# Patent

## Title
Compounds of reverse turn mimetics and the use thereof

## Abstract

Conformationally constrained compounds that are novel and mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins and having bicyclic framework are disclosed, as well as their prodrugs. Such reverse-turn mimetic structures and prodrugs have utility over a wide range of fields, including use as diagnostic and therapeutic agents. The invention also relates to a use of such compounds for the preparation of a medicament for treating or preventing cancer including an acute myeloid leukemia.

## Background
TECHNICAL FIELD
The present invention relates generally to novel compounds of reverse-turn mimetics and their application in the treatment of medical conditions, e.g., cancer diseases, and pharmaceutical compositions comprising the mimetics.
BACKGROUND ART
Random screening of molecules for possible activity as therapeutic agents has occurred for many years and resulted in a number of important drug discoveries. While advances in molecular biology and computational chemistry have led to increased interest in what has been termed “rational drug design,” such techniques have not proven as fast or reliable as initially predicted. Thus, in recent years there has been a renewed interest and return to random drug screening. To this end, particular strides having been made in new technologies based on the development of combinatorial chemistry libraries, and the screening of such libraries in search for biologically active members.
Initially, combinatorial chemistry libraries were generally limited to members of peptide or nucleotide origin.
While combinatorial libraries containing members of peptide and nucleotide origin are of significant value, there is still a need in the art for libraries containing members of different origin. For example, traditional peptide libraries to a large extent merely vary the amino acid sequence to generate library members. While it is well recognized that the secondary structures of peptides are important to biological activity, such peptide libraries do not impart a constrained secondary structure to its library members.
To this end, some researchers have cyclized peptides with disulfide bridges in an attempt to provide a more constrained secondary structure (Tumelty et al., J. Chem. Soc. 1067-68, 1994; Eichler et al., Peptide Res. 7:300-306, 1994). However, such cyclized peptides are generally still quite flexible and are poorly bioavailable, and thus have met with only limited success.
More recently, non-peptide compounds have been developed which more closely mimic the secondary structure of reverse-turns found in biologically active proteins or peptides. For example, U.S. Pat. No. 5,440,013 to Kahn and published PCT Applications Nos. WO94/03494, WO01/00210A1, and WO01/16135A2 to Kahn each disclose conformationally constrained, non-peptidic compounds, which mimic the three-dimensional structure of reverse-turns. In addition, U.S. Pat. No. 5,929,237 and its continuation-in-part U.S. Pat. No. 6,013,458, both to Kahn, disclose conformationally constrained compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins. The synthesis and identification of conformationally constrained, reverse-turn mimetics and their application to diseases were well reviewed by Obrecht (Advances in Med. Chem., 4, 1-68, 1999).
While significant advances have been made in the synthesis and identification of conformationally constrained, reverse-turn mimetics, there remains a need in the art for small molecules which mimic the secondary structure of peptides. There is also a need in the art for libraries containing such members, as well as techniques for synthesizing and screening the library members against targets of interest, particularly biological targets, to identify bioactive library members.
In the mean time, a proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. c-Myc (MYC) is known as one of the proto-oncogenes, and dysregulation of c-Myc is considered one of a series of oncogenic events required for mammalian tumorigenesis (Pelengaris S, Khan M. The many faces of c-MYC. Arch Biochem Biophys. 2003; 416:129-136). MYC dysregulation, via a variety of mechanisms, was also found to be associated with myeloid leukemias (Hoffman B, Amanullah A, Shafarenko M, Liebermann D A. The proto-oncogene c-myc in hematopoietic development and leukemogenesis. Oncogene. 2002; 21: 3414-3421). In addition, c-Myc was found to rapidly induce acute myeloid leukemia (Hui Luo et al. “c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations,” Blood, 1 Oct. 2005, volume 106, Number 7, pp 2452 ̃2461).
As c-Myc can be upregulated in acute myeloid leukemia, the oncogenic function of c-Myc has been studied and its exact role in myeloid leukemogenesis has been studied. Recently, some scientist found that Myc preferentially stimulated the growth of myeloid progenitor cells in methylcellulose and showed that Myc is a critical downstream effector of myeloid leukemogenesis (ibid.).
The finding that c-Myc plays a critical role in myeloid leukemogenesis indicates that by inhibiting an activation of c-Myc protein, an acute myeloid leukemia can be cured or prevented.
On the other hand, enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. The human cytochrome P450 (CYP) 3A subfamily, includes CYP3A4, which is most abundant in the human liver ( ̃40%) and metabolizes more than 50% of clinically used drugs (Shimada et al 1994; Rendic and Di Carlo 1997).
Due to the key role of CYP3A4 in drug metabolism, significant inactivation of this enzyme could result in marked pharmacokinetic drug-drug interactions. Inhibition of CYP3A4 may cause severe drug toxicity through the enhanced exposure to coadministered drugs (Dresser et al 2000). For example, when irreversible CYP3A4 inhibitors such as erythromycin or clarithromycin are coadministered with terfenadine, astemizole, or pimozide patients may experience Torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) (Spinier et al 1995; Dresser et al 2000). Cancer patients, at times, undergo multiple treatment regimes, which increases the risk of drug-drug interactions followed by adverse drug reactions.
Therefore, in developing therapeutic agents, especially when it is to be administered in combination with other drugs, there is a need for providing compounds having less CYP3A4 inhibitory activity.
DISCLOSURE OF INVENTION
Technical Problem
The object of the present invention is to provide novel compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins and have biological activity such as anti-cancer effect.
Another object of the present invention is to provide novel compounds which inhibit Wnt signaling.
Yet another object of the present invention is to provide novel compounds which can be used as pharmaceuticals, in particular having less CYP3A4 inhibitory activity (higher IC50).
Yet another object of the present invention is to provide novel compounds for a treatment or a prevention of acute myeloid leukemia.
Technical Solution
The present invention is directed to a new type of conformationally constrained compounds and derivatives including prodrugs thereof, which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins. This invention also discloses libraries containing such compounds, as well as the synthesis and screening thereof.
The compounds of the present invention have the following general Formula (I):




wherein E is —ZR3— or —(C═O)—, wherein Z is CH or N; W is —(C═O)—, —(C═O)NH—, —(C═O)O—, —(C═O)S—, —S(O)2— or a bond; and each of R1, R2, R3, R4 and R5 is the same or different and independently an amino acid side chain moiety or an amino acid side chain derivative. The reverse turn mimetic compound may be present as an isolated stereoisomer or a mixture of stereoisomers or as a pharmaceutically acceptable salt thereof.

In certain embodiments, R1 of compounds of Formula (I) is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl, benzothiazolyl, substituted benzothiazolyl, benzimidazolyl, substituted benzimidazolyl, benzothiophenyl, substituted benzothiophenyl, benzodioxolyl, substituted benzodioxolyl, benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted benzisoxazolyl, chromonyl, substituted chromonyl, tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or substituted benzyl, aminocarbonylC1-6alkyl, C1-3alkylthiazolyl-aminocarbonylC1-6alkyl, dibenzofuranyl, acetylenyl, or styrenyl.
Specific examples of R1, R2, R3, R4 and R5 are provided in the following detailed description.
In an embodiment wherein E is CHR3, the compounds of this invention have the following Formula (II):




wherein W is as defined above, and R1, R2, R3, R4 and R5 are as defined in the following detailed description.

In certain embodiments, the compounds of this invention have the following general Formula (III):




wherein R1, R4, R6, X1, X2, and X3 are defined in the following detailed description.

The present invention is also related to prodrugs using the libraries containing one or more compounds of Formula (I). A prodrug is typically designed to release the active drug in the body during or after absorption by enzymatic and/or chemical hydrolysis. The prodrug approach is an effective means of improving the oral bioavailability or i.v. administration of poorly water-soluble drugs by chemical derivatization to more water-soluble compounds. The most commonly used prodrug approach for increasing aqueous solubility of drugs containing a hydroxyl group is to produce esters containing an ionizable group; e.g., phosphate group, carboxylate group, alkylamino group (Fleisher et al., Advanced Drug Delivery Reviews, 115-130, 1996; Davis et al., Cancer Res., 7247-7253, 2002, Golik et al., Bioorg. Med. Chem. Lett., 1837-1842, 1996).
Examples of the functional group which may be released in the body may include phosphate,




but any other functional groups that are conventionally used as the ionizable group in a prodrug can be used.

In certain embodiments, the prodrugs of the present invention have the following general Formula (IV):

(III)-R7  (IV)

wherein (III) is Formula (III) as described above; one of R1, R4, R6, X1, X2, and X3 is linked to R7 via Y; Y is an oxygen, sulfur, or nitrogen in R1, R4, or R6, or an oxygen in X1, X2, or X3; and R7 is hydroxyalkyl, glycosyl, phosphoryloxymethyloxycarbonyl, substituted or unsubstituted piperidine carbonyloxy, or a salt thereof; or Y—R7 is an amino acid residue, a combination of amino acid residues, phosphate, hemimalate, hemisuccinate, dimethylaminoalkylcarbamate, dimethylaminoacetate, or a salt thereof; and when not linked to R7: R1, R4, R6, X1, X2, and X3 are defined in the following detailed description.

In certain embodiments, the prodrugs of the present invention are capable of serving as a substrate for a phosphatase, a carboxylase, or other enzymes and are thereby converted to compounds having general Formula (III). The present invention is also directed to libraries containing one or more compounds of Formula (I) above, as well as methods for synthesizing such libraries and methods for screening the same to identify biologically active compounds.
In a related aspect, the present invention further provides novel compounds which have less CYP3A4 inhibitory activity. The present invention also provides novel compounds which have inhibition activity against Wnt signaling. The present invention also provides novel compounds which can be used for the preparation of a medicament for a treatment or a prevention of acute myeloid leukemia.
Advantageous Effects
The present invention provides novel compounds of reverse-turn mimetics. The compounds of the present invention exhibit less CYP3A4 inhibitory activity (higher IC50) which allows the compounds as potential pharmaceuticals, especially when it is to be administered in combination with other drugs. The compounds of the present invention showed strong inhibition activity against Wnt signaling. The compounds inhibited the growth of AML cancer cells and it can be used in the treatment or prevention of an acute myeloid leukemia.



BRIEF DESCRIPTION OF THE DRAWING
Reference will now be made in detail to the preferred embodiment of the present invention, examples of which are illustrated in the drawings attached herein. The embodiments are described below so as to explain the present invention by referring to the figures.
FIG. 1 provides a general synthetic scheme for preparing revers-turn mimetics of the present invention.
FIGS. 2A to 2E show an effect of test compounds (Compounds A ̃E) on the CYP3A4 activity. The graph is based on the measurement of IC50 for Compounds A ̃E of the present invention of CYP3A4 inhibition assay, wherein inhibition of activity of CYP3A4 was measured at various concentrations of the compound to obtain the IC50 value. Detailed procedures are disclosed in Example 1.
FIG. 3 shows the results of the measurement of IC50 of Compound F for SW480 cells on TopFlash Reporter Gene Bioassay.
FIG. 4 shows inhibition of growth of AML cancer cells by the test compound according to the concentration of the test compound (Compound B).



BEST MODE FOR CARRYING OUT THE INVENTION
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
“Amino” refers to the —NH2 radical.
“Amidino” refers to the —C(═NH)—NH2 radical. One or both hydrogens of the amine group of the amidino may be replaced with one or two alkyl groups, as defined herein. The alkyl-derivatized amidino radicals are also referred to as “alkylamidino” and “dialkylamidino,” respectively.
“Cyano” refers to the —CN radical.
“Carboxy” refers to the —COOR radical, wherein R is hydrogen or alkyl, as defined herein.
“Acyl” refers to the —COR radical, wherein R is alkyl, aryl, cycloalkyl, heterocyclyl, as defined herein. For example, R can be methyl, butenyl, cyclopropyl, and the like. The alkyl or aryl can be optionally substituted with the substituents as described for an alkyl or an aryl group, respectively. Exemplary acyl groups include, without limitation, phenylacyl, benzylacyl, C1-6acyl (e.g., acetyl) and the like.
“Alkylsulfonate” refers to —S(O)2—OR radical, wherein R is alkyl, as defined herein.
“Amidosulfonate” refers to the radical —OS(O)2—NR2, each R is independently hydrogen or alkyl. Exemplary amidosulfonates include —OS(O)2NH2, —OS(O)2NHMe.
“Aminocarbonyl” refers to the radical —C(O)NR2, each R is independently hydrogen, alkyl, amino, cycloalkylalkyl, heterocyclyl, alkoxyalkyl, hydroxyalkyl, hydroxyl, alkoxy, arylalkyl, heterocyclylalkyl, or two R is together with the nitrogen atom to which they are attached form a heterocyclyl, as defined herein. When one of the R is hydrogen, the other R is C1-4alkyl, aminocarbonyl can be represented by “C1-4alkylformamidyl.”
“N-formamidyl” refers to the radical —NHC(O)H.
“Phenylsulfonyl” refers to the —S(O)2—R radical, wherein R is phenyl, the phenyl can be further substituted with alkyl or chloro.
“Phenylsulfonate” refers to the —O—S(O)2—R radical, wherein R is phenyl, the phenyl can be further substituted with alkyl or chloro.
“Alkylsulfonyl” refers to the —S(O)2—R radical, wherein R is alkyl, as defined herein. Exemplary alkylsulfonyl radicals include methylsulfonyl.
“Alkylthio” refers to the —SR radical wherein R is alkyl, as defined herein.
“Arylthio” refers to the —SR radical wherein R is aryl, as defined herein. The aryl group of the arylthio can be further substituted with alkyl or chloro.
“Aryloxy” refers to the —OR radical wherein R is aryl, as defined herein. The aryl group can be further substituted with alkyl, alkoxy and the like.
“Acyloxyalkyl” refers to the —R′—OC(O)—R radical, wherein R is alkyl, aryl, cycloalkyl, heterocyclyl, as defined herein; and R′ is an alkyl.
“Guanidino” refers to the —NH—C(═NH)—NH2 radical. One or both hydrogens of the amine group of the guanidino may be replaced with one or two alkyl groups, as defined herein. The alkyl-derivatized guanidine radicals are also referred to as “alkylguanidino” and “dialkylguanidino,” respectively.
“Nitro” refers to the —NO2 radical.
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms. An alkyl may be saturated (containing carbons linked together by single bonds only) or unsaturated (containing carbons linked together by at least one double bond or triple bond.) An alkyl having one to twelve carbon atoms is also referred to as “lower chain alkyl moieties” and can be presented by “C1-12alkyl.” In other embodiments, an alkyl may comprise one to four carbon atoms and be represented by “C1-4alkyl.” In other embodiments, an alkyl may comprise two to five carbon atoms and be represented by “C2-5alkyl.” An alkyl is attached to the rest of the molecule by a single bond. Examples of saturated alkyls include, without limitation, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Examples of unsaturated alkyls include, without limitation, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl (i.e., acytylenyl), prop-1-ynyl and the like.
An alkyl may also be a monocyclic or bicyclic hydrocarbon ring radical, which may include fused or bridged ring systems. A cyclic alkyl is also referred to as “cycloalkyl.” In certain embodiments, a cycloalkyl may comprise three to six carbon atoms and be represented by “C3-6cycloalkyl.” Examples of monocyclic cycloalkyl radicals include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated cycloalkyl contains an endo double bond (i.e., a double bond in the ring). Examples of an unsaturated cycloalkyl include cyclohexenyl. Examples of bicyclic cycloalkyl radicals include, for example, norbornyl (i.e., bicyclo[2.2.1]heptyl), 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.
Unless stated otherwise specifically in the specification, the term “alkyl” is meant to include both alkyl and “substituted alkyl,” which refers to an alkyl radical in which one or more hydrogen atoms are replaced by one or more substituents independently selected from: acyl, amidino, alkylamidino, dialkylamidino, alkoxy, aryl, cyano, cycloalkyl, guanidino, alkylguanidino, dialkylguanidino, halo, heterocyclyl, hydrazinyl, hydroxyl, nitro, —OC(O)—R11, —C(O)OR11, —C(O)N(R11)2, —N(R11)C(O)OR11, —N(R11)C(O)R11, —N(R11)S(O)tR11 (where t is 1 or 2), —S(O)tOR11 (where t is 1 or 2), —S(O)pR11 (where p is 0, 1 or 2), and —S(O)tN(R11)2 (where t is 1 or 2) where each R11 is independently hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, as defined herein.
“Alkoxy” refers to a radical represented by the formula alkyl-O—, wherein alkyl is as defined herein. The alkyl portion can be further substituted by one or more halogen. An alkoxy may also be represented by the number of the carbons in the alkyl group, for example, C1-6alkoxy or C1-3alkoxy.
“Aryl” refers to a radical derived from an aromatic monocyclic or bicyclic ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or bicyclic hydrocarbon ring system comprises six to twelve carbon atoms (i.e., C6-12aryl), wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Optionally, one or two ring atoms of the aryl may be heteroatoms selected from nitrogen, oxygen or sulfur. Examples of aryl radicals include, but are not limited to, phenyl and naphthyl. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include both aryl and “substituted aryl,” which refers to an aryl radical in which one or more hydrogen atoms are replaced by one or more substituents independently selected from: alkyl, acyl, amidino, amidosulfonate, alkoxy, aryloxy, cyano, guanidino, alkylguanidino, dialkylguanidino, halo, hydrazinyl, hydroxyl, nitro,
heterocyclyl, —OC(O)—R11, —N(R11)2, —C(O)OR11, —C(O)N(R11)2, —N(R11)C(O)OR11, —N(R11)C(O)R11, —N(R11)S(O)tR11 (where t is 1 or 2), —S(O)tOR11 (where t is 1 or 2), —S(O)pR11 (where p is 0, 1 or 2), and —S(O)tN(R11)2 (where t is 1 or 2) where each R11 is independently hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl.
“Arylalkyl” refers to an alkyl radical wherein one or more hydrogens of the alkyl are replaced with one or more aryl groups, as defined herein. In various embodiments, arylalkyls include from 7 to 15 carbons and can be represented by C7-15arylalkyl. In certain embodiments, arylalkyl is arylC1-4alkyl wherein a C1-4alkyl is substituted with one aryl or two aryl groups, the latter being also referred to as “diarylalkyl” or “bisarylalkyl”. Examples of arylC1-4alkyl include, but are not limited to arylmethyl, arylethyl, arylpropyl, arylbutyl, bisarylmethyl, bisarylethyl, bisarylpropyl, bisarylbutyl. Exemplary arylalkyl radicals include, without limitation, benzyl, naphthylmethyl, diphenylmethyl, 3,3-bisphenylpropyl and the like. Unless stated otherwise specifically in the specification, the term “arylalkyl” is meant to include both arylalkyl and “substituted arylalkyl,” wherein the alkyl part and/or the aryl part of the arylalkyl radical may be substituted as described herein for the alkyl radical and aryl radical, respectively.
“Cycloalkylalkyl” refers to an alkyl radical wherein one or more hydrogens of the alkyl are replaced with one or more c groups, as defined herein. In certain embodiments, cycloalkylalkyl is cycloalkylC1-2alkyl such as cycloalkylmethyl, cycloalkylethyl and the like. Exemplary cycloalkylalkyl radicals include, without limitation, cyclohexylalkyl (e.g., cyclohexylmethyl and cyclohexylethyl), and cyclopentylalkyl (e.g., cyclopentylmethyl and cyclopentylethyl) and the like. Unless stated otherwise specifically in the specification, the term “cycloalkylalkyl” is meant to include both cycloalkylalkyl and “substituted cycloalkylalkyl,” wherein the alkyl part and/or the cycloalkyl part of the cycloalkylalkyl radical may be substituted as described herein for the alkyl radical and cycloalkyl radical, respectively.
“Glycosyl” refers to a radical by removing the hemiacetal hydroxyl group from a cyclic form of a monosaccharide (e.g., glucose), disaccharide, oligosaccharide (comprising three to ten monosaccharides), or polysaccharide (comprising more than ten monosaccharides).
“Halo” or “halogen” refers to fluoro, chloro, bromo or iodo radicals.
“Haloalkyl” refers to an alkyl radical, as defined herein, which is substituted by one or more halo radicals, as defined herein. Exemplary haloalkyls include, without limitation: trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. An alkyl substituted with one or more fluoro is also referred to as “perfluoroalkyl,” for example, “perfluoC1-4alkyl.” The alkyl part of the haloalkyl radical may be optionally substituted as defined herein for an alkyl group.
“Heterocyclyl” refers to a stable heterocyclic ring radical that comprises two to eleven carbon atoms and from one to three heteroatoms selected from nitrogen, oxygen and sulfur. In certain embodiments, the heterocyclyl contains one or two heteroatoms. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic or bicyclic ring system, which may include fused or bridged ring systems. In certain embodiments, the heterocyclyl may be a 5-, 6- or 7-membered monocyclic ring. In other embodiments, the heterocyclyl may be an 8-, 9-, 10-, 11- or 12-membered fused bicyclic ring. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. The heterocyclyl radical may be non-aromatic or aromatic (i.e., at least one ring in the heterocyclyl radical has a delocalized (4n+2) π-electron system in accordance with the Hückel theory.) The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of non-aromatic heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl (also referred to as “piperidyl”), piperazinyl, 4-piperidonyl, 3-pyrrolinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, and thiamorpholinyl. Examples of aromatic heterocyclyl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzoisoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrazolyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, carbazolyl, chromone, cinnolinyl, cyclopenta[d]pyrimidinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl (also referred to as pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydrocarbazolyl, 5,6,7,8-tetrahydroquinazolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazin-2-yl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the twin “heterocyclyl” is meant to include both heterocyclyl and “substituted heterocyclyl,” which refers to a heterocyclyl radical substituted by one or more substituents selected from alkyl, acyl, oxo (e.g., pyridinonyl, pyrrolidonyl), aryl, arylalkyl, acyloxyalkyl, amidino, alkoxy, cyano, guanidino, alkylguanidino, dialkylguanidino, halo, hydrazinyl, hydroxyl, nitro, —OC(O)—R11, —N(R11)2, —C(O)OR11, —C(O)N(R11)2, —N(R11)C(O)OR11, —N(R11)C(O)R11, —N(R11)S(O)tR11 (where t is 1 or 2), —S(O)tOR11 (where t is 1 or 2), —S(O)pR11 (where p is 0, 1 or 2), and —S(O)tN(R11)2 (where t is 1 or 2) where each R11 is independently hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl.
“Heterocyclylalkyl” refers to an alkyl radical wherein one or more hydrogens of the alkyl are replaced with one or more heterocyclyl groups, as defined herein. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. In certain embodiments, the alkyl part of the heterocyclylalkyl contains 1-4 carbon atoms and can be represented by heterocyclylC1-4alkyl. Examples of heterocyclylalkyl radicals include, without limitation, morpholinylalkyl such as morpholinylmethyl, piperidylalkyl such as piperidylmethyl, imidazolidinylalkyl such as imidazolidinylmethyl and the like. Additional examples of heterocyclylalkyl radicals, wherein the heterocyclyl part is aromatic, include, but are not limited to: pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, quinolinylmethyl, quinolinylethyl, quinolinylpropyl, quinolinylbutyl, indazolylmethyl, indazolylethyl, indazolylpropyl, indazolylbutyl, benzpyrazolylmethyl, benzpyrazolylethyl, benzpyrazolylpropyl, benzpyrazolylbutyl, isoquinolinylmethyl, isoquinolinylethyl, isoquinolinylpropyl, iso quinolinylbutyl, benzotriazolylmethyl, benzotriazolylethyl, benzotriazolylpropyl, benzotriazolylbutyl and the like. Unless stated otherwise specifically in the specification, the term “heterocyclylalkyl” is meant to include both heterocyclylalkyl and “substituted heterocyclylalkyl,” wherein the alkyl part and/or the heterocyclyl part of the heterocyclylalkyl radical may be substituted as described herein for the alkyl radical and the heterocyclyl radical, respectively.
The compounds, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers (e.g., ds or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
As used herein, “amino acid” is meant to include naturally occurring α-amino acids and/or unnatural amino acids, such as β-amino acids and homoamino acids. Examples of the amino acids include, but are not limited to: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tort-butylglycine, 3,5-dibromotyrosine and 3,5-diiodotyrosine.
“Amino acid residue” or “amino acid side chain moiety” refers to the portion of an amino acid that remains after losing a water molecule (or alcohol) when the amino acid is condensed with a molecule. Typically, an amino acid is condensed with a molecule, including a compound of any of Formulae (I)-(IV), by forming a peptide bond. In certain embodiments, the amino functional group of the amino acid can be condensed with a carboxylic acid group or its reactive equivalent (e.g., carboxylic anhydride) of the molecule. In other embodiments, the carboxylic acid functional group of the amino acid can be condensed with an amine group of the molecule. Typically, a molecule of water is lost during the formation of the peptide bond. Examples of the “amino acid residues” or “amino acid side chain moiety” include, but are not limited to, residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glycosylated serine, and glycosylated asparagine.
An “amino acid side chain derivative” refers to a derivative of any of the amino acid side chain moiety as described in Table 1. In certain embodiments, the amino acid side chain derivative is alkyl, acyl, alkoxy, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl, as defined herein.










TABLE 1







Amino Acid Side Chain Moiety
Amino Acid









—H
Glycine



—CH3
Alanine



—CH(CH3)2
Valine



—CH2CH(CH3)2
Leucine



—CH(CH3)CH2CH3
Isoleucine



—(CH2)4NH3+
Lysine



—(CH2)3NHC(NH2)NH2+
Arginine



 







Histidine



 



—CH2COO−
Aspartic acid



—CH2CH2COO−
Glutamic acid



—CH2CONH2
Asparagine



—CH2CH2CONH2
Glutamine



 







Phenylalanine



 







Tyrosine



 







Tryptophan



 



—CH2SH
Cysteine



—CH2CH2SCH3
Methionine



—CH2OH
Serine



—CH(OH)CH3
Threonine



 







Proline



 







Hydroxyproline










A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. It is therefore contemplated that various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
“Prodrugs” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A. C. S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxyl, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino or free mercapto group, respectively. Examples of the prodrugs include, but are not limited to, acetate, succinate, phosphate, hemisuccinate, malate, hemimalate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like. Other examples of the prodrugs include, but are not limited to, amino acid derivatives of alcohol or amine functional groups in the active compounds and the like.
The present invention is directed to conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biological peptide and proteins (also referred to herein as “reverse-turn mimetics,” and is also directed to chemical libraries relating thereto.
The reverse-turn mimetic structures of the present invention are useful as bioactive agents, including (but not limited to) use as diagnostic, prophylactic and/or therapeutic agents. The reverse-turn mimetic structure libraries of this invention are useful in the identification of bioactive agents having such uses. In the practice of the present invention, the libraries may contain from tens to hundreds to thousands (or greater) of individual reverse-turn structures (also referred to herein as “members”).
In one aspect of the present invention, a reverse-turn mimetic structure is disclosed having the following Formula (I):




wherein E is —ZR3— or —(C═O)—, wherein Z is CH or N; W is —(C═O)—, —(C═O)NH—, —(C═O)O—, —(C═O)S—, —S(O)2— or a bond; and each of R1, R2, R3, R4 and R5 is the same or different and independently an amino acid side chain moiety or an amino acid side chain derivative. The reverse turn mimetic compound may be present as an isolated stereoisomer or a mixture of stereoisomers or as a pharmaceutically acceptable salt thereof.

In certain embodiments, R1 of compounds of Formula (I) is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl, benzothiazolyl, substituted benzothiazolyl, benzimidazolyl, substituted benzimidazolyl, benzothiophenyl, substituted benzothiophenyl, benzodioxolyl, substituted benzodioxolyl, benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted benzisoxazolyl, chromonyl, substituted chromonyl, tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or substituted benzyl, aminocarbonylC1-6alkyl, C1-3alkylthiazolyl-aminocarbonylC1-6alkyl, dibenzofuranyl, acetylenyl, or styrenyl.
In certain embodiments, R1 of compounds of Formula (I) may be:
substituted phenyl having one or more substituents independently selected from: halogen, nitro, cyano, hydroxyl, C1-12alkoxy, substituted C1-12alkoxy, C1-12alkyl, carbonyl, carboxy, acetyl, C1-12alkylthio, C6-12arylthio, thiophenyl, sulfonyl, C6-12aryloxy, substituted C6-12aryloxy, indanyloxy, amino, aldoaminoC1-12alkylbenzylamino, amide, C1-12alkyl-sulfonic acid, C1-12alkyl phosphoric acid, phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl, substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, phosphatemethyl, and imidazolyl;
substituted pyridinyl having one or more substituents independently selected from: halogen, cycloalkyl, phenyl, substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl, C1-12alkyl, carbonyl, amide, and carboxy;
substituted pyrimidinyl having one or more substituents independently selected from phenyl and amino;
substituted indolyl having one or more substituents independently selected from: phenyl, substituted phenyl, substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl, carbonyl, C1-12alkyl, acyloxy C1-12alkyl, C1-12alkoxy, halogen, monoxide, and cyano;
substituted benzothiazolyl having one or more substituents independently selected from: halogen, and phosphate disodium amino;
substituted benzimidazolyl having one or more substituents independently selected from: carbonyl, monoxide, thio, perfluoroC1-4alkyl, cyanoC1-4alkyl, and C1-12alkyl;
substituted benzothiophenyl having one or more substituents independently selected from: nitro, amino, C1-4alkylamino, bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo, aldoamino, and carbonyl;
substituted benzodioxolyl having one or more substituents independently selected from: nitro and halogen;
substituted benzoxazolyl having one or more substituents independently selected from: monoxide, and thio;
substituted benzisoxazolyl having one or more substituents independently selected from: amino;
substituted chromonyl having one or more substituents independently selected from: phenyl; or
substituted tetrahydro-carbazolyl having one or more substituents independently selected from: sulfonyl.
In certain embodiment of the compounds described in the preceding paragraph, substituted phenyl is halo-phenyl, cyano phenyl, C1-12alkoxy phenyl, hydroxy phenyl, carboxy phenyl, acetamide phenyl, aminocarbonyl phenyl, amino phenyl, alkylsulfonyl phenyl, or alkylthio phenyl;
substituted benzyl is nitro-benzyl, or amino-benzyl;
amide group is C1-6alkylamide, carbamide, C1-6alkycarbamide, C1-6alkylcarbamate, C1-6alkylalkoxycarbamate, formamide, C1-6alkylformamide, carbamoylurea, or acetamide;
carbonyl group is cycloalkylcarbonyl, C1-12alkoxycarbonyl, morpholinylcarbonyl, aminocarbonyl, C1-12alkylaminocarbonyl, di C1-12alkylaminocarbonyl, C1-12alkynylaminocarbonyl, C2-13alkoxyalkylaminocarbonyl thiophenyl C1-12alkylaminocarbonyl, benzylaminocarbonyl, dihydropyrrolylcarbonyl, cycloalkyl C1-12alkylcarbonyl, cycloalkenyl C1-12alkylcarbonyl, C2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl, hydroxyaminocarbonyl, hydroC1-12alkylaminocarbonyl, hydrazinylcarbonyl, C1-12alkylformatehydrazinylcarbonyl, or tetrahydrofuranylC1-12alkylaminocarbonyl;
sulfonyl group is tosyl, phenyl sulfonyl, C1-12alkyl sulfonyl, C1-12alkylsulfonylamino, aminosulfonylamino or halo-phenyl sulfonyl;
substituted alkoxy is morpholinyl C1-12alkoxy, dihalo-C1-12alkoxy, or piperazinyl C1-12alkoxy;
substituted aryloxy is halo-C6-12aryloxy;
substituted pyridinyl is halo-pyridinyl, C1-12alkoxy pyridinyl, amino pyridinyl, or morpholinyl pyridinyl; or
substituted tetrahydro-carbazolyl is phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
In certain embodiments, R2, R4 and R5 of compounds of Formula (I) are independently selected from the group consisting of
C1-12alkyl or substituted C1-12alkyl having one or more substituents independently selected from: halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, aminocarbonyl, morpholinyl, methyl-piperazinyl, phenyl and hydroxyl;
C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from: amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from: halogen, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C1-6alkoxy, diC1-5alkylamino; C6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or substituted C6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from: halogen, C1-6alkyl, C1-6alkoxy, cyano, amino, amide, monoxide, thio, and hydroxyl; and
C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from: amino, amidino, amide, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, urea, thiourea, ureaC1-4alkyl, carbamoylurea, carbonyl, carbonylamino, aminosulfo, amidesulfo, acetylenyl, allyl, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-6alkyl, C1-6alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
R3 is selected from the group consisting of:
hydrogen;
C1-12alkyl or substituted C1-12alkyl having one or more substituents independently selected from: halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from: amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from: halogen, amino, guanidino, C1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C1-6alkoxy;
C6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or substituted C6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from: halogen, C1-6alkyl, C1-6alkoxy, cyano, and hydroxyl; and
C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-6alkyl, C1-6alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl.
In certain embodiments, R2, R4 and R5 of compounds of Formula (I) are independently selected from the group consisting of:
aminoC2-5alkyl; guanidinoC2-5alkyl; C1-4alkylguanidinoC2-5alkyl, diC1-4alkylguanidino-C2-5alkyl; amidinoC2-5alkyl; C1-4alkylamidinoC2-5alkyl; diC1-4alkylamidinoC2-5alkyl; C1-3alkoxy;
C1-12alkyl; C6-12aryl; C6-12arylalkyl; C2-12alkenyl;
phenyl or substituted phenyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
naphthyl or substituted naphthyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl;
benzyl or substituted benzyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, C1-4alkyl, carbonyl, aminoC1-4alkyl, acetylenyl, sulfuryl and hydroxyl;
bisphenylmethyl or substituted bisphenylmethyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4 dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; pyridinyl or substituted pyridinyl having one or more substituents independently selected from: amino, amide, monoxide, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyridinylC1-4alkyl, or substituted pyridinylC1-4alkyl having one or more substituents independently selected from: amino, amide, monoxide, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyrimidinylC1-4alkyl, or substituted pyrimidinylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, monoxide, amide, and hydroxyl;
triazin-2-ylC1-4alkyl, or substituted triazin-2-ylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
imidazolylC1-4alkyl or substituted imidazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, monoxide and hydroxyl;
tetrazolylC1-4alkyl or substituted tetrazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
triazolylC1-4alkyl or substituted triazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
indolylC1-4alkyl or substituted indolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
indazolylC1-4alkyl or substituted indazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
benzoxazolylC1-4alkyl or substituted benzoxazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
benzimidazolylC1-4alkyl or substituted benzimidazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, thio, monoxide and hydroxyl;
benzotriazolylC1-4alkyl or substituted benzotriazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
benzodioxolylC1-4alkyl, substituted benzodioxolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, carbonyl, aminoC1-4alkyl, sulfuryl, monoxide and hydroxyl;
N-amidinopiperazinyl-N—C0-4alkyl, N-amidinopiperidinylC1-4alkyl;
4-aminocyclohexylC0-2alkyl; thiophenylC1-4alkyl, bipiperidinylcarbonyloxy; amideC1-4alkyl; ureaC1-4alkyl; amino C1-4alkyl; cycloalkylC1-4alkyl and diaminosulfurylC1-4alkyl; and
R3 is selected from the group consisting of:
hydrogen; aminoC2-5alkyl; guanidinoC2-5alkyl; C1-4alkylguanidinoC2-5alkyl, diC1-4alkylguanidino-C2-5alkyl; amidinoC2-5alkyl; C1-4alkylamidinoC2-5alkyl; diC1-4alkylamidinoC2-5alkyl; C1-3alkoxy;
C1-12alkyl; C6-12aryl; C6-12arylalkyl; C2-12alkenyl;
phenyl or substituted phenyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
naphthyl or substituted naphthyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl;
benzyl or substituted benzyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
bisphenylmethyl or substituted bisphenylmethyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyridinyl or substituted pyridinyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyridinylC1-4alkyl, or substituted pyridinylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyrimidinylC1-4alkyl, or substituted pyrimidinylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
triazin-2-ylC1-4alkyl, or substituted triazin-2-ylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
imidazolylC1-4alkyl or substituted imidazolylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
N-amidinopiperazinyl-N—C0-4alkyl, N-amidinopiperidinylC1-4alkyl; and
4-aminocyclohexylC0-2alkyl.
In certain embodiments, R2, R4 and R5 of compounds of Formula (I) are independently selected from the group consisting of:
C1-12alkyl or substituted C1-12alkyl having one or more substituents independently selected from acyl, carboxy, alkylthio, aminocarbonyl, morpholinyl, methyl-piperazinyl, phenyl, cyano, C1-5alkylamino, diC1-5alkylamino, hydroxyl, C1-6alkoxy, and phenylsulfonyl;
C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from acyl, carboxy, alkylthio, and phenylsulfonyl;
substituted C6-12aryl substituted with amidosulfonate;
arylC1-4alkyl or substituted arylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfluoroC1-4alkyl, C1-6alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl, C1-6alkyloxyC1-6acyl, morphorlinylC1-6alkyl, aryl, aryloxy, (alkyl)(arylalkyl)amino, heterocyclyl, acyl, amidosulfonate, aminocarbonyl, alkylsulfonate, alkylsulfonyl, alkylthio, arylthio, phenylsulfonate, phenylsulfonyl, morphorlinylC1-3alkoxy, N-formamidyl, amide, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, urea, thiourea, ureaC1-4alkyl, carbamoylurea, carbonyl, carbonylamino, aminosulfo, amidesulfo, aminoC1-4alkyl, allyl, acetylenyl, and pyrrolidonyl;
heterocyclyl or substituted heterocyclyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-6alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
heterocyclylC1-4alkyl or substituted heterocyclylC1-4alkyl having one or more substituents independently selected from: amino, amide, monoxide, thio, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfluoroC1-4alkyl, C1-6alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl, C1-6alkyloxyC1-6acyl, morphorlinylC1-6alkyl, arylalkyl, aryl, heterocyclyl, acyl, phenylsulfonyl, cycloalkylalkyl, acyloxyalkyl, aminocarbonyl, and C1-6alkylformamidyl;
cycloalkyl or substituted cycloalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
cycloalkylalkyl or substituted cycloalkylalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
R3 is selected from the group consisting of:
hydrogen;
C1-12alkyl or substituted C1-12alkyl having one or more substituents independently selected from acyl, carboxy, alkylthio, and phenylsulfonyl;
C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from acyl, carboxy, alkylthio, and phenylsulfonyl;
substituted C6-12aryl substituted with amidosulfonate;
arylC1-4alkyl or substituted arylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfluoroC1-4alkyl, C1-6alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl, C1-6alkyloxyC1-6acyl, morphorlinylC1-6alkyl, aryl, aryloxy, (alkyl)(arylalkyl)amino, heterocyclyl, acyl, amidosulfonate, aminocarbonyl, alkylsulfonate, alkylsulfonyl, alkylthio, arylthio, phenylsulfonate, phenylsulfonyl, morphorlinylC1-3alkoxy, N-formamidyl, and pyrrolidonyl;
heterocyclyl or substituted heterocyclyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
heterocyclylC1-4alkyl or substituted heterocyclylC1-4alkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, C3-6cycloalkyl, halogen, perfluoroC1-4alkyl, C1-6alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl, C1-6alkyloxyC1-6acyl, morphorlinylC1-6alkyl, arylalkyl, aryl, heterocyclyl, acyl, phenylsulfonyl, cycloalkylalkyl, acyloxyalkyl, aminocarbonyl and C1-4alkylformamidyl;
cycloalkyl or substituted cycloalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
cycloalkylalkyl or substituted cycloalkylalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl.
In certain embodiment of the compounds described in the preceding paragraph, arylC1-4alkyl is benzyl, bisphenylmethyl, naphthylmethyl or 3,3-bisphenylpropyl; and
heterocyclylC1-4alkyl is benzotriazolylC1-4alkyl, benzopyrazolylC1-4alkyl, indazolylC1-4alkyl, isoquinolylC1-4alkyl, benzothiazolylC1-4alkyl, quinolinylC1-4alkyl, imidazolinylC1-4alkyl, thienylC1-4alkyl, tetrahydrofuranylC1-4alkyl, pyridinylC1-4alkyl, pyrimidinylC1-4alkyl, benzimidazolylC1-4alkyl, thiophenylC1-4alkyl tetrazolylC1-4alkyl, benzoxazolylC1-4alkyl, benzodioxolylC1-4alkyl or indolylC1-4alkyl.
In the embodiment where E is CHR3, the reverse turn mimetic compound of this invention has a structure of Formula (II):




wherein W is —(C═O)—, —(C═O)NH—, —(C═O)O—, —(C═O)S—, —S(O)2— or a bond; and each of R1, R2, R3, R4 and R5 is the same or different and independently an amino side chain moiety or an amino acid side chain derivative.

In certain embodiments, R1 of compounds of Formula (II) is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl, benzothiazolyl, substituted benzothiazolyl, benzimidazolyl, substituted benzimidazolyl, benzothiophenyl, substituted benzothiophenyl, benzodioxolyl, substituted benzodioxolyl, benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted benzisoxazolyl, chromonyl, substituted chromonyl, tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or substituted benzyl, aminocarbonylC1-6alkyl, C1-3alkylthiazolyl-aminocarbonylC1-6alkyl, dibenzofuranyl, acetylenyl, or styrenyl.
In certain embodiment of the compounds described in the preceding paragraph,
R2, R4 and R5 are independently selected from the group consisting of:
C1-12alkyl or substituted C1-12alkyl having one or more substituents independently selected from: halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, aminocarbonyl, morpholinyl, methyl-piperazinyl, phenyl, and hydroxyl;
C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from: amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from: halogen, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C1-6alkoxy; diC1-5alkylamino;
C6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or substituted C6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from: halogen, C1-6alkyl, C1-6alkoxy, cyano, amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, perfluoroC1-4alkyl, nitro, carboxy, carbonyl, aminoC1-4alkyl, sulfuryl, thio, monoxide and hydroxyl; and
C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-6alkyl, C1-6alkoxy, nitro, carboxy, cyano, sulfuryl, amide, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, urea, thiourea, ureaC1-4alkyl, carbamoylurea, carbonyl, carbonylamino, aminosulfo, amidesulfo, aminoC1-4alkyl, allyl, C1-4alkyl, aminoC1-4alkyl, acetylenyl, hydroxyl, phosphate, dimethylaminoacetate, dimethylaminoalkylcarbamate, and diethyl-phosphono-acetamido; and
R3 is selected from the group consisting of
hydrogen;
C1-12alkyl or substituted C1-12alkyl having one or more substituents independently selected from: halogen, cyano, C1-6alkoxy, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C2-12alkenyl or substituted C2-12alkenyl having one or more substituents independently selected from: amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from: halogen, amino, guanidino, C1-4alkylguanidino, diC1-4alkylguanidino, amidino, C1-4alkylamidino, diC1-4alkylamidino, C1-5alkylamino, diC1-5alkylamino, and hydroxyl;
C1-6alkoxy;
C6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or substituted C6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur and has one or more substituents independently selected from: halogen, C1-6alkyl, C1-6alkoxy, cyano, and hydroxyl; and
C7-13arylalkyl or substituted C7-13arylalkyl having one or more substituents independently selected from: amino, amidino, guanidino, hydrazino, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-6alkyl, C1-6alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl.
In certain embodiment of the compounds described in the preceding paragraph, R1 of compounds of Formula (II) is selected from the group consisting of substituted phenyl having one or more substituents independently selected from: halogen, nitro, cyano, hydroxyl, C1-12alkoxy, substituted C1-12alkoxy, C1-12alkyl, carbonyl, carboxy, acetyl, C1-12alkylthio, C6-12arylthio, thiophenyl, sulfonyl, C6-12aryloxy, substituted C6-12aryloxy, indanyloxy, amino, aldoaminoC1-12alkylbenzylamino, amide, C1-12alkyl-sulfonic acid, C1-12alkyl phosphoric acid, phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl, substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and imidazolyl;
substituted pyridinyl having one or more substituents independently selected from: halogen, cycloalkyl, phenyl, substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl, C1-12alkyl, carbonyl, amide, and carboxy;
substituted pyrimidinyl having one or more substituents independently selected from phenyl and amino;
substituted indolyl having one or more substituents independently selected from: phenyl, substituted phenyl, substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl, carbonyl, C1-12alkyl, acyloxy C1-12alkyl, C1-12alkoxy, halogen, monoxide, and cyano;
substituted benzimidazolyl having one or more substituents independently selected from: carbonyl, monoxide, thio, perfluoroC1-4alkyl, cyanoC1-4alkyl, and C1-12alkyl;
substituted benzothiophenyl having one or more substituents independently selected from: nitro, amino, C1-4alkylamino, bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo, aldoamino, and carbonyl;
substituted benzodioxolyl having one or more substituents independently selected from: nitro and halogen;
substituted benzoxazolyl having one or more substituents independently selected from: monoxide, and thio;
substituted benzisoxazolyl having one or more substituents independently selected from: amino;
substituted chromonyl having one or more substituents independently selected from: phenyl; and
substituted tetrahydro-carbazolyl having one or more substituents independently selected from: sulfonyl;
R2 and R5 are independently C1-12alkyl, C6-12aryl, C7-12arylalkyl, C6-11heterocyclylalkyl, hydroxybenzyl, or substituted benzyl having a substituents selected from phosphate, dimethylaminoacetate, (2-dimethylamino-ethyl)-carbamate, and diethyl-phosphono-acetamido;
R3 is hydrogen or C1-12alkyl; and
R4 is C1-12alkyl, C7-12arylalkyl, or C2-12alkenyl.
In certain embodiment of the compounds described in the preceding paragraph, substituted phenyl is halo-phenyl, cyano phenyl, C1-12alkoxy phenyl, hydroxy phenyl, carboxy phenyl, acetamide phenyl, aminocarbonyl phenyl, amino phenyl, alkylsulfonyl phenyl, or alkylthio phenyl;
substituted benzyl is nitro-benzyl, or amino-benzyl;
amide group is C1-6alkylamide, carbamide, C1-6alkylcarbamide, C1-6alkylcarbamate, C1-6alkylalkoxycarbamate, formamide, C1-6alkylformamide, carbamoylurea, or acetamide;
carbonyl group is cycloalkylcarbonyl, C1-12alkoxycarbonyl, morpholinylcarbonyl, aminocarbonyl, C1-12alkylaminocarbonyl, di C1-12alkylaminocarbonyl, C1-12alkynylaminocarbonyl, C2-13alkoxyalkylaminocarbonyl thiophenyl C1-12alkylaminocarbonyl, benzylaminocarbonyl, dihydropyrrolylcarbonyl, cycloalkyl C1-12alkylcarbonyl, cycloalkenyl C1-12alkylcarbonyl, C2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl, hydroxyaminocarbonyl, hydroC1-12alkylaminocarbonyl, hydrazinylcarbonyl, C1-12alkylformatehydrazinylcarbonyl, or tetrahydrofuranylC1-12alkylaminocarbonyl;
sulfonyl group is tosyl, phenyl sulfonyl, C1-12alkyl sulfonyl, C1-12alkylsulfonylamino, aminosulfonylamino or halo-phenyl sulfonyl;
substituted alkoxy is morpholinyl C1-12alkoxy, dihalo-C1-12alkoxy, or piperazinyl C1-12alkoxy;
substituted aryloxy is halo-C6-12aryloxy;
substituted pyridinyl is halo-pyridinyl, C1-12alkoxy pyridinyl, amino pyridinyl, or morpholinyl pyridinyl;
substituted tetrahydro-carbazolyl is phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
These compounds may be prepared by utilizing appropriate starting component molecules (hereinafter referred to as “component pieces”). Briefly, in the synthesis of reverse-turn mimetic structures having Formula (I), the reverse-turn mimetic structures of Formula (I) may be prepared by sequential coupling of the individual component pieces either stepwise in solution or by solid phase synthesis as commonly practiced in solid phase peptide synthesis, followed by cyclizing to yield the reverse-turn mimetic structures of this invention. Alternatively, first and second component pieces are coupled to form a combined first-second intermediate, if necessary, third and/or fourth component pieces are coupled to form a combined third-fourth intermediate (or, if commercially available, a single third intermediate may be used), the combined first-second intermediate and third-fourth intermediate (or third intermediate) are then coupled to provide a first-second-third-fourth intermediate (or first-second-third intermediate) which is cyclized to yield the reverse-turn mimetic structures of this invention.
Specific component pieces and the assembly thereof to prepare compounds of the present invention are illustrated in FIG. 1. For example, a “first component piece” may have the following formula S1:




wherein R1 is as defined above, and R is a protective group suitable for use in peptide synthesis, where this protection group may be joined to a polymeric support to enable solid-phase synthesis. Suitable R groups include alkyl groups and, in a preferred embodiment, R is a methyl group. In FIG. 1, one of the R groups is a polymeric (solid) support, indicated by “Pol” in the Figure. Such first component pieces may be readily synthesized by reductive amination of H2N—C—R1 with CH(OR)2—CHO, or by a displacement reaction between H2N—C—R1 and CH(OR)2—CH2-LG (wherein LG refers to a leaving group, e.g., a halogen (Hal) group).
A “second component piece” may have the following formula S2:




where P is an amino protection group suitable for use in peptide synthesis, L1 is hydroxyl or a carboxyl-activation group, and R2 is as defined above. Preferred protection groups include t-butyl dimethylsilyl (TBDMS), t-butyloxycarbonyl (BOC), methyloxycarbonyl (MOC), 9H-fluorenylmethyloxycarbonyl (FMOC), and allyloxycarbonyl (Alloc). N-Protected amino acids are commercially available; for example, FMOC amino acids are available from a variety of sources. In order for the second component piece to be reactive with the first component piece, L1 is a carboxyl-activation group, and the conversion of carboxyl groups to activated carboxyl groups may be readily achieved by methods known in the art for the activation of carboxyl groups. Suitable activated carboxylic acid groups include acid halides where L1 is a halide such as chloride or bromide, acid anhydrides where L1 is an acyl group such as acetyl, reactive esters such as N-hydroxysuccinimide esters and pentafluorophenyl esters, and other activated intermediates such as the active intermediate formed in a coupling reaction using a carbodiimide such as dicyclohexylcarbodiimide (DCC). Accordingly, commercially available N-protected amino acids may be converted to carboxylic activated forms by means known to one of skill in the art.

In the case of the azido derivative of an amino acid serving as the second component piece, such compounds may be prepared from the corresponding amino acid by the reaction disclosed by Zaloom et al. (J. Org. Chem. 46:5173-76, 1981).
A “third component piece” of this invention may have the following formula S3:




where R4, E, and L1 are as defined above. Suitable third component pieces are commercially available from a variety of sources or can be prepared by methods well known in organic chemistry.
FIG. 1 illustrates the preparation of compounds of Formula (I).
Thus, as illustrated above, the reverse-turn mimetic compounds of Formula (I) may be synthesized by reacting a first component piece with a second component piece to yield a combined first-second intermediate, followed by reacting the combined first-second intermediate with third component pieces sequentially to provide a combined first-second-third-fourth intermediate, and then cyclizing this intermediate to yield the reverse-turn mimetic structure.
The syntheses of representative component pieces of this invention are described in Preparation Examples.
The reverse-turn mimetic structures of Formula (I) and (II) may be made by techniques analogous to the modular component synthesis disclosed above, but with appropriate modifications to the component pieces.
The reverse-turn mimetic structures of the present invention are useful as bioactive agents, such as diagnostic, prophylactic, and therapeutic agents. For example, the reverse-turn mimetic structures of the present invention may be used for modulating a cell signaling transcription factor related peptides in a warm-blooded animal, by a method comprising administering to the animal an effective amount of the compound of Formula (I).
Further, the reverse-turn mimetic structures of the present invention may also be effective for inhibiting peptide binding to PTB domains in a warm-blooded animal; for modulating G protein coupled receptor (GPCR) and ion channel in a warm-blooded animal; for modulating cytokines in a warm-blooded animal.
It has been found that the compounds of the Formula (I), especially compounds of Formula (III) are effective for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer.




Formula (III) is shown above, wherein each of R1, R4, and R6 is the same or different and independently an amino acid side chain moiety or an amino acid side chain derivative, X1 may be hydrogen, hydroxyl, or halogen, and X2 and X3 may be independently hydrogen, hydroxyl, or any groups that may make the compound a prodrug, such as phosphate, carboxylate, carbamate and substituted amine.
In certain embodiments of the compounds of Formula (III),
R1 is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl, benzothiazolyl, substituted benzothiazolyl, benzimidazolyl, substituted benzimidazolyl, benzothiophenyl, substituted benzothiophenyl, benzodioxolyl, substituted benzodioxolyl, benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted benzisoxazolyl, chromonyl, substituted chromonyl, tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or substituted benzyl, aminocarbonylC1-6alkyl, C1-3alkylthiazolyl-aminocarbonylC1-6alkyl, dibenzofuranyl, acetylenyl, or styrenyl;
R4 is C1-6alkyl, C1-6alkoxy, C2-6alkenyl or perfluoroC1-6alkyl;
R6 is C6-12aryl or substituted C6-12aryl having one or more substituents independently selected from the group consisting of: halogen; hydroxyl; cyano; C1-6alkyl; and C1-6alkoxy; or C5-12heterocyclyl or substituted C5-12heterocyclyl having one or more substituents independently selected from: halogen, hydroxyl, cyano, C1-6alkyl, and C1-6alkoxy;
X1 is hydrogen, hydroxyl or halogen; and
each of X2 and X3 is independently hydrogen, hydroxyl, phosphate, dimethylaminoacetate, (2-dimethylamino-ethyl)-carbamate, diethyl-phosphono-acetamido or halogen.
In certain embodiment of the compounds described in the preceding paragraph,
R1 is selected from the group consisting of:
substituted phenyl having one or more substituents independently selected from: halogen, nitro, cyano, hydroxyl, C1-12alkoxy, substituted C1-12alkoxy, C1-12alkyl, carbonyl, carboxy, acetyl, C1-12alkylthio, C6-12arylthio, thiophenyl, sulfonyl, C6-12aryloxy, substituted C6-12aryloxy, indanyloxy, amino, aldoaminoC1-12alkylbenzylamino, amide, C1-12alkyl-sulfonic acid, C1-12alkyl phosphoric acid, phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl, substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and imidazolyl;
substituted pyridinyl having one or more substituents independently selected from: halogen, cycloalkyl, phenyl, substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl, carbonyl, amide, and carboxy;
substituted pyrimidinyl having one or more substituents independently selected from phenyl and amino:
substituted indolyl having one or more substituents independently selected from: phenyl, substituted phenyl, substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl, carbonyl, C1-12alkyl, acyloxy C1-12alkyl, C1-12alkoxy, halogen, monoxide, and cyano;
substituted benzimidazolyl having one or more substituents independently selected from: carbonyl, monoxide, thio, perfluoroC1-4alkyl, cyanoC1-4alkyl, and
substituted benzothiophenyl having one or more substituents independently selected from: nitro, amino, C1-4alkylamino, bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo, aldoamino, and carbonyl;
substituted benzodioxolyl having one or more substituents independently selected from: nitro and halogen;
substituted benzoxazolyl having one or more substituents independently selected from: monoxide, and thio;
substituted benzisoxazolyl having one or more substituents independently selected from: amino;
substituted chromonyl having one or more substituents independently selected from: phenyl; and
substituted tetrahydro-carbazolyl having one or more substituents independently selected from: sulfonyl;
R4 is C1-3alkyl or allyl; and
R6 is phenyl or substituted phenyl having one or more substituents independently selected from: halogen, hydroxyl, cyano, C1-6alkyl and C1-6alkoxy; or pyridyl or substituted pyridyl having one or more substituents independently selected from: halogen, hydroxyl, cyano, C1-6alkyl and C1-6alkoxy.
In certain embodiment of the compounds described in the preceding paragraph,
substituted phenyl is halo-phenyl, cyano phenyl, C1-12alkoxy phenyl, hydroxy phenyl, carboxy phenyl, acetamide phenyl, aminocarbonyl phenyl, amino phenyl, alkylsulfonyl phenyl, or alkylthio phenyl;
substituted benzyl is nitro-benzyl, or amino-benzyl;
amide group is C1-6alkylamide, carbamide, C1-6alkylcarbamide, C1-6alkylcarbamate,
C1-6alkylalkoxycarbamate, formamide, C1-6alkylformamide, carbamoylurea, or acetamide;
carbonyl group is cycloalkylcarbonyl, C1-12alkoxycarbonyl, morpholinylcarbonyl, aminocarbonyl, C1-12alkylaminocarbonyl, di C1-12alkylaminocarbonyl, C1-12alkynylaminocarbonyl, C2-13alkoxyalkylaminocarbonyl thiophenyl C1-12alkylaminocarbonyl, benzylaminocarbonyl, dihydropyrrolylcarbonyl, cycloalkyl C1-12alkylcarbonyl, cycloalkenyl C1-12alkylcarbonyl, C2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl, hydroxyaminocarbonyl, hydroC1-12alkylaminocarbonyl, hydrazinylcarbonyl, C1-12alkylformatehydrazinylcarbonyl, or tetrahydrofuranylC1-12alkylaminocarbonyl;
sulfonyl group is tosyl, phenyl sulfonyl, C1-12alkyl sulfonyl, C1-12alkylsulfonylamino, aminosulfonylamino or halo-phenyl sulfonyl;
substituted alkoxy is morpholinyl C1-12alkoxy, dihalo-C1-12alkoxy, or piperazinyl C1-12alkoxy;
substituted aryloxy is halo-C6-12aryloxy;
substituted pyridinyl is halo-pyridinyl, C1-12alkoxy pyridinyl, amino pyridinyl, or morpholinyl pyridinyl; or
substituted tetrahydro-carbazolyl is phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
In another aspect of this invention, prodrugs derived from compounds having general Formula (I) are disclosed. The prodrugs generally increase aqueous solubility and thus bioavailability of compounds having general Formula (I). In certain embodiments, the prodrugs of the present invention have the following general Formula (IV):

(III)-R7  (IV)

wherein one of R1, R4, R6, X1, X2, and X3 is linked to R7 via Y, wherein:
Y is an oxygen, sulfur, or nitrogen in R1, R4, or R6, or an oxygen in X1, X2, or X3; and
R7 is hydroxyalkyl, glycosyl, phosphoryloxymethyloxycarbonyl, substituted or =substituted piperidine carbonyloxy, or a salt thereof; or Y—R7 is an amino acid residue, a combination of amino acid residues, phosphate, hemimalate, hemisuccinate, dimethylaminoalkylcarbamate, dimethylaminoacetate, or a salt thereof; and
when not linked to R7: R1, R4, R6, X1, X2, and X3 are defined as they are in Formula (III).
In another aspect of this invention, libraries containing reverse-turn mimetic structures of the present invention are disclosed. Once assembled, the libraries of the present invention may be screened to identify individual members having bioactivity. Such screening of the libraries for bioactive members may involve; for example, evaluating the binding activity of the members of the library or evaluating the effect the library members have on a functional assay. Screening is normally accomplished by contacting the library members (or a subset of library members) with a target of interest, such as, for example, an antibody, an enzyme, a receptor or a cell line. Library members which are capable of interacting with the target of interest are referred to herein as “bioactive library members” or “bioactive mimetics”. For example, a bioactive mimetic may be a library member which is capable of binding to an antibody or receptor, or which is capable of inhibiting an enzyme, or which is capable of eliciting or antagonizing a functional response associated, for example, with a cell line. In other words, the screening of the libraries of the present invention determines which library members are capable of interacting with one or more biological targets of interest. Furthermore, when interaction does occur, the bioactive mimetic (or mimetics) may then be identified from the library members. The identification of a single (or limited number) of bioactive mimetic(s) from the library yields reverse-turn mimetic structures which are themselves biologically active, and thus are useful as diagnostic, prophylactic or therapeutic agents, and may further be used to significantly advance identification of lead compounds in these fields.
Synthesis of the peptide mimetics of the library of the present invention may be accomplished using known peptide synthesis techniques, in combination with the first, second and third component pieces of this invention. More specifically, any amino acid sequence may be added to the N-terminal and/or C-terminal of the conformationally constrained reverse-turn mimetic. To this end, the mimetics may be synthesized on a solid support (such as PAM resin) by known techniques (see, e.g., John M. Stewart and Janis D. Young, Solid Phase Peptide Synthesis, 1984, Pierce Chemical Comp., Rockford, Ill.) or on a silyl-linked resin by alcohol attachment (see Randolph et al., J. Am. Chem. Soc. 117:5712-14, 1995).
In addition, a combination of both solution and solid phase synthesis techniques may be utilized to synthesize the peptide mimetics of this invention. For example, a solid support may be utilized to synthesize the linear peptide sequence up to the point that the conformationally constrained reverse-turn is added to the sequence. A suitable conformationally constrained reverse-turn mimetic structure which has been previously synthesized by solution synthesis techniques may then be added as the next “amino acid” to the solid phase synthesis (i.e., the conformationally constrained reverse-turn mimetic, which has both an N-terminus and a C-terminus, may be utilized as the next amino acid to be added to the linear peptide). Upon incorporation of the conformationally constrained reverse-turn mimetic structures into the sequence, additional amino acids may then be added to complete the peptide bound to the solid support. Alternatively, the linear N-terminus and C-terminus protected peptide sequences may be synthesized on a solid support, removed from the support, and then coupled to the conformationally constrained reverse-turn mimetic structures in solution using known solution coupling techniques.
In one aspect of this invention, methods for constructing the libraries are disclosed. Traditional combinatorial chemistry techniques (see, e.g., Gallop et al., J. Med. Chem. 37:1233-1251, 1994) permit a vast number of compounds to be rapidly prepared by the sequential combination of reagents to a basic molecular scaffold. Combinatorial techniques have been used to construct peptide libraries derived from the naturally occurring amino acids. For example, by taking 20 mixtures of 20 suitably protected and different amino acids and coupling each with one of the 20 amino acids, a library of 400 (i.e., 202) dipeptides is created. Repeating the procedure seven times results in the preparation of a peptide library comprised of about 26 billion (i.e., 208) octapeptides.
Specifically, synthesis of the peptide mimetics of the library of the present invention may be accomplished using known peptide synthesis techniques, for example, the General Scheme of Reverse-Turn Mimetic Library, as follows:




Synthesis of the peptide mimetics of the libraries of the present invention was accomplished using a FlexChem Reactor Block which has 96 well plates by known techniques. In the above scheme ‘Pol’ represents a bromoacetal resin (Advanced ChemTech) and detailed procedure is illustrated below:

Step 1
A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of R1-amine in DMSO (1.4 mL) were placed in a Robbins block (FlexChem) having 96 well plates. The reaction mixture was shaken at 60° C. using a rotating oven [Robbins Scientific] for 12 hours. The resin was washed with DMF, MeOH, and then DCM
Step 2
A solution of commercially available Fmoc-NH—CH(R2)—COOH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.), and DIEA (12 equiv.) in DMF was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.
Step 3
To the resin swollen by DMF before reaction was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This deprotection step was repeated again and the resin was washed with DMF, Methanol, and then DCM. A solution of hydrazine acid (4 equiv.), HOBt (4 equiv.), and DIC (4 equiv.) in DMF was added to the resin and the reaction mixture was shaken for 12 hours at room temperature. The resin was washed with DMF, MeOH, and then DCM.
Step 4
The resin obtained in Step 3 was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under a reduced pressure using SpeedVac [SAVANT] to give the product as oil. The product was diluted with 50% water/acetonitrile and then lyophilized after freezing.
To generate these block libraries the key intermediate hydrazine acids were synthesized according to the procedure illustrated in Preparation Example 1.
Table 2 shows the compounds which were prepared according to the present invention, of which representative preparation is given in Preparation Examples.







TABLE 2







REVERSE TURN MIMETICS LIBRARY












M.W.



NO
Structure
Formula
M + H













1




599.66 C30H29N7O5S
600


 


2




597.69 C31H31N7O4S
598


 


3




570.66 C30H30N6O4S
571


 


4




610.73 C33H34N6O4S
611


 


5




596.70 C31H32N8O3S
597


 


6




623.72 C33H33N7O4S
624


 


7




637.75 C34H35N7O4S
638


 


8




653.75 C34H35N7O5S
654


 


9




595.71 C32H33N7O3S
596


 


10




624.71 C32H32N8O4S
625


 


11




614.71 C32H34N6O5S
615


 


12




644.74 C33H36N6O6S
645


 


13




673.80 C33H35N7O5S2
674


 


14




638.74 C33H34N8O4S
639


 


15




628.74 C33H36N6O5S
629


 


16




626.73 C33H34N6O5S
627


 


17




681.76 C34H35N9O5S
682


 


18




624.71 C33H32N6O5S
625


 


19




623.72 C33H33N7O4S
624


 


20




640.71 C33H32N6O6S
641


 


21




639.72 C33H33N7O5S
640


 


22




623.72 C33H33N7O4S
624


 


23




637.75 C34H35N7O4S
638


 


24




610.73 C33H34N6O4S
611


 


25




653.75 C34H35N7O6S
654


 


26




653.75 C34H35N7O5S
654


 


27




639.72 C33H33N7O5S
640


 


28




619.74 C34H33N7O3S
620


 


29




638.74 C33H34N8O4S
639


 


30




652.77 C34H36N8O4S
653


 


31




653.75 C34H35N7O5S
654


 


32




654.74 C33H34N8O5S
655


 


33




667.78 C35H37N7O5S
668


 


34




609.74 C33H35N7O3S
610


 


35




637.75 C34H35N7O4S
638


 


36




609.74 C33H35N7O3S
610


 


37




637.75 C34H35N7O4S
638


 


38




635.74 C34H33N7O4S
636


 


39




620.72 C33H32N8O3S
621


 


40




631.14 C32H31ClN6O4S
632


 


41




675.60 C32H31BrN6O4S
676


 


42




674.79 C32H34N8O5S2
675


 


43




722.60 C32H31IN6O4S
723


 


44




621.71 C33H31N7O4S
622


 


45




572.64 C27H28N10O3S
573


 


46




637.75 C33H35N9O3S
638


 


47




605.71 C33H31N7O3S
606


 


48




638.74 C33H34N8O4S
639


 


49




622.74 C33H34N8O3S
623


 


50




658.17 C33H32ClN7O4S
659


 


51




589.67 C28H31N9O4S
590


 


52




674.79 C33H34N6O6S2
675


 


53




602.66 C29H30N8O5S
603


 


54




637.71 C33H31N7O5S
638


 


55




610.73 C32H34N8O3S
611


 


56




636.72 C33H32N8O4S
637


 


57




652.79 C33H32N8O3S2
653


 


58




620.72 C33H32N8O3S
621


 


59




621.71 C32H31N9O3S
622


 


60




610.73 C33H34N6O4S
611


 


61




570.67 C29H30N8O3S
571


 


62




654.80 C33H34N8O3S2
655


 


63




589.71 C30H35N7O4S
590


 


64




604.72 C30H36N8O4S
605


 


65




556.68 C30H32N6O3S
557


 


66




612.71 C31H32N8O4S
613


 


67




632.74 C31H36N8O5S
633


 


68




659.79 C32H33N7O5S2
660


 


69




575.69 C29H33N7O4S
576


 


70




590.71 C29H34N8O4S
591


 


71




632.74 C31H36N8O5S
633


 


72




618.72 C30H34N8O5S
619


 


73




646.77 C32H38N8O5S
647


 


74




598.69 C30H30N8O4S
599


 


75




626.76 C28H34N8O5S2
627


 


76




561.71 C29H35N7O3S
562


 


77




547.68 C28H33N7O3S
548


 


78




640.79 C29H36N8O5S2
641


 


79




597.70 C30H31N9O3S
598


 


80




597.70 C30H31N9O3S
598


 


81




625.71
627


 


82




612.71
614


 


83




625.71
627


 


84




598.69
600


 


85




614.68
616


 


86




649.75
651


 


87




765.79
767


 


88




705.81
707


 


89




727.8 
729


 


90




800.31
801


 


91




634.72 C36H38N6O5
636


 


92




660.76 C38H40N6O5
662


 


93




732.86
733


 


94




620.70 C35H36N6O5
622


 


95




593.6  C31H30F3N5O4
595


 


96




589.63 C32H33F2N5O4
590


 


97




603.66 C33H35F2N5O4
605


 


98




623.7  C34H37N7O5
625


 


99




583.64 C31H33N7O5
585


 


100




676.74 C32H36N8O7S
678


 


101




612.68 C33H36N6O6
614


 


102




626.7  C34H38N6O6
628


 


103




596.68 C33H36N6O5
598


 


104




641.72 C34H39N7O6
643


 


105




596.68 C33H36N6O5
598


 


106




641.67 C33H35N7O7
643


 


107




721.61 C32H34N7Na2O8P
723


 


108




764.67 C35H39N6Na2O9P
766


 


109




567.64 C31H33N7O4
569


 


110




673.74 C32H35N9O6S
675


 


111




661.67 C34H34F3N7O4
663


 


112




594.66 C32H34N8O4
596


 


113




621.73 C35H39N7O4
623


 


114




618.69 C34H34N8O4
620


 


115




672.76 C33H36N8O6S
674


 


116




579.66
581


 


117




567.64 C32H33N5O5
569


 


118




633.69 C36H35N5O6
635


 


119




652.52 C32H31Cl2N5O6
654


 


120




597.66 C32H35N7O5
599


 


121




618.7  C31H34N6O6S
620


 


122




640.69 C33H36N8O6
642


 


123




632.73 C32H36N6O6S
634


 


124




633.72 C31H35N7O6S
635


 


125




640.72
642


 


126




652.77
654


 


127




689.21
690


 


128




640.72
642


 


129




653.76
655


 


130




623.7  C34H37N7O5
625


 


131




647.72 C37H37N5O6
649


 


132




666.55 C33H33Cl2N5O6
668


 


133




622.74 C34H34N6O4S
624


 


134




611.69 C33H37N7O5
613


 


135




610.74
612


 


136




638.75
640


 


137




610.74
612


 


138




700.86
702


 


139




700.86
702


 


140




582.26 C32H34N6O5
584


 


141




600.63
602


 


142




571.65
573


 


143




594.67
596


 


144




596.64
598


 


145




612.71
614


 


146




580.64
582


 


147




599.64
601


 


148




640.72
642


 


149




570.67
572


 


150




595.66
597


 


151




595.66
597


 


152




611.72
613


 


153




630.17
631


 


154




652.77
654


 


155




610.74
612


 


156




668.77
670


 


157




667.79
669


 


158




638.75
640


 


159




688.83
690


 


160




653.76
655


 


161




580.64
582


 


162




790.99
792


 


163




652.82
654


 


164




694.9 
696


 


165




613.71
615


 


166




652.77
654


 


167




668.77
670


 


168




734.68
736


 


169




639.74 C39H37N5O4
641


 


170




639.74 C39H37N5O4
641


 


171




620.72 C30H29FN6O4S2
622


 


172




650.67 C32H29F3N6O4S
652


 


173




628.72 C33H33FN6O4S
630


 


174




683.58 C32H29Cl2FN6O4S
685


 


175




634.75 C31H31FN6O4S2
636


 


176




674.74 C34H35FN6O6S
676


 


177




638.71 C34H31FN6O4S
640


 


178




628.72 C33H33FN6O4S
630


 


179




610.73 C33H34N6O4S
612


 


180




615.68 C31H30FN7O4S
617


 


181




674.74 C34H35FN6O6S
676


 


182




639.70 C33H30FN7O4S
641


 


183




670.78 C35H38N6O6S
672


 


184




735.66 C32H32N7Na2O7PS
737


 


185




859.60 C32H31N7Na4O10P2S
861


 


186




632.68 C32H30F2N6O4S
634


 


187




683.58 C32H29Cl2FN6O4S
685


 


188




782.64 C33H30FN6Na2O9PS
784


 


189




790.97 C43H50N8O5S
792


 


190




620.74 C32H37FN6O4S
622


 


191




646.73 C37H38N6O5
648


 


192




814.95 C45H46N6O7S
816


 


193




794.92 C45H42N6O6S
796


 


194




620.70 C35H36N6O5
622


 


195




603.67 C34H33N7O4
605


 


196




826.93 C46H43FN6O6S
828


 


197




592.69 C34H36N6O4
594


 


198




655.75 C38H37N7O4
657


 


199




608.69 C34H36N6O5
610


 


200




800.92 C44H44N6O7S
802


 


201




578.66 C33H34N6O4
580


 


202




660.76 C38H40N6O5
662


 


203




654.76 C39H38N6O4
656


 


204




672.75 C39H37FN6O4
674


 


205




732.85 C40H40N6O6S
734


 


206




743.83 C40H37N7O6S
745


 


207




620.74 C36H40N6O4
622


 


208




753.27 C39H37ClN6O6S
755


 


209




613.11 C33H33ClN6O4
615


 


210




795.30 C41H39ClN6O7S
797


 


211




579.65 C32H33N7O4
581


 


212




732.85 C40H40N6O6S
734


 


213




732.85 C40H40N6O6S
734


 


214




725.81 C37H39N7O7S
727


 


215




578.66 C33H34N6O4
580


 


216




699.78 C35H37N7O7S
701


 


217




774.88 C42H42N6O7S
776


 


218




733.84 C39H39N7O6S
735


 


219




856.79 C40H39N6Na2O9PS
735


 


220




716.85 C40H40N6O5S
718


 


221




756.87 C42H40N6O6S
758


 


222




858.74 C40H39IN6O6S
860


 


223




898.83 C42H41N6Na2O10PS
900


 


224




744.64 C35H35N6Na2O8P
746


 


225




919.25 C41H38ClN6Na2O10PS
921


 


226




877.21 C39H36ClN6Na2O9PS
879


 


227




857.78 C39H38N7Na2O9PS
859


 


228




692.80 C39H44N6O6
694


 


229




762.87 C41H42N6O7S
764


 


230




767.29 C40H39ClN6O6S
769


 


231




770.68 C37H37N6Na2O8P
772


 


232




853.96 C42H43N7O9S2
855


 


233




814.91 C40H46N8O9S
816


 


234




840.95 C42H48N8O9S
842


 


235




918.86 C45H41N6Na2O9PS
920


 


236




778.70 C39H37N6Na2O79
780


 


237




664.75 C37H40N6O6
666


 


238




713.78 C40H39N7O6
715


 


239




683.80 C40H41N7O4
685


 


240




654.68 C31H32F2N6O6S
656


 


241




668.71 C32H34F2N6O6S
670


 


242




561.62 C31H33F2N5O3
563


 


243




574.62 C31H32F2N6O3
576


 


244




603.62 C32H31F2N5O5
605


 


245




732.73 C37H38F2N6O8
734


 


246




618.63 C32H32F2N6O5
620


 


247




756.71 C37H38N6Na2O9
758


 


248




583.64 C31H33N7O5
585


 


249




582.65 C32H34N6O5
584


 


250




627.65 C32H33N7O7
629


 


251




626.70 C34H38N6O6
628


 


252




612.68 C33H36N6O6
614


 


253




611.69 C33H37N7O5
613


 


254




640.73 C35H40N6O6
642


 


255




597.66 C32H35N7O5
599


 


256




652.74 C36H40N6O6
654


 


257




610.70 C34H38N6O5
612


 


258




666.77 C37H42N6O6
668


 


259




701.79 C35H39N7O7S
703


 


260




596.68 C33H36N6O5
598


 


261




636.74 C36H40N6O5
638


 


262




661.73 C32H35N7O7S
663


 


263




636.74 C36H40N6O5
638


 


264




624.73 C35H40N6O5
626


 


265




634.72 C36H38N6O5
636


 


266




650.77 C37H42N6O5
652


 


267




650.77 C37H42N6O5
652


 


268




697.78 C37H43N7O7
699


 


269




598.65 C32H34N6O6
600


 


270




583.64 C31H33N7O5
585


 


271




672.77 C39H40N6O5
674


 


272




696.84 C39H48N6O6
698


 


273




664.79 C38H44N6O5
666


 


274




678.82 C39H46N6O5
680


 


275




673.76 C38H39N7O5
675


 


276




648.71 C35H36N8O5
650


 


277




690.83 C40H46N6O5
692


 


278




636.74 C36H40N6O5
638


 


279




679.79 C36H37N7O5S
681


 


280




678.80 C37H38N6O5S
680


 


281




597.66 C32H35N7O5
599


 


282




712.75 C37H40N6O9
714


 


283




736.82 C39H44N8O7
738


 


284




579.65 C32H33N7O4
581


 


285




636.70 C34H36N8O5
638


 


286




583.63 C32H33N5O6
585


 


287




662.71 C32H34N6O8S
664


 


288




584.62 C31H32N6O6
586


 


289




633.63 C32H36N5O7P
635


 


290




595.71 C33H33N5O4S
597


 


291




612.68 C33H36N6O6
614


 


292




617.72 C32H35N5O6S
619


 


293




607.66 C32H33N9O4
609


 


294




659.73 C38H37N5O6
661


 


295




564.63 C32H32N6O4
566


 


296




581.66 C33H35N5O5
583


 


297




632.71 C36H36N6O5
634


 


298




607.66 C34H33N5O6
609


 


299




694.80 C37H38N6O6S
696


 


300




597.66 C33H35N5O6
599


 


301




619.51 C30H31BrN6O4
621


 


302




642.66 C33H34N6O8
644


 


303




619.51 C30H31BrN6O4
621


 


304




595.71 C33H33N5O4S
597


 


305




585.72 C32H35N5O4S
587


 


306




584.62 C31H32N6O6
586


 


307




554.64 C31H34N6O4
556


 


308




623.74 C35H41N7O4
625


 


309




616.71 C36H36N6O4
618


 


310




616.71 C36H36N6O4
618


 


311




580.68 C33H36N6O4
582


 


312




607.66 C32H33N9O4
609


 


313




604.10 C32H34ClN5O5
606


 


314




651.15 C36H35ClN6O4
652


 


315




582.62 C32H31FN6O4
584


 


316




582.62 C32H31FN6O4
584


 


317




634.70 C36H35FN6O4
636


 


318




617.70 C35H35N7O4
619


 


319




662.80 C37H38N6O4S
664


 


320




615.72 C37H37N5O4
617


 


321




646.74 C37H38N6O5
648


 


322




696.84 C39H48N6O6
698


 


323




641.72 C37H35N7O4
643


 


324




580.68 C33H36N6O4
582


 


325




620.74 C36H40N6O4
622


 


326




676.74 C33H36N6O8S
678


 


327




634.70 C36H35FN6O4
636


 


328




634.70 C36H35FN6O4
636


 


329




595.69 C34H37N5O5
597


 


330




625.76 C36H43N5O5
627


 


331




619.62 C32H31F2N5O6
621


 


332




658.75 C38H38N6O5
660


 


333




632.71 C36H36N6O5
634


 


334




648.55 C32H34BrN5O5
650


 


335




646.74 C37H38N6O5
648


 


336




701.81 C40H43N7O5
703


 


337




608.73 C35H40N6O4
610


 


338




587.64 C32H34FN5O5
589


 


339




616.71 C36H36N6O4
618


 


340




646.74 C37H38N6O5
648


 


341




595.65 C32H33N7O5
597


 


342




686.77 C37H43FN6O6
688


 


343




617.70 C35H35N7O4
619


 


344




646.74 C37H38N6O5
648


 


345




631.72 C37H37N5O5
633


 


346




683.75 C40H37N5O6
685


 


347




672.77 C39H40N6O5
674


 


348




605.69 C34H35N7O4
607


 


349




639.74 C36H41N5O6
641


 


350




598.65 C32H34N6O6
600


 


351




617.14 C33H37ClN6O4
619


 


352




645.75 C38H39N5O5
647


 


353




658.79 C39H42N6O4
660


 


354




631.72 C37H37N5O5
633


 


355




640.73 C38H36N6O4
642


 


356




687.81 C35H41N7O6S
689


 


357




629.70 C37H35N5O5
631


 


358




674.79 C33H34N6O6S2
676


 


359




617.70 C35H35N7O4
619


 


360




681.86 C40H51N5O5
683


 


361




645.75 C38H39N5O5
647


 


362




618.52 C31H32BrN5O4
620


 


363




595.69 C34H37N5O5
597


 


364




651.79 C38H45N5O5
653


 


365




679.74 C38H38FN5O6
681


 


366




653.77 C37H43N5O6
655


 


367




625.71 C35H39N5O6
627


 


368




598.69 C34H38N4O6
600


 


369




701.81 C41H43N5O6
703


 


370




636.51 C31H31BrFN5O4
638


 


371




621.75 C35H35N5O4S
623


 


372




646.74 C37H38N6O5
648


 


373




714.23 C37H36ClN5O6S
716


 


374




645.75 C38H39N5O5
647


 


375




682.23 C37H36ClN5O4S
684


 


376




760.26 C38H38ClN5O8S
762


 


377




616.71 C36H36N6O4
618


 


378




616.71 C36H36N6O4
618


 


379




631.72 C36H37N7O4
633


 


380




630.74 C37H38N6O4
632


 


381




772.91 C43H44N6O6S
774


 


382




646.74 C37H38N6O5
648


 


383




646.74 C37H38N6O5
648


 


384




634.70 C36H35FN6O4
636


 


385




634.70 C36H35FN6O4
636


 


386




487.55 C27H29N5O4
489


 


387




692.85 C39H48N8O4
694


 


388




595.65 C32H33N7O5
597


 


389




678.76 C33H38N6O8S
680


 


390




629.70 C34H39N5O7
631


 


391




599.68 C33H37N5O6
601


 


392




723.62 C33H36N5Na2O9P
725


 


393




792.73 C37H43N6Na2O9P
794


 


394




746.66 C35H37N6Na2O8P
748


 


395




611.73 C35H41N5O5
613


 


396




587.64 C32H34FN5O5
589


 


397




595.73 C35H41N5O4
597


 


398




583.68 C33H37N5O5
585


 


399




625.76 C36H43N5O5
627


 


400




597.70 C34H39N5O5
599


 


401




703.59 C32H32N7Na2O7P
705


 


402




553.65 C32H35N5O4
555


 


403




719.63 C34H36N5Na2O8P
721


 


404




595.69 C34H37N5O5
597


 


405




565.66 C33H35N5O4
567


 


406




711.58 C32H33FN5Na2O8P
713


 


407




628.63 C32H32N6O8
630


 


408




732.67 C35H39N6Na2O7P
734


 


409




728.04 C32H33ClN5Na2O8P
730


 


410




619.11 C32H35ClN6O5
621


 


411




600.66 C32H36N6O6
602


 


412




605.63 C32H33F2N5O5
607


 


413




743.56 C32H30F2N5Na2O9P
745


 


414




732.67 C35H39N6Na2O7P
734


 


415




724.61 C32H35N6Na2O9P
726


 


416




646.73 C37H38N6O5
648


 


417




623.70 C35H37N5O6
625


 


418




725.57 C33H36IN5O6
727


 


419




719.65 C33H32N5Na2O7PS
721


 


420




709.66 C32H34N5Na2O7PS
701


 


421




788.01 C43H57N5O7S
790


 


422




749.70 C36H42N5Na2O8P
751


 


423




651.84 C39H49N5O4
653


 


424




761.93 C40H51N5O8S
763


 


425




678.58 C31H33N6Na2O7P
680


 


426




627.71 C33H33N5O6S
629


 


427




632.71 C36H36N6O5
634


 


428




646.74 C37H38N6O5
648


 


429




641.72 C37H35N7O4
643


 


430




646.74 C37H38N6O5
648


 


431




556.62 C29H32N8O4
558


 


432




753.65 C37H34N5Na2O8P
755


 


433




636.70 C34H36N8O5
638


 


434




534.62 C28H34N6O5
536


 


435




548.65 C29H36N6O5
550


 


436




562.67 C30H38N6O5
564


 


437




592.70 C31H40N6O6
594


 


438




604.71 C32H40N6O6
606


 


439




625.73 C34H39N7O5
627


 


440




611.71 C33H37N7O5
613


 


441




611.71 C33H37N7O5
613


 


442




611.71 C33H37N7O5
613


 


443




617.73 C31H35N7O5S
619


 


444




631.76 C32H37N7O5S
633


 


445




618.72 C30H34N8O5S
620


 


446




522.62 D488C26H30N6O4S
524


 


447




572.68 C30H32N6O4S
574


 


448




572.68 C30H32N6O4S
574


 


449




573.66 C30H31N5O5S
575


 


450




598.72 C32H34N6O4S
600


 


451




587.69 C31H33N5O5S
589


 


452




574.65 C29H30N6O5S
576


 


453




574.65 C29H30N6O5S
576


 


454




574.65 C29H30N6O5S
576


 


455




586.71 C31H34N6O4S
588


 


456




557.66 C30H31N5O4S
559


 


457




571.69 C31H33N5O4S
573


 


458




585.72 C32H35N5O4S
587


 


459




599.74 C33H37N5O4S
601


 


460




529.65 C29H31N5O3S
531


 


461




543.68 C30H33N5O3S
545


 


462




557.71 C31H35N5O3S
559


 


463




571.73 C32H37N5O3S
573


 


464




615.75 C32H37N7O4S
617


 


465




615.70 C31H33N7O5S
617


 


466




614.76 C33H38N6O4S
616


 


467




614.72 C32H34N6O5S
616


 


468




600.78 C33H40N6O3S
602


 


469




600.73 C32H36N6O4S
602


 


470




657.78 C34H39N7O5S
659


 


471




670.83 C35H42N8O4S
672


 


472




586.71 C31H34N6O4S
588


 


473




628.74 C33H36N6O5S
630


 


474




641.78 C34H39N7O4S
643


 


475




597.73 C33H35N5O4S
599


 


476




599.70 C32H33N5O5S
601


 


477




585.72 C32H35N5O4S
587


 


478




583.70 C32H33N5O4S
585


 


479




569.72 C32H35N5O3S
571


 


480




584.69 C31H32N6O4S
586


 


481




612.74 C33H36N6O4S
614


 


482




626.77 C34H38N6O4S
628


 


483




615.75 C32H37N7O4S
617


 


484




629.77 C33H39N7O4S
631


 


485




629.73 C32H35N7O5S
631


 


486




611.72 C32H33N7O4S
613


 


487




630.76 C33H38N6O5S
632


 


488




616.73 C32H36N6O5S
618









Belows are NMR data of some of the compounds prepared according to the above procedure:
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-((1-(3-nitrobenzyl)-1H-indol-7-yl)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=9.0 Hz, 1H), δ 7.65 (d, J=6.0 Hz, 2H), δ 7.44 (t, J=6.0 Hz, 1H), 7.35 ̃7.20 (m, 6H), δ 7.11 ̃7.05 (m, 2H), δ 6.95 ̃6.87 (m, 3H), δ 6.66 ̃6.62 (m, 4H), δ 5.51 ̃5.30 (m, 3H), δ 5.02 ̃4.94 (m, 2H), δ 4.61 (d, J=18.0 Hz, 1H), δ 4.44 ̃4.25 (m, 3H), δ 3.42 ̃2.99 (m, 8H).
(6S,9aS)-2-allyl-8-((1-(3-aminobenzyl)-1H-indol-7-yl)methyl)-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.63 ̃7.58 (m, 1H), δ 7.38 ̃7.20 (m, 5H), δ 7.05 ̃6.94 (m, 4H), δ 6.87 (d, J=6.0 Hz, 1H), δ 6.67 ̃6.57 (m, 3H), δ 6.45 (d, J=6.0 Hz, 1H), δ 6.19 (d, J=9.0 Hz, 2H), δ 5.54 ̃5.38 (m, 3H), 5.32 ̃5.24 (m, 1H), δ 5.11 (t, J=6.0 Hz, 1H), δ 5.00 (d, J=12.0 Hz, 1H), δ 4.77 ̃4.65 (m, 2H), δ 4.44 ̃4.26 (m, 2H), δ 3.39 ̃3.17 (m, 5H), δ 2.94 (d, J=9.0 Hz, 2H).
(6S,9aR) 2-allyl-8-(2,4-difluoro-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.25-7.36 (m, 7H), 7.04 (d, J=8.4 Hz, 2H), 6.62-6.89 (m, 6H), 5.68-5.82 (m, 3H), 5.16-5.24 (m, 2H), 4.42 (d, J=6.0 Hz, 2H), 4.01-4.06 (m, 1H), 3.38-3.71 (m, 8H), 3.20 (dd, J=3.6, 11.4 Hz, 2H), 2.80-3.02 (m, 4H), 2.46-2.52 (m, 1H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(2,3,4-trimethoxy-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.404 ̃7.245 (m, 5H), δ 7.001 ̃6.973 (d, J=8.4 Hz, 2H), 6.958 ̃6.930 (d, J=8.4 Hz, 1H), 7.742 ̃7.701 (t, J=6.0 Hz, 1H), 6.675 ̃6.647 (d, J=8.4 Hz, 2H), 6.647 ̃6.619 (d, J=8.4 Hz, 2H), 5.695 ̃5.561 (dt, J=6.6 Hz, J=16.8 Hz, 1H), 5.534 ̃5.520 (dd, J=4.2 Hz, J=10.8 Hz, 1H), 5.390 ̃5.340 (dd, J=4.8 Hz, J=10.2 Hz, 1H), 5.284 ̃5.248 (t, J=5.4 Hz, 1H), 5.175 ̃5.140 (d, J=10.5 Hz, 1H), 5.080 ̃5.022 (d, J=17.4 Hz, 1H), 4.882 ̃4.834 (d, J=17.4 Hz, 1H), 4.486 ̃4.306 (dt, J=6.0 Hz, J=15.0 Hz, 2H), 3.875 (s, 3H), 3.546 ̃3.253 (m, 8H).
(6S,9aS) 2-allyl-8-(3,4-dimethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.395 ̃7.233 (m, 6H), δ 6.8314.682 (m, 4H), 6.985 ̃6.958 (d, J=8.1 Hz, 2H), 6.637 ̃6.610 (d, J=8.1 Hz, 2H), 5.678 ̃5.545 (dt, J=6.3 Hz, J=16.8 Hz, 1H), 5.454 ̃5.405 (dd, J=3.9 Hz, J=10.5 Hz, 1H), 5.323 ̃5.286 (d, J=5.7 Hz, 1H), 5.162 ̃5.127 (d, J=10.5 Hz, 1H), 5.028 ̃4.971 (d, J=16.8 Hz, 1H), 4.916 ̃4.868 (d, J=14.4 Hz, 1H), 4.467 ̃4.294 (dt, J=6.3 Hz, J=15.0 Hz, 2H), 5.390 ̃5.340 (dd, J=4.8 Hz, J=10.2 Hz, 1H), 5.284 ̃5.248 (t, J=5.4 Hz, 1H), 4.269 ̃4.221 (d, J=14.4 Hz, 1H), 3.864 (s, 6H), 3.499 ̃3.223 (m, 7H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-[1-(toluene-4-sulfonyl)-1H-indol-7-ylmethyl]-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz): δ 7.66 (d, J=4.0 Hz, 1H), 7.31-7.48 (m, 6H), 7.16-7.23 (m, 4H), 7.03 (d, J=8.4 Hz, 2H), 6.90 (d, J=7.8 Hz, 1H), 6.67-6.70 (m, 3H), 5.49-5.61 (m, 2H), 5.31-5.47 (m, 2H), 4.92-5.14 (m, 3H), 4.26-4.44 (m, 2H), 3.29-3.50 (m, 6H), 2.32 (s, 3H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(1H-indol-7-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 9.95 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.28-7.37 (m, 4H), 7.23-7.25 (m, 1H), 6.90-7.00 (m, 4H), 6.67 (m, 1H), 6.55-6.58 (m, 3H), 5.60 (m, 1H), 5.12-5.28 (m, 4H), 4.93 (d, J=17.1 Hz, 1H), 4.32-4.41 (m, 3H), 3.21-3.39 (m, 8H).
(6S,9aS) 2-allyl-7-(2-fluoro-4-methoxy-benzyl)-5-(4-hydroxy-benzyl)-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 7.39 ̃7.24 (m, 5H), 6.96 (d, J=8.3 Hz, 2H), 6.79 (s, 1H), 6.73 ̃6.67 (m, 2H), 6.62 ̃6.58 (m, 3H), 5.70 ̃5.57 (m, 1H), 5.45 (dd, J=10.7 Hz 4.0 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 5.18 (d, J=10.3 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.80 (d, J=5.6 Hz, 1H), 4.48 ̃4.30 (m, 3H), 3.79 (s, 3H), 3.54 ̃3.25 (m, 8H).
(6S,9aS)-2-allyl-N-benzyl-8-(4-butoxybenzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.73 ̃7.23 (m, 6H), δ 7.12 (d, J=9.0 Hz, 2H), δ 6.98 (d, J=9.0 Hz, 2H), δ 6.86 (d, J=9.0 Hz, 2H), δ 6.71 (t, J=6.0 Hz, 1H), δ 6.65 (d, J=9.0 Hz, 2H), δ 5.67 ̃5.48 (m, 2H), δ 5.32 (t, J=6.0 Hz, 1H), δ 5.13 (d, J=12.0 Hz, 2H), δ 5.00 (d, J=3.0 Hz, 1H), δ 4.93 (s, 1H), δ 4.46 ̃4.30 (m, 2H), δ 3.19 (d, J=18.0 Hz, 1H), δ 3.93 (t, J=9.0 Hz, 2H), δ 3.44 ̃3.21 (m, 7H), δ 1.78 ̃1.71 (m, 2H), δ 1.54 ̃1.41 (m, 2H), δ 0.96 (t, J=15.0 Hz, 3H).
(6S,9aS)-2-allyl-N-benzyl-8-(3-chloro-4-methoxybenzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.39 ̃7.23 (m, 6H), δ 7.09 (d, J=9.0 Hz, 2H), δ 6.98 (d, J=9.0 Hz, 2H), δ 6.89 (d, J=9.0 Hz, 1H), δ 6.73 ̃6.53 (m, 3H), δ 5.67 ̃5.58 (m, 1H), δ 5.38 (dd, J=3.0 Hz, J=9.0 Hz, 1H), δ 5.21 (t, J=6.0 Hz, 1H), δ 5.17 (d, J=12.0 Hz, 1H), δ 5.03 (d, J=15.0 Hz, 1H), δ 4.76 (dd, J=3.0 Hz, J=18.0 Hz, 1H), δ 4.45 ̃4.29 (m, 3H), δ 3.88 (s, 3H), 3.49 ̃3.18 (m, 8H).
(6S,9aS)-2-allyl-N-benzyl-8-(3-fluoro-4-methoxybenzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.39 ̃7.23 (m, 6H), δ 7.09 (d, J=9.0 Hz, 2H), δ 6.98 (d, J=9.0 Hz, 2H), δ 6.89 (d, J=9.0 Hz, 1H), δ 6.73 ̃6.53 (m, 3H), δ 5.67 ̃5.58 (m, 1H), δ 5.38 (dd, J=3.0 Hz, J=9.0 Hz, 1H), δ 5.21 (t, J=6.0 Hz, 1H), δ 5.17 (d, J=12.0 Hz, 1H), δ 5.03 (d, J=15.0 Hz, 1H), δ 4.76 (dd, J=3.0 Hz, J=18.0 Hz, 1H), δ 4.45 ̃4.29 (m, 3H), δ 3.88 (s, 3H), 3.49 ̃3.18 (m, 8H).
(6S,9aS) 2-allyl-7-(4-allyloxy-benzyl)-5-(4-hydroxy-benzyl)-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 7.39 ̃7.23 (m, 4H), 7.15 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.89 (brs, OH), 6.88 (d, J=8.4 Hz, 2H), 6.70 (t, J=6.0 Hz, NH), 6.63 (d, J=8.4 Hz, 2H), 6.10 ̃5.97 (m, 1H), 5.67 ̃5.53 (m, 1H), 5.48 ̃5.26 (m, 4H), 5.14 (d, J=10.3 Hz, 1H), 4.98 (d, J=17.2 Hz, 1H), 4.90 (d, J=14.4 Hz, 1H), 4.52 (d, J=5.3 Hz, 2H), 4.46 ̃4.29 (m, 2H), 4.25 (d, J=4.4 Hz, 1H), 3.49 ̃3.20 (m, 8H).
(6S,9aS) 2-allyl-8-(2-bromo-pyridin-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.29-3.40 (m, 4H), 3.50-3.59 (m, 4H), 4.39 (qd, J=5.9 Hz, 2H), 4.61 (d, J=15.8 Hz, 1H), 4.85 (d, J=15.8 Hz, 1H), 5.16 (d, 1H), 5.21 (d, 1H), 5.32 (t, J=5.1 Hz, 1H), 5.48 (dd, J=3.7 Hz, J=10.6 Hz, 1H), 5.60-5.69 (m, 1H), 6.68 (d, J=8.3 Hz, 2H), 6.73 (t, J=5.9 Hz, NH), 6.94 (d, J=8.3 Hz, 2H), 7.07 (brs, OH), 7.23-7.39 (m, 7H), 8.30 (d, J=2.9 Hz, 1H).
(6S,9aS) 2-allyl-8-(3-bromo-4-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.17 (dd, J=4.1 Hz, J=11.7 Hz, 1H), 3.26-3.46 (m, 7H), 3.87 (s, 3H), 4.28-4.35 (m, 2H), 4.43 (dd, J=5.9 Hz, J=14.8 Hz, 1H), 4.73 (d, J=15 Hz, 1H), 5.05 (d, J=15 Hz, 1H), 5.29 (t, J=5.6 Hz, 1H), 5.34 (dd, J=4 Hz, J=10.6 Hz, 1H), 5.57-5.62 (m, 1H), 6.53 (s, OH), 6.61 (d, J=8.4 Hz, 1H), 6.69 (t, J=6 Hz, NH), 6.83 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 2H), 7.11 (dd, J=2 Hz, J=8.4 Hz, 1H), 7.28-7.38 (m, 5H), 7.44 (d, J=2.1 Hz, 1H).
(6S,9aS) 2-allyl-8-(4-tert-butyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 1.3 (s, 9H), 3.19-3.44 (m, 8H), 4.26-4.36 (m, 2H), 4.39 (dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.88 (d, J=14.9 Hz, 1H), 5.12 (d, J=10.3 Hz, 1H), 5.32 (t, J=5.8 Hz, 1H), 5.45 (dd, J=4.1 Hz, J=10.7 Hz, 1H), 5.55-5.64 (m, 1H), 6.13 (s, OH), 6.62 (d, J=8.4 Hz, 2H), 6.72 (t, J=6 Hz, NH), 7.01 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.29-7.40 (m, 7H).
(6S,9aS) 2-allyl-8-[4-fluoro-3-(2-morpholin-4-yl-ethoxy)-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 207-2.73 (m, 2H), 2.80-2.94 (m, 4H), 3.29-3.35 (m, 2H), 3.42-3.55 (m, 5H), 3.57 (d, J=16.9 Hz, 1H), 3.74-3.87 (m, 5H), 4.05-4.08 (m, 1H), 4.16 (dd, J=5.4 Hz, 1H), 4.22-4.26 (m, 1H), 4.43 (dd, J=6.7 Hz, 1H), 4.81 (dd, J=3 Hz, J=10.5 Hz, 1H), 5.17-5.21 (m, 3H), 5.41 (d, J=15.4 Hz, 1H), 5.64-5.68 (ddd. 1H), 6.47 (d, J=6.6 Hz, 1H), 6.58 (t, J=6.0 Hz, NH), 6.63 (d, J=7.6 Hz, 2H), 6.84 (d, J=7.6 Hz, 2H), 7.01 (dd, J=8.3 Hz, 1H), 7.23-7.26 (m, 2H), 7.30 (t, J=5.5 Hz, 1H), 7.39 (t, J=5.5 Hz, 2H).
(6S,9aS)-2-allyl-N-benzyl-8-(4-ethoxybenzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.40 ̃7.23 (m, 4H), δ 7.15 (d, J=9.0 Hz, 2H), δ 6.98 (d, J=6.0 Hz, 2H), δ 6.85 (d, J=6.0 Hz, 2H), δ 6.69 (t, J=6.0 Hz, 1H), δ 6.64 ̃6.61 (m, 2H), δ 5.65 ̃5.58 (m, 1H), δ 5.45 (dd, J=3.0 Hz, J=9.0 Hz, 1H), δ 5.32 ̃5.29 (m, 1H), δ 5.14 (d, J=9.0 Hz, 1H), δ 5.01 ̃4.86 (m, 2H), δ 4.47 ̃4.23 (m, 3H), δ 4.02 (q, J=15.0 Hz, 2H), δ 3.49 ̃3.19 (m, 7H), δ 1.40 (t, J=6.0 Hz, 3H).
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-(pentyloxy)benzyl)-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.39 ̃7.23 (m, 4H), δ 7.15 (d, J=9.0 Hz, 2H), δ 6.98 (d, J=6.0 Hz, 2H), δ 6.86 (d, J=9.0 Hz, 2H), δ 6.69 (t, J=6.0 Hz, 1H), δ 6.63 (d, J=9.0 Hz, 2H), δ 5.65 ̃5.55 (m, 1H), δ 5.45 (dd, 3.0 Hz, J=9.0 Hz, 1H), 65.30 (t, J=6.0 Hz, 1H), 65.14 (d, J=9.0 Hz, 1H), δ 5.01 ̃4.88 (m, 2H), δ 4.47 ̃4.21 (m, 3H), δ 3.93 (t, J=6.0 Hz, 2H), δ 3.44 ̃3.19 (m, 7H), δ 1.82 ̃1.73 (m, 2H), δ 1.46 ̃1.34 (m, 4H), δ 0.93 (t, J=6.0 Hz, 3H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-propoxy-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.390 ̃7.227 (m, 5H), 7.156 ̃7.127 (d, J=8.7 Hz, 2H), 6.989 ̃6.961 (d, J=8.4 Hz, 2H), 6.868 ̃6.840 (d, J=8.4 Hz, 2H), 6.717 ̃6.677 (t, J=6.0 Hz, 1H), 6.640 ̃6.612 (d, J=8.4 Hz, 2H), 5.667 ̃5.533 (dt, J=6.6 Hz, J=12.6 Hz, 1H), 5.460 ̃5.412 (dd, J=3.9 Hz, J=10.5 Hz, 1H), 5.321 ̃5.283 (t, J=11.4 Hz, 1H), 5.010 ̃4.953 (d, J=17.1 Hz, 1H), 4.910 ̃4.862 (d, J=14.4 Hz, 1H), 4.460 ̃3.876 (dd, J=6.6 Hz, J=6.6 Hz, 2H), 3.443 ̃3.204 (m, 7H), 1.827 ̃1.734 (m, 4H), 1.048 ̃0.999 (t, J=7.2 Hz, 3H).
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-phenethyl-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 7.40 ̃7.17 (m, 10H), 6.95 (d, J=8.4 Hz, 2H), 6.67 (t, J=4.0 Hz, NH), 6.62 (d, J=8.5 Hz, 2H), 6.38 (s, OH), 5.67 ̃5.54 (m, 1H), 5.28 ̃5.07 (m, 4H), 4.46 ̃4.29 (m, 2H), 3.83 ̃3.74 (m, 1H), 3.49 ̃3.10 (m, 9H), 3.04 ̃2.78 (m, 2H).
(6S,9aS)-8-((3-acetyl-1-tosyl-1H-indol-7-yl)methyl)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 8.360 (s, 1H), δ 8.39 (d, J=8.1 Hz, 1H), δ 7.50 (d, J=8.4 Hz, 2H), δ 7.31 ̃7.16 (m, 8H), δ 6.96 ̃6.86 (m, 3H), δ 6.74 ̃6.61 (m, 3H), δ 5.58 ̃5.51 (m, 2H), δ 5.34 (t, J=5.7 Hz, 1H), δ 5.16 ̃4.99 (m, 3H), δ 4.82 (d, J=16.2 Hz, 1H), δ 4.42 ̃4.22 (m, 2H), δ 3.47 ̃3.26 (m, 7H), δ 3.07 ̃3.02 (m, J=4.2, J=12.0 Hz, 1H), δ 2.58 (s, 3H), δ 2.36 (s, 3H).
(6S,9aS)-8-((3-acetyl-1H-indol-7-yl)methyl)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 8.42 ̃3.96 (d, J=7.9 Hz, 1H), δ 8.01 (s, 1H), δ 7.91 ̃7.90 (d, J=3.0 Hz, 1H), δ 7.41 ̃7.18 (m, 4H), δ 7.07 (d, J=7.2 Hz, 1H), δ 6.91 (d, J=8.4 Hz, 2H), δ 6.75 (t, J=6.1 Hz, 1H), δ 6.60 (d, J=8.4 Hz, 2H), δ 5.65 ̃5.56 (m, 1H), δ 5.42 (t, J=7.2 Hz, 1H), δ 5.29 ̃5.15 (m, 3H), δ 4.97 (d, J=17.4 Hz, 1H), δ 4.48 ̃4.32 (m, 3H), δ 3.43 ̃3.22 (m, 7H), δ 2.88 (s, 3H).
(6S,9aS)-2-allyl-8-(2-(allyloxy)benzyl)-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.39 ̃7.19 (m, 7H), δ 6.98 ̃6.93 (m, 2H), δ 6.86 (d, J=8.1 Hz, 2H), δ 6.72 (t, J=6.0 Hz, 1H), δ 6.62 (d, J=8.4 Hz, 2H), δ 6.06 ̃5.96 (m, 1H), δ 5.65 ̃5.56 (m, 1H), δ 5.48 (dd, J=4.2 Hz, J=10.5 Hz, 1H), δ 5.40 ̃5.23 (m, 3H), δ 5.13 (d, J=10.2 Hz, 1H), δ 5.00 (d, J=17.1 Hz, 1H), δ 4.88 (d, J=14.7 Hz, 1H), δ 4.59 ̃4.53 (m, 3H), δ 4.46 ̃4.31 (m, 2H), δ 3.53 ̃3.27 (m, 7H).
(6S,9aS) 2-allyl-8-(2-allyloxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 1.87-1.91 (m, 4H), 3.04-3.14 (m, 5H), 3.27-3.48 (m, 7H), 4.32 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.39 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.59 (d, J=15.2 Hz, 1H), 4.90-4.97 (m, 2H), 5.07 (d, J=10.3 Hz, 1H), 5.38 (t, J=5.6 Hz, 1H), 5.48-5.58 (m, 2H), 6.65-6.69 (m, 3H), 6.65 (d, J=9 Hz, 3H), 6.94-6.98 (m, 2H), 7.01 (d, J=9 Hz, 3H), 7.23-7.38 (m, 6H).
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(3-phenyl-allyl)-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, D2O): δ 7.39 ̃7.24 (m, 10H), 6.98 (d, J=8.5 Hz, 2H), 6.91 (s, OH), 6.72 (t, J=6.0 Hz, NH), 6.61 (d, J=8.3 Hz, 2H), 6.52 (d, J=15.9 Hz, 1H), 6.18 ̃6.08 (m, 1H), 5.71 ̃5.58 (m, 1H), 5.47 (dd, J=10.7 Hz 4.0 Hz, 1H), J=5.6 Hz, 1H), 5.17 (d, J=8.8 Hz, 1H), 5.12 (d, J=15.9 Hz, 1H), 4.48 ̃4.31 (m, 3H), 4.03 (dd, J=15.0 Hz 7.5 Hz, 1H), 3.59 ̃3.28 (m, 9H).
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-((6-nitrobenzo[d][1,3]dioxol-5-yl)methyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.50 (s, 1H), δ 7.34 ̃7.18 (m, 5H), δ 7.96 (d, J=8.4 Hz, 2H), δ 6.70 ̃6.54 (m, 3H), δ 6.06 (d, J=13.2 Hz, 2H), δ 5.66 ̃5.55 (m, 1H), δ 5.3 ̃15.12 (m, 5H), δ 4.60 (d, J=16.5 Hz, 1H), δ 4.40 ̃4.24 (m, 2H), δ 3.59 ̃3.18 (m, 8H).
(6S,9aS) 2-allyl-8-(2,2-difluoro-benzo[1,3]dioxol-4-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.28-3.35 (m, 5H), 3.47-3.62 (m, 3H), 4.32 (dd, J=6.0 Hz, 1H), 4.41 (dd, J=6.0 Hz, 1H), 4.53 (d, J=15.0 Hz, 1H), 4.86 (d, J=15.0 Hz, 1H), 5.10 (d, J=17.4 Hz, 1H), 5.19 (d, J=10 Hz, 1H), 5.30 (t, J=5.6 Hz, 1H), 5.45 (dd, J=4.0 Hz, J=10.0 Hz, 1H), 5.59-5.65 (m, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.71 (t, J=5.8 Hz, NH), 6.97-7.10 (m, 4H), 7.24-7.40 (m, 6H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(1H-indol-7-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid (pyridin-2-ylmethyl)-amide
1H-NMR (300 MHz, CDCl3): δ 3.26-3.51 (m, 8H), 4.29 (d, J=14 Hz, 1H), 4.48 (dd, J=5.4 Hz, J=16 Hz, 1H), 4.51 (dd, J=5.4 Hz, J=16 Hz, 1H), 4.97 (d, J=17 Hz, 1H), 5.13 (d, J=10 Hz, 1H), 5.24-5.37 (m, 3H), 5.70-5.72 (m, 1H), 6.54 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.97-7.01 (m, 1H), 7.20-7.28 (m, 4H), 7.4 (t, J=5.5 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.67-7.72 (m, 1H), 8.54 (d, J=4.8 Hz, 1H), 9.96 (s, NH).
(6S,9aS) 2-allyl-8-(2-difluoromethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.10-7.39 (m, 10H), 6.95 (d, J=8.4 Hz, 2H), 6.71 (t, J=5.7 Hz, 1H), 6.63 (d, J=8.4 Hz), 5.56-5.66 (m, 1H), 5.43 (dd, J=3.9 Hz, 10.5 Hz, 1H), 5.30 t, J=5.4 Hz, 1H), 5.08-5.16 (m, 2H), 4.80 (d, J=15 Hz, 1H), 4.59 (d, J=15 Hz, 1H), 4.29-4.46 (m, 2H), 3.25-3.54 (m, 8H).
(6S,9aS)-2-allyl-N-benzyl-8-((3-(cyclopropanecarbonyl)-1-tosyl-1H-indol-7-yl)methyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 8.56 (s, 1H), δ 8.34 (d, J=7.5 Hz, 1H), δ 7.56 (d, J=8.4 Hz, 2H), δ 7.36 ̃7.20 (m, 7H), δ 7.00 (d, J=8.4 Hz, 1H), δ 6.92 (d, J=7.5 Hz, 1H), δ 6.72 (t, J=6.0 Hz, 1H), δ 6.65 (d, J=8.1 Hz, 2H), δ 6.52 (s, 1H), δ 5.83 ̃5.71 (m, 1H), δ 5.59 (dd, J=6.0 Hz, J=11.1 Hz, 1H), δ 5.39 (t, J=5.7 Hz, 1H), δ 5.20 ̃4.87 (m, 4H), δ 4.67 ̃4.27 (m, 2H), δ 3.57 ̃3.29 (m, 7H), δ 3.08 (dd, J=4.2 Hz, J=12.0 Hz, 1H), δ 2.54 ̃2.48 (m, 1H), δ 1.27 ̃1.24 (m, 2H), δ 1.07 ̃1.03 (m, 2H).
(6S,9aS) 2-allyl-8-[1-(4-chloro-benzenesulfonyl)-1H-indol-7-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.614 ̃7.601 (d, J=12.0 Hz, 1H), 7.526 ̃7.498 (d, J=8.4 Hz, 2H), 7.434 ̃7.410 (d, J=7.2 Hz, 1H), 7.361 ̃7.218 (m, 8H), 6.954 ̃6.929 (d, J=7.5 Hz, 1H), 6.718 ̃6.670 (m, 3H), 5.682 ̃5.506 (m, 2H), 5.541 ̃5.342 (m, 2H), 5.155 ̃5.091 (dd, J=10.5 Hz, J=10.5 Hz, 1H), 5.034 ̃5.924 (dd, J=16.5 Hz, J=16.5 Hz, 1H), 4.455 ̃4.462 (dt, J=6.0 Hz, J=15.0 Hz, 2H), 3.515 ̃3.318 (m, 6H), 3.130 ̃3.077 (dd, J=4.2 Hz, J=12.0 Hz, 1H).
(6S,9aS)-2-allyl-N-benzyl-8-((3-(cyclopropanecarbonyl)-1H-indol-7-yl)methyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 8.42 (d, J=7.8 Hz, 1H), δ 8.04 (d, J=3.0 Hz, 2H), δ 7.40 ̃7.17 (m, 5H), δ 7.07 (d, J=6.6 Hz, 1H), δ 6.92 (d, J=8.4 Hz, 1H), δ 6.77 (t, J=6.0 Hz, 1H), δ 6.59 (d, J=8.4 Hz, 2H), δ 5.64 ̃5.55 (m, 1H), δ 5.45 (t, J=6.0 Hz, 1H), δ 5.35 ̃5.26 (m, 2H), δ 5.16 (d, J=10.2 Hz, 1H), δ 4.95 (d, 17.1 Hz, 1H), δ 4.46 ̃4.29 (m, 3H), δ 3.43 ̃3.20 (m, 8H), δ 2.51 ̃2.44 (m, 1H), δ 1.26 ̃1.20 (m, 2H), δ 0.97 ̃0.92 (m, 2H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-prop-2-ynyl-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.23 ̃7.38 (m, 5H), 6.91 (d, J=8.4 Hz, 2H), 6.75 (s, 1H), 6.70 (t, J=6.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 5.59 ̃5.73 (m, 1H), 5.42 (dd, J=4.2 Hz, 10.8 Hz, 1H), 5.17 ̃5.28 (m, 3H), 4.29 ̃4.56 (m, 3H), 3.99 ̃4.05 (m, 1H), 3.37 ̃3.68 (m, 8H).
3-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-benzoic acid methyl ester
1H NMR (CDCl3): δ 7.993 ̃7.957 (m, 1H), 7.906 (s, 1H), 7.446 ̃7.245 (m, 7H), 6.991 ̃6.963 (d, J=8.4 Hz, 2H), 6.702 ̃6.662 (t, J=6.0 Hz, 1H), 6.629 ̃6.601 (d, J=8.4 Hz, 2H), 5.666 ̃5.532 (dt, J=6.3 Hz, J=8.1 Hz, 1H), 5.467 ̃5.417 (dd, J=4.2 Hz, J=10.8 Hz, 1H), 5.348 ̃5.310 (t, J=5.7 Hz, 1H), 5.145 ̃5.110 (d, J=10.5 Hz, 1H), 5.014 ̃4.957 (d, J=17.1 Hz, 1H), 4.919 ̃4.870 (d, J=14.7 Hz, 1H), 4.483 ̃4.454 (d, J=8.7 Hz, 1H), 4.483 ̃4.282 (dd, J=5.7 Hz, J=14.7 Hz, 2H), 3.911 (s, 3H), 3.454 ̃3.212 (m, 8H).
3-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-benzoic acid
1H NMR (CDCl3): δ 7.976 ̃7.954 (d, J=6.6 Hz 1H), 7.665 (s, 1H), 7.426 ̃7.211 (m, 6H), 7.006 ̃6.981 (d, =7.5 Hz, 2H), 6.847 ̃6.739 (dd, J=8.4 Hz, J=13.2 Hz, 2H), 6.574 ̃6.535 (t, J=5.7 Hz, 1H), 5.616 ̃5.504 (dt, J=4.2 Hz, J=6.3 Hz, 1H), 5.209 ̃4.859 (m, 5H), 4.235 ̃3.939 (m, 4H), 3.539 ̃3.094 (m, 4H).
(6S,9aS) 2-allyl-8-benzo[b]thiophen-3-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 3.18 ̃3.3 (m, 5H), 3.34 ̃3.41 (m, 3H), 4.27 (dd, J=6 Hz, J=15 Hz, 1H), 4.36 (dd, J=6 Hz, J=15 Hz, 1H), 4.47 (d, J=14.7 Hz, 1H), 4.70 (d, J=17.1 Hz, 1H), 4.99 (d, J=10.5 Hz, 1H), 5.26 ̃5.34 (m, 2H), 5.37 ̃5.54 (m, 2H), 6.56 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.19 ̃7.42 (m, 8H), 7.82 ̃7.89 (m, 2H).
2-{3-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-benzoylamino}-pentanedioic acid
1H NMR (DMSO-D6): δ 8.180 ̃8.108 (m, 1H), 7.812 ̃7.227 (m, 10H), 6.881 ̃6.853 (d, J=8.4 Hz, 2H), 6.599 ̃6.572 (d, J=8.4 Hz, 2H), 5.873 ̃5.737 (m, 1H), 5.352 ̃5.288 (m, 1H), 5.105 ̃5.036 (m, 3H), 4.852 ̃4.803 (d, J=13.2 Hz, 1H), 4.384 ̃4.142 (m, 4H), 3.689 ̃3.477 (m, 4H), 3.283 ̃3.028 (m, 5H), 2.411 ̃1.860 (m, 4H).
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-7-[2-(4-methoxy-phenyl)-pyridin-3-ylmethyl]-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 8.59 (dd, J=4.8 Hz 1.5 Hz, 1H), 7.42 ̃7.20 (m, 9H), 6.97 ̃6.93 (m, 4H), 6.75 (brs, OH), 6.66 (t, J=5.9 Hz, NH), 6.60 (d, J=8.5 Hz, 2H), 5.64 ̃5.50 (m, 1H), 5.41 (dd, J=10.6 Hz 3.7 Hz, 1H), 5.24 (t, J=5.5 Hz, 1H), 5.13 (d, J=9.8 Hz, 1H), 5.01 (d, J=17.1 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.70 (d, J=15.5 Hz, 1H), 4.43 ̃4.25 (m, 2H), 3.83 (s, 3H), 3.46 ̃3.18 (m, 7H), 2.92 (dd, J=11.8 Hz 3.9 Hz, 1H)
(6S,9aS) 8-[3-Acetyl-1-(4-chloro-benzenesulfonyl)-1H-indol-7-ylmethyl]-2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 8.34 (s, 2H) δ 7.60 (d, J=9.7 Hz, 2H) δ 7.36 ̃7.21 (m, 6H) δ 6.99 (d, J=8.2 Hz, 2H) δ 6.93 (d, J=8.3 Hz, 1H) δ 6.73 ̃6.65 (m, 1H) δ 5.66 ̃5.52 (m, 2H) δ 5.37 (t, J=5.6 Hz, 1H) δ 5.29 (s, 1H) δ 5.24 ̃5.04 (m, 3H) δ 4.81 (d, J=6.2 Hz, 1H) δ 4.45 ̃4.26 (dd, J=5.0 Hz, J=5.0 Hz, 2H) δ 3.51 ̃3.31 (m, 7H) δ 3.71 ̃3.61 (m, 2H) δ 3.13 ̃3.07 (dd, J=4.0 Hz, J=3.9 Hz, 1H) δ 2.58 (s, 3H)
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-(2-(methylthio)benzyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
1H NMR (CDCl3, 300 MHz) δ 7.38 ̃7.23 (m, 6H), δ 7.15 (t, J=7.5 Hz, 1H), δ 7.08 (d, J=7.5 Hz, 2H), δ 7.01 (d, J=8.4 Hz, 2H), δ 6.70 ̃6.63 (m, 3H), δ 6.37 (s, 1H), δ 5.63 ̃5.49 (m, 1H), δ 5.35 (t, J=5.4 Hz, 1H), δ 5.10 (d, J=10.2 Hz, 1H), δ 4.98 ̃4.88 (m, 3H), δ 4.65 (d, J=15.0 Hz, 1H), δ 4.47 ̃4.27 (m, 2H), δ 3.47 ̃3.28 (m, 8H), δ 2.45 (s, 3H)
(6S,9aS) 2-allyl-8-dibenzofuran-4-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.87 ̃7.95 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.21 ̃7.38 (m, 9H), 7.45 (t, J=7.2 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 6.65 (t, J=6.0 Hz, 1H), 6.54 (d, J=8.4 Hz, 2H), 5.46 ̃5.51 (m, 2H), 5.34 (t, J=5.7 Hz, 1H), 5.17 (m, 1H), 4.75 ̃4.97 (m, 3H), 4.32 ̃4.41 (m, 2H), 3.22 ̃3.58 (m, 8H)
(2S,6S,9aS) 2-allyl-7-(2,3-dimethoxy-benzyl)-5-(4-hydroxy-benzyl)-4,6-dioxo-octahydro-[1,7]naphthyridine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 7.38 ̃7.29 (m, 3H), 7.19 (d, J=7.1 Hz, 2H), 6.98 (dd, J=8.1 Hz 8.1 Hz, 1H), 6.88 ̃6.77 (m, 4H), 6.51 (d, J=8.4 Hz, 2H), 5.68 ̃5.55 (m, 1H), 5.26 (t, J=5.0 Hz, 1H), 5.05 (d, J=9.7 Hz, 1H), 5.00 (d, J=18.6 Hz, 1H), 4.87 (d, J=14.5 Hz, 1H), 4.58 ̃4.25 (m, 6H), 3.84 (s, 3H), 3.69 (s, 3H), 3.47 ̃3.34 (m, 2H), 3.26 ̃3.20 (m, 2H), 2.58 ̃2.41 (m, 2H), 2.23 (t, J=7.4 Hz, 2H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(2-methanesulfonyl-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.04 (d, J=7.8 Hz, 1H), δ 7.62 (t, J=6.6 Hz, 1H), δ 7.46 (d, J=7.5 Hz, 1H), δ 7.38 ̃7.17 (In, 3H), δ 6.97 ̃6.87 (m, 3H), δ 6.75 ̃6.66 (m, 3H), δ 5.71 ̃5.52 (m, 2H), δ 5.36 ̃5.29 (m, 2H), δ 5.21 ̃5.12 (m, 2H), δ 4.85 (d, J=16.2 Hz, 1H), δ 4.46 ̃4.29 (m, 2H), δ 3.70 ̃3.32 (m, 8H), δ 3.14 (s, 3H)
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-7-[2-(4-hydroxy-phenyl)-pyridin-3-ylmethyl]-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 8.54 ̃8.45 (m, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.34 ̃7.18 (m, 8H), 6.89 (d, J=8.2 Hz, 2H), 6.66 ̃6.63 (m, 3H), 6.59 (d, J=8.3 Hz, 2H), 5.60 ̃5.47 (m, 1H), 5.16 ̃5.07 (m, 4H), 4.96 (d, J=17.3 Hz, 1H), 4.45 (d, J=15.7 Hz, 1H), 4.40 ̃4.21 (m, 2H), 3.46 ̃3.12 (m, 7H), 2.87 ̃2.83 (m, 1H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(1-methyl-1H-indol-3-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carb oxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.19 (d, J=16.8 Hz, 1H), 3.27 ̃3.40 (m, 7H), 3.75 (s, 3H), 4.27 (dd, J=6 Hz, J=15 Hz, 1H), 4.40 ̃4.46 (m, 2H), 4.75 (d, J=17 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.13 (d, J=14.4 Hz, 1H), 5.26 (t, J=5.7 Hz, 1H), 5.38 (dd, J=4.5 Hz, J=9.9 Hz, 1H), 5.48 ̃5.61 (m, 1H), 5.97 (s, OH), 6.57 (d, J=8.4 Hz, 2H), 6.67 (d, J=6 Hz, NH), 6.97 (d, J=8.4 Hz, 3H), 7.13 (t, J==7.5 Hz, 1H), 7.29 ̃7.39 (m, 6H), 7.65 (d, J=8.4 Hz, 1H)
(6S,9aS) 2-allyl-8-[2-(4-chloro-phenylsulfanyl)-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.391 ̃7.073 (m, 16H), 6.993 ̃6.965 (d, J=8.4 Hz, 2H), 7.906 (s, 1H), 7.446 ̃7.245 (m, 7H), 6.991 ̃6.963 (d, J=8.4 Hz, 2H), 6.719 ̃6.679 (t, J=−6.0 Hz, 1H), 6.652 ̃6.624 (d, J=8.4 Hz, 2H), 5.660 ̃5.526 (dt, J=6.3 Hz, J=16.8 Hz, 1H), 5.500 ̃5.452 (dd, J=3.9 Hz, J=10.5 Hz, 1H), 5.338 ̃5.303 (t, J=5.1 Hz, 1H), 5.148 ̃5.114 (d, J=10.1 Hz, 1H), 5.043 ̃4.986 (d, J=17.1 Hz, 1H), 4.835 ̃4.824 (d, J=0.3 Hz, 1H), 4.477 ̃4.283 (dd, J=3.0 Hz, J=5.7 Hz, 2H), 3.485 ̃3.125 (m, 8H),
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-[1-(toluene-4-sulfonyl)-1H-indol-3-ylmethyl]-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.969 ̃7.942 (d, J=83 Hz, 1H), 7.782 ̃7.754 (d, J=8.4 Hz, 2H), 7.626 ̃7.600 (d, J=7.8 Hz, 1H), 7.483 (s, 1H), 7.399 ̃7.180 (m, 11H), 6.978 ̃6.950 (d, J=8.4 Hz, 2H), 6.691 ̃6.650 (t, J=6.0 Hz, 1H), 6.631 ̃6.603 (d, J=8.4 Hz, 2H), 5.663 ̃5.466 (m, 1H), 5.319 ̃5.038 (m, 4H), 4.882 ̃4.825 (d, J=17.1 Hz, 1H), 4.481 ̃4.378 (m, 3H), 3.460 ̃3.247 (m, 8H), 2.284 (s, 3H)
(6S,9aS) 2-allyl-8-[2-(4-chloro-benzenesulfonyl)-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 8.156 ̃8.126 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 7.780 ̃7.751 (d, J=6.9 Hz, 2H), 7.622 ̃7.223 (m, 10H), 7.137 ̃7.112 (d, J=7.5 Hz, 1H), 6.994 ̃6.966 (d, J=8.4 Hz, 2H), 6.731 ̃6.691 (t, J=6.0 Hz, 1H), 6.669 ̃6.641 (d, J=8.4 Hz, 2H), 5.689 ̃5.555 (dt, J=6.6 Hz, J=10.5 Hz, 1H), 5.511 ̃5.462 (dd, J=3.9 Hz, J=10.8 Hz, 1H), 5.362 ̃5.327 (t, J=5.3 Hz, 1H), 5.196 ̃5.161 (d, J=10.5 Hz, 1H), 5.134 ̃5.107 (d, J=8.1 Hz, 1H), 5.077 ̃5.054 (d, J=6.9 Hz, 1H), 4.841 ̃4.788 (d, J=15.9 Hz, 1H), 4.461 ̃4.273 (dd, J=6.3 Hz, J=15.0 Hz, 2H), 3.519 ̃3.322 (m, 8H), 4.461 ̃4.273 (dd, J=3.6 Hz, J=11.7 Hz, 1H)
Toluene-4-sulfonic acid 2-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-6-methoxy-phenyl ester
1H NMR (CDCl3, 300 MHz) δ 7.86 (d, J=8.7 Hz), 7.52 (d, J=7.2 Hz, 2H), 7.19-7.39 (m, 6H), 7.00 (d, J=8.4 Hz, 2H), 6.71-6.84 (m, 3H), 6.64 (d, J=8.4 Hz, 2H), 5.50-5.67 (m, 2H), 5.36 (t, J=5.4 Hz, 1H), 5.30 (s, 1H), 5.07-5.17 (m, 2H), 4.76-4.93 (m, 2H), 4.30-4.47 (m, 2H), 3.27-3.61 (m, 11H)
(6S,9aS) 2-allyl-8-(3-allyloxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.23 (d, J=17 Hz, 1H), 3.30-3.37 (m, 4H), 3.41-3.49 (m, 3H), 4.27 (dd, J=6 Hz, J=15 Hz, 1H), 4.38 (dd, J=6 Hz, J=1 Hz, 1H), 4.49-4.56 (m, 3H), 4.78 (d, J=15 Hz, 1H), 4.95 (d, J=17 Hz, 1H), 5.07 (d, J=10 Hz, 1H), 5.19-5.27 (m, 2H), 5.30 (dd, J=1.5 Hz, J=17.4 Hz, 1H), 5.38 (dd, J=4.2 Hz, J=10.8 Hz, 1H), 5.51-5.67 (m, 1H), 5.92-6.02 (m, 1H), 6.35 (s, OH), 6.57 (d, J=8.4 Hz, 2H), 6.64 (t, J=6.3 Hz, NH), 6.81 (d, J=8.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 3H), 7.16-7.20 (m, 3H), 7.27-7.36 (m, 4H)
(6S,9aS) 2-allyl-8-(3-tert-butyl-2-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 1.345 (s, 9H), 3.08 (dd, J=3.9 Hz, J=12 Hz, 1H), 3.22 (d, J=17.1 Hz, 1H), 3.32-3.43 (m, 6H), 3.72 (s, 3H), 4.24 (dd, J=6 Hz, J=15 Hz, 1H), 4.37 (dd, J=6 Hz, J=15 Hz, 1H), 4.47 (d, J=15 Hz, 1H), 4.87 (d, J=18 Hz, 1H), 5.04-5.11 (m, 2H), 5.34 (t, J=5.7 Hz, 1H), 5.49-5.58 (m, 2H), 6.61-6.67 (m, 3H), 6.85 (s, OH), 6.90-6.93 (m, 1H), 6.98-7.02 (m, 3H), 7.19-7.23 (m, 4H), 7.30-7.36 (m, 2H)
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(4-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 8.22 (dd, J=4.8 Hz 1.5 Hz, 1H), 7.38 ̃7.21 (m, 6H), 7.02 (d, J=8.4 Hz, 2H), 6.93 (dd, J=7.6 Hz 4.9 Hz, 1H), 6.77 ̃6.63 (m, 3H), 5.68 ̃5.54 (m, 1H), 5.42 (dd, J=11.4 Hz 3.9 Hz, 1H), 5.36 (t, J=5.2 Hz, 1H), 5.15 (d, J=10.3 Hz, 1H), 5.07 (d, J=17.0 Hz, 1H), 4.78 (d, J=15.4 Hz, 1H), 4.48 (d, J=15.4 Hz, 1H), 4.43 ̃4.26 (m, 2H), 3.50 ̃3.24 (m, 9H), 3.02 ̃2.68 (m, 7H), 2.36 ̃1.70 (m, 8H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(3-methoxy-2-vinyloxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.23-7.39 (m, 5H), 6.97-7.07 (m, 4H), 6.61-6.88 (m, 7H), 6.00-6.09 (m, 1H), 5.55-5.60 (m, 1H), 5.48 (dd, J=4.2 Hz, 10.8 Hz, 1H), 4.92-5.33 (m, 7H), 4.29-4.59 (m, 6H), 3.85 (s, 3H), 3.23-3.47 (m, 10H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-phenoxy-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.18-3.44 (m, 8H), 4.29 (dd, J=5.6 Hz, J=15.1 Hz, 1H), 4.38-4.45 (m, 2H), 4.72 (d, J=14.8 Hz, 1H), 4.98 (d, J=17 Hz, 1H), 5.03 (d, J=10.4 Hz, 1H), 5.26 (t, J=5.8 Hz, 1H), 5.41 (dd, J=3.9 Hz, J=10.7 Hz, 1H), 5.55-5.64 (m, 1H), 6.32 (s, OH), 6.57 (d, J=8.4 Hz, 2H), 6.60 (t, J=6 Hz, NH), 6.87-6.99 (m, 7H), 7.07 (t, J=7.4 Hz, 1H), 7.21 (s, 1H), 7.27-7.37 (m, 7H)
(6S,9aS) 2-allyl-8-[2-(benzyl-methyl-amino)-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 7.35 ̃6.00 (m, 18H) δ 6.70 ̃6.63 (m, 3H) δ 5.59 ̃5.40 (m, 2H) δ 5.38 (t, J=5.7 Hz, 1H) δ 5.02 (d, J=10.3 Hz, 1H) δ 4.98 ̃4.81 (dd, J=5.7 Hz, J=5.5 Hz, 2H) δ 4.44 ̃4.28 (dd, J=4.9 Hz, J=4.9 Hz, 1H) δ 3.97 (s, 2H) δ 3.46 ̃3.25 (m, 7H) δ 3.19 ̃3.14 (dd, J=4.1 Hz, J=4.2 Hz, 1H) δ 2.54 (s, 3H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[3-(3-methyl-but-2-enoyl)-1-(toluene-4-sulfonyl)-1H-indol-7-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.41 (d, J=9.3 Hz, 2H), δ 7.53 (d, J=8.4 Hz, 2H), δ 7.35 ̃7.20 (m, 8H), δ 7.01 (d, J=8.4 Hz, 2H), δ 6.93 (d, J=7.8 Hz, 1H), δ 6.75 (t, J=6.0 Hz, 1H), δ 6.66 (d, J=8.4 Hz, 2H), δ 5.69 ̃5.56 (m, 2H), δ 5.40 (t, J=5.7 Hz, 1H), δ 5.21 ̃4.90 (m, 4H), δ 4.46 ̃4.16 (m, 2H), δ 3.51 ̃3.30 (m, 6H), δ 3.10 (dd, J=3.9 Hz, J=11.7 Hz, 1H), δ 2.35 (s, 3H), 2.27 (s, 3H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[3-(3-methyl-but-2-enoyl)-1H-indol-7-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.49 (d, J=7.8 Hz, 1H), δ 7.90 (d, J=3.0 Hz, 1H), δ 7.40 ̃7.17 (m, 6H), δ 7.06 (d, J=4.5 Hz, 1H), δ 6.90 (d, J=8.4 Hz, 2H), δ 6.81 (t, J=6.0 Hz, 1H), δ 6.63 ̃6.55 (m, 3H), δ 5.65 ̃5.54 (m, 1H), δ 5.30 ̃5.14 (m, 3H), δ 3.44 ̃3.20 (m, 8H), δ 2.24 (s, 3H), δ 1.90 (s, 3H)
(6S,9aS)-2-allyl-8-[3-(3-ethoxy-butyryl)-1,1-indol-7-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.40 (d, J=8.1 Hz, 1H), δ 7.85 (dd, J=3.0 Hz, J=21.9 Hz, 1H), δ 7.37 ̃7.15 (m, 5H), δ 7.04 (d, f=7.2 Hz, 1H), δ 6.82 (t, J=8.1 Hz, 2H), δ 6.71 ̃6.68 (m, 1H), δ 6.51 ̃6.47 (m, 2H), δ 5.66 ̃5.47 (m, 1H), δ 4.57 ̃4.30 (m, 3H), δ 3.61 ̃3.11 (m, 8H), δ 2.84 ̃2.71 (m, 1H), δ 1.57 (s, 3H), δ 1.14 ̃1.09 (m, 3H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[5-methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 2.28 (s, 3H), 3.24-3.38 (m, 8H), 3.80 (s, 3H), 4.38-4.47 (m, 3H), 4.88 (d, J=17.2 Hz, 1H), 4.94 (d, J=14.9 Hz, 1H), 5.10 (d, J=11 Hz, 1H), 5.25-5.32 (m, 1H), 6.01 (s, OH), 6.59 (d, J=8.5 Hz, 2H), 6.66 (t, J=6.1 Hz, NH), 6.92-6.96 (m, 3H), 7.11 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.2 Hz, 2H), 7.32-7.42 (m, 6H), 7.72 (d, J=8.4 Hz, 2H), 7.82 (d, J=9 Hz, 1H)
Dodecane-1-sulfonic acid 2-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-phenyl ester
1H-NMR (300 MHz, CDCl3): δ 0.84 (t, J=6.9 Hz, 3H), 1.23 (brs, 15H), 1.39-1.46 (m, 2H), 1.93 (q, T=7.7 Hz, 2H), 3.12 (dd, J=4.1 Hz, J=11.8 Hz, 1H), 3.21 (d, J=17.1 Hz, 1H), 3.26-3.45 (m, 9H), 4.25-4.30 (m, 2H), 4.38 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.77 (d, J=7.2 Hz, 1H), 5.01 (d, J=10.4 Hz, 1H), 5.22-5.27 (m, 2H), 6.58 (d, J=8.3 Hz, 2H), 6.66 (t, J=6 Hz, NH), 6.93 (d, J=8.3 Hz, 2H), 7.19-7.38 (m, 9H)
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(2-piperazin-1-yl-pyridin-3-ylmethyl)-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 9.11 ̃8.71 (brs, 1H), 7.29 ̃6.87 (m, 9H), 6.89 (d, J=7.6 Hz, 2H), 6.67 ̃6.61 (m, 3H), 5.54 ̃5.44 (brs, 2H), 5.23 ̃5.20 (m, 1H), 5.17 ̃5.13 (m, 1H), 5.03 (d, J=10.1 Hz, 1H), 4.86 (d, J=16.5 Hz, 1H), 4.71 (d, J=14.1 Hz, 1H), 4.55 (d, J=14.4 Hz, 1H), 4.32 ̃4.16 (m, 2H), 3.50 ̃2.98 (m, 16H)
(6S,9aS) 2-allyl-8-(3,5-di-tert-butyl-2-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 7.38 ̃7.31 (q, J=6.1 Hz, 3H) δ 7.28 ̃7.22 (m, 4H) δ 7.04 ̃7.00 (m, 3H) δ 6.89 (s, 1H) δ 6.67 (t, J=6.2 Hz, 1H) δ 6.62 (d, J=9.2 Hz, 2H) δ 5.71 ̃5.66 (dd, J=4.2 Hz, J=4.1 Hz, 1H) δ 5.58 ̃5.47 (m, 1H) δ 5.29 (d, J=14.2 Hz, 1H) δ 5.05 (d, J=10.3 Hz, 1H) δ 4.83 (d, J=17.1 Hz, 1H) δ 3.73 (s, 3H) δ 3.39 (d, J=4.5 Hz, 2H) δ 3.33 (d, J=9.6 Hz, 2H) δ 3.25 ̃3.11 (m, 2H) δ 1.37 (s, 9H) δ 1.26 (s, 9H)
(6S,9aS) 2-allyl-8-[3-chloro-1-(toluene-4-sulfonyl)-1H-indol-7-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.65 (s, 1H), 7.47 (d, J=8.32 Hz, 2H), 7.43 (d, J=7.63 Hz, 1H), 7.35 ̃7.15 (m, 7H), 7.03 (d, J=8.3 Hz, 2H), 6.98 (d, J=7.52 Hz, 1H), 6.68 (m, 3H), 5.60 (m, 2H), 5.37 (m, 2H), 5.10 (m, 2H), 4.95 (d, J=16.3 Hz, 1H), 4.34 (ddd, J=32.9, 14.9, 6.0 Hz, 2H), 3.40 (m, 7H), 3.07 (dd, J=11.8, 3.97 Hz, 1H), 2.32 (s, 3H)
(6S,9aS) 2-allyl-8-(2-allyloxy-3-tert-butyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 7.38 ̃7.22 (m, 7H) δ 7.07 ̃6.94 (m, 4H) δ 6.75 (s, 1H) δ 6.69 (d, J=6.0 Hz, 1H) δ 6.64 (d, J=8.4 Hz, 2H) δ 6.08 ̃5.99 (m, 1H) δ 5.61 ̃5.48 (m, 1H) δ 5.42 ̃5.35 (m, 1H) δ 5.27 (d, J=9.4 Hz, 1H) δ 5.10 ̃4.90 (m, 2H) δ 4.53 (d, J=15.1 Hz, 1H) δ 4.46 ̃4.33 (m, 2H) 4.29 ̃4.23 (m, 2H) δ 3.43 (d, J=6.4 Hz, 2H) δ 3.38 (d, J=3.3 Hz, 2H) δ 3.33 (d, J=15.7 Hz, 2H) δ 1.37 (s, 9H)
(6S,9aS) 2-allyl-8-(3-chloro-1H-indol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 9.99 (s, NH), 7.61 (d, J=7.96 Hz, 1H), 7.37 ̃7.2 (m, 6H), 7.05 (d, J=7.77 Hz, 1H), 6.97 (d, J=6.92 Hz, 1H), 6.89 (d, J=8.39 Hz, 2H), 6.65 (t, J=6.14 Hz, NH), 6.54 (d, J=8.4 Hz, 2H), 5.87 (s, 1H), 5.57 (m, 1H), 5.37 (t, J=7.5 Hz, 1H), 5.24 (m, 2H), 5.14 (d, J=10.2 Hz, 1H), 4.95 (d, J=17.0 Hz, 1H), 4.35 (m, 3H), 3.30 (m, 7H)
(6S,9aS) 2-allyl-8-(3,5-di-tert-butyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.40 ̃7.20 (m, 6H), 7.07 (d, J=1.70 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.68 (t, J=6.0 Hz, NH), 6.62 (d, J=8.40 Hz, 2H), 6.20 (brs, OH), 5.64 ̃5.55 (m, 1H), 5.37 (t, J=6.2 Hz, 1H), 5.15 ̃5.02 (m, 2H), 4.85 (d, J=17.2 Hz, 1H), 4.40 (ddd, J=32.2, 14.8, 6.0 Hz, 2H), 4.15 (d, J=14.4 Hz, 1H), 3.50 ̃3.20 (m, 8H), 1.30 (s, 18H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[3-methoxy-2-(2-piperidin-1-yl-ethoxy)-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.22-7.43 (m, 6H), 7.11 (t, J=3.3 Hz, 1H), 6.63-6.97 (m, 8H), 5.59-5.68 (m, 1H), 5.04-5.22 (m, 5H), 4.25-4.40 (m, 6H), 3.88 (s, 3H), 3.25-3.63 (m, 14H), 1.80-1.88 (m, 4H), 1.43-1.64 (m, 2H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(5-methoxy-1H-indol-3-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.24 (d, J=17 Hz, 1H), 3.33-3.45 (m, 7H), 3.84 (s, 3H), 4.33 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.87 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.55 (d, J=14.6 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.95 (d, J=14.6 Hz, 1H), 5.06 (d, J=10.4 Hz, 1H), 5.26-5.31 (m, 2H), 5.52-5.57 (m, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.69 (t, J=5.4 Hz, NH), 6.84 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 7.01 (d, J=2.3 Hz, 1H), 7.19-7.24 (m, 3H), 7.29-7.38 (m, 3H), 8.24 (s, 1H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[3-(morpholine-4-carbonyl)-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.426 ̃7.226 (m, 9H), 7.135 (s, 1H), 6.946 ̃6.918 (d, J=8.4 Hz, 2H), 6.629 ̃6.601 (m, 3H), 5.707 ̃5.574 (dt, T=6.0 Hz, J=10.2 Hz, 1H), 5.287 ̃5.254 (t, J=5.1, 1H), 5.196 ̃5.082 (m, 2H), 4.919 ̃4.869 (d, J=15.0 Hz, 1H), 4.424 ̃4.255 (m, 3H), 3.522 ̃3.154 (m, 8H), 1.669 (s, 3H), 1.257 (s, 3H)
(6S,9aS) 2-allyl-8-(3-cyclopentylcarbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.724 ̃7.700 (d, J=7.2 Hz, 1H), 7.409 ̃7.208 (m, 8H), 6.891 ̃6.863 (d, J=8.4 Hz, 2H), 6.367 ̃6.554 (m, 3H), 5.700 ̃5.566 (dt, J=6.6 Hz, J=10.5 Hz, 1H), 5.265 ̃4.964 (m, 4H), 3.568 ̃3.304 (m, 7H), 2.090 ̃1.257 (m, 9H)
Octane-1-sulfonic acid 2-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-6-methoxy-phenyl ester
1H NMR (CDCl3, 300 MHz) δ 7.19-7.39 (m, 5H), 6.93-7.00 (m, 3H), 6.62-6.80 (m, 4H), 5.56-5.66 (m, 1H), 5.46 (dd, J=3.9 Hz, 11.1 Hz, 1H), 5.33 (t, J=5.4 Hz, 1H), 5.04-5.15 (m, 2H), 4.80 (q, J=15.0 Hz, 2H), 4.27-4.47 (m, 2H), 3.87 (s, 3H), 3.23-3.59 (m, 10H), 1.95-2.04 (m, 2H), 1.17-1.69 (m, 16H), 0.83-0.90 (m, 4H)
CWP232017
(6S,9aS) 2-allyl-8-(2-cyclopropylmethoxy-3-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 0.21 (dd, J=4.8 Hz, J=10.1 Hz, 2H), 0.50 (dd, J=5.5 Hz, T=12.4 Hz, 2H), 1.14 ̃1.27 (m, 1H), 3.30-3.51 (m, 8H), 3.73-3.79 (m, 2H), 3.82 (s, 3H), 4.29 (dd, J=6 Hz, J=14 Hz, 1H), 4.37 (dd, J=6 Hz, J=14 Hz, 1H), 4.56 (d, J=14.6 Hz, 1H), 4.97-5.03 (m, 2H), 5.09 (d, J=10.3 Hz, 1H), 5.30 (t, J=5.4 Hz, 1H), 5.45 (dd, J=4 Hz, J=10.7 Hz, 1H), 5.56-5.63 (m, 1H), 6.61 (d, J=8.3 Hz, 2H), 6.68 (t, J=5.9 Hz, NH), 6.76 (d, J=7.6 Hz, 1H), 6.83 (d, T=7.3 Hz, 1H), 6.96-7.04 (m, 3H), 7.22-7.37 (m, 5H)
(6S,9aS) 2-allyl-8-(2-cyclopentyloxy-3-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 1.65-1.75 (m, 8H), 3.12 (dd, J=4.1 Hz, J=12 Hz, 1H), 3.19 (d, J=17.1 Hz, 1H), 3.30-3.47 (m, 6H), 3.79 (s, 3H), 4.24 (dd, J=5.8 Hz, J=14.9 Hz, 1H), 4.31 (dd, J=5.8 Hz, J=14.9 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H), 4.75-4.83 (m, 2H), 4.93 (d, J=17.4 Hz, 1H), 5.05 (d, J=10.3 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H), 5.42 (dd, J=3.8 Hz, J=10.8 Hz, 1H), 5.51-5.59 (m, 1H), 6.57 (d, J=8.3 Hz, 2H), 6.68 (d, J=7.6 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.93-7.00 (m, 3H), 7.27-7.34 (m, 5H)
(6S,9aS) 2-allyl-8-[2-(3-fluoro-phenoxy)-3-methoxy-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.11 (dd, J=4 Hz, J=11.7 Hz, 1H), 3.19-3.25 (m, 3H), 3.27-3.38 (m, 4H), 3.69 (s, 3H), 4.25 (dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.35-4.42 (m, 2H), 4.71 (d, J=14.7 Hz, 1H), 4.96-5.13 (m, 3H), 5.31 (dd, T=4 Hz, J=10.7 Hz, 1H), 5.51-5.60 (m, 1H), 6.38 (dt, J=2.4 Hz, 1H), 6.54-6.66 (m, 5H), 6.84-6.94 (m, 4H), 7.10-7.20 (m, 3H), 7.28-7.35 (m, 3H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[2-(indan-2-yloxy)-3-methoxy-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.17 ̃7.35 (m, 7H), 7.15 ̃7.05 (m, 2H), 7.0 (t, J=7.9 Hz, 1H), 6.90 ̃6.80 (m, 3H), 6.75 (d, J=7.5 Hz, 1H), 6.65 (t, J=5.9 Hz, NH), 6.54 (d, J=8.3 Hz, 2H), 5.57 (m, 1H), 5.32 ̃3.25 (m, 2H), 5.16 (t, J=5.6 Hz, 1H), 5.12 (d, J=10.3 Hz, 1H), 5.03 (d, J=17.2 Hz, 1H), 4.49 ̃4.25 (m, 4H), 3.81 (s, 3H), 3.44 (s, 1H), 3.35 (d, J=6.0 Hz, 2H), 3.30 ̃3.15 (m, 4H), 3.05 (t, J=3.8 Hz, 4H), 2.94 (dd, J=12.0, 4.0 Hz, 1H).
(6S,9aS) 2-allyl-8-(3-cyclohexylcarbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.741 ̃7.717 (d, J=7.2 Hz, 1H), 7.444 ̃7.222 (m, 15H), 6.871 ̃6.843 (d, J=8.4 Hz, 2H), 6.646 ̃6.572 (m, 3H), 5.692 ̃5.602 (m, 2H), 5.234 ̃4.895 (m, 4H), 3.406 ̃3.273 (m, 3H), 3.3.571 ̃3.305 (m, 7H), 2.047 ̃1.1.251 (m, 11H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-{3-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-benzyl}-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3): δ 7.966 ̃7.902 (m, 1H), 7.483 ̃7.200 (m, 8H), 6.824 ̃6.796 (d, J=8.4 Hz, 1H), 6.667 ̃6.611 (t, J=8.4 Hz, 2H), 6.534 ̃6.508 (d, J=7.8 Hz, 1H), 5.763 ̃5.681 (m, 1H), 5.503 ̃5.326 (m, 1H), 5.261 ̃5.167 (m, 3H), 4.963 ̃4.825 (m, 1H), 4.516 ̃4.203 (m, 2H), 3.942 ̃3.465 (m, 8H), 2.187 ̃1.406 (m, 7 H)
(6S,9aS) 2-allyl-8-(3-amino-benzo[d]isoxazol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ 3.23-3.37 (m, 5H), 3.50-3.54 (m, 3H), 3.74 (t, J=11.2 Hz, 1H), 4.29 (s, NH), 4.77 (d, J=15.3 Hz, 2H), 4.93 (d, J=15.3 Hz, 1H), 5.02 (d, J=17.3 Hz, 1H), 5.05 (d, J=10.3 Hz, 1H), 5.21 (t, J=5.4 Hz, 1H), 5.41 (dd, J=3.9 Hz, J=10.7 Hz, 1H), 5.72-5.77 (m, 1H), 6.62 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 7.20-7.25 (m, 4H), 7.30-7.34 (m, 3H), 7.69 (d, J=7.7 Hz, 1H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(2-nitro-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.03 (d, J=8.1 Hz, 1H), δ 7.61 (t, J=7.5 Hz, 2H), δ 7.45 (t, J=7.8 Hz, 1H), 7.37 ̃7.21 (m, 5H), δ 7.01 (d, J=7.8 Hz, 1H), δ 6.99 (d, J=8.1 Hz, 2H), δ 6.78 ̃6.68 (m, 3H), δ 5.65 ̃5.50 (m, 2H), δ 5.37 ̃5.13 (m, 4H), δ 4.74 (d, J=17.1 Hz, 1H), δ 4.44 ̃4.29 (m, 2H), δ 3.65 ̃3.23 (m, 8H)
(6S,9aS) 2-allyl-8-(3-cyano-2-fluoro-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.59 ̃7.48 (m, 3H), δ 7.32 (m, 6H), δ 6.93 (d, J=8.4 Hz, 2H), δ 6.75 (t, J=6.0 Hz, 1H), δ 6.63 (d, J=8.4 Hz, 2H), δ 5.70 ̃5.61 (m, 1H), δ 5.44 (dd, J=3.9 Hz, J=10.8 Hz, 1H), δ 5.29 ̃5.11 (m, 3H), δ 4.73 ̃4.62 (m, 2H), δ 4.45 ̃4.36 (m, 2H), δ 3.69 ̃3.30 (m, 8H)
(6S,9aS) 2-allyl-8-(2-amino-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.85 ̃7.59 (m, 6H), δ 7.08 (t, J=5.8 Hz, 1H), δ 6.93 ̃6.82 (m, 4H), δ 6.67 ̃6.59 (m, 4H), δ 5.63 ̃5.50 (m, 1H), δ 5.36 (dd, J=4.3 Hz, J=10.5 Hz, 1H), δ 5.21 (t, J=5.7 Hz, 1H), δ 5.08 (d, J=10.3 Hz, 1H), δ 4.92 ̃4.86 (m, 2H), δ 4.39 ̃4.22 (m, 2H), δ 4.16 ̃4.04 (m, 1H), δ 3.41 ̃3.18 (m, 8H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-oxo-2-phenyl-4H-chromen-8-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.14 ̃8.10 (m, 1H), δ 7.87 (d, J=6.2 Hz, 2H), δ 7.53 ̃7.47 (m, 3H), δ 7.40 ̃7.20 (m, 8H), δ 6.98 (d, J=8.3 Hz, 2H), δ 6.78 (s, 1H), δ 6.72 ̃6.68 (m, 3H), δ 5.59 ̃5.50 (m, 1H), δ 5.38 (dd, J=3.8 Hz, J=10.7 Hz, 2H), δ 5.13 ̃4.97 (m, 4H), δ 4.41 ̃4.29 (m, 2H), δ 3.60 ̃3.32 (m, 8H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-oxo-4H-chromen-8-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.16 (d, J=7.3 Hz, 1H), δ 8.03 (d, J=6.0 Hz, 1H), δ 7.69 (d, J=7.4 Hz, 1H), δ 7.43 ̃7.22 (m, 8H), δ 5.70 ̃5.61 (m, 1H), δ 5.20 ̃5.10 (m, 3H), δ 5.03 (dd, J=4.3 Hz, J=10.1 Hz, 1H), δ 4.90 (d, J=14.6 Hz, 1H), δ 4.75 ̃4.68 (m, 4H), δ 4.37 ̃4.30 (m, 3H), δ 3.68 ̃3.16 (m, 8H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(2-phenyl-pyridin-3-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.49 (d, J=3.4 Hz, 1H), δ 7.09 ̃7.35 (m, 12H), δ 6.83 (d, J=8.3 Hz, 1H), δ 6.54 (t, J=5.9 Hz, 1H), δ 6.49 (d, J=8.4 Hz, 2H), δ 6.05 (s, 1H) δ 5.36 ̃5.54 (m, 1H), δ 5.23 (dd, J=10.6 Hz, J=3.9 Hz, 2H), δ 5.08 (t, J=5.3 Hz, 1H), δ 5.01 (d, J=10.4 Hz, 1H), δ 4.89 (d, J=14.1 Hz, 1H), δ 4.70 (d, J=15.5 Hz, 1H), δ 4.55 (d, J=15.5 Hz, 1H), δ 4.28 (dd, J=14.8 Hz, J=6.4 Hz, 1H), δ 4.17 (dd, J=14.8 Hz, J=6.4 Hz, 1H), δ 3.05 ̃3.33 (m, 6H), δ 2.77 (dd, J=11.8 Hz, J=3.9 Hz, 1H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(1-pyridin-2-yl-1H-indol-7-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.54 (m, 1H), 7.87 (td, J=1.8 Hz, 7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.14 ̃7.36 (m, 10H), 6.92-6.98 (m, 3H), 6.58-6.69 (m, 5H), 5.39-5.49 (m, 2H), 4.91-5.10 (m, 4H), 4.69 (d, J=16.8 Hz, 1H), 4.22-4.42 (m, 4H), 3.10-3.48 (m, 8H), 2.88 (dd, J=4.2 Hz, 12.0 Hz, 1H)
(6S,9aS) 2-allyl-8-(1,1-dioxo-1H-16-benzo[b]thiophen-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.74 (d, J=9.0 Hz, 1H), δ 7.65 ̃7.52 (m, 3H), δ 7.41 ̃7.26 (m, 4H), δ 6.98 (d, J=9.0 Hz, 2H), δ 6.78 ̃6.68 (m, 3H), δ 6.41 (s, 1H), δ 5.66 ̃5.60 (m, 1H), δ 5.32 ̃5.11 (m, 4H), δ 4.68 (d, J=6.0 Hz, 2H), δ 4.48 ̃4.37 (m, 2H), δ 3.59 ̃3.30 (m, 8H)
(6S,9aS) 2-allyl-8-(6-bromo-pyridin-2-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.52 (t, J=9.0 Hz, 1H), δ 7.40 ̃7.34 (m, 4H), δ 7.25 (d, J=6.0 Hz, 1H), δ 7.15 (d, J=6.0 Hz, 1H), δ 6.99 (d, J=6.0 Hz, 2H), δ 6.74 (t, J=6.0 Hz, 1H), δ 6.63 (d, J=9.0 Hz, 2H), δ 5.71 ̃5.55 (m, 2H), δ 5.32 (t, J=6.0 Hz, 1H), δ 4.58 (d, J=15.0 Hz, 1H), δ 4.45 ̃4.33 (m, 2H), δ 3.88 (t, J=9.0 Hz, 1H), δ 3.63 ̃3.31 (m, 7H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(6-phenyl-pyridin-2-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J=6.0 Hz, 1H), δ 7.78 ̃7.65 (m, 2H), δ 7.47 ̃7.38 (m, 5H), δ 7.33 ̃7.16 (m, 2H), δ 7.17 (d, J=6.0 Hz, 1H), δ 7.00 (d, J=9.0 Hz, 2H), δ 6.72 (t, J=6.0 Hz, 1H), δ 6.62 (d, J=6.0 Hz, 2H), δ 5.64 ̃5.58 (m, 2H), δ 5.39 (t, J=6.0 Hz, 1H), δ 4.45 ̃4.37 (m, 2H), δ 3.91 (t, J=12.0 Hz, 1H), 3.57 ̃3.28 (m, 7H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[6-(2-methoxy-phenyl)-pyridin-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.80 ̃7.66 (m, 3H), δ 7.39 ̃7.32 (m, 3H), δ 7.30 ̃7.24 (m, 2H), δ 7.13 (t, J=6.0 Hz, 1H), δ 7.06 ̃6.97 (m, 4H), δ 6.72 (t, J=6.0 Hz, 1H), δ 6.62 (d, J=6.0 Hz, 2H), δ 5.66 ̃5.57 (m, 21 ̃1), δ 5.38 (t, J=6.0 Hz, 1H), δ 5.09 ̃4.91 (m, 3H), δ 4.60 (d, J=15.0 Hz, 1H), δ 4.42 ̃4.38 (m, 2H), δ 3.91 (t, J=12.0 Hz, 1H), δ 3.85 (s, 3H), δ 3.50 ̃3.26 (m, 7H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-methanesulfonyl-phenyl)-pyridin-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.18 (d, J=8.4 Hz, 2H), 8.01 (d, J=9.3 Hz, 2H), 7.71-7.83 (m, 2H), 7.24-7.40 (m, 5H), 6.89 (d, J=8.4 Hz, 2H), 6.74 (t, J=6.0 Hz, 1H), 6.49 (d, J=8.4 Hz, 2H), 5.59-5.68 (m, 1H), 5.51 (dd, J=4.2 Hz, 10.8 Hz, 1H), 5.29-5.36 (m, 1H), 5.13 (d, J=10.2 Hz, 1H), 5.02 (d, J=17.1 Hz, 1H), 4.85 (d, J=15.3 Hz, 1H), 4.66 (d, J=13.5 Hz, 1H), 4.30-4.49 (m, 2H), 3.84 (t, J=11.2 Hz, 1H), 3.31-3.68 (m, 7H), 3.07 (s, 3H)
(6S,9aS) 2-allyl-8-[6-(4-fluoro-phenyl)-pyridin-2-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz)), δ 7.98 ̃7.94 (m, 2H), δ 7.73 (t, J=6.0 Hz, 1H), δ 7.61 (d, J=9.0 Hz, 1H), δ 7.24 (m, 4H), δ 7.16 ̃7.09 (m, 3H), δ 6.98 (d, J=9.0 Hz, 2H), δ 6.72 (t, J=6.0 Hz, 1H), δ 6.60 (d, J=9.0 Hz, 2H), δ 6.62 (s, 13H), δ 5.65 ̃5.56 (m, 2H), δ 5.37 (t, J=6.0 Hz, 1H), δ 5.09 (d, J=12.0 Hz, 1H), δ 4.92 (t, J=15.0 Hz, 2H), δ 4.63 (d, J=15.0 Hz, 1H), δ 4.49 ̃4.31 (m, 2H), δ 3.86 (t, J=9.0 Hz, 1H), δ 3.59 ̃3.27 (m, 7H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-methoxy-phenyl)-pyridin-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.93 (d, J=9.0 Hz, 2H), δ 7.71 (t, J=6.0 Hz, 1H), δ 7.60 (d, J=9.0 Hz, 1H), δ 7.40 ̃7.25 (m, 4H), δ 7.10 (d, J=6.0 Hz, 1H), δ 6.99 (t, J=9.0 Hz, 4H), δ 6.72 (t, J=6.0 Hz, 1H), δ 6.62 (d, J=9.0 Hz, 2H), δ 5.64 ̃5.59 (m, 2H), δ 5.40 (t, J=6.0 Hz, 1H), δ 5.10 ̃4.90 (m, 3H), δ 4.57 (d, J=15.0 Hz, 1H), δ 4.45 ̃4.37 (m, 2H), δ 3.90 (t, J=9.0 Hz, 1H), δ 3.84 (s, 3H), δ 3.57 ̃3.27 (m, 7H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-methylsulfanyl-phenyl)-pyridin-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=9.0 Hz, 2H), δ 7.75 ̃7.61 (m, 2H), δ 7.40 ̃7.25 (m, 5H), δ 7.13 (d, J=9.0 Hz, 1H), δ 7.00 (d, J=9.0 Hz, 2H), δ 6.73 (t, J=6.0 Hz, 1H), δ 6.60 (t, J=9.0 Hz, 2H), δ 6.44 (s, 1H), δ 5.64 ̃5.59 (m, 2H), δ 5.40 (t, J=6.0 Hz, 1H), δ 5.09 (d, J=12.0 Hz, 1H), δ 4.99 ̃4.90 (m, 2H), δ 4.59 (d, J=15.0 Hz, 1H), δ 4.45 ̃4.39 (m, 2H), δ 3.90 (t, J=9.0 Hz, 1H), δ 3.58 ̃3.28 (m, 7H), δ 2.52 (s, 3H)
(6S,9aS) 2-allyl-8-(1-benzenesulfonyl-3-phenyl-1,1-indol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.67 (s, 1H), 7.54 (m, 3H), 7.45 ̃7.35 (m, 5H), 7.35 ̃7.20 (m, 7H), 7.13 (d, J=6.8 Hz, 3H), 6.96 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.4 Hz, 2H), 5.57 (m, 1H), 5.32 ̃3.25 (m, dd, J=10.5, 5.7 Hz, 1H), 5.50 (m, 1H), 5.36 (d, J=5.7 Hz, 1H), 5.31 (d, J=16.2 Hz, 1H), 5.05 (d, J=10.3 Hz, 1H), 4.99 (d, J=4.5 Hz, 1H), 4.94 (d, J=3.1 Hz, 1H), 4.26 (ddd, J=26.5, 15.0, 5.9 Hz, 2H), 3.50 ̃3.20 (m, 6H), 3.05 (dd, J=11.7, 4.0 Hz, 1H).
(6S,9aS) 2-allyl-8-[6-(3-cyano-phenyl)-pyridin-2-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.28 ̃8.22 (m, 1H), δ 7.81 (t, J=9.0 Hz, 1H), δ 7.69 ̃7.66 (m, 2H), δ 7.57 (t, J=9.0 Hz, 1H), δ 7.40 ̃7.31 (m, 3H), δ 7.27 ̃7.25 (m, 2H), δ 6.97 (d, J=9.0 Hz, 2H), δ 6.73 (t, J=6.0 Hz, 1H), δ 6.59 (t, J=9.0 Hz, 2H), δ 5.70 ̃5.53 (m, 2H), δ 5.36 (t, J=6.0 Hz, 1H), δ 5.16 ̃4.99 (m, 2H), δ 4.77 (d, J=6.0 Hz, 2H), δ 4.51 ̃4.32 (m, 2H), δ 3.85 (t, J=9.0 Hz, 1H), δ 3.64 ̃3.31 (m, 7H)
(6S,9aS) 2-allyl-8-(3-bromo-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 7.42 ̃7.32 (m, 4H) δ 7.30 ̃7.14 (m, 5H) δ 6.99 ̃6.63 (m, 4H) δ 6.34 (s, 1H) δ 5.63 ̃5.57 (m, 1H) δ 5.39 ̃5.32 (m, 2H) δ 5.16 (d, J=10.2 Hz, 1H) δ 4.91 (dd, J=18.3 Hz, J=15.4 Hz, 2H) δ 4.41 ̃4.36 (m, 4H) δ 3.46 (d, J=6.1 Hz, 2H) δ 3.41 (d, J=4.5 Hz, 2H) δ 3.35 (d, J=9.2 Hz, 2H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-phenyl-1H-indol-7-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 10.09 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.3 Hz, 2H), 7.40 ̃7.20 (m, 8H), 7.03 (t, J=7.5 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.53 (d, J=8.3 Hz, 2H), 6.43 (brs, OH), 5.51 (m, 1H), 5.42 ̃5.27 (m, 2H), 5.21 (m, 1H), 5.09 (d, J=10.2 Hz, 1H), 4.90 (d, J=17.0 Hz, 1H), 4.42 ̃4.20 (m, 3H), 3.40 ̃3.30 (m, 5H), 3.16 (d, J=17.0 Hz, 1H).
(6S,9aS) 2-allyl-8-(6-cyclopropyl-pyridin-2-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.49 (t, J=9.0 Hz, 1H), δ 7.39 ̃7.24 (m, 3H), δ 7.03 ̃6.92 (m, 4H), δ 6.85 (s, 1H), δ 6.73 (t, J=6.0 Hz, 1H), δ 6.63 (t, J=9.0 Hz, 2H), δ 5.70 ̃5.53 (m, 2H), δ 5.32 (t, J=6.0 Hz, 1H), δ 5.20 ̃5.10 (m, 2H), δ 4.83 (d, J=15.0 Hz, 1H), δ 4.48 ̃4.32 (m, 3H), δ 3.77 (t, J=12.0 Hz, 1H), δ 3.55 ̃3.29 (m, 1H), δ 2.01 ̃1.19 (m, 1H), δ 0.95 ̃0.93 (m, 4H)
(6S,9aS) 2-allyl-8-[2,3]bipyridinyl-6-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 9.13 (s, 1H), δ 8.56 (d, J=3.0 Hz, 1H), δ 8.27 (d, J=6.0 Hz, 1H), δ 7.76 (t, J=6.0 Hz, 1H), δ 7.64 (d, J=9.0 Hz, 1H), δ 7.39 ̃7.19 (m, 6H), δ 6.92 (d, J=9.0 Hz, 2H), δ 6.66 (t, J=6.0 Hz, 1H), δ 6.58 (d, J=9.0 Hz, 2H), δ 5.60 ̃5.55 (m, 2H), δ 5.44 (dd, J=3.0 Hz, J=12.0 Hz, 1H), δ 5.31 (t, J=6.0 Hz, 1H), δ 5.19 (d, J=9.0 Hz, 1H), δ 5.09 (d, J=15.0 Hz, 1H), δ 4.99 (dd, J=15.0 Hz, J=27.0 Hz, 2H), δ 4.45 ̃4.25 (m, 2H), δ 3.76 (t, J=12.0 Hz, 1H), δ 3.58 ̃3.26 (m, 7H)
CWP232066
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[2-(2-methoxy-phenyl)-pyridin-3-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.61 (d, J=4.7 Hz, 1H), δ 7.22 ̃7.58 (m, 9H), δ 6.92 ̃7.07 (m, 4H), δ 6.92 ̃6.95 (m, 3H), δ 5.05 ̃5.65 (m, 1H), δ 5.41 (d, J=8.0 Hz, 1H), δ 5.19 ̃5.29 (m, 1H), δ 5.12 (t, J=11.0 Hz, 1H), δ 4.81 ̃5.07 (m, 2H), δ 4.62 (q, J=15.2 Hz, 1H), δ 4.27 ̃4.45 (m, 2H), δ 3.73 (d, J=13.7 Hz, 3H), δ 3.03 ̃3.48 (m, 7H), δ 2.89 ̃2.93 (m, 1H)
(6S,9aS) 2-allyl-8-(2-cyclopropyl-pyridin-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.41 (d, J=3.6 Hz, 1H), δ 7.25 ̃7.41 (m, 7H), δ 7.00 ̃7.06 (m, 3H), δ 6.65 ̃6.71 (m, 3H), δ 6.29 (s, 1H), δ 5.49 ̃5.64 (m, 1H) δ 5.48 (dd, J=10.5 Hz, J=3.9 Hz 1H), δ 5.35 (t, J=5.5 Hz, 1H), δ 5.06 ̃5.20 (m, 2H), δ 4.92 (d, J=17.2 Hz, 1H), δ 4.45 (d, J=15.0 Hz, J=5.9 Hz, 1H), δ 4.35 (dd, J=15.0 Hz, J=5.9 Hz, 1H), δ 3.30 ̃3.51 (m, 7H), δ 3.18 (dd, J=11.7 Hz, J=3.2 Hz, 1H), δ 2.02 ̃2.18 (m, 1H), δ 1.14 ̃1.23 (m, 1H), δ 0.93 ̃1.02 (m, 3H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-hydroxy-phenyl)-pyridin-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.82 (d, J=9.0 Hz, 2H), δ 7.66 (t, J=9.0 Hz, 1H), δ 7.51 (d, J=9.0 Hz, 1H), δ 7.38 ̃7.22 (m, 4H), δ 7.05 (d, J=6.0 Hz, 1H), δ 6.99 (d, J=9.0 Hz, 4H), δ 6.84 (d, J=9.0 Hz, 2H), δ 6.73 (t, J=6.0 Hz, 1H), δ 6.63 (d, J=9.0 Hz, 2H), δ 5.67 ̃5.51 (m, 2H), δ 5.44 (t, J=6.0 Hz, 1H), δ 5.06 (d, J=9.0 Hz, 1H), δ 4.41 ̃4.36 (m, 2H), δ 3.85 (t, J=12.0 Hz, 1H), δ 3.53 ̃3.25 (m, 7H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[6-(3-methoxy-phenyl)-pyridin-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.75 ̃7.53 (m, 5H), δ 7.37 ̃7.22 (m, 6H), δ 7.15 (d, J=9.0 Hz, 1H), δ 7.01 (d, J=6.0 Hz, 2H), δ 6.93 (d, J=9.0 Hz, 1H), δ 6.73 (t, J=6.0 Hz, 1H), δ 6.64 (d, J=9.0 Hz, 2H), δ 5.70 ̃5.56 (m, 2H), δ 5.39 (t, J=6.0 Hz, 1H), δ 5.07 ̃4.89 (m, 3H), δ 4.57 (d, J=15.0 Hz, 1H), δ 4.41 ̃4.37 (m, 2H), 3.93 ̃3.84 (m, 4H), δ 3.53 ̃3.26 (m, 7H)
(6S,9aS) 2-allyl-8-(3-cyano-1H-indol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 10.75 (s, 1H), 7.72 (m, 2H), 7.36 ̃7.04 (m, 6H), 6.83 (d, J=8.4 Hz, 2H), 6.73 (t, J=6.0 Hz, 1H), 6.50 (d, J=8.4 Hz, 2H), 5.59 (m, 1H), 5.42 (t, J=6.5 Hz, 1H), 5.24 (t, J=5.7 Hz, 1H), 5.14 (m, 1H), 5.10 (d, J=17.1 Hz, 1H), 4.50 ̃4.27 (m, 3H), 3.42 ̃3.20 (m, 8H)
(6S,9aS) 2-allyl-8-(1-benzenesulfonyl-3-cyano-1H-indol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.25 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H), 7.35 ̃7.15 (m, 7H), 6.96 (d, J=8.3 Hz, 2H), 6.92 (d, J=7.8 Hz, 1H), 5.73 (s, 1H), 5.57 (m, 1H), 5.45 (dd, J=1039, 3.5 Hz, 1H), 5.32 (t, J=5.4 Hz, 1H), 5.21 ̃5.00 (m, 3H), 4.75 (d, J=16.2 Hz, 1H), 4.30 (ddd, J=36.6, 15.2, 6.4 Hz, 2H), 3.50 ̃3.25 (m, 7H), 3.0 (dd, J=12.2, 3.6 Hz, 1H).
(6S,9aS) 2-allyl-8-[2,3′]bipyridinyl-3-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.65 (d, J=2.0 Hz, 1H), δ 8.54 ̃8.59 (m, 2H), δ 7.75 (d, J=7.9 Hz, 1H), 7.12 ̃7.39 (m, 8H), δ 6.88 (d, J=8.4 Hz, 2H), δ 6.55 ̃6.60 (m, 3H), δ 5.46 ̃5.56 (m, 1H), δ 5.31 (dd, J=10.7 Hz, J=3.9 Hz, 1H), δ 5.17 (t, J=5.2 Hz, 1H), δ 5.07 (d, J=10.3 Hz, 1H), δ 4.96 (d, J=17.2 Hz, 1H), δ 4.83 (d, J=15.8 Hz, 1H), δ 4.45 (d, J=15.7 Hz, 1H), δ 4.31 (dd, J=14.9 Hz, J=6.0 Hz, 1H), δ 4.21 (dd, J=14.9 Hz, J=6.0 Hz, 1H), δ 3.17 ̃3.41 (m, 7H), δ 2.88 (dd, J=11.5 Hz, J=3.9 Hz, 1H). MS ESI 618.2 (M+H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-pyridin-3-yl-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 8.88 (s, 1H) δ 8.63 (d, J=5.3 Hz, 1H) δ 7.93 (d, J=6.3 Hz, 1H) δ 7.48 (d, J=5.7 Hz, 1H) δ 7.46 ̃7.39 (m, 4H) δ 7.36 ̃7.26 (m, 5H) δ 7.22 ̃6.94 (m, 4H) δ 6.65 (s, 1H) δ 6.55 (d, J=11.2 Hz, 1H) δ 5.65 ̃5.55 (m, 2H) δ 5.26 (s, 1H) δ 4.50 ̃4.14 (dd, J=7.1 Hz, J=5.9 Hz, 2H) δ 4.82 (d, J=10.6 Hz, 1H) δ 4.01 (d, J=15.2 Hz, 1H) δ 3.58 ̃3.47 (m, 2H) δ 3.42 ̃3.35 (m, 2H) δ 3.31 ̃3.17 (m, 2H)
(6S,9aS) 2-allyl-8-[2-(3-cyano-phenyl)-pyridin-3-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.62 (d, J=4.2 Hz, 1H), δ 7.79 s, 1H), δ 7.70 (d, J=8.0 Hz, 3H), δ 7.55 (t, J=7.7 Hz, 1H), δ 7.45 (d, J=7.8 Hz, 1H), δ 7.21 ̃7.38 (m, 5H), δ 6.95 (d, J=8.3 Hz, 1H), δ 6.60 ̃6.69 (m, 3H), δ 6.09 (s, 1H), δ 5.56 ̃5.66 (m, 1H), δ 5.33 (dd, J=10.5 Hz, J=3.6 Hz, 1H), δ 5.24 (t, J=5.2 Hz, 1H), δ 5.16 (d, J=10.3 Hz, 1H), δ 5.05 (d, J=17.1 Hz, 1H), δ 4.85 (d, J=15.7 Hz, 1H), δ 4.50 (d, J=15.7 Hz, 1H), δ 4.40 (dd, J=14.9 Hz, J=5.9 Hz, 1H), δ 4.29 (dd, J=14.9 Hz, J=5.9 Hz, 1H), δ 3.25 ̃3.49 (m, 6H), δ 2.94 (dd, J=11.6 Hz, J=3.9 Hz, 1H). MS ESI 642.2 (M+H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-[2-(3-methoxy-phenyl)-pyridin-3-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 8.60 (d, J=2.7 Hz, 1H), δ 7.46 (d, J=18.9 Hz, 1H), δ 7.20 ̃7.37 (m, 7H), δ 6.94 ̃7.03 (m, 5H), δ 6.59 ̃6.63 (m, 2H), δ 6.55 ̃6.60 (m, 3H), δ 6.24 (t, J=6.5 Hz, 1H), δ 5.63 ̃5.77 (m, 3H), 5.15 ̃5.23 (m, 2H), δ 4.80 (dd, J=15.5 Hz, J=5.5 Hz, 1H), δ 4.29 ̃4.67 (m, 4H), δ 3.83 (d, J=4.3 Hz, 3H), δ 3.16 ̃3.42 (m, 6H), δ 2.79 (dd, J=11.5 Hz, J=3.9 Hz, 1H).
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-pyridin-4-yl-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 8.69 (d, J=6 Hz, 2H) δ 7.57 (d, J=6 Hz, 2H) δ 7.52 ̃7.33 (m, 4H) δ 7.31 ̃7.29 (m, 5H) δ 7.26 ̃6.96 (m, 4H) δ 6.72 (s, 1H) δ 6.57 (d, J=8.2 Hz, 1H) δ 5.58 ̃5.56 (m, 2H) δ 5.38 (d, J=7.1 Hz, 1H) δ 5.17 ̃5.01 (dd, J=11.8 Hz, J=17.1 Hz, 2H) δ 4.75 ̃4.31 (m, 4H) δ 3.50 (d, J=5.3 Hz, 2H) δ 3.46 ̃3.41 (m, 2H) δ 3.35 (d, J=9.2 Hz, 2H)
(6S,9aS) 2-allyl-8-[6-(3,3-dimethyl-but-1-ynyl)-pyridin-2-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.60 (t, J=9.0 Hz, 1H), δ 7.41 ̃7.25 (m, 5H), δ 7.08 (d, J=9.0 Hz, 1H), δ 7.02 (d, J=9.0 Hz, 2H), δ 6.73 (t, J=6.0 Hz, 1H), δ 6.66 (d, J=9.0 Hz, 2H), δ 5.65 ̃5.53 (m, 2H), δ 5.32 (t, J=6.0 Hz, 1H), δ 5.25 ̃5.20 (m, 2H), δ 4.42 ̃4.37 (m, 2H), δ 3.80 (t, J=12.0 Hz, 1H), δδ 3.60 ̃3.29 (m, 7H), δ 1.33 (s, 9H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(1-propyl-1H-indol-3-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.66 (d, J=7.5 Hz, 1H), 6.97-7.39 (m, 9H), 6.59-6.69 (m, 3H), 5.79 (s, 1H), 5.52 (m, 1H), 5.18-5.30 (m, 3H), 5.01 (d, J=10.8 Hz, 1H), 4.75 (d, J=17.4 Hz, 1H), 4.31-4.43 (m, 3H), 4.04 (t, J=6.3 Hz, 2H), 3.20-3.41 (m, 8H), 1.85 (q, J=7.5 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H)
Acetic acid 2-{3-[(6S,9aS) 2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-indol-1-yl}-ethyl ester
1H NMR (CDCl3, 300 MHz) δ 7.66 (d, J=7.8 Hz, 1H) 6.96-7.36 (m, 9H), 6.58-6.68 (m, 3H), 6.73 (s, 1H), 5.50-5.56 (m, 1H), 5.24-5.34 (m, 2H), 5.06 (m, 2H), 4.81 (d, J=17.1 Hz, 1H), 4.56 (d, J=14.7 Hz, 1H), 4.28-4.45 (m, 6H), 3.22-3.44 (m, 8H), 2.00 (s, 3H)
(6S,9aS) 2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(2-phenyl-pyrimidin-4-ylmethyl)-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 8.75 (d, J=5.0 Hz, 1H), 8.42 ̃8.39 (m, 2H), 7.47 ̃7.45 (m, 3H), 7.39 ̃7.25 (m, 5H), 7.04 (d, J=5.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.73 (t, J=4.0 Hz, NH), 6.62 (d, J=8.4 Hz, 2H), 6.52 ̃6.46 (brs, OH), 5.69 ̃5.56 (m, 2H), 5.40 (t, J=5.6 Hz, 1H), 5.12 (d, J=10.1 Hz, 1H), 5.00 (d, J=17.2 Hz, 1H), 4.88 (d, J=16.1 Hz, 1H), 4.58 (d, J=16.1 Hz, 1H), 4.60 ̃4.33 (m, 2H), 3.92 (t, J=11.3 Hz, 1H), 3.60 ̃3.33 (m, 7H)
(6S,9aS) 2-allyl-7-(2-amino-pyrimidin-4-ylmethyl)-5-(4-hydroxy-benzyl)-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3): δ 8.18 (d, J=5.1 Hz, 1H), 7.40 ̃7.23 (m, 5H), 6.83 (d, J=8.3 Hz, 2H), 6.73 (t, J=6.0 Hz, NH), 6.59 (d, J=8.4 Hz, 2H), 6.46 (d, J=5.1 Hz, 1H), 5.75 ̃5.62 (m, 1H), 5.56=5.46 (brs, NH2), 5.36 (dd, J=8.1 Hz 5.5 Hz, 1H), 5.23 ̃5.17 (m, 3H), 5.01 (d, J=16.3 Hz, 1H), 4.49 ̃4.25 (m, 2H), 3.91 (d, J=16.2 Hz, 1H), 3.70 ̃3.37 (m, 7H), 3.29 (dd, J=13.8 Hz 5.6 Hz, 1H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-thiophen-3-yl-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, TFA-d) δ 7.53 ̃7.47 (m, 3H) δ 7.32 ̃7.27 (m, 4H) δ 7.10 ̃7.02 (m, 5H) δ 6.97 ̃6.94 (m, 4H) δ 6.65 ̃6.62 (m, 3H) δ 5.52 ̃5.51 (m, 2H) δ 5.24 ̃5.21 (m, 1H) δ 5.07 (d, J=10.3 Hz, 2H) δ 4.60 (d, J=15.1 Hz, 2H) δ 3.72 (d, J=18.2 Hz, 2H) δ 3.58 ̃3.54 (m, 2H) δ 3.49 (s, 2H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-pyridin-2-yl-benzyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 8.68 (d, J=5.1 Hz, 1H) δ 7.91 (d, J=11.2 Hz, 2H) δ 7.75 (d, J=11.2 Hz, 2H) δ 7.46 (t, J=8.5 Hz, 1H) δ 7.29 ̃7.22 (m, 5H) δ 7.38 ̃7.33 (m, 2H) δ 7.00 ̃6.97 (m, 2H) δ 6.68 (t, J=6.3 Hz, 1H) δ 6.62 ̃6.59 (m, 3H) δ 5.57 ̃5.53 (m, 1H) δ 5.00 ̃4.96 (dd, J=4.3 Hz, J=7.2 Hz, 2H) δ 4.41 ̃4.33 (dd, J=6.2 Hz, J=6.3 Hz, 2H) δ 3.45 ̃3.37 (m, 6H)
(6S,9aS) 2-allyl-8-(3′-cyano-biphenyl-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3): δ3.23-3.29 (m, 4H), 3.31 ̃3.44 (m, 4H), 4.24 (dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.35 (dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.49 (d, J=14.8 Hz, 1H), 4.77 (d, J=14.8 Hz, 1H), 4.91 (d, J=17 Hz, 1H), 5.05 (d, J=10.3 Hz, 1H), 5.28 (t, J=5.5 Hz, 1H), 5.38-5.41 (m, 1H), 5.52-5.58 (m, 1H), 6.53 (d, J=8.3 Hz, 2H), 6.66 (t, J=6 Hz, NH), 6.90 (d, J=8.3 Hz, 2H), 7.18-7.24 (m, 4H), 7.29 (dd, J=7.9 Hz, J=15.4 Hz, 1H), 7.38-7.43 (m, 3H), 7.47-7.52 (m, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.80 (s, 1H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(3′-methoxy-biphenyl-3-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 7.51 ̃7.40 (m, 4H) δ 7.37 ̃7.30 (m, 5H) δ 7.24 ̃7.22 (m, 4H) δ 7.19 ̃6.88 (m, 4H) 6.65 (s, 1H) δ 6.56 (d, J=9.0 Hz, 1H) δ 5.658 ̃5.556 (m, 2H) δ 5.63 ̃5.54 (m, 1H) δ 5.323 ̃5.306 (m, 2H) δ 4.97 ̃4.81 (dd, J=17.1 Hz, J=15.7 Hz, 2H) δ 4.40 ̃4.30 (m, 2H) δ 3.85 (s, 3H) δ 3.43 (d, J=10.3 Hz, 2H) δ 3.39 ̃3.35 (m, 2H) δ 3.31 ̃3.25 (m, 2H)
(6S,9aS) 2-allyl-6-(4-hydroxy-benzyl)-8-(2′-methoxy-biphenyl-3-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 7.47 ̃7.37 (m, 4H) δ 7.35 ̃7.29 (m, 5H) δ 7.28 ̃7.15 (m, 4H) δ 7.05 ̃6.96 (m, 4H) δ 6.69 (t, J=6.3 Hz, 1H) δ 6.59 (d, J=9.2 Hz, 2H) δ 5.55 ̃5.46 (m, 2H) δ 5.10 ̃5.04 (m, 2H) δ 4.40 ̃4.34 (m, 2H) δ 4.31 ̃4.27 (m, 2H) δ 3.77 (s, 3H) δ 3.41 (d, J=7.1 Hz, 2H) δ 3.35 (d, J=6.6 Hz, 2H) δ 3.30 ̃3.24 (dd, J=5.4 Hz, J=4.7 Hz, 2H)
(6S,9aS) 8-(3-Acetylbenzyl)-2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (300 MHz, CDCl3) δ 2.60 (s, 3H), 3.24-3.52 (m, 9H), 4.31 (dd, J=6.0, 14.7 Hz, 1H), 4.42 (dd, J=6.0, 14.7 Hz, 1H), 4.57 (d, J=14.7 Hz, 1H), 4.80 (d, J=14.7 Hz, 1H), 5.03 (d, J=17.4 Hz, 1H), 5.14 (d, J=10.8 Hz, 1H), 5.33 (t, J=6.0 Hz, 1H), 5.43 (dd, J=4.2, 10.8 Hz, 1H), 5.55-5.66 (m, 1H), 6.62 (d, J=8.4 Hz, 2H), 6.70 (t, J=6.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 7.22-7.32 (m, 5H), 7.34-7.39 (m, 2H), 7.44-7.49 (m, 2H), 7.83 (s, 1H), 7.88 (ddd, J=1.5, 11.5 Hz, 1H)
(6S,9aS) 2-allyl-8-[3-(6-fluoro-pyridin-3-yl)-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H-NMR (300 MHz, CDCl3) δ 8.44 (d, J=4.0 Hz, 1H) δ 8.02 ̃7.96 (m, 1H) δ 7.44 ̃7.35 (m, 4H) δ 7.31 ̃7.16 (m, 9H) δ 7.04 ̃7.01 (m, 1H) δ 6.60 (s, 1H) δ 6.55 (d, J=8.2 Hz, 1H) δ 5.29 ̃5.25 (m, 2H) δ 5.67 ̃5.58 (m, 1H) δ 5.15 ̃5.03 (m, 4H) δ 4.42 ̃4.25 (m, 2H) δ 3.45 (s, 2H) δ 3.37 ̃3.31 (dd, J=6.1 Hz, J=5.6 Hz, 2H) δ 3.26 ̃3.21 (dd, J=4.2 Hz, J=3.8 Hz, 2H)
(6S,9aS) 2-allyl-8-[1-benzenesulfonyl-2-(2-fluoro-phenyl)-3-methyl-1H-indol-7-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
1H NMR (CDCl3, 300 MHz) δ 7.42-7.47 (m, 1H), 6.97-7.36 (m, 17H), 6.66-6.71 (m, 4H), 4.94-5.63 (m, 7H), 4.25-4.43 (m, 2H), 3.28-3.48 (m, 7H), 2.38 (s, 1H)
2-allyl-6-(4-hydroxy-benzyl)-8-(2′-hydroxy-biphenyl-3-ylmethyl)-4,7-dioxo hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.806 ̃7.765 (t, J=6.2 Hz, 1H), δ 7.462 ̃7.433 (d, J=8.5 Hz, 2H), δ 7.351 ̃7.289 (m, 3 H), δ 7.234 ̃7.165 (t, J=6.4 Hz, 3H), δ 7.144 ̃7.119 (d, J=7.5 Hz, 1H), δ 7.045 ̃7.020 (d, J=7.6 Hz, 1H), δ 6.941 ̃6.915 (d, J=7.9 Hz, 1H), δ 6.873 ̃6.830 (t, J=6.6 Hz, 2H), δ 6.558 ̃6.531 (d, J=8.3 Hz, 2H), δ 5.848 ̃5.747 (m, 1H), δ 5.419 ̃5.271 (dd, J=3.9 Hz, J=3.8 Hz, 1H), δ 5.064 ̃5.014 (d, J=9.2 Hz, 2H), δ 4.795 ̃4.746 (d, J=14.8 Hz, 1H), δ 4.381 ̃4.331 (d, J=14.9 Hz, 1H), δ 4.290 ̃4.127 (dd, J=6.6 Hz, J=6.6 Hz, 2H), δ 3.651 ̃3.438 (m, 4H), δ 3.292 (s, 8H), δ 3.126 ̃3.108 (d, J=5.4 Hz, 2H)
3′-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-biphenyl-3-carboxylic acid




1H NMR (CDCl3): δ 8.237 (s, 1H), δ 8.076δ8.055 (d, J=3.6 Hz, 1H), δ 7.788δ7.644 (d, J=7.2 Hz, 1H), δ 7.750 (s, 2H), δ 7.431 ̃7.383 (t, J=7.2 Hz, 2H), 7.311 ̃7.232 (m, 6H), δ 7.201 ̃6.161 (t, J=6.1 Hz, 3H), δ 6.946 ̃6.919 (d, J=8.0 Hz, 2H), δ 6.690 ̃6.656 (t, J=5.1 Hz, 1H), δ 5.594 ̃5.569 (d, J=7.8 Hz, 2H), 5.564 (m, 1H), δ 5.325 ̃5.232 (m, 2H), δ 5.118 ̃5.083 (d, J=10.4 Hz, 1H), δ 5.021 ̃4.964 (d, J=17.1 Hz, 1H), δ 4.815 ̃4.520 (dd, J=15.5 Hz, J=15.5 Hz, 2H), δ 4.356 ̃4.341 (d, J=4.7 Hz, 2H), δ 3.500 ̃3.243 (m, 8H)
2-allyl-8-(3-carbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.506 (s, 1H), δ 7.821 ̃7.796 (d, J=7.6 Hz, 1H), δ 7.604 (s, 1H), δ 7.469 ̃7.379 (m, 3H), δ 7.346 ̃7.320 (m, 2H), δ 7.234 ̃7.210 (d, J=6.9 Hz, 2H), δ 7.010 (s, 1H), δ 6.9166.888 (d, J=8.5 Hz, 3H), δ 6.766 ̃6.737 (d, J=8.5 Hz, 2H), δ 6.570 ̃6.530 (t, J=6.0 Hz, 1H), 5.810 ̃5.755 (d, J=16.6 Hz, 1H), δ 5.715 ̃5.581 (m, 1H), δ 5.213 ̃5.163 (m, 3H), δ 4.873 ̃4.832 (dd, J=6.5 Hz, J=6.5 Hz, 1H), δ 3.892 ̃3.837 (d, J=16.6 Hz, 1H), δ 3.633 ̃3.576 (d, J=17.2 Hz, 2H), δ 3.504 ̃3.283 (m, 6H)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(6-methoxy-pyridin-3-yl)-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.427 ̃8.419 (d, J=2.2 Hz, 1H), δ 8.846 ̃8.809 (dd, J=2.5 Hz, J=2.5 Hz, 2H), 7.438 ̃7.368 (m, 4H), δ 7.321 ̃7.218 (m, 7H), δ 7.166 ̃7.145 (d, J=6.4 Hz, 1H), δ 6.989 ̃6.961 (d, J=8.4 Hz, 2H), δ 6.891 ̃6.862 (d, J=8.6 Hz, 1H), δ 6.682 ̃6.654 (d, J=8.4 Hz, 2H), δ 6.585 ̃6.546 (t, J=5.7 Hz, 1H), δ 5.682 ̃5.591 (dd, J=10.3 Hz, J=10.3 Hz, 1H), 5.423 ̃5.371 (d, J=15.4 Hz, 1H), δ 5.277 ̃5.247 (t, J=3.6 Hz, 1H), 5.171 ̃5.133 (d, J=11.4 Hz, 2H), δ 4.883 ̃4.835 (dd, J=3.9 Hz, J=3.9 Hz, 1H), δ 4.504 ̃4.432 (dd, J=6.8 Hz, J=6.8 Hz, 1H), δ 4.218 ̃4.105 (m, 2H), δ 4.045 (s, 3H) δ 3.573 ̃3.516 (dd, J=3.1 Hz, J=3.1 Hz, 1H), δ 3.492 ̃3.464 (d, J=8.5 Hz, 2H) δ 3.420 ̃3.309 (m, 3H) δ 3.223 ̃3.172 (dd, J=3.8 Hz, J=3.8 Hz, 1H)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(6-morpholin-4-yl-pyridin-3-yl)-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1.2.4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.30 (s, 1H), δ 7.390 ̃7.314 (m, 3H), δ 7.250 ̃7.213 (m, 11H), δ 7.129 (s, 2H), δ 7.078 ̃7.059 (d, J=5.6 Hz, 3H), δ 6.933 ̃6.905 (d, J=8.5 Hz, 3H), δ 6.741 ̃6.711 (d, J=8.9 Hz, 2H), δ 6.620 ̃6.592 (d, J=8.4 Hz, 3H), δ 6.516 ̃6.476 (t, J=6.0 Hz, 1H), δ 5.581 (m, 1H), δ 5.492 ̃5.442 (d, J=15.5 Hz, 2H), δ 5.520 ̃5.186 (m, 1H), δ 5.126 ̃5.039 (t, J=16.9 Hz, 3H), δ 4.745 ̃4.698 (dd, J=3.5 Hz, J=3.5 Hz, 1H), δ 4.461 ̃4.390 (dd, J=6.6 Hz, J=6.6 Hz, 1H), δ 4.159 ̃4.092 (dd, J=5.4 Hz, J=5.4 Hz, 1H), δ 4.002 ̃3.950 (d, J=15.5 Hz, 1H) δ 3.840 ̃3.808 (m, 3H), δ 3.546 ̃3.489 (m, 7H) δ 3.460 ̃3.418 (t, J=6.2 Hz, 6H) δ 3.365 ̃3.134 (m, 10H)
2-allyl-8-(3′-carbamoyl-biphenyl-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.043 ̃8.018 (d, J=7.6 Hz, 1H), δ 7.802 (s, 1H), δ 7.737 ̃7.711 (d, J=7.8 Hz, 1H), δ 7.621 ̃7.536 (m, 2H), δ 7.492 ̃7.345 (m, 4H), δ 7.260 (s, 7H), δ 7.142 ̃7.118 (d, J=7.1 Hz, 2H), δ 7.075 (s, 1H), δ 6.921 ̃6.893 (d, J=8.4 Hz, 2H), δ 6.651 ̃6.611 (t, J=6.0 Hz, 1H), δ 6.450 ̃6.422 (d, J=8.4 Hz, 2H), δ 6.257 (s, 1H), δ 5.819 ̃5.765 (d, J=16.1 Hz, 2H), δ 5.697 ̃5.638 (m, 1H), δ 5.251 ̃5.201 (m, 3H), δ 5.050 (s, 1H), δ 4.398 ̃4.170 (dd′dd, J=6.6 Hz, J=6.6 Hz, J=5.9 Hz, J=5.9 Hz, 2H), δ 3.929 ̃3.875 (d, J=16.1 Hz, 1H), δ 3.647 ̃3.381 (m, 8H)
6-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-pyridine-2-carboxylic acid ethyl ester




1H NMR (CDCl3): δ 8.030 ̃8.005 (d, J=7.1 Hz, 1H), δ 7.842 ̃7.791 (t, J=7.7 Hz, 1H), δ 7.393 ̃7.237 (m, 8H), δ 7.013 ̃6.986 (d, J=8.4 Hz, 2H), δ 6.744 ̃6.705 (t, J=5.9 Hz, 1H), δ 6.652 ̃6.624 (d, J=8.4 Hz, 2H), δ 6.096 (s, 1H), δ 5.705 ̃5.539 (m, 2H), δ 5.350 ̃5.312 (t, J=5.6 Hz, 1H), δ 5.209 ̃5.152 (m, 2H), δ 4.890 ̃4.720 (dd, J=15.4 Hz, J=15.4 Hz, 2H), δ 4.472 ̃4.307 (m, 4H), δ 3.900 ̃3.825 (t, J=11.4 Hz, 1H), δ 3.617 ̃3.300 (m, 7H), δ 2.171 (s, 2H), δ 1.424 ̃1.377 (t, J=3.3 Hz, 3H)
2-allyl-8-(5-carbamoyl-pyridin-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.977 (s, 1H), δ 8.634 (s, 1H), δ 7.623 (s, 1H), δ 7.419 ̃7.304 (m, 4H), δ 7.262 (s, 2H), δ 7.216 ̃7.193 (d, J=7.0 Hz, 2H), δ 6.884 ̃6.856 (d, J=8.4 Hz, 2H), δ 6.695 ̃6.667 (d, J=8.4 Hz, 2H), δ 6.619 ̃6.578 (t, J=6.0 Hz, 1H), 6.406 (s, 1H), δ 5.775 ̃5.720 (d, J=16.4 Hz, 1H), δ 5.709 ̃5.596 (m, 1H), 5.240 ̃5.185 (m, 3H), 4.808 ̃4.764 (dd, J=6.8 Hz, J=6.8 Hz, 1H), δ 4.421 ̃4.155 (dd'dd, J=5.8 Hz, J=5.8 Hz, J=5.8 Hz, J=5.8 Hz, 2H), δ 3.899 ̃3.845 (d, J=16.3 Hz, 1H), δ 3.504 ̃3.283 (m, 7 II) δ 3.232 ̃3.183 (dd, J=3.0 Hz, J=3.0 Hz, 1H),
2-allyl-6-(4-hydroxy-benzyl)-8-(3-methoxycarbamoyl-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.845 ̃8.819 (d, J=7.6 Hz, 1H), δ 7.504 ̃7.208 (m, 5H), δ 7.261 ̃7.233 (m, 4H), δ 6.925 ̃6.897 (d, J=8.4 Hz, 3H), δ 6.777 ̃6.749 (d, J=8.4 Hz, 2H), δ 6.636 ̃6.595 (t, J=6.1 Hz, 1H), δ 5.849 ̃5.794 (d, J=16.6 Hz, 1H), δ 5.697 ̃5.584 (m, 1H), δ 5.226 (s, 1H), δ 5.190 ̃5.172 (d, J=5.6 Hz, 2H), δ 4.647 ̃4.603 (dd, J=2.7 Hz, J=2.7 Hz, 1H), δ 4.507 ̃4.124 (dd′dd, J=6.9 Hz, T=6.9 Hz, J=6.9 Hz, J=6.9 Hz, 2H), 3.789 (s, 3H), δ 3.680 ̃3.243 (dd'dd, J=2.9 Hz, J=2.9 Hz, J=2.9 Hz, J=2.9 Hz, 2H), δ 3.547 (s, 1H), δ 3.503 ̃3.404 (m, 5H)
2-allyl-6-(4-hydroxy-benzyl)-8-(3-hydroxycarbamoyl-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.714 (s, 1H), δ 7.365 ̃7.318 (t, J=6.7 Hz, 3H), δ 7.260 (m, 10H), δ 6.910 ̃6.778 (m, 4H), δ 6.708 (s, 1H), δ 6.543 (s, 1H), δ 5.847 ̃5.792 (d, J=16.6 Hz, 1H), δ 5.701 ̃5.579 (m, 1H), 5.213 ̃5.174 (d, J=11.7 Hz, 4H), δ 4.846 ̃4.814 (d, J=8.2 Hz, 1H), δ 4.436 ̃4.147 (dd, J=12.5 Hz, J=12.5 Hz, 2H), δ 3.771 ̃3.713 (d, J=17.5 Hz, 2H), δ 3.645 ̃3.210 (dd, J=16.5 Hz, J=16.5 Hz, 4H), δ 3.484 ̃3.216 (m, 7H)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(2-hydroxy-ethylcarbamoyl)-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.883 ̃7.868 (d, J=8.5 Hz, 1H), δ 7.465 ̃7.269 (m, 6H), δ 7.225 (s, 4H), δ 7.176 ̃7.152 (d, J=8.5 Hz, 2H), δ 7.049 (s, 1H), δ 6.660 ̃6.502 (dd, J=2.7 Hz, J=2.7 Hz, 4H), δ 5.704 ̃5.570 (m, 1H), δ 5.503 ̃5.451 (d, J=6.1 Hz, 1H), δ 5.262 (s, 1H), δ 5.221 ̃5.089 (dd, J=2.7 Hz, J=2.7 Hz, 2H), δ 4.817 ̃4.772 (dd, J=2.7 Hz, J=2.7 Hz, 1H), δ 4.376 ̃4.199 (dd′dd, J=6.9 Hz, J=6.9 Hz, J=6.9 Hz, J=6.9 Hz, 2H), δ 4.159 (s, 1H), δ 3.816 ̃3.178 (m, 13H)
2-allyl-8-(3-cyano-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.603 ̃7.568 (m, 1H), δ 7.436 (s, 1H), δ 7.376 ̃7.352 (d, J=8.4 Hz, 2H), δ 7.326 ̃7.303 (d, J=6.8 Hz, 1H), δ 7.260 (s, 3H), δ 7.237 (s, 1H), δ 6.991 ̃6.963 (d, J=10.3 Hz, 2H), δ 6.712 ̃6.684 (d, J=17.1 Hz, 2H), δ 5.659 ̃5.637 (m, 1H), δ 5.332 ̃5.280 (m, 2H), 5.211 ̃5.177 (d, J=15.1 Hz, 1H), δ 5.116 ̃5.059 (d, J=5.4 Hz, 1H), δ 4.784 ̃4.734 (d, J=5.9 Hz, 1H), δ 4.486 ̃4.382 (dd, J=7.1 Hz, J=7.1 Hz, 2H), δ 4.158 ̃4.086 (dd, J=6.6 Hz, J=6.6 Hz, 1H), δ 3.534 ̃3.334 (m, 7H), δ 3.226 ̃3.174 (dd, J=3.9 Hz, J=3.9 Hz, 1H)
6-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-pyridine-2-carboxylic acid




1H NMR (CDCl3): δ 8.065 ̃8.041 (d, J=7.4 Hz, 1H), δ 7.973 ̃7.922 (t, J=7.8 Hz, 1H), δ 7.415 ̃7.389 (d, J=7.6 Hz, 1H), δ 7.344 ̃7.201 (m, 5H), δ 6.940 ̃6.912 (d, J=8.4 Hz, 2H), δ 6.657 ̃6.629 (d, J=8.4 Hz, 2H), δ 5.853 ̃5.762 (m, 1H), δ 5.466 ̃5.418 (dd, J=3.8 Hz, J=3.8 Hz, 1H), δ 5.253 ̃5.102 (m, 3H), δ 4.921 ̃4.619 (dd, J=15.8 Hz, J=15.8 Hz, 2H), 4.317 (s, 2H), δ 4.129 ̃4.057 (dd, J=7.2 Hz, J=7.2 Hz, 1H), δ 3.995 ̃3.919 (t, J=11.5 Hz, 1H), δ 3.679 ̃3.552 (m, 3H), δ 3.391 ̃3.223 (m, 7H)
(6S,9aS)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-8-((6-carbamoylpyridin-2-yl)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 8.190 ̃8.165 (d, J=7.5 Hz, 1H), 8.055 (m, 1H), 7.900 ̃7.849 (t, J=7.5 Hz, 1H), 7.472 ̃7.447 (d, J=7.5 Hz, 1H), 7.397 ̃7.372 (d, J=7.5 Hz, 1H), 7.335 ̃7.311 (d, 7.5 Hz, 1H), 7.271 ̃7.247 (m, 4H), 6.636 ̃6.596 (t, J=6.0 Hz, 1H), 6.575 ̃6.547 (d, J=8.4 Hz, 2H), 6.477 ̃6.449 (d, J=8.4 Hz, 2H), 5.897 (m, 1H), 5.724 ̃5.666 (m, 1H), 5.264 ̃5.145 (m, 4H), 4.973 ̃4.926 (dd, J=3.6, 10.5 Hz, 1H), 4.46 ̃4.39 (dd, J=6.0 Hz, 1H), 4.34 ̃4.27 (dd, J=6.0 Hz, 1H), 4.030 ̃4.021 (d, J=3.6 Hz, 1H), 3.996 ̃3.928 (m, 1H), 3.778 ̃3.705 (t, J=11.1 Hz, 1H), 3.705 ̃3.383 (m, 5H), 3.302 ̃3.238 (dd, J=5.4, 13.5 Hz, 1H)
(6S,9aS)-8-(3-(6-chloropyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 8.632 ̃8.624 (d, J=2.4 Hz, 1H), 7.888 ̃7.852 (dd, J=2.4, 8.1 Hz, 1H), 7.461 ̃7.252 (m, 12H), 7.10 (s, 1H), 6.956 ̃6.928 (d, J=8.4 Hz, 2H), 6.607 ̃6.579 (m, 3H), 5.671 ̃5.580 (m, 1H), 5.288 ̃5.256 (t, J=5.4 Hz, 1H), 5.188 ̃5.024 (m, 4H), 4.474 ̃4.403 (dd, J=6.3, 14.7 Hz, 1H), 4.353 ̃4.302 (d, J=15.3 Hz, 1H), 4.251 ̃4.202 (dd, J=6.3, 14.7 Hz, 1H), 3.530 ̃3.217 (m, 8H)
(6S,9aS)-8-(3 ̃cyano-4-fluorobenzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.465 ̃7.146 (m, 13H), 6.960 ̃6.938 (d, J=6.6 Hz, 2H), 6.725 ̃6.668 (m, 4H), 6.371 ̃6.338 (m, 1H), 4.786 ̃4.736 (d, J=1.5 Hz, 1H), 4.437 ̃4.341 (m, 3H), 3.554 ̃3.299 (m, 8H), 3.232 ̃3.167 (tt, J=3.9, 8.1 Hz, 1H)
(6S,9aS)-8-(3-(1H-tetrazol-5-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.953 ̃7.927 (d, J=7.8 Hz, 1H), 7.890 (m, 1H), 7.502 ̃7.451 (t, J=7.8 Hz, 1H), 7.321 ̃7.183 (m, 6H), 6.890 ̃6.862 (d, J=7.8 Hz, 2H), 6.569 ̃6.541 (d, J=7.8 Hz, 2H), 5.797 ̃5.663 (m, 1H), 5.315 ̃5.266 (dd, J=3.9, 10.8 Hz, 1H), 5.228 ̃5.194 (t, J=4.8 Hz, 1H), 5.035 ̃4.964 (m, 2H), 4.808 ̃4.759 (d, J=14.7 Hz, 1H), 4.604 ̃4.554 (d, J=14.7 Hz, 1H), 4.270 (m, 2H), 3.720 ̃3.644 (t, J=11.4 Hz, 1H), 3.560 ̃3.504 (m, 3H), 3.344 ̃3.209 (m, 4H)
(6S,9aS)-8-(3-(2-methoxypyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 8.180 ̃8.157 (dd, J=1.8, 5.1 Hz, 2H), 7.626 ̃7.595 (dd, J=1.8, 5.1 Hz, 2H), 7.514 ̃7.141 (m, 13H), 7.001 ̃7.960 (m, 3H) m, 6.711 ̃6.671 (t, J=6.0 Hz, 1H), 6.598 ̃6.570 (m, 2H), 6.481 (m, 1H), 5.676 ̃5.519 (m, 1H), 5.424 ̃5.375 (dd, J=4.2, 10.5 Hz, 1H), 5.336 ̃5.299 (t, J=5.7 Hz, 1H), 5.110 ̃5.074 (d, J=10.5 Hz, 1H), 4.980 ̃4.915 (m, 2H), 4.469=4.286 (m, 4H), 3.947 (s, 3H), 3.470 ̃3.246 (m, 9H)
(6S,9aS)-6-(4-hydroxy-benzyl)-2-allyl-8-((3-aminobenzo[d]isoxazol-5-yl)methyl)-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.442 ̃7.225 (m, 9H), 6.827 ̃6.800 (d, J=8.1 Hz, 2H), 6.777 ̃6.739 (t, J=8.1 Hz, 1H), 6.608 ̃6.580 (d, J=8.1 Hz, 2H), 5.733 ̃5.568 (m, 1H), 5.228 ̃5.019 (m, 5H), 4.432 ̃4.251 (m, 3H), 4.159 ̃4.088 (dd, J=7.2, 14.4 Hz, 1H), 3.582 ̃3.272 (m, 9H)
(6S,9aS)-8-(3-(N-Boc hyhdrazinic carbonyl))benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 9.446 (s, 1H), 7.910 (m, 1H), 7.492 ̃7.245 (m, 5H), 7.010 (s, 1H), 6.708 ̃6.624 (m, 3H), 6.589 ̃6.528 (t, J=6.3 Hz, 1H), 5.734 ̃5.578 (m, 2H), 5.236 ̃5.127 (m, 3H), 4.830 ̃4.799 (d, J=6.3 Hz, 1H), 4.531 ̃4.457 (q, J=7.2 Hz, 1H), 4.143 ̃4.081 (dd, J=3.9, 14.4 Hz, 1H), 3.820 ̃3.767 (d, J=15.9 Hz, 1H), 3.585 ̃3.299 (m, 7H), 1.384 (s, 9H)
(6S,9aS)-8-(3-(piperidine-1-carbonyl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.407 ̃7.178 (m, 10H), 6.949 ̃6.921 (d, J=8.4 Hz, 2H), 6.854 (m, 1H), 6.680 ̃6.633 (m, 3H), 5.669 ̃5.578 (m, 1H), 5.298 ̃5.050 (m, 4H), 4.705 ̃4.580 (m, 2H), 4.440 ̃4.369 (dd, J=6.3, 15.3 Hz, 1H), 4.350 ̃4.280 (dd, J=6.3, 15.3 Hz, 1H), 3.749 ̃3.360 (m, 2H), 3.500 ̃3.169 (m, 10H), 1.778 (m, 3H), 1.669 (m, 4H), 1.492 (m, 2H)
(6S,9aS)-8-(3-(pyrrolidine-1-carbonyl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.389 ̃7.195 (m, 12H), 6.920 ̃6.892 (d, J=8.4 Hz, 2H), 6.663 ̃6.635 (d, J=8.4 Hz, 2H), 5.635 ̃5.579 (m, 1H), 5.271 ̃5.240 (t, J=4.8 Hz, 1H), 5.175 ̃5.058 (m, 3H), 4.842 ̃4.792 (d, J=1.5 Hz, 1H), 4.466 ̃4.272 (m, 3H), 3.675 ̃3.632 (t, J=6.3 Hz, 2H), 3.506 ̃3.168 (m, 11H), 1.928 (m, 2H), 1.846 (m, 2H), 1.669 (m, 4H)
(6S,9aS)-8-(3-(2-fluoropyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 8.201 ̃8.185 (d, J=4.8 Hz, 1H), 7.909=7.845 (m, 1H), 7.512=7.223 (m, 10H), 6.983 ̃6.955 (d, J=8.4 Hz, 2H), 6.742 ̃6.702 (t, J=6.0 Hz, 1H), 6.634 ̃6.606 (d, J=8.4 Hz, 2H), 5.666 ̃5.419 (m, 2H), 5.351 ̃5.315 (t, J=4.8 Hz, 1H), 5.127 ̃5.092 (d, J=10.5 Hz, 1H), 4.999 ̃4.946 (d, J=10.5 Hz, 1H), 4.463 ̃4.291 (m, 3H), 3.490 ̃3.278 (m, 7H)
(9aS)-8-(2-(1H-tetrazol-1-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.623 ̃7.573 (t, J=7.5 Hz, 1H), 7.518 ̃7.470 (t, J=7.5 Hz, 1H), 7.392 ̃7.230 (m, 7H), 6.930 ̃6.902 (d, J=8.4 Hz, 2H), 6.779 ̃6.739 (t, J=6.0 Hz, 1H), 6.676 ̃6.658 (d, J=8.4 Hz, 2H), 5.659 ̃5.602 (m, 1H), 5.407 ̃5.359 (dd, J=6.3, 10.5 Hz, 1H), 5.237 ̃5.113 (m, 3H), 4.694 ̃4.641 (d, J=15.9 Hz, 1H), 4.397 ̃4.293 (m, 3H), 3.552 ̃3.155 (m, 7H)
(6S,9aS)-8-(3-(benzylcarbamoyl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.830 ̃7.805 (d, J=7.5 Hz, 1H), 7.760 ̃7.714 (m, 1H), 7.447 ̃7.014 (m, 12H), 6.847 ̃6.817 (dd, J=2.7, 6.3 Hz, 2H), 6.629 ̃6.601 (m, 2H), 6.553 ̃6.512 (t, J=6.0 Hz, 1H), 5.700 ̃5.582 (m, 1H), 5.534 ̃5.480 (d, J=16.2 Hz, 1H), 5.205 ̃5.024 (m, 4H), 4.279 ̃4.212 (dd, J=4.5, 16.3 Hz, 1H), 4.070 ̃3.879 (m, 3H), 3.636 ̃3.311 (m, 7H)
(6S,9aS)-8-(3-(2-oxo-1,2-dihydropyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide




1H NMR (CDCl3): δ 7.620 ̃7.555 (m, 2H), 7.504 (m, 1H), 7.390 ̃7.166 (m, 6H), 6.905 ̃6.878 (d, J=8.1 Hz, 2H), 6.698 ̃6.659 (t, J=6.0 Hz, 1H), 6.599 ̃6.571 (d, J=8.1 Hz, 2H), 6.334 ̃6.289 (t, J=6.0 Hz, 1H), 5.667 ̃5.533 (m, 1H), 5.295 ̃5.024 (m, 4H), 4.828 ̃4.779 (d, J=14.7 Hz, 1H), 4.486 ̃4.437 (d, J=14.7 Hz, 1H), 4.332 ̃4.290 (t, J=6.3 Hz, 2H)
2-allyl-6-(4-hydroxy-benzyl)-8-(6-methylcarbamoyl-pyridin-2-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 8.205 ̃8.180 (d, J=7.7 Hz, 1H), 7.892 ̃7.840 (t, J=7.8 Hz, 1H), 7.469 ̃7.271 (m, 7H), 6.646 ̃6.604 (t, J=6.1 Hz, 1H), 6.481 ̃6.453 (d, J=8.5 Hz, 2H), 6.381 ̃6.352 (d, J=8.5 Hz, 2H), 5.813 ̃5.701 (td, J=10.2 Hz, J=6.5 Hz, 1H), 5.679 ̃5.119 (m, 4H), 4.961 ̃4.914 (dd, J=3.7 Hz, J=10.6 Hz, 1H), 4.498 ̃4.317 (qd, J=15.0 Hz, J=6.2 Hz, 2H), 4.167 ̃4.117 (dd, J=3.7 Hz, J=11.1 Hz, 1H), 3.927 ̃3.222 (m, 9H), 2.983 ̃2.966 (d, J=4.3 Hz, 3H)
2-allyl-6-(4-hydroxy-benzyl)-8-(3-methylcarbamoyl-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.796 ̃7.770 (d, J=7.6 Hz, 1H), 7.444 ̃7.221 (m, 9H), 6.911 (s, 1H), 6.827 ̃6.799 (d, J=8.5 Hz, 2H), 6.648 ̃6.620 (d, J=8.5 Hz, 2H), 5.813 ̃5.701 (td, J=11.0 Hz, J=6.3 Hz, 1H), 5.623 ̃5.569 (d, J=16.1 Hz, 1H), 5.246 ̃5.191 (m, 4H), 5.050 ̃5.006 (dd, J=3.0 Hz, J=10.3 Hz, 1H), 4.461 ̃4.236 (qd, J=15.1 Hz, J=6.5 Hz, 2H), 3.938 ̃3.884 (d, J=16.1 Hz, 1H), 3.686 ̃3.314 (m, 8H), 2.949 ̃2.934 (d, J=4.7 Hz, 3H)
2-allyl-8-[3-(2,5-dihydro-pyrrole-1-carbonyl)-benzyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.421 ̃7.193 (m, 11H), 6.909 ̃6.881 (d, J=8.4 Hz, 2H), 6.652 ̃6.624 (d, J=8.5 Hz, 2H), 6.624 ̃6.582 (t, J=6.1 Hz, 1H), 5.623 ̃5.836 (dd, J=2.0 Hz, J=4.4 Hz, 1H), 5.673 ̃5.645 (m, 2H), 5.254 ̃5.222 (t, J=4.8 Hz, 1H), 5.168 ̃5.035 (m, 3H), 4.898 ̃4.848 (d, J=15.1 Hz, 1H), 4.455 ̃4.053 (m, 7H), 3.492 ̃3.150 (m, 8H)
2-allyl-8-(3-dimethylcarbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.4027.235 (m, 9H), 7.168 (s, 1H), 6.931 ̃6.914 (d, J=8.4 Hz, 2H), 6.658 ̃6.642 (d, J=8.4 Hz, 2H), 5.698 ̃5.589 (td, J=16.6 Hz, J=6.2 Hz, 1H), 5.278 ̃5.259 (t, J=4.8 Hz, 1H), 5.180 ̃5.078 (m, 3H), 4.806 ̃4.777 (d, J=15.0 Hz, 1H), 4.510 ̃4.480 (d, J=15.0 Hz, 1H), 4.418 ̃4.282 (qd, J=15.0 Hz, J=2.7 Hz, 2H), 3.530 ̃3.300 (m, 7H), 3.204 ̃3.173 (dd, J=3.8 Hz, J=11.7 Hz, 1H), 3.123 (s, 3H), 2.923 (s, 3H),
3-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-2-nitro-benzoic acid methyl ester




1H NMR (CDCl3): δ 7.961 ̃7.945 (d, J=7.6 Hz, 1H), 7.584 ̃7.552 (t, J=7.8 Hz, 1H), 7.480 ̃7.465 (d, J=7.6 Hz, 1H), 7.386 ̃7.238 (m, 6H), 6.986 ̃6.969 (d, J=8.3 Hz, 2H), 6.738 ̃6.714 (t, J=5.9 Hz, 1H), 6.665 ̃6.648 (d, J=8.3 Hz, 2H), 5.673 ̃5.618 (td, J=10.2 Hz, J=4.0 Hz, 1H), 5.430 ̃5.401 (dd, J=3.8 Hz, J=10.8 Hz, 1H), 5.332 ̃5.312 (t, J=5.2 Hz, 1H), 5.223 ̃5.149 (d, J=10.3 Hz, 1H), 5.183 ̃5.149 (d, J=17.1 Hz, 1H), 4.826 ̃4.795 (d, J=15.7 Hz, 1H), 4.442 ̃4.306 (m, 3H), 3.900 (s, 3H), 3.583 ̃3.474 (m, 4H), 3.403 ̃3.314 (m, 3H), 3.191 ̃3.159 (dd, J=3.9 Hz, J=11.7 Hz, 1H),
2-allyl-8-(1-carbamoylmethyl-1H-benzoimidazol-4-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.610 (s, 1H), 7.321 ̃7.220 (m, 5H), 7.132 ̃7.117 (d, J=7.4 Hz, 2H), 6.878 (s, 1H), 6.685 ̃6.662 (t, J=5.6 Hz, 1H), 6.635 ̃6.619 (d, J=7.9 Hz, 2H), 6.328 ̃6.313 (d, J=7.9 Hz, 2H), 6.223 (s, 1 H), 5.698 ̃5.619 (td, J=16.7 Hz, J=6.3 Hz, 1H), 5.391 ̃5.363 (d, J=14.2 Hz, 1H), 5.211 ̃5.154 (m, 3H), 4.543 (s, 2H), 4.455 ̃4.427 (d, J=14.3 Hz, 1H), 4.262 ̃4.153 (qd, J=15.3 Hz, J=6.1 Hz, 2H), 3.912 ̃3.894 (d, J=9.0 Hz, 1H), 6.635 ̃6.619 (t, J=11.0 Hz, 1H), 3.486 ̃3.345 (m, 4H), 3.201 ̃3.345 (dd, J=5.3 Hz, J=13.3 Hz, 1H),
2-allyl-8-(3-carbamoyl-2-nitro-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide




1H NMR (CDCl3): δ 7.655 ̃7.565 (m, 2H), 7.348 ̃7.565 (m, 6H), 6.939 ̃6.911 (d, J=8.5 Hz, 2H), 6.691 ̃6.663 (d, J=8.5 Hz, 2H), 5.861 ̃5.726 (td, J=16.8 Hz, J=6.4 Hz, 1H), 5.436 ̃5.388 (dd, J=3.7 Hz, J=10.7 Hz, 1H), 5.225 ̃4.976 (m, 4H), 4.342 ̃4.289 (m, 3H), 3.767 ̃3.692 (t, J=11.5 Hz, 1H)
{4-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazino[2,1-c][1,2,4]triazin-8-ylmethyl]-benzyl}-phosphonic acid




1H NMR (DMSO-D6): δ 8.176 (s, 3H), 7.805 ̃7.769 (t, J=5.6 Hz, 1H), 7.362 ̃7.189 (m, 7H), 7.031 ̃7.005 (d, J=7.5 Hz, 2H), 6.829 ̃6.801 (d, J=8.2 Hz, 2H), 6.551 ̃6.525 (d, J=8.2 Hz, 2H), 5.887 ̃5.751 (m, 1H), 5.267 ̃5.092 (m, 3H), 5.024 ̃4.992 (t, J=4.8 Hz, 2H), 4.910 ̃4.859 (d, J=15.4 Hz, 1H), 4.282 ̃4.152 (m, 2H), 4.038 ̃3.975 (m, 1H), 3.691 ̃3.487 (m, 4H), 3.286 ̃2.814 (m, 6H).
The libraries of the present invention were screened for bioactivity by various techniques and methods. In general, the screening assay may be performed by (1) contacting the mimetics of a library with a biological target of interest, such as a receptor, to allow binding between the mimetics of the library and the target to occur, and (2) detecting the binding event by an appropriate assay, such as the calorimetric assay disclosed by Lam et al. (Nature 354:82-84, 1991) or Griminski et al. (Biotechnology 12:1008-1011, 1994) (both of which are incorporated herein by reference). In a preferred embodiment, the library members are in solution and the target is immobilized on a solid phase. Alternatively, the library may be immobilized on a solid phase and may be probed by contacting it with the target in solution.
Inhibition activity against Wnt signaling was measured by the TopFlash reporter. The lower IC50 value means the higher inhibition activity. A compound can be classified as active if IC50 is 10 μM or below. When IC50 is 5 ̃10 μM, the compound can be a candidate for a pharmaceutical. A compound is deemed strong if IC50 is 1 ̃5 μM, and a compound is deemed very strong if IC50 is 1 μM or below.
Most of the compounds of the present invention showed IC50 of 5 μM or below, that means they have strong inhibition activity against Wnt signaling.
Table 3 below shows compounds for bioactivity test selected from the library of the present invention and IC50 values thereof, which were measured by the Reporter gene assay as described in Example 2.







TABLE 3







IC50 (μM) MEASURED BY TopFlash REPORTER GENE ASSAY OF SELECTED


LIBRARY COMPOUNDS












M.W.
RGA, IC50 (μM)


NO
Structure
Formula
TopF













1




800.92 C44H44N6O7S
 0.081 ± 0.0086


 


2




774.88 C42H42N6O7S
0.084 ± 0.016


 


3




620.70 C35H36N6O5
0.098 ± 0.014


 


4




646.73 C37H38N6O5
 0.14 ± 0.025


 


5




612.68 C33H36N6O6
0.16 ± 0.08


 


6




795.30 C41H39ClN6O7S
 0.18 ± 0.076


 


7




634.70 C36H35FN6O4
0.26 ± 0.08


 


8




634.70 C36H35FN6O4
0.27 ± 0.03


 


9




624.73 C35H40N6O5
0.30 ± 0.02


 


10




654.76 C39H38N6O4
0.30 ± 0.06


 


11




743.83 C40H37N7O6S
0.31 ± 0.09


 


12




616.71 C36H36N6O4
0.34 ± 0.12


 


13




753.65 C37H34N5Na2O8P
0.36 ± 0.13


 


14




735.66 C32H32N7Na2O7PS
0.37 ± 0.07


 


15




859.60 C32H31N7Na4O10P2S
0.37 ± 0.07


 


16




636.51 C31H31BrFN5O4
0.39 ± 0.05


 


17




585.72 C32H35N5O4S
0.42 ± 0.04


 


18




672.77 C39H40N6O5
0.42 ± 0.12


 


19




613.11 C33H33ClN6O4
0.43 ± 0.08


 


20




753.27 C39H37ClN6O6S
0.43 ± 0.10


 


21




613.71
0.45 ± 0.05


 


22




778.70 C39H37N6Na2O7P
0.45 ± 0.29


 


23




622.74 C34H34N6O4S
0.47 ± 0.13


 


24




734.68
0.48 ± 0.11


 


25




636.74 C36H40N6O5
0.52 ± 0.04


 


26




629.70 C37H35N5O5
 0.52 ± 0.048


 


27




794.92 C45H42N6O6S
0.52 ± 0.09


 


28




634.70 C36H35FN6O4
0.52 ± 0.06


 


29




699.78 C35H37N7O7S
0.53 ± 0.24


 


30




584.62 C31H32N6O6
0.54 ± 0.06


 


31




723.62 C33H36N5Na2O9P
0.54 ± 0.08


 


32




640.72
0.56 ± 0.07


 


33




634.70 C36H35FN6O4
0.56 ± 0.44


 


34




616.71 C36H36N6O4
 0.58 ± 0.132


 


35




719.65 C33H32N5Na2O7PS
 0.59 ± 0.066


 


36




595.71 C33H33N5O4S
0.59 ± 0.10


 


37




636.70 C34H36N8O5
0.60 ± 0.13


 


38




664.79 C38H44N6O5
0.61 ± 0.09


 


39




700.86
0.61 ± 0.19


 


40




631.72 C36H37N7O4
0.63 ± 0.06


 


41




683.58 C32H29Cl2FN6O4S
0.63 ± 0.09


 


42




709.66 C32H34N5Na2O7PS
 0.66 ± 0.0079


 


43




630.17
0.66 ± 0.06


 


44




638.71 C34H31FN6O4S
0.67 ± 0.05


 


45




668.77
0.67 ± 0.09


 


46




597.66 C33H35N5O6
0.69 ± 0.15


 


47




732.86
0.69 ± 0.19


 


48




597.66 C32H35N7O5
 0.7 ± 0.26


 


49




579.65 C32H33N7O4
0.71 ± 0.43


 


50




623.72 C33H33N7O4S
 0.72 ± 0.075


 


51




694.9
0.72 ± 0.15


 


52




618.52 C31H32BrN5O4
0.73 ± 0.09


 


53




678.80 C37H38N6O5S
0.73 ± 0.03


 


54




650.77 C37H42N6O5
0.74 ± 0.05


 


55




700.86
0.74 ± 0.08


 


56




672.77 C39H40N6O5
0.74 ± 1.46


 


57




582.26 C32H34N6O5
0.76 ± 0.12


 


58




605.63 C32H33F2N5O5
0.78 ± 0.13


 


59




640.72
0.78 ± 0.15


 


60




658.75 C38H38N6O5
0.79 ± 0.10


 


61




616.71 C36H36N6O4
0.80 ± 0.07


 


62




701.81 C40H43N7O5
0.81 ± 0.15


 


63




826.93 C46H43FN6O6S
0.82 ± 0.25


 


64




732.85 C40H40N6O6S
0.82 ± 0.33


 


65




578.66 C33H34N6O4
0.83 ± 0.22


 


66




652.82
0.84 ± 0.09


 


67




592.69 C34H36N6O4
 0.85 ± 0.089


 


68




610.74
0.86 ± 0.09


 


69




582.62 C32H31FN6O4
0.87 ± 0.32


 


70




686.77 C37H43FN6O6
0.9 ± 0.2


 


71




621.73 C35H39N7O4
 0.9 ± 0.08


 


72




621.75 C35H35N5O4S
0.90 ± 0.13


 


73




581.66 C33H35N5O5
0.90 ± 0.27


 


74




593.6 C31H30F3N5O4
0.91 ± 0.11


 


75




640.72
0.92 ± 0.14


 


76




636.74 C36H40N6O5
0.94 ± 0.04


 


77




782.64 C33H3OFN6Na2O9PS
0.94 ± 0.07


 


78




554.64 C31H34N6O4
0.95 ± 0.15


 


79




639.74 C36H41N5O6
0.95 ± 0.21


 


80




650.67 C32H29F3N6O4S
0.96 ± 0.13


 


81




646.74 C37H38N6O5
0.97 ± 0.18


 


82




630.74 C37H38N6O4
0.99 ± 0.14


 


83




620.70 C35H36N6O5
0.99 ± 0.24


 


84




594.66 C32H34N8O4
  1 ± 0.25


 


85




652.77
 1.0 ± 0.22


 


86




767.29 C40H39ClN6O6S
 1.0 ± 0.25


 


87




607.66 C34H33N5O6
1.01 ± 0.24


 


88




733.84 C39H39N7O6S
1.02 ± 0.11


 


89




625.76 C36H43N5O5
1.03 ± 0.11


 


90




625.71 C35H39N5O6
1.03 ± 0.16


 


91




640.73 C35H40N6O6
1.04 ± 0.18


 


92




703.59 C32H32N7Na2O7P
1.04 ± 0.18


 


93




661.67 C34H34F3N7O4
1.07 ± 0.2 


 


94




746.66 C35H37N6Na2O8P
1.09 ± 0.16


 


95




580.68 C33H36N6O4
1.10 ± 0.12


 


96




608.73 C35H40N6O4
1.11 ± 0.25


 


97




582.62 C32H31FN6O4
1.13 ± 0.05


 


98




646.74 C37H38N6O5
1.17 ± 0.15


 


99




736.82 C39H44N8O7
1.17 ± 0.27


 


100




610.74
1.21 ± 0.14


 


101




678.82 C39H46N6O5
1.24 ± 0.07


 


102




596.68 C33H36N6O5
1.25 ± 0.21


 


103




628.72 C33H33FN6O4S
1.26 ± 0.19


 


104




634.75 C31H31FN6O4S2
1.27 ± 0.10


 


105




760.26 C38H38ClN5O8S
1.27 ± 0.24


 


106




666.77 C37H42N6O6
1.28 ± 0.10


 


107




620.72 C30H29FN6O4S2
1.3 ± 0.2


 


108




580.68 C33H36N6O4
1.31 ± 0.33


 


109




626.7 C34H38N6O6
1.35 ± 0.15


 


110




877.21 C39H36ClN6Na2O9PS
1.39 ± 0.36


 


111




638.75
1.41 ± 0.21


 


112




732.67 C35H39N6Na2O7P
1.41 ± 0.21


 


113




596.68 C33H36N6O5
1.41 ± 0.38


 


114




650.77 C37H42N6O5
1.42 ± 0.51


 


115




631.72 C37H37N5O5
1.43 ± 0.27


 


116




620.74 C36H40N6O4
1.43 ± 0.26


 


117




604.10 C32H34ClN5O5
1.44 ± 0.22


 


118




679.79 C36H37N7O5S
1.47 ± 0.19


 


119




749.70 C36H42N5Na2O8P
1.51 ± 0.16


 


120




587.64 C32H34FN5O5
1.51 ± 0.34


 


121




646.74 C37H38N6O5
1.53 ± 0.17


 


122




617.14 C33H37ClN6O4
1.54 ± 0.07


 


123




595.69 C34H37N5O5
1.55 ± 0.21


 


124




619.62 C32H31F2N5O6
1.56 ± 0.33


 


125




619.51 C30H31BrN6O4
1.57 ± 0.29


 


126




640.73 C38H36N6O4
1.58 ± 0.27


 


127




645.75 C38H39N5O5
1.61 ± 0.31


 


128




658.79 C39H42N6O4
1.61 ± 0.59


 


129




648.55 C32H34BrN5O5
1.64 ± 0.27


 


130




690.83 C40H46N6O5
1.66 ± 0.18


 


131




642.66 C33H34N6O8
1.66 ± 0.27


 


132




564.63 C32H32N6O4
1.71 ± 0.28


 


133




743.56 C32H30F2N5Na2O9P
1.73 ± 0.22


 


134




646.74 C37H38N6O5
1.73 ± 0.35


 


135




696.84 C39H48N6O6
1.77 ± 0.15


 


136




719.63 C34H36N5Na2O8P
1.83 ± 0.32


 


137




645.75 C38H39N5O5
1.86 ± 0.30


 


138




728.04 C32H33ClN5Na2O8P
1.86 ± 0.38


 


139




653.77 C37H43N5O6
1.89 ± 0.38


 


140




645.75 C38H39N5O5
1.91 ± 0.24


 


141




634.70 C36H35FN6O4
1.91 ± 0.28


 


142




652.77
1.92 ± 0.28


 


143




651.79 C38H45N5O5
1.93 ± 0.18


 


144




615.72 C37H37N5O4
1.94 ± 0.48


 


145




595.69 C34H37N5O5
1.96 ± 0.27


 


146




631.72 C37H37N5O5
1.99 ± 0.12


 


147




619.11 C32H35ClN6O5
1.99 ± 0.32


 


148




632.71 C36H36N6O5
10.01 ± 1.7 


 


149




565.66 C33H35N5O4
10.13 ± 2.38 


 


150




681.86 C40H51N5O5
10.15 ± 1.55 


 


151




668.71 C32H34F2N6O6S
10.19 ± 2.3 


 


152




629.70 C34H39N507
10.78 ± 1.9 


 


153




583.64 C31H33N7O5
10.8 ± 1.97


 


154




625.76 C36H43N5O5
11.8 ± 0.9 


 


155




667.79
11.85 ± 1.61 


 


156




632.71 C36H36N6O5
12.16 ± 2.02 


 


157




620.72 C33H32N8O3S
12.41 ± 2.36 


 


158




632.68 C32H30F2N6O4S
12.47 ± 2.66 


 


159




620.74 C36H40N6O4
14.05 ± 2.30 


 


160




597.66 C32H35N7O5
14.23 ± 2.05 


 


161




761.93 C40H51N5O8S
14.42 ± 2.77 


 


162




638.74 C33H34N8O4S
15.10 ± 3.34 


 


163




651.84 C39H49N5O4
15.67 ± 1.87 


 


164




607.66 C32H33N9O4
15.69 ± 3.22 


 


165




646.74 C37H38N6O5
17.21 ± 4.11 


 


166




672.75 C39H37FN6O4
17.54 ± 5.57 


 


167




724.61 C32H35N6Na2O9P
19.41 ± 3.40 


 


168




583.64 C31H33N7O5
2.01 ± 0.20


 


169




595.69 C34H37N5O5
2.01 ± 0.34


 


170




714.23 C37H36ClN5O6S
2.07 ± 0.43


 


171




732.67 C35H39N6Na2O7P
2.10 ± 0.34


 


172




792.73 C37H43N6Na2O9P
2.21 ± 0.35


 


173




696.84 C39H48N6O6
2.26 ± 0.16


 


174




732.85 C40H40N6O6S
2.33 ± 0.64


 


175




599.68 C33H37N5O6
2.36 ± 0.57


 


176




617.70 C35H35N7O4
2.37 ± 0.22


 


177




619.51 C30H31BrN6O4
2.37 ± 0.35


 


178




856.79 C40H39N6Na2O9PS
2.38 ± 0.75


 


179




662.80 C37H38N6O4S
2.42 ± 0.32


 


180




646.73 C37H38N6O5
2.42 ± 0.47


 


181




632.73 C32H36N6O6S
2.47 ± 0.37


 


182




612.68 C33H36N6O6
2.48 ± 0.22


 


183




596.68 C33H36N6O5
52.5 ± 0.32


 


184




623.70 C35H37N5O6
2.56 ± 0.29


 


185




638.75
2.61 ± 0.19


 


186




616.71 C36H36N6O4
2.66 ± 0.74


 


187




655.75 C38H37N7O4
2.67 ± 0.28


 


188




617.72 C32H35N5O6S
2.67 ± 0.59


 


189




636.74 C36HN6O5
2.68 ± 0.48


 


190




676.74 C32H36N8O7S
2.79 ± 0.24


 


191




641.72 C37H35N7O4
2.81 ± 0.52


 


192




599.66 C30H29N7O5S
2.85 ± 0.79


 


193




587.64 C321134FN5O5
2.86 ± 0.49


 


194




612.68 C33H36N6O6
2.89 ± 0.50


 


195




653.76
20.91 ± 3.94 


 


196




589.63 C32H33F2N5O4
21.2 ± 2.15


 


197




611.69 C33H37N7O5
21.77 ± 3.69 


 


198




617.70 C35H35N7O4
22.25 ± 5.69 


 


199




692.85 C39H48N8O4
25.9 ± 3.38


 


200




790.99
25.92 ± 4.72 


 


201




653.76
26.10 ± 7.10 


 


202




689.21
28.76 ± 5.69 


 


203




725.57 C33H36N5O6
3.03 ± 0.36


 


204




713.78 C40H39N7O6
3.13 ± 0.44


 


205




579.65 C32H33N7O4
3.14 ± 0.68


 


206




610.74
3.18 ± 0.75


 


207




582.65 C32H34N6O5
3.25 ± 0.41


 


208




646.74 C37H38N6O5
3.27 ± 0.80


 


209




605.69 C34H35N7O4
 3.3 ± 0.58


 


210




697.78 C37H43N707
3.57 ± 0.89


 


211




732.85 C40H40N6O6S
3.61 ± 0.47


 


212




652.74 C36H40N6O6
3.62 ± 0.63


 


213




683.80 C40H41N7O4
3.62 ± 0.65


 


214




611.73 C35H41N5O5
3.72 ± 0.47


 


215




595.65 C32H33N7O5
3.75 ± 0.32


 


216




711.58 C32H33FN5Na2O8P
3.8 ± 1.1


 


217




617.70 C35H35N7O4
3.87 ± 0.45


 


218




646.74 C37H38N6O5
3.96 ± 0.93


 


219




682.23 C37H36ClN5O4S
3.97 ± 0.57


 


220




840.95 C42H48N8O9S
33.10 ± 4.07 


 


221




623.74 C35H41N7O4
36.10 ± 2.69 


 


222




670.78 C35H38N6O6S
36.4 ± 2.0 


 


223




578.66 C33H34N6O4
4.01 ± 0.96


 


224




674.74 C34H35FN6O6S
4.3 ± 0.7


 


225




597.66 C32H35N7O5
 4.3 ± 0.67


 


226




701.81 C41H43N5O6
4.33 ± 0.50


 


227




898.83 C42H41N6Na2O10PS
4.33 ± 1.59


 


228




580.64
4.51 ± 0.72


 


229




661.73 C32H35N7O7S
4.78 ± 0.69


 


230




598.69 C34H38N4O6
4.83 ± 0.71


 


231




573.64 C30H28FN5O4S
4.85 ± 0.57


 


232




570.66 C30H30N6O4S
4.97 ± 0.73


 


233




598.65 C32H34N6O6
4.98 ± 0.69


 


234




631.14 C32H31ClN6O4S
40.2 ± 5.7 


 


235




675.60 C32H31BrN6O4S
40.7 ± 6.4 


 


236




595.73 C35H41N5O4
41.7 ± 4.2 


 


237




620.72 C33H32N8O3S
46.7 ± 6.13


 


238




620.74 C32H37FN6O4S
49.8 ± 4.8 


 


239




634.72 C36H38N6O5
5.09 ± 1.32


 


240




610.70 C34H38N6O5
5.41 ± 0.89


 


241




919.25 C41H38ClN6Na2O10PS
5.50 ± 2.4 


 


242




722.63 C34H37N4Na2O9P
5.80 ± 0.99


 


243




633.72 C31H35N7O6S
5.81 ± 0.58


 


244




628.63 C32H32N6O8
5.98 ± 1.03


 


245




628.72 C33H33FN6O4S
6.19 ± 0.73


 


246




688.83
6.59 ± 0.86


 


247




597.70 C34H39N5O5
6.66 ± 0.88


 


248




632.71 C36H36N6O5
6.71 ± 1.57


 


249




583.68 C33H37N5O5
6.8 ± 1.5


 


250




652.77
6.98 ± 1.45


 


251




618.63 C32H32F2N6O5
1.14 ± 0.07


 


252




679.74 C38H38FN5O6
7.05 ± 0.87


 


253




608.69 C34H36N6O5
7.10 ± 0.99


 


254




599.64
7.13 ± 1.35


 


255




639.70 C33H3OFN7O4S
7.17 ± 1.33


 


256




626.70 C34H38N6O6
7.20 ± 1.06


 


257




641.72 C37H35N7O4
7.26 ± 1.30


 


258




641.67 C33H35N707
7.51 ± 2.1 


 


259




600.63
7.62 ± 1.89


 


260




648.71 C35H36N8O5
8.43 ± 2.07


 


261




694.80 C37H38N6O6S
8.48 ± 0.90


 


262




600.66 C32H36N6O6
8.48 ± 1.37


 


263




627.71 C33H33N5O6S
9.09 ± 0.67


 


264




556.62 C29H32N8O4
9.11 ± 1.82


 


265




598.65 C32H34N6O6
 9.3 ± 0.53


 


266




857.78 C39H38N7Na2O9PS
9.43 ± 1.65


 


267




636.70 C34H36N8O5
6.63 ± 1.35









It has been found according to the present invention that compounds of general Formula (I) have less CYP3A4 inhibitory activity (higher IC50). The details of the less measurement of CYP3A4 inhibitory activity are disclosed in Example 1. Less CYP3A4 inhibitory activity means that the compounds of the present invention are more pharmacologically favorable in terms of adverse reactions.
Table 4 below shows compounds for bioactivity test selected from the library of the present invention and IC50 values thereof, which were measured by the P450 CYP3A4 Inhibitory Activity Screening as described in Example 1.







TABLE 4







IC50(μM) MEASURED BY P450 CYP3A4 INHIBITORY ACTIVITY 


SCREENING OF SELECTED LIBRARY COMPOUNDS













CYP3A4 inhibition,




M.W.
IC50 (μM)


NO
Structure
Formula
fluorescent assay













1




636.74 C36H40N6O5
5.00


 


2




596.68 C33H36N6O5
5.23


 


3




619.51 C30H31BrN6O4
5.33


 


4




618.69 C34H34N8O4
5.40


 


5




632.71 C36H36N6O5
5.84


 


6




694.80 C37H38N6O6S
6.78


 


7




692.85 C39H48N8O4
6.84


 


8




661.73 C32H35N7O7S
6.95


 


9




607.66 C34H33N5O6
6.95


 


10




632.71 C36H36N6O5
7.02


 


11




597.66 C33H35N5O6
7.58


 


12




636.74 C36H40N6O5
7.65


 


13




596.68 C33H36N6O5
8.00


 


14




621.73 C35H39N7O4
8.42


 


15




581.66 C33H35N5O5
8.79


 


16




701.79 C35H39N7O7S
9.00


 


17




666.77 C37H42N6O6
9.02


 


18




632.73 C32H36N6O6S
9.16


 


19




564.63 C32H32N6O4
9.65


 


20




652.74 C36H40N6O6
10.10


 


21




626.7  C34H38N6O6
10.20


 


22




610.70 C34H38N6O5
11.60


 


23




673.74 C32H35N9O6S
12.00


 


24




659.73 C38H37N5O6
12.90


 


25




597.66 C32H35N7O5
13.10


 


26




607.66 C32H33N9O4
13.50


 


27




640.69 C33H36N8O6
16.80


 


28




596.68 C33H36N6O5
17.90


 


29




487.55 C27H29N5O4
18.10


 


30




617.72 C32H35N5O6S
18.70


 


31




612.68 C33H36N6O6
18.90


 


32




641.72 C34H39N7O6
19.90


 


33




612.68 C33H36N6O6
24.20


 


34




618.7 C31H34N6O6S
24.50


 


35




676.74 C32H36N8O7S
26.40


 


36




595.71 C33H33N5O4S
26.7


 


37




597.66 C32H35N7O5
34.30


 


38




640.73 C35H40N6O6
34.60


 


39




611.69 C33H37N7O5
35.30


 


40




567.64 C31H33N7O4
39.10


 


41




612.68 C33H36N6O6
41.40Q


 


42




626.70 C34H38N6O6
44.10


 


43




627.65 C32H33N7O7
44.40


 


44




583.64 C31H33N7O5
45.10


 


45




661.67 C34H34F3N7O4
>10


 


46




623.7  C34H37N7O5
>50


 


47




594.66 C32H34N8O4
>50


 


48




567.64 C32H33N5O5
>50


 


49




633.69 C36H35N5O6
>50


 


50




652.52 C32H31Cl2N5O6
>50


 


51




756.71 C37H38N6Na2O9
>50


 


52




583.64 C31H33N7O5
>50


 


53




582.65 C32H34N6O5
>50


 


54




583.63 C32H33N5O6
>50


 


55




662.71 C32H34N6O8S
>50


 


56




584.62 C31H32N6O6
>50


 


57




633.63 C32H36N5O7P
>50


 


58




636.70 C34H36N8O5
>50


 


59




794.92 C45H42N6O6S
2.63


 


60




620.70 C35H36N6O5
4.84


 


61




646.73 C37H38N6O5
5.92









The present invention is also related to methods for preventing or treating an acute myeloid leukemia comprising administering to the subject the compound having Formula (I) above.
In one aspect, the present invention provides compounds that inhibit the formation of a complex of β-catenin, p300 and TCF binding onto c-Myc protein and formation of a complex of β-catenin, p300 and TCF binding onto survivin promoter.
In another aspect, the present invention provides compounds, in particular those having Formula (II), that control c-Myc protein.
It has been found according to the present invention that compounds of general Formula (I) affect the cell proliferation and inhibit the growth of AML cancer cells, as described in Example 3.
GI50 of MV-4-11 shows cell growth inhibition activity against AML cancer cells. The lower GI50 value means the higher inhibition activity. A compound can be classified as active if GI50 is 10 μM or below. When GI50 is 5 ̃10 μM, the compound can be a candidate for a pharmaceutical. A compound is deemed strong if GI50 is 1 ̃5 and a compound is deemed very strong if GI 50 is 1 uM or below.
Most of the compounds of the present invention showed GI50 of 5 μM or below, that means they have strong inhibition activity against AML cancer cells.
Table 5 below shows compounds for bioactivity test selected from the library of the present invention and GI50 values thereof, which were measured by Cell Growth Inhibition Assay) as described in Example 3.







TABLE 5







CELL GROWTH INHIBITION ACTIVITY (GI50) ON AML CANCER


CELLS OF SELECTED LIBRARY COMPOUNDS









NO
Structure
MV-4-11, GI50 (μM)












1




0.19


 


2




0.6


 


3




0.18


 


4




0.17


 


5




0.05


 


6




0.04


 


7




0.27


 


8




0.05


 


9




0.07


 


10




1.32


 


11




1.97


 


12




2.99


 


13




2.01


 


14




0.16


 


15




2.14


 


16




0.63


 


17




0.36


 


18




0.36


 


19




0.45


 


20




2.24


 


21




0.3


 


22




0.74


 


23




0.96


 


24




2.03


 


25




0.24


 


26




0.78


 


27




1.11


 


28




1.35


 


29




0.39


 


30




0.82


 


31




5.75


 


32




N.D upto 50 uM


 


33




0.65


 


34




1.25


 


35




1.12


 


36




0.9


 


37




0.24


 


38




0.18


 


39




0.96


 


40




0.27


 


41




1.56


 


42




0.64


 


43




0.31


 


44




0.55


 


45




2.79









The following non-limiting examples illustrate the compounds, and the use of this invention.
Preparation Example 1,
Preparation of (N-Fmoc-N′—R4-hydrazino)-acetic acid




(1) Preparation of N-Fmoc-N′-Methyl Hydrazine




2 L, two-neck, round-bottomed-flask was fitted with a glass stopper and a calcium tube. A solution of R4-hydrazine (20 g, 139 mmol, where R4 is methyl) in THF (300 mL) was added and a solution of DiBoc (33 g, 153 mmol) in THF was added. Saturated sodium bicarbonate aqueous solution (500 mL) was added dropwise via addition funnel over 2 hours with vigorous stirring. After 6 hours, a solution of Fmoc-Cl (39 g, 153 mmol) in THF was added slowly. The resulting suspension was stirred for 6 hours at 0° C. The mixture was extracted with ethyl acetate (EA, 500 mL) and the organic layer was retained. The solution was dried with sodium sulfate and evaporated in vacuo. The next step proceeded without purification.
A 1 L, two-necked, round-bottom-flask was fitted with a glass stopper and a calcium tube. A solution of the product from the previous step in MeOH (300 mL) was added and conc. HCl (30 mL, 12 N) was added slowly via addition funnel with magnetic stirring in ice water bath and stirred overnight. The mixture was extracted with EA (1000 mL) and the organic layer was retained. The solution was dried with sodium sulfate and evaporated in vacuo. The residue was purified by recrystallization with n-hexane and EA to give N-Fmoc-N′-methyl hydrazine (32.2 g, 83%). 1HNMR (DMSO-D6) δ 7.90 ̃7.88 (d, j=6 Hz, 2H,), δ 7.73 ̃7.70 (d, J=9 Hz, 2H,), 7.44 ̃7.31 (m, 4H), 4.52 ̃4.50 (d, J=6 Hz, 2H), 4.31 ̃4.26 (t, J=6 Hz, 1H), 2.69 (s, 1H).
(2) Preparation of (N-Fmoc-N′—R4-hydrazino)-acetic acid t-butyl ester




1 L, two-necked, round-bottom-flask was fitted with a glass stopper and reflux condenser connected to a calcium tube. A solution of N-Fmoc-N′—R4 hydrazine (20 g, 75 mmol) in toluene (300 mL) was added. A solution of t-butylbromo acetate (22 g, 111 mmol) in toluene (50 mL) was added slowly. Cs2CO3 (49 g, 149 mmol) was added slowly. NaI (11 g, 74 mmol) was added slowly with vigorous stirring. The reaction mixture was stirred at reflux temperature over 1 day. The product mixture was filtered and extracted with EA (500 mL). The solution was dried over sodium sulfate and evaporated in vacuo. The product was purified by chromatography with hexane:EA=2:1 solution to give (N-Fmoc-N′-methyl-hydrazino)-acetic acid t-butyl ester (19.8 g, 70%). 1H-NMR (CDCl3-d) δ 7.78 ̃7.75 (d, J=9 Hz, 2H,), δ 7.61 ̃7.59 (d, J=6 Hz, 2H,), 7.43 ̃7.26 (m, 4H), 4.42 ̃4.40 (d, J=6 Hz, 2H), 4.23 (b, 1H), 3.57 (s, 2H), 2.78 (s, 3H), 1.50 (s, 9H).
(3) Preparation of (N-Fmoc-N′-methyl-hydrazino)-acetic acid




1 L, two-neck, round-bottomed-flask was fitted with a glass stopper and reflux condenser connected to a calcium tube. (N-Fmoc-N′—R4-hydrazino)-acetic acid t-butyl ester (20 g, 52 mmol) was added. A solution of HCl (150 mL, 4 M solution in dioxane) was added slowly with vigorous stirring in an ice water bath. The reaction mixture was stirred at RT over 1 day. The solution was concentrated completely under reduced pressure at 40° C. A saturated aq. NaHCO3 solution (100 mL) was added and the aqueous layer was washed with diethyl ether (100 mL). Conc. HCl was added dropwise slowly at 0° C. (pH 2-3). The mixture was extracted and the organic layer was retained (500 mL, MC). The solution was dried with sodium sulfate and evaporated in vacuo. The residue was purified by recrystallization with n-hexane and ethyl acetate to give (N-Fmoc-N′-methyl-hydrazino)-acetic acid (12 g, 72%). 1H-NMR (DMSO-d6) δ 12.38 (s, 1H), 8.56 (b, 1H), 7.89 ̃7.86 (d, J=9 Hz, 2H,), 7.70 ̃7.67 (d, J=9 Hz, 2H,), 7.43 ̃7.29 (m, 4H), 4.29 ̃4.27 (d, J=6 Hz, 2H), 4.25 ̃4.20 (t, J=6 Hz, 1H), 3.47 (s, 2H), 2.56 (s, 3H).
Preparation Example 2
Title Compound:




To prepare the title compound, the General Scheme of Reverse-Turn Mimetic Library which is described in the above in this specification has been performed by the following scheme:




In the above scheme ‘Pol’ represents a bromoacetal resin (Advanced ChemTech) and detailed procedure is illustrated below.
Step 1
A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of 2-(4-(aminomethyl)-1H-benzo[d]imidazol-1-yl)acetamide in DMSO (1.4 mL) were placed in a Robbins block (FlexChem) having 96 well plates. The reaction mixture was shaken at 60° C. using a rotating oven [Robbins Scientific] for 12 hours. The resin was washed with DMF, MeOH, and then DCM
Step 2
A solution of commercial available Fmoc-Tyr(OtBu)-OH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.), and DIEA (12 equiv.) in DMF was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.
Step 3
To the resin swollen by DMF before reaction was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This deprotection step was repeated again and the resin was washed with DMF, Methanol, and then DCM. A solution of hydrazine acid (4 equiv.), HOBt (4 equiv.), and DIC (4 equiv.) in DMF was added to the resin and the reaction mixture was shaken for 12 hours at room temperature. The resin was washed with DMF, MeOH, and then DCM.
Step 4
The resin obtained in Step 3 was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under a reduced pressure using SpeedVac [SAVANT] to give the product as oil. The product was diluted with 50% water/acetonitrile and then lyophilized after freezing. 1H NMR (CDCl3): δ 7.610 (s, 1H), 7.321 ̃7.220 (m, 5H), 7.132 ̃7.117 (d, J=7.4 Hz, 2H), 6.878 (s, 1H), 6.685 ̃6.662 J=5.6 Hz, 1H), 6.635 ̃6.619 (d, J=7.9 Hz, 2H), 6.328 ̃6.313 (d, J=7.9 Hz, 2H), 6.223 (s, 1H), 5.698 ̃5.619 (td, J=16.7 Hz, J=6.3 Hz, 1H), 5.391 ̃5.363 (d, J=14.2 Hz, 1H), 5.211 ̃5.154 (m, 3H), 4.543 (s, 2H), 4.455 ̃4.427 (d, J=14.3 Hz, 1H), 4.262 ̃4.153 (qd, J=15.3 Hz, J=6.1 Hz, 2H), 3.912 ̃3.894 (d, J=9.0 Hz, 1H), 6.635 ̃6.619 (t, J=11.0 Hz, 1H), 3.486 ̃3.345 (m, 4H), 3.201 ̃3.345 (dd, J=5.3 Hz, J=13.3 Hz, 1H).
Preparation Example 3
Title Compound




To prepare the title compound, the General Scheme of Reverse-Turn Mimetic Library which is described in the above in this specification has been performed by the following scheme:




In the above scheme ‘Pol’ represents a bromoacetal resin (Advanced ChemTech) and detailed procedure is illustrated below.
Step 1
A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of 6-(aminomethyl)picolinamide in DMSO (1.4 mL) were placed in a Robbins block (FlexChem) having 96 well plates. The reaction mixture was shaken at 60° C. using a rotating oven [Robbins Scientific] for 12 hours. The resin was washed with DMF, MeOH, and then DCM
Step 2
A solution of commercial available Fmoc-Tyr(OtBu)-OH (4 equiv.), PyBob (4 equiv), HOAt (4 equiv), and DIEA (12 equiv) in DMF was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.
Step 3
To the resin swollen by DMF before reaction was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This deprotection step was repeated again and the resin was washed with DMF, Methanol, and then DCM. A solution of hydrazine acid (4 equiv), HOBt (4 equiv), and DIC (4 equiv) in DMF was added to the resin and the reaction mixture was shaken for 12 hours at room temperature. The resin was washed with DMF, MeOH, and then DCM.
Step 4
The resin obtained in Step 3 was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under a reduced pressure using SpeedVac [SAVANT] to give the product as oil. The product was diluted with 50% water/acetonitrile and then lyophilized after freezing.
1H NMR (CDCl3): δ 8.190 ̃8.165 (d, J=7.5 Hz, 1H), 8.055 (m, 1H), 7.900 ̃7.849 (t, J=7.5 Hz, 1H), 7.472 ̃7.447 (d, J=7.5 Hz, 1H), 7.397 ̃7.372 (d, J=7.5 Hz, 1H), 7.335 ̃7.311 (d, 7.5 Hz, 1H), 7.271 ̃7.247 (m, 4H), 6.636 ̃6.596 (t, J=6.0 Hz, 1H), 6.575 ̃6.547 (d, J=8.4 Hz, 2H), 6.477 ̃6449 (d, J=8.4 Hz, 2H), 5.897 (m, 1H), 5.724 ̃5.666 (m, 1H), 5.264 ̃5.145 (m, 4H), 4.973 ̃4.926 (dd, J=3.6, 10.5 Hz, 1H), 4.46 ̃4.39 (dd, J=6.0 Hz, 1H), 4.34 ̃4.27 (dd, J=6.0 Hz, 1H), 4.030 ̃4.021 (d, J=3.6 Hz, 1H), 3.996 ̃3.928 (m, 1H), 3.778 ̃3.705 (t, J=11.1 Hz, 1H), 3.705 ̃3.383 (m, 5H), 3.302 ̃3.238 (dd, J=5.4, 13.5 Hz, 1H)
Preparation Example 4
Title Compound




To prepare the title compound, the General Scheme of Reverse-Turn Mimetic Library which is described in the above in this specification has been performed by the following scheme:




In the above scheme ‘Pol’ represents a bromoacetal resin (Advanced ChemTech) and detailed procedure is illustrated below.
Step 1
A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of 3-(aminomethyl)benzamide in DMSO (1.4 mL) were placed in a Robbins block (FlexChem) having 96 well plates. The reaction mixture was shaken at 60° C. using a rotating oven [Robbins Scientific] for 12 hours. The resin was washed with DMF, MeOH, and then DCM
Step 2
A solution of commercial available Fmoc-Tyr(OtBu)-OH (4 equiv.), PyBob (4 equiv.), HOAt (4 equiv.), and DIEA (12 equiv.) in DMF was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.
Step 3
To the resin swollen by DMF before reaction was added 25% piperidine in DMF and the reaction mixture was shaken for 30 min at room temperature. This deprotection step was repeated again and the resin was washed with DMF, Methanol, and then DCM. A solution of hydrazine acid (4 equiv.), HOBt (4 equiv.), and DIC (4 equiv.) in DMF was added to the resin and the reaction mixture was shaken for 12 hours at room temperature. The resin was washed with DMF, MeOH, and then DCM.
Step 4
The resin obtained in Step 3 was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under a reduced pressure using SpeedVac [SAVANT] to give the product as oil. The product was diluted with 50% water/acetonitrile and then lyophilized after freezing.
1H NMR (CDCl3): δ 8.506 (s, 1H), δ 7.821 ̃7.796 (d, J=7.6 Hz, 1H), δ 7.604 (s, 1H), δ 7.469 ̃7.379 (m, 3H), δ 7.346 ̃7.320 (m, 2H), δ 7.234 ̃7.210 (d, J=6.9 Hz, 2H), δ 7.010 (s, 1H), δ 6.916 ̃6.888 (d, J=8.5 Hz, 3H), δ 6.766 ̃6.737 (d, J=8.5 Hz, 2H), δ 6.570 ̃6.530 (t, J=6.0 Hz, 1H), 5.810 ̃5.755 (d, J=16.6 Hz, 1H), δ 5.715 ̃5.581 (m, 1H), δ 5.213 ̃5.163 (m, 3H), δ 4.873 ̃4.832 (dd, J=6.5 Hz, J=6.5 Hz, 1H), δ 3.892 ̃3.837 (d, J=16.6 Hz, 1H), δ 3.633 ̃3.576 (d, J=17.2 Hz, 2H), δ 3.504 ̃3.283 (m, 6H)
Example 1
P450 CYP3A4 Inhibitory Activity Screening
Test Compounds:




Assay was conducted in a 200 μL volume in 96-well microtiter plates using cDNA-expressed human hepatic CYP3A4 (supersome, BD GentestTM #456202). 7-Benzyloxy-4-trifluoromethyl-coumarin (BFC) was used as a substrate for CYP3A4. Test articles and substrate BFC were dissolved in 100% acetonitrile. The final volume of acetonitrile in the incubation mixture was less than 1% (volume/volume). Potassium phosphate buffer (pH 7.4, final concentration 0.1 M), MgCl2 (final concentration 8.3 mM), EDTA (final concentration 1.67 mM), a test article stock solution, a CYP3A4 supersome and NADPH (final concentration 0.25 mM) were added to each well. The reaction was initiated by the addition of substrate (BFC, final concentration 30 M) after a 10 min pre-incubation at 37° C. After 10 min incubation at 37° C., the reaction was terminated by the addition of 75 μL of acetonitrile:0.5 M Tris-base=4:1 (volume/volume). Thereafter, Fluorescent signal was measured using a fluorometer. BFC metabolite, 7-hydroxy-4-trifluoromethyl-coumarin, was measured using an excitation wavelength of 409 nm and an emission wavelength of 530 nm. FIGS. 2A to 2E show IC50 of the test compounds of CYP3A4 inhibition assay. Compounds A to E showed weak inhibition of CYP3A4 enzyme.







TABLE 6







IC50 values of Compounds against CYP3A4 activity










Test Compound
IC50 (μM)














A
13.1



B
34.6



C
24.2



D
10.2



E
>10










Example 2
TopFlash Reporter Gene Bioassay for the Measurement of IC50 Against SW480 Cells
Test Compound:




SW480 cells were transfected with the usage of SuperfectTM transfect reagent (Qiagen, 301307). Cells were trypsinized briefly 1 day before transfection and plated on 6 well plate (5×105 cells/well) so that they were 50-80% confluent on the day of transfection.
Four microgram (TopFlash) and one microgram (pRL-null) of DNAs were diluted in 150 μl of serum-free medium, and 30 μl of SuperfectTM transfect reagent was added. The DNA-Superfect mixture was incubated at room temperature for 15 min, and then, 1 ml of 10% FBS DMEM was added to this complex for an additional 3 hours of incubation. While complexes were forming, cells were washed with PBS twice without antibiotics.
The DNA-SuperfectTM transfect reagent complexes were applied to the cells before incubating at 37° C. at 5% CO2 for 3 hours. After incubation, recovery medium with 10% FBS was added to bring the final volume to 1.18 ml. After 3 hours incubation, the cells were harvested and reseeded to a 96 well plate (3×104 cells/well). After overnight incubation at 37° C. at 5% CO2, the cells were treated with Compound F for 24 hours. Finally, the activity was checked by means of luciferase assay (Promega, E1960).
FIG. 3 illustrates the results of the measurement of IC50 of Compound F for SW480 cells. IC50 was 0.73±0.08 μM.
Example 3
Cell Growth Inhibition Activity on AML Cancer Cells (Cell Growth Inhibition Assay)
Test Compound:




Cell growth Inhibition assay was performed to investigate the rate of inhibition of cell proliferation by the test compounds. MV-4-11 (human, Acute Myeloid Leukemia cell line) cells were cultured in Iscove's modified Dulbecco's medium (IMDM) including 10% fetal bovine serum (FBS), 1× penicillin/streptomycin (10,000 units/ml Penicillin, 10,000 g/ml Streptomycin in 0.85% NaCl). MV-4-11 cells were harvested with IMDM medium and 5×104 cells/well were transferred to each well of 96 well culture plates (Nunc, #167008). The test compounds were treated with the serial dilution and duplicated for each concentration. For the serial dilution, the test compounds were repeatedly diluted with the same volume of media onto 96-well assay block (costar, #3956). After the dilution, each compound was added to each well. The background absorbance was also measured during the test compounds treatment by adding the IMDM media in replacement of test compound to the negative control plate. The plates were incubated for 3 days (72 hours) at 37° C. in the humidified incubator containing 5% CO2. On the last day, 20 μL of CellTiter 96 Aqueous One Solution (Promega #G3581) was added to the culture in each well and the plates were incubated for a few hours at 37° C. in the humidified incubator containing 5% CO2. After the incubation, the absorbance of each cell was measured at 490 nm using an EnVision (Perkinelmer, USA). The GI50 values were calculated using a Prism 3.0 program. The results showed that the test compounds affected the cell proliferation and inhibited the growth of AML cancer cells. FIG. 4 shows the result of the inhibition. GI50 of Compound B was 0.188 μM.
As described above, the present invention provides new compounds of revers-turn mimetics, which can be used as pharmaceutical compounds, especially on AML cancer cells. The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

## Claims

1. A compound having the structure of Formula (III):




wherein:
R1 is indolyl substituted by C1-12alkyl and —COR12, wherein R12 is C1-12alkyl;
R6 is phenyl;
R4 is allyl;
X1 is hydrogen; and
each of X2 and X3 is independently hydrogen and hydroxyl.

2. A compound having the structure of Formula (IV):


(III)-R7 


wherein (III) is the formula:



R1 is indolyl substituted by C1-12alkyl and —COR12, wherein R12 is C1-12alkyl;
R6 is phenyl;
R4 is allyl;
X1 is hydrogen;
each of X2 and X3 is independently hydrogen and hydroxyl;
either X2 or X3 is linked to R7 via Y;
Y is an oxygen in X2 or X3; and
R7 is hydroxyalkyl, glycosyl, phosphoryloxymethyoxycarbonyl, substituted or unsubstituted piperidine carbonyloxy, or a salt thereof; or Y—R7 is an amino acid residue, a combination of amino acid residues, phosphate, hemimalate, hemisuccinate, dimethylaminoalkylcarbamate, dimethylaminoacetate, acetate, succinate, malate, formate, benzoate, or a salt thereof.

3. A method for treating an acute myeloid leukemia, comprising administering to a patient in need thereof an effective amount of the compound according to claim 1.

4. A method for treating an acute myeloid leukemia, comprising administering to a patient in need thereof an effective amount of the compound according to claim 2.