was vigorously stirred overnight at room temperature. The reaction mixture was then carefully poured into a mixture of crushed ice (400 mL) and 10% hydrochloric acid (200 mL). The resulting suspension was left overnight at 4°C, and the solid was collected by filtration and washed with water. The crude solid was dissolved in 5:1 dichloromethane/methanol and the solution was dried over magnesium sulfate and evaporated to give the product as an off-white solid (7.60 g, 87%).

¹ H-NMR (CDCl ₃ /CD ₃ OD, 500 MHz) δ 2.51 (3H, s), 7.22 (1H, s), 7.69 (1H, s), 7.94 (1H, s). Mass spectrum: 211.03 (MH) ⁺ .

7-Methylindazole-5-carbaldehyde

5-Bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in mineral oil, 1.27 g, 1.1 eq.) were weighed into a flame-dried (flame-dried) glass equipped with a magnetic stir bar. -dried) in a round bottom flask. Dry tetrahydrofuran (30 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, during which time the mixture became homogeneous. The stirred mixture was cooled to -70 °C and a solution of sec-butyllithium in cyclohexane (1.4M, 45 mL, 2.2 equiv) was added over several minutes. After 1 hour at -70°C, dimethylformamide (10 mL) was added over several minutes. The mixture was warmed to room temperature and stirred overnight. It was then cooled to 0°C and treated carefully with 1N hydrochloric acid (60 mL). After a few minutes, solid sodium bicarbonate was added to basify the mixture to pH 9-10. The layers were separated and the aqueous phase was washed twice with ethyl acetate. The combined organic phases were extracted with 0.8M sodium bisulfate (3 x 125 mL). The combined aqueous phases were washed with ethyl acetate (100 mL), and then the pH was adjusted to about 10 with solid sodium hydroxide. The resulting suspension was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were washed with brine, dried (magnesium sulfate) and evaporated to give the product as a light brown solid (3.01 g, 65%). ¹ H-NMR (CDCl ₃ , 500 MHz) δ 2.63 (3H, s), 7.73 (1H, s), 8.12 (1H, s), 8.25 (1H, s), 10.03 (1H, s). Mass spectrum: 161.06 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(7-methyl-1H-indazol-5-yl)-methyl acrylate

A stirred solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (5.51 g, 1.2 equiv) in tetrahydrofuran (30 mL) was treated with tetramethylguanidine (1.91 mL, 1.1 equiv) at room temperature. After 10 minutes, a solution of 7-methylindazole-5-carbaldehyde (2.22 g, 13.86 mmol) in tetrahydrofuran (20 mL) was added. Disappearance of starting material was monitored by TLC and LC/MS. After 5 days at room temperature, the solvent was evaporated and the residue 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%).

¹ H-NMR (CDCl ₃ , 500MHz) δ2.43(3H, s), 3.80(3H, s), 5.12(2H, s), 6.66(1H, s), 7.28(5H, brs), 7.33(1H , s), 7.47 (1H, s), 7.74 (1H, s), 7.96 (1H, s). Mass spectrum: 366.16 (MH) ⁺ .

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

2-Benzyloxycarbonylamino-3-(7-methyl-1H-indazol-5-yl)-methyl acrylate (4.93 g, 13.49 mmol) in methanol (125 mL) was bubbled through nitrogen for 30 min The solution was degassed and then 10% palladium on charcoal (0.6 g) was added carefully. The mixture was hydrogenated overnight in a Parr shaker at 40 psi. 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).

¹ H-NMR (CD ₃ OD, 500MHz) δ2.45 (3H, s), 2.99 (1H, Abq), 3.22 (1H, Abq), 3.74 (3H, s), 3.89 (1H, m), 6.91 ( 1H, s), 7.31 (1H, s), 7.73 (1H, s). Mass spectrum: 234.11 (MH) ⁺ .

Example 12

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

(±)-2-Amino-3-(7-methyl-1H-indazol-5-yl)-propionic acid methyl ester (162.9 mg, 0.698 mmol) was dissolved in dichloromethane (3 mL) at room temperature A stirred solution of , was treated with carbonyldiimidazole (113.2 mg, 1 equiv). After 1.5 hours at room temperature, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (161.5 mg, 1 eq.) was added. The mixture was stirred overnight at room temperature. A white precipitate formed, indicating that it was the desired product. The solvent was evaporated and the residue was triturated with dichloromethane. The product was collected by filtration, washed with dichloromethane, and dried in vacuo to give a white solid (241.5 mg, 71%). Some product remained in the mother liquor.

¹ H-NMR (dimethylformamide-d7, 500MHz) δ1.75 (4H, m), 2.78 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, m), 3.86 (3H , s), 4.44(2H, s), 4.57(1H, m), 4.72(1H, m), 7.11(3H, m), 7.31(1H, s), 7.34(2H, m), 7.72(1H, s), 9.34 (1H, s). Mass spectrum: 491.13 (MH) ⁺ .

Prepare similarly:

Example 13

3-(7-methyl-1H-indazol-5-yl)-2-[2′,3′-dihydro-2′-oxospiro-(piperidine-4,4′-(1H)- Quinazoline)carbonylamino]-propionic acid methyl ester

¹ H-NMR (DMSO-d ₆ ) δ1.59 (4H, m), 2.46 (3H, s), 3.00-3.08 (4H, m), 3.6 (3H, s), 3.78-3.81 (2H, m) , 4.30-4.32(1H, m), 6.78-6.88(4H, m), 7.03(1H, s), 7.10(IH, m), 7.13(1H, s), 7.41(1H, s), 7.96(1H , s), 9.12 (1H, s). Mass spectrum: 477.11 (MH) ⁺ .

Example 14

3-(7-Methyl-1H-indazol-5-yl)-2-(1,2-dihydro-2-oxospiro-4H-3,1-dihydro-benzoxazine-4' 4-piperidine-carbonylamino)-propionic acid methyl ester

Mass spectrum: 478.15 (MH) ⁺ .

3-(7-Methyl-1H-indazol-5-yl)-2{3′,4′-dihydro-2′-oxospiro-(piperidine-4,4′-(1H)-quinone Phenylcarbonylamino}-propionic acid methyl ester

¹ H-NMR (DMSO-d ₆ ) δ1.42-1.56 (4H, m), 2.47 (3H, s), 2.50-2.54 (1H, d), 2.60-2.64 (1H, d), 2.98-3.06 4H , m), 3.60(3H, s), 3.80(2H, m), 4.30(1H, m), 6.86(2H, d), 6.95(2H, m), 7.15(1H, m), 7.40(1H, s ), 7.95 (1H, s), 8.32 (1H, s), 10.14 (1H, s), 13.05 (1H, s). Mass spectrum: 476.17 (MH) ⁺ .

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

¹ H-NMR (DMSO-d ₆ ) δ1.50 (2H, m), 1.68 (2H, m), 2.46 (3H, s covered by DMSO), 3.05 (2H, m), 3.30 (2H, m), 3.60(3H,s), 3.86(2H,m), 4.28(1H,m), 6.98(1H,d), 7.04(1H,s), 7.40(1H,s), 7.58(2H,m), 7.65 (1H, m), 8.00 (1H, s), 8.04 (2H, m). Mass spectrum: 489.15 (MH) ⁺ .

Example 15

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

At room temperature, (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole A suspension of phen-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (240.0 mg, 0.489 mmol) in 1:1 tetrahydrofuran/methanol (20 mL) was treated with lithium hydroxide (140.5 mg , 7 eq) in water (10 mL). Within 1 min, the mixture became homogeneous and it was left at 4°C overnight. The solvent was evaporated at about 30°C, and the pH was adjusted to about 1 with 1N hydrochloric acid. The resulting white suspension was stored at 4°C for several hours, and the product was collected by filtration, washed with as little water as possible, and dried in vacuo (169.0 mg, 73%). Solid sodium chloride was added to the filtrate to give a product-rich precipitate (5.2 mg, 75% overall yield).

¹ H-NMR (CD ₃ OD, 500MHz) δ1.2-1.7 (4H, m), 2.58 (3H, s), 2.5-3.2 (4H, m), 3.35 (2H, m), 4.15 (2H, m ), 4.36(1H, m), 4.60(1H, m), 6.79(1H, d), 6.96(1H, t), 7.18(3H, m), 7.49(1H, s), 8.00(1H, s) . Mass spectrum: 477.13 (MH) ⁺ .

Prepare similarly:

3-(7-methyl-1H-indazol-5-yl)-2-[2′,3′-dihydro-2′-oxospiro-(piperidine-4,4′-(1H)- Quinazoline Carbonylamino]-Propionic Acid

¹ H-NMR (DMSO-d ₆ ) δ1.58 (4H, m), 2.46 (3H, s), 3.00-3.23 (3H, m), 3.78-3.91 (3H, m), 3.88 (2H, m) 4.28(1H,s), 6.70(1H,d), 6.75-6.85(3H,m), 7.04(1H,d), 7.11(1H,m), 7.18(1H,s), 7.96(1H,s), 13.02 (1H, m). Mass spectrum: 463.09 (MH) ⁺ .

3-(7-Methyl-1H-indazol-5-yl)-2-(1,2-dihydro-2-oxospiro-4H-3,1-dihydro-benzoxazine-4' 4-piperidine-carbonylamino)-propionic acid methyl ester

¹ H-NMR (DMSO-d ₆ ) δ1.63-1.98 (4H, m), 2.46 (3H, s, 7-Me covered by DMSO), 2.98-3.32 (4H, m), 3.90 (2H, m) , 4.28(1H,m), 6.78(1H,d), 6.87(2H,m), 6.96(1H,m), 7.05(1H,s), 7.24(1H,m), 7.41(1H,s), 7.96 (1H, s), 10.22 (1H, s) 12.42 (1H, br.) 13.02 (1H, m). Mass spectrum: 464.07 (MH) ⁺ .

3-(7-Methyl-1H-indazol-5-yl)-2{3′,4′-dihydro-2′-oxospiro-(piperidine-4,4′-(1H)-quinone Phenyl-carbonylamino}-propionic acid

¹ H-NMR (DMSO-d ₆ ) δ1.39-1.45 (2H, m), 1.53-1.56 (2H, m), 2.46 (3H, s), 2.50-2.54 (1H, d), 2.60-2.63 ( 1H, d), 2.88-3.00 (3H, m), 3.09-3.11 (1H, m), 3.78-3.81 (2H, m), 4.27 (1H, m), 6.69-6.70 (1H, d), 6.86- 6.87(1H, d), 6.93-6.94(1H, m), 6.99-7.00(1H, m), 7.05(1H, m), 7.41(1H, s), 7.95(1H, s), 10.13(1H, s ), 12.50 (1H, m), 13.03 (1H, m). Mass spectrum: 462 (MH) ⁺ .

3-(7-Methyl-1H-indazol-5-yl)-2-[2'-phenyl-1',3',8'-triaza-spiro(4',5')decane- 1-ene-8-carbonylamino]-propionic acid

¹ H-NMR (DMSO-d ₆ ) δ1.36 (2H, m), 1.63 (2H, m), 2.46 (3H, s covered by DMSO), 2.98-3.03 (2H.m), 3.09-3.11 (2H , m), 3.86(2H, m), 4.21(1H, m), 6.69(1H, m), 7.04(1H, s), 7.40(1H, s), 7.52-7.58(3H, m), 7.99( 3H, m), 11.55 (1H, m), 13.00 (1H, m). Mass spectrum: 475.08 (MH) ⁺ .

Example 16

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

At 0°C, (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinone A stirred solution of oxazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (65.7 mg, 0.138 mmol) in 2:1 dimethylformamide/dichloromethane (1.5 mL) was used with 4-(1-Piperidinyl)-piperidine (46.5 mg, 2 eq), diisopropylethylamine (0.048 mL, 2 eq) and PyBOP( ^R) (75.5 mg, 1.05 eq) were treated. The ice bath was allowed to melt, and the mixture was stirred at room temperature overnight. The solvent was removed under high vacuum and the residue was purified by flash chromatography on silica gel, eluting with 18:1 dichloromethane/methanol containing 1% triethylamine, to give the product as a light yellow solid (80.4 mg, 93%).

¹ H-NMR (CD ₃ OD, 500MHz) δ-0.28 (1H, m), 0.75 (1H, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m ), 2.59(3H, s), 2.68(2H, m), 2.90(4H, m), 3.08(4H, m), 3.9-5.1(4H, some m), 6.81(1H, d), 6.96(1H , t), 7.16 (3H, m), 7.49 (1H, s), 8.03 (1H, s). Mass spectrum: 627.29 (MH) ⁺ .

Prepare similarly:

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

¹ H-NMR (CD ₃ OD, 500MHz) δ0.87 (1H, m), 1.33 (1H, m), 1.47 (2H, m), 1.80 (6H, m), 2.57 (3H, s), 2.89 ( 2H, m), 3.06 (2H, m), 3.18 (4H, m), 3.40 (2H, m), 3.61 (1H, m), 4.16 (1H, m), 4.28 (1H, Abq), 4.43 (1H , m), 5.02(1H, m), 6.51(1H, d), 6.79(1H, d), 6.96(1H, t), 7.11(1H, d), 7.15(1H, t), 7.48(1H, s), 8.01 (1H, s). Mass spectrum: 544.24 (MH) ⁺ .

Example 18

(±)-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

¹ H-NMR (CD ₃ OD, 500MHz) δ1.12 (2H, d), 1.64 (2H, m), 2.57 (3H, s), 2.74 (1H, m), 2.87 (3H, s), 2.89 ( 3H, s), 2.86(2H, m), 3.07(2H, m), 3.20(1H, m), 4.17(1H, m), 4.25(1H, Abq), 4.43(1H, m), 4.97(1H , m), 6.79 (1H, d), 6.95 (1H, t), 7.0-7.4 (3H, m), 7.48 (1H, d), 8.01 (1H, s). Mass spectrum: 504.15 (MH) ⁺ .

Example 19

(±)-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

¹ H-NMR (CD ₃ OD, 500MHz) δ1.30 (2H, m), 1.66 (2H, m), 1.78 (1H, m), 1.90 (1H, m), 2.00 (3H, s), 2.19 ( 1H, m), 2.35 (1H, m), 2.58 (3H, s), 2.88 (2H, m), 3.09 (2H, d), 3.10-3.45 (3H, m), 3.66 (1H, m), 4.19 (2H,d), 4.20(2H,s), 4.43(1H,m), 4.98(1H,t), 6.80(1H,d), 6.95(1H,t), 7.11(2H,m), 7.16( 1H,t), 7.47(1H,s), 8.02(1H,s). Mass spectrum: 559.23 (MH) ⁺ .

Example 20

(±)-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

¹ H-NMR (CD ₃ OD, 500MHz) δ1.40-1.90 (5H, m), 2.02 (3H, brs), 2.57 (3H, s), 2.86 (1H, m), 2.89 (2H, q), 3.09(2H,m), 3.16(1H,m), 3.25(2H,m), 3.40(1H,m), 3.56(1H,m), 4.17(2H,d), 4.27(2H,s), 4.40 (1H,m), 4.69(1H,t), 6.80(1H,d), 6.95(1H,t), 7.10(1H,s), 7.16(1H,m), 7.48(1H,s), 7.53( 1H, m), 8.01 (1H, s). Mass spectrum: 530.19 (MH) ⁺ .

Example 21

(±)-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

¹ H-NMR (CD ₃ OD, 500MHz) δ1.38(1H, t), 1.68(2H, m), 1.81(1H, m), 2.30(1H, m), 2.53(3H, s), 2.95( 4H,m), 3.13(2H,d), 3.22(1H,m), 3.35-3.65(4H,m), 3.79(1H,m), 4.18(2H,d), 4.31(2H,s), 4.42 (1H,m), 4.99(1H,t), 6.64(2H,d), 6.80(1H,d), 6.89(1H,m), 6.96(1H,t), 7.14(3H,m), 7.51( 1H, s), 7.99 (1H, s), 8.10 (2H, d), 8.16 (1H, m). Mass spectrum: 622.26 (MH) ⁺ .

Example 22

(±)-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

¹ H-NMR (CD ₃ OD, 500MHz) δ1.27 (1H, m), 1.38 (1H, m), 1.67 (2H, m), 1.84 (1H, m), 2.54 (3H, s), 2.65 ( 1H,m), 2.88(2H,m), 3.15(4H,m), 3.35(1H,m), 3.58(3H,m), 3.77(1H,m), 4.18(2H,d), 4.30(2H , s), 4.42(1H, m), 5.01(1H, t), 6.62(1H, d), 6.70(1H, t), 6.80(1H, d), 6.95(1H, t), 7.103H, m ), 7.50 (1H, s), 7.54 (1H, t), 7.99 (1H, s), 8.05 (1H, 7). Mass spectrum: 622.25 (MH) ⁺ .

Example 23

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4-bipiperidinyl]-1-yl-2-oxoethyl]-2' , 3'-Dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.2-1.73 (14H, m), 2.46 (3H, s), 2.75-3.24 (12H, m), 3.87 (2H, m), 4.45 (1H, m), 4.78-4.85(1H, m), 6.80(1H, m), 6.86(1H, m), 7.05(1H, m), 7.12(1H, m), 7.21(1H, m), 7.27(2H , m), 7.98 (1H, m), 9.23 (1H, m). Mass spectrum: 613.25 (MH) ⁺ .

Example 24

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

¹ H-NMR (CD ₃ OD, 500MHz) δ0.87 (1H, m), 1.28-1.47 (5H, m), 1.74-1.85 (4H, m), 2.53 (3H, s), 3.02-3.38 (8H , m), 3.92(2H, m), 5.02(1H, m), 6.82(1H, d), 6.99(1H, d), 7.04-7.09(2H, m), 7.17(1H, m), 7.32( 2H, s), 7.45 (1H, s), 7.96 (1H, s). Mass spectrum: 530.17 (MH) ⁺ .

Example 25

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

¹ H-(DMSO-d ₆ , 500MHz)δ1.88(14H, m), 2.64(3H, s), 2.78(12H, m), 4.0(2H, m), 4.4(1H, m), 4.85( 1H, m), 6.80-6.88 (2H, m), 7.03 (2H, m), 7.11 (1H, m), 7.23 (1H, m), 7.36 (2H, m), 7.97 (1H, m). Mass spectrum: 614.73 (MH) ⁺ .

Example 26

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

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.15-1.91 (10H, m), 2.47 (3H, s), 2.95-3.05 (6H, m) 3.40 (4H, m) 3.95 (2H, d) , 4.81(1H,m), 6.81(1H,d), 6.88(1H,d), 6.94(1H,m), 6.99(1H,m), 7.04(1H,s), 7.24(1H,m), 7.37(1H,s), 7.96(1H,s). Mass spectrum: 531.23 (MH) ⁺ .

Example 27

(±)-[1-Dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-1′,2′-dihydro-2′-oxo Spiro-[4H-3′,1-benzoxazine-4,4′-piperidine]-1-carboxamide

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.68-1.88 (4H, m), 2.47 (3H, m), 2.79 (6H, s), 2.89-3.04 (4H, m), 3.96 (2H, d), 4.75(1H, m), 6.81(1H, d), 6.88(1H, m), 6.93(1H, m), 6.98(1H, m), 7.05(1H, s), 7.24(1H, m ), 7.43 (1H, s), 7.97 (1H, m), 8.32 (1H, s). Mass spectrum: 491.14 (MH) ⁺ .

Example 28

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

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.40-1.95 (15H, m), 2.46 (3H, m), 2.89-3.07 (4H, m), 3.81 (1H, m), 3.90 (2H, m), 4.48(1H,m), 6.74(2H,m), 6.86(1H,d), 6.97(1H,m), 7.11(1H,s), 7.24(1H,m), 7.36(1H,s ), 7.44 (1H, s), 7.96 (1H, s). Mass spectrum: 597.27 (MH) ⁺ .

Example 29

(±)-1′,2′-dihydro-2′-oxospiro-[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

LC/MS: _tR = 1.56 min, 609.14 (MH) ⁺ .

Example 30

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

LC/MS: _tR = 1.49 min, 553.12 (MH) ⁺ .

Example 31

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4-bipiperidinyl]-1-yl-2-oxoethyl]3', 4'-Dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinoline]-1-carboxamide

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.20-2.00 (14H, m), 2.46 (3H, s), 2.38-3.03 (12H, m), 3.87 (2H, m), 4.34 (1H, m), 4.76-4.87(1H, m), 6.65(1H, m), 6.82-7.64(3H, m), 7.13-7.23(2H, m), 7.36(3h, m), 7.96(1H, s) . Mass spectrum: 612.32 (MH) ⁺ .

Example 32

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

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.10-1.68 (10H, m), 2.46 (3H, s), 2.50-2.60 (2H, m), 2.82-2.97 (4H, m), 3.39 ( 2H, m), 3.85 (2H, m), 4.80 (1H, m), 6.68 (1H, m), 6.87 (1H, d), 6.94 (1H, m), 7.03 (1H, s), 7.06 (1H , m), 7.15 (1H, m), 7.37 (1H, s), 7.40 (1H, s), 7.96 (1H, s). Mass spectrum: 529.25 (MH) ⁺ .

Example 33

(±)-[1-Dimethylcarbamoyl-2-(7-methyl-1H-indazol-5-yl)-ethyl]-3',4'-dihydro-2'-oxo Spiro-[piperidine-4,4'-(1H)-quinoline]-1-carboxamide

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.43 (2H, m), 1.56 (2H, m), 2.46 (3H, s), 2.56 (2H, m), 2.79 (3H, s), 2.90 (5H,m), 3.84(2H,m), 4.731H,m), 6.69(1H,d), 2.69(1H,d), 6.94(1H,m), 7.05(2H,m), 7.14(1H , m), 7.37 (1H, s), 7.42 (1H, s), 7.96 (1H, s). Mass spectrum: 489.2 (MH) ⁺ .

Example 34

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

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.34-2.00 (14H, m), 2.48 (3H, s overlaps with DMSO), 2.70-3.30 (12H, m), 3.90 (2H, m), 4.40 (1H, m), 4.82 (1H, m), 6.82 (1H, m), 7.04 (1H, s), 7.37 (2H, m), 7.56 (3H, m), 7.98 (3H, m). Mass spectrum: 625.29 (MH) ⁺ .

Example 35

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

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.10-1.62 (6H, m), 1.73 (4H, m), 2.48 (3H, s), 3.00 (6H, m), 3.39 (2H, m) , 3.93(2H,m), 4.82(1H,m), 6.78(1H,m), 7.05(1H,s), 7.37(2H,s), 7.40(1H,s), 7.53(2H,m), 7.98 (2H, m). Mass spectrum: 543.26 (MH) ⁺ .

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

¹ H-NMR (DMSO-d ₆ , 500MHz) δ1.28-1.61 (4H, m), 2.78 (4H, m), 2.90 (6H, m), 3.94 (2H, m), 4.74 (1H, m) , 6.77 (1H, m), 7.05 (1H, s), 7.37 (4H, s), 7.42 (1H, s), 7.52 (2H, m), 7.98 (2H, m). Mass spectrum: 502.21 (MH) ⁺ .

Example 37

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

LC/MS: _tR = 1.51 min, 674 (MH) ^- .

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-carboxylate benzyl ester

LC/MS: _tR = 1.74 min, 665 (MH) ⁺ .

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

To 4-(3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1-Carbonyl]-amino}-propionyl)-piperazine-1-carboxylate benzyl ester (280 mg, 0.42 mmol) in methanol (50 ml) was added to a degassed solution of 10% palladium on charcoal (50 mg). The mixture was shaken in a Parr apparatus for 3 hours under a hydrogen atmosphere of 50 psi. The mixture was filtered through celite. The filtrate was concentrated under reduced pressure to afford the desired product in 91% yield. LC/MS: _tR = 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-ylmethyl)- A stirred solution of 2-oxo-2-piperazin-1-yl-ethyl]-amide (100mg, 0.188mmol) in methanol (25mL) was treated with 2-methyl-butyraldehyde (0.03ml, 0.376mmol) . After 1 hour at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was stirred overnight. The solution was filtered through an SCX cartridge. The cartridge was eluted first with methanol and then with 1M ammonia in methanol. The solvent was removed in vacuo to give the desired product in 50% yield. LC/MS: _tR = 1.31 min, 601 (MH) ⁺ .

General Experimental Procedures for Preparation of Examples 40b-40k

The appropriate aldehyde (0.04 mmol) was added to a solution of Example 39 piperazine (0.02 mmol) in methanol (2.0 mL), and the resulting solution was shaken at room temperature for 1 hour. Sodium triacetoxyborohydride (0.2 mmol) was then added and the solution was stirred overnight at room temperature. The solution was then 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.

Table 1. Examples 40b-40k

Example 41a

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

To (±)-2-amino-3-(7-methyl-1H-indazol-5-yl)-propinic acid (20mg, 0.042mmoles), 4-(dimethylamino)pyridine ( 2.5 mg, 0.02 mmoles) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmoles) in dichloromethane (2 mL) and dimethyl To a stirred solution in formamide (1 mL) was added cyclohexanol (13.3 μL, 0.126 mmoles). 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 (9.4 mg, 40%) as a white solid.

¹ H-NMR (CD ₃ OD, 500MHz) δ1.32-1.87 (14H, m), 2.57 (3H, s), 2.86 (2H, m), 3.11-3.26 (2H, m), 4.13-4.22 (3H , m), 4.46(1H, m), 4.55(1H, m), 4.80(1H, m), 6.79(1H, d), 6.97(1H, m), 7.08-7.18(2H, m), 7.35( 1H, s), 7.47 (1H, s), 8.01-8.02 (1H, m). Mass spectrum: 559.22 (MH) ⁺ .

Prepare similarly:

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

LC/MS: _tR = 1.76 min, 650.30 (MH) ⁺ .

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

LC/MS: _tR = 1.59 min, 574.27 (MH) ⁺ .

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

LC/MS: _tR = 2.69 min, 635.29 (MH) ⁺ .

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

LC/MS: _tR = 1.66 min, 582.22 (MH) ⁺ .

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

LC/MS: _tR = 1.65 min, 582.23 (MH) ⁺ .

4-Bromo-2-chloro-6-methylphenyldiazo-tert-butylsulfide

4-Bromo-2-chloro-6-methylaniline (4.0 g, 18.3 mmol) was suspended in 24% hydrochloric acid (5 mL). The stirred mixture was cooled to -20°C and treated dropwise with a solution of sodium nitrite (1.32 g, 1.05 equiv) in water (2 mL) over 10 minutes while keeping the temperature below -5°C. After an additional 30 min at -5°C to -20°C, the mixture was buffered to pH ~5 with solid sodium acetate. This mixture (kept at about -10°C) was added portionwise to a stirred solution of tert-butylmercaptan (2.06 mL, 1 equiv) in ethanol (18.5 mL) at 0°C over a period of about 10 minutes . After the addition, the mixture was stirred at 0 °C for 30 min, and then crushed ice (ca. 50 mL) was added. Store the mixture in the freezer overnight. The resulting beige solid was collected by filtration, washed with water, and dried under high vacuum for several hours (4.60 g, 78%). Mass spectrum: 323.03 (MH) ⁺ .

5-Bromo-7-chloroindazole

4-Bromo-2-chloro-6-methylphenyldiazo-tert-butyl sulfide (4.60 g, 14.4 mmol) and potassium tert-butoxide (16.1 g, 10 equivalents) were flame-dried (flame- dried) in a round bottom flask. A stir bar was added and the mixture was placed under nitrogen. To this mixture was added dry DMSO (50 mL). The mixture was stirred vigorously at room temperature for 10 min. The reaction mixture was then carefully poured into a mixture of crushed ice (150 mL) and 10% hydrochloric acid (74 mL). The resulting suspension was left at 4°C overnight, and the solid was 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. ¹ H-NMR (CDCl ₃ , 500 MHz) δ 7.52 (d, J=1.5, 1H), 7.82 (d, J=1.5, 1H), 8.08 (s, 1H). Mass spectrum: 230.90 (MH) ⁺ .

7-Chlorindazole-5-carbaldehyde

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 equipped with a magnetic stir bar. Dry tetrahydrofuran (30 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, during which time the mixture became homogeneous. The stirred mixture was cooled to -78°C and tert-butyllithium in pentane (1.7M, 10.5 mL, 2.0 equiv) was added over several minutes. After 30 min at -78 °C, the reaction was gradually warmed to -50 °C, held at this condition for 15 min, and cooled again 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 separatory funnel containing ether and water. The aqueous solution was acidified by the addition of 1M potassium bisulfate and neutralized by the addition of sodium bicarbonate. The aqueous solution was extracted with diethyl ether (3x), which was washed with water then brine, dried over magnesium sulfate, and concentrated to afford 1.7 g (100%) of nearly pure material. Analytical pure samples were obtained by recrystallization from hot methanol.

¹ H-NMR (CDCl ₃ , 500 MHz) δ 7.97 (s, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.02 (s, 1H). Mass spectrum: 181.09(MH) ⁺ .

2-Benzyloxycarbonylamino-3-(7-chloro-1H-indazol-5-yl)-methyl acrylate

A stirred suspension of potassium tert-butoxide (375 mg, 1.2 eq) in dichloromethane (20 mL) was cooled to -20°C and treated with trimethyl N-benzyloxycarbonyl-α-phosphonoglycine (1.11 g, 1.2 equivalent) in dichloromethane (5 mL). After 10 minutes, a solution of 7-chloroindazole-5-carbaldehyde (0.50 g, 2.79 mmol) in dichloromethane (5 mL) was added. The reaction was gradually warmed to room temperature and stirred for 3 days. Pour the reaction into a separatory funnel containing water and ether. The aqueous solution was extracted with ether (3x), which was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography yielded 0.40 g (37%) of product and 0.20 g (40%) of starting material.

¹ H-NMR (CDCl ₃ , 500MHz) δ3.64(s, 3H), 5.11(s, 2H), 6.44(bs, 1H), 7.30(bs, 5H), 7.43(s, 1H), 7.62(s , 1H), 7.80(s, 1H), 8.07(s, 1H). Mass spectrum: 386.16 (MH) ⁺ .

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

Under sufficient nitrogen, a solution of 2-benzyloxycarbonylamino-3-(7-chloro-1H-indazol-5-yl)-methyl acrylate (300 mg, 0.78 mmol) in methanol (10 mL) was washed with trifluoro Treat with acetic acid (0.2 mL) followed by 10% palladium on charcoal (30 mg). Fill the flask with hydrogen and stir under a hydrogen atmosphere. After 4 days, all starting material was consumed. The reaction was flushed with nitrogen, filtered through celite, and concentrated. After column chromatography, 78mg (40%) was obtained.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.31(bs, 3H), 2.95(dd, J=13.7, 7.9, 1H), 3.18(dd, J=13.7, 5.2, 1H), 3.48(s, 3H ), 3.78 (dd, J=7.9, 5.2, 1H), 7.23 (s, 1H), 7.46 (s, 1H), 8.00 (s, 1H). Mass spectrum: 254.06 (MH) ⁺ .

Example 42

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

A stirred solution of (±)-2-amino-3-(7-chloro-1H-indazol-5-yl)-propionic acid methyl ester (78 mg, 0.31 mmol) in THF (2 mL) at 0 °C Treat with carbonyldiimidazole (50 mg, 1 equiv). The reaction was stirred for 5 min, allowed to warm to room temperature, stirred for 10 min, and treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (78 mg, 1.1 equiv). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography to give 148 mg (94%) of a white powder.

¹ H-NMR (DMSO-d ₆ , 500 MHz) δ1.46 (m, 4H), 2.55-2.80 (m, 2H), 3.05 (dd, J=13.7, 10.7, 1H), 3.15 (m, 1H), 3.62(s, 3H), 4.04(d, J=13.4, 2H), 4.11(s, 2H), 4.22-4.39(m, 2H), 6.76(d, J=7.9, 1H), 6.87(dd, J = 7.3, 7.3, 1H), 6.90 (d, J = 8.2, 1H), 7.08 (d, J = 7.6, 1H), 7.12 (dd, J = 7.6, 7.6, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.15 (s, 1H), 9.18 (s, 1H), 13.48 (s, 1H). Mass spectrum: 511.18 (MH) ⁺ .

Example 43

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

At room temperature, (±)-3-(7-chloro-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline -3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (15 mg, 0.029 mmol) in 1:1 tetrahydrofuran/methanol (1 mL) was dissolved in lithium hydroxide (3.0 mg, 2.5 eq) in water (0.25 mL), and the resulting solution was stirred for 1.5 hours. The solution was cooled to 0 °C, treated with 1M aqueous potassium bisulfate (60 μL, 2.0 equiv), and concentrated to give the crude acid, which was used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and washed sequentially with dichloromethane (0.15 mL), 4-piperidinyl-piperidine (10.1 mg, 2 equiv), diisopropylethyl Amine (10 μL, 2 equiv) and PyBOP ^(R ) (16.5 mg, 1.1 equiv) treatment. The solution was stirred for 30 min and concentrated. The product was purified by column chromatography to give 14.7 mg (77%, 2 steps).

¹ H-NMR (CDCl ₃ , 500MHz) δ1.30-1.60 (m, 8H), 1.65-1.88 (m, 5H), 2.14 (m, 1H), 2.23 (m, 1H), 2.30-2.70 (m, 7H), 2.80-3.20(m, 5H), 3.94(d, J=13.4, 13.1, 1H), 4.10-4.30(m, 4H), 4.55(m, 1H), 4.62(dd, J=13.1, 12.8 , 1H), 5.19 (m, 1H), 5.91 (dd, J=30.2, 22.3, 1H), 6.70 (d, J=7.6, 1H), 6.92 (dd, J=7.6, 7.3, 1H), 7.01 ( dd, J, 7.9, 7.6, 1H), 7.13(s, 0.4H), 7.15(dd, J=7.9, 7.6, 1H), 7.24(s, 0.6H), 7.33(s, 0.4H), 7.43( s, 0.6H), 7.49 (bs, 1H), 7.91 (s, 0.4H), 7.95 (s, 0.6H), 11.25 (bd, J=50.7, 1H). Mass spectrum: 647.37 (MH) ⁺ .

4-Bromo-2-ethyl-6-methyl-phenylamine

2-Ethyl-6-methyl-phenylamine (14 mL, 100 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and water (220 mL) and cooled to 0°C. Bromine (5.1 mL, 1 equiv) was added dropwise thereto. Rapid formation of a white precipitate. The precipitate was filtered and washed with ether. The precipitate was suspended in water and neutralized with aqueous potassium carbonate. The resulting oil was extracted into ether. The ether extract was dried over potassium carbonate, filtered, and concentrated to afford 7.0 g (33%) of a purple oil which was used without purification. Mass Spectrum: 214.01(MH) ⁺ .

4-Bromo-2-ethyl-6-methylphenyldiazo-tert-butylsulfide

4-Bromo-2-ethyl-6-methylaniline (7.0 g, 33 mmol) was suspended in 7.8M hydrochloric acid (30 mL). The stirred mixture was cooled to -20°C and treated dropwise with a solution of sodium nitrite (2.27 g, 1.05 equiv) in water (5 mL) over 10 minutes while keeping the temperature below -5°C. After an additional 30 min at -5°C to -20°C, the mixture was buffered to pH ~5 with solid sodium acetate. This mixture (kept at about -10°C) was added portionwise to a stirred solution of tert-butylmercaptan (3.7 mL, 1 equiv) in ethanol (50 mL) at 0°C for about 10 minutes. After the addition, the mixture was stirred at 0 °C for 30 min, and then crushed ice (ca. 50 mL) was added. Store the mixture in the freezer for 2 hours. The resulting beige solid was collected by filtration, washed with water, and dried under high vacuum for several hours (9.47 g, 92%). Mass spectrum: 315.05 (MH) ⁺ .

5-Bromo-7-ethyl-1H-indazole

To a stirred solution of potassium tert-butoxide (33.6 g, 10 equiv) in DMSO (200 mL) was added 4-bromo-2-ethyl-6-methylphenyldiazo-tert-butylsulfide ( 9.4 g, 30 mmol) in DMSO (100 mL). The mixture was stirred vigorously for 1 hour. The reaction mixture was then carefully poured into a mixture of crushed ice (500 mL), concentrated hydrochloric acid (25 mL) and water (100 mL). The resulting precipitate was filtered, washed with water, dissolved in methanol, and concentrated to afford 5.7 g (85%) of a tan solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.39(t, J=7.6, 3H), 2.92(q, J=7.6, 2H), 7.30(s, 1H), 7.75(s, 1H), 8.04( s, 1H). Mass spectrum: 225.00 (MH) ⁺ .

7-Ethyl-1H-indazole-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 equipped with a magnetic stir bar in the flask. Dry tetrahydrofuran (60 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes. The stirred mixture was cooled to -78°C and a solution of tert-butyllithium in pentane (1.7M, 10.5 mL, 2.0 equiv) was added over several minutes. After 15 min at -78°C, the reaction was gradually warmed to -50°C and cooled again 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 1M potassium bisulfate (25 mL). The resulting suspension was extracted with ether, washed with water then brine, dried over magnesium sulfate, and concentrated. Column chromatography yielded 160 mg (10%) of a white solid.

¹ H-NMR (CD ₃ OD, 500MHz) δ1.38(t, J=7.6, 3H), 2.98(q, J=7.6, 2H), 7.71(s, 1H), 8.22(s, 1H), 8.24 (s, 1H), 9.96 (s, 1H). Mass spectrum: 175.08 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(7-ethyl-1H-indazol-5-yl)-methyl acrylate

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

¹ H-NMR (CDCl ₃ , 500MHz) δ1.33(t, J=7.6, 3H), 2.86(q, J=7.3, 2H), 3.83(s, 3H), 5.11(s, 2H), 6.39( bs, 1H), 7.29 (bs, 5H), 7.43 (s, 1H), 7.50 (s, 1H), 7.78 (s, 1H), 8.04 (s, 1H). Mass spectrum: 380.17 (MH) ⁺ .

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

To a solution of methyl 2-benzyloxycarbonylamino-3-(7-ethyl-1H-indazol-5-yl)-acrylate (330 mg, 0.78 mmol) in methanol (5 mL) was added palladium under nitrogen Charcoal (10%, 33 mg). The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 210 mg (98%) which was used without purification.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.34 (t, J=7.6, 3H), 2.85 (q, J=7.6, 2H), 2.96 (dd, J=13.7, 7.6, 1H), 3.19 (dd , J=13.7, 8.6, 1H), 3.48(s, 2H), 3.73(s, 3H), 3.80(dd, J=7.6, 5.2, 1H), 6.99(s, 1H), 7.38(s, 1H) , 7.97 (s, 1H). Mass spectrum: 248.15 (MH) ⁺ .

Example 44

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

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

¹ H-NMR (CDCl ₃ , 500MHz) δ1.36(t, J=7.6, 3H), 1.69(m, 4H), 2.86(m, 2H), 2.90(q, J=7.6, 2H), 3.22( dd, J=5.5, 4.9, 2H), 3.75(s, 3H), 4.03(dd, J=44.0, 13.7, 2H), 4.26(s, 2H), 4.51(m, 1H), 4.84(m, 1H ), 5.02(m, 1H), 6.70(d, J=7.9, 1H), 6.90-7.05(m, 4H), 7.16(dd, J=7.6, 7.6, 1H), 7.34(s, 1H), 8.03 (s, 1H). Mass spectrum: 505.29 (MH) ⁺ .

Example 45

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

To (±)-3-(7-ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- Base)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (15 mg, 0.03 mmol) in methanol (0.6 mL) was added an aqueous solution of lithium hydroxide monohydrate (3.0 mg, 2.5 eq) (0.1 mL), and the resulting solution was stirred for 6 hours. The solution was cooled to 0 °C, treated with 1M aqueous potassium bisulfate (60 μL, 2.0 equiv), and concentrated to give the crude acid, which was used without purification. The crude acid was dissolved in dimethylformamide (0.4 mL), cooled to 0 °C, and washed sequentially with dichloromethane (0.2 mL), 4-piperidinyl-piperidine (11 mg, 2.2 equiv), di Treat with isopropylethylamine (12 μL, 2.3 equiv) and PyBOP ^(R) (19 mg, 1.2 equiv). The solution was stirred at 0 C for 15 min, warmed to room temperature, stirred for 1.5 h, and concentrated. The product was purified by column chromatography to give 14.5 mg (76%, 2 steps).

¹ H-NMR (CDCl ₃ , 500MHz) δ1.28-1.48(m, 10H), 1.52(m, 2H), 1.60-1.82(m, 6H), 1.95(m, 1.4H), 2.06(m, 1.6 H), 2.20-2.50(m, 5H), 2.77-2.93(m, 5H), 2.96-3.17(m, 2H), 3.76(d, J=13.4, 0.4H), 3.86(d, J=13.7, 0.6H), 4.10-4.20(m, 2H), 4.26(s, 2H), 4.57(m, 2H), 5.10-5.24(m, 1H), 5.67(d, J=8.2, 0.6H), 5.74( d, J = 7.9, 0.4H), 6.67 (d, J = 7.9, 1H), 5.67 (d, J = 8.2, 0.6H), 5.74 (d, J = 7.9, 0.4H), 6.67 (d, J =7.9, 1H), 6.93(dd, J=7.6, 7.3, 1H), 6.96(s, 0.4H), 7.03(dd, J=7.0, 6.7, 1H), 7.09(m, 1.6H), 7.15( dd, J = 7.0, 6.7, 1H), 7.31 (s, 0.4H), 7.38 (s, 0.6H), 7.94 (s, 0.4H), 7.95 (s, 0.6H). Mass spectrum: 641.50 (MH) ⁺ .

(3,4-Dinitro-phenyl)-methanol

At -20°C, borane-tetrahydrofuran complex (1M solution in tetrahydrofuran, 800mL, 800mmol) was added to 3,4-dinitrobenzoic acid (93.5g, 441mmol) in tetrahydrofuran (300mL) over a period of 45min. ) solution. The resulting mixture was stirred at -20 °C for 1 h, and then allowed to warm to room temperature and stir overnight. It was quenched by adding 32 mL of 1:1 acetic acid/water. The solvent was removed in vacuo and the residue was poured into ice-cold 1000 mL of saturated sodium bicarbonate with vigorous stirring 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 (100%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ7.91(d, J=8.0Hz, 1H), 7.89(s, 1H), 7.71(dd, J=8.5, 1.0Hz, 1H), 4.87(s, 2H ), 2.30(s, 1H).

3,4-Dinitro-benzaldehyde

A solution of (3,4-dinitro-phenyl)-methanol (95.3 g, 481 mmol) in dichloromethane (500 mL) was added all at once to pyridinium chlorochromate (156 g, 722 mmol) in dichloromethane (900 mL) in the suspension. The mixture was stirred at room temperature for 1.5 hours, and then diethyl ether (1500 mL) was added. The supernatant was decanted from the resulting black gum, and the insoluble residue was washed well with dichloromethane (3 x 250 mL). The combined organic solutions were filtered through a pad of magnesium silicate to give a light yellow clear solution. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using dichloromethane as eluent to afford the title compound as a yellow solid (71%).

¹ H-NMR (CDCl ₃ , 300MHz) δ8.45 (d, J=1.5Hz, 1H), 8.28 (dd, J=8.1, 1.5Hz, 1H), 8.07 (d, J=8.1Hz, 1H). ¹³ CNMR (CD ₃ OD, 125 MHz) δ 187.7, 139.2, 134.2, 126.2, 125.7.

2-Benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-methyl acrylate

1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added to N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (114.1 g, 344 mmol) in THF at room temperature (800mL) solution. The mixture was stirred at room temperature for 15 min, and then 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 and then allowed to warm to room temperature overnight. The solvent was removed in vacuo, and the yellow residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of 1 N sulfuric acid, water (twice), 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). The yellow crystals were collected and further purified by silica gel chromatography using dichloromethane as eluent. The title compound (77%) was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ , 500MHz) δ7.85 (d, J=1.5Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.62 (dd, J=8.5, 1.5Hz, 1H), 7.35-7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H), 6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H).

Prepare similarly:

2-Benzyloxycarbonylamino-3-(3-hydroxy-4-nitro-phenyl)-methyl acrylate

¹ H-NMR (CDCl ₃ , 500MHz) δ7.93(d, J=9.0Hz, 1H), 7.32(br s, sH), 7.28(brs, 2H), 7.17(s, 1H), 7.16(d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.0, 2.0 Hz, 1H), 6.74 (brs, 1H), 5.06 (s, 2H), 3.86 (s, 3H).

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

Place the oven-dried 500 mL Shlenck flask into a nitrogen-filled glove-bag. After the glove bag was evacuated and filled with nitrogen (3x), the flask was sealed, removed from the glove bag and weighed. Return it to the glove bag, evacuate and fill with nitrogen (3x), then charge (-)-1,2-bis((2R,5R)-2,5-diethylphospholanyl ) Benzene (cyclooctadiene) rhodium (I) triflate. The flask was sealed, removed from the glove bag and weighed (784 mg, 1.08 mmol). 2-Benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-methyl acrylate (8.72 g, 21.7 mmol) was added to another 500 mL Schlenck flask, evacuated and filled with nitrogen ( 3x). Dichloromethane (350 mL, degassed with nitrogen for 2 hours) was added and the resulting solution was transferred via cannula to the catalyst flask. After flushing with hydrogen (4x) and filling the flask, 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/hexane (1:1) as eluent to give the title compound as a light brown gummy solid (99% yield by HPLC analysis For 99.2% enantiomeric excess (ee), the following conditions were used: Chiral pak AD column (4.6×250mm, 10um; A=ethanol, B=hexane; 40%B@1.0mL/min, 14min; retention time : 10.9 min for the R enantiomer and 6.9 min for the S enantiomer).

¹ H-NMR (CDCl ₃ , 500MHz) δ7.80(d, J=8.0Hz, 1H), 7.63(s, 1H), 7.45(d, J=8.0Hz, 1H), 7.38-7.31(m, 5H ), 5.37(d, J=6.0Hz, 1H), 5.13-5.05(m, 2H), 4.68(d, J=6.0Hz, 1H), 3.71(s, 3H), 3.36(dd, J=13.5, 5.0 Hz, 1H), 3.17 (dd, J = 13.5, 6.0 Hz, 1H).

Prepare similarly:

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

¹ H-NMR (CDCl ₃ , 500MHz) δ7.97(d, J=9.0Hz, 1H), 7.36-7.30(m, 5H), 6.90(s, 1H), 6.71(d, J=8.5Hz, 1H ), 5.29 (d, j = 7.0Hz, 1H), 5.11 (d, J = 12.5Hz, 1H), 5.07 (d, J = 12.0Hz, 1H), 4.68 (dd, j = 13.0, 6.0Hz, 1H ), 3.74 (s, 3H), 3.20 (dd, j=13.5, 5.0Hz, 1H), 3.05 (dd, J=13.5, 6.0Hz, 1H).

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

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

(R)-2-Benzyloxycarbonylamino-3-(2-methyl-1H-benzimidazol-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 at 130°C for 4 hours. The mixture was then poured into water and cooled to 0 °C. The pH was adjusted to 8 by slowly 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 (95%) as a brown foamy solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ7.39(d, J=8.5Hz, 1H), 7.35(s, 1H), 7.26-7.22(m, 5H), 7.06(d, J=8.0Hz, 1H ), 5.03(d, J=12.5Hz, 1H), 4.99(d, J=13.0hz, 1H), 4.51(dd, J=8.5, 5.5Hz, 1H), 3.70(s, 3H), 3.27(dd , J=13.5, 5.0Hz, 1H), 3.03(dd, J=14.0, 9.0Hz, 1H), 2.55(s, 3H). Mass spectrum: 368.19 (MH) ⁺ .

(R)-2-Benzyloxycarbonylamino-3-[2-methyl-3-(2-trimethylsilyl-ethanesulfonyl)-3H-benzimidazol-5-yl]-propionic acid methyl ester

and

(R)-2-Benzyloxycarbonylamino-3-[2-methyl-1-(2-trimethylsilyl-ethanesulfonyl)-1H-benzimidazol-5-yl]-propionic acid methyl ester

Pure 2-trimethylsilyl-ethanesulfonyl chloride was added all at once to (R)-2-benzyloxycarbonylamino-3-(2-methyl-1H-benzimidazol-5-yl)-propane A suspension of methyl ester (533 mg, 1.96 mmol) and sodium carbonate in acetonitrile (20 mL). The mixture was stirred overnight at room temperature. The solvent was removed and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:2) as eluent to give the title compound as a waxy solid (1:1 mixture of N1 and N3 isomers , 66%).

¹ H-NMR (CDCl ₃ , 500MHz) δ7.68(d, J=8.5hz, 0.5H), 7.55(d, J=8.5Hz, 0.5H), 7.53(s, 0.5H), 7.41(s, 0.5H), 7.34-7.29(m, 5H), 7.06-7.04(m, 1H), 5.22(d, J=8.0Hz, 0.5H), 5.17(d, J=7.5Hz, 0.5H), 5.11- 5.07(m, 2H), 4.72-4.69(m, 1H), 3.75(s, 1.5H), 3.72(s, 1.5H), 3.24-3.17(m, 2H), 2.79(s, 3H), 0.92- 0.83 (m, 2H), -0.02 (s, 4.5H), -0.05 (s, 4.5H). Mass spectrum: 532.26 (MH) ⁺ .

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

and

(R)-2-Amino-3-[2-methyl-3-(2-trimethylsilyl-ethanesulfonyl)-3H-benzimidazol-5-yl]-propionic acid methyl ester

Under 40 psi hydrogen at room temperature, (R)-2-benzyloxycarbonylamino-3-[2-methyl-3-(2-trimethylsilyl-ethanesulfonyl)-3H-benzimidazole -5-yl]-propionic acid methyl ester and (R)-2-benzyloxycarbonylamino-3-[2-methyl-1-(2-trimethylsilyl-ethanesulfonyl)-1H-benzene A suspension of imidazol-5-yl]-propionic acid methyl ester (1:1 mixture, 600 mg) and 10% palladium on charcoal (180 mg) in methanol (50 mL) was shaken overnight in a Parr apparatus. After replacing the hydrogen with nitrogen, the mixture was filtered through a pad of celite. The solvent was removed in vacuo to give the title compound (80%) as a tan solid.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.81(d, J=8.5, 0.5Hz, 0.5H), 7.70(s, 0.5H), 7.58(d, J=8.5Hz, 0.5H), 7.49 (s, 0.5H), 7.25 (d, J = 9.0Hz, 1H), 3.89 (dd, J = 14.0, 6.5Hz, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.55 -3.51(m, 2H), 3.18(d, J=6.0Hz, 1H), 3.22-3.18(m, 0.5H), 3.14-3.09(m, 0.5H), 2.81(s, 1.5H), 2.80( s, 1.5H), 0.92-0.88 (m, 2H), 0.02 (s, 4.5H), 0.01 (s, 4.5H); ¹³ CNMR (CD ₃ OD, 125MHz) δ174.3, 174.1, 153.5, 153.3, 141.7, 140.6, 133.9, 133.82, 133.78, 132.7, 126.5, 126.3, 119.7, 119.0, 114.1, 113.4, 55.6, 51.8, 51.7, 51.6, 40.2, 39.8, 15.83, 15.77, 9.9, -3.07, 1. 398.20(MH) ⁺ .

(R)-3-[2-Methyl-1-(2-trimethylsilyl-ethanesulfonyl)-1H-benzimidazol-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-trimethylsilyl-ethanesulfonyl)-3H-benzimidazol-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- was prepared as above Preparation of [1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester. Purification by chromatography on silica gel using 1% triethylamine in ethyl acetate as eluent afforded the title compound (87%) as an off-white solid.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.82(d, J=8.5Hz, 0.5H), 7.80(s, 0.5H), 7.59(d, J=8.0Hz, 0.5H), 7.55(s , 0.5H), 7.33-7.30(m, 1H), 7.16(t, J=8.0Hz, 1H), 7.12(t, J=7.5Hz, 1H), 6.95(t, J=7.5Hz, 1H), 6.79(d, J=7.5Hz, 1H), 4.60-4.55(m, 1H), 4.45-4.40(m, 1H), 4.29-4.27(m, 2H), 4.15-4.10(m, 2H), 3.77( s, 1.5H), 3.74(s, 1.5H), 3.56-3.51(m, 2H), 3.35-3.31(m, 2H), 3.21-3.15(m, 1H), 2.91-2.80(m, 2H), 2.78(s, 1.5H), 2.77(s, 1.5H), 1.76-1.73(m, 1H), 1.66-1.61(m, 2H), 0.92-0.87(m, 2H), 0.009(s, 4.5H) , -0.007 (s, 4.5H). ¹³ CNMR (CD ₃ OD, 125MHz) 173.8, 173.7, 158.2, 158.1, 155.6, 153.4, 153.2, 141.6, 140.3, 137.2, 135.3, 135.1, 133.7, 132.5, 128.2, 126.4, 126.3, 1225.1, 0 , 118.8, 118.4, 114.0, 113.4, 113.2, 57.3, 56.2, 51.9, 51.7, 51.5, 43.8, 43.7, 42.9, 37.6, 37.2, 28.4, 17.4, 15.7, 15.6, 9.9, -3.1, -3.2. Mass spectrum: 655.36 (MH) ⁺ .

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

(R)-3-[2-methyl-1-(2-trimethylsilyl-ethanesulfonyl)-1H-benzimidazol-5-yl]-2-{[4-(2-oxo (R)-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester and (R)-3-[2-methyl-3- (2-Trimethylsilyl-ethanesulfonyl)-3H-benzimidazol-5-yl]-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- A 1:1 mixture of 3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester was treated as above (R)-2-{[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl ]-propionic acid for processing. The hydrolysis conditions (lithium hydroxide/methanol-tetrahydrofuran-water (1:1:1) were used at -15°C overnight. The title compound was obtained as a white solid (25%). Mass spectrum: 477.24 (MH) ⁺ .

Example 46

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

(R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4′]linked Piperidin-1′-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide Method preparation. Purification by silica gel chromatography using dichloromethane:methanol:triethylamine (93:5:2) as eluent afforded 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 afford the title compound as a white solid (11% yield). LC/MS: _tR = 1.59 min, 627.34 (MH) ⁺ .

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

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

¹ H-NMR (CD ₃ OD, 500MHz) δ7.34-7.28(m, 5H), 7.20(d, J=8.0hz, 1H), 6.88(s, 1H), 6.78(d, J=7.5Hz, 1H), 5.05-5.00(m, 2H), 4.42(dd, J=8.5, 5.0Hz, 1H), 3.70(s, 3H), 3.65(s, 1H), 3.33(br s, 2H), 3.11( dd, J=14.0, 5.0 Hz, 1H), 2.90 (dd, J=13.5, 9.0 Hz, 1H). ¹³ CNMR ( _CD3OD , 125MHz) 172.5, 157.4, 151.2, 140.2, 137.0, 128.5, 128.0, 127.7, 123.8, 120.9, 117.0, 116.9, 67.2, 55.7, 52.0, 37.2. Mass spectrum: 345.20 (MH) ⁺ .

(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

A solution of carbonyldiimidazole (498 mg, 3.07 mmol) in dichloromethane (15 mL) was added to (R)-3-(4-amino-3-hydroxy-phenyl)-2-benzyloxycarbonyl at 0°C In a solution of methyl amino-propionate (1.17g, 3.07mmol), diisopropylethylamine (1.60mL, 9.21mmol) and dichloromethane (85mL). The mixture was stirred at 0 °C for 4 hours. 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 (51%) as a white solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ9.07(s, 1H), 7.37-7.29(m, 5H), 6.96(s, 1H), 6.90(d, J=8.0Hz, 1H), 6.87(d , J=8.0Hz, 1H), 5.36(d, J=8.0Hz, 1H), 5.11(d, J=12.0Hz, 1H), 5.07(d, J=12.5Hz, 1H), 4.65(dd, J =13.5, 5.5Hz, 1H), 3.74(s, 3H), 3.17(dd, J=14.0, 5.5Hz, 1H), 3.07(dd, J=14.0, 6.0Hz, 1H). ¹³ CNMR (CDCl ₃ , 125MHz) δ171.9, 155.7, 155.5, 144.1, 136.2, 130.8, 128.6, 128.42, 128.38, 128.2, 125.1, 111.1, 109.8, 67.2, 55.1, 52.6, 38.3. Mass spectrum: 3H71. ⁺ .

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

(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester (310 mg) was added via cannula at 4.4% A solution of formic acid in methanol (20 ml, freshly prepared in degassed methanol) was added to a suspension of 10% palladium charcoal in 4.4% formic acid in methanol (20 ml, freshly prepared in degassed methanol). The resulting mixture was stirred at room temperature for 4 hours. After filtration through a pad of celite, the solvent was removed in vacuo to give a tan solid. This solid was dissolved in a mixture of ethyl acetate (50 mL), toluene (10 mL) and ethanol (40 mL) and solid sodium bicarbonate (3.1 g) was added. The mixture was stirred at room temperature for 2 hours and filtered. The solvent was removed in vacuo to give the title compound.

¹ H-NMR (CD ₃ OD, 500MHz) δ8.41(br s, 2H), 7.17(s, 1H), 7.09(br s, 2H), 4.32(s, 1H), 3.83(s, 3H), 3.33(s, 1H), 3.30(s, 1H), 3.22(s, 1H). Mass spectrum: 237.20 (MH) ⁺ .

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

As above for the preparation of (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}- Preparation of 3-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester. Purification by chromatography on silica gel using dichloromethane:methanol:triethylamine (93:5:2) as eluent afforded the title compound (33%) as a white solid.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.17-7.13(m, 3H), 7.08(d, J=7.9hz, 1H), 7.03(d, J=8.0Hz, 1H), 6.95(t, J=7.0Hz, 1H), 6.79(d, J=8.0Hz, 1H), 4.55-4.51(m, 1H), 4.44-4.41(m, 1H), 4.33(s, 2H), 4.14-4.10(m , 2H), 3.74(s, 3H), 3.33(br s, 2H), 3.23(dd, j=13.7, 5.2Hz, 1H), 3.03(dd, J=14.0, 9.7Hz, 1H), 2.92-2.82 (m, 2H), 1.79-1.63 (m, 4H). ¹³ CNMR (CD ₃ OD, 125MHz) 173.8, 158.2, 156.2, 155.6, 144.4, 137.1, 132.7, 129.3, 128.2, 125.7, 125.0, 122.2, 118.4, 113.4, 110.6, 109.6, 56.2, 52.4, 398. , 37.3, 28.4. Mass spectrum: 494.30 (MH) ⁺ .

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

As above for the preparation of (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}- 3-[1-(2-Trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid. Using the hydrolysis conditions (lithium hydroxide/methanol-tetrahydrofuran-water (1:1:1) at -15°C overnight. The title compound was obtained as a white solid (95%). Mass spectrum: 480.30 (MH) ⁺ .

Example 47

(R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine- 1′-yl-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide

As above for the preparation of (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4' ]bipiperidin-1'-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}- Preparation of amides. The crude product was purified by silica gel chromatography using dichloromethane:methanol:triethylamine (93:5:2) as eluent to give 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 (70%) as a white solid.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.20-7.14(m 4H), 7.08(d, J=9.0Hz, 1H), 6.96(td, J=7.5, 1.0Hz, 1H), 6.79(d , J=8.0Hz, 1H), 4.99-4.94(m, 1H), 4.61-4.58(m, 1H), 4.47-4.43(m, 1H), 4.39(s, 1H), 4.23-4.16(m, 2H ), 4.08-4.04(m, 1H), 3.06-2.88(m, 5H), 2.74-2.69(m, 2H), 2.59-2.52(m, 2H), 2.41-2.33(m, 2H), 1.96-1.89 (m, 1H), 1.88-1.47 (m, 16H). LC/MS: _tR = 1.86 min, 630.31 (MH) ⁺ .

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

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

¹ H-NMR (CD ₃ OD, 500MHz) δ7.75(d, J=8.5Hz, 1H), 7.58(s, 1H), 7.31-7.25(m, 5H), 7.18(d, J=8.5Hz, 1H), 5.39(d, J=8.0Hz, 1H), 5.10(d, J=12.0Hz, 1H), 5.05(d, J=12.0Hz, 1H), 4.74(dd, j=13.5, 6.0Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J=14.0, 5.5 Hz, 1H), 3.22 (dd, J=13.5, 6.0 Hz, 1H). ¹³ CNMR (CD ₃ OD, 125 MHz) δ 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spectrum 355.18 (MH) ⁺ .

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

Prepared following the procedure described above for the preparation of (R)-2-amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester.

¹ H-NMR (CD ₃ OD, 500MHz) δ8.38(br s, 2H), 7.89(d, J=7.5Hz, 1H), 7.81(s, 1H), 7.40(d, J=7.5Hz, 1H ), 4.44(s, 1H), 3.81(s, 3H), 3.48-3.45(m, 1H), 3.40-3.37(m, 1H), 3.33(br s, 1H). ¹³ CNMR (CD ₃ OD, 125 MHz) δ 169.8, 139.4, 138.9, 133.0, 127.6, 115.52, 115.47, 54.3, 52.6, 36.7. Mass spectrum 221.15 (MH) ⁺ .

Example 48

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

As above for the preparation of (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}- 3-[1-(2-Trimethylsilyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester was prepared except that carbonyldiimidazole was used instead of N,N-disuccinate Imidocarbonate (DSC).

¹ H-NMR (CD ₃ OD, 300MHz) δ7.82(d, J=8.4Hz, 1H), 7.24(s, 1H), 7.39(dd, J=8.7, 1.2Hz, 1H), 7.15-7.08( m, 2H), 6.94(td, J=7.5, 0.9Hz, 1H), 6.75(d, J=7.8Hz, 1H), 4.67-4.60(m, 1H), 4.39-4.31(m, 1H), 4.15 (s, 2H), 4.08-4.03 (m, 2H), 3.72 (s, 3H), 3.38 (dd, J=13.9, 5.5Hz, 1H), 3.32-3.29 (m, 1H), 3.17 (dd, J = 13.9, 10.3 Hz, 1H), 2.87-2.71 (m, 2H), 1.64-1.48 (m, 4H). Mass spectrum 478.30 (MH) ⁺ .

Example 49

(R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(1H-benzotriazole-5- Methyl)-2-[1,4']bipiperidin-1'-yl-2-oxo-ethyl]-amide

As above for the preparation of (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4' ]bipiperidin-1'-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}- Preparation of amides. Purification by silica gel chromatography using dichloromethane/methanol/triethylamine (93:5:2) as eluent.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.83d, J=8.2Hz, 0.75H), 7.79(d, J=8.5Hz, 0.25H), 7.71(s, 0.25H), 7.69(s, 0.75 H), 7.33(d, J=9.2Hz, 1H), 7.16-7.12(m, 2H), 6.96-6.91(m, 1H), 6.78(d, J=8.0Hz, 0.75H), 6.77(d, J=8.0Hz, 0.25H), 5.07-5.03(m, 1H), 4.58-4.55(m, 1H), 4.45-4.40(m, 1H), 4.34(s, 1.25H), 4.24(s, 0.75H ), 4.20-4.05(m, 2.25H), 4.00-3.96(m, 0.75H), 3.24-3.09(m, 2H), 2.91-2.78(m, 4H), 2.64-2.61(m, 2H), 2.56 -2.42(m, 2H), 2.15-2.10(m, 1.25H), 2.02-1.98(m, 1.75H), 1.95-1.90(m, 1H), 1.68-1.60(m, 8H), 1.54-1.46( m, 6H). LC/MS: _tR = 1.86 min, 614.28 (MH) ⁺ .

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

PyHBr ₃ (1.28 g, 4.02 mmol) was added in small portions to (R)-2-benzyloxycarbonylamino-3-(1H-indol-5-yl)- Methyl propionate (0.47 g, 1.34 mmol) in tert-butanol (10 mL) while maintaining the reaction temperature at 25-30°C. The resulting mixture was stirred at room temperature for 3.5 hours. The solvent was removed in vacuo and the residue was extracted with ethyl acetate (2x). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, the solvent was removed and the residue was azeotropically dried with absolute ethanol. The residue was dissolved in glacial acetic acid (10 mL), and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred overnight at room temperature. After removal of acetic acid in vacuo, the residue was chromatographed on silica gel using ethyl acetate/hexane [first (1:3) and then (3:2)] as eluents to afford the title as a white solid Compound (41%, 2 steps).

¹ H-NMR (CDCl ₃ , 500MHz) δ8.03(s, 1H), 7.36-7.31(m, 5H), 6.94(s, 1H), 6.91(d, J=8.0Hz, 1H), 6.73(d , J=7.5Hz, 1H), 5.26(d, J=8.0Hz, 1H), 5.11(d, J=12.0Hz, 1H), 5.05(d, j=12.5Hz, 1H), 4.61(dd, J =13.5, 6.0hz, 1H), 3.72(s, 3H), 3.45(s, 2H), 3.10(dd, J=14.0, 5.5Hz, 1H), 3.00(dd, J=14.0, 6.0Hz, 1H) . ¹³ CNMR (CDCl ₃ , 125MHz) δ177.7, 172.2, 155.7, 141.7, 136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1, 55.1, 52.5, 38.0, 36. Mass spectrum 369.20 (MH) ⁺ .

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

Prepared following the procedure described above for the preparation of (R)-2-amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester.

¹ H-NMR (CD ₃ OD, 500MHz) δ8.48(br s, 2H), 7.16(s, 1H), 7.10(s, 1H), 6.89(s, 1H), 4.21(s, 1H), 3.81 (s, 3H), 3.54(s, 1H), 3.33(s, 2H), 3.20(s, 1H), 3.12(s, 1H). ¹³ CNMR (CD ₃ OD, 125 MHz) δ 178.9, 170.7, 143.3, 129.0, 128.6, 126.9, 125.6, 110.0, 57.3, 54.6, 52.3, 37.0. Mass spectrum 235.30 (MH) ⁺ .

(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 (2M, 0.158mL, 0.30mmol) was added to vigorously stirred (R)-2-amino-3-(2-oxo-2,3-dihydro-1H-indole-5- Methyl)-propionic acid methyl ester (70 mg, 0.25 mmol) in a mixture of dichloromethane (15 mL) and saturated sodium bicarbonate (7.5 mL). After the mixture was stirred at room temperature for 30 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, and washed with 0.25N hydrochloric acid saturated with solid sodium chloride. The organic layer was dried over sodium sulfate. After filtration, the solvent was removed to give the title compound as a tan viscous oil. LC/MS: _tR = 2.01 min, 492.10 (MH) ⁺ .

Example 50

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

(R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4′]linked Piperidin-1′-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide method prepared. Purification by flash chromatography on silica gel using dichloromethane/methanol/triethylamine (93:5:2) as eluent.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.20-7.09(m, 4H), 6.97(t, J=7.3Hz, 1H), 6.88(d, J=7.9Hz, 0.65H), 6.84(d , J=7.6Hz, 0.35H), 6.80(d, J=7.7Hz, 1H), 5.51(s, 0.65H), 5.23(s, 0.35H), 4.99-4.95(m, 0.65H), 4.92- 4.88(m, 0.35H), 4.60-4.56(m, 1.65H), 4.46-4.41(m, 1.35H), 4.39(s, 1.3H), 4.36(s, 0.7H), 4.24-4.17(m, 2H), 4.05-4.02(m, 1H), 3.65-3.61(m, 2H), 3.52-3.47(m, 1H), 3.20-3.16(m, 1H), 3.00-2.88(m, 2H), 2.70- 2.64 (m, 2H), 2.53-2.46 (m, 2H), 2.40-2.34 (m, 2H), 1.94-1.46 (m, 15H), 1.39-1.36 (m, 2H). LC/MS: _tR = 1.83 min, 628.40 (MH) ⁺ .

2-(Di-tert-butoxycarbonylamino)-methyl acrylate

To a solution of 2-tert-butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (10.0 g, 39 mmol) and di-tert-butyl dicarbonate (21.8 g, 2.6 equiv) in acetonitrile (40 mL) at room temperature 4-Dimethylaminopyridine (0.48 g, 0.1 equiv) was added. The solution was stirred overnight and concentrated. The residue was dissolved in ether, washed sequentially with 1M potassium bisulfate (2x), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give 15.6 g (quantitative) of an oil. ¹ H NMR showed a mixture of the title compound and 2-(di-tert-butoxycarbonylamino)-3-tert-butoxycarbonyloxy-propionic acid methyl ester. Since both were later found to react with secondary amines to give the same product, this mixture was used without isolation. 2-(Di-tert-butoxycarbonylamino)-methyl acrylate: ¹ H-NMR (CDCl ₃ ) δ1.45 (s, 18H), 3.78 (s, 3H), 5.63 (s, 1H), 6.33 ( s, 1H). Mass spectrum: 324.14 (M+Na) ⁺ . 2-(Di-tert-butoxycarbonylamino)-3-tert-butoxycarbonyloxy-propionic acid methyl ester: ¹ H-NMR (CDCl ₃ , 500MHz) δ1.46(s, 9H), 1.49(s , 18H), 3.72 (s, 3H), 4.42 (dd, J=11.6, 9.2, 1H), 4.75 (dd, J=11.3, 4.6, 1H), 5.30 (dd, J=9.2, 4.6, 1H). Mass spectrum: 442.21 (M+Na) ⁺ .

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

To a solution of 2-(di-tert-butoxycarbonylamino)-methyl acrylate (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 resulting suspension was heated by microwave at 80°C for 2 hours. The reaction was concentrated, dissolved in water, and extracted with dichloromethane (3x). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to give 1.47 g (97%) which was used without purification. Mass spectrum: 503.56 (MH) ⁺ .

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

To 3-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-(di-tert-butoxycarbonylamino)-propionic acid methyl ester (1.47g, 2.9mmol) in methanol To a stirred solution in (17 mL) was added an aqueous solution (2.85 mL) of lithium hydroxide monohydrate (0.50 g, 4 equiv). The reaction mixture was stirred at room temperature for 3 hours, cooled to 0 °C, treated with concentrated hydrochloric acid (0.99 mL), and concentrated to give the crude acid, half of which was used in the following step. The crude acid was dissolved in dichloromethane (6 mL), cooled to 0 °C, and washed sequentially with 4-piperidinyl-piperidine (0.25 g, 1 eq), triethylamine (0.31 mL, 2.5 eq) and Bis-2-oxo-3-oxazolidinyl)phosphinic chloride (0.38 g, 1 eq.) was treated. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by preparative HPLC to afford 489 mg (52%, 2 steps). Mass spectrum: 639.41 (MH) ⁺ .

Example 51

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

At 0°C, to 4-benzyloxy-1-[3-[1,4']bipiperidin-1'-yl-2-(di-tert-butoxycarbonylamino)-3-oxo- To a stirred solution of propyl]-1H-pyridin-2-one in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 2 hours, the reaction was concentrated to afford the crude amine as its trifluoroacetate salt (151 mg, 97%) [mass spectrum: 439.61 (MH) ⁺ ], which was split in two and half used in the following step. To a solution of crude amine (75 mg, 0.11 mmol) and diisopropylethylamine (80 μL, 4 eq) in dichloromethane (3 mL) at 0 °C was added carbonyldiimidazole (29 mg, 1.6 eq, in two portions) . After stirring for 10 minutes, the solution was treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazoline-2-acetic acid (40 mg, 1.15 equiv). The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep-TLC to give 40.8 mg (53%).

¹ H-NMR (CD ₃ OD, 500MHz) δ1.25-1.56 (m, 4H), 1.56-1.84 (m, 9H), 1.90-2.08 (m, 2H), 2.60-2.95 (m, 8H), 3.11 (dd, J=24.1, 12.8, 1H), 3.89 (ddd, J=22.0, 13.2, 9.2, 1H), 4.10 (dd, J=14.3, 14.1, 2H), 4.27-4.54 (m, 5H), 4.60 (bd, J=11.9, 1H), 5.08 (dd, J=13.2, 12.2, 2H), 5.26 (ddd, J=9.4, 9.4, 4.8, 1H), 6.05 (dd, J=13.7, 2.7, 1H) , 6.16(m, 1H), 6.77(d, J=8.0, 1H), 6.84(ddd, J=7.6, 7.6, 2.1, 1H), 7.04(d, J=7.6, 1H), 7.12(dd, J = 7.6, 7.4, 1H), 7.28-7.43 (m, 5H), 7.48 (d, J = 7.6, 1H). Mass spectrum: 696.85 (MH) ⁺ .

Example 52

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

¹ H-NMR (CD ₃ OD, 500MHz) δ1.40-1.85 (m, 12H), 2.04 (dd, J=27.4, 17.0, 2H), 2.66 (dd, J=21.1, 11.0, 1H), 2.80- 3.19(m, 8H), 3.95(ddd, J=49.8, 12.5, 7.9, 1H), 4.07-4.28(m, 3H), 4.34(bs, 2H), 4.36-4.59(m, 2H), 4.63(bd , J=12.8, 1H), 5.20(m, 1H), 5.75(dd, J=7.3, 2.1, 1H), 5.97(dd, J=8.9, 7.6, 1H), 6.78(d, J=7.6, 1H ), 6.93 (dd, J=7.6, 7.3, 1H), 7.08-7.18 (m, 2H), 7.33 (dd, J=18.3, 11.0, 1H). Mass spectrum: 606.32 (MH) ⁺ .

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

To a solution of 2-(di-tert-butoxycarbonylamino)-acrylate methyl ester (1.0 g, 3.0 mmol) in acetonitrile (10 mL) was added piperidin-4-ol (0.33 g, 1.1 equiv). A gentle stream of nitrogen was passed through the reaction while stirring overnight. The resulting crude oil was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.38 g (quantitative) of an oil which was used without purification. Mass spectrum: 403.42 (MH) ⁺ .

(±)-1-[1,4']bipiperidin-1'-yl-2-(di-tert-butoxycarbonylamino)-3-(4-hydroxy-piperidin-1-yl)-propane -1-one

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

(±)-2-Amino-1-[1,4′]bipiperidin-1′-yl-3-(4-hydroxy-piperidin-1-yl)-propan-1-one

At 0°C, to 1-[1,4']bipiperidin-1'-yl-2-(di-tert-butoxycarbonylamino)-3-(4-hydroxyl-piperidin-1-yl) - To a solution of propan-1-one (310 mg, 0.58 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL). The ice bath was removed and the reaction was stirred for 30 minutes. The reaction was concentrated to give the desired product as its trifluoroacetate salt (400 mg, quant), which was used without purification. Mass spectrum: 339.46 (MH) ⁺ .

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

To 2-amino-1-[1,4']bipiperidin-1'-yl-3-(4-hydroxy-piperidin-1-yl)-propan-1-one (trifluoroacetate, 300mg , 0.58 mmol) and diisopropylethylamine (0.30 mL, 4 eq) in tetrahydrofuran (5 mL) was added di-tert-butyl dicarbonate (128 mg, 1 eq). The resulting solution was stirred at room temperature for 1 hour, 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%) which was used without purification. Mass spectrum: 439.65 (MH) ⁺ .

(±)-[2-[1,4']bipiperidin-1'-yl-2-oxo-1-(4-oxo-piperidin-1-ylmethyl)-ethyl]-amino tert-butyl formate

To 1-[1,4']bipiperidin-1'-yl-2-(di-tert-butoxycarbonylamino)-3-(4-hydroxy-piperidin-1-yl)-prop-1- To a solution of the ketone (200 mg, 0.37 mmol) in dichloromethane (4 mL) was added Dess-Martin periodinane (316 mg, 2 equiv) in two portions. After 1 hour, the reaction was quenched by addition of saturated sodium bicarbonate and extracted into dichloromethane (3x). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to give 187 mg (94%) which was used without purification. Mass spectrum: 437.63 (MH) ⁺ .

(±)-1-(2-Amino-3-[1,4′]bipiperidin-1′-yl-3-oxo-propyl)-piperidin-4-one

At 0°C, to [2-[1,4′]bipiperidin-1′-yl-2-oxo-1-(4-oxo-piperidin-1-ylmethyl)-ethyl] - To a solution of tert-butyl carbamate (100 mg, 0.23 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid. The ice bath was removed, stirring was continued for 1 hour, and the reaction was concentrated to give 150 mg (96%) as its trifluoroacetate salt which was used without purification. Mass spectrum: 337.64(MH) ⁺ .

Example 53

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

At 0°C, to 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiper Dichloropyridin-1'-yl-1-(4-hydroxy-piperidin-1-ylmethyl)-2-oxo-ethyl]-amide (3 trifluoroacetate, 200mg, 0.39mmol) To a solution in methane (5 mL) was added diisopropylethylamine (0.27 mL, 3.9 equiv) and carbonyldiimidazole (63 mg, 1 equiv). 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 warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep-TLC to afford 130 mg (56%) of an oil. LC/MS: _tR = 1.17 min, 596.44 (MH) ⁺ .

tert-butyl 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylate

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (10 g, 50 mmol) was dissolved in dimethylformamide dimethyl acetal (50 mL) and heated to reflux for 1.25 hours. The solution was cooled, concentrated, and purified by flash chromatography to give 2.55g (19%). Mass spectrum: 255.16 (MH) ⁺ .

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

To a solution of tert-butyl 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylate (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). The solution was heated to reflux, immediately cooled to room temperature, and concentrated to afford 1.4 g (63%) which was used without purification. Mass spectrum: 224.11 (MH) ⁺ .

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

Dissolve tert-butyl 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate (0.70 g, 3.1 mmol) in trifluoroacetic acid (10 mL ), stirred for 1 hour, and concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-hydrochloride salt precipitated as a white solid which was filtered to yield 510 mg (83%). The free base was prepared when required by dissolving the salt in water, loading it onto an SCX cartridge, flushing with methanol, and eluting with 2M ammonia in methanol.

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

To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (160 mg) in 2.5 mL of methanol was added 2-(di-tert-butoxycarbonylamino)-methacrylate Esters (400mg). The reaction was concentrated to approximately 1.5 mL by applying a gentle flow of nitrogen. The solution was stirred overnight at room temperature. The reaction was concentrated, dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was sufficiently pure to be used without purification.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.44(s, 9H), 2.73(m, 3H), 2.91(m, 1H), 3.06(dd, J=13.4, 8.6, 1H), 3.22(dd, J = 13.4, 8.2, 1H), 3.54 (d, J = 13.4, 1H), 3.63 (d, J = 13.4, 1H), 3.71 (s, 3H), 5.11 (dd, J = 8.5, 5.2, 1H) , 7.25 (s, 1H). Mass spectrum: 425.23 (MH) ⁺ .

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

To 2-(di-tert-butoxycarbonylamino)-3-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester ( To a solution of 0.55 g, 1 equiv) in dichloromethane (5 mL, 0°C) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring was continued for 2 hours. The solution was concentrated, redissolved in methanol, and passed through a column of strong cation exchange resin. After rinsing with methanol, the product was removed from the column by eluting with 2M ammonia in methanol to give the product in its free base form (275 mg, 95%).

¹ H-NMR (CDCl ₃ , 500MHz) δ2.71(dd, J=12.8, 8.6, 1H), 2.74-2.91(m, 6H), 3.48(s, 2H), 3.54(d, J=13.4, 1H ), 3.62 (d, J=13.4, 1H), 3.69 (dd, J=8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spectrum: 225.16 (MH) ⁺ .

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

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

¹ H-NMR (CDCl ₃ , 500MHz) δ1.09(s, 6H), 1.47(s, 9H), 2.47(dd, J=6.4, 6.4, 2H), 3.41(m, 2H), 3.70(m, 2H). Mass spectrum: 250.12 (M+Na) ⁺ .

tert-butyl 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylate

3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5g, 22mmol) was dissolved in dimethylformamide dimethyl acetal (25mL) and heated under reflux Heat for 2 hours. The reaction mixture was then heated by microwave at 130° C. for 1 hour and concentrated to give 6.43 g (quantitative) of an oil which was used without purification.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.07(s, 6H), 1.45(s, 9H), 3.06(s, 6H), 3.37(m, 2H), 4.57(m, 2H), 7.41(bs , 1H).

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

To a solution of tert-butyl 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylate (6.35 g, 22 mmol) in methanol (15 mL) was added hydrazine hydrate (1.2 mL, 1.1 equiv). The solution was stirred overnight at room temperature and concentrated to afford 5.3 g (94%) which was used without purification. Mass spectrum: 252.19(MH) ⁺ .

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

At 0°C, to 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (5.3g, 21mmol) To the solution in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction was warmed to room temperature, stirred for 15 minutes, and treated with additional trifluoroacetic acid (5 mL). After 1 hour, the reaction was concentrated, dissolved in ethanol (10 mL), cooled to 0 °C, treated with concentrated hydrochloric acid (3 mL), and concentrated. The resulting solid was triturated with ethanol and filtered to afford 3.02 g (64%) of its bis-hydrochloride salt form. The free base was prepared when required by dissolving the salt in water, loading it onto an SCX cartridge, flushing with methanol, and eluting with 2M ammonia in methanol.

¹ H-NMR (D ₂ O, 500 MHz) δ 1.49 (s, 6H), 3.46 (s, 2H), 4.39 (s, 2H), 7.86 (s, 1H). Mass spectrum: 152.14 (MH) ⁺ .

(±)-2-(di-tert-butoxycarbonylamino)-3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine -5-yl)-methyl propionate

To a solution of 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (160 mg) in methanol (3 mL) was added 2-(di-tert Butoxycarbonylamino)-methyl acrylate (331 mg). A gentle flow of nitrogen was applied and the reaction was stirred overnight. The next morning, its volume was greatly reduced. Traces of solvent were removed under high vacuum to afford 490 mg (quantitative), which was used without purification.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.24(s, 3H), 1.26(s, 3H), 1.38(s, 18H), 2.33(d, J=11.3, 1H), 2.57(d, J= 11.3, 1H), 3.09 (dd, J=13.1, 5.5, 1H), 3.15 (dd, J=13.4, 9.5, 1H), 3.35 (d, J=12.8, 1H), 3.57 (d, J=12.8, 1H), 3.68 (s, 3H), 5.13 (dd, J = 9.5, 3.7, 1H), 7.16 (s, 1H). Mass spectrum: 453.30 (MH) ⁺ .

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

To 2-(di-tert-butoxycarbonylamino)-3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5- To a solution of methyl propionate (0.49 g, 1 eq) in dichloromethane (5 mL, 0° C.) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring was continued for 2 hours. The solution was concentrated, redissolved in methanol, and packed on a strong cation exchange resin column. After rinsing with methanol, the product was obtained as its free base (250 mg, 94%) by eluting the product from the column with 2M ammonia in methanol.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.27(s, 3H), 1.28(s, 3H), 2.41(d, J=11.3, 1H), 2.50(d, J=11.3, 1H), 2.69( dd, J = 12.5, 7.9, 1H), 2.82 (dd, J = 12.5, 5.2, 1H), 3.45 (d, J = 12.8, 1H), 3.52 (d, J = 12.8, 1H), 3.67 (m, 1H), 3.69(s, 3H), 7.19(s, 1H). Mass spectrum: 253.16 (MH) ⁺ .

(±)-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 (260 mg, 1 equivalent) in dichloromethane (2 mL, 0°C) was added carbonyldiimidazole (188 mg, 1 eq) to the solution. 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 was continued overnight. The reaction was concentrated and purified by column chromatography to give 118 mg (21%).

¹ H-NMR (CDCl ₃ , 500MHz) δ1.60-1.80 (m, 4H), 2.70-3.05 (m, 8H), 3.45 (s, 2H), 3.56 (d, J=13.4, 1H), 3.62 ( d, J=13.4, 1H), 3.75(s, 3H), 4.02(d, J=13.1, 1H), 4.10(d, J=12.5, 1H), 4.24(s, 2H), 4.45-4.57(m , 2H), 5.79 (bs, 1H), 6.68 (d, J=7.94, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 7.00 (d, J=7.3, 1H), 7.13 (dd, J = 7.6, 7.3, 1H), 7.25(s, 1H), 7.82(s, 1H). Mass spectrum: 482.27 (MH) ⁺ .

Example 54

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

To 2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-(1,4,6 , To a solution of methyl 7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionate (16 mg, 1 equivalent) in methanol (0.6 mL) was added lithium hydroxide monohydrate (3 mg , 2.2 equivalents) in water (0.1 mL), and stirred at room temperature for 4 hours. The solution was cooled to 0 °C, treated with 1M aqueous potassium bisulfate (60 μl, 1.8 eq) and concentrated to give the crude acid which was used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and washed sequentially with dichloromethane (0.15 mL), 4-piperidinyl-piperidine (11 mg, 2 equivalents), diisopropylethylamine (12 μL, 2 equiv) and PyBOP ^(R) (19 mg, 1.1 equiv). The solution was stirred for 30 minutes and concentrated. The product was purified by column chromatography to yield 17.6 mg (85%, 2 steps).

¹ H-NMR (CDCl ₃ , 500MHz) δ1.30-1.60 (m, 9H), 1.62-1.78 (m, 5H), 1.81 (bd, J=11.0, 2H), 2.23-2.49 (m, 6H), 2.55-3.10(m, 11H), 3.59(d, J=7.3, 2H), 4.00-4.20(m, 3H), 4.23(s, 2H), 4.50(m, 1H), 4.63(m, 1H), 5.03 (m, 1H), 5.71 (d, J=7.3, 1H), 6.67 (d, J=7.9, 1H), 6.91 (dd, J=7.6, 7.3, 1H), 7.02 (dd, J=7.9, 7.3, 1H), 7.14 (dd, J = 7.6, 7.6, 1H), 7.24 (s, 1H), 7.39 (s, 1H), 10.76 (bs, 1H). Mass spectrum: 618.34 (MH) ⁺ .

Example 55

(±)-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

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

¹ H-NMR (CDCl ₃ , 500MHz) δ1.30(s, 3H), 1.31(s, 3H), 1.60-1.80(m, 4H), 2.43(d, J=11.6, 1H), 2.53(d, J=11.3, 1H), 2.80-2.95(m, 4H), 3.51(dd, J=20.4, 13.1, 2H), 3.74(s, 3H), 4.00(d, J=13.7, 1H), 4.10(d , J = 12.2, 1H), 4.25 (dd, J = 16.2, 14.4, 2H), 4.86 (m, 2H), 6.66 (d, J = 7.6, 1H), 6.92 (dd, J = 7.6, 7.3, 1H ), 7.02 (d, J=7.3, 1H), 7.14 (dd, J=7.6, 7.6, 1H), 7.24 (s, 1H). Mass spectrum: 510.27 (MH) ⁺ .

Example 56

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

To 3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-{[4-(2-oxo Add -1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino)-propionic acid methyl ester (20 mg, 1.0 equivalent) in methanol (0.6 mL) Aqueous solution (0.1 mL) of lithium hydroxide monohydrate (4 mg, 2.2 eq) was stirred at room temperature for 4 hours. The solution was cooled to 0°C, treated with 1M aqueous potassium bisulfate (75 μl, 1.8 eq) and concentrated to give the crude acid which was used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and washed sequentially with dichloromethane (0.15 mL), 4-piperidinyl-piperidine (13 mg, 2 equivalents), diisopropylethylamine (14 μL, 2 equiv) and PyBOP ^(R) (22 mg, 1.1 equiv). The solution was stirred for 1.5 hours and concentrated. The product was purified by column chromatography to give a product contaminated with HOBT. The product was passed through a basic alumina column to remove HOBT, eluting with 10% methanol in dichloromethane. Concentration afforded 18.3 mg (72% over 2 steps).

¹ H-NMR (CDCl ₃ , 500MHz) δ1.25-1.32 (m, 6H), 1.40 (m, 4H), 1.54 (m, 5H), 1.65 (m, 4H), 1.83 (m, 2H), 2.30 -2.56(m, 8H), 2.81(m, 4H), 3.04(dt, J=57.1, 12.2, 1H), 3.43-3.60(m, 2H), 4.00-4.17(m, 2H), 4.18-4.26( m, 3H), 4.49(m, 1H), 4.62(m, 1H), 5.03(m, 1H), 5.80(dd, J=16.8, 9.8, 1H), 6.69(d, J=7.9, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 6.99 (dd, J=7.6, 7.3, 1H), 7.13 (dd, J=7.6, 7.6, 1H), 7.19 (s, 1H), 7.66 (bd, J = 12.8, 1H). Mass spectrum: 646.43 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(6-methoxy-pyridin-3-yl)-methyl acrylate

To a suspension of potassium tert-butoxide (1.23 g, 1.5 eq) in dichloromethane (70 mL, -20 °C) was added trimethyl N-benzyloxycarbonyl-α-phosphonoglycine (3.63 g, 1.5 eq ) in dichloromethane (15 mL). The resulting solution was stirred for 5 minutes and treated with a solution of 6-methoxy-pyridine-3-carbaldehyde (1.0 g, 7.3 mmol) in dichloromethane (15 mL). After stirring for 1.5 hours, the reaction was allowed to warm to 0°C and stirred for 1 hour. The reaction was quickly poured into a separatory funnel containing ethyl acetate and water. Brine was added to help separate the layers. The aqueous layer was extracted with ethyl acetate (3X), washed with brine, dried over magnesium sulfate, and concentrated to give 2.63 g (quantitative), which was used without purification. Mass spectrum: 343.08 (MH) ⁺ .

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

A mixture containing 2-benzyloxycarbonylamino-3-(6-methoxy-pyridin-3-yl)-methyl acrylate (620 mg), palladium charcoal (10%, 100 mg), ethyl acetate (10 mL) and A methanol (20 mL) flask was bubbled with sufficient nitrogen, then hydrogen, and finally connected to a hydrogen balloon. The reaction was stirred overnight. The flask was flushed with nitrogen, filtered through celite, and concentrated to give 390 mg (quantitative), which was used without purification. Mass spectrum: 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

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

Example 57

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

To 3-(6-methoxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- To a solution of methyl 1-carbonyl]-amino}-propanoate (160 mg) in methanol (6 mL) was added an aqueous solution (1 mL) of lithium hydroxide monohydrate (29 mg). The reaction was stirred at room temperature for 4 hours and cooled to 0 °C. The reaction was treated with 1N hydrochloric acid (0.6 mL) and concentrated. The resulting residue was dissolved in dichloromethane (5 mL), and treated with 4-piperidinyl-piperidine (75 mg), triethylamine (0.14 mL) and bis-2-oxo-3-oxazole in sequence Alkyl)phosphinyl chloride (104 mg). The reaction was stirred overnight, concentrated, and purified by preparative HPLC to afford 94 mg (45%). LC/MS: _tR = 1.86 min, 604.51 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(2-methoxy-pyrimidin-5-yl)-methyl acrylate

To a suspension of potassium tert-butoxide (1.23 g) in dichloromethane (70 mL, -30 °C) was added N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (3.63 g) in dichloromethane ( 15mL) solution. The resulting solution was stirred for 5 minutes and treated with a solution of 2-methoxy-pyrimidine-5-carbaldehyde (1.0 g) in dichloromethane (15 mL). After stirring for 1.5 hours, the reaction was warmed to 0 °C and stirred for 1 hour. The reaction was quickly poured into a separatory funnel containing ethyl acetate and water. Add brine to help separate the layers. 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 spectrum: 344.10 (MH) ⁺ .

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

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

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

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

Example 58

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

To 3-(2-methoxy-pyrimidin-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- To a solution of methyl 1-carbonyl]-amino}-propanoate (99 mg) in methanol (6 mL) was added an aqueous solution (1 mL) of lithium hydroxide monohydrate (18 mg). The reaction was stirred at room temperature for 4 hours and cooled to 0 °C. The reaction was treated with 1N hydrochloric acid (0.4 mL) and concentrated. The resulting residue was dissolved in dichloromethane (3 mL) and washed sequentially with 4-piperidinyl-piperidine (50 mg), triethylamine (88 μL) and bis-2-oxo-3-oxazolidine base) phosphinyl chloride (71 mg). The reaction was stirred overnight, concentrated, and purified by preparative HPLC to afford 103 mg (45%). LC/MS: _tR = 1.23 min, 605.54 (MH) ⁺ .

2-Benzyloxy-5-bromo-pyridine

In an apparatus equipped with a Dean-Stark trap, combine 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, .05 equiv) A suspension of benzyl alcohol (1.1 mL, 1.3 equiv) and potassium hydroxide (1.1 g, 2.4 equiv) in toluene (30 mL) was heated at reflux for 3 hours. The suspension was cooled, concentrated, then suspended in water and extracted into dichloromethane. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85%) which was used without purification. Mass spectrum: 264.25 (MH) ⁺ .

6-Benzyloxy-pyridine-3-carbaldehyde

To a solution of 2-benzyloxy-5-bromo-pyridine (1.64 g, 6.2 mmol) in tetrahydrofuran (25 mL, -78°C) was added n-butyllithium (2.5M in hexane, 2.61 mL, 1.05 equiv). 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 quickly poured into a stirred solution of 5% aqueous sodium bicarbonate (50 mL) and extracted with diethyl ether (3x). The ethereal solution was washed with brine, dried over magnesium sulfate, and concentrated to give 1.16 g (quantitative), which was used without purification. Mass spectrum: 186.34 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-methyl acrylate

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

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

A flask was charged with methyl 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-acrylate (0.50 g, 1.2 mmol), Wilkinson's catalyst (200 mg, 0.2 equiv), methanol (5mL) and toluene (3mL). The flask was bubbled with sufficient nitrogen and then hydrogen, heated to 35° C., and stirred under a hydrogen atmosphere for 4 days. The reaction was flushed with nitrogen, diluted with methanol, filtered, and concentrated to give the crude product, which was purified by column chromatography to give 145 mg (29%).

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

To a stirred solution of 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester (130 mg, 0.31 mmol) in dichloromethane (5 mL, 0 °C) Trimethylsilyl iodide (44 μL, 1.0 equiv) was added. The ice bath was removed and stirring was continued 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 afford 81 mg (91%) which was used without purification. Mass spectrum: 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

To a stirred solution of 2-amino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester (60 mg, 0.21 mmol) in dichloromethane (1 mL, 0 °C) was added carbonyldiimidazole (34 mg, 1.0 equiv). After 15 minutes, a solution of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 1.2 equiv) in dichloromethane (0.5 mL) was added via cannula. The ice bath was removed and stirring was continued overnight. The reaction was concentrated and purified by column chromatography to give 59 mg (52%). Mass spectrum: 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']bipiperidin-1'-yl-2-oxo-ethyl]-amide

To 3-(6-benzyloxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- To a stirred solution of 1-carbonyl]-amino}-propionic acid methyl ester (59 mg, 0.11 mmol) in methanol (3 mL) was added an aqueous solution (0.5 mL) of lithium hydroxide monohydrate (9.1 mg, 2 equiv). The reaction was stirred at room temperature for 2 hours, cooled to 0 °C, quenched by addition of 1N hydrochloric acid (0.15 mL), and concentrated. The crude product was used without purification. The crude acid was dissolved in dichloromethane (2 mL, 0 °C) and washed sequentially with 4-piperidino-piperidine (34 mg, 1.8 equiv), triethylamine (35 μL, 2.3 equiv) and bis-2 -Oxo-3-oxazolidinyl)phosphinyl chloride (34 mg, 1.2 equiv). The ice bath was removed and the reaction was stirred overnight. The reaction was concentrated and purified by prep-TLC to give 30.3 mg (41%). LC/MS: _tR = 1.49 min, 680.29 (MH) ⁺ .

Example 60

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

Charge the flask with 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(6-benzyloxy-pyridine- 3-ylmethyl)-2-[1,4']bipiperidin-1'-yl-2-oxo-ethyl]-amide (27mg, 0.04mmol), palladium on charcoal (10%, 4mg) and methanol (1 mL). The flask was bubbled with sufficient nitrogen, then hydrogen, and stirred overnight under a hydrogen atmosphere. The flask was flushed with nitrogen and the reaction was filtered through celite to give 22.1 mg (94%). LC/MS: _tR = 0.93 min, 590.32 (MH) ⁺ .

1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate

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

¹ H NMR (C ₆ D ₆ , 500 MHz) δ 3.88 (q, J=7.5 Hz, 2H), 2.52 (m, 1H), 1.60-1.48 (m, 8H), 1.42 (s, 9H), 0.92 ( t, 3H). Mass spectrum: 280.44 (M+Na) ⁺ .

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

To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (8.23 g, 0.032 mol) in tetrahydrofuran (85 mL) was slowly added sodium bis(trimethylsilyl)amide (44 mL , 0.044mol) solution. After the resulting mixture was stirred at -78°C for 1 hour, a solution of 2-nitrobenzyl bromide (8.21 g, 0.038 mol) was added. The reaction mixture was warmed to room temperature and stirred overnight. It was then concentrated and the residue was partitioned between water and ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The final product was purified from the complex reaction mixture by silica gel column chromatography (eluent-hexane-ethyl acetate 4:1) to give the desired product (1.61 g, 13%) as a brown oil . Mass spectrum: 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 4-ethyl ester (1.61 g, 4.102 mmol) and 10% palladium on charcoal (0.10 g) in The mixture in ethanol (190 mL) was hydrogenated under 50 psi hydrogen overnight. The resulting mixture was filtered through a celite plug, and the filtrate was concentrated in vacuo to give the desired product (1.29 g, 99%) as a colorless oil. Mass spectrum: 363.45 (MH) ⁺ .

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

To a solution of 1-tert-butyl 4-ethyl 4-(2-amino-benzyl)-piperidine-1,4-dicarboxylate (1.29 g, 4.102 mmol) in dichloromethane (15 mL) was added 4.0 M Hydrogen chloride in dioxane (5 mL). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo to afford the title compound (1.23 g, 100%) as a white solid, which was used in the next step without purification. Mass spectrum: 263.40 (MH) ⁺ .

3,4-Benzo-2,9-diazaspiro[5.5]undecane-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 at room temperature overnight. The solution was diluted one-fold with water and passed through a short plug of AG ^(R) 1-X2 ion exchange resin (100-200 mesh) in the hydroxide form, eluting with 50% methanol in water. The collected fractions were evaporated to give the desired product (0.89 g, 100%) as a white solid. ¹ H-NMR (CD ₃ OD, 500MHz) δ7.23(m, 2H), 7.05(d, J=7.5Hz, 1H), 6.89(d, J=8.0Hz, 1H), 3.46-3.41(m, 2H), 3.34-3.30 (m, 2H), 2.14-2.09 (m, 2H), 1.73-1.67 (m, 4H). Mass spectrum: 217.46 (MH) ⁺ .

(R)-2-Amino-3-benzo[b]thiophen-3-yl-1-[1,4′]bipiperidin-1′-yl-propan-1-one, dihydrochloride

To well stirred 3-benzo[b]thiophen-3-yl-(2R)-2-tert-butoxycarbonylamino-propionic acid (1.0 g, 3.1 mmol) in dichloromethane (30 mL) at room temperature 4-piperidinopiperidine (573mg, 3.4mmol), triethylamine (1.3mL, 9.3mmol) were added to the solution in , followed by 3-(diethoxyphosphoryloxy)-1 , 2,3-Benzotriazin-4(3H)-one (1.02 g, 3.4 mmol). After 3 hours, the reaction mixture was treated with aqueous sodium bicarbonate (15 mL), brine (20 mL), and dried (sodium sulfate). The crude mixture was purified by flash chromatography using 5% methanol in dichloromethane to afford (1R)-1-benzo[b]thiophen-3-ylmethyl-2-[1 in 82% yield ,4']bipiperidin-1'-yl-2-oxo-ethyl)-tert-butyl carbamate. (1R)-1-Benzo[b]thiophen-3-ylmethyl-2-[1,4′]bipiperidin-1′-yl-2-oxo-ethyl)-carbamic acid tert-butyl A solution of the dichloromethane (5 mL) of the base ester (1.2 g, 2.54 mmol) was added to a saturated solution of hydrogen chloride in dioxane (20 mL) and stirred for 2 hours. Removal of solvent afforded (2R)-2-amino-3-benzo[b]thiophen-3-yl-1-[1,4']bipiperidin-1'-yl-prop-1 in 98% yield - Ketone, dihydrochloride.

¹ H-NMR (500MHz, CD ₃ OD): δ7.98-7.88(m, 2H), 7.55-7.40(m, 3H), 4.85-4.83(m, 1H), 3.66-2.68(m, 9H), 1.92-1.44 (m, 12H). Mass spectrum: 372 (MH) ⁺ .

Example 61

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

To 2-amino-3-benzo[b]thiophen-3-yl-1-[1,4′]bipiperidin-1′-yl-propan-1-one (50.0mg, 0.135mmol) of 1, To a solution of 2-dichloroethane (1.5 mL) were added N,N'-disuccinimidyl carbonate (34.6 mg, 0.135 mmol) and diisopropylethylamine (0.09 mL, 0.500 mmol). The resulting solution was stirred for 1 hour at which time 3,4-benzo-2,9-diazaspiro[5.5]undecan-1-one (30.4 mg, 0.140 mmol) was added. The reaction mixture was stirred overnight at room temperature and concentrated. Purification was achieved by reverse phase preparative HPLC to afford the desired product (75.5 mg, 77%) as a brown oil.

¹ H-NMR (CD ₃ OD, 500MHz) δ7.92-7.85(m, 2H), 7.44-7.34(m, 3H), 7.21-7.16(m, 2H), 7.00(t, J=7.0Hz, 1H ), 6.86(t, J=8.5Hz, 1H), 5.15-5.02(m, 1H), 4.72-4.45(m, 1H), 3.95-3.20(m, 8H), 3.18-2.92(m, 4H), 2.92-2.75 (m, 2H), 2.75-2.63 (m, 1H), 2.40-2.30 (m, 1H), 2.08-1.64 (m, 8H), 1.58-1.20 (m, 6H). Mass spectrum: 614.37 (MH) ⁺ .

Example 62

N-[(1R)-1-(benzo[b]thiophen-3-ylmethyl)-2-[1,4-bipiperidinyl]-1-yl-2-oxoethyl]-3' , 4′-Dihydro-2-oxospiro-[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] The method of thiophen-3-ylmethyl-2-[1,4′]bipiperidin-1′-yl-2-oxo-ethyl)-amide, from 3′,4′-dihydro- 2-Oxospiro-[piperidine-4,4'(1H)-quinoline] was prepared (M.S.Chambers, et al., J.Med.Chem., 1992, 35, 2033-2039; WO-94/13696) .

¹ H-NMR (CDCl ₃ , 500MHz) δ-0.35 (1H, m), 0.79 (1H, m), 1.2-2.1 (12H, m), 2.22 (5H, m), 2.38 (2H, m), 2.74 (2H,ABq), 3.19(3H,m), 3.33(2H,m), 3.65(1H,d), 3.80(1H,m), 3.93(1H,t), 4.49(1H,d), 5.31( 1H,t), 5.96(1H,t), 6.89(1H,d), 7.05(1H,t), 7.18(1H,d), 7.26(1H,m), 7.33(1H,m), 7.40(1H , m), 7.78 (1H, m), 7.96 (1H, Abq), 9.01 (1H, brs), 9.17 (1H, brs). Mass spectrum: 614.36 (MH) ⁺ .

Example 63

N-[(1R)-1-(benzo[b]thiophen-3-ylmethyl)-2-[1,4-bipiperidinyl]-1-yl-2-oxoethyl]-2' , 3′-Dihydro-1-oxospiro-[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] The method of thiophen-3-ylmethyl-2-[1,4′]bipiperidin-1′-yl-2-oxo-ethyl)-amide, from 2′,3′-dihydro- 1-Oxospiro-[piperidine-4,4'(1H)-isoquinoline] was prepared (M.S.Chambers, et al., J.Med.Chem., 1992, 35, 2033-2039; WO-94/13696 ).

¹ H-NMR (CDCl ₃ , 500MHz) δ0.01(1H, m), 0.78(1H, m), 1.1-2.0(12H, m), 2.15-2.30(5H, m), 2.74(1H, t) , 3.0-3.6(9H), 3.89(2H, m), 4.46(1H, d), 5.29(1H, m), 5.62(1H, d), 6.47(1H, brs), 7.38(5H, m), 7.51(1H,m), 7.77(1H,m), 7.85(1H,m), 8.11(1H,d). Mass spectrum: 614.42 (MH) ⁺ .

Example 64

N-[(1R)-1-(benzo[b]thiophen-3-ylmethyl)-2-[1,4'-bipiperidine]-1'-yl-2-oxoethyl]- 1,2-Dihydro-2-oxospiro-[4H-3,1-benzoxazine-4,4′-piperidine]-1′-carboxamide

According to the preparation of (R)-1-oxo-3,4-benzo-2,9-diaza-spiro[5.5]undec-3-ene-9-carboxylic acid (1-benzo[b] Thiophene-3-ylmethyl-2-[1,4′]bipiperidin-1′-yl-2-oxo-ethyl)-amide, by 1,2-dihydro-2-oxo Spiro-[4H-3,1-benzoxazine-4,4'-piperidine] was prepared (as described in Takai, et al; Chem.Pharm.Bull.1985, 33, 1129-1139), The title compound (76%) was obtained. Mass spectrum: 616 (MH) ⁺ _.Rf = 1.42.

Succinate Intermediates and Examples

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

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

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

A suspension of 3-benzo[b]thiophen-3-yl-acrylic acid: (5.6 g, 0.027 mol) and 10% Pd/C (600 mg) in 1:1 methanol/ethyl acetate (50 mL) was added at 50 psi Hydrogenation was carried out overnight in a Parr apparatus under hydrogen. The mixture was filtered and concentrated to give the crude product without further purification (about 100% conversion). Mass spectrum: 205 (MH) ^- .

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

To a solution of 3-benzo[b]thiophen-3-yl-propionic acid (2.1 g, 0.010 mol), triethylamine (4.12 g, 0.040 mol) in anhydrous tetrahydrofuran (100 mL) was added fresh Valeryl chloride (1.38 mL, 0.011 mol). After stirring at 0° C. for 1.5 hours, lithium chloride (0.475 g, 0.011 mol) and (R)-4-benzyl-2-oxazolidinoe (1.988 g, 0.011 mol) were added. The reaction mixture was warmed 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 give crude product. Flash chromatography on silica gel eluting with 100% dichloromethane gave the title product as a brown oil (90%). This compound was used directly in the next step.

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

To 3-(3-benzo[b]thiophen-3-yl-propionyl)-4-benzyl-oxazolidin-2-one (3.35 g, 9.18 mmol) in 100 mL of anhydrous To the tetrahydrofuran solution was added a solution of lithium diisopropylamide in tetrahydrofuran (6.1 mL, 11.01 mmol), and the reaction mixture was stirred for 30 min. After adding tert-butyl bromoacetate (1.62 mL, 11.01 mmol) at -78°C, the mixture was stirred overnight while it was warmed to room temperature. The solvent was evaporated, and the residue was diluted with ethyl acetate. The organic layer was washed with water (3 x 100 mL), dried, filtered, and concentrated to give crude product. Filtration through a pad of silica eluting with dichloromethane afforded the title product (49%).

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

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

3(S)-Benzo[b]thiophen-3-ylmethyl-4-[1,4′]bipiperidin-1′-yl-4-oxo-butyric acid tert-butyl ester

2-Benzo[b]thiophen-3-ylmethyl-4-tert-butyl succinate (1.8420g, 5.76mmol), piperidinylpiperidine (1.2240g, 7.28mmol) and triethylamine (0.7353g , 7.28mmol) in 100mL of dichloromethane with 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 1.8953g, 6.34mmol) deal with. The mixture was stirred overnight, and then washed with water (3 x 40 mL). The organic layer was dried, filtered, and concentrated in vacuo to give crude product. This was further purified by flash chromatography on silica gel, eluting with 0-10% 2M ammonia in methanol/dichloromethane, to afford the desired product. The product was used without further purification.

3(S)-Benzo[b]thiophen-3-ylmethyl-4-[1,4′]bipiperidin-1′-yl-4-oxo-butanoic acid

A solution of 3-benzo[b]thiophen-3-ylmethyl-4-[1,4′]bipiperidin-1′-yl-4-oxo-butyric acid tert-butyl ester in 15 mL of dichloromethane Trifluoroacetic acid (3 mL) was treated and the reaction mixture was stirred overnight at room temperature. Evaporation of the solvent gave the corresponding trifluoroacetate salt of the title product (99%).

Example 65

1-[1,4']bipiperidin-1'-yl-2-(3(S)-benzo[b]thiophen-3-ylmethyl)-4-[1',2'-dihydro -2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione

At room temperature, 3-benzo[b]thiophen-3-ylmethyl-4-[1,4']bipiperidin-1'-yl-4-oxo-butanoic acid (25.0mg, 0.060mmol ), 1,2-dihydro-2-oxospiro-4H-3,1-dihydro-benzoxazine-4'4-piperidine (15.7mg, 0.072mmol) and triethylamine (7.3mg, 0.072mmol) in 5mL of dichloromethane with 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 21.5mg, 0.072mmol )deal with. The solution was stirred overnight, and then washed with water (3 x 5 mL). The organic layer was dried, concentrated, and the crude product was purified by flash chromatography on silica gel, eluting with 0-10% 2M ammonia in methanol/dichloromethane, to give the desired product in 60% yield. LC/MS: _tR = 1.34 min, 615.45 (MH) ⁺ .

2-(7-Methyl-1H-indazol-5-ylmethylene)-1-methyl succinate

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

(±)-2-(7-Methyl-1H-indazol-5-ylmethyl)-1-methyl succinate

2-(7-Methyl-1H-indazol-5-ylmethylene)-succinic acid 1-methyl ester (0.4440 g, 1.62 mmol) and 10% Pd/C (0.04 g) were dissolved in ethyl acetate ( 15 mL) and methanol (5 mL) was hydrogenated overnight in a Parr apparatus under 50 psi hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to give the desired product as a yellow solid (100%). Mass spectrum: 277 (MH) ⁺ .

Example 66

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxospiro-[4H -3′,1-Benzoxazin-4,4′-piperidinyl]-butyric acid methyl ester

2-(7-Methyl-1H-indazol-5-ylmethyl)-1-methyl succinate (0.2253g, 0.82mmol), 1,2-dihydro-2-oxospiro-4H- A solution of 3,1-dihydro-benzoxazine-4'4-piperidine (0.1938g, 0.89mmol) and triethylamine (0.099g, 0.98mmol) in dichloromethane (15mL) was treated with 3-(diethyl Oxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 0.2685 g, 0.90 mmol). The mixture was stirred overnight, and then washed with water (3 x 5 mL). The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-10% 2M ammonia in methanol/dichloromethane, to afford the desired product (53%). LC/MS: _tR = 1.40 min, 477.28 (MH) ⁺ .

Prepare similarly:

Example 67

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

¹ H-NMR (400MHz, CDCl ₃ ) δ8.02(1H, s), 7.98(1H, m), 7, 90(1H, m), 7.35-6.89(4H, m), 6.72(1H, m) , 4.71(1H, m), 4.57(1H, m), 4.27(1H, s), 4.22(1H, m), 3.85(1H, m), 3.65(3H, m), 3.30(1H, m), 3.11 (2H, m), 2.83 (2H, m), 2.81-2.54 (4H, m), 2.35 (1H, m), 1.73-1.67 (4H, m). Mass spectrum: 490.32 (MH) ⁺ .

(±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxospiro-[4H -3′,1-Benzoxazin-4,4′-piperidinyl]-butanoic acid

2-(7-Methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxospiro-[4H-3′ , 1-benzoxazin-4,4'-piperidinyl]-butyric acid methyl ester (0.1911 g, 0.40 mmol) and lithium hydroxide (19.3 mg, 0.80 mmol) in tetrahydrofuran (10 mL) and water (8 mL) The solution in was stirred overnight at room temperature. The reaction mixture was acidified to about pH 1 with 1N hydrochloric acid and concentrated in vacuo to remove THF to give a white solid precipitate which was collected by filtration. The solid was washed twice with a small amount of water and dried under vacuum overnight (100%). Mass spectrum: 477 (MH) ⁺ .

Example 68

(±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1',2'- Dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione

At room temperature, 2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxospiro-[ 4H-3', 1-benzoxazin-4,4'-piperidinyl]-butanoic acid (0.020g, 0.04mmol), piperidinylpiperidine (0.0087g, 0.05mmol) and triethylamine (0.09 g, 0.08mmol) in dichloromethane (5mL) was treated with 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 0.0155g, 0.05mmol) treatment. The mixture was stirred overnight, and then washed with water (3 x 5 mL). The organic layer was dried, and the solvent was removed in vacuo. The crude product was purified by prep-TLC on silica gel (10% 2M ammonium hydroxide/methanol in dichloromethane) to give the desired product (36%). LC/MS: _tR = 1.18 min, 613.47 (MH) ⁺ .

Prepare similarly:

Example 69

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

¹ H-NMR (400MHz, CDCl ₃ ) δ7.99 (1H, m), 7.62 (1H, m), 7.38 (1H, m), 7.14 (1H, m), 7.04-6.90 (3H, m), 6.70 (2H, d, J=8.0Hz), 4.70-4.58 (3H, m), 4.24 (2H, m), 4.00 (2H, m), 3.70 (1H, m), 3.18-2.72 (5H, m), 2.64-2.22 (8H, m), 2.18-0.82 (17H, m). Mass spectrum: 626.34 (MH) ⁺ .

Example 70

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

¹ H-NMR (400MHz, CDCl ₃ ) δ8.06(1H, s), 7.75(1H, m), 7.36(1H, m), 7.14(1H, m), 7.01-6.79(3H, m), 6.70 (1H, m), 4.70-4.49 (2H, m), 4.23 (2H, m), 3.98 (1H, m), 3.87 (3H, m), 3.65-3.44 (4H, m), 3.26 (1H, m ), 3.10-2.88 (3H, m), 2.75 (1H, m), 2.51 (3H, s), 2.35 (1H, m), 2.00 (1H, m), 1.70-1.00 (9H, m). Mass spectrum: 601.38 (MH) ⁺ .

Example 71

(±)-1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(7-methyl-1H-indazol-5-ylmethyl) -4-[1′,2′-Dihydro-2′-oxospiro-[4H-3′,1-benzoxazin-4,4′-piperidinyl]-butane-1,4- diketone

¹ H-NMR (400MHz, CDCl ₃ ) δ9.27 (1H, m), 8.00 (1H, s), 7.37 (1H, m), 7.23 (1H, m), 7.10-6.99 (3H, m), 6.87 (1H, m), 4.54 (1H, m), 3.97-3.50 (10H, m), 3.30 (1H, m), 3.16-2.76 (4H, m), 2.53 (3H, s), 2.35 (1H, m ), 2.20-1.00 (9H, m). Mass spectrum: 588.36 (MH) ⁺ .

Example 72

(±)-N, N-dimethyl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1, 4-Dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanamide

LC/MS: _tR = 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: _tR = 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

¹ H-NMR (400MHz, CDCl ₃ ) δ8.06 (1H, b), 7.60-6.73 (7H, m), 4.71 (1H, m), 4.54 (2H, m), 4.26 (2H, m), 4.05 -3.89 (2H, m), 3.65 (1H, m), 3.09-2.81 (4H, m), 2.61 (3H, s), 2.41 (2H, m), 1.76-0.51 (15H, m). Mass spectrum: 557.38 (MH) ⁺ .

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: _tR = 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 '-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butyramide

LC/MS: _tR = 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′- Oxospiro-[4H-3′,1-benzoxazin-4,4′-piperidinyl]-butane-1,4-dione

¹ H-NMR (400MHz, CDCl ₃ ) δ9.26-9.01 (1H, m), 8.09 (1H, s), 7.42-6.89 (7H, m), 4.56 (1H, m), 3.84 (1H, m) , 3.65(3H,m), 3.30(2H,m), 3.05(3H,m), 2.81(1H,m), 2.60(3H,s), 2.39(1H,m), 2.09(2H,m), 1.85 (1H, m), 1.43-0.79 (9H, m). Mass spectrum: 530.34 (MH) ⁺ .

Example 78

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

¹ H-NMR (400MHz, CDCl ₃ ) δ8.02(1H, s), 7.82(1H, m), 7.37(1H, m), 7.14(1H, m), 7.04-6.90(3H, m), 6.73 (1H, d, J=8.0Hz), 4.69(1H, m), 4.56(1H, m), 4.24(2H, d, J=7.2Hz), 4.02(1H, m), 3.65(2H, m) , 3.33(3H, m), 3.07(3H, m), 2.78(1H, m), 2.55(3H, s), 2.36(1H, m), 1.80-1.50(4H, m), 1.43(4H, b ), 1.26(2H,b), 0.81(2H,b). Mass spectrum: 543.40 (MH) ⁺ .

Example 79

(±)-1-[1,4']bipiperidin-1'-yl-2-(1H-indazol-5-ylmethyl)-4-[1',2'-dihydro-2' -oxospiro-[4H-3′,1-benzoxazin-4,4′-piperidinyl]-butane-1,4-dione

¹ H-NMR (400MHz, CDCl ₃ ) δ8.86 (1H, m), 7.98 (1H, s), 7.54-6.85 (7H, m), 4.73-4.48 (3H, m), 3.96-.80 (3H , m), 3.73-3.58 (3H, m), 3.17-2.78 (5H, m), 2.55-2.24 (5H, m), 2.02-1.79 (6H, m), 1.70-0.79 (7H, m). Mass spectrum: 599.31 (M+Na) ⁺ .

Example 80

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

LC/MS: _tR = 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: _tR = 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]-butanamide

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

Example 83

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

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

Example 84

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

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

Aspartate intermediates and examples

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

To N-tert-butoxycarbonyl-L-aspartic acid-α-benzyl ester (1.4g, 4.33mmol) and 3,4-dihydro-3-(4-piperidinyl-2(1H)- To a stirred solution of quinazolinone (1.26 g, 4.33 mmol) in dichloromethane (12 mL) was added 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine- 4(3H)-ketone (DEPBT, 1.425g, 4.76mmol), followed by dropwise addition of triethylamine (0.724mL, 5.20mmol).The resulting suspension gradually became homogeneous under stirring, and stirred overnight at room temperature ( 15 hours). The mixture was diluted with dichloromethane and washed with sodium hydroxide (0.5N) and water. The layers were separated and the organic layer was dried over sodium sulfate and concentrated in vacuo to give a pale yellow foam. The crude product was passed through Purification by flash column chromatography (10% methanol in dichloromethane) afforded a colorless oil. Mass Spectrum: 559 (M+Na) ⁺ .

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

To 2-tert-butoxycarbonylamino-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine in a Parr bottle To a solution of benzyl-1-yl]-butyrate (1.48 g, 2.76 mmol) in ethyl acetate/methanol (16 mL, 1:1) was added 10% palladium on charcoal (150 mg) in one portion. Hydrogenation was carried out at 52 psi hydrogen for 1 hour using a Parr apparatus. TLC (10% methanol in dichloromethane) 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']bipiperidine-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinone Azolin-3-yl)-piperidin-1-yl]-propyl}-tert-butyl carbamate

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ8.86-8.55 (1H, br), 7.05 (1H, br), 6.93 (1H, br), 6.82 (1H, br), 6.72 (1H, d, J= 7.6Hz), 6.10-5.68(1H, br), 5.20(1H, m), 54.70-4.40(2H, br), 4.20(2H, br), 4.01-3.82(2H, br.), 3.10-2.88( 3H, br), 2.99 (3H, br), 2.53 (6H, br), 1.90-1.10 (23H, m). Mass spectrum: 597 (MH) ⁺ .

(L)-2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-butane-1,4-dione

To stirred {1-([1,4']bipiperidine-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazole To a solution of tert-butyl carbamate (1.05 g, 1.76 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature until complete conversion (monitored by LCMS, about 15 hours). The mixture was then diluted with water and sodium hydroxide (1.5 g) was added slowly with stirring. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a pale yellow foam (860 mg, 98%). Mass spectrum: 497 (MH) ⁺ .

Example 86

(L)-1-[1,4']bipiperidin-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']bipiperidin-1'-yl-4-[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione (52mg, 0.105mmol) and N-tert-BOC-5 -Bromo-indole (prepared as described in Tetrahedron 2000, pp 8473-8482) (31 mg, 0.105 mmol) in tetrahydrofuran (1 mL) was added 2-dicyclohexylphosphino-2'-(N,N- Dimethylamino)-biphenyl (4.1 mg, 0.0105 mmol), Pd2(dba)3 (4.8 mg, 0.005 mmol) and cesium carbonate (54.6 mg, 0.168 mmol). The vial was sealed with a teflon ^(R) -lined cap. The dark orange reaction mixture was heated at 80°C with stirring. The reaction was continued overnight at 80°C. After 17 hours, conversion reached approximately 50%. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane and filtered. The desired product was purified by preparative TLC (10% methanol in dichloromethane) to afford the tert-butoxycarbonyl-protected product (11 mg, 15%). Mass spectrum: 712 (MH) ⁺ . This intermediate (11 mg) was dissolved in 3 mL of dichloromethane and treated with trifluoroacetic acid (1.5 mL). The colorless solution turned brown and was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo and dried under high vacuum to give a brown powder (15 mg, 100%). Mass spectrum: 612 (MH) ⁺ .

Example 87

(L)-1-[1,4']bipiperidin-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

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

Example 88

(L)-1-[1,4']bipiperidin-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

Under microwave irradiation, in a microwave vial, 2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1,4-di Hydrogen-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione (22.3mg, 0.045mmol) and 4,6-dichloropyrimidine (16mg, 0.095mmol ) in 2-propanol (0.5 mL) was heated at 130°C for 40 minutes. LC/MS indicated 90% conversion. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and 1N 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% (1 N ammonia in methanol) in dichloromethane) to give a white solid (23 mg, 84%).

¹ H-NMR (400MHz, CDCl ₃ ) δ8.36 (1H, d, J = 12.8Hz), 8.04-7.81 (1H, 2s), 7.14 (1H, t, J = 7.6Hz), 7.10-6.80 (2H , m), 6.74 (1H, t, J=8.2Hz), 6.52-6.42 (1H, m), 5.90-5.50 (1H, br), 4.85-4.40 (3H, m), 4.40-4.05 (3H, m ), 4.05-3.82(1H, m), 3.20-3.00(2H, m), 3.00-2.68(2H, m), 2.68-2.30(8H, m), 2.05-1.90(2H, m), 1.90-0.70 (12H, m). Mass spectrum: 609 (MH) ⁺ .

Prepare similarly:

Example 89

(L)-1-[1,4']bipiperidin-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: _tR = 1.10 min, 649 (MH) ⁺ .

Example 90

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

LC/MS: _tR = 1.12 min, 649 (MH) ⁺ .

Example 91

(L)-1-[1,4']bipiperidin-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

In a Parr bottle, to 2-(4-amino-6-methyl-5-nitro-pyrimidin-2-ylamino)-1-[1,4′]bipiperidin-1′-yl-4- 2:1 methanol/ To the ethyl acetate (6 mL) solution was added 10% palladium on charcoal (60 mg). The mixture was shaken under a 55 psi hydrogen atmosphere for 20 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to give a colorless solid (41.2 mg, 49.2%, two steps). LC/MS: _tR = 0.86 min, 619 (MH) ⁺ .

Example 92

(L)-1-[1,4']bipiperidin-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- diketone

To stirred 1-[1,4']bipiperidin-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 (10.6mg, 0.0125mmol) in acetic acid (1.5 mL) solution was added sodium nitrite (24 mg), followed by a few drops of water. The resulting pale 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: _tR = 1.07 min, 630 (MH) ⁺ .

The synthetic general method of embodiment 93-95:

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

Example 93

(L)-1-[1,4']bipiperidin-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: _tR = 0.87 min, 588 (MH) ⁺ .

Example 94

(L)-1-[1,4']bipiperidin-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: _tR = 0.92 min, 626 (MH) ⁺ .

Example 95

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

LC/MS: _tR = 1.08 min, 600 (MH) ⁺ .

Example 96

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

In a Parr bottle, 1-[1,4']bipiperidin-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 (21mg) solution was dissolved in 4mL ethyl acetate/methanol (1:1 ), 10% palladium on charcoal (10 mg) was added. Hydrogenation was performed overnight at 55 psi hydrogen in a Parr 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 spectrum: 575 (MH) ⁺ .

Example 97

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

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

Example 98

(L)-1-[1,4']bipiperidin-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

To the stirred 2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- yl)-piperidin-1-yl]-butane-1,4-dione (20.6 mg, 0.0415 mmol) and 4-imidazole formaldehyde (carboxyylaldehyde) (4 mg, 0.0415 mmol) in dichloromethane (1.0 mL) Sodium cyanoborohydride (8.8 mg, 0.0415 mmol) was added in one portion. The suspension was stirred at room temperature for 2 days and then partitioned between dichloromethane and 1N sodium hydroxide. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (10% (IN ammonia in methanol) in dichloromethane) to give the desired product as a colorless oil which solidified on standing (6.1 mg, 26%).

¹ H-NMR (400MHz, CDCl ₃ ) δ7.61 (1H, d, J = 4.8Hz), 7.16 (1H, t, J = 7.6Hz), 7.10-6.85 (3H, m), 6.67 (1H, d , J=8.0Hz), 4.85-4.63 (2H, m), 4.63-4.40 (1H, m), 4.40-3.65 (7H, m), 3.25-2.40 (10H, m), 2.15-0.70 (18H, m ). Mass spectrum: 577 (MH) ⁺ .

Example 99

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

To 2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -Piperidin-1-yl]-butane-1,4-dione (91.5mg, 0.184mmol) and p-methoxybenzoyl chloride (34.6mg, 0.203mmol) in a stirred mixture in dichloromethane was added two Triethylamine (35 μL) was dropped. The pale yellow solution was stirred at room temperature for 2.5 hours to achieve complete conversion. The reaction mixture was washed with sodium hydroxide (1N), and then the aqueous layer was extracted with dichloromethane. The combined organic layers were passed through a column of celite and concentrated in vacuo to give a glassy solid. The crude product was purified by flash column chromatography (10% (1 N ammonia in methanol) in dichloromethane) to give a glassy solid (92.8 mg, 80%).

¹ H-NMR (400MHz, CDCl ₃ ) δ8.55-8.47 (1H, d), 8.10-7.78 (3H, m), 7.09 (1H, t, J=7.4Hz), 6.96-6.74 (4H, m) , 5.62-5.44(1H,br), 4.75-4.40(3H,m), 4.40-4.05(3H,m), 4.05-3.82(1H,br), 3.76(3H,s), 3.18-2.88(3H, m), 2.88-2.70 (1H, m), 2.70-2.30 (8H, m), 2.05-1.19 (14H, m). Mass spectrum: 631 (MH) ⁺ .

Example 100

(L)-N-{1-([1,4']bipiperidine-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-propyl}-4-hydroxyl-benzamide

The stirred N-{1-([1,4']bipiperidine-1'-carbonyl)-3-oxo Generation-3-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-propyl}-4-methoxy-benzene A solution of formamide in dichloromethane (69 mg). The resulting suspension was stirred at room temperature for 7 hours, and then the reaction was quenched with excess triethylamine followed by methanol. The solvent was removed in vacuo, and the residue was dissolved in methanol and purified by preparative HPLC. LC/MS: _tR = 1.03 min, 617 (MH) ⁺ .

Example 101

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

To stirred pyrazole-3-carboxylic acid (4mg, 0.036mmol) and 2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1 , 4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione (13 mg, 0.026 mmol) in dichloromethane (1 mL) once 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 8.6 mg, 0.036 mmol) was added rapidly, followed by a drop of triethylamine. The resulting mixture was stirred overnight (15 hours) at room temperature. The mixture was then partitioned between sodium hydroxide (0.5N) and dichloromethane. The layers were separated, and the aqueous layer was extracted with dichloromethane (3x). LCMS indicated product remained in the aqueous layer. The product was purified by preparative HPLC to give a yellow oil (17.2 mg, 94%). Mass spectrum: 591 (MH) ⁺ .

General method for the synthesis of Examples 102-134:

The raw material amine, 2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-butane-1,4-dione distributed in 1 mL of dichloroethane in a 96-well micro-reactor (mini-reactor) (about 10 mg per well) . The different acid chlorides (about 2 equiv) were added separately, followed by the resin-bound solid phase piperidine base (4 equiv). The partitioned reaction blocks were shaken overnight. Approximately 4 equivalents of tri-amine resin were added to each well and the micro-reaction plate was shaken for an additional 5 hours. The reaction mixture was filtered and purified by preparative HPLC or by SCX cartridge or both. The HPLC retention times and mass spectral data for each example are listed in Table 2.

Table 2. Amides and carbamates

General method for the synthesis of Examples 135-200:

The raw material amine, 2-amino-1-[1,4']bipiperidin-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-butane-1,4-dione was distributed in dichloroethane (1 mL) in a 96-well micro-reaction plate (10 mg per well). Different isocyanates (about 2 equivalents) were added to each well. The partitioned reaction plate was shaken for 2 days. Approximately 4 equivalents of tri-amine resin were added to each well and the micro-reaction plate was shaken for an additional two days. The reaction mixture was filtered and purified by preparative HPLC or by SCX cartridge or both. The HPLC retention times and mass spectral data for each example are listed in Table 3.

Table 3. Urea

2-(1H-Indazol-5-ylamino)-4-tert-butyl 1-ethyl succinate

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

¹ H-NMR (400 MHz, CDCl ₃ ) δ7.89 (1H, s), 7.40-7.27 (1H, m), 6.98-6.77 (2H, m), 4.42-4.35 (1H, m), 4.30-4.12 ( 3H, m), 2.80 (2H, d, J=4.4Hz), 1.43 (9H, s), 1.27-1.17 (4H, m). Mass spectrum: 356.24 (M+Na) ⁺ , 278.23 (M- ^t Bu) ⁺ , t _R = 1.287 min.

2-(1H-Indazol-5-ylamino)-1-ethyl succinate

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

2-(1H-Indazol-5-ylamino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-ethyl butyrate

To a stirred solution of 1-ethyl 2-(1H-indazol-5-ylamino)-succinate (84 mg, 0.215 mmol) in dichloromethane (1 mL) was added the 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 and then diluted with ethyl acetate and washed with half saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to a brown oil. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in dichloromethane, to afford the desired product as a reddish oil (36.2 mg, 34.5%, two steps).

¹ H-NMR (400MHz, CDCl ₃ ) δ7.90 (2H, d, J = 4.4Hz), 7.33 (1H, d, J = 8.4Hz), 7.20-7.14 (1H, m), 7.00-6.80 (4H , m), 6.70(1H, t, J=6.8Hz), 4.58-4.48(1H, m), 4.65-4.40(2H, m), 4.34-4.05(3H, m), 4.02-3.82(1H, m ), 3.20-2.99 (2H, m), 2.99-2.84 (1H, m), 2.70-2.52 (1H, m), 1.80-1.50 (5H, m), 1.35-1.12 (5H, m). LC/MS: _tR = 1.130 min, 491.37 (MH) ⁺ .

2-(1H-Indazol-5-ylamino)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-butanoic acid

To a solution of the ethyl ester (34 mg, 0.069 mmol) in tetrahydrofuran (0.3 mL) was added an aqueous solution of lithium hydroxide (1M, 280 μL, 4 equiv), and the mixture was stirred at room temperature for 17 hr. The solution was dried under nitrogen flow. To the residue were added 0.2 mL of tetrahydrofuran and 0.2 mL of anhydrous benzene, and the suspension was blown dry again with a stream of nitrogen. LC/MS: _tR = 0.900 min, 463.30 (MH) ⁺ .

Example 201

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

To 2-(1H-indazol-5-ylamino)-4-oxo-4-[4-(2-oxo-1, 4-Dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid ethyl ester (0.069 mmol) in dimethylformamide (0.5 mL) was added piperidinyl piperidine (14.3 mg, 0.076 mmol, 1.1 eq), DEPBT (22.8 mg, 1.1 eq) and triethylamine (8 drops, about 160 μL). The mixture was stirred overnight at room temperature. The final product was purified by preparative HPLC to give the desired product as a tan solid (15 mg, 26%, two steps). LC/MS: _tR = 0.917 min, 613.54 (MH) ⁺ .

Another 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 mixed in ethanol (20 mL). The resulting suspension was stirred at room temperature for 20 min, then a solution of sodium borohydride (0.25 g, 6.61 mmol) in ethanol (5 mL) was added dropwise over 10 min. After the addition was complete, the reaction was stirred for 1 hour, cooled to 0°C, and concentrated ammonium chloride was added to the reaction mixture until no bubbling was observed. The solvent was evaporated in vacuo and the resulting crude mixture was dissolved in water (10 mL) and dichloromethane (10 mL). The layers were separated, and the organic layer was washed with water (2x) and brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 1.5 g (70%) of the desired product. LC/MS: _tR = 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 powder (1 g, excess) were dissolved in 75% aqueous acetic acid (16 mL) mixed and stirred at 60°C for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the resulting crude product was dissolved in water (10 mL), followed by addition of ammonium hydroxide until pH 3 was reached. The solution was extracted with dichloromethane (3x). The organic layers were collected together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 0.8 g (73%) of the desired product.

¹ H-NMR (CD ₃ OD) δ2.50 (m, 2H), 3.20 (m, 2H), 3.49 (dd, J=7.0, 7.3, 1H), 3.62 (m, 4H), 4.20 (s, 2H) ), 4.36 (s, 2H), 7.04 (m, 2H), 7.32 (dd, J=7.3, 7.6, 1H), 7.41 (d, J=7.9, 1H), 7.50 (m, 5H). Mass spectrum: 296.40 (MH) ⁺ .

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 sulfonamide (0.64 g, 6.78 mmol) in pyridine was refluxed Heat for 14 hours. After cooling to room temperature, the solvent was evaporated and the crude product was dissolved in water. After adjusting to pH 9 with 6N sodium hydroxide, the resulting mixture was extracted with dichloromethane (2x). The extract was washed with water (2x), dried over sodium sulfate, filtered, and concentrated to give an oily residue which was dissolved in ethyl acetate (4 mL). This solution was mixed with 4N HCl in 1,4-dioxane (2 mL), followed by addition of diethyl ether until the product precipitated out. 0.7 g (53%) of the desired product was obtained by filtration. LC/MS: _tR = 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 (0.46g, 1.29 mmol) in methanol (10 mL) was flushed with nitrogen and treated with palladium on charcoal (10%, 46 mg). The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography afforded 0.26 g (75%) of the desired material.

¹ H-NMR (CD ₃ OD) δ1.53-1.61 (m, 2H), 1.80 (m, 2H), 2.55 (m, 2H), 2.95-3.05 (m, 2H), 3.30 (m, 2H), 3.70 (m, 2H), 4.65 (s, 2H), 6.70 (d, J=7.9, 1H), 7.40 (dd, J=8.2, 6.7, 1H), 7.10 (m, 2H). Mass spectrum: 268.10 (MH) ⁺ .

6-Bromo-3-piperidin-4-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 a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (0.5 mL) dropwise over a period of 5 minutes. After stirring at room temperature for 1 hour, the reaction mixture was diluted with dichloromethane, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to give 0.16 g (59%), which was used without further purified and used directly. LC/MS: _tR = 0.91 min, 310.15 (MH) ⁺ .

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

6-Bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.16g, 0.52mmol), zinc cyanide (37mg, 0.31mmol) and tetrakis( Triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was mixed in dimethylformamide (4 mL). The reaction flask was connected to high vacuum and degassed (3x) by freeze-thaw method, then heated at 90 °C with stirring 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 afford 50 mg (38%) of the desired nitrile.

¹ H-NMR (CD ₃ OD) δ1.99 (m, 2H), 2.08-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, 1H), 4.40 ( m, 1H), 4.47 (s, 2H), 6.93 (d, J=8.1, 1H), 4.10 (m, 2H). Mass spectrum: 257.13 (MH) ⁺ .

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

(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-ethylcarbodiimide (2.3 g, 12.03 mmol) were mixed in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.1 mmol), and the reaction mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2x), 5% sodium bicarbonate, brine (2x), dried over sodium sulfate, and concentrated to give 3.5 g (98%) of the desired product . LC/MS: _tR = 1.24 min, 354.30 (MH) ⁺ .

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

N-(1-Benzyl-piperidin-4-yl)-2-(2-nitro-phenyl)-acetamide (3.2 g, 9.06 mmol) and lithium aluminum hydride (1.0 g, 18.12 mmol) were dissolved in Mix in a flame-dried flask. 1,4-Dioxane (15 mL) was added, and the mixture was slowly refluxed for 1 hour and stirred at reflux for 16 hours. The reaction mixture was cooled to 0 °C and excess lithium aluminum hydride was destroyed by the dropwise addition of methanol followed by careful addition of 20% potassium hydroxide. The aluminum salt was filtered, and the filtrate was concentrated and used in the next reaction.

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

[2-(2-Amino-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine (0.44 g, 1.42 mmol) was dissolved in tetrahydrofuran (5 mL) at 0 °C A stirred solution of , was treated with carbonyldiimidazole (0.23 g, 1.42 mmol). The reaction was stirred at 0 °C for 30 min and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to give 100 mg (21%) of the desired product. LC/MS: _tR = 1.29 min, 336.34 (MH) ⁺ .

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

3-(1-Benzyl-piperidin-4-yl)1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (100mg, 0.3mmol ) in methanol (5 mL) was flushed with nitrogen and treated with palladium on charcoal (10%, 10 mg). The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography afforded 50 mg (68%) of the desired material. LC/MS: _tR = 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 mixed in ethanol (30 mL). The resulting suspension was stirred at room temperature for 20 min, then a solution of sodium borohydride (1.13 g, 29.9 mmol) in ethanol (10 mL) was added dropwise over 10 min. After the addition was complete, the reaction was stirred at room temperature for 1 hour, cooled to 0°C, and concentrated ammonium chloride was added to the reaction mixture until no bubbling was observed. The solvent was evaporated in vacuo and the resulting crude mixture was dissolved in water (30 mL) and dichloromethane (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 afford 5.8 g (57%) of the desired product. LC/MS: _tR = 0.95 min, 342.27 (MH) ⁺ .

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

(1-Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine (0.25 g, 0.7 mmol) and zinc powder (0.2 g, excess) in 75% aqueous acetic acid (8 mL ) and stirred at 60°C for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the resulting crude mixture was dissolved in water (10 mL), followed by the addition of ammonium hydroxide until pH 3 was reached. The solution was extracted with dichloromethane (3x). The organic layers were collected together, washed with water (2x), brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 0.18 g (79%) of the desired product.

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

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

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

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

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

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

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

N-(1-Benzyl-piperidin-4-yl)-2-methoxy-6-nitro-benzamide (1.0 g, 2.8 mmol) and lithium aluminum hydride (0.31 g, 8.45 mmol) were mixed in Mix in a flame-dried flask. To this mixture was added dry 1,4-dioxane (15 mL). The mixture was slowly refluxed for 1 hour and stirred at reflux for 16 hours. The reaction mixture was cooled to 0 °C and excess lithium aluminum hydride was destroyed by the dropwise addition of methanol followed by careful addition of 20% potassium hydroxide. The aluminum salt was filtered, and the filtrate was concentrated and used in the next reaction.

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

Stirred (2-amino-6-methoxy-benzyl)-(1-benzyl-piperidin-4-yl)-amine (0.2 g, 0.62 mmol) in tetrahydrofuran (3 mL) was stirred at 0°C The solution was treated with carbonyldiimidazole (99 mg, 0.62 mmol). The reaction was stirred at 0 °C for 30 min and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to give 150 mg (68%) of the desired product. LC/MS: _tR = 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) The solution was flushed with nitrogen and treated with palladium on charcoal (10%, 10 mg). The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography afforded 68 mg (93%) of the desired material. LC/MS: _tR = 1.11 min, 262.23 (MH) ⁺ .

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

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

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

N-(1-Benzyl-piperidin-4-yl)-2-chloro-6-nitro-benzamide (1.67 g, 4.47 mmol) and lithium aluminum hydride (0.51 g, 13.43 mmol) were flame dried mixed in the flask. Anhydrous 1,4-dioxane (15 mL) was added thereto. The mixture was slowly refluxed and stirred for 16 hours. The reaction mixture was cooled to 0 °C and excess lithium aluminum hydride was destroyed by the dropwise addition of methanol followed by careful addition of 20% potassium hydroxide. The aluminum salt was filtered, and the filtrate was concentrated and used in the next reaction.

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

A stirred solution of (2-amino-6-chloro-benzyl)-(1-benzyl-piperidin-4-yl)-amine (0.66 g, 2.0 mmol) in tetrahydrofuran (8 mL) was dissolved at 0°C with Carbonyldiimidazole (0.36 g, 2.05 mmol) was treated. The reaction was stirred at 0 °C for 30 min and refluxed for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to give 0.58 g (82%) of the desired product. LC/MS: _tR = 1.40 min, 356.25 (MH) ⁺ .

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

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

5-Bromo-1H-indole-3-carbonitrile

A mixture of 5-bromo-indole-3-carbaldehyde (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 heated at reflux 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and water was added to the dark residue. After a short time, 5-bromo-1H-indole-3-carbonitrile precipitated rapidly. The solid was filtered, washed several times with water, and dried for several hours to afford 4.3 g (86%) of the desired product.

¹ H-NMR (CD ₃ OD) δ 7.40 (m, 2H), 7.77 (s, 1H), 7.97 (s, 1H). Mass spectrum: 222.95 (MH) ⁺ .

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 weighed into a flame-dried round bottom equipped with a magnetic stir bar in the flask. Dry tetrahydrofuran (24 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, during which time it became homogeneous. The stirred mixture was cooled to -78°C and a solution of sec-butyllithium in cyclohexane (1.4M, 30.2 mL, 2.2 equiv) was added over several minutes. After 1 h at -78 °C, dimethylformamide (6.0 mL) was added slowly, and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0°C and carefully treated with 1N hydrochloric acid (45 mL). After a few minutes, solid sodium bicarbonate was added until the pH reached 9-10. The two layers were separated and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography afforded 2.4 g (72%) of pure material. LC/MS: _tR = 0.99 min, 171.07 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(3-cyano-1H-indol-5-yl)-methyl acrylate

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

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

A solution of methyl 2-benzyloxycarbonylamino-3-(3-cyano-1H-indol-5-yl)-acrylate (0.5 g, 1.3 mmol) in methanol (8 mL) was flushed with nitrogen and washed with palladium Charcoal (10%, 50mg) treatment. The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography afforded 0.3 g (92%) of the desired material. LC/MS: _tR = 0.80 min, 244.20 (MH) ⁺ .

Example 202

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

A stirred solution of 2-amino-3-(3-cyano-1H-indol-5-yl)-propionic acid methyl ester (25 mg, 0.11 mmol) in tetrahydrofuran (3 mL) was washed with carbonyl di Imidazole (17.5 mg, 1.1 equiv) was treated. The reaction was stirred at 0°C for 5 minutes, warmed to room temperature, stirred for 10 minutes, and treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (25 mg, 1.1 Equivalent) processing. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography to give 40 mg (75%) of a white powder. LC/MS: _tR = 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']bipiperidine- 1'-yl-1-(3-cyano-1H-indol-5-yl-methyl)-2-oxo-ethyl]-amide

At room temperature, 3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- Base)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (15mg, 0.03mmol) in methanol (0.6mL) and lithium hydroxide monohydrate (3.0mg, 2.5eq) in water (0.1mL ) solution treatment. The solution was stirred at room temperature for 2 hours. The solution was cooled to 0 °C and treated with 1M aqueous potassium bisulfate (60 μL, 2.0 eq) and the solvent was evaporated to give the crude acid which was used without purification. The crude acid was dissolved in dimethylformamide (0.4 mL), cooled to 0 °C, and washed sequentially with dichloromethane (0.2 mL), 4-piperidinyl-piperidine (11 mg, 2.2 equiv), N , N-diisopropylethylamine (12 μL, 2.3 equiv) and PyBop (19 mg, 1.2 equiv). The solution was stirred at 0 °C for 15 min, warmed to room temperature, stirred for 1.5 h, and concentrated. The product was purified by column chromatography to give 10.1 mg (52%, 2 steps).

¹ H-NMR (CD ₃ OD) δ1.60-2.10 (m, 14H), 2.53 (d, J=13.0, 1H), 2.58 (d, J=12.2, 1H), 2.65-3.00 (m, 7H) , 3.12(d, J=7.0, 1H), 3.17(d, J=7.0, 1H), 3.84(s, 1H), 3.46(bs, 1H), 4.08-4.86(m, 5H), 4.70(m, 1H), 5.02(dd, J=8.2, 6.7, 1H), 6.79(d, J=7.6, 1H), 6.9(m, 1H), 7.10(dd, J=7.3, 7.9, 1H), 9.18(s , 1H), 7.15 (dd, J=7.3, 7.6, 1H), 7.30 (m, 1H), 7.50 (m, 1H), 8.00 (s, 1H). Mass spectrum: 647.41 (MH) ⁺ .

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

Under ice cooling, concentrated hydrochloric acid (15 mL), water (40 mL) and sodium nitrite (2.74 g, 39.7 mmol) in water (40 mL) to give the diazonium salt. The solution was transferred dropwise to a solution of 50% potassium hydroxide (16 mL) and ethyl-2-methylacetoacetate (5.38 mL, 38 mmol) in ethanol (50 mL) at 0°C. After the addition was complete, the reaction mixture was poured into ice-water (150 mL), and extracted with ethyl acetate. The organic layer was washed with brine (2x), dried over sodium sulfate, filtered, and concentrated to afford 7.5 g (66%) of the title compound, which was used without purification.

¹ H-NMR (CD ₃ OD) δ1.80 (t, J=7.0, 3H), 2.13 (s, 3H), 2.29 (s, 3H), 4.26 (dd, J=5.8, 7.0, 1H), 4.30 (dd, J = 5.8, 7.0, 1H), 7.26 (m, 2H), 7.43 (m, 1H). Mass spectrum: 323.07 (MNa) ⁺ .

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 at reflux in a Dean-Stark water trap for 1.5 hours. To this solution was added ethyl 5-bromo-7-methyl-1H-indole-2-carboxylate (7.5 g, 25.0 mmol) in toluene (40 mL) and the reaction mixture was heated at reflux for 5 hours. 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 collected together and washed with sodium bicarbonate (2x), brine (2x), dried over sodium sulfate, filtered and concentrated. Silica gel column chromatography afforded 5.5 g (78%) of the title compound.

¹ H-NMR (CD ₃ OD) δ1.35(t, J=7.0, 3H), 2.52(s, 3H), 4.36(q, J=7.0, 2H), 7.13(s, 1H), 7.14(s , 1H), 7.70(s, 1H), 11.90(s, 1H). Mass spectrum: 284.09 (MH) ⁺ .

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

Ethyl 5-bromo-7-methyl-1H-indole-2-carboxylate (5.3 g, 18.7 mmol) was added to a 1:1 water/ethanol mixture (20 mL) of potassium hydroxide solution and heated at reflux Under heating for 12 hours. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue was transferred to 6N hydrochloric acid solution (20 mL). The white precipitate formed was filtered, washed several times with water, and dried for several hours. The crude solid was dissolved in quinoline (14 mL) and heated at 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. Attempts to recrystallize the desired product from isopropanol resulted in apparent decomposition. Flash chromatography on silica gel afforded 1.5 g of the title compound (38% over 2 steps). LC/MS: _tR = 1.72 min, 210.05 (MH) ⁺ .

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

5-Bromo-7-methyl-1H-indole (1.2 g, 5.71 mmol) was dissolved in acetonitrile (6 mL) and slowly transferred to bromomethylenedimethyl Ammonium bromide (1.36 g, 6.28 mmol) in acetonitrile (9 mL). 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 room temperature, the crude mixture was extracted with ethyl acetate (2x). The organic layers were collected together and washed with brine (2x), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel afforded 0.7 g (52% over 2 steps) of the desired compound.

¹ H-NMR (CD ₃ OD) δ 2.50 (s, 3H), 7.24 (s, 1H), 8.34 (m, 1H), 9.93 (s, 1H). Mass spectrum: 238.05 (MH) ⁺ .

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

A mixture of 5-bromo-indole-3-carbaldehyde (0.7 g, 2.94 mmol), diammonium hydrogen phosphate (2.05 g, 15.5 mmol) in 1-nitropropane (9 mL) and acetic acid (3 mL) was refluxed Heat for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and water was added to the dark residue. After a short time, 5-bromo-1H-indole-3-carbonitrile precipitated rapidly, was filtered, washed several times with water, and dried for several hours to afford 0.6 g (87%) of the desired nitrile. LC/MS: _tR = 1.71 min, 235.01 (MH) ⁺ .

5-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 (flame- dried) in a round bottom flask. Dry tetrahydrofuran (9 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, during which time it became homogeneous. The stirred mixture was cooled to -78°C and a solution of sec-butyllithium in cyclohexane (1.4M, 3.8 mL, 2.2 equiv) was added over several minutes. After 1 h at -78 °C, dimethylformamide (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 carefully treated with 1N hydrochloric acid. After a few minutes, solid sodium bicarbonate was added until the pH reached 9-10. The two layers were separated and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography yielded 60 mg (14%) of the desired product and 0.4 g of unreacted starting material. LC/MS: _tR = 1.21 min, 185.10 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(3-cyano-7-methyl-1H-indol-5-yl)-methyl acrylate

A stirred solution of N-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (180 mg, 0.54 mmol) in tetrahydrofuran (3 mL) was treated with tetramethylguanidine (40 μL, 1.1 equiv) at room temperature. After 10 minutes, 5-formyl-7-methyl-1H-indole-3-carbonitrile (50 mg, 0.27 mmol) was added. After stirring at room temperature for 3 days, the solvent was evaporated and the residue was washed with water (2x), brine (2x), dried over sodium sulfate and concentrated. Column chromatography afforded 100 mg (95%) of pure material. LC/MS: _tR = 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)-methyl acrylate (0.1 g, 0.26 mmol) in methanol (2.5 mL) The solution was flushed with nitrogen and treated with palladium on charcoal (10%, 10 mg). The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated. By column chromatography, 60 mg (90%) of the desired material were obtained. LC/MS: _tR = 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']bipiperidine- 1'-yl-1(3-cyano-7-methyl-1H-indol-5-yl-methyl)-2-oxo-ethyl]-amide

Prepared according to the method of the above-mentioned Example 203: ¹ H-NMR (CD ₃ OD) δ1.55-2.10 (m, 16H), 2.50 (s, 3H), 2.80-3.20 (m, 9H), 4.10-4.40 ( m, 7H), 4.90(m, 3H), 6.72(d, J=7.9, 1H), 6.93(dd, J=8.5, 8.5, 1H), 7.40(s, 1H), 7.88(s, 1H), 7.90(s, 1H), 7.99(s, 1H). Mass spectrum: 651.57 (MH) ⁺ .

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 a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (5 mL) dropwise over a period of 10 minutes. After stirring at room temperature for 1 hour, the reaction mixture was diluted with dichloromethane, washed with water (2x), saturated sodium thiosulfate (2x), saturated sodium bicarbonate (2x) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel afforded 7.6 g (quantitative) of the desired product. LC/MS: _tR = 1.37 min, 230.07 (MH) ⁺ .

4-Bromo-2-isopropyl-6-methyl-phenyldiazo-tert-butylsulfide

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 with a solution of sodium nitrite (2.4 g, 1.05 equiv) in water (5 mL) over 30 min while keeping the temperature below -5°C. After an additional 30 min at -5°C to -20°C, the mixture was buffered to pH ~5 with solid sodium acetate. This mixture (maintained at about -10°C) was added portionwise to a stirred solution of tert-butylmercaptan (3.77 mL, 1.0 equiv) in ethanol (25 mL) at 0°C over a period of about 30 minutes. After the addition, the mixture was stirred at 0 °C for 30 min, and then crushed ice (ca. 50 mL) was added. The resulting light brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours to afford 7.9 g (72%) of the desired product.

¹ H-NMR (CDCl ₃ ) δ1.15 (t, J=6.7, 3H), 1.58 (s, 9H), 2.00 (s, 3H), 2.54 (m, 1H), 7.20 (s, 1H), 7.28 (s, 1H). Mass spectrum: 331.08 (MNa) ⁺ .

5-Bromo-7-isopropyl-1H-indazole

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

7-Isopropyl-1H-indazole-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 (flame-dried) equipped with a magnetic stir bar. in a round bottom flask. Dry tetrahydrofuran (18 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, during which time it became homogeneous. The stirred mixture was cooled to -78°C and a solution of sec-butyllithium in cyclohexane (1.4M, 20 mL, 2.2 equiv) was added over several minutes. After 1 h at -78 °C, dimethylformamide (3.0 mL) was added slowly, and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0°C and treated carefully with 1N hydrochloric acid (35 mL). After a few minutes, solid sodium bicarbonate was added until the pH reached 9-10. The two layers were separated and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography afforded 2.1 g (92%) of pure material. LC/MS: _tR = 1.15 min, 189.12 (MH) ⁺ .

Methyl 2-benzyloxycarbonylamino-3-(7-isopropyl-1H-indazol-5-yl)acrylate

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

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

A solution of methyl 2-benzyloxycarbonylamino-3-(7-isopropyl-1H-indazol-5-yl)acrylate (0.35 g, 0.89 mmol) in methanol (7 mL) was flushed with nitrogen and washed with palladium Charcoal (10%, 35 mg) treatment. The flask was filled with hydrogen and stirred overnight under a hydrogen atmosphere. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography afforded 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-quinazoline-3- base)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester

As described above for the preparation of 3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- Base)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester is prepared. LC/MS: _tR = 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']bipiperidine- 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-quinone was prepared as described in Example 203 above. Azolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester was prepared to give:

¹ H-NMR (CD ₃ OD) δ1.45 (m, 6H), 1.60-2.05 (m, 14H), 2.20-2.50 (m, 4H), 2.73 (d, J=13.7, 1H), 2.90 (m , 4H), 4.05(d, J=14.0, 1H), 4.20(m, 2H), 4.35(s, 1H), 4.65(dd, J=12.2, 14.3, 1H), 4.95(m, 2H), 6.79 (d, J=7.9, 1H), 6.92 (dd, J=7.6, 6.1, 1H), 7.13(m, 1H), 7.80(s, 1H), 7.45(s, 1H), 8.05(s, 1H) . Mass spectrum: 655.40 (MH) ⁺ .

4-Bromo-2,6-diethylphenyldiazo-tert-butylsulfide

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 with a solution of sodium nitrite (2.0 g, 1.05 equiv) in water (5 mL) over 30 min while keeping the temperature below -5°C. After an additional 30 min at -5°C to -20°C, the mixture was buffered to about pH 5 with solid sodium acetate. This mixture (kept at about -10°C) was added portionwise to a stirred solution of tert-butylmercaptan (3.15 mL, 1.0 equiv) in ethanol (25 mL) at 0°C over about 30 minutes. After the addition, the mixture was stirred at 0 °C for 30 min, and then crushed ice (ca. 50 mL) was added. The resulting light brown solid was collected by filtration, washed with water, and dried under high vacuum for several hours to afford 6.0 g (66%) of the desired product.

¹ H-NMR (CDCl ₃ ) δ 1.15 (t, J=7.6, 6H), 1.50 (s, 9H), 2.27 (m, 4H), 7.21 (s, 2H). Mass spectrum: 331.08 (MH) ⁺ .

5-Bromo-7-ethyl-3-methylindazole

Into a flame-dried round bottom flask was added 4-bromo-2,6-diethylphenyldiazo-tert-butylsulfide (4.0 g, 12.1 mmol) and potassium tert-butoxide (13.2 g, 10 equivalents). A stir bar was added and the mixture was placed under nitrogen. Dry dimethyl sulfoxide (35 mL) was added thereto. The mixture was vigorously stirred overnight at room temperature. The reaction mixture was carefully poured into a mixture of crushed ice (130 mL) and 10% hydrochloric acid (60 mL). The resulting suspension was collected by filtration and washed several times with water. The solid was collected and dried in vacuo to yield 2.85 g (98%) of a beige solid. ¹ H-NMR (CD ₃ OD) δ 1.32 (t, J=7.6, 3H), 2.50 (s, 3H), 2.88 (m, 2H), 7.25 (s, 1H), 7.68 (s, 1H). Mass spectrum: 239.26 (MH) ⁺ .

7-Ethyl-3-methylindazole-5-carbaldehyde

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 (flame-dried) equipped with a magnetic stir bar. ) in a round bottom flask. Dry tetrahydrofuran (15 mL) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, during which time it became homogeneous. The stirred mixture was cooled to -78°C and a solution of tert-butyllithium in pentane (1.4M, 18.7 mL, 2.0 equiv) was added over several minutes. After 1 hour 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 carefully treated with 1N hydrochloric acid (30 mL). After a few minutes, solid sodium bicarbonate was added until the pH reached 9-10. The two layers were separated and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were washed with water (2x), brine (2x), dried over sodium sulfate, and concentrated. Column chromatography afforded 1.5 g (67%) of pure material. LC/MS: _tR = 1.15 min, 189.12 (MH) ⁺ .

2-Benzyloxycarbonylamino-3-(7-ethyl-3-methyl-1H-indazol-5-yl)-methyl acrylate

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

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

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

¹ H-NMR (CD ₃ OD) δ1.32 (m, 3H), 2.50 (s, 3H), 2.88 (dd, J=7.3, 7.6, 1H), 2.89 (dd, J=7.6, 7.6, 1H) , 3.02(dd, J=6.4, 7.0, 1H), 3.11(dd, J=7.6, 5.8, 1H), 3.35(s, 1H), 3.65(m, 3H), 7.00(s, 1H), 7.33( s, 1H). Mass spectrum: 262.24 (MH) ⁺ .

Example 207

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

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

¹ H-NMR (CD ₃ OD) δ1.35 (m, 3H), 1.85-2.20 (m, 4H), 2.50 (s, 1H), 2.70 (m, 2H), 2.85 (s, 3H), 2.88- 3.25(m, 7H), 3.35(s, 1H), 3.47(dd, J=7.3, 7.3, 1H), 4.00-4.40(m, 7H), 4.70(m, 1H), 5.00(m, 3H), 6.79 (d, J=7.6, 1H), 6.93 (dd, J=7.3, 7.3, 1H), 7.10 (m, 1H), 7.15 (dd, J=7.3, 7.6, 1H), 7.45 (m, 1H) . Mass spectrum: 655.50 (MH) ⁺ .

Example 208

(±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-1'-yl-1(7-methyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide

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

¹ H-NMR (CD ₃ OD) δ1.20-2.10(m, 12H), 2.20-2.60(m, 6H), 2.90(m, 6H), 3.78-4.11(m, 4H), 4.60(s, 3H) ), 4.90(m, 1H), 6.70(d, J=8.1, 1H), 6.79(dd, J=7.67, 7.3, 1H), 7.44(s, 1H), 7.10(m, 1H), 7.13(m , 3H), 8.03 (s, 1H). Mass spectrum: 663.60 (MH) ⁺ .

Example 209

(±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-1'-yl-1(7-ethyl-3-methyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl base]-amide

Prepared from 3-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide as described in Example 203: ¹ H -NMR (CD ₃ OD) δ1.35 (m, 3H), 1.42-2.05 (m, 10H), 2.40 (m, 3H), 2.55 (s, 3H), 2.67-3.12 (m, 7H), 3.85 ( m, 1H), 3.97(s, 1H), 4.03(m, 3H), 4.65(m, 4H), 4.95(dd, J=4.9, 5.8, 1H), 6.73(d, J=7.9, 1H), 6.98 (dd, J = 7.3, 6.4, 1H), 7.20 (m, 2H), 7.88 (s, 1H). Mass spectrum: 691.51 (MH) ⁺ .

Example 210

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

As described above for the preparation of 3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- )-piperidine-1-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' ]bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide

Prepared from 2-oxo-3-piperidin-4-yl-1,2,3,4-tetrahydro-quinazoline-6-carbonitrile as described above in Example 203: ¹ H-NMR (CD ₃ OD) δ1.80(m, 12H), 2.4 0(m, 4H), 2.60(s, 3H), 2.70-3.20(m, 10H), 4.00-4.30(m, 6H), 5.00(m, 1H) ), 5.50 (s, 2H), 6.90 (d, J=7.8, 1H), 7.21 (s, 1H), 7.50 (m, 4H), 8.05 (s, 1H). Mass spectrum: 652.64 (MH) ⁺ .

Example 212

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

Prepared from 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one as described above in Example 203: ¹ H-NMR (CD ₃ OD) δ1.40-2.00 (m, 12H), 2.30-2.60 (m, 8H), 2.70-3.20 (m, 10H), 3.70 (m, 2H), 3.60 (d, J =9.5, 1H), 4.00-4.30(m, 4H), 4.70(m, 1H), 5.00(m, 1H), 6.90(m, 2H), 7.10(m, 3H), 7.20(s, 1H), 7.50(s, 1H), 8.05(s, 1H). Mass spectrum: 652.64 (MH) ⁺ .

Example 213

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

Prepared from 6-hydroxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one as described above in Example 203: LC/MS: _tR = 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 ']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide

Prepared from 8-methoxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one as described above in Example 203: ¹ H-NMR (CD ₃ OD) δ1.40-2.00(m, 12H), 2.40(m, 2H), 2.50(s, 3H), 2.80(m, 3H), 3.00-3.20(m, 3H), 3.50(m, 2H), 4.00-4.60(m, 6H), 5.00(m, 2H), 6.70(dd, J=8.5, 10.1, 1H), 6.85(m, 2H), 7.10(m, 1H), 7.20(s, 1H), 7.47(s, 1H). Mass spectrum: 657.41 (MH) ⁺ .

Example 215

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

Prepared from 2-chloro-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one as described above in Example 203: ¹ H-NMR (CD ₃ OD) δ1.40-2.00(m, 14H), 2.30-2.60(m, 8H), 2.80(m, 4H), 3.50(m, 3H), 3.98(s, 1H), 4.10(m, 4H), 4.40( m, 2H), 4.60(m, 1H), 4.95(m, 1H), 6.95(dd, J=7.9, 7.9, 1H), 7.10(m, 1H), 7.26(dd, J=6.7, 7.6, 1H ), 7.47 (m, 1H), 8.04 (s, 1H). Mass spectrum: 661.27 (MH) ⁺ .

Example 216

(±)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine -1-yl)prop-2-yl)-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide

Prepared according to the method used for the preparation of 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)prop-2-yl)-2,4-dihydro-2′-oxospiro-(piperidine-4,4′-1H-benzo[d][1,3]oxazine)- 1-formamide

Prepared according to the method used for the preparation of Example 203: LC/MS: t _R =1.48 minutes, 642.61 (MH) ⁺ .

tert-Butyl 2-fluorophenylcarbamate

To a solution of di-tert-butyl dicarbonate (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 for 6 hours. It was cooled, concentrated, dissolved in pentane, washed with 5% citric acid, then 1M potassium bisulfate (2x), then water, then 20% potassium hydroxide, then brine, dried over magnesium sulfate, and Concentration afforded 48.0 g (quantitative) of a pale yellow oil which was used without purification.

¹ H-NMR (CDCl ₃ , 500 MHz) δ1.52 (s, 9H), 6.68 (bs, 1H), 6.85-7.20 (m, 3H), 8.07 (dd, J=8.1, 8.1, 1H). Mass spectrum: 234.18 (MNa) ⁺ .

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

To a solution of tert-butyl 2-fluorophenylcarbamate (44.0 g, 208 mmol) in tetrahydrofuran (660 mL) was added dropwise a solution of tert-butyllithium in pentane (1.7M, 306 mL, 2.5 equiv) at -78°C. After the addition was complete, the reaction was stirred at -78°C for 30 minutes. The solution was gradually brought to -20°C, then cooled again to -78°C, and transferred via cannula to a slurry of carbon dioxide (excess) and tetrahydrofuran (500 mL). The solution was slowly warmed to room temperature. The reaction mixture was concentrated to remove most of the THF and poured into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted two more times with ether. The ether extracts were removed. The aqueous layer was acidified with 5% citric acid and extracted with ether (3x). The ether extracts were dried over magnesium sulfate and concentrated to give a bright yellow solid which was recrystallized from hot toluene to give 37.1 g (70%) of a pale yellow solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.50(s, 9H), 6.25(bs, 1H), 7.18(ddd, J=7.9, 7.9, 4.9, 1H), 7.33(dd, J=9.5, 9.2 , 1H), 7.79 (d, J=7.9, 1H), 7.94 (s, 1H). Mass spectrum: 278.21 (MNa) ⁺ .

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

To 2-(tert-butoxycarbonylamino)-3-fluoro-benzoic acid (37.1 g, 145 mmol), 4-amino-1-benzylpiperidine (35.6 mL, 1.20 equivalents), 1-hydroxybenzotriazole (21.6g, 1.1eq) and triethylamine (44.1g, 3.0eq) in ethyl acetate (450mL) were added in one go with 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine hydrochloride (30.7 g, 1.1 equiv). Initially, each was added to solution, but a precipitate formed very quickly. The reaction was fitted with a reflux condenser and heated at reflux for 5 hours. The reaction was diluted with ethyl acetate, washed with water (2x), then 1 N sodium hydroxide (2x), then brine, dried over magnesium sulfate, and concentrated to afford 67.0 g (quantitative) of a white solid that was used without purification And use.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.48 (s, 9H), 1.55 (m, 2H), 1.99 (bd, J=11.0, 2H), 2.17 (dd, J=11.0, 11.0, 2H), 2.84(bd, J=11.3, 2H), 3.51(s, 2H), 3.94(m, 1H), 6.13(bd, J=7.6, 1H), 7.10-7.28(m, 4H), 7.31(m, 4H ), 7.59(s, 1H). Mass spectrum: 428.41 (MH) ⁺ .

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

To a solution of tert-butyl 2-(1-benzylpiperidin-4-ylcarbamoyl)-6-fluorophenylcarbamate (67.0 g, 157 mmol) in dichloromethane (700 mL) was added Trifluoroacetic acid (100 mL). The ice bath was removed and the reaction was 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), which was 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 spectrum: 328.33 (MH) ⁺ .

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

To a refluxing suspension of lithium aluminum hydride (16.1 g, 424 mmol, 3.50 equiv) in dioxane (800 mL) was added 2-amino-N-(1-benzyl (250 mL) in dioxane (250 mL). Once the addition was complete, the resulting suspension was heated at 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 eluate was concentrated to give 36.3 g (96%) of a bright yellow oil without used for purification. Mass spectrum: 314.29 (MH) ⁺ .

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

Carbonyldiimidazole (20.7 g, 1.10 equivalents). The reaction was stirred at room temperature for 3 hours, heated at reflux for 30 minutes, and concentrated. The resulting solid was dissolved in 1:1 ether/ethyl acetate, washed with water (3x), then brine, dried over magnesium sulfate, and concentrated to give the crude product as a wet yellow solid. The solid was triturated with ether and filtered to afford 30.0 g (76%) of a white powder.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.68 (m, 2H), 1.86 (dddd, J=11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, J=11.6, 10.1, 2H), 2.98 (d, J=11.6, 2H), 3.51(s, 2H), 4.34-4.44(m, 3H), 6.71(bs, 1H), 6.79-6.89(m, 2H), 6.94(dd, J=9.2, 9.2, 1H), 7.21-7.34 (m, 5H). Mass spectrum: 340.30 (MH) ⁺ .

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

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

¹ H-NMR (CDCl ₃ , 500MHz) δ1.71(m, 4H), 2.75(m, 2H), 3.16(m, 2H), 4.38(s, 2H), 4.46(m, 1H), 6.77(bs , 1H), 6.81-6.89 (m, 2H), 6.95 (m, 1H). Mass spectrum: 250.22 (MH) ⁺ .

3-(1-Benzylpiperidin-4-yl)-8-fluoroquinazoline-2,4(1H,3H)-dione

To a solution of 2-amino-N-(1-benzylpiperidin-4-yl)-3-fluorobenzamide (750 mg, 2.29 mmol) in dichloromethane (30.0 mL) was added triphosgene at 0 °C (227 mg, 0.33 equiv) in dichloromethane (5 mL). The ice bath was removed and the reaction was heated at reflux for 6 hours. The reaction was concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate, then water, then brine, dried over magnesium sulfate, and concentrated to give 700 mg of a white solid. The crude product was purified by flash chromatography to afford 205 mg (25%) of a white solid. Mass spectrum: 354.13 (MH) ⁺ .

8-Fluoro-3-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione

3-(1-benzylpiperidin-4-yl)-8-fluoroquinazoline-2,4(1H,3H)-dione (75.0mg, 0.21mmol) and palladium charcoal (8.00mg, 0.035 equiv) in methanol (3.00 mL) was filled first with nitrogen and then with hydrogen. The reaction was stirred overnight under an atmosphere of hydrogen. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 53 mg (95%) of a white solid which was used without purification. Mass spectrum: 264.25 (MH) ⁺ .

8'-fluoro-2',3'-dihydro-2'-oxospiro-(1-phenylmethylpiperidine)-4,4'-quinazoline

Polyphosphoric acid (110 mL) was added to a 500 mL 3-neck flask equipped with a stirrer, nitrogen inlet and bubbler on top. The flask was filled 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 N-(2-fluorophenyl)urea (21.3 g, 1.2 equiv) in small portions over a period of 2 hours. The reaction was heated to 160°C with vigorous stirring. After 2 hours, the reaction was quenched by pouring onto crushed ice and neutralized with 20% potassium hydroxide. The reaction mixture was extracted with dichloromethane, washed with water, then brine, dried over magnesium sulfate, and concentrated. The entire bulk was purified by preparative HPLC (-130 injections) to give a more pure product. The product was repurified by flash chromatography to give a solid which was triturated with ether and filtered to give 275 mg (0.7%) of a white solid.

¹ H-NMR (CDCl ₃ , 500MHz) δ1.91 (dd, J=13.7, 2.1, 2H), 2.10 (ddd, J=13.1, 13.1, 4.3, 2H), 2.27 (ddd, J=12.5, 12.5, 2.1, 2H), 2.86(m, 2H), 3.57(s, 2H), 5.40(bs, 1H), 6.90(bs, 1H), 6.90-7.05(m, 3H), 7.27(m, 1H), 7.32 (m, 4H). Mass spectrum: 326.13 (MH) ⁺ .

8'-fluoro-2',3'-dihydro-2'-oxospiro-piperidine-4,4'-quinazoline

To 8'-fluoro-2', 3'-dihydro-2'-oxospiro-(1-phenylmethylpiperidine)-4,4'-quinazoline (250mg, 0.77mmol) in methanol ( 4 mL) and dichloromethane (4 mL) was added palladium on charcoal (30.0 mg, 0.037 equiv). The reaction was flushed with hydrogen and stirred overnight under an atmosphere of hydrogen. The balloon was removed and the reaction was flushed with nitrogen, filtered through celite, washed with additional methanol, and concentrated to give 158 mg (87%) of a white solid which was used without purification.

¹ H-NMR (CDCl ₃ /CD ₃ OD, 500MHz) δ1.87 (d, J=12.8, 2H), 2.15 (ddd, J=14.0, 14.0, 5.5, 2H), 3.10 (m, 4H), 6.84 (m, 2H), 6.93 (d, J=7.0, 1H). Mass spectrum: 236.11 (MH) ⁺ .

Example 218

(±)-N-(3-(7-Ethyl-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 according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ1.24 (m, 2H), 1.55-2.07 (m, 5H), 2.57 (m, 1H), 2.82 ( m, 4H), 3.08(m, 2H), 3.30(m, 3H), 3.35(m, 5H), 3.48(m, 3H), 3.65(m, 1H), 4.14(m, 2H), 4.27(m , 2H), 4.33-4.57(m, 2H), 5.06(dd, J=6.7, 6.7, 1H), 5.22(d, J=1.8, 2H), 6.78(d, J=7.6, 1H), 6.93( m, 1H), 7.00-7.18 (m, 3.5H), 7.37 (d, J = 9.8, 1H), 7.46 (s, 0.5H), 7.91 (dd, J = 10.1, 1.8, 1H). Mass spectrum: 596.43 (MH) ⁺ .

Example 219

(±)-N-(3-(7-ethyl-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 ) piperidine-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ1.11 (m, 3H), 1.50-1.80 (m, 4H), 2.87 (m, 4H), 3.10 ( m, 2H), 3.32(m, 9H), 3.48(m, 4H), 4.00-4.45(m, 6H), 5.05-5.25(m, 2H), 6.77(d, J=6.1, 1H), 6.93( m, 1H), 7.13 (m, 3H), 7.30-7.60 (m, 2H), 7.95 (m, 1H). Mass spectrum: 624.49 (MH) ⁺ .

Example 220

(±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido) -3-(7-Methyl-1H-indazol-5-yl)propionate

As above for the preparation of 3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- base)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester: ¹ H-NMR (CDCl ₃ , 500MHz) δ1.53-1.68 (m, 4H), 2.48 (s, 3H) , 2.82 (m, 2H), 3.05 (m, 6H), 3.09 (dd, J _AB = 13.7, 6.1, 1H), 3.14 (dd, J _AB = 14.0, 6.1, 1H), 3.35 (bs, 1H), 3.68(s, 3H), 3.88-4.02(m, 2H), 4.22(d, _JAB =15.6, 1H), 4.25(d, _JAB =15.3, 1H), 4.44(m, 1H), 4.71(dd , J=6.1, 6.1, 1H), 6.78(d, J=7.3, 1H), 6.84(ddd, J=7.6, 7.6, 4.9, 1H), 6.88-6.95(m, 2H), 7.28(s, 1H ), 7.91(s, 1H). Mass spectrum: 509.25 (MH) ⁺ .

Example 221

(±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-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 according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ-0.25 (m, 1H), 0.82 (m, 1H), 1.25-2.10 (m, 13H), 2.20- 2.63(m, 6H), 2.68-2.98(m, 4H), 3.00-3.22(m, 3H), 3.31(m, 2H), 3.44(bs, 1H), 4.00-4.50(m, 6H), 4.64( m, 1H), 4.96(m, 1H), 6.85-7.05(m, 3H), 7.08(s, 0.4H), 7.20(s, 0.6H), 7.46(d, J=7.0, 1H), 7.99( s, 0.4H), 8.05 (d, J=2.4, 0.6H). Mass spectrum: 645.58 (MH) ⁺ .

Example 222

(±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazole- 5-yl)-1-oxo-1-(4-phenylpiperazin-1-yl)prop-2-yl)piperidine-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CDCl ₃ , 500MHz) δ1.73 (m, 4H), 2.49 (m, 4H), 2.80-3.26 (m, 7H), 3.43 (m , 2H), 3.65-3.95(m, 3H), 4.14(dd, J=21.7, 14.3, 2H), 4.32(s, 2H), 4.51(m, 1H), 5.15(dd, J=7.9, 6.4, 1H), 5.90(bs, 1H), 6.80(d, J=7.3, 1H), 6.83-7.01(m, 4H), 7.06(dd, J=7.6, 7.3, 1H), 7.10(s, 1H), 7.26-7.33 (m, 2H), 7.44 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H). Mass spectrum: 639.36 (MH) ⁺ .

Example 223

(±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(4-fluorophenyl)piper Azin-1-yl)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl)piperidine-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CDCl ₃ , 500 MHz) δ1.73 (m, 4H), 2.26 (dd, J=7.9, 7.6, 1H), 2.49 (s, 3H) , 2.75-3.05(m, 4H), 3.09(m, 2H), 3.19-3.45(m, 3H), 3.63(m, 1H), 3.78(m, 2H), 4.13(dd, J=16.5, 15.3, 2H), 4.32(s, 2H), 4.50(m, 1H), 5.15(dd, J=8.2, 6.1, 1H), 5.85(bs, 1H), 6.70-6.84(m, 3H), 6.85-7.02( m, 5H), 7.09 (s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 8.06 (s, 1H). Mass spectrum: 657.35 (MH) ⁺ .

Example 224

(±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(2-fluorophenyl)piper Azin-1-yl)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl)piperidine-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CDCl ₃ , 500MHz) δ1.62-1.78 (m, 4H), 2.24 (dd, J=7.9, 8.2, 1H), 2.50 (s, 3H), 2.70-2.85(m, 2H), 2.85-2.96(m, 2H), 2.00(m, 1H), 3.08(dd, _JAB =13.1, 8.6, 1H), 3.12(m, 1H), 3.30 (m, 1H), 3.57(m, 1H), 3.73(m, 2H), 4.13(dd, J=19.8, 15.0, 2H), 4.33(s, 2H), 4.53(m, 1H), 5.18(dd , J=8.2, 5.8, 1H), 5.82 (bs, 1H), 6.58 (dd, J=8.2, 8.2, 1H), 6.81 (d, J=7.6, 1H), 6.85-7.05 (m, 5H), 7.09(s, 1H), 7.44(s, 1H), 7.58(s, 1H), 8.05(s, 1H). Mass spectrum: 657.37 (MH) ⁺ .

Example 225

(±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazole- 5-yl)-1-oxo-1-(4-o-tolylpiperazin-1-yl)prop-2-yl)piperidine-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CDCl ₃ , 500MHz) δ1.60-1.79 (m, 4H), 2.03 (dd, J=8.5, 8.2, 1H), 2.22 (s, 3H), 2.49(s, 3H), 2.54(dd, J=8.6, 8.5, 1H), 2.65(m, 1H), 2.81(m, 1H), 2.85-2.97(m, 2H), 3.05-3.22( m, 3H), 3.38(m, 1H), 3.50-3.65(m, 2H), 3.83(m, 1H), 4.15(dd, J=15.9, 15.3, 2H), 4.31(s, 2H), 4.53( m, 1H), 5.19 (dd, J=7.9, 5.8, 1H), 5.84 (bs, 1H), 6.54 (d, J=7.6, 1H), 6.81 (d, J=7.6, 1H), 6.89 (ddd , J=7.6, 7.6, 5.2, 1H), 6.96 (m, 2H), 7.00-7.23 (m, 4H), 7.39 (s, 1H), 7.43 (s, 1H), 8.04 (s, 1H). Mass spectrum: 653.38 (MH) ⁺ .

Example 226

(±)-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)propionate

As described above for the preparation of 3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- Base)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester is prepared by:

¹ H-NMR (CD ₃ OD, 500MHz) δ1.33(m, 3H), 1.39-1.72(m, 4H), 2.70-2.95(m, 3H), 3.06(m, 1H), 3.25(m, 1H ), 3.70(m, 3H), 3.95-4.30(m 4H), 4.38(m, 1H), 4.57(m, 1H), 6.80-7.05(m, 3H), 7.08(s, 1H), 7.38(s , 1H). Mass spectrum: 537.47 (MH) ⁺ .

Example 227

(±)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine -1-yl)prop-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ-0.36 (m, 1H), 0.70 (m, 1H), 1.21 (bd, J=11.9, 1H), 1.28-2.00(m, 19H), 2.31(dd, J=11.6, 11.3, 1H), 2.40(dd, J=13.1, 11.6, 1H), 2.79-3.16(m, 7H), 3.72(m, 1H) , 3.85-4.03(m, 1H), 4.10-4.48(m, 5H), 4.53(bd, J=11.0, 1H), 5.05(m, 1H), 6.85-7.03(m, 3H), 7.08(s, 0.2H), 7.18(s, 0.8H), 7.37(s, 1H). Mass spectrum: 673.42 (MH) ⁺ .

Example 228

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1-formamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ0.71 (m, 1H), 1.26 (m, 1H), 1.40-2.15 (m, 13H), 2.50- 3.29(m, 9H), 3.32-3.64(m, 3H), 4.14(d, JAB=12.8, 1H), 4.17(d, JAB=11.6, 1H), 4.32-4.45(m, 3H), 4.68(bd , J=13.4, 1H), 4.92 (m, 1H), 6.87-7.22 (m, 6H). Mass spectrum: 648.47 (MH) ⁺ .

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'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ-0.23(m, 1H), 0.85(m, 1H), 1.20-2.10(m, 22H), 2.25- 2.55(m, 7H), 2.58(s, 3H), 2.74(d, J=11.3, 1H), 2.94(dd, J=12.5, 12.2, 2H), 3.00-3.20(m, 5H), 3.40-3.65 (m, 2H), 3.80-4.15 (m, 4H), 4.55-4.73 (m, 2H), 4.96 (dd, J=7.9, 7.6, 1H), 5.01 (dd, J=10.4, 5.8, 1H), 6.65-7.15 (m, 5H), 7.21 (s, 1H), 7.47 (s, 1H), 7.96 (m, 1H), 8.04 (s, 1H). Mass spectrum: 631.29 (MH) ⁺ .

Example 230

(±)-4-(8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-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

Prepared according to the method used to prepare Example 203: ¹ H-NMR (CD ₃ OD, 500MHz) δ-0.26 (m, 1H), 0.81 (m, 1H), 1.20-2.10 (m, 11H), 2.20- 2.80(m, 9H), 2.90(m, 3H), 3.10(m, 3H), 3.34(m, 1H), 3.44(m, 1H), 4.06(bd, J=13.4, 1H), 4.17(d, JAB=15.9, 1H), 4.22(d, JAB=13.1, 1H), 4.64(dd, J=24.4, 13.1, 1H), 4.91-5.13(m, 2H), 7.00-7.25(m, 2H), 7.44 (m, 2H), 7.81 (m, 1H), 7.92-8.08 (m, 1H). Mass spectrum: 659.59 (MH) ⁺ .

(R)-Methyl 2-amino-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate

A mixture of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester (500mg, 1.20mmol) and trifluoroacetic acid (6mL) was heated at 80°C Heat for 16 hours. The reaction mixture was poured into ice water (75 mL), neutralized to pH 7 with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (2 x 250 mL). The organic extracts were dried over sodium sulfate, filtered and evaporated to give the title compound (459 mg, 84% yield) as the trifluoroacetate salt. ¹ H-NMR (CDCl ₃ , 300MHz) δ7.37(bs, 1H) 7.35(bs, 1H), 7.17(d, J=8.4Hz, 1H), 4.70(s, 2H), 3.85(dd, J= 8.4, 4.8Hz, 1H), 3.77(s, 3H), 3.30(dd, J=13.9, 4.8Hz, 1H), 2.97(dd, J=13.5, 8.4Hz, 1H). Mass spectrum: 288 (MH) ⁺ .

(R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2-( Trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate

Urethane (R)-methyl 2-amino-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate (230mg, 0.51mmol), diiso A solution of propylethylamine (262 mg, 2.03 mmol) and disuccinimidyl carbonate (129 mg, 0.51 mmol) in a mixture of dichloromethane/dimethylformamide (15:1 ratio) was stirred at room temperature 30 minutes. To the solution was added 4-(2-keto-1-benzimidazolinyl)piperidine, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove any solids and then purified by flash column chromatography (95:3:2 dichloromethane/methanol/triethylamine) to afford the title compound (215 mg, 77% yield) as a tan solid. ¹ H-NMR (CDCl ₃ , 300MHz) δ7.67 (d, J=8.4Hz, 1H), 7.39 (s, 1H), 7.21-7.16 (m, 1H), 7.05-6.94 (m, 3H), 6.70 -6.68(m, 2H), 5.11(d, J=7.3Hz, 1H), 4.78(dd, J=12.1, 5.5Hz, 1H), 4.42(d, J=4.4Hz, 2H), 4.29(d, J=12.1Hz, 1H), 3.82-3.72(m, 2H), 3.74(s, 3H), 3.44(dd, J=13.9, 5.5Hz, 1H), 3.22(dd, J=13.9, 5.5Hz), 2.95-2.83 (m, 3H), 2.18-2.03 (m, 2H), 1.79-1.68 (m, 2H). Mass spectrum: 545 (MH) ⁺ .

(R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoro Methyl)-1H-benzo[d]imidazol-5-yl)propionic acid

At 0°C, to ester (R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido) - A solution of 3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate (220mg, 0.40mmol) in tetrahydrofuran and methanol (1:1 mixture, 20mL) An aqueous solution (10 mL) of lithium hydroxide (36 mg, 1.51 mmol) was added to the solution. The mixture was stirred at 0°C for 2 hours and then kept at -15°C for 16 hours. The organic solvent was evaporated. The aqueous solution was extracted with ethyl acetate while adjusting the pH to 4 with 1N HCl (3 mL). The organic extracts were dried over sodium sulfate, filtered and evaporated to give the title compound (176 mg, 82% yield). LC/MS: _tR = 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) prop-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl) piperidine-1-carboxamide

To the stirred acid (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2 -(Trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanoic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) in dichloromethane (2 mL) To a solution of PyBOP (33 mg, 0.06 mmol) and 4-piperidinopiperidine (12 mg, 0.07 mmol) in dichloromethane (1 mL) was added. The reaction mixture was stirred at room temperature for 16 hours and purified by preparative thin layer chromatography (1:10 2M ammonia in methanol/dichloromethane) to afford the title compound (4.6 mg, 12% yield).

¹ H-NMR (CD ₃ OD, 500MHz) δ7.73-7.71(m, 1H), 7.62(bs, 1H), 7.39-7.36(m, 1H), 7.19-7.11(m, 2H), 6.96(t , J=7.2Hz, 1H), 6.81(d, J=7.9Hz, 1H), 5.06-5.02(m, 1H), 4.67-4.58(m, 1H), 4.49-4.40(m, 1H), 4.38( s, 1H), 4.33 (bs, 1H), 4.25-4.16 (m, 2H), 4.10-4.03 (m, 1H), 3.22-3.14 (m, 3H), 3.04-2.87 (m, 4H), 2.79- 2.71(m, 1H), 2.58-2.48(m, 1H), 2.44-2.33(m, 1H), 2.31-2.22(m, 1H), 2.04-1.92(m, 1H), 1.86-1.43(m, 11H ), 1.33-1.29 (m, 1H), 0.94-0.84 (m, 1H), -0.04--0.12 (m, 1H). LC/MS: _tR = 1.97 min, 681 (MH) ⁺ .

Example 232

N-((R)-1-(dimethylcarbamoyl)-2-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethyl)-4-( 1,2-Dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamide

The preparation was as described in Example 231 above.

¹ H-NMR (CD ₃ OD, 300MHz) δ7.69-7.56(m, 2H), 7.34(d, J=7.7Hz, 1H), 7.17-7.08(m, 2H), 6.92(t, J=7.7 Hz, 1H), 6.77(d, J=8.4Hz, 1H), 6.56(d, J=7.7Hz, 1H), 5.02-4.97(m, 1H), 4.46-4.35(m, 1H), 4.29(s , 2H), 4.15 (d, J=12.8Hz, 1H), 3.26-3.11 (m, 5H), 2.87 (s, 6H), 1.86-1.68 (m, 2H), 1.66-1.59 (m, 2H). LC/MS: _tR = 2.37 min, 558 (MH) ⁺ .

Benzyl (R)-1-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)ethylcarbamate

To a diluted solution of (R)-methyl 2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionate (600 mg, 1.44 mmol) in THF (125 mL) was added triethylamine (320 mg, 3.17 mmol), followed by the addition of 1,1'-carbonyldiimidazole (280 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then filtered to remove solids. The filtrate was evaporated and flash column chromatography (1:12 methanol/dichloromethane) afforded the title compound (313 mg, 59% yield).

¹ H-NMR (CD ₃ OD, 300MHz) δ7.28-7.21(m, 5H), 6.94-6.83(m, 3H), 5.06-4.95(m, 2H), 4.46-4.41(m, 1H), 3.68 (s, 3H), 3.17-3.11 (m, 1H), 2.95-2.88 (m, 1H). LC/MS: _tR = 2.11 min, 370 (MH) ⁺ .

(R)-Methyl 2-amino-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propionate

Using a Parr apparatus under 50 psi hydrogen, (R)-1-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl) Benzyl ethyl carbamate (265 mg, 0.72 mmol) and 10% palladium on carbon (30 mg) were stirred in methanol (15 mL) for 1.5 hours. The reaction mixture was subjected to 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of Celite ^(R) , and the pad was rinsed with several portions of methanol. Evaporation of the methanol filtrate gave the title compound (168 mg, quantitative yield).

¹ H-NMR (CD ₃ OD, 300MHz) δ6.97(d, J=8.1Hz, 1H), 6.87(s, 1H), 6.86(d, J=8.2Hz, 1H), 3.71-3.64(m, 1H), 3.67 (s, 3H), 3.04-2.89 (m, 2H). LC/MS: _tR = 0.87 min, 236 (MH) ⁺ .

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)propionate

(R)-Methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method.

¹ H-NMR (CD ₃ OD, 300MHz) δ7.16-7.08(m, 2H), 6.98-6.90(m, 4H), 6.76(d, J=8.1Hz, 1H), 4.52-4.47(m, 1H ), 4.39-4.35(m, 1H), 4.27(s, 2H), 4.13-4.05(m, 2H), 3.70(s, 3H), 3.21-3.14(m, 1H), 3.04-2.96(m, 1H ), 2.89-2.74 (m, 2H), 1.78-1.59 (m, 4H). LC/MS: _tR = 1.77 min, 493 (MH) ⁺ .

(R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2,3-di Hydrogen-2-oxo-1H-benzo[d]imidazol-6-yl)propionic acid

(R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-( 2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method.

¹ H-NMR (CD ₃ OD, 300MHz) δ7.16-7.09(m, 2H), 6.99-6.90(m, 4H), 6.76(d, J=7.3Hz, 1H), 4.53-4.48(m, 1H ), 4.28(s, 2H), 4.13-4.03(m, 2H), 3.07-2.97(m, 1H), 2.89-2.77(m, 2H), 1.79-1.60(m, 4H), 1.28-1.21(m , 1H). LC/MS: _tR = 1.83 min, 479 (MH) ⁺ .

Example 234

N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)-1-oxo-1(4-piperidine-1- Base) piperidin-1-yl) prop-2-yl)-4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl) piperidine-1-carboxamide

The preparation was as described in Example 231 above.

¹ H-NMR (CD ₃ OD, 300MHz) δ7.17-7.10 (m, 2H), 7.01 (s, 1H), 6.95-6.90 (m, 3H), 6.78 (d, J=8.1Hz, 1H), 4.98-4.93(m, 1H), 4.62-4.55(m, 1H), 4.41-4.33(m, 2H), 4.20-4.16(m, 2H), 4.04-3.96(m, 1H), 3.05-2.85(m , 7H), 2.71-2.57(m, 1H), 2.53-2.32(m, 1H), 1.86-1.76(m, 2H), 1.70-1.61(m, 8H), 1.50-1.41(m, 2H), 1.03 -0.89(m, 1H), 0.10--0.02(m, 1H). Mass spectrum: 629.22 (MH) ⁺ .

Example 235

N-((R)-1-(dimethylcarbamoyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)ethyl)- 4-(1,2-Dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.96 min, 506 (MH) ⁺ .

(R)-methyl 2-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H)-quinazoline)carbonylamino]-3-2, 3-Dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propionate

(R)-Methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method.

¹ H-NMR (DMSO-d ₆ , 500MHz) δ10.54(s, 1H), 10.50(s, 1H), 9.22(s, 1H), 7.21(s, 1H), 7.13-7.10(m, 1H) , 6.96-6.79(m, 7H), 4.29-4.25(m, 1H), 3.82-3.78(m, 2H), 3.60(s, 3H), 3.32-3.23(m, 1H), 3.16-3.14(m, 1H), 3.00-2.90 (m, 2H), 2.08 (s, 1H), 1.67-1.55 (m, 4H). LC/MS: _tR = 1.62 min, 479 (MH) ⁺ .

(R)-2-[2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-(1H)-quinazoline)carbonylamino]-3-2,3- Dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)propionic acid

(R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-( 2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method.

¹ H-NMR (CD ₃ OD, 300MHz) δ7.19-7.14(m, 1H), 7.05-6.95(m, 5H), 6.81(d, J=7.7Hz, 1H), 5.04-4.90(m, 1H ), 4.57-4.52 (m, 1H), 3.96-3.84 (m, 2H), 3.24-3.14 (m, 2H), 3.07-2.95 (m, 1H), 1.94-1.73 (m, 4H). LC/MS: _tR = 1.67 min, 465 (MH) ⁺ .

Example 236

N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)-1-oxo-1(4-piperidine-1- Base) piperidin-1-yl) prop-2-yl)-4-(2',3'-dihydro-2'-oxospiro(piperidin-4,4'-(1H)-quinazoline ) Formamide (carboxamide)

The preparation was as described in Example 231 above. 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 dichloromethane (800 mL) was added triethylamine (121 g, 1.19 mol). The solution became clear. Then, acetic anhydride (81 g, 0.79 mol) was added, and the reaction mixture was stirred at room temperature for 60 hours. 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 give the title compound (43 g, 56% yield) as a tan solid.

¹ H-NMR (d ₆ -DMSO, 300 MHz) δ 9.36 (s, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). LC/MS: _tR = 1.22 min, 194 (MH) ⁺ .

4-acetamido-3-methyl-5-nitrobenzoic acid

To a solution of 60% nitric acid in sulfuric acid (410 mL) was added small portions of 4-acetamido-3-methylbenzoic acid (43 g, 0.22 mol) over a period of 40 min while cooling in an ice bath. After all the amide addition was complete, the reaction mixture was stirred at 0 °C for 1 hour and then poured very slowly onto 1500 mL of ice. The yellow solid was collected by filtration and washed with ice-cold water to afford the title compound (38 g, 72% yield).

¹ H-NMR (CD ₃ OD, 300 MHz) δ8.29 (s, 1H), 8.18 (s, 1H), 2.39 (s, 3H), 2.16 (s, 3H). Mass spectrum: 237 (MH) ⁺ .

4-Amino-3-methyl-5-nitrobenzoic acid

A suspension of 4-acetamido-3-methyl-5-nitrobenzoic acid (38 g, 0.16 mol) in 3N hydrochloric acid (800 mL) was heated at reflux for 8 hours and then stirred at room temperature for 8 hours. The yellow solid was collected by filtration and transferred to a 2 L flask containing a mixture of dichloromethane and methanol. The solvent was evaporated under high vacuum to afford the title compound (23 g, 74% yield).

¹ H-NMR (DMSO-d6, 300 MHz) δ 12.79 (bs, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.61 (s, 2H), 2.34 (s, 3H). ¹³ C-NMR (d ₆ -DMSO, 75 MHz) δ 166.0, 147.0, 135.1, 130.0, 126.4, 125.9, 116.7, 17.9. LC/MS: t _R =1.23 min, 195(MH) ^- .

3-methyl-4,5-dinitrobenzoic acid

To a suspension of 4-amino-3-methyl-5-nitrobenzoic acid (5.0 g, 25.5 mmol) in trifluoroacetic acid (200 mL) was added hydrogen peroxide (50 wt-%, 15 mL). The reaction mixture was heated at 50°C for 2 hours, and the solution finally changed from a dark orange clear solution to a pale yellow clear solution. The reaction mixture was slowly poured into ice water (800 mL). The solid was collected by filtration and dried in vacuo to afford the title compound (4.0 g, 70% yield) as an off-white solid.

¹ H-NMR (CD ₃ OD, 300 MHz) δ8.59 (s, 1H), 8.40 (s, 1H), 2.45 (s, 3H). ¹³ C-NMR (CD ₃ OD, 75 MHz) δ 165.8, 147.4, 142.0, 139.3, 134.8, 134.6, 125.4, 17.2. Mass spectrum: 225.14 (MH) ^- .

(3-Methyl-4,5-dinitrophenyl)methanol

A solution of 3-methyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran (200 mL) was cooled to -70 °C with a dry ice/acetone bath. To this solution was added borane-THF (1M in THF, 35.4 mL). The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction was incomplete and cooled again to -50°C and additional borane-THF (1M in THF, 35.4 mL) was added. Again, the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction was quenched with a mixture of acetic acid and water (1:1, 30 mL) while cooling at 0 °C. After stirring for 30 minutes, all organic solvent was evaporated and the aqueous material was neutralized by pouring small portions into ice-cold saturated sodium bicarbonate (350 mL). The aqueous layer was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was subjected to flash column chromatography (1:2 hexane/ethyl acetate) to afford the title compound (3.2 g, 86% yield).

¹ H-NMR (CDCl ₃ , 300 MHz) δ8.00 (s, 1H), 7.62 (s, 1H), 4.82 (s, 2H), 2.41 (s, 3H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 144.5, 143.3, 140.9, 134.3, 132.9, 120.8, 63.0, 17.4.

3-methyl-4,5-dinitrobenzaldehyde

Manganese(IV) oxide (36.0 g, 414 mmol) was azeotropically dried with toluene in a flame-dried flask. Then, a solution of (3-methyl-4,5-dinitrophenyl)methanol (3.2 g, 15 mmol) in chloroform (100 mL) was transferred to the flask containing manganese dioxide. The reaction mixture was heated at 50 °C for 3 hours with stirring. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite ^(R) to remove the manganese dioxide, and the Celite was washed several times with chloroform. The filtrate was evaporated to give the title compound (1.4 g, 44% yield).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 10.09 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 2.51 (s, 3H).

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 THF (40 mL) was added 1,1,3,3-tetramethyl Guanidine (729mg, 6.33mmol), 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 allowed to warm slowly to room temperature and then stirred at room temperature for 16 hours. The solvent was evaporated and the residue was subjected to flash column chromatography (gradient, 1:2 to 1:1 ethyl acetate/hexane). The product was then recrystallized from ethyl acetate/hexane (1:1) to afford the title compound (1.7 g, 62% yield).

¹ H-NMR (CDCl ₃ , 300MHz) δ8.01(s, 1H), 7.55(s, 1H), 7.33-7.22(m, 6H), 6.94(bs, 1H), 5.06(s, 2H), 3.89 (s,3H), 2.29(s,3H). ¹³ C-NMR (CDCl ₃ , 75MHz) δ164.7, 152.5, 143.1, 140.6, 137.7, 137.0, 135.3, 132.5, 128.8, 128.7, 128.6, 127.1, 123.5, 123.2, 68.3, 53.5, 17.4. Mass Spectrum: 414.20 MH) ^- .

Benzyl (R)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl)ethylcarbamate

In a glove bag subjected to 3 vacuum/nitrogen purge cycles, an AIRFREE( ^R ) (Schlenk) reaction flask equipped with a stir bar was charged with (-)-1,2-bis(( 2R,5R)-2,5-diethylphospholano(phospholano))benzene(cyclooctadiene)rhodium(I) triflate (125 g, 0.173 mmol, 4 mol%), with rubber The rubber septum was sealed and removed from the glove bag. Benzyl (Z)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl)vinylcarbamate (1.65 g, 3.97 mmol) was weighed into the installation Place in a second AIRFREE( ^R ) (Schlenk) reaction flask with a stirrer and seal with a rubber septum. After 3 vacuum/nitrogen purge cycles, it was dissolved in a mixture of anhydrous dichloromethane (40 mL). After adding nitrogen by sparging, the solvent was deoxygenated for at least 1 h. In this solution, the mixture was again subjected to 3 vacuum/nitrogen purge cycles. The dehydroamino acid solution was introduced through a canula into an AIRFREE( ^R ) (Schlenk) reaction flask containing the catalyst. The reaction mixture was subjected to 5 vacuum/hydrogen purge cycles before the flask was undocked to a hydrogen atmosphere at 1 atm. After 16 hours, the reaction mixture was subjected to 3 vacuum/nitrogen purge cycles. The solvent was evaporated and the residue was subjected to column chromatography (1:1 ethyl acetate/hexane) to give the title compound (1.58 g, 95%).

¹ H-NMR (CDCl ₃ , 300MHz) δ7.75(s, 1H), 7.39-7.33(m, 6H), 5.37(d, J=7.0Hz, 1H), 5.15-5.04(m, 2H), 4.70 -4.46(m, 1H), 3.77(s, 3H), 3.30(dd, J=13.9, 5.5Hz, 1H), 3.12(dd, J=13.9, 6.2Hz, 1H), 2.33(s, 3H). LC/MS: _tR = 2.71 min, 418 (MH) ⁺ .

(R)-1-(methoxycarbonyl)-2-(3,4-diamino-5-methylphenyl)ethylcarbamate benzyl ester

At 0°C, solid ammonium formate (755 mg, 11.9 mmol) was added in small portions to (R)-1-(methoxycarbonyl)-2-(3-methyl-4,5-dinitrophenyl ) in a suspension of benzyl ethyl carbamate (500 mg, 1.20 mmol) and zinc dust (470 mg, 7.19 mmol) in methanol (20 mL, degassed with nitrogen for 2 hours). The resulting mixture was stirred at room temperature for 60 hours. Incomplete response. The reaction mixture was cooled to 0 °C again and additional zinc powder (470 mg, 7.19 mmol) was added. The reaction was stirred for 4 hours at which time it was complete. 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 were dissolved, then it was washed with water, brine, dried over sodium sulfate and evaporated. The residue was then redissolved in ethyl acetate and 4N hydrogen chloride in dioxane (4 mL) was added. Evaporation of the solvent gave the title compound (515 mg, quantitative yield) as the dihydrochloride salt.

¹ H-NMR (CD ₃ OD, 300MHz) δ7.35-7.30(m, 5H), 6.94-6.93(m, 2H), 5.03(s, 2H), 4.42-4.37(m, 1H), 3.70(s , 3H), 3.09-3.03 (m, 1H), 2.87-2.79 (m, 1H), 2.25 (s, 3H). LC/MS: _tR = 1.79 min, 358 (MH) ⁺ .

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) was added dropwise a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL). The resulting mixture was stirred at room temperature for 30 minutes, then cooled to 0 °C. A mixture of ammonium hydroxide and water (1:1, 15 mL) was added to adjust the pH to 11. 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 afford the title compound (155 mg, 72% yield) as a tan solid.

¹ H-NMR (CDCl ₃ , 300MHz) δ7.34(s, 1H), 7.32-7.28(m, 6H), 6.93(s, 1H), 5.40(d, J=8.1Hz, 1H), 5.13-5.02 (m, 2H), 4.76-4.69 (m, 1H), 3.73 (s, 3H), 3.28 (dd, J=13.9, 5.5Hz, 1H), 3.16 (dd, J=13.9, 6.2Hz, 1H), 2.64(s, 3H). LC/MS: _tR = 2.30 min, 369 (MH) ⁺ .

(R)-Methyl 2-amino-3-(7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propionate

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 4.4% formic acid in methanol. The reaction flask containing this solution was fitted with a magnetic stir bar and then flushed with nitrogen for several minutes. To this solution was added palladium on carbon (10%, 200 mg) and the reaction was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered through a pad of Celite ^(R) , which was washed several times with methanol. The filtrate was evaporated to afford the title compound (quantitative yield).

¹ H-NMR (CDCl ₃ , 300MHz) δ8.40(bs, 1H), 7.55(s, 1H), 7.14(s, 1H), 4.29-4.24(m, 1H), 3.78(s, 3H), 3.39 -3.19 (m, 2H), 2.69 (s, 3H). LC/MS: _tR = 1.18 min, 235 (MH) ⁺ .

(R)-methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(7-methyl Base-1H-benzo[d][1,2,3]triazol-5-yl)propionate

(R)-Methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. LC/MS: _tR = 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)propionic acid

(R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-( 2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. LC/MS: _tR = 2.11 min, 492 (MH) ⁺ .

Example 237

4-(1,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-((R)-3-(7-methyl-1H-benzo[d ][1,2,3]triazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine- 1-formamide

The preparation was as described in Example 231 above.

¹ H-NMR (CD ₃ OD, 300MHz) δ8.01(d, J=8.1Hz, 1H), 7.63(t, J=7.5Hz, 1H), 7.28-7.11(m, 4H), 5.06-5.00( m, 1H), 4.70-4.60(m, 1H), 4.31-4.17(m, 2H), 3.50-3.44(m, 1H), 3.20-2.82(m, 7H), 2.75-2.47(m, 6H), 2.12-2.02(m, 2H), 1.93-1.67(m, 11H), 1.37-1.28(m, 2H, 0.97-0.79(m, 2H), 0.23-0.09(m, 1H). Mass spectrum: 642(MH) ⁺ .

(R)-2-Benzyloxycarbonylamino-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester (373 mg, 1.01 mmol), N - A mixture of chlorosuccinimide (168 mg, 1.26 mmol), silica gel (EM Scientific, 230-400 mesh, 3.73 g) in dichloroethane (20 mL) was heated at 90° C. for 16 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:2) as eluent to afford the title compound (40 mg, 9.8%) as well as 2-benzyloxycarbonylamino-3-(5- Chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester (78 mg, 19%). 2-Benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl) prepared by 2D NMR by reaction with -Methyl propionate was compared to determine the structure.

¹ H-NMR (CD ₃ COCD ₃ , 500MHz) δ7.37-7.27(m, 5H), 7.18(d, J=1.0Hz, 1H), 7.16(s, 1H), 6.76(d, J=8.5hz , 1H), 5.06(d, J=12.5Hz, 1H), 5.02(d, J=12.5Hz, 1H), 4.55-4.51(m, 1H), 3.72(s, 3H), 3.26(dd, J= 14.0, 5.0Hz, 1H), 3.04 (dd, J=14.0, 9.5Hz, 1H); ¹³ C-NMR (CD ₃ COCD ₃ , 125MHz) δ172.2, 156.4, 154.0, 144.8, 137.6, 133.3, 128.7, 128.2, 128.0, 127.9, 125.0, 66.3, 55.9, 52.0, 37.3; mass spectrum 405 (MH ⁺ ).

(R)-2-Benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

N-Chlorosuccinimide (315mg, 2.36mmol) was added to (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxane at room temperature Azol-6-yl)-propionic acid methyl ester (700 mg, 1.89 mmol) in acetic acid (50 mL). The mixture was heated at 100°C for 16 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexanes (4:6) then (1:1) as eluents to afford the title compound (242 mg, 32%) as a yellow solid. The structure of the product was confirmed by 2D NMR.

¹ H-NMR (CD ₃ COCD ₃ , 500MHz) δ10.47(s, 1H), 7.36-7.28(m, 6H), 7.20(s, 1H), 6.80(d, J=8.5Hz, 1H), 5.05 (d, J=12.5Hz, 1H), 5.00(d, J=12.5Hz, 1H), 4.65-4.60(m, 1H), 3.73(s, 3H), 3.43(dd, J=14.0, 5.0Hz, 1H), 3.08 (dd, J=14.0, 10.5Hz, 1H); ¹³ C-NMR (CD ₃ COCD ₃ , 125MHz) δ172.2, 156.5, 154.5, 143.1, 137.5, 130.8, 129.0, 128.9, 128.7, 128.2 , 128.0, 112.8, 110.9, 66.3, 54.3, 52.1, 35.8; mass spectrum 405 (MH ⁺ ).

(R)-2-Benzyloxycarbonylamino-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester (418 mg, 1.13 mmol), N - A mixture of bromosuccinimide (221 mg, 1.24 mmol), silica gel (EM Scientific, 230-400 mesh, 2.51 g) and dichloromethane (70 mL) was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (2:3) as eluent to afford the title compound.

¹ H-NMR (CD ₃ COCD ₃ , 500MHz) δ10.71(s, 1H), 7.35-7.28(m, 6H), 7.21(s, 1H), 6.75(d, J=7.5Hz, 1H), 5.06 (d, 12.5Hz, 1H), 5.02(d, J=12.5Hz, 1H), 4.56-4.51(m, 1H), 3.73(s, 3H), 3.26(dd, J=14.0, 5.0Hz, 1H) , 3.03 (dd, J=14.0, 10.0Hz, 1H); ¹³ C-NMR (CD ₃ COCD ₃ , 125MHz) δ172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128.7, 128.2, 128.0, 127.8 , 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; mass spectrum 448.03 (MH ⁺ ).

(R)-2-Benzyloxycarbonylamino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester (1.07g, 2.89mmol), A mixture of N-bromosuccinimide (643 mg, 3.61 mmol) and acetic acid (150 mL) was heated at 105 °C for 14 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:3) then (1:1) as eluents to afford the title compound (446 mg, 34%). The structure of the title compound was confirmed by 2D NMR.

¹ H-NMR (CD ₃ COCD ₃ , 500MHz) δ10.46(s, 1H), 7.36-7.28(m, 7H), 6.82(d, J=8.5Hz, 1H), 5.05(d, J=12.5Hz , 1H), 5.00(d, J=12.5Hz, 1H), 4.67-4.62(m, 1H), 3.73(s, 3H), 3.43(dd, J=14.0, 5.0Hz, 1H), 3.10(dd, J=14.0, 10.5Hz, 1H); ¹³ C-NMR (CD ₃ COCD ₃ , 125MHz) δ172.2, 156.4, 154.2, 143.7, 137.6, 131.1, 130.6, 128.7, 128.2, 128.0, 118.2, 113.9, 112.9, 66.2, 54.3, 52.1, 38.3; mass spectrum 448.03 (MH ⁺ ).

(R)-2-Benzyloxycarbonylamino-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester (324mg, 0.87mmol), I A mixture of (PyH) _2BF4 (409 _mg , 1.08 mmol), silica gel (EM Scientific, 230-400 mesh, 3.24 g) and dichloroethane (20 mL) was heated at 90 °C for 6 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:2) as eluent to afford the title compound (175 mg, 40%). The structure of the title compound was confirmed by 2D NMR.

¹ H-NMR (CD ₃ COCD ₃ , 500MHz) δ10.47(s, 1H), 7.46(s, 1H), 7.37-7.29(m, 5H), 7.22(s, 1H), 6.74(d, J= 8.5Hz, 1H), 5.07(d, J=12.5Hz, 1H), 5.02(d, J=12.5Hz, 1H), 4.54-4.49(m, 1H), 3.72(s, 3H), 3.23(dd, J=14.0, 5.0Hz, 1H), 3.01 (dd, J=14.0, 9.5Hz, 1H); ¹³ C-NMR (CD ₃ COCD ₃ , 125MHz) δ172.2, 156.4, 153.4, 143.3, 137.6, 134.1, 133.64, 133.60, 128.7, 128.2, 128.0, 110.7, 71.1, 66.3, 56.0, 52.0, 37.1; mass spectrum 496.01 (MH ⁺ ).

(R)-2-Amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

Trimethylsilyl iodide (73 mL, 0.73 mmol) was added to azeotropically dried (R)-2-benzyloxycarbonylamino-3-(5-bromo-2-oxo-2,3 -Dihydro-benzoxazol-6-yl)-propionic acid methyl ester (146 mg, 0.33 mmol) in acetonitrile (10 mL) and the resulting mixture was stirred at room temperature for 2 hours. Triethylamine (0.12 mL) was added, and the mixture was stirred at room temperature for 15 minutes. 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. The solvent was removed and the residue was used directly in the next step. Mass spectrum 315.10 (MH) ⁺ .

(R)-2-Amino-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

Prepared according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester as described above . Mass spectrum 315.06 (MH) ⁺ .

(R)-2-Amino-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

Prepared according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester as described above . Mass spectrum 271.10 (MH) ⁺ .

(R)-2-Amino-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester

Prepared according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester as described above . Mass spectrum 271.16 (MH) ⁺ .

(R)-2-Amino-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester:

Prepared according to the method for preparing (R)-2-amino-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid methyl ester as described above . Mass spectrum 363.04 (MH) ⁺ .

(R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2′-oxospiro-(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 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 481.20 (MH) ⁺ .

(R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2′-oxospiro-(piperidine -4,4'-1H-quinazoline)-1-carbonyl]-amino}-propionic acid methyl ester

(R)-Methyl 2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 480.24 (MH) ⁺ .

(R)-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 528.16 (MH) ⁺ .

(R)-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 528.20 (MH) ⁺ .

(R)-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 572.20 (MH) ⁺ .

(R)-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 572.15 (MH) ⁺ .

(R)-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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 was prepared as described above -(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionate was prepared by the method. Mass spectrum 620.20 (MH) ⁺ .

(R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2′-oxospiro-(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-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 467.18 (MH) ⁺ .

(R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[2,4-dihydro-2′-oxospiro-(piperidine -4,4'-1H-quinazoline)-1-carbonyl]-amino}-propionic acid

(R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-( 2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 466.20 (MH) ⁺ .

(R)-3-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 514.20 (MH) ⁺ .

(R)-3-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 514.24 (MH) ⁺ .

(R)-3-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 558.30 (MH) ⁺ .

(R)-3-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 558.25 (MH) ⁺ .

(R)-3-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-{[4-(2-oxo-1,4-di Hydrogen-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-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propionic acid can be prepared by the method. Mass spectrum 606.10 (MH) ⁺ .

Example 238

(R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1 -yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 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-piperazine- 1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.71 min, 590.34 (MH) ⁺ .

Example 240

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.64 min, 617.34 (MH) ⁺ .

Example 241

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.69 min, 617.35 (MH) ⁺ .

Example 242

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1, 3] oxazine)-1-carboxamide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.57 min, 577.32 (MH) ⁺ .

Example 243

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-quinazoline)-1- Formamide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.74 min, 616.37 (MH) ⁺ .

Example 244

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-base) piperazin-1-yl) prop-2-yl) -2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1- Formamide

Prepared as above. LC/MS: _tR = 1.79 min, 616.36 (MH) ⁺ .

Example 245

(R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1-methyl Amide

The preparation was as described in Example 231 above. LC/MS: _tR = 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′]bipiperidine- 1′-yl-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 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′]bipiperidine- 1′-yl-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.91 min, 664.34 (MH) ⁺ .

Example 248

(R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine- 1′-yl-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 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′]bipiperidine- 1′-yl-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.96 min, 708.31 (MH) ⁺ .

Example 250

(R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine- 1′-yl-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide

The preparation was as described in Example 231 above. LC/MS: _tR = 1.97 min, 756.36 (MH ⁺ ).

Example 251

(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′ ,2′-Dihydro-2′-oxospiro-[4H-3′,1-benzoxazin-4,4′-piperidinyl]-butanamide

(±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.38 min, 596 (MH) ⁺ .

Example 252

(±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4- (2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanamide

(±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.50 min, 609 (MH) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.90 (1H, s), 7.64-7.84 (1H, m), 6.71-7.42 (11H, m), 4.58 (1H, m), 3.82-4.50 (6H, m), 2.21-3.52 (13H, m), 1.42-1.87 (4H, m).

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']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.43 min, 630 (M+Na) ⁺ .

Example 254

(±)-1-[1,4']bipiperidin-1'-yl-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-2-(7-methyl-1H-indazol-5-ylmethyl)-butane-1,4-dione

(±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.18 min, 644 (MH) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.00 (1H, s), 6.82-7.40 (6H, m), 4.48-4.70 (3H, m), 4.31 (2H, s), 3.85-4.11 (2H, m ), 3.65 (1H, m), 2.70-3.16 (5H, m), 2.53 (3H, s), 0.72-2.52 (23H, m).

Example 255

(±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[2',3'- Dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline]-butane-1,4-dione

(±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.09 min, 612 (MH) ⁺ .

2-oxo-2,3-dihydro-benzoxazole-6-carbaldehyde

Under nitrogen, a solution of 6-bromo-3H-benzoxazol-2-one (0.9236 g, 4.31 micromol) in anhydrous THF (25 mL) and dimethylformamide (3 mL) was cooled to -78 °C, followed by the addition of n-butyllithium (2.5 M in hexane) (3.8 mL, 2.2 equiv). After stirring at -78°C for 10 min, 24 mL of sec-butyllithium (1.4 M in cyclohexane, 8 equiv.) was added. The reaction was stirred while slowly warming to -40°C. When this temperature was reached, the reaction was quenched by adding methanol. The reaction mixture was concentrated in vacuo, and water was added. The aqueous layer was acidified with 1N HCl (approximately pH 5) and extracted with ethyl acetate (3 x 50 mL), dried over sodium sulfate, filtered and concentrated to give the product, 0.6402 g (91%). MS (ESI) 164 (MH) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ9.90 (1H, s), 7.79 (1H, d, J=8.0Hz), 7.74 (1H, s), 7.28 (1H, d, J=8.0Hz).

3-(2-Oxo-2,3-dihydro-benzoxazol-6-ylmethylene)-glutaric acid monomethyl ester

Prepared following the procedure described above for the preparation of 1-methyl 2-(7-methyl-1H-indazol-5-ylmethylene)-succinate (1.4 g, 90% yield). MS (ESI) 300 (M+Na) ⁺ .

(±)-3-(2-Oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-glutaric acid monomethyl ester

Prepared following the procedure described above for the preparation of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-succinic acid 1-methyl ester (1.4 g, 99% yield). MS (ESI) 302 (M+Na) ⁺ .

(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid methyl ester

As above for the preparation of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxo It can be prepared by substituting spiro-[4H-3′,1-benzoxazin-4,4′-piperidinyl]-butyric acid methyl ester. MS (ESI) 493 (MH) ⁺ .

(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2′,3′-dihydro-2′ -Oxospiro-(piperidine-4,4'-quinazoline)]-butyric acid methyl ester

As above for the preparation of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxo It can be prepared by substituting spiro-[4H-3′,1-benzoxazin-4,4′-piperidinyl]-butyric acid methyl ester. MS (ESI) 479 (MH) ⁺ .

(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[2′,3′-dihydro-2′ -oxospiro-(piperidine-4,4'-quinazoline)]-butanoic acid

As above for the preparation of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxo Substituting spiro-[4H-3', 1-benzoxazin-4,4'-piperidinyl]-butyric acid to prepare it. MS (ESI) 465 (MH) ⁺ .

(±)-4-oxo-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[4-(2-oxo-1,4 -Dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid

As above for the preparation of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1′,2′-dihydro-2′-oxo Substituting spiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butyric acid to prepare it. MS (ESI) 479 (MH) ⁺ .

Example 256

(±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

As above for the preparation of (±)-1-[1,4′]bipiperidin-1′-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.10 min, 629 (MH) ⁺ .

Example 257

(±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

As above for the preparation of (±)-1-[1,4′]bipiperidin-1′-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.08 min, 629 (MH) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ9.89(1H, s), 8.28(1H, d, J=11.2Hz), 6.90-7.25(5H, m), 6.75(1H, d, J=8.0Hz) , 4.40-4.79(3H, m), 4.35(2H, s), 2.27-3.98(19H, m), 1.46-2.10(9H, m), 1.36(1H, m), 1.08(1H, m), 0.12 (1H, m).

Example 258

(±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [2′,3′-Dihydro-2′-oxospiro-(piperidine-4,4′-quinazoline)]-butane-1,4-dione

As above for the preparation of (±)-1-[1,4′]bipiperidin-1′-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.02 min, 615 (MH) ⁺ .

Example 259

(±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 2′,3′-Dihydro-2′-oxospiro-(piperidine-4,4′-quinazoline)]-butane-1,4-dione

As above for the preparation of (±)-1-[1,4′]bipiperidin-1′-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1 ', 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butane-1,4-dione get. LC/MS: _tR = 1.04 min, 615 (MH) ⁺ .

Example 260

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

Prepared according to the above method for the preparation of Example 16.

¹ H-NMR (CD ₃ OD, 500MHz) δ0.81(1H, m), 0.89(1H, m), 1.02(1H, m), 1.1-2.0(12H, m), 2.23(1H, d), 2.47(1H,d), 2.61(3H,s), 2.90(4H,t), 3.08(4H,m), 3.2-3.5(4H,m), 3.82(1H,m), 4.14(2H,d) , 4.29 (2H, s), 4.40 (1H, t), 6.80 (1H, d), 6.95 (1H, t), 7.12 (3H, m), 7.47 (1H, s), 8.01 (1H, s). Mass spectrum: 627.47 (MH) ⁺ .

Example 261

(±)-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 according to the above method for the preparation of Example 16. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester

(±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- Base)-piperidine-1-carbonyl]-amino}-propionic acid (50mg, 0.105mmol) and dicyclohexylcarbodiimide (25mg, 0.12mmol) in dimethylformamide was stirred at room temperature for 30 minutes, And then pentafluorophenol (26 mg, 1.3 mmol) was added. Stirring was continued overnight at room temperature, and then the solvent was removed and the residue was dried under high vacuum for 4 hours. The crude pentafluorophenyl ester was used in the next step without further purification. To a solution of tert-butanol (10 eq) in tetrahydrofuran was added 1.4M sec-butyllithium in cyclohexane (10 eq) at -78°C under nitrogen. After 10-15 minutes, a solution of pentafluorophenol ester (1 eq.) in THF 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 give the desired compound.

¹ H-NMR (CD ₃ OD) δ1.40 (s, 9H) 1.56 (m, 4H), 2.54 (s, 3H) 2.85 (m, 2H) 3.05 (m, 1H) 3.19 (m, 1H) 4.14 ( m, 4H) 4.44 (m, 2H) 6.76 (d, J = 7.68Hz, 1H) 6.93 (t, J = 7.5Hz, 1H) 7.10 (m, 3H) 7.14 (s, 1H) 7.97 (s, 1H) . LC/MS: _tR = 2.19 min, 533.36 (MH) ⁺ .

Example 263

(±)-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-methylcyclohexyl

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester is prepared. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester

To (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline-3- Base)-piperidine-1-carbonyl]-amino}-propionic acid (50 mg, 0.105 mmol), EDCI (100 mg) and 4-dimethylaminopyridine (0.2 equiv.) in dimethylformamide solution was added aza - bicyclo[2.2.2]octan-3-yl alcohol (0.525 mmol, 5 equiv). The mixture was stirred overnight at room temperature. 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 give the desired compound. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-piperidin-4-yl propionate

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester is prepared. LC/MS: _tR = 1.58 min, 560.37 (MH) ⁺ .

Example 266

(±)-4-(3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)-piperidine-1-carbonyl]-amino}-propionyloxy)-piperidine-1-carboxylic acid tert-butyl ester

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester is prepared. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid 3,4,5,6-tetrahydro-2H-[1,4′]bipyridine-4-yl ester

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester is prepared. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester is prepared. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-2-phenyl-ethyl ester

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester is prepared. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-3-phenyl-propyl ester

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester is prepared. LC/MS: _tR = 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 )-piperidine-1-carbonyl]-amino}-propionic acid ethyl ester

As above for the preparation of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazole Lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester is prepared. LC/MS: _tR = 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'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide

Prepared according to the above method for the preparation of Example 16. LC/MS: _tR = 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'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide

Prepared according to the above method for the preparation of Example 16. LC/MS: _tR = 1.56 min, 608.18 (MH) ⁺ .

Example 274

(±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylcarbamoyl)-2-oxoethyl Base] -2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide

Prepared according to the above method for the preparation of Example 16. LC/MS: _tR = 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′-oxospiro-[4H-3′,1-benzoxazine-4,4′-piperidine]-1-carboxamide

Prepared according to the above method for the preparation of Example 16. LC/MS: _tR = 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′-oxospiro-[4H-3′,1-benzoxazine-4,4′-piperidine]-1-carboxamide

Prepared according to the above method for the preparation of Example 16. LC/MS: _tR = 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']bipiperidine- 1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl]amide

Prepared according to the above method for the preparation of Example 16.

¹ H-NMR (CD ₃ OD, 500MHz) δ-0.27 (1H, m), 0.75 (1H, m), 1.1-2.0 (12H, m), 2.10 (2H, m), 2.4-2.5 (3H, m ), 2.57(3H, s), 2.68(2H, m), 2.92(4H, m), 3.10(4H, m), 3.9-5.1(4H, multiple m), 6.82(1H, d), 6.96( 1H,t), 7.18(3H,m), 7.50(1H,s), 8.05(1H,s). LC/MS: _tR = 1.68 min, 627.42 (MH) ⁺ .

Example 278

(R)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1,4-bipiperidinyl]-1-yl-2-oxoethyl]-2' , 3'-Dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide

Prepared according to the above method for the preparation of Example 16. LC/MS: _tR = 1.63 min, 613.36 (MH) ⁺ .

Other compounds contemplated within the scope of the invention and which can be prepared according to the descriptions provided herein or by methods known to those skilled in the art include the following projected examples.

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

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2-oxo-2,3 -Dihydro-benzoxazol-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-benzoxazol-6-ylmethyl)-ethyl]-amide

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(4-Methyl-2-oxo-2,3-dihydro-benzoxazol-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 -Dioxy-benzoxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-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-benzoxazol-6-yl)-ethyl]-amide

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-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 -Dioxy-benzoxazol-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- Dihydro-benzoxazol-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 [2-[1,4']bipiperidin-1'-yl -1-(4-Ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide

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

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

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

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide

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

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

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-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}-cyclohexyl propionate

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

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

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

CGRP binding test

Tissue culture. SK-N-MC was cultured at 37°C and 5% CO in a _medium consisting of Earle's salt-containing MEM and L-glutamine (Gibco) supplemented with 10% fetal bovine serum (Gibco). Cells grow in monolayers.

cell granules. The cells were washed twice with phosphate-buffered saline (155 mM NaCl, 3.3 mM Na ₂ HPO ₄ , 1.1 mM KH ₂ PO ₄ , pH 7.4), and then incubated at 4°C in a solution containing 10 mM Tris (pH 7.4) and 5 mM EDTA. Incubate in hypotonic lysis buffer for 5-10 minutes. Cells were transferred from the plate into polypropylene tubes (16 x 100 mm) and then homogenized using a polytron (homogenizer). The homogenate was centrifuged at 32,000 xg for 30 minutes. The pellets were resuspended in cold hypotonic lysis buffer containing 0.1% mammalian protease inhibitor cocktail (Sigma) and protein concentrations were determined. The SK-N-MC homogenate was then divided into aliquots and stored at -80°C until use.

Radioligand Binding Assay. Compounds of the invention were dissolved in 100% DMSO and serially diluted. An aliquot of the serial dilution of the compound of the present invention was further diluted 25-fold with assay buffer (50 mM Tris-Cl pH 7.5, 5 mM MgCl ₂ , 0.005% Triton X-100) and transferred (50 μl amount) to a 96-well assay plate . [ ¹²⁵ I]-CGRP (Amersham Biosciences) was diluted to 60 pM in assay buffer and added in a volume of 50 μl per well. The SK-N-MC pellets were thawed, diluted in assay buffer containing fresh 0.1% mammalian protease inhibitor cocktail (Sigma), and homogenized again. SK-N-MC homogenate (5 μg/well) was added in a volume of 100 μl. The assay plates were then incubated at room temperature for two hours. The assay was terminated by the addition of excess cold wash buffer (20 mM Tris-Cl pH 7.5, 0.1% BSA) followed by immediate filtration through glass fiber filters (Whatman GF/B) pre-soaked in 0.5% PEI. Non-specific binding was defined as 1 μM β-CGRP. Determine protein-bound radioactivity using a gamma or scintillation counter. _IC50 is defined as the concentration of compound of the invention required to displace 50% of radioligand binding.

In the table below, the results are expressed as follows: A≤10nM; 10nM<B≤100nM; 100nM<C≤1000nM; D>1000nM.

Table 4. CGRP Binding, cAMP Function, and In Vitro Human Cerebral Artery Data Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 1 C * * 2 A A A 3 B B B 4 B B * 5 A A * 6 A A A 7 C C * 8 C C * 9 B B * 10 C B * 11 B B * 12 B C * 13 C * * 14 D. * * 15 C C * 16 A A A 17 A A A 18 A B A 19 A A A 20 A A A twenty one A A A twenty two A A * twenty three A A A twenty four B B * 25 A A A Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 26 B B * 27 B C * 28 C * * 29 A * * 30 B * * 31 A A * 32 C * * 33 C * * 34 A A * 35 B B * 36 B B * 37 A B * 38 B B * 39 C C * 40a A A * 40b B * * 40c D. * * 40d C * * 40e D. * * 40f D. * * 40g D. * * 40h D. * * 40i B * * 40j D. * * 40k D. * * 41a B * * 41b A * * 41c A * * Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 41d B * * 41e A * * 41f B * * 42 C * * 43 A A A 44 C * * 45 A * * 46 B B * 47 A A A 48 D. * * 49 A * * 50 A * * 51 D. * * 52 D. * * 53 D. * * 54 B C A 55 C * * 56 A A * 57 C * * 58 D. * * 59 C * * 60 C * * 61 C C * 62 B B * 63 C C * 64 B * B 65 A B B 66 C * * Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 67 B C B 68 A A A 69 A A A 70 A A A 71 A A A 72 A A A 73 B B * 74 A A A 75 A B * 76 B B A 77 B B * 78 A A * 79 B C * 80 C * * 81 B C * 82 B C * 83 B C * 84 B B * 85 C * * 86 C B C 87 B B * 88 C B * 89 C B * 90 B * * 91 C * * 92 B C * 93 C * * 94 C C * Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 95 C * * 96 D. * * 97 D. * * 98 D. * * 99 D. D. * 100 C * * 101 D. * * 102 C * * 103 C * * 104 C * * 105 C * * 106 C * * 107 C * * 108 C * * 109 C * * 110 C * * 111 C * * 112 C * * 113 C * * 114 C * * 115 C * * 116 C * * 117 C * * 118 C * * 119 C * * 120 C * * 121 C * * 122 C * * Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 123 B * * 124 C * * 125 C * * 126 C * * 127 C * * 128 C * * 129 C * * 130 C * * 131 C * * 132 C * * 133 C * * 134 C * * 135 C * * 136 C * * 137 C * * 138 C * * 139 C * * 140 B * * 141 C * * 142 C * * 143 C * * 144 C * * 145 C * * 146 B * * 147 C * * 148 B * * 149 B * * 150 B * * Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 151 C * * 152 C * * 153 C * * 154 C * * 155 C * * 156 C * * 157 C * * 158 B * * 159 B * * 160 C * * 161 B * * 162 C * * 163 C * * 164 C * * 165 C * * 166 C * * 167 C * * 168 C * * 169 C * * 170 C * * 171 B * * 172 B * * 173 C * * 174 C * * 175 C * * 176 B * * 177 B * * 178 B * * Examples# CGRP binding ¹ IC ₅₀ (nM) cAMP function ² IC ₅₀ (nM) Cerebral artery ³ EC ₅₀ (nM) 179 C * * 180 C * * 181 C * * 182 C * * 183 C * * 184 B * * 185 C * * 186 C * * 187 C * * 188 C * * 189 C * * 190 C * * 191 C * * 192 C * * 193 B * * 194 C * * 195 C * * 196 B * * 197 C * * 198 C * * 199 B * * 200 B * * 201 C * *

Ring AMP Test

functional antagonism. Antagonism of the compounds of the invention was determined by measuring the formation of cyclic AMP (3'5-cyclic AMP) in SK-N-MC cells endogenously expressing the human CGRP receptor. The CGRP receptor complex is combined with the Gs protein (couple), and the binding of CGRP to this complex results in the generation of cyclic adenosine monophosphate through the activation of a Gs-dependent adenylyl cyclase (Juaneda C et al., TiPS, 2000; 21:432-438; incorporated herein by reference). Thus, CGRP receptor antagonists inhibit CGRP-induced cyclic AMP production in SK-N-MC cells (Doods H et al., Br J Pharmacol 2000; 129(3):420-423; incorporated herein by reference) . To measure cyclic AMP, SK-N-MC cells were incubated with 0.3 nM CGRP alone or in the presence of different concentrations of compounds of the invention at room temperature for 30 minutes. Compounds of the invention were pre-incubated with SK-N-MC cells for 15 minutes to allow receptor occupancy (Edvinsson et al., Eur JPharmacol, 2001, 415:39-44; incorporated herein by reference) prior to addition of CGRP ). CAMP was extracted with (cell) lysis reagent, and its concentration was measured by radioimmunoassay using RPA559 cAMPSPA Direct Screening Assay Kit (RPA559 cAMPSPA Direct Screening Assay Kit, Amersham Pharmacia Biotech). IC50 values were calculated using Excel fit. Since the test compound of the present invention exhibited a dose-dependent inhibitory effect on CGRP-mediated cyclic AMP production, the test compound of the present invention was determined to be an antagonist. See Table 3 for an overview of the results.

Schild analysis. Schild analysis can be used to characterize the antagonism of the compounds of the invention, CGRP alone, or in the presence of different concentrations of the compounds of the invention to perform a dose response of CGRP-stimulated cyclic AMP production. Antagonist dose is set on the X-axis, and against it, the dose ratio (defined as the IC50 of agonist alone divided by the IC50 of agonist in the presence of compound) minus 1 is the Y-axis. Linear regression was then performed on both the X-axis and the Y-axis log-transformed. A slope that is not significantly different from unity (1) indicates competitive antagonism. _Kb is the dissociation constant of the antagonist.

Table 5. Schild analysis Examples# K _b (nM) slope 2 0.16 0.94 3 55 0.96 5 3 0.92 6 0.36 0.93 16 1.3 17 1.1 0.92 18 1 0.8 twenty one 0.018 0.89 Examples# K _b (nM) slope 43 0.018 1.2 45 1.4 47 0.1 0.93 69 0.016 1 70 0.71 71 2 0.87

See Figure 1. Schild analysis.

In Vitro Analysis of Human Cerebral Arteries

Fundamentals and overview. An in vitro assay has been designed to provide direct evidence for the ability of new compounds to reverse CGRP-mediated dilation of blood vessels in the human brain. Briefly, isolated vascular rings were placed in a tissue bath, the vessels were preconstricted with potassium chloride (KCl), fully dilated with hCGRP, and then relaxed by cumulatively added CGRP-receptor antagonists. Reversal (full details below).

Tissue samples. Dissected samples of human arteries were obtained from suppliers (ABS Inc. or NDRI). Transfer all vessels to ice-cold HEPES buffer (composition (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 )middle. After receipt, the blood vessels were placed in cold Kreb's buffer (composition (mM): 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), The buffer was saturated with carbogen (5% _CO2 and 95% oxygen).

Isolated Tissue Baths. The connective tissue on the blood vessels was removed and cut into 4-5mm long cylindrical segments. The blood vessel is placed between two stainless steel hooks in a tissue bath, one of which is fixed and the other is attached to a force displacement transducer. Vascular tension was recorded continuously using a data acquisition system (Powerlab, ADInstruments, Mountain View, CA) connected to the transducer. The temperature (37° C.) and pH (7.4) of the tissue bath containing Krebs buffer and placed blood vessels were controlled with continuous sparging of carbogen. The arterial segment was equilibrated for approximately 30-45 minutes until it reached a stable resting tone. Prior to testing, vessels were primed (conditioned) with 100 mM KCl and then washed. Blood vessels were preconstricted with 10 mM KCl and then fully dilated with 1 nM hCGRP. Concentration-response curves of CGRP-receptor antagonists were obtained by accumulating added drug in half-log units in fully dilated vessels. At each concentration, the effect of the drug is expressed as % reversal of CGRP-mediated relaxation in each vessel. The actual measurement and data analysis were carried out for each blood vessel individually, and the concentration-response data were fitted to a four-parameter logistic equation through nonlinear regression analysis, thereby inferring the EC50 value. A summary of the results is shown in Table 3.

Non-terminal Method (Non-Terminal Method) to small molecule CGRP-receptor antagonists in mammals

Evaluation of In Vivo Potency

review. Blocking calcitonin gene-related peptide (CGRP)-mediated dilation of cerebral arteries has been proposed as a treatment for migraine, however, new small-molecule CGRP-receptor antagonists have been shown to differ , which is relatively inactive in rodents (Mallee et al., J Biol Chem 2002277:14294), thus requiring new models to assess efficacy in vivo. Non-human primates (such as marmosets) are the only animals known to have humanized (humanized) CGRP receptor pharmacology, characterized by the presence in their RAMP1 sequence of amino acid residues characteristic of the human receptor phenotype (Trp74) (Mallee et al., J Biol Chem 2002, 277:14294). Since the general migraine model mainly uses rats (Escott et al., Brain Res 1995 669: 93; Williamson et al., Cephalalgia 1997 17: 525), or is an invasive terminal procedure in primates (Doods et al., Br J Pharmacol 2000 129:420), a new non-invasive survival model for assessing the in vivo efficacy of CGRP-receptor antagonists in non-human primates, as described in the present invention, is an important contribution. Although stimulation of the trigeminal nerve is known to increase blood flow in the brain (Goadsby and Edvinsson, 1993) and the face (Doods et al., 2000), evidence for a direct relationship between facial blood flow and cerebral artery dilatation in conspecifics is still unknown. Therefore, before initiating studies in non-human primates, it was first demonstrated that measurement of laser Doppler facial blood flow in rats could serve as a surrogate for cerebral artery dilation in the final study measuring Changes in cerebral artery diameter and facial blood flow in animals (see Figure 2. Facial blood flow in rats as a surrogate for direct evidence of cerebral artery dilation). In both measurements, a comparable increase was mediated by iv infusion of CGRP followed by blocking with the peptide antagonist hαCGRP(8-37). Subsequently, the method of intravenous infusion of CGRP-mediated changes in facial blood flow was validated as a recovery model using hαCGRP(8-37) in propofol-anesthetized rats. Subsequent survival protocols were developed in non-human primates and dose-response studies characterized by intravenous infusion of CGRP activity were completed (see Figure 3. Dose- reaction). Validation of non-human primate models using peptide and small molecule CGRP-receptor antagonists. Pretreatment with a small molecule antagonist or hαCGRP(8-37) dose-dependently inhibited intravenous CGRP-stimulated increases in primate facial blood flow (see Figure 4. CGRP-mediated nonhuman primate Inhibition of changes in facial blood flow), without altering blood pressure (see Figure 5. Effect of CGRP antagonists on blood pressure in nonhuman primates). Post-treatment with antagonists also reversed the CGRP-mediated increase in facial blood flow (not shown). This survival model provides a novel, non-invasive approach to recovery to assess the efficacy of humanized RAMP1 (Trp74), which has similar CGRP receptor pharmacology, in nonhuman primates. effect) in transgenic animals for the prevention and abort effect of CGRP-receptor antagonists as a surrogate marker of cerebral vessel diameter.

animal. The test subjects were adult male and female common marmosets (Callithrix jacchus), purchased from Harlan, weighing 350-500 g. Other mammals that endogenously express RAMP1 with Trp74 or transgenic mammals that have humanized RAMP1 with Trp74 can also be used in the methods described herein.

Anesthesia and surgical preparation. Animals were anesthetized by inhalation of isoflurane in an induction chamber (4-5% rapid inhalation, 1-2.5% maintenance; Solomon et al., 1999). Anesthesia was maintained with a constant supply of gases: air:oxygen (50:50) and isoflurane, either by mask or by intubation and ventilation (in combination with blood gas testing). Their body temperature was maintained at 38±0.5°C by placing them on an automatically temperature-controlled surface equipped with a rectal probe (thermo)probe. Apply a depilatory cream to remove and/or shave a small area (approximately 1.5 cm2) of hair on one or both sides of the face. Surgical areas are clipped and prepared with betadine. An IV line is placed in any accessible vein to administer test compound and CGRP-receptor agonist, and if necessary, blood samples (up to 2.5 mL, 10%) are drawn for blood gas monitoring and assay. Intravenous infusion of 5% dextrose solution to maintain blood sugar levels. Depth of anesthesia was monitored by measuring blood pressure and heart rate, respectively, using the non-invasive arm cuff method and pulse oximeter. Guanethidine 5-10 mg/kg can be given intravenously, followed by a supplemental 5 mg/kg intravenously if necessary to stabilize the peak flow of facial blood flow seen in repetitive stimulation-mediated changes in blood flow (Escott et al., 1999; in incorporated by reference). Microvascular blood flow was monitored by affixing a self-adhesive laser Doppler flow probe to the facial skin.

Compound administration The test compound can be administered by intravenous injection (0.01-5mg/kg), intramuscular injection (0.01-0.5ml/kg), subcutaneous injection (0.01-5ml/kg) or orally (0.1-10ml/kg ) (Diehl et al., 2001; incorporated herein by reference). CGRP-receptor agonists can be administered by intravenous injection (0.01-5 ml/kg), intravenous infusion (i.d.) (10-100 μl/site) or subcutaneous injection (10-100 μl/site).

Laser Doppler flowmeter By administering vasodilators such as CGRP (0.05-100 μg/kg iv) or 2-20 pmol/site intravenous infusion (i.d.)) or adrenomedullin (ADM, 0.05-5 mg/kg iv Or 10-100pmol/site intravenous infusion) causes a controllable increase in facial blood flow. The test compound or vehicle is administered either before (pre-treatment) or after (post-treatment) the continuous administration of the vasodilator to provide the ability to assess prophylactic or therapeutic effects. Blood pressure is constantly monitored to ensure appropriate depth of anesthesia, and anesthesia is adjusted to maintain a steady level matching pre-treatment values. During the acquisition of laser Doppler flow data, isoflurane can be reduced to 0.25-0.75% as previous electrophysiological studies in marmosets have found that they are sensitive to isoflurane concentrations (Solomon, 1999; incorporated herein by reference) . To reduce the number of animals used, the effect of test compounds on changes in blood flow mediated by intravenous vasodilators can be replicated up to 6 times in a single series of experiments.

Recovery Return the animal to a transport cage placed on a temperature-controlled surface to keep the animal warm until it is fully awake and ambulatory. Animals may be retested after 7-14 days of rest, and may be repeated at intervals of 7-14 days depending on the animal's health.

See Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C. Good practice guidelines for dosing and taking blood samples, including dosing and sampling routes and volumes. (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; Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Introduction to the pharmacology of BIBN4096BS - the first selective small molecule CGRP-receptor antagonist. (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: treatment complications. (Calcitonin gene-related peptide(CGRP) and thepathophysiology of headache: therapeutic implications.) CNS Drugs 2001;15(10):745-53; Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal nerve stimulation in rats Section Increased facial skin blood flow: a major role for calcitonin gene-related peptide. (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; Goadsby PJ, Edvinsson L. Trigeminal neurovascular system and bias Headache: a study of characterization of cerebrovascular and neuropeptide alterations in humans and cats. (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 JB, Ols CGRP may be responsible for migraines. (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 non-peptide CGRP receptor antagonism The species selectivity of the agent. (RAMP1 determines the species selectivity of non-peptide CGRP receptor antagonists.) JBiol Chem. 2002 Feb 14 [to be published]; Solomon SG, White AJ, Martin PR. Temporary comparison in the lateral geniculate nucleus of a New World monkey Callithrix jacchus marmoset sensitivity. (Temporal contrast sensitivity in the lateral geniculate nucleus of a New World monkey, themarmoset Callithrix jacchus.) J Physiol. 1999 Jun 15;517(Pt 3):907-17; all documents are hereby incorporated by reference.

Differences from other migraine models. The present invention proposes a new model of migraine that is distinctly different from other models of migraine. Some salient features of the method of the invention include: (i) the only in vivo model of migraine in any species; (ii) the only model demonstrating the effect of CGRP antagonists on the termination (postconditioning) of activity-mediated increases in blood flow; ( iii) the only demonstration of a direct relationship between facial blood flow and intracranial arterial dilation in the same species; (iv) the only model that employs non-invasive surgical techniques and does not require catheterization, intubation, or neuromuscular blockade (v) the only primate model to apply exogenous CGRP as a stimulus and demonstrate block by CGRP antagonist preconditioning and reversal by CGRP antagonist postconditioning; (vi) apply isoflurane anesthesia in spontaneously breathing animals The only migraine model. This model is described in: Williamson et al. Inhibitory effect of sumatriptan on neurogenic dural vascular dilation in an in vivo microscopy study of anesthetized rats. (Sumatriptan inhibits neurogenic vasodilation of dual 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 microscopy study of the effect of calcitonin gene-related peptide on the diameter of dural vessels in anesthetized rats. (Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on duravessel diameter in the anaesthetized rat.) Cephalalgia. 1997 Jun; 17(4): 518-24; Escott KJ et al. Increased facial skin blood flow: a major role for calcitonin gene-related peptide. (Trigeminal ganglion stimulation increases facial skin bloodflow in the rat: a major role for calcitonin gene-related peptide.) Brain Res.1995Jan 9; 669(1): 93-9; Chu DQ et al., Calcitonin gene-related peptide (CGRP ) antagonist CGRP(8-37) blocks the dilation of blood vessels in inflamed rat skin: adrenomedullin is involved in addition to CGRP. (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 cutaneous vasodilation and edema induced by stimulation of the saphenous vein nerve in rats. (Effct of a calcitonin gene-related peptide antagonist(CGRP8-37) on skin vasodilatation and oedema induced by stimulation of the ratsaphenous 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 13-53 and calcitonin gene-related peptide receptor in microvasculature of rat and hamster. (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. Amylin and calcitonin In vivo interactions of gene-related peptide receptors in the microvasculature of the hamster cheek pouch. (Interaction of amylin with calcitoningene-related peptide receptors in the microvasculature of the hamster cheekpouch in vivo.) Br J Pharmacol.1999 Jan; 126(1):280-4; and Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS: the first selective small molecule CGRP-receptor antagonist. Br J Pharmacol.2000 Feb;129(3):420-3, none of the above documents contain the salient features of the method of the present invention.

In the table below, the meanings of the results are as follows: W≤25%; 25%<X≤50%; 50%<Y≤75%; Z>75%.

Table 6. CGRP-Mediated Inhibition of Laser Doppler Facial Blood Flow Increase in Non-Human Primates (eg Common Marmoset) Non-Human Primate (% Inhibition) CGRP-Mediated (10 μg/kg, IV) Increase in Laser Doppler Facial Blood Flow Examples# 0.01mg/kg, iv 0.03mg/kg, iv 0.1mg/kg, iv 0.3mg/kg, iv 1mg/kg, iv 2 W x x Y Z 6 Z 16 Y 69 Y Z hCGRP(8-37) Z W≤25%; 25%<X≤50%;50%<Y≤75%;Z>75%.

See Figure 5. Effect of CGRP antagonists on blood pressure in non-human primates.

Claims (6)

1. A compound selected from the group consisting of: (±)-3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 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']bipiperidine- 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-quinazoline-3- Base)-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']bipiperidine- 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']bipiperidine- 1'-yl-1-(7-ethyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide ; (±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-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' ]bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-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']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(6-Hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4 ']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(8-Chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-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'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide; (±)-N-(3-(7-Ethyl-3-methyl 1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine- 1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1,3]oxazine)- 1-formamide; (±)-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 ) piperidine-1-carboxamide; (±)-Methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3- (7-Methyl-1H-indazol-5-yl)propionate; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-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; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazole- 5-yl)-1-oxo-1-(4-phenylpiperazin-1-yl)prop-2-yl)piperidine-1-carboxamide; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(4-fluorophenyl)piper Azin-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)piper Azin-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-indazole- 5-yl)-1-oxo-1-(4-o-tolylpiperazin-1-yl)prop-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)propionate; (±)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine -1-yl)prop-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-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1-formamide; (±)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl) Propan-2-yl)-8'-fluoro-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide; (±)-4-(8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-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; 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)propionate; N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)-1-oxo-1-(4-piperidine-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-piperidine-1 -yl)piperidin-1-yl)prop-2-yl)-4-(2',3'-dihydro-2'-oxospiro(piperidin-4,4'-(1H)-quinazole phylloline) formamide; 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-formamide; (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1 -yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-isopropyl-piperazine- 1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl)piperidin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1, 3] (oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-quinazoline)-1- Formamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1- Formamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1-methyl amides; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-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'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butanamide; (±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanamide; (±)-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']bipiperidin-1'-yl-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-2-(7-methyl-1H-indazol-5-ylmethyl)-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[2',3'- Dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline]-butane-1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane-1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane-1,4-dione; (±)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-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 )-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-methylcyclohexyl; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-piperidin-4-yl propionate; (±)-4-(3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)-piperidine-1-carbonyl]-amino}-propionyloxy)-piperidine-1-carboxylate tert-butyl; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 3,4,5,6-tetrahydro-2H-[1,4']bipyridine-4-yl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-3-phenyl-propyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid ethyl ester; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-2-oxoethyl]-2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl]-2' , 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylcarbamoyl)-2-oxoethyl Base] -2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl]-1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide; (±)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-2-yl-piperazinyl]-2-oxoethyl]-1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1d-carboxylic acid [2-[1,4']bipiperidine- 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-bipiperidinyl]-1-yl-2-oxoethyl]-2' , 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound selected from the group consisting of: 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-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 -Dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2-oxo-2,3 -Dihydro-benzoxazol-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-benzoxazol-6-ylmethyl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3 -Dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-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-benzoxazol-6-yl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-6-yl)-1-dimethylcarbamoyl-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3 -Dihydro-benzoxazol-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- Dihydro-benzoxazol-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 [2-[1,4']bipiperidin-1'-yl -1-(4-Ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Chloro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3,7-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-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}-cyclohexyl propionate; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-carbonyl]-amino}-cyclohexyl propionate; 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; 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; or a pharmaceutically acceptable salt or solvate thereof. 3. A pharmaceutical composition comprising a compound selected from the group consisting of: (±)-3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 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']bipiperidine- 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-quinazoline-3- Base)-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']bipiperidine- 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']bipiperidine- 1'-yl-1-(7-ethyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide ; (±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-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' ]bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-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']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(6-Hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4 ']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(8-Chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-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'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide; (±)-N-(3-(7-Ethyl-3-methyl 1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine- 1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1,3]oxazine)- 1-formamide; (±)-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 ) piperidine-1-carboxamide; (±)-Methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3- (7-Methyl-1H-indazol-5-yl)propionate; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-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; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazole- 5-yl)-1-oxo-1-(4-phenylpiperazin-1-yl)prop-2-yl)piperidine-1-carboxamide; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(4-fluorophenyl)piper Azin-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)piper Azin-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-indazole- 5-yl)-1-oxo-1-(4-o-tolylpiperazin-1-yl)prop-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)propionate; (±)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine -1-yl)prop-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-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-base) piperidin-1-yl) prop-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1-formamide; (±)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl) Propan-2-yl)-8'-fluoro-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide; (±)-4-(8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-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; 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)propionate; N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)-1-oxo-1-(4-piperidine-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-piperidine-1 -yl)piperidin-1-yl)prop-2-yl)-4-(2',3'-dihydro-2'-oxospiro(piperidin-4,4'-(1H)-quinazole phylloline) formamide; 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-formamide; (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1 -yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-isopropyl-piperazine- 1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl)piperidin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1, 3] (oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-quinazoline)-1- Formamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1- Formamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1-methyl amides; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butyramide; (±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanamide; (±)-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']bipiperidin-1'-yl-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-2-(7-methyl-1H-indazol-5-ylmethyl)-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[2',3'- Dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline]-butane-1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane-1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane-1,4-dione; (±)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-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 )-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-hydrogen-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-methylcyclohexyl; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-piperidin-4-yl propionate; (±)-4-(3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)-piperidine-1-carbonyl]-amino}-propionyloxy)-piperidine-1-carboxylate tert-butyl; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 3,4,5,6-tetrahydro-2H-[1,4']bipyridine-4-yl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-3-phenyl-propyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid ethyl ester; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-2-oxoethyl]-2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl]-2' , 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylcarbamoyl)-2-oxoethyl Base] -2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl]-1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide; (±)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-2-yl-piperazinyl]-2-oxoethyl]-1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide; (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3 base)-piperidine-1d-carboxylic acid [2-[1,4']bipiperidine-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-bipiperidinyl]-1-yl-2-oxoethyl]-2' , 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 4. A pharmaceutical composition comprising a compound selected from the group consisting of: 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-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 -Dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2-oxo-2,3 -Dihydro-benzoxazol-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-benzoxazol-6-ylmethyl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3 -Dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-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-benzoxazol-6-yl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-6-yl)-1-dimethylcarbamoyl-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3 -Dihydro-benzoxazol-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- Dihydro-benzoxazol-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 [2-[1,4']bipiperidin-1'-yl -1-(4-Ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Chloro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3,7-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-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}-cyclohexyl propionate; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-carbonyl]-amino}-cyclohexyl propionate; 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; 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; or a pharmaceutically acceptable salt or solvate thereof. 5. Use of a compound selected from the following, a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of migraine: (±)-3-(3-cyano-1H-indol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 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']bipiperidine- 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-quinazoline-3- Base)-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']bipiperidine- 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']bipiperidine- 1'-yl-1-(7-ethyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-yl-methyl)-2-oxo-ethyl]-amide ; (±)-4-(2,2-dioxo-1,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-piperidine-1-carboxy Acid [2-[1,4']bipiperidin-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' ]bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-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']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(6-Hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(8-methoxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4 ']bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl}-amide; (±)-4-(8-Chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-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'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide; (±)-N-(3-(7-Ethyl-3-methyl 1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine- 1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1,3]oxazine)- 1-formamide; (±)-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 ) piperidine-1-carboxamide; (±)-Methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3- (7-Methyl-1H-indazol-5-yl)propionate; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-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; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazole- 5-yl)-1-oxo-1-(4-phenylpiperazin-1-yl)prop-2-yl)piperidine-1-carboxamide; (±)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1-(4-(4-fluorophenyl)piper Azin-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)piper Azin-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-indazole- 5-yl)-1-oxo-1-(4-o-tolylpiperazin-1-yl)prop-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)propionate; (±)-N-(3-(7-Ethyl-3-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidine -1-yl)prop-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-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1-formamide; (±)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl) Propan-2-yl)-8'-fluoro-2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)-1-carboxamide; (±)-4-(8-fluoro-1,2-dihydro-2,4-dioxoquinazolin-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; 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)propionate; N-((R)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)-1-oxo-1-(4-piperidine-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-piperidine-1 -yl)piperidin-1-yl)prop-2-yl)-4-(2',3'-dihydro-2'-oxospiro(piperidin-4,4'-(1H)-quinazole phylloline) formamide; 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-formamide; (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-1 -yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-isopropyl-piperazine- 1-yl)-2-oxo-1-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-ethyl]-amide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl)piperidin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-benzo[d][1 , 3] oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-benzo[d][1, 3] (oxazine)-1-carboxamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(piperidine- 1-yl) piperidin-1-yl) prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidin-4,4'-1H-quinazoline)-1- Formamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(cyclohexyl- 1-yl)piperazin-1-yl)prop-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1- Formamide; (R)-N-((R)-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-oxo-1-(4-(propan-2 -yl)piperazin-1-yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-1H-quinazoline)-1-methyl amides; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(5-chloro-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(5-bromo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidine- 1'-yl-1-(4-iodo-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; (±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazin-4,4'-piperidinyl]-butyramide; (±)-N-(1-benzyl-2-hydroxyl-ethyl)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanamide; (±)-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']bipiperidin-1'-yl-4-[4-(8-fluoro-2-oxo-1,4-dihydro-2H-quinazoline-3 -yl)-piperidin-1-yl]-2-(7-methyl-1H-indazol-5-ylmethyl)-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[2',3'- Dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline]-butane-1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione; (±)-1-[1,4']bipiperidin-1'-yl-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4- [2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane-1,4-dione; (±)-1-(4-cyclohexyl-piperazin-1-yl)-2-(2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-4-[ 2',3'-dihydro-2'-oxospiro-(piperidine-4,4'-quinazoline)]-butane-1,4-dione; (±)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-cyclohexyl-piperazine-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 )-piperidine-1-carbonyl]-amino}-propionic acid tert-butyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-methylcyclohexyl; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-piperidin-4-yl propionate; (±)-4-(3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)-piperidine-1-carbonyl]-amino}-propionyloxy)-piperidine-1-carboxylate tert-butyl; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 3,4,5,6-tetrahydro-2H-[1,4']bipyridine-4-yl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1-diethylamino-1-methyl-ethyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-2-phenyl-ethyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid 1,1-dimethyl-3-phenyl-propyl ester; (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidine-1-carbonyl]-amino}-propionic acid ethyl ester; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-methyl]-2-oxoethyl]-2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl]-2' , 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-methyl-1H-indazol-5-ylmethyl)-2-[(2-dimethylamino-ethyl-ethylcarbamoyl)-2-oxoethyl Base] -2', 3'-dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide; (±)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-4-yl-piperazinyl]-2-oxoethyl]-1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide; (±)-1-(7-Methyl-1H-indazol-5-ylmethyl)-2-[1-pyridin-2-yl-piperazinyl]-2-oxoethyl]-1' , 2'-dihydro-2'-oxospiro-[4H-3',1-benzoxazine-4,4'-piperidine]-1-carboxamide; (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3 base)-piperidine-1d-carboxylic acid [2-[1,4']bipiperidine-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-bipiperidinyl]-1-yl-2-oxoethyl]-2' , 3'-Dihydro-2'-oxospiro-[piperidine-4,4'-(1H)-quinazoline]-1-carboxamide. 6. Use of a compound selected from the following, a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing migraine: 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-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 -Dihydro-benzoxazol-6-ylmethyl)-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-oxo-1-(2-oxo-2,3 -Dihydro-benzoxazol-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-benzoxazol-6-ylmethyl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3 -Dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-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-benzoxazol-6-yl)-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(4-chloro-2-oxo-2,3- Dihydro-benzoxazol-6-yl)-1-dimethylcarbamoyl-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-methyl-2-oxo-2,3 -Dihydro-benzoxazol-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- Dihydro-benzoxazol-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 [2-[1,4']bipiperidin-1'-yl -1-(4-Ethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Chloro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(3,7-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl]-amide; 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidin-1'-yl -1-(7-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-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}-cyclohexyl propionate; 3-(7-Ethyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-carbonyl]-amino}-cyclohexyl propionate; 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; 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.

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