Imidazolyl derivatives

BACKGROUND OF THE INVENTION

[0001] The present invention is directed to compounds and compositions containing said compounds which bind selectively to somatostatin receptor subtypes and the use of said compounds for treating medical disorders which are mediated by somatostatin receptor subtypes. Somatostatin (somatotropin release inhibiting factor, SRIF), a tetradecapeptide hormone, originally isolated from bovine hypothalami (Brazeau, P. et al., Science 179, 77-79, 1973) has been shown to have a wide range of regulatory effects on the release of a variety of hormones such as growth hormone, prolactin, glucagon, insulin, gastrin (Bloom, S. R. and Poldack, J. M., Brit. Med. J. 295, 288-289, 1987). In addition, antiproliferative properties (Reichlin, S., N. Engl. J . Med. 309, 1495-1501, 1983) have been obtained with somatostatin analogs in metastatic prostatic cancer (Parmar, H. et al, Clin. Exp. Metastasis, 10, 3-11, 1992) and in several other neuroendocrine neoplasms in man (Anthony, L. et al, Acta Oncol., 32, 217-223, 1993). Metabolism of somatostatin by aminopeptidases and carboxypeptidases leads to a short duration of action.

[0002] The actions of somatostatin are mediated via membrane bound receptors. The heterogeneity of its biological functions has led to studies to identify structure-activity relationships of peptides analogs at the somatostatin receptors which resulted in the discovery of five receptor subtypes (Yamada, et al, Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are under extensive investigation. Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases. Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are restenosis, inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. Somatostatin agonists can also be used for decreasing body weight in a patient.

[0003] In drug research, it is a key issue to minimize side effects by developing highly potent and selective drug molecules. Recent work on the development of nonpeptide structures (Hirschmann, R. et al, J.Am.Chem.Soc. 115, 12550-12568, 1993; Papageorgiou, C. and Borer, X., Bioorg. Med.Chem.Lett. 6, 267-272, 1996) have described compounds with low somatostatin receptor affinity.

[0004] The present invention is directed to a family of nonpeptide compounds, which are selective and potent somatostatin receptor ligands.

SUMMARY OF THE INVENTION

[0005] In one aspect the present invention is directed to a compound of the formula (I),

[0006] the racemic-diastereomeric mixtures and optical isomers of said compound of formula (I), the pharmaceutically-acceptable salts and prodrugs thereof or a pharmaceutically acceptable salt thereof, wherein

[0007] — represents an optional bond;

[0008] R1 is H, —(CH2)m—C(O)—(CH2)m-Z1, —(CH2)m-Z1, —(CH2)m—O-Z1 or —(C0-C6)alkyl-C(O)—NH—(CH2)m-Z3;

[0009] Z1 is an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,

[0010] R2 is H or (C1-C6)alkyl;

[0011] or R1 and R2 are taken together with the nitrogen atoms to which they are attached to form a compound of formula (Ia), (Ib) or (Ic),

[0012] R3 is —(CH2)m-E-(CH2)m-Z2;

[0013] E is O, S,—C(O)—, —C(O)—O—, —NH—C(O)—O— or a bond;

[0014] Z2 is H, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, (C1-C12)alkylguanidino, or an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl and naphthyl;

[0015] R4 is H or —(CH2)m-A1;

[0016] A1 is —C(═Y)—N(X1X2), —C(═Y)—X2, —C(═NH)—X2 or X2;

[0017] Y is O or S;

[0018] X1 is H, (C1-C12)alkyl, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-(C1-C6)alkyl or —(CH2)m-aryl;

[0019] X2 is —(CH2)m—Y1—X3 or optionally substituted (C1-C12)alkyl;

[0020] Y1 is O, S, NH, C═O, (C2-Cl2)alkenyl having one or more double bonds, —NH—CO—, —CO—NH—, —NH—CO—O—(CH2)m—, —C≡C—, SO2 or a bond;

[0021] X3 is H, an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —CH-di-(C1-C12)alkoxy, pyrrolidinyl, pyridinyl, thiophene, imidazolyl, piperidinyl, piperazinyl, benzothiazolyl, furanyl, indolyl, morpholino, benzo[b]furanyl, quinolinyl, isoquinolinyl, —(CH2)m-phenyl, naphthyl, fluorenyl, phthalamidyl, pyrimidinyl,

[0022] or X1 and x2 are taken together with the nitrogen to which they are attached to form an optionally substituted moiety selected from the group consisting of thiazolyl

[0023] Y2 is CH—X4, N—X4, —C(X4X4), O or S;

[0024] X4 for each occurrence is independently —(CH2)m—Y3—X5;

[0025] Y3 is —C(O)—, —C(O)O— or a bond;

[0026] X5 is hydroxy, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, or an optionally substituted moiety selected from the group consisting of aryl, aryl(C1-C4)alkyl, furanyl, pyridinyl, indolyl, —CH(phenyl)2,

[0027] R5 is (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O-Z5, (C0-C6)alkyl-C(O)—NH—(CH2)m-Z3 or optionally substituted aryl;

[0028] Z3 for each occurrence is independently amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —NH—C(O)—O—(CH2)m-phenyl —NH—C(O)—O—(CH2)m—(C1-C6)alkyl or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl, morpholino, piperidinyl, piperazinyl, pyrazolidinyl, furanyl and thiophene;

[0029] R6 is H or (C1-C6)alkyl;

[0030] R7 is (C1-C12)alkyl or —(CH2)m-Z4;

[0031] Z4 is an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, indolyl, thiophene, benzo[b]furan, benzo[b]thiophene, isoxazolyl,

[0032] Z5 is H, (C1-C12)alkyl, (CH2)m-aryl;

[0033] wherein an optionally substituted moiety is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF3, CN, N3, NO2, OH, SO2NH2, —OCF3, (C1-C12)alkoxy, —(CH2)m-phenyl-(X6)n, —S-phenyl-(X6)n, —S—(C1-C12)alkyl, —O—(CH2)m-phenyl-(X6)n, —(CH2)m—C(O)—O—(C1-C6)alkyl, (CH2)m—C(O)—(C1-C6)alkyl, —O—(CH2)m—NH2, —O—(CH2)m—NH—(C1-C6)alkyl, —O—(CH2)m—N-di-((C1-C6)alkyl) and —(C0-C12)alkyl-(X6);

[0034] X6 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, N3, CN, OH, —CF3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)m—NH2, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-((C1-C6)alkyl) and —(CH2)m-phenyl;

[0035] m for each occurrence is independently O or an integer from 1 to 6; and

[0036] n for each occurrence is independently an integer from 1 to 5;

[0037] provided that:

[0038] (a) when R5 is (C1-C12)alkyl, or —C(O)—O-Z5 and Z5 is (C1-C12)alkyl or optionally substituted aryl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl or Z4 and Z4 is thiophene or optionally substituted phenyl, then R3 is not —C(O)—O—(CH2)m-Z where m is 0 and Z is H or (C1-C12)alkyl or where m is 1 to 6 and Z is H;

[0039] (b) when R5 is (C1-C12)alkyl or optionally substituted phenyl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl and R3 is —O—(CH2)-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl, and naphthyl; and

[0040] (c) when R5 is H or (C1-C12)alkyl; R6 is (C1-C6)alkyl; R7 is (C1-C12)alkyl; and R3 is —O-Z2 or —S-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, thiophene, benzothienyl and indolyl.

[0041] A preferred compound of formula I is where R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0042] where A1 is —C(═Y)—N(X1X2);

[0043] Y is O; X1 is H or methyl;

[0044] X2 is —(CH2)m—Y1—X3;

[0045] m in the definition of X2 is 0, 1, 2 or 3; Y1 is a bond or O; and X3 is N-methylpyrrolidin-2-yl, diethylamino, pyridinyl, thiophene, imidazolyl, diethoxymethyl, 1-benzyl-piperidin-4-yl, optionally substituted phenyl or

[0046] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0047] where A1 is —C(═Y)—N(X1X2);

[0048] Y is O;

[0049] X1 is benzyl and X2 is 2-hydroxyethyl;

[0050] or X1 and X2 are taken together with the nitrogen atom to which they are attached to form

[0051] where Y2 is C—X4 or N—X4;

[0052] X4 is —(CH2)m—Y3—X5 where m in the definition of X4 is 0 or 1; and

[0053] X5 is selected from the group consisting of furanyl, benzyl, phenyl, amino,

[0054] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0055] where A1 is —C(═Y)—X2;

[0056] Y is O; X2 is —(CH2)m—Y1—X3;

[0057] where m in the definition of X2 is 0, 1 or 2;

[0058] Y1 is O, —NH—CO—, —CO—NH—, —NH—CO—O—CH2—, SO2 or a bond; and

[0059] X3 is methyl, furanyl, pentyl, phenyl, indolyl, p-NO2-phenyl, naphthyl, fluorenyl, —CH(phenyl)2, benzothiazolyl, phthalamidyl, N,N-dimethylamino,

[0060] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;

[0061] A1 is —C(═Y)—N(X1X2);

[0062] Y is O or S; X1 is H; x2 is —(CH2)m—Y1—X3;

[0063] m in the definition of X2 is 0, 1 or 2;

[0064] Y1 is a bond; and X3 is phenyl, o-Cl-phenyl, m-Cl-phenyl, p-phenyloxy-phenyl, 2,6-di-isopropylphenyl, m-CF3-phenyl, p-ethoxycarbonyl-phenyl, 2,4-difluorophenyl, m-NO2-phenyl, p-benzyloxyphenyl, o-isopropylphenyl, n-hexyl, 4-moropholino, naphthyl or

[0065] Another compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;

[0066] where A1 is —C(═Y)—X2;

[0067] Y is O; X2 is —(CH2)m—Y1—X3;

[0068] where m in the definition of x2 is 0, 1 or 2;

[0069] Y1 is O, —CO—NH—, —NH—CO—O—CH2— or a bond; and X3 is methyl, 3-pentyl, phenyl, p-NO2-phenyl, phthalamidyl, N,N-dimethylamino, p-aminophenyl, fluorenyl or

[0070] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;

[0071] where A1 is —C(═Y)—N(X1X2);

[0072] Y is O; X1 is hydrogen; X2 is —(CH2)m—Y1—X3;

[0073] where m in the definition of X2 is 0, 1, 2 or 3;

[0074] Y1 is O, or a bond; and X3 is cyclopentyl, 4-OH-butyl, N,N-diethylamino, N-methyl-pyrrolidin-3-yl, —CH(ethoxy)2, phenyl, p-SO2NH2-phenyl p-OH-phenyl, o-CF3-phenyl, p-Cl-phenyl, —CH(phenyl)2,

[0075] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is (CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;

[0076] where A1 is —C(═Y)—X2;

[0077] Y is O; X2 is —(CH2)m—Y1—X3;

[0078] where m in the definition of X2 is 0, 1, 2 or 3;

[0079] Y1 is —NH—CO, —C═C—, —C≡C— or a bond; and X3 is t-butyl, 1-methylcarbonyl-piperidin-4-yl, phenyl, p-Cl-phenyl, m-CF3-phenyl, 4-nitro-naphthyl, p-methoxy-phenyl, m-(phenylethyl)-phenyl, indol-3-yl or p-aminophenyl.

[0080] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl; R6 is H;

[0081] where A1 is —C(═Y)—N(X1X2);

[0082] Y is O; X1 is H; x2 is —(CH2)m—Y1—X3;

[0083] where m in the definition of X2 is 0;

[0084] Y1 is a bond; and X3 is o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, o-Cl-phenyl, m-Cl-phenyl, p-Cl-phenyl, o-nitro-phenyl, m-nitro-phenyl, p-nitro-phenyl, o-CF3-phenyl, m-CF3-phenyl, p-CF3-phenyl, p-F-phenyl, 2,4-di-F-phenyl, 2,5-di-F-phenyl, 2,5-di-methoxy-phenyl, m-OMe-phenyl, p-OMe-phenyl, 2-CF3-4-Cl-phenyl or 3-nitro-4-F-phenyl.

[0085] Of the immediately above compounds it is preferred that when R5 is phenyl and R3 is —(CH2)-indol-3-yl that the stereochemistry at the carbon to which R3 is attached is in the R-configuration.

[0086] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-methoxyphenyl, p-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl; R6 is H;

[0087] where A1 is —C(═Y)—X2;

[0088] Y is O; X2 is —(CH2)m—Y1—X3;

[0089] where m in the definition of X2 is 1;

[0090] Y1 is a bond; and X3 is phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, o-Cl-phenyl, m-Cl-phenyl, p-Cl-phenyl, o-nitrophenyl, m-nitro-phenyl, p-nitro-phenyl, O-CF3-phenyl, m-CF3-phenyl, p-CF3-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, N,N-di-methylamino-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4,5-tri-OMe-phenyl, p-Me-phenyl, p-OH-phenyl or 2,4-di-F-phenyl.

[0091] Of the immediately foregoing compounds when R5 is phenyl or o-OMe-phenyl and R3 is —(CH2)-indol-3-yl; it is preferred that the compounds are the separated enantiomers (R or S configuration) according to the carbon to which R3 is attached.

[0092] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0093] where A1 is —C(═Y)—X2;

[0094] Y is O; X2 is —(CH2)m—Y1—X3;

[0095] where m in the definition of X2 is 0, 1 or 2;

[0096] Y1 is S, SO2 or a bond; and X3 is phenyl, 3,4-di-Cl-phenyl, 3,4,5-tri-OMe-phenyl, p-Me-phenyl, p-OH-phenyl, 2,4-di-F-phenyl, 2-furanyl, 2-pyridinyl, 3-pyridinyl, naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 8-quinolinyl, 1-isoquinolinyl, 2-thiophene or 2-pyrimidinyl.

[0097] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0098] where A1 is —C(═Y)—X2;

[0099] Y is O; X2 is —(CH2)m—Y1—X3;

[0100] where m in the definition of X2 is 0, 1, 2 or 3;

[0101] Y1 is a bond; and X3 is 5-indolyl, 3-indolyl, 4-indolyl, 2-indolyl, 5-OMe-indol-3-yl, 5-OMe-indol-2-yl, 5-OH-indol-2-yl, 5-OH-indol-3-yl, 5-Br-indol-3-yl, 2-Me-indol-3-yl, 2-benzothiophene, 3-benzothiophene or 2-benzofuran.

[0102] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)m-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-OMe-phenyl or p-OMe-phenyl; R6 is H;

[0103] where A1 is X2;

[0104] X2 is —(CH2)m—Y1—X3;

[0105] where m in the definition of X2 is 1, 2 or 3;

[0106] Y1 is S, O or a bond; and X3 is phenyl, o-OH-phenyl, p-OH-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, o-CF3-phenyl, o-OMe-phenyl, m-OMe-phenyl, o-nitro-phenyl, p-nitro-phenyl, 3,4-di-Cl-phenyl, 2-nitro-3-OMe-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2-thiophene, 3,4,5-tri-OMe-phenyl, p-N,N-dimethylamino-phenyl, p-OCF3-phenyl, p(3-(N,N-dimethylamino)propoxy)phenyl, 3-F-4-OMe-phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-Cl-quinolin-3-yl, 2-quinolinly, methyl, n-butyl, n-pentyl, n-hexyl, 3,3-dimethyl-butyl, benzyl, cyclohexyl or p-t-Bu-phenyl.

[0107] Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0108] where A1 is X2;

[0109] X2 is —(CH2)m—Y1—X3;

[0110] where m in the definition of X2 is 1, 2 or 3;

[0111] Y1 is O or a bond; and X3 is phenyl, o-OH-phenyl, p-OH-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, o-CF3-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, o-nitro-phenyl, p-nitro-phenyl, 3,4-di-Cl-phenyl, 2-nitro-3-OMe-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, p-phenyl-phenyl, 2-thiophene, 3,4,5-tri-OMe-phenyl, p-N,N-dimethylamino-phenyl, p-benzyloxy-phenyl, p-OCF3-phenyl, p-(3-(N,N-dimethylamino)propoxy)phenyl, 3-F-4-OMe-phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-Cl-quinolin-3-yl, 2-quinolinly, 3-indolyl, 6-methoxycarbonyl-indol-3-yl, 1-methyl-indol-3-yl, 2-methyl-indol-3-yl, methyl, n-butyl, n-pentyl, n-hexyl, 3,3-dimethyl-butyl, benzyl, cyclohexyl or p-t-Bu-phenyl.

[0112] Another preferred compound of formula (I) is where R1 is —(CH2)—CO-Z1; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu, —(CH2)4—NH—CO—O-benzyl, —(CH2)-phenyl or —(CH2)-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;

[0113] where Z1 is ethyl, phenyl, p-OMe-phenyl, p-phenyl-phenyl, p-C1-phenyl, p-Br-phenyl, p-N3-phenyl, p-F-phenyl, m-nitro-phenyl, p-nitro-phenyl, p-CN-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, N,N-dimethylamino-phenyl, 3-methyl-4-Cl-phenyl or naphthyl;

[0114] A1 is —C(═Y)—X2;

[0115] Y is O; X2 is —(CH2)m—Y1—X3;

[0116] where m in the definition of X2 is O;

[0117] Y1 is O; and X3 is t-Bu.

[0118] Another preferred compound of formula (I) is where R1 is —(CH2)—CO—(CH2)m-Z1 where m in the definition of R1 is 0, 1 or 2; R2 is H; R3 is —(CH2)-indol-3-yl or —(CH2)4—NH—CO—O-t-Bu; R4 is H or —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-OMe-phenyl, p-nitro-phenyl, p-Br-phenyl, t-Bu, —CH(CH3)2—CO—NH—(CH2)2—CO—O-t-Bu, —CH(CH3)2—CO—NH—(CH2)3-imidazol-1-yl, —CH(CH3)2—CO—NH—(CH2)2-pyridin-2-yl, —CH(CH3)2—CO—NH—(CH2)3-4-morpholino, —CH(CH3)2—CO—NH—(CH2)-pyridin-4-yl or —CH(CH3)2—CO—NH—(CH2)2-N,N-diethylamino; R6 is H;

[0119] where Z1 is ethyl, propyl, phenyl, p-OMe-phenyl, p-Cl-phenyl, p-Br-phenyl, p-F-phenyl, p-nitro-phenyl, m-nitro-phenyl, p-CN-phenyl, p-N3-phenyl, p-phenyl-phenyl, 3-Me-4-Cl-phenyl, p-N,N-diethylamino-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4-di-F-phenyl, p-OCF3-phenyl, p-benzyloxy-phenyl, p-pentyl-phenyl, 3,4,-tri-OMe-phenyl, 3-nitro-4-Cl-phenyl, 3-Cl-nitro-phenyl, 3-methyl-5-chloro-benzothiophen-2-yl, 2-benzofuranyl, 3-benzothiophene, 3-phenyl-isoxazol-5-yl, 3-(2,4-di-Cl-phenyl)-isoxazol-5-yl, 3-indolyl, 5-Br-thiophen-2-yl, naphthyl,

[0120] A1 is —C(═Y)—X2;

[0121] Y is O; X2 is —(CH2)m—Y1—X3;

[0122] where m in the definition of X2 is O;

[0123] Y1 is O; and X3 is t-Bu.

[0124] Another preferred compound of formula (I) is where R1 and R2 are taken together to form a compound of formula (Ib) or (Ic);

[0125] R3 is —(CH2)-indol-3-yl, —(CH2)-phenyl, —(CH2)4—NH—CO—O-benzyl or —(CH2)4—NH2;

[0126] R5 is phenyl, o-OMe-phenyl, p-OMe-phenyl, p-Br-phenyl, p-nitro-phenyl, t-Bu or —CH(CH3)2—CO—NH—(CH2)2—NH2; R6 is H;

[0127] R7 is ethyl, propyl, phenyl, p-OMe-phenyl, p-Cl-phenyl, p-Br-phenyl, p-F-phenyl, p-nitro-phenyl, m-nitro-phenyl, p-CN-phenyl, p-N3-phenyl, p-phenyl-phenyl, 3-Me-4-Cl-phenyl, p-N,N-diethylamino-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4-di-F-phenyl, p-OCF3-phenyl, p-benzyloxy-phenyl, p-pentyl-phenyl, 3,4,5-tri-OMe-phenyl, 3-nitro-4-Cl-phenyl, 3-Cl-4-nitro-phenyl, 3-methyl-5-chloro-benzothiophen-2-yl, 2-bezofuranyl, 3-benzothiophene, 3-phenyl-isoxazol-5-yl, 3-(2,4di-Cl-phenyl)-isoxazol-5-yl, 3-indolyl, 5-Br-thiophen-2-yl, naphthyl,

[0128] In another aspect, the present invention is directed to a compound of the formula (II),

[0129] the racemic-diastereomeric mixtures and optical isomers of said compound of formula (II), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug,

[0130] wherein

[0131] — represents an optional bond;

[0132] R1 is H, —(CH2)m—C(O)—(CH2)m-Z1, —(CH2)m-Z1, —(CH2)m—O-Z1 or —(C0-C6)alkyl-C(O)—NH—(CH2)m-Z3;

[0133] Z1 is an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,

[0134] R2 is H or (C1-C6)alkyl;

[0135] or R1 and R2 are taken together with the nitrogen atoms to which they are attached to form a compound of formula (IIa), (IIb) or (IIc),

[0136] R3 is —(CH2)m-E-(CH2)m-Z2;

[0137] E is O, S, —C(O)—, —C(O)—O—, —NH—C(O)—O—, —N(C1-C6)alkyl-C(O)—O— or a bond;

[0138] Z2 is H, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, (C1-C12)alkylguanidino, or an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl and naphthyl;

[0139] R4 is H or —(CH2)m-A1;

[0140] A1 is —C(═Y)—N(X1X2), —C(═Y)—X2, —C(═NH)—X2 or X2;

[0141] Y is O or S;

[0142] X1 is H, (C1-C12)alkyl, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m-N-di-(C1-C6)alkyl or —(CH2)m-aryl;

[0143] X2 is —(CH2)m—Y1—X3 or optionally substituted (C1-C12)alkyl;

[0144] Y1 is O, S, NH, C═O, (C2-C12)alkenyl having one or more double bonds, —NH—CO—, —CO—NH—, —NH—CO—O—(CH2)m—, —C≡C—, SO2 or a bond;

[0145] X3 is H, an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —CH-di-(C1-C12)alkoxy, pyrrolidinyl, pyridinyl, thiophene, imidazolyl, piperidinyl, piperazinyl, benzothiazolyl, furanyl, indolyl, morpholino, benzo[b]furanyl, quinolinyl, isoquinolinyl, —(CH2)m-phenyl, naphthyl, fluorenyl, phthalamidyl, pyrimidinyl,

[0146] or X1 and X2 are taken together with the nitrogen to which they are attached to form an optionally substituted moiety selected from the group consisting of thiazolyl,

[0147] Y2 is CH—X4, N—X4, —C(X4X4), O or S;

[0148] X4 for each occurrence is independently H or —(CH2)m—Y3—X5;

[0149] Y3 is —C(O)—, —C(O)O— or a bond;

[0150] X5 is hydroxy, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, or an optionally substituted moiety selected from the group consisting of aryl, aryl(C1-C4)alkyl, furanyl, pyridinyl, indolyl, piperidinyl, —CH(phenyl)2,

[0151] R5 is (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O-Z5, (C0-C6)alkyl-C(O)—NH—(CH2)m-Z3 or optionally substituted aryl;

[0152] Z3 for each occurrence is independently amino, (C1-C12)alkylamino, amino(C1-C12)alkyl, (C5-C7)cycloalkylamino, amino(C5-C7)cycloalkyl, N—(C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —NH—C(O)—O—(CH2)m-phenyl, —NH—C(O)—O—(CH2)m—(C1-C6)alkyl, —CH(phenyl)2, (C5-C7)cycloalkyl,

[0153] or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl, morpholino, piperidinyl, piperazinyl, pyrazolidinyl, furanyl, phenyl, indolyl and thiophene, provided that when m is 0 in the formula for R5 then Z3 is not —NH—C(O)—O—(CH2)m-phenyl or —NH—C(O)—O—(CH2)m—(C1-C6)alkyl;

[0154] R6 is H or (C1-C6)alkyl;

[0155] R1 is (C1-C12)alkyl or —(CH2)m-Z4;

[0156] Z4 is an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, indolyl, thiophene, benzo[b]furan, benzo[b]thiophene, isoxazolyl,

[0157] Z5 is H, (C1-C12)alkyl, or —(CH2)m-aryl;

[0158] wherein an optionally substituted moiety is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF3, CN, N3, NO2, OH, SO2NH2, —OCF3, (C1-C12)alkoxy, —(CH2)m-phenyl-(X6)n, —S-phenyl-(X6)n, —S—(C1-C12)alkyl, —O—(CH2)m-phenyl-(X6)n, —(CH2)m—C(O)—O—(C1-C6)alkyl, —(CH2)m—C(O)—(C1-C6)alkyl, —O—(CH2)m—NH2, —O—(CH2)m—NH—(C1-C6)alkyl, —O—(CH2)m—N-di-((C1-C,)alkyl), —(C0-C12)alkyl-(X6)n and —(CH2)m-phenyl-X7;

[0159] X6 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, N3, CN, OH, —CF3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)mNH2, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-((C1-C8)alkyl) and —(CH2)m-phenyl;

[0160] X1 is —NH—C(═NH.HI)—X8, wherein X8 is thiophene, (C1-C6)alkyl or phenyl;

[0161] m for each occurrence is independently O or an integer from 1 to 6; and

[0162] n for each occurrence is independently an integer from 1 to 5; provided that:

[0163] (a) when R1 is (C1-C12)alkyl, or —C(O)—O-Z5 and Z5 is (C1-C12)alkyl or optionally substituted aryl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl or Z4 and Z4 is thiophene or optionally substituted phenyl, then R3 is not —C(O)—O—(CH2)m-Z where m is 0 and Z is H or (C1-C12)alkyl or where m is 1 to 6 and Z is H;

[0164] (b) when R1 is (C1-C12)alkyl or optionally substituted phenyl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl and R3 is —O—(CH2)-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl, and naphthyl; and

[0165] (c) when R5 is H or (C1-C12)alkyl; R6 is (C1-C6)alkyl; R7 is (C1-C12)alkyl; and R3 is —O-Z2 or —S-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, thiophene, benzothienyl and indolyl.

[0166] A preferred group of compounds of formula (II) have the following formula:

[0167] wherein

[0168] Z3 is —CH2—NH2, —(CH2)2—NH2, —(CH2)3—NH2 or ; and

[0169] X1 is —(CH2)2—N(CH3)2 and X2 is benzyl; or

[0170] X1 and X2 are taken together with the nitrogen atom to which they are attached, to form

[0171] Another preferred group of compounds of formula (II) have the following formula:

[0172] wherein

[0173] X1 is —(CH2)2—N(CH3)2 and X2 is benzyl; or

[0174] X1 and X2 are taken together with the nitrogen atom to which they are attached, to form

[0175] Yet another preferred group of compounds of formula (II) have the following formula:

[0176] wherein X2 is p-chloro-phenyl, p-methoxy-phenyl, 2,4difluoro-phenyl or thienyl.

[0177] Still another preferred group of compounds of formula (II) have the following formula:

[0178] wherein X2 is p-chloro-phenyl, p-methoxy-phenyl, phenyl or thienyl.

[0179] Further still a preferred compound of formula (II) has the following formula:

[0180] Further still another preferred compound of formula (II) has the following formula:

[0181] Further still another preferred group of compounds of formula (II) have the following formula:

[0182] wherein

[0183] R5 is

[0184] and R7 is m-nitro-phenyl or 2-phenyl-ethyl; or

[0185] R5 is

[0186] and R7 is

[0187] R5 is

[0188] and R7 is 3,4-dichlorophenyl or

[0189] R5 is

[0190] and R7 is 3,4-dichlorophenyl.

[0191] In another aspect, this invention is directed to a pharmaceutical composition comprising one or more of a compound of formula (I) or formula (II), as defined hereinabove, and a pharmaceutically acceptable carrier.

[0192] In another aspect, the present invention is directed to a method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.

[0193] In another aspect, the present invention is directed to a method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.

[0194] In another aspect, the present invention is directed to a method of binding one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.

[0195] In another aspect, the present invention is directed to a method of treating acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.

[0196] In another aspect, the present invention is directed to a method of treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.

[0197] In another aspect, the present invention is directed to a method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, to said subject.

DETAILED DESCRIPTION OF THE INVENTION

[0198] One of ordinary skill will recognize that certain substituents listed in this invention may have reduced chemical stability when combined with one another or with heteroatoms in the compounds. Such compounds with reduced chemical stability are not preferred.

[0199] In general, the compounds of Formula I or II can be made by processes which include processes known in the chemical arts for the production of compounds. Certain processes for the manufacture of Formula I or II compounds are provided as further features of the invention and are illustrated by the following reaction schemes and examples.

[0200] In the above structural formulae and throughout the instant application, the following terms have the indicated meanings unless expressly stated otherwise:

[0201] The alkyl groups are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

[0202] When the definition “C0-alkyl” occurs in the definition, it means a single covalent bond.

[0203] The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

[0204] The term halogen or halo is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.

[0205] The term cycloalkyl is intended to include a mono-cycloalkyl group or a bi-cycloalkyl group of the indicated carbon number known to those of skill in the art.

[0206] The term aryl is intended to include aromatic rings known in the art, which can be mono-cyclic, bi-cyclic or tri-cyclic, such as phenyl, naphthyl and anthracene.

[0207] The term heterocycle includes mono-cyclic, bi-cyclic and tri-cyclic systems having one or more heteroatoms, such as oxygen, nitrogen and/or sulfur. The ring systems may be aromatic, for example pyridine, indole, quinoline, pyrimidine, thiophene (also known as thienyl), furan, benzothiophene, tetrazole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, and thiadiazole. The ring systems may be non-aromatic, for example pyrrolidine, piperidine, morpholine and the like.

[0208] The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions. Accordingly, such compounds are less preferred.

[0209] When a chemical structure as used herein has an arrow emanating from it, the arrow indicates the point of attachment. For example, the structure

[0210] is a pentyl group. When an arrow is drawn through a cyclic moiety, the arrow indicates that the cyclic moiety can be attached at any of the available bonding points, for example

[0211] means that the phenyl can be bonded ortho, meta or para to the X group. When an arrow is drawn through a bi-cyclic or a tri-cyclic moiety, the arrow indicates that the bi-cyclic or tri-cyclic ring can be attached at any of the available bonding points in any of the rings, for example

[0212] means that the indole is bonded either through the phenyl portion of the ring or the nitrogen containing ring portion.

[0213] The compounds of the instant invention have at least one asymmetric center as noted by the asterisk in the structural formula (I), (Ia) and (Ib), above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the scope of the instant invention.

[0214] The instant compounds can be generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, acetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.

[0215] The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula (I) or (II) and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.

[0216] As is known in the art, agonists and antagonists of somatostatin are useful for treating a variety of medical conditions and diseases, such as inhibition of H. pylori proliferation, acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux and in treating endocrinological diseases and/or conditions, such as Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, and polycystic ovary disease; in treating various types of cancer such as thyroid cancer, hepatome, leukemia, meningioma and conditions associated with cancer such as cancer cachexia; in the treatment of such conditions as hypotension such as orthostatic hypotension and postprandial hypotension and panic attacks; GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 subtype receptor has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. Somatostatin agonists can also be used for decreasing body weight in a patient. Accordingly, the compounds of the instant invention are useful for the foregoing methods.

[0217] Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula (I) or (II) in association with a pharmaceutically acceptable carrier.

[0218] The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.

[0219] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

[0220] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.

[0221] Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

[0222] Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.

[0223] Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.

[0224] Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents. U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. application Ser. No. 08/740,778 filed Nov. 1, 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan. 29, 1998, teaches absorbable sustained release compositions of a bioactive agent. The teachings of the foregoing patents and applications are incorporated herein by reference.

[0225] In general, an effective dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment, all of which are within the realm of knowledge of one of ordinary skill in the art. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals.

[0226] A preferred dosage range is 0.01 to 10.0 mg/kg of body weight daily, which can be administered as a single dose or divided into multiple doses.

[0227] Compounds of the instant invention can be and were assessed for its ability to bind to a somatostatin subtype receptor according to the following assays. Human somatostatin subtype receptor binding studies:

[0228] The affinity of a compound for human somatostatin subtype receptors 1 to 5 (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measuring the inhibition of [125I-Tyr11]SRIF-14 binding to CHO—K1 transfected cells.

[0229] The human sst, receptor gene was cloned as a genomic fragment. A 1.5 Kb Pstl-Xmnl segment containg 100 bp of the 5′-untranslated region, 1.17 Kb of the entire coding region, and 230 bp of the 3′-untranslated region was modified by the Bg1ll linker addition. The resulting DNA fragment was subcloned into the BamHI site of a pCMV-81 to produce the mammalian expression plasmid (provided by Dr. Graeme Bell, Univ. Chicago). A clonal cell line stably expressing the sst, receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method (1). The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.

[0230] The human sst2 somatostatin receptor gene, isolated as a 1.7 Kb BamHI-HindIII genomic DNA fragment and subcloned into the plasmid vector pGEM3Z (Promega), was kindly provided by Dr. G. Bell (Univ. of Chicago). The mammalian cell expression vector is constructed by inserting the 1.7 Kb BamH1-HindII fragment into compatible restriction endonuclease sites in the plasmid pCMV5. A clonal cell line is obtained by transfection into CHO—K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as a selectable marker.

[0231] The human sst3 was isolated at genomic fragment, and the complete coding sequence was contained within a 2.4 Kb BamHI/HindIII fragment. The mammalian expression plasmid, pCMV-h3 was constructed by inserting the a 2.0 Kb NcoI-HindIII fragment into the EcoR1 site of the pCMV vector after modification of the ends and addition of EcoR1 linkers. A clonal cell line stably expressing the sst3 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.

[0232] The human sst4 receptor expression plasmid, pCMV-HX was provided by Dr. Graeme Bell (Univ. Chicago). The vector contains the 1.4 Kb Nhel-Nhel genomic fragment encoding the human sst4, 456 bp of the 5′-untranslated region and 200 bp of the 3′-untranslated region, clone into the Xbal/EcoR1 sites of PCMV-HX. A clonal cell line stably expressing the sst4 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.

[0233] The human sst5 gene was obtained by PCR using a λ genomic clone as a template, and kindly provided by Dr. Graeme Bell (Univ. Chicago). The resulting 1.2 Kb PCR fragment contained 21 base pairs of the 5′-untranslated region, the full coding region, and 55 bp of the 3′-untranslated region. The clone was inserted into EcoR1 site of the plasmid pBSSK(+). The insert was recovered as a 1.2 Kb HindIII-XbaI fragment for subcloning into pCVM5 mammalian expression vector. A clonal cell line stably expressing the SST5 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture. CHO—K1 cells stablie expressing one of the human sst receptor are grown in RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin. Cells are collected with 0.5 mM EDTA, and centrifuged at 500 g for about 5 min. at about 4° C. The pellet is resuspended in 50 mM Tris, pH 7.4 and centrifuged twice at 500 g for about 5 min. at about 4° C. The cells are lysed by sonication and centrifuged at 39000 g for about 10 min. at about 4° C. The pellet is resuspended in the same buffer and centrifuged at 50000 g for about 10 min. at about 4° C. and membranes in resulting pellet are stored at −80° C.

[0234] Competitive inhibition experiments of [125I-Tyr11]SRIF-14 binding are run in duplicate in polypropylene 96 w II plates. Cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-14 (0.05 nM) for about 60 min. at about 37° C. in 50 mM HEPES (pH 7.4), 0.2% BSA, 5 mM MgCl2, 200 KIU/ml Trasylol, 0.02 mg/ml bacitracin and 0.02 mg/ml phenylmethylsulphonylfluoride.

[0235] Bound from free [125I-Tyr11]SRIF-14 is separated by immediate filtration through GF/C glass fiber filter plate (Unifilter, Packard) presoaked with 0.1% polyethylenimine (P.E.I.), using Filtermate 196 (Packard) cell harvester. Filters are washed with 50 mM HEPES at about 0-4° C. for about 4 sec. and assayed for radioactivity using Packard Top Count.

[0236] Specific binding is obtained by subtracting nonspecific binding (determined in the presence of 0.1 μM SRIF-14) from total binding. Binding data are analyzed by computer-assisted nonlinear regression analysis (MDL) and inhibition constant (Ki) values are determined.

[0237] The determination of whether a compound of the instant invention is an agonist or an antagonist is determined by the following assay.

[0238] Functional assay: Inhibition of CAMP intracellular production:

[0239] CHO—K1 Cells expressing human somatostatin (SRIF-14) subtype receptors are seeded in 24-well tissue culture multidishes in RPMI 1640 media with 10% FCS and 0.4 mg/ml geneticin. The medium is changed the day before the experiment.

[0240] Cells at 105 cells/well are washed 2 times by 0.5 ml and fresh RPMI with 0.2% BSA supplemented with 0.5 mM (1) 3isobutyl-1-methylxanthine (IBMX) and incubated for about 5 min at about 37° C.

[0241] Cyclic AMP production is stimulated by the addition of 1 mM forskolin (FSK) for about 15-30 minutes at about 37° C.

[0242] The agonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10−12 M to 10−6 M) and a test compound (10−10 M to 10−5 M).

[0243] The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and a test compound (10−10 M to 10−5 M).

[0244] The reaction medium is removed and 200 ml 0.1 N HCl is added. cAMP is measured using radioimmunoassay method (Kit FlashPlate SMP001A, New England Nuclear).

[0245] The compounds of the instant invention are synthesized according to the following procedures and examples.

Synthesis of Bromoketones

[0246] General Procedure: Two different methods can be applied: starting either from a carboxylic acid or an arylketone.

[0247] First method: Starting from a carboxylic acid (Macholan, L.; Skursky, L., Chemlstry 1955, 49, 1385-1388. Bestman, H. J., Seng, F., Chem. Ber., 1963, 96, 465-469).

[0248] A carboxylic acid is first converted into an acyl chloride using oxalyl chloride or thionyl chloride or activated as a mixed anhydride with an alkylchloroformate (isobutylchloroformate (Krantz, A., Copp, L. J., Biochemistry, 1991, 30, 4678-4687) or ethylchloroformate (Podlech, J., Seebach, D., Liebigs Ann., 1995, 1217-1228)) in the presence of a base (triethylamine or N-methyl morpholine).

[0249] The activated carboxyl group is then transformed into a diazoketone using ethereal diazomethane or trimethylsilyldiazomethane (Aoyama, T., Shiori, T., Chem. Pharm. Bull., 1981, 29, 3249-3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran or acetonitrile.

[0250] The bromination is then carried out using a brominating agent such as HBr in acetic acid, hydrobromic acid in water or in diethyl ether.

Preparation 1

1-Bromo-3-(4-chloro-phenoxy)-3-methyl-butan-2-one

[0251]

[0252] To a solution of chloro-4-phenoxy-2-isobutyric acid (2.15 g, 10 mmol) in 10 ml of anhydrous dichloromethane at about 0° C. were added oxalyl chloride (5.5 ml, 11 mmol of a 2M solution in dichloromethane) and DMF (2 drops, catalytic amount) via a septum under nitrogen atmosphere. The solution was stirred and allowed to warm up to room temperature over about 3 hrs. Concentration under reduced pressure afforded the crude acid chloride which was used directly without further purification.

[0253] The acylchloride was added dropwise at about 0° C. to a solution of TMSCHN2 (11 ml, 22 mmol) in THF-acetonitrile (1:1, 10 ml). The mixture was stirred at about 25° C. for about 1 hour and then evaporated in vacuo.

[0254] A solution of the diazoketone in dichloromethane (10 ml) was added dropwise during about 10 minutes to a vigorously stirred mixture of concentrated hydrobromic acid (5 ml) in dichloromethane (20 ml). Nitrogen was evolved and a slight temperature rise occurred. After stirring for about a further 10 min., the mixture was diluted and the organic layer was washed with water (3 times 20 ml), dried over magnesium sulfate and evaporated. Flash chromatography of the residue eluting with AcOEt/Heptane (1:4) afforded the desired product with a yield of 79% (2.3 g).

[0255]

1
H-NMR in CDCl3 (100 MHz) δ: 7.05 (m, 4 H, arom. H), 4.41 (s, 2 H, CH2), 1.53 (s, 6H, 2 CH3).

Preparations 2-6

[0256] The following compounds were prepared analogously to the procedure described for Preparation 1:

Prep. #RYield2

78%3

60%4

10%5

79%6

41%*Compounds already described in literature.

[0257] Second method: Starting from a methyl ketone

[0258] A methyl ketone is converted to a bromoketone by using different brominating agents:

[0259] CuBr2 (King, L. C., Ostrum, G. K., J. Org. Chem., 1964, 29, 3459-3461) heated in AcOEt or dioxane.

[0260] N-bromosuccinimide in CCl4.

[0261] Bromine in glacial acetic acid or sulfuric acid.

[0262] Phenyltrimethylammonium tribromide (Sanchez, J. P., Parcell, R. P., J. Heterocyclic Chem., 1988, 25, 469-474) at 20-80° C. in an aprotic solvent such as THF.

[0263] Use of a polymer supported brominating agent such as perbromide on Amberlyst A-26, poly(vinylpyridinium hydrobromide perbromide) resin (Frechet, J. M. J., Farrall, M. J., J. Macromol. Sci. Chem., 1977, 507-514) in a protic solvent such as methanol at about 20-35° C. for about 2-100 h.

Preparation 7

1-Bromo-2-(3,4,5-trimethoxy-phenyl)-ethanone

[0264]

[0265] To a solution of 3,4,5-trimethoxyacetophenone (2.1 g, 10 mmol) in methanol (30 ml) was added pyridine hydrobromide perbromide polymer (1.4 eq). The resulting mixture was shaken at room temperature for about 2 hours and the reaction was stopped by filtration. The polymer was washed with methanol and the filtrate was evaporated in vacuo. The product was then purified by flash chromatography (AcOEt/Heptane, 1:4) affording 1.5 g (53%) of a white solid.

[0266]

1
H-NMR in CDCl3 (100 MHz) δ: 7.2 (s, 2H, H arom.), 4.4 (s, 2H, CH2), 3.9 (m, 9H, 3 OCH3).

Preparations 8-17

[0267] The following compounds were prepared analogously to the procedure described for Preparation 7:

Prep. #RReaction time (h)Yield8

8789

77210

856211

26212

105613

25314

8.52715

34316

37717

395*Compound already described in literature.

Synthesis of Imidazoyl Compounds

[0268] General Procedure: An amino acid is transformed to its cesium salt using cesium carbonate in a polar solvent such as DMF/H2O (1:1) or EtOH/H2O (1:1). An ester is then obtained using an appropriate bromoketone in a polar aprotic solvent such as dry DMF. The cesium bromide formed is filtered off and ammonium acetate is added in an aprotic solvent having a high boiling point such as xylene or toluene or in a protic acidic solvent such as acetic acid. The mixture is refluxed using a Dean-Stark trap for about 0.5-10 hours. In the scheme immediately below, PG is a protecting group, preferably a carbamate, such as t-Boc or benzyl carbamate.

EXAMPLE 1

2-{(1S)-1-[tertbutoxycarbonylamino]-2-[(1H)-indol-3-yl]ethyl}-4-(2-methoxyphenyl)-1H-imidazole

[0269]

[0270] A solution of Boc-(D,L)-Trp-OH (10 g, 32.8 mmol) and cesium carbonate (0.5 eq., 5.34 g) in EtOH/H2O (1:1, 70 ml) was shaken for about 30 minutes at room temperature, and then concentrated in vacuo at about 40° C.

[0271] To the resulting salt in 40 mL of dry DMF was added 40 ml of a solution of 2-bromo-2′-methoxyacetophenone (7.66 g, 1 eq.) in dry DMF. The mixture was stirred for about 1 hr at room temperature under argon and then concentrated under reduced pressure. Ethyl acetate was added (100 ml), the mixture filtered, and the CsBr washed with ethyl acetate. The filtrate was then concentrated under reduced pressure.

[0272] A solution of the foregoing filtrate and ammonium acetate (50.5 9, 20 eq.) in xylene (240 ml) was refluxed for about 3 hours at about 150° C. Excess NH4OAc and H2O were removed using a Dean-Stark trap. The progress of the reaction was monitored by t.l.c. (eluent: CH2Cl2:MeOH, 95:5). The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous NaHCO3 solution until basic pH, and with brine until neutral pH. The organic layer was then dried over MgSO4, and concentrated under reduced pressure.

[0273] Purification of the resulting residue by flash chromatography (eluent: CH2Cl2:MeOH, 95:5) afforded the desired compound (8.7 g, yield: 61%).

[0274]

1
H-NMR (CDCl3, 100 MHz) δ: 8.00 (s, 1H, NH), 7.80 (m, 2H, arom. H), 7.20 (m, 9H, arom. H, NH), 5.40 (m, 1H, NH), 5.10 (m, 1H, CH), 3.80 (s, 3H, OCH3), 3.50 (m, 2H, CH2), 1.50 (s, 9H, 6 CH3). LC/MS: m/z=433.3 (M+H).

EXAMPLE 2

N-[2-tertbutoxycarbonylamino ethyl]-2-{2-[(1S)-1-(tertbutoxycarbonylamino)-2-(1H)-indol-3-yl)ethyl]-1H-imidazol-4-yl}-isobutyramide

[0275]

[0276] A solution of the 2-{2-[(1S)-1-(tertbutoxycarbonylamino)-2-(indol-3-yl)ethyl]-1H-imidazol-4-yl}-2-methyl-propionic acid-methyl ester 1 (2.6 g, 6 mmol), (prepared according to the procedure described in Example 1) and LiOH.H2O (1.7 g, 6.6 eq.) in THF (50 ml) were stirred at about 80° C. for about 3 hours. The progress of the reaction was monitored by t.l.c. (CH2Cl2:MeOH, 95:5). The resulting mixture was then concentrated in vacuo. About 50 ml of water was added to the residue which was then acidified with glacial acetic acid until about pH 5. The product of the reaction was then extracted with ethyl acetate (3×50 ml) and washed with brine until neutral pH. The organic layer was dried with MgSO4, and concentrated under reduced pressure. The resulting intermediate 2 was obtained after crystallization in diethyl ether with a yield of 80% (2 g). 1H-NMR (400 MHz, DMSO) δ: 10.9 (s, 1H, NH), 7.1 (m, 7H, arom. H, NH), 5.00 (m, 1H, CH), 3.3 (m, 2H, CH2), 1.3 (m, 15H, 5 CH3). LC/MS: m/z=525.1 (M+TFA), m/z=413.2 (M+H).

[0277] The 2-{2-[(1S)-1-(tertbutoxycarbonylamino)-2-[(1H)-indol-3-yl]ethyl]-1H-imidazol-4-yl}-2-methyl-propionic acid 2 can be activated preferentially by carbonyldiimidazole in an aprotic solvent such as THF or DMF at about 20-100° C. for about 1-4 hours.

[0278] A solution of the acid 2 (1 g, 2.4 mmol) and carbonyldiimidazole (0.39 g, 2.4 mmol) in dry THF (20 ml) was shaken for about 1 hour at room temperature (25° C.).

[0279] N-Boc-ethylene-diamine (0.43 g, 2.7 mmol) was added and the mixture was shaken for about 1 hour at about 25° C.

[0280] The mixture was diluted in ethyl acetate (100 ml) and washed with saturated aqueous NaHCO3 solution (2×50 ml) and brine until neutral pH. The organic layer was then dried over MgSO4, and concentrated in vacuo.

[0281] Purification of the resulting residue by flash-chromatography (in CH2Cl2:MeOH, 95:5) afforded the desired product 3 with a yield of 77% (1 g).

[0282]

1
H-NMR (400 MHz, DMSO) δ: 11.6 (s, 1H, NH), 10.7 (s, 1H, NH), 7.00 (m, 9H, arom. H, NH), 4.8 (m, 1H, CH), 3.00 (m, 6H, 3 CH2), 1.3 (m, 24H, 8 CH3). LC/MS: m/z=667.3 (M+TFA), 555.3 (M+H).

EXAMPLES 3-1178

[0283] The following compounds were prepared analogously to the procedure described for Example 1 or 2 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (PG(2 substituents)R3 (12 substituents)(R5 (49 substituents))=1176.

[0284] PG can also be hydrogen in the foregoing formula,

[0285] R3:

[0286] R5:

*for this substituent, the corresponding imidazole derivative was obtained after deprotection via catalytic hydrogenation of the benzyloxyphenyl substituent **for this substituent, the corresponding imidazole derivative was obtained after deprotection via catalytic hydrogenation of the nitrophenyl substituent

[0287] Z3:

Synthesis of Amides from Imidazoyl Intermediates

[0288]

[0289] General procedure: Carboxylic acids are activated overnight at room temperature with carbonyldiimidazole in an aprotic solvent such as chloroform, THF or THF/DMF before addition of an amino starting material as shown above followed by a further 12-15 hours of stirring. The excess acylating agent is quenched with aminomethylated resin for about 12-15 hours and then purified on silica gel pad with dichloromethane or ethyl acetate as eluent.

[0290] For protected basic derivatives (R3═(CH2)4NHBoc and/or X2 containing NHBoc group), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.

EXAMPLE 1179

2-{(1S)-1-[(2-Furanyl)carbonylamino]-2-[indol-3-yl]ethyl}-4phenyl-1H-imidazole (C24H20N4O2, MW=396.45)

[0291]

[0292] 2-Furancarboxylic acid (12.6 mg, 0.11 mmol) was activated overnight at about 22° C. with carbonyldiimidazole (0.11 mmol, 0.2M in chloroform). 2-{(1S)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (0.1 mmol, 0.5M in chloroform) was added to the media and the mixture was stirred for about 12 hours at about 22° C. Aminomethylated resin was then added (50-60 mg, 1.2 mmol/g, Novabiochem) in order to quench the excess of acylating agent for about 12 hours. Purification on silica gel pad (200 mg, Alltech) with ethyl acetate as eluent gave the expected product (37.2 mg, 94%). 1H-NMR (CDCl3, 100 MHz) δ: 8.36 (br s, 1H); 7.67-6.4 (m, 16H); 5.48 (qd, J=7.1 Hz, 1H); 3.6 (ABX system, 2H). LC/MS: m/z=397 (M+H).

EXAMPLES 1180-3615

[0293] The following compounds were prepared analogously to the procedure described for Example 1179 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and X2, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (4 substituents))(R5 (7 substituents))(X2 (87 substituents))=2436.

[0294] R3:

[0295] R5:

[0296] X2:

Synthesis of Ureas and Thioureas from Imidazoyl Intermediates

[0297] From Isocyanates and Isothiocyanates:

[0298] General procedure: Isocyanates or isothiocyanates are shaken overnight at room temperature with an imidazoyl intermediate in an aprotic solvent like dichloromethane, chloroform or chloroform/DMF. The reaction is quenched by addition of aminomethylated resin for about 12-15 hours and purified on silica gel pad with ethyl acetate as eluent.

[0299] For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.

EXAMPLE 3616

2-{(1R)-1-[(2, 4-Difluorophenyl)aminocarbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C26H21F2N5O, MW=457.49)

[0300]

[0301] 2,6-Difluorophenylisocyanate (36 μL, 0.3 mmol) and 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (60.4 mg, 0.2 mmol) were stirred overnight in 2 mL of anhydrous dichloromethane. Filtration and purification by flash chromatography on silica gel (ethyl acetate/heptane 1:1 as eluent) afforded the expected product as a white powder (27 mg, 30%). 1H-NMR (DMSO D6, 400 MHz) δ: 12.03 (s, 1H); 10.77 (s, 1H); 8.47 (s, 1H); 8.1 (dd, 1H); 7.8-6.92 (m, 14H); 5.11 (dd, J=7 and 14 Hz, 1H); 3.3 (m, 2H). LC/MS. m/z=458 (M+H).

EXAMPLES 3617-4435

[0302] The following compounds were prepared analogously to the procedure described for Example 3616, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5, and X2 with Y is O or X2 with Y is S, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (3 substituents))(R5 (7 substituents))(X2 (39 substituents))=819.

[0303] X2 when Y is O:

[0304] X2 when Y is S:

[0305] From Carbamate Intermediates and Primary and Secondary Amines:

[0306] General Procedure: The preparation of carbamate intermediates is described in the literature (Takeda, K. et al., Tetrahedron Letters 1983, 24, 4569-4572; Nimura, N. et al., Anal. Chem. 1986, 58, 2372-2375) from amino derivatives and N,N′-disuccinimidylcarbonate in acetonitrile at room temperature.

EXAMPLE 4436

2-{(1R)-1-[(2,5-Dioxo-1-pyrrrolidinyloxy)carbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C24H21N5O4, MW=443.46)

[0307]

[0308] 302.4 mg (1 mmol) of 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole previously dissolved in 20 mL of anhydrous acetonitrile was added dropwise to a solution of N,N′-disuccinimidylcarbonate (528 mg, 2 mmol, DSC) in 20 mL of anhydrous acetonitrile during 1.5 hour. After a further 4 hours of stirring at room temperature, the solvent was evaporated in vacuo and the residue redissolved in 30 mL of chloroform. Excess DSC was then discarded and the organic layer washed with water (4×30 mL), dried over MgSO4 and concentrated to obtain a brown solid (215 mg 49%). 1H-NMR (CDCl3, 100 MHz) δ: 8.22 (br s, 1 H) ; 8.1-7.08 (m, 12H); 5.9 (br s, 1H); 4.97 (dd, J=3.6 and 9.3 Hz, 1H); 3.75 (dd, J=3.6 and 14.8 Hz, 1H); 3.06 (dd, J=9.7 and 14.6 Hz, 1H); 2.96 (s, 2H); 2.89 (s, 2H). LC/MS: m/z=329 ((M+H)-SuOH.

[0309] General procedure: A primary or secondary amine is stirred for about 2-15 hours at room temperature with a carbamate intermediate in an aprotic solvent like acetonitrile. Tetrahydrofuran and aminomethylated resin are then added and the reaction is then stirred for about 12-15 hours. Ureas are isolated after filtration, rinsed with ethyl acetate and evaporated in vacuo.

[0310] For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.

EXAMPLE 4437

2-{(1R)-1-[(Benzylamino)carbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C27H25N5O, MW=435.53)

[0311]

[0312] Benzylamine (5 μL, 50 mmol) and 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-phenyl-1H-imidazole (24 mg, 54 mmol) were stirred for about 2 hours at room temperature in anhydrous acetonitrile. Aminomethylated resin (50 mg, 0.75 mmol/g, Novabiochem) was then added and after further stirring overnight, the title product was obtained by filtration on silica gel pad (200 mg) and evaporated in vacuo as a brown powder (20 mg, 92%). 1H-NMR (DMSO D6, 100 MHz) δ: 10.8 (br s, 1H); 7.9-6.88 (m, 17H); 6.53 (m, 2H); 5.12 (dd, J=6 and 14.6 Hz, 1H); 4.28 (m, 2H); 3.25 (m, 2H). LC/MS: m/z=436 (M+H).

EXAMPLES 4438-8469

[0313] The following compounds were prepared analogously to the procedure described for Example 4437, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and NX1X2, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (3 substituents))(R5 (12 substituents))(NX1X2 (112 substituents))=4032.

[0314] R3:

[0315] R5:

[0316] Z3:

[0317] X1X2N:

[0318] Primary Amines

[0319] Secondary Amines

100

101

Synthesis of Secondary Amines by Reductive Aminations of Imidazolyl Intermediates

[0320] (Kaldor, S. W. Siegel, M. G.; Fritz, J. E. Dressman, B. A.; Hahn, P. J. Tetrahedron Letters 1996, 37, 7193-7196)

102

[0321] General procedure: Condensation of aldehydes with an imidazolyl intermediate in a protic solvent like methanol yields imines which are reduced in presence of AMBERLITE® IRA-400 borohydride. The slurry is then shaken overnight and the excess amino intermediate is quenched by addition of dichloromethane and aldehyde Wang resin. After further overnight stirring, the mixture is filtered, evaporated and purified on silica gel pad with ethyl acetate as eluent.

[0322] For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.

EXAMPLE 8470

2-{(1R)-1-[(4-Methoxybenzyl)amino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C27H26N4O, MW=422.54)

[0323]

103

[0324] 2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (36.3 mg, 0.12 mmol) and p-anisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA-400) was then added and the slury was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and evaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H) 2.26 (s, 1H). LC/MS: m/z=423 (M+H).

EXAMPLES 8471-9331

[0325] The following compounds were prepared analogously to the procedure described for Example 8470, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and A1, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (3 substituents))(Rs (7 substituents))(X2 (41 substituents))=861.

104

[0326] R3:

105

[0327] R5:

106

[0328] A1:

107

108

Synthesis of Amidines by Condensation of an Imidazolyl with Thioimidates

[0329]

109

[0330] A series of thioimidates were previously synthesized by condensation of thioamides and iodomethane in acetone at room temperature. The precipitate was collected and then rinsed with acetone. Thioimidates so formed were used without further purification.

[0331] General procedure: Thioimidates are stirred overnight at room temperature with an amino intermediate in 2-propanol or 2-propanol/DMF before addition of tetrahydrofuran and aminomethylated resin. Further stirring overnight followed by filtration and washing with ethyl acetate yields an iodohydrate amidine after evaporation in vacuo.

[0332] For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.

EXAMPLE 9332

2-{(1R)-1-[(2-Thienyl(imino)methyl)amino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole hydroiodide (C24H21N5S.HI, MW=539.43)

[0333]

110

[0334] 2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (15.1 mg, 0.05 mmol) and S-methyl-2-thiophenethiocarboximide hydroiodide (13 mg, 0.06 mmol) were shaken in 1 mL of 2-propanol for about 16 hours. Aminomethylated resin (50 mg, 1.31 mmol/g, Novabiochem) was then added and after further stirring overnight, a brown solid (19.8 mg, 84%) was isolated by filtration and evaporation in vacuo. 1H-NMR (MeOD, 100 MHz) δ: 8.15 (m, 1H); 7.84-6.96 (m, 13H); 5.3 (m, 1H); 3.61 (m, 2H). LC/MS :m/z=412 (M+H).

EXAMPLES 9333-9920

[0335] The following compounds were prepared analogously to the procedure described for Example 9332, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and X2, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (7 substituents))(R5 (7 substituents))(X2 (12 substituents))=588.

111

[0336] R3:

112

[0337] R5:

113

[0338] X2:

114

Synthesis of Amidines by Condensation of an Aniline with Thioimidates

[0339]

115

EXAMPLES 9921-9926

[0340] The following compounds were prepared analogously to the procedure described for Example 9332, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R4 and X7, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R4 (2 substituents))(X7 (3 substituents))=6.

116

Imidazole Derivatives N-Alkylation

[0341]

117

[0342] General procedure: A solution of an imidazole intermediate, an alkylating agent such as an α-bromoketone, an α-bromoester, an aryl or alkyl bromide or a sulfonyl chloride, in the presence of an organic or non-organic base which can be or not be supported on a resin such as polystyrene resin, in an aprotic solvent like THF, CH3CN, DMF is heated at 20-80° C. for 2-48 hours. The resulting N-alkylated compound can be isolated either by aqueous work-up followed by flash chromatography on silica gel, or by addition to the reaction mixture of a nucleophile supported on polymer (to trap the excess of electrophile) such as aminomethyl or thiomethyl polystyrene resin followed by filtration and then rapid purification of the resulting residue on a silica gel pad (using Alltech silica cartridge and Alltech manifold).

EXAMPLE 9927

2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole

[0343]

118

[0344] To a solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-phenylethyl]-4-phenyl-1H-imidazole (100 mg, 1 eq) in DMF (2 mL) were successively added morpholinomethyl polystyrene resin (Novabiochem, loading: 3.51 mmol/g, 159 mg, 2 eq) and 1-bromo-2-butanone (28 mL, 2 eq). After about 18 hours of stirring at about 20° C., 2 mL DMF were added to the reaction mixture followed by aminomethylpolystyrene resin (Novabieochem, loading: 1.73 mmol/g, 319 mg). The mixture was stirred overnight at 20° C. and filtered. The filtrate was concentrated under reduced pressure and then purified by a rapid filtration on a silica gel pad (Alltech silica cartridges) with ethylacetate as eluent to yield 107 mg (90% yield) of the title compound. NMR (1H, 400 MHz, CDCl3) δ: 7.80-6.98 (m, 11H, arom. H), 5.45 (d, 1H, NH), 4.80 (m, 1H, CH), 4.40 (AB, J=18 Hz, NCH2CO), 3.33 (m, 2H, CH2Ph), 2.25 (m, 2H, CH2CH3), 1.0 (t, 3H, CH3). LC/MS: calculated MW=433.5, m/z=434.2 (M+H), m/z=432.2 (M−H).

EXAMPLES 9928-12307

[0345] The following compounds were prepared analogously to the procedure described for Example 9927, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and R1, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R1 (34 substituents {see definitions of Z1}))(R3 (5 substituents))(R5 (14 substituents))=2380.

119

[0346] R1:

120

[0347] R3:

121

[0348] R5:

122

*In case of bromide derivatives, cesium carbonate was used instead of morpholinomethylpolystyrene resin and thiomethyl resin was used instead of aminomethylresin.

123

124

125

[0349] General procedure: Intermediate (a) is treated with an acidic solution preferably TFA in DCM at about 20-30° C. for about 1-4 hours. The mixture is then concentrated under reduced pressure to afford a dihydro-imidazo-pyrazine.

EXAMPLE 12308

5,8-Dihydro-8-(3-indolyl)methyl-2,6-diphenyl-imidazo[1,2-a]pyrazine

[0350]

126

[0351] A solution of 2-[1(S)-{1,1-dimethylethoxy)carbonylamino}-2-(3-indolyl)ethyl]-1-(benzoylmethyl)-4-phenyl-1H-imidazole (prepared as described previously) (100 mg) in a mixture of 10% TFA in DCM (1.3 mL) was stirred for about 3 hours at about 20° C. and concentrated under reduced pressure to yield the expected dihydro-imidazo-pyrazine (yield=95%). LC/MS: calculated MW: 402.19, m/z=403.2 (M+H).

EXAMPLES 12309-12532

[0352] The following compounds were prepared analogously to the procedure described for Example 12308, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R5 and R7, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R5 (7 substituents))(R7 (32 substituents))=224.

127

[0353] R5:

128

[0354] R7:

129

130

[0355] General procedure: Intermediate (b) is treated with an acidic solution preferably TFA in DCM at 20-30° C. for 14 hours. The mixture is then concentrated under reduced pressure to afford compound (c) which is oxidized to the corresponding fully aromatized imidazopyrazine either by keeping it in solution in methanol or DMSO for 5 hours-3 days at about 20° C. or by using an oxidative reagent such as manganese dioxide in a protic or aprotic solvent such as MeOH, toluene or chloroform at 20-70° C. for 2-10 hours or chromic acid supported or not on a resin in a protic solvent like methanol at 40-70° C. for 3-15 hours.

EXAMPLE 12533

2,6-Diphenyl-imidazo[1,2-a]pyrazine-8-butanamine

[0356]

131

[0357] A solution of 2-[1,5-bis{(1,1-dimethylethoxy)carbonylamino}pentyl]-4-phenyl-1H-imidazole (50 mg) in a mixture of TFA/DCM 10% (700 mL) was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure to yield the intermediate dihydro-imidazo-pyrazine as its trifloroacetate salt. This salt was dissolved in MeOH (1 mL) and manganese dioxide (30 mg) was added. After about 3 hours of stirring at about 20° C., the mixture was filtered on a CELITE® pad and the filtrate concentrated under reduced pressure to afford the fully aromatized imidazo-pyrazine (78% yield). NMR (1H, 400 MHz, CD3OD): 8.75-7.34 (m, 12H, arom. H), 3.32 (m, 4H, CH2), 2.10 (m, 2H, CH2), 1.90 (m, 2H, CH2). LC/MS: calculated MW=342.4, m/z=343.2 (M+H).

EXAMPLES 12534-13773

[0358] The following compounds were prepared analogously to the procedure described for Example 12533, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3 and R7, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (5 substituents))(R5 (8 substituents))(R7 (31 substituents))=1240.

132

[0359] R3:

133

[0360] R5:

134

[0361] R7:

135

136

[0362] General procedure: Intermediate (d) is treated with an acidic solution preferably TFA in DCM at 20-30° C. for 14 hours. The mixture is then concentrated under reduced pressure to afford the intermediate dihydro-imidazopyrazine (e). Reduction of (e) to the corresponding tetrahydro-imidazopyrazine is achieved by catalytic hydrogenation or by using any reducing agent such as NaBH4 (which can be supported on a resin), NaBH(OAc)3, NaBH3CN in a protic solvent such as MeOH at pH maintained weakly acidic (around pH 5) by addition of acetic acid or TFA.

EXAMPLE 13774

6-Ethyl-5,6,7,8-tetrahydro-2-phenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine

[0363]

137

[0364] 2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich, 2.5 mmol BH4−/g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazo-pyrazine was obtained as a single diastereoisomer in 86% yield (38 mg). NMR (1H, 400 MHz, CDCl3) δ: 7.80-7.10 (m, 11H, arom. H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10. Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CH3). NMR (13C, 100 MHz, CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0.

[0365] LC/MS: calculated MW=317.43, m/z=318.20 (M+H).

EXAMPLE 13775

[0366] The following compound was prepared analogously to the procedure described for Example 13774 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein.

138

[0367] General procedure: A compound of formula (f) can react with isocyanates, isothiocyanates, N-succinimidyl carbamates, acyl chlorides or activated carboxylic acids in an aprotic solvent at 20-70° C. for 2-18 hours. The resulting derivative can be isolated by evaporation of the mixture followed by flash chromatography on silica gel or by addition to the mixture of a nucleophile supported on polymer such as aminomethyl or thiomethyl polystyrene resin followed by a filtration.

EXAMPLE 13776

5,6,7,8-Tetrahydro-7-(methoxymethylcarbonyl)-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine

[0368]

139

[0369] To a solution of 5,6,7,8-tetrahydro-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine (29 mg) in chloroform were successively added morpholinomethylpolystyrene resin (Novabiochem, loading=3.51 mmol/g, 50 mg, 2eq) and methoxyacetylchloride (10 mL, 1.3 eq). After about 3 hours of stirring at about 20° C., chloroform was added to the mixture followed by aminomethylpolystyrene resin (Novabiochem, loading=1.2 mmol/g, 132 mg, 2 eq). The reaction mixture was stirred for another 2 hours and then filtered. The filtrate was concentrated under reduced pressure to afford 23 mg of the title compound (yield=68%). NMR (1H, 100 MHz, CDCl3): 7.9-7.0 (m, 16H, arom. H), 6.6 (m, 1H, Ha), 5.3 (m, 1H, H6), 4.6 (dd, 1H, 2J=13 Hz, H5), 4.35 (dd, 1H, 2J=13 Hz, 3J=5 Hz, H5′), 3.7-2.9 (m, 5H, CH2Ph, OCH3).

[0370] The following tables of compounds illustrate some of the compounds of the present invention that were synthesized and provide the hplc retention time (denoted Rt or Tr) in minutes and mass spectra results of each compound.

[0371] Mass spectra were acquired on a single quadrupole electrospray mass spectrometer (Micromass, Platform model), 0.8 Da resolution. A monthly calibration, between 80 and 1000 Da, is performed with sodium and rubidium iodide solution isopropanol/water (1/1 Vol.).

[0372] HPLC retention times were acquired on an HPLC system: HP1100 (Hewlett-Packard) equipped with a photodiode array UV detector.

[0373] The HPLC conditions are as follows and the conditions used for each of the following tables of compounds are noted below, the wavlength of the UV detector is noted in parenthesis after the formula number.

3Condition A:Solvent:A: Water + 0.4% Formic acidB: Acetonitrile + 0.4% Formic acidT(min)A %B % 09010 59010164060171090201090Flow rate: 1 ml/min Injection volume volume: 20 μL Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d. Temp.: 40° C.

[0374]

4

Condition A2:

Solvent: A:

Water + 0.4% Formic acid

B: Acetonitrile + 0.4% Formic acid

T(min)
A %
B %

0
90
10

2
90
10

14
10
90

20
10
90

Flow rate: 1 ml/min

Injection volume: 20 μL

Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.

Temp.: 40° C.

[0375]

5

Condition A3:

Solvent:

A: Water + 0.4% Formic acid

B: Acetonitrile + 0.4% Formic acid

T(min)
A %
B %

0
90
10

5
90
10

16
46
54

17.5
10
90

22
10
90

Flow rate: 1 ml/min

Injection volume: 20 μL

Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.

Temp.: 40° C.

[0376]

6

Condition A4:

Solvent:

A: Water + 0.4% Formic acid

B: Acetonitrile + 0.4% Formic acid

T(min)
A %
B %

0
90
10

5
90
10

20
10
90

25
10
90

Flow rate: 1 ml/min

Injection volume: 20 μL

Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.

Temp.: 40° C.

[0377]

7

Condition A5:

Solvent:

A: Water + 0.4% Formic acid

B: Acetonitrile + 0.4% Formic acid

T(min)
A %
B %

0
90
10

5
90
10

25
10
90

30
10
90

Flow rate: 1 ml/min

Injection volume: 20 μL

Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.

Temp.: 40° C.

[0378]

8

Condition B:

Solvent:

A: Water + 0.02% Trifluoroacetic acid

B: Acetonitrile

T(min)
A %
B %

0
100
0

1
100
0

8
30
70

10
30
70

Flow rate: 1.1 ml/min

Injection volume: 5 μL

Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d.

Temp.: 40° C.

[0379]

9

Condition C:

Solvent:

A: Water + 0.02% Trifluoroacetic acid

B: Acetonitrile

T(min)
A %
B %

0
100
0

1
100
0

10
85
25

12
85
25

Flow rate: 1.1 ml/min

Injection volume: 5 μL

Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d

Temp.: 40° C.

[0380]

10

Condition D:

Solvent:

A: Water + 0.04% Trifluoroacetic acid

B: Acetonitrile

T(min)
A %
B %

0
100
0

1
100
0

8
30
70

10
30
70

Flow rate: 1.1 ml/min

Injection volume: 5 μL

Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d

Temp.: 40° C.

[0381]

11

Condition E:

Solvent:

A: Water + 0.04% Trifluoroacetic acid

B: Acetonitrile

T(min)
A %
B %

0
90
10

1
90
10

8
0
100

10
0
100

Flow rate: 1.1 ml/min

Injection volume: 5 μL

Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d

Temp.: 40° C.

[0382] In the following description Formula numbers are noted in bold and the the wavelength is in parenthesis.

[0383] Method A=Used for Tables of compounds of Formulas: 17 (250), 18 (250) and 57 (220).

[0384] Method A4=Used for Tables of compounds of Formulas: 58 (210).

[0385] Method B=Used for Tables of compounds of Formulas: 7 (220), 8 (220), 9 (220), 10 (220), 11 (220), 12 (250), 19 (220), 20 (260), 21 (250), 25 (240), 26 (220), 27 (220), 28 (220), 29 (220), 37 (220), 38 (220), 39 (220), 40 (240), 44 (220), 45 (220), 46 (220), 47 (220), 48 (220), 49 (250), 55 (260), and 56 (220).

[0386] Method C=Used for Tables of compounds of Formulas: 1 (220), 2 (220), 3 (220), 4 (260), 5 (220), 6 (220), 13 (220), 14 (220), 16 (260), 23 (250), 24 (250), 30 (220), 31 (254), 32 (250), 33 (250), 34 (250), 35 (250), and 36 (254).

[0387] Method D=Used for Tables of compounds of Formulas: 15 (220), 51 (220), 52 (220), 53 (220), and 54 (220).

[0388] Method E=Used for Tables of compounds of Formulas: 22 (250), 41 (220), 42 (250), 43 (220), and 50 (250).

12FORMULA 1

140

AnalysisR1R2Rt (min)[M + H]+1

141

142

7.0666.52

143

144

7.1668.53

145

146

6.2712.54

147

148

6.1698.55

149

150

5.0649.56

151

152

7.2656.57

153

154

6.2658.58

155

156

6.4643.59

157

158

6.7661.510

159

160

7.0689.511

161

162

5.8661.412

163

164

5.3657.513

165

166

5.4701.514

167

168

6.2733.515

169

170

6.7653.516

171

172

5.5659.517

173

174

4.8611.418

175

176

6.4681.519

177

178

6.4667.520

179

180

5.4671.521

181

182

7.2680.522

183

184

7.2682.523

185

186

6.4726.524

187

188

6.2712.525

189

190

5.1663.526

191

192

7.2670.527

193

194

6.3672.528

195

196

6.6657.529

197

198

6.8675.530

199

200

7.1703.531

201

202

5.9675.432

203

204

5.4671.533

205

206

5.5715.534

207

208

6.3747.535

209

210

6.8667.536

211

212

5.6673.537

213

214

4.9625.538

215

216

6.5681.539

217

218

6.5695.540

219

220

5.5685.541

221

222

7.2694.542

223

224

7.3696.543

225

226

6.4740.544

227

228

6.3726.545

229

230

5.2677.546

231

232

7.3684.547

233

234

6.4686.548

235

236

6.6671.549

237

238

6.8689.550

239

240

7.1717.551

241

242

6.0689.552

243

244

5.5685.553

245

246

5.5729.554

247

248

6.4761.555

249

250

6.9681.456

251

252

5.6687.557

253

254

5.0639.558

255

256

6.6709.559

257

258

6.6695.560

259

260

5.5699.561

261

262

7.68 + 7.8748.562

263

264

7.7750.563

265

266

7.0794.564

267

268

6.8780.565

269

270

5.8731.666

271

272

7.8738.567

273

274

6.9743.568

275

276

7.2725.569

277

278

7.3743.570

279

280

7.6771.571

281

282

6.5743.572

283

284

6.0739.573

285

286

6.0783.574

287

288

6.8815.675

289

290

7.4735.576

291

292

6.1741.577

293

294

5.6693.578

295

296

7.1 + 7.2749.579

297

298

7.1 + 7.2753.580

299

300

6.0753.5

[0389]

13

FORMULA 2

301

R1
R3
Rt (min.)
[M + H]+

1

302

303

5.5
566.3

2

304

305

5.6
568.3

3

306

307

4.9
612.3

4

308

309

4.8
598.3

5

310

311

3.8
549.4

6

312

313

5.6
556.3

7

314

315

5.3
540.3

8

316

317

4.9
543.3

9

318

319

5.1
561.3

10

320

321

5.4
589.3

11

322

323

4.3
561.3

12

324

325

4.1
557.3

13

326

327

4.1
601.3

14

328

329

4.9
633.4

15

330

331

5.3
533.3

16

332

333

4.2
559.3

17

334

335

3.5
511.3

18

336

337

3.5
481.3

19

338

339

3.5
467.3

20

340

341

4.1
571.3

21

342

343

5.6
580.4

22

344

345

5.6
582.4

23

346

347

4.9
626.4

24

348

349

4.8
612.4

25

350

351

3.8
563.4

26

352

353

5.6
570.4

27

354

355

5.4
554.3

28

356

357

4.9
557.3

29

358

359

5.1
575.3

30

360

361

5.4
603.3

31

362

363

4.4
575.3

32

364

365

4.1
571.3

33

366

367

4.1
615.4

34

368

369

4.9
647.4

35

370

371

5.3
567.3

36

372

373

4.2
573.3

37

374

375

3.5
525.3

38

376

377

3.5
495.3

39

378

379

3.5
481.3

40

380

381

4.1
585.4

41

382

383

5.6
594.4

42

384

385

5.6
596.4

43

386

387

5.0
640.4

44

388

389

4.8
626.4

45

390

391

5.6
584.4

46

392

393

5.7
568.3

47

394

395

5
571.3

48

396

397

5.1
589.4

49

398

399

5.5
617.4

50

400

401

4.4
589.3

51

402

403

4.1
585.4

52

404

405

4.2
629.4

53

406

407

4.9
661.5

54

408

409

4.3
587.4

55

410

411

3.6
539.4

56

412

413

3.6
509.4

57

414

415

3.5
495.3

58

416

417

4.1
599.3

59

418

419

5.8
648.5

60

420

421

5.9
650.5

61

422

423

5.2
694.5

62

424

425

5
680.5

63

426

427

5.9
638.5

64

428

429

5.2
625.5

65

430

431

5.4
643.5

66

432

433

5.7
671.4

67

434

435

4.6
643.4

68

436

437

4.4
639.5

69

438

439

4.4
689.5

70

440

441

5.2
715.5

71

442

443

4.5
641.5

72

444

445

3.9
593.4

[0390]

14

FORMULA 3

446

Analysis

Structure
Rt (min)
[M + H]+

1

447

9.1
842.5

2

448

9.2
844.5

3

449

8.3
888.5

4

450

8.1
874.5

5

451

6.9
825.5

6

452

9.2
832.5

7

453

8.2
834.5

8

454

8.6
819.4

9

455

8.7
837.5

10

456

9
865.5

11

457

7.8
837.4

12

458

7.1
833.5

13

459

7.1
877.5

14

460

8.1
909.5

15

461

8.7
829.5

16

462

7.2
835.5

17

463

6.7
787.4

18

464

8.5
843.5

19

465

8.5
857.5

20

466

7.1
847.5

21

467

4.5
710.5

22

468

4.1
754.5

23

469

4
740.5

24

470

3.1
691.6

25

471

4.5
698.5

26

472

3.9
700.5

27

473

4.1
685.5

28

474

4.2
703.5

29

475

3.1
721.4

30

476

3.3
743.5

31

477

4.2
695.5

32

478

3.4
701.5

33

479

3
653.4

34

480

4.1
709.5

35

481

4
723.5

36

482

3.2
623.4

[0391]

15

FORMULA 4

483

R1
R2
Tr (min)
(M + H)+

1

484

485

4.53
454.24

2

486

487

4.87
488.21

3

488

489

4.79
465.24

4

490

491

4.53
454.25

[0392]

16

FORMULA 5

492

R1
R2
Tr (min)
[M + H]+

1

493

494

8.0
732.2

2

495

496

7.7
706.2

3

497

498

6.4
755.2

4

499

500

7.3
697.3

5

501

502

7.6
731.2

6

503

504

7.6
760.3

7

505

506

7.9
794.3

8

507

508

7.8
743.4

9

509

510

7.5
774.4

10

511

512

7.8
808.3

11

513

514

7.8
757.4

12

515

516

7.6
743.4

13

517

518

7.8
785.4

14

519

520

7.6
774.4

15

521

522

7.8
763.4

16

523

524

8.5
783.3

17

525

526

8.9
817.3

[0393]

17

FORMULA 6

527

R2
Tr (min)
[M + H]+

1

528

4.7
525.3

2

529

6.0
534.3

3

530

6.4
536.3

4

531

6.5
597.3

5

532

6.1
510.4

6

533

4.9
559.3

7

534

6.4
611.4

*8

535

7.1
620.4

[0394]

18

FORMULA 7

536

R2
Tr (min)
[M + H]+

1

537

4.6
469.4

2

538

5.0
533.3

3

539

4.6
485.4

4

540

4.9
489.4

5

541

5.3
523.3

[0395]

19

FORMULA 8

542

R2
Tr (min)
[M + H]+

1

543

7.0
687.5

2

544

7.3
751.3

3

545

6.9
703.4

4

546

7.2
707.4

5

547

7.5
741.3

[0396]

20

FORMULA 9

548

R2
Tr (min)
[M + H]+

1

549

3.8; 3.4
420.3

2

550

3.8; 3.6
417.3

3

551

3.8; 3.5
439.3

4

552

3.7; 3.4
403.3

5

553

3.9; 3.6
411.4

[0397]

21

FORMULA 10

554

R2
Tr (min)
[M + H]+

1

555

4.4
520.2

2

556

4.5
517.2

3

557

4.4
539.3

4

558

4.4
503.2

5

559

4.5
511.3

6

560

5.1
523.3

7

561

5.5
559.3

[0398]

22

FORMULA 11

562

Analyses

* = (M + TFA − H)−

R2
Tr (min)
(M + H)+

1

563

4.6
455.2

2

564

4.9
515.2

3

565

4.8
473.2

4

566

4.9
612.2*

5

567

4.8
500.2

6

568

4.2
526.3

7

569

5.4
539.2

8

570

5.1
539.1

9

571

5.1
483.3

10

572

5.0
495.2

11

573

4.1
519.2*

12

574

4.4
524.3

[0399]

23

FORMULA 12

575

Analyses

R2
Tr (min)
[M + H]+

1

576

6.9
673.3

2

577

7.0
733.3

3

578

7.0
691.3

4

579

7.1
718.3

5

580

7.0
718.3

6

581

7.4
744.4

7

582

7.6
757.3

8

583

7.3
757.2

9

584

7.3
701.3

10

585

7.2
713.3

11

586

6.5
625.3

12

587

6.3
742.3

[0400]

24

FORMULA 13

588

Analyses

R2
Tr (min)
[M + H]+

1

589

3.8
425.3

2

590

4.2
485.4

3

591

4.0
438.4

4

592

4.0
403.3

5

593

3.9
425.4

6

594

3.6
452.4

7

595

3.8
403.3

8

596

5.1
438.3

9

597

4.6
432.3

10

598

6.2
506.4

11

599

3.8
409.3

[0401]

25

FORMULA 14

600

Analysis

R2
Tr (min)
[M + H]+

1

601

4.6
525.3

2

602

5.0
585.3

3

603

4.8
538.3

4

604

4.9
503.3

5

605

4.6
525.4

6

606

4.3
552.3

7

607

4.6
503.3

[0402]

26

FORMULA 15

608

Analysis

R1
R2
Tr (min)
[M + H]+

1

609

610

5.9
623.4

2

611

612

7.6
699.4

3

613

614

7.9
733.3

4

615

616

7.9
682.4

5

617

618

7.7
668.4

6

619

620

7.9
710.3

7

621

622

7.7
699.4

8

623

624

7.9
688.3

9

625

626

8.2
722.3

10

627

628

7.5
712.4

11

629

630

7.6
634.4

12

631

632

7.3
673.3

13

633

634

7.6
707.3

14

635

636

7.6
656.4

15

637

638

7.4
642.4

16

639

640

7.6
684.3

17

641

642

7.4
673.3

18

643

644

7.6
662.3

19

645

646

7.9
696.3

20

647

648

7.2
686.4

21

649

650

7.3
608.4

22

651

652

6.0
722.3

23

653

654

6.4
756.3

24

655

656

6.3
705.4

25

657

658

6.1
691.4

26

659

660

6.4
733.3

27

661

662

6.1
722.3

28

663

664

6.3
711.3

29

665

666

6.7
745.2

30

667

668

5.9
735.3

31

669

670

6.0
657.4

[0403]

27

FORMULA 16

671

Analysis

R1
R2
Tr (min)
[M + H]+

1

672

673

5.7
477.2

2

674

675

6.0
511.1

3

676

677

6.1
540.2

4

678

679

6.3
574.1

5

680

681

6.0
523.3

6

682

683

4.4
437.3

7

684

685

4.2
423.3

8

686

687

4.8
443.3

9

688

689

6.8
563.2

10

690

691

7.0
597.2

11

692

693

6.1
479.3

12

694

695

6.5
513.2

13

696

697

6.0
462.3

14

698

699

5.8/5.9
448.3

15

700

701

6.4
490.2

16

702

703

6.1
479.3

17

704

705

6.4
468.2

18

706

707

6.8
502.2

19

708

709

6.0
492.3

20

710

711

6.5
512.2

21

712

713

5.9
453.3

22

714

715

6.2
487.2

23

716

717

5.7
436.3

24

718

719

5.5/5.6
422.3

25

720

721

6.2
464.2

26

722

723

5.9/6.0
453.3

27

724

725

6.1
442.2

28

726

727

6.5
476.2

29

728

729

5.7
466.3

30

730

731

6.2
486.2

31

732

733

4.7
502.2

32

734

735

5.0
536.2

33

736

737

4.6
485.3

34

738

739

4.5
471.3

35

740

741

5.0
513.2

36

742

743

4.7
502.2

37

744

745

4.9
491.2

38

746

747

5.3
525.2

39

748

749

4.6
515.2

40

750

751

5.0
535.1

[0404]

28

FORMULA 17

752

Analysis

R1
R2
Tr (min)
[M + H]+

1

753

754

14.3
403.2

2

755

756

15.0
479.2

3

757

758

14.8
453.2

4

759

760

14.4
463.2

5

761

762

14.6
437.1

6

763

764

15.0
471.1

7

765

766

14.8
451.1

8

767

768

14.8
481.0

9

769

770

14.5
421.2

10

771

772

14.3
428.1

11

773

774

14.6
444.2

12

775

776

14.5
448.1

13

777

778

14.5
448.1

14

779

780

14.0
355.2

15

781

782

14.3
403.2

16

783

784

15.2
479.2

17

785

786

14.9
453.2

18

787

788

14.4
433.2

19

789

790

14.5
463.2

20

791

792

14.8
437.1

21

793

794

15.1
474.1

22

795

796

15.0
451.1

23

797

798

14.8
481.0

24

799

800

14.5
421.2

25

801

802

14.4
428.1

26

803

804

14.7
444.1

27

805

806

14.6
448.1

28

807

808

14.5
448.1

29

809

810

13.9
355.2

30

811

812

15.2
364.2

31

813

814

16.3
440.2

32

815

816

15.9
414.2

33

817

818

15.1
394.2

34

819

820

15.1
424.2

35

821

822

15.1
435.2

36

823

824

15.8
398.1

37

825

826

16.8
432.1

38

827

828

16.3
412.1

39

829

830

16.1
442.0

40

831

832

15.6
409.1

41

833

834

15.6
409.1

42

835

836

14.4
316.2

43

837

838

15.1
479.2

44

839

840

15.6
529.2

45

841

842

15.0
509.2

46

843

844

15.2
539.2

47

845

846

15.2
550.2

48

847

848

15.6
513.1

49

849

850

16.0
547.1

50

851

852

15.8
527.2

51

853

854

15.6
557.0

52

855

856

15.2
497.2

53

857

858

15.7
520.2

54

859

860

15.4
524.2

55

861

862

14.5
431.2

[0405]

29

FORMULA 18

863

Analyses

R1
R2
Tr (min)
[M + H]+

1

864

865

15.4
521.2

2

866

867

16.5
597.1

3

868

869

16.1
571.2

4

870

871

15.3
551.2

5

872

873

15.3
581.2

6

874

875

15.8
592.2

7

876

877

16.1
555.1

8

878

879

16.7
589.0

9

880

881

16.4
569.1

10

882

883

16.1
599.0

11

884

885

15.6
539.1

12

886

887

15.4
546.2

13

888

889

15.8
562.1

14

890

891

15.8
566.1

15

892

893

15.7
566.1

16

894

895

14.8
473.2

17

896

897

15.5
521.2

18

898

899

16.5
597.1

19

900

901

16.1
571.1

20

902

903

15.4
551.2

21

904

905

15.4
581.1

22

906

907

15.9
592.2

23

908

909

16.3
555.1

24

910

911

16.8
589.0

25

912

913

16.7
569.1

26

914

915

16.4
599.0

27

916

917

15.8
539.1

28

918

919

15.6
546.1

29

920

921

16.0
562.1

30

922

923

15.9
566.1

31

924

925

15.8
566.1

32

926

927

15.0
473.2

33

928

929

16.7
482.2

34

930

931

18.0
558.2

35

932

933

16.4
512.2

36

934

935

16.5
542.2

37

936

937

17.0
553.2

38

938

939

17.6
516.1

39

940

941

18.2
550.1

40

942

943

18.0
530.1

41

944

945

17.7
560.0

42

946

947

16.9
500.2

43

948

949

16.7
507.2

44

950

951

17.2
523.2

45

952

953

16.9
527.2

46

954

955

16.8
527.2

47

956

957

15.8
434.2

48

958

959

15.8
597.2

49

960

961

16.8
673.2

50

962

963

16.5
647.2

51

964

965

15.8
627.2

52

966

967

15.8
657.2

53

968

969

16.5
631.1

54

970

971

17.2
665.1

55

972

973

16.7
645.1

56

974

975

16.5
675.1

57

976

977

16.0
615.1

58

978

979

15.9
622.1

59

980

981

16.1
638.2

60

982

983

16.1
642.1

61

984

985

16.2
642.1

62

986

987

15.4
549.2

63

988

989

15.9
563.2

64

990

991

17.0
639.2

65

992

993

16.5
613.2

66

994

995

15.7
593.2

67

996

997

15.8
623.2

68

998

999

16.2
634.2

69

1000

1001

16.6
597.1

70

1002

1003

17.4
631.1

71

1004

1005

17.0
611.1

72

1006

1007

16.7
641.1

73

1008

1009

16.1
581.2

74

1010

1011

15.9
588.2

75

1012

1013

16.2
604.2

76

1014

1015

16.2
608.2

77

1016

1017

16.1
608.2

78

1018

1019

15.3
515.3

[0406]

30

FORMULA 19

1020

Analyses

* = [M + TFA − H]−

R1
R2
Tr
[M + H]+

1

1021

1022

6.2
433.2

2

1023

1024

7.0
509.2

3

1025

1026

6.8
483.2

4

1027

1028

6.2
463.2

5

1029

1030

6.5
493.2

6

1031

1032

5.4
504.3

7

1033

1034

6.5
467.2

8

1035

1036

6.9
501.1

9

1037

1038

6.8
481.2

10

1039

1040

6.6
511.1

11

1041

1042

6.3
451.2

12

1043

1044

6.2
458.2

13

1045

1046

6.5
474.2

14

1047

1048

6.3
478.2

15

1049

1050

6.3
478.2

16

1051

1052

5.7
385.2

17

1053

1054

6.9
433.2

18

1055

1056

7.0
509.2

19

1057

1058

6.7
483.2

20

1059

1060

6.2
463.2

21

1061

1062

6.3
493.2

22

1063

1064

5.3
504.3

23

1065

1066

6.5
467.2

24

1067

1068

6.8
501.1

25

1069

1070

6.7
481.2

26

1071

1072

6.5
511.1

27

1073

1074

6.2
451.2

28

1075

1076

6.1
458.2

29

1077

1078

6.4
474.2

30

1079

1080

6.3
478.2

31

1081

1082

6.3
478.2

32

1083

1084

5.6
385.2

33

1085

1086

6.5
481.1

34

1087

1088

7.4
557.1

35

1089

1090

7.1
531.1

36

1091

1092

6.6
511.1

37

1093

1094

6.8
541.1

38

1095

1096

5.7
552.2

39

1097

1098

6.9
515.0

40

1099

1100

7.3
549.0

41

1101

1102

7.1
529.1

42

1103

1104

7.0
670.1*

43

1105

1106

6.6
499.1

44

1107

1108

6.6
506.1

45

1109

1110

6.8
522.1

46

1111

1112

6.8
526.1

47

1113

1114

6.7
526.1

48

1115

1116

6.0
433.1

49

1117

1118

6.6
448.2

50

1119

1120

7.7
524.2

51

1121

1122

7.4
498.2

52

1123

1124

6.6
478.2

53

1125

1126

6.7
508.2

54

1127

1128

5.8
519.2

55

1129

1130

7.2
482.1

56

1131

1132

7.7
516.1

57

1133

1134

7.5
496.2

58

1135

1136

7.3
526.1

59

1137

1138

6.8
466.2

60

1139

1140

6.8
473.2

61

1141

1142

7.1
489.2

62

1143

1144

7.1
493.1

63

1145

1146

7.0
493.2

64

1147

1148

5.8
400.2

65

1149

1150

5.8
383.2

66

1151

1152

6.8
459.2

67

1153

1154

6.5
433.2

68

1155

1156

5.9
413.2

69

1157

1158

6.2
443.3

70

1159

1160

5.0
454.3

71

1161

1162

6.3
417.2

72

1163

1164

6.6
451.1

73

1165

1166

6.5
431.2

74

1167

1168

6.3
461.1

75

1169

1170

6.0
401.2

76

1171

1172

5.8
408.2

77

1173

1174

6.2
424.2

78

1175

1176

6.0
428.2

79

1177

1178

6.0
428.2

80

1179

1180

5.3
335.3

[0407]

1181

FORMULA 20
LFPlb2-02fon/xls

Analyses

R1
R2
Tr (min)
[M+H]+

1

1182

1183

6.9
487.2

2

1184

1185

6.3
461.3

3

1186

1187

6.3
447.3

4

1188

1189

6.2
493.3

5

1190

1191

6.7
482.2

6

1192

1193

7.2
509.3

7

1194

1195

7.7
473.4

8

1196

1197

5.8
472.3

9

1198

1199

7.3
507.2

10

1200

1201

6.6
459.3

11

1202

1203

6.6
487.2

12

1204

1205

6.7
470.3

13

1206

1207

7.2
538.2

14

1208

1209

6.6
456.3

15

1210

1211

6.6
431.3

16

1212

1213

6.5
439.3

17

1214

1215

7.1
517.3

18

1216

1217

6.5
491.3

19

1218

1219

6.4
477.3

20

1220

1221

6.4
523.3

21

1222

1223

6.9
512.3

22

1224

1225

7.3
539.3

23

1226

1227

7.8
503.4

24

1228

1229

6.0
502.3

25

1230

1231

7.4
537.3

26

1232

1233

6.8
489.3

27

1234

1235

6.8
517.2

28

1236

1237

6.8
500.3

29

1238

1239

7.4
562.2

30

1240

1241

6.7
486.4

31

1242

1243

6.8
461.3

32

1244

1245

6.7
469.3

33

1246

1247

7.4
532.3

34

1248

1249

6.6
506.3

35

1250

1251

6.6
492.3

36

1252

1253

6.6
538.3

37

1254

1255

7.3
527.2

38

1256

1257

7.5
554.3

39

1258

1259

8.1
518.3

40

1260

1261

6.1
517.3

41

1262

1263

8.1
552.2

42

1264

1265

7.0
504.3

43

1266

1267

7.2
532.1

44

1268

1269

7.4
515.3

45

1270

1271

8.1
583.2

46

1272

1273

6.8
501.3

47

1274

1275

5.9
476.3

48

1276

1277

7.0
484.3

49

1278

1279

7.3
565.2

50

1280

1281

6.7
539.2

51

1282

1283

6.7
525.2

52

1284

1285

6.7
571.2

53

1286

1287

7.1
560.1

54

1288

1289

7.6
587.2

55

1290

1291

8.0
551.3

56

1292

1293

6.3
550.2

57

1294

1295

7.7
585.1

58

1296

1297

7.0
537.2

59

1298

1299

7.0
565.0

60

1300

1301

7.2
548.2

61

1302

1303

7.7
616.1

62

1304

1305

7.0
534.2

63

1306

1307

7.0
509.2

64

1308

1309

6.9
517.2

65

1310

1311

6.8
467.3

66

1312

1313

6.1
444.3

67

1314

1315

6.1
427.3

68

1316

1317

6.1
473.4

69

1318

1319

6.6
462.3

70

1320

1321

7.1
489.4

71

1322

1323

7.6
453.4

72

1324

1325

5.6
452.3

73

1326

1327

7.2
487.3

74

1328

1329

6.5
439.3

75

1330

1331

6.5
467.2

76

1332

1333

6.5
450.3

77

1334

1335

7.1
518.2

78

1336

1337

6.3
436.3

79

1338

1339

6.5
411.3

80

1340

1341

6.4
419.3

[0408]

1342

FORMULA 21
Analyses

* = [M + TFA − H]

R1
R2
Tr (min)
[M + H]+

1

1343

1344

7.0
551.2

2

1345

1346

7.8
627.2

3

1347

1348

7.5
601.2

4

1349

1350

7.1
581.2

5

1351

1352

7.1
611.2

6

1353

1354

7.5
622.3

7

1355

1356

7.4
585.2

8

1357

1358

7.7
619.1

9

1359

1360

7.7
599.2

10

1361

1362

7.4
629.1

11

1363

1364

7.1
569.2

12

1365

1366

7.0
576.2

13

1367

1368

7.3
592.2

14

1369

1370

7.2
596.2

15

1371

1372

7.1
596.2

16

1373

1374

6.6
503.3

17

1375

1376

7.0
551.2

18

1377

1378

7.8
627.2

19

1379

1380

7.5
601.2

20

1381

1382

7.0
581.2

21

1383

1384

7.1
611.2

22

1385

1386

7.5
622.3

23

1387

1388

7.4
585.2

24

1389

1390

7.7
619.1

25

1391

1392

7.6
599.2

26

1393

1394

7.4
629.1

27

1395

1396

7.1
569.2

28

1397

1398

6.9
576.2

29

1399

1400

7.3
704.2*

30

1401

1402

7.1
596.2

31

1403

1404

7.0
596.2

32

1405

1406

6.5
503.2

33

1407

1408

8.1
599.1

34

1409

1410

9.0
675.1

35

1411

1412

8.7
649.1

36

1413

1414

8.1
629.1

37

1415

1416

8.0
659.1

38

1417

1418

8.4
670.2

39

1419

1420

8.6
633.1

40

1421

1422

9.0
667.0

41

1423

1424

8.8
647.1

42

1425

1426

8.6
677.0

43

1427

1428

8.3
617.1

44

1429

1430

8.2
624.1

45

1431

1432

8.4
640.1

46

1433

1434

8.4
644.1

47

1435

1436

8.3
644.1

48

1437

1438

7.6
551.1

49

1439

1440

8.7
566.2

50

1441

1442

9.7
542.2

51

1443

1444

9.3
616.2

52

1445

1446

8.6
596.2

53

1447

1448

8.7
626.2

54

1449

1450

9.1
637.2

55

1451

1452

9.2
600.1

56

1453

1454

9.6
634.1

57

1455

1456

9.5
614.1

58

1457

1458

9.3
644.1

59

1459

1460

8.8
584.2

60

1461

1462

8.7
591.2

61

1463

1464

9.0
607.2

62

1465

1466

8.9
611.1

63

1467

1468

8.8
611.1

64

1469

1470

8.2
518.2

65

1471

1472

6.7
501.3

66

1473

1474

7.5
577.2

67

1475

1476

7.2
551.3

68

1477

1478

6.8
531.3

69

1479

1480

6.9
561.2

70

1481

1482

7.3
572.3

71

1483

1484

7.0
535.2

72

1485

1486

7.3
569.1

73

1487

1488

7.3
549.2

74

1489

1490

7.1
579.1

75

1491

1492

6.8
519.2

76

1493

1494

6.6
526.3

77

1495

1496

7.0
542.2

78

1497

1498

6.8
546.2

79

1499

1500

6.7
546.2

80

1501

1502

6.2
453.3

[0409]

1503

FORMULA 22

Analysis

R1
R2
Tr (min)
[M + H]+

1

1504

1505

6.6
605.3

2

1506

1507

6.3
579.3

3

1508

1509

6.3
565.3

4

1510

1511

6.3
611.3

5

1512

1513

6.5
600.2

6

1514

1515

6.6
627.3

7

1516

1517

6.9

8

1518

1519

5.9
590.3

9

1520

1521

6.9
625.2

10

1522

1523

6.5
577.3

11

1524

1525

6.6
(605.12) THEO

12

1526

1527

6.6
588.3

13

1528

1529

7.0
656.2

14

1530

1531

6.4
574.3

15

1532

1533

6.5
549.3

16

1534

1535

6.5
557.3

17

1536

1537

6.5
635.3

18

1538

1539

6.2
609.3

19

1540

1541

6.2
595.3

20

1542

1543

6.2
641.3

21

1544

1545

6.4
630.2

22

1546

1547

6.5
657.3

23

1548

1549

6.8
621.4

24

1550

1551

5.9

25

1552

1553

6.7
655.2

26

1554

1555

6.4
607.2

27

1556

1557

6.4
635.2

28

1558

1559

6.5
618.3

29

1560

1561

6.7
686.2

30

1562

1563

.2 OU 6.3 ?
604.3

31

1564

1565

6.4
579.3

32

1566

1567

6.3
587.2

33

1568

1569

7.3
650.2

34

1570

1571

7.0
624.2

35

1572

1573

7.0
610.2

36

1574

1575

7.0
656.3

37

1576

1577

7.0
645.1

38

1578

1579

7.3
672.3

39

1580

1581

7.6
636.3

40

1582

1583

7.8
635.2

41

1584

1585

7.5 ?
670.2 ?

42

1586

1587

7.3 ?
622.2 ?

43

1588

1589

7.3
650.1

44

1590

1591

7.3
633.2

45

1592

1593

7.6
701.2

46

1594

1595

7.2
594.3

47

1596

1597

7.2
602.2

48

1598

1599

7.0
(683.14) THEO

49

1600

1601

6.7
657.2

50

1602

1603

6.7
643.1

51

1604

1605

6.7
689.2

52

1606

1607

7.0 ?
678.1 ?

53

1608

1609

7.0
705.2

54

1610

1611

7.2
699.3

55

1612

1613

7.3
668.1

56

1614

1615

9.5
703.0

57

1616

1617

8.6
655.0

58

1618

1619

8.7
683.0

59

1620

1621

9.0
666.1

60

1622

1623

9.8
734.0

61

1624

1625

8.0
652.1

62

1626

1627

8.5
627.1

63

1628

1629

8.5
635.1

64

1630

1631

7.3
585.2

65

1632

1633

6.7
559.2

66

1634

1635

6.7
545.2

67

1636

1637

6.7
591.3

68

1638

1639

7.0
580.2

69

1640

1641

7.6
607.3

70

1642

1643

8.0
571.3

71

1644

1645

6.1
570.3

72

1646

1647

7.6
605.2

73

1648

1649

7.1
557.2

74

1650

1651

7.0
585.1

75

1652

1653

7.1
568.2

76

1654

1655

7.6
636.2

77

1656

1657

6.8
554.2

78

1658

1659

7.1
529.3

79

1660

1661

6.9
537.2

[0410]

1662

FORMULA 23

Analysis

R1
Tr
[M + H]+

1

1663

5.6
448.3

2

1664

5.8
482.2

3

1665

5.9
482.2

4

1666

5.7
478.3

5

1667

6.2
516.2

6

1668

6.5
504.3

7

1669

5.7
484.3

8

1670

6.3
532.2

9

1671

6.2
530.2

10

1672

5.6
506.3

11

1673

5.5
454.2

12

1674

5.0
386.3

[0411]

1675

FORMULA 24

Analysis

R1
R2
R3
Tr
[M + H]+

1

1676

1677

1678

5.6
403.1

2

1679

1680

1681

4.9
335.2

3

1682

1683

1684

5.3
403.2

4

1685

1686

1687

4.8
335.3

5

1688

1689

1690

5.1
442.2

6

1691

1692

1693

4.7
374.2

7

1694

1695

1696

5.2
442.2

8

1697

1698

1699

4.7
374.2

9

1700

1701

1702

4.5
392.2

10

1703

1704

1705

4.3
324.3

11

1706

1707

1708

4.8
456.2

12

1709

1710

1711

4.5
387.2

13

1712

1713

1714

5.3
373.2

14

1715

1716

1717

4.7
305.2

[0412]

1718

FORMULA 25

Analysis

R1
Tr
[M + H]+

1

1719

5.1
436.4

2

1720

6.5
520.3

3

1721

6.0
486.4

4

1722

5.0
436.4

5

1723

5.3
436.4

6

1724

6.4
474.4

7

1725

6.4
532.4

8

1726

6.6
488.4

[0413]

1727

FORMULA 26

Analysis

R1
Tr
[M + H]+

1

1728

6.1
435.3

2

1729

5.9
451.3

3

1730

5.8
451.3

4

1731

6.2
453.3

5

1732

6.2
465.3

6

1733

6.1
465.3

7

1734

6.2
465.3

8

1735

6.2
480.4

9

1736

6.2
480.4

10

1737

6.7
503.3

11

1738

6.4
510.4

12

1739

6.5
513.3

13

1740

6.0
441.3

14

1741

6.1
525.4

15

1742

7.0
541.4

16

1743

6.1
453.4

17

1744

6.5
479.4

18

1745

6.6
503.4

19

1746

6.9
511.4

20

1747

6.4
513.3

21

1748

5.8
478.4

22

1749

6.8
519.3

23

1750

5.1
536.5

24

1751

6.2
483.4

25

1752

7.0
491.4

26

1753

6.5
513.3

27

1754

6.9
557.4

[0414]

1755

FORMULA 27

Analysis

[M +

R1
R2
Tr
H]+

1

1756

1757

6.4
478.3

2

1758

1759

5.6
444.3

3

1760

1761

4.8
394.3

4

1762

1763

4.9
394.3

5

1764

1765

4.8
394.3

6

1766

1767

6.4
478.3

7

1768

1769

5.6
444.3

8

1770

1771

4.7
394.3

9

1772

1773

4.9
394.3

10

1774

1775

4.9
424.3

11

1776

1777

6.6
508.3

12

1778

1779

5.7
474.3

13

1780

1781

4.9
424.3

14

1782

1783

5.0
424.3

15

1784

1785

4.9
424.3

16

1786

1787

6.5
508.3

17

1788

1789

5.6
474.3

18

1790

1791

4.9
424.3

19

1792

1793

5.0
424.3

20

1794

1795

4.9
424.3

21

1796

1797

6.5
508.3

22

1798

1799

5.6
474.3

23

1800

1801

4.9
424.3

24

1802

1803

5.0
424.3

[0415]

1804

FORMULA 28

Analysis

R1
R2
Tr
[M + H]+

1

1805

1806

6.1
441.2

2

1807

1808

6.4
471.1

3

1809

1810

5.8
359.3

4

1811

1812

6.1
373.3

5

1813

1814

5.8
391.2

6

1815

1816

6.2
387.3

7

1817

1818

7.1
437.5

8

1819

1820

6.3
399.3

9

1821

1822

6.8
449.3

10

1823

1824

6.4
387.3

11

1825

1826

6.1
471.2

12

1827

1828

6.5
501.1

13

1829

1830

5.8
389.3

14

1831

1832

6.1
403.3

15

1833

1834

5.8
421.2

16

1835

1836

6.2
417.3

17

1837

1838

7.0
467.2

18

1839

1840

6.3
429.3

19

1841

1842

6.9
479.3

20

1843

1844

6.4
417.3

21

1845

1846

6.0
471.2

22

1847

1848

6.4
501.1

23

1849

1850

6.0
403.3

24

1851

1852

6.1
417.3

25

1853

1854

6.9
467.1

26

1855

1856

6.3
429.3

27

1857

1858

6.8
479.3

28

1859

1860

6.4
417.3

29

1861

1862

6.0
471.2

30

1863

1864

6.4
501.1

31

1865

1866

5.8
389.3

32

1867

1868

6.2
417.3

33

1869

1870

6.9
467.1

34

1871

1872

6.3
429.3

35

1873

1874

6.8
479.3

36

1875

1876

6.4
417.3

[0416]

1877

FORMULA 29

Analysis

R1
Tr
[M + H]+

1

1878

5.9
393.3

2

1879

5.7
409.3

3

1880

5.6
409.3

4

1881

6.1
411.3

5

1882

6.0
423.3

6

1883

6.1
423.3

7

1884

6.1
438.3

8

1885

6.6
461.2

9

1886

6.2
468.3

10

1887

6.4
471.2

11

1888

5.9
399.3

12

1889

5.9
483.4

13

1890

6.3
471.2

14

1891

6.7
477.3

15

1892

6.5
494.4

16

1893

6.1
441.3

17

1894

6.3
387.3

18

1895

6.4
437.3

19

1896

6.4
399.4

20

1897

6.9
449.4

21

1898

6.5
387.4

[0417]

1899

FORMULA 30

Analysis

R1
Tr
[M + H]+

1

1900

5.4
458.2

2

1901

5.7
460.2

3

1902

5.3
499.3

4

1903

6.1
522.3

5

1904

6.3
531.3

6

1905

6.4
533.3

7

1906

6.6
543.3

8

1907

5.1
547.3

9

1908

6.5
551.3

10

1909

6.1
563.3

11

1910

6.9
567.2

12

1911

7.2
568.2

13

1912

6.5
578.2

14

1913

6.1
564.3

15

1914

6.8
567.2

16

1915

4.9
534.3

17

1916

7.0
546.3

18

1917

6.8
578.3

19

1918

5.1
591.3

20

1919

7.1
601.3

21

1920

6.2
602.3

22

1921

6.9
567.2

23

1922

5.2
549.2

24

1923

6.7
528.2

25

1924

7.1
561.3

26

1925

7.0
568.2

27

1926

6.5
591.3

28

1927

6.0
588.2

29

1928

5.7
571.2

30

1929

5.7
551.2

31

1930

6.9
653.3

32

1931

7.4
612.3

33

1932

6.0
563.3

34

1933

6.0
623.3

35

1934

5.2
549.3

36

1935

4.4
558.3

37

1936

6.6
551.3

[0418]

1937

FORMULA 31

Analysis

R1
Tr
[M + H]+

1

1938

4.7
473.3

2

1939

6.6
484.3

3

1940

6.3
492.3

4

1941

6.2
508.3

5

1942

6.5
522.3

6

1943

6.1
552.3

7

1944

4.8
482.3

8

1945

6.0
568.2

9

1946

6.4
537.2

10

1947

6.5
472.3

11

1948

4.7
479.3

12

1949

4.8
493.3

13

1950

4.8
515.3

14

1951

5.9
543.3

15

1952

6.0
553.2

16

1953

6.6
538.2

17

1954

5.5
510.3

18

1955

4.9
514.3

19

1956

6.1
444.3

20

1957

5.8
610.3

21

1958

7.0
554.3

22

1959

4.9
479.3

23

1960

6.5
512.2

24

1961

7.2
582.3

25

1962

6.6
506.3

26

1963

4.8
485.3

27

1964

6.7
526.2

28

1965

6.4
510.3

29

1966

6.4
510.3

30

1967

6.7
526.2

31

1968

6.8
570.2

32

1969

6.7
546.2

33

1970

6.8
546.2

34

1971

4.8
479.3

35

1972

6.3
508.3

36

1973

6.4
512.2

37

1974

6.3
496.3

38

1975

6.2
496.3

39

1976

6.3
496.3

40

1977

4.5
528.3

[0419]

1978

FORMULA 32

Analysis

R1
Tr
[M + H]+

1

1979

6.4
498.2

2

1980

6.6
498.2

3

1981

6.6
498.2

4

1982

6.4
542.1

5

1983

6.6
542.1

6

1984

6.7
542.1

7

1985

6.3
482.2

8

1986

6.3
500.2

9

1987

6.4
500.2

10

1988

6.3
509.2

11

1989

6.4
509.2

12

1990

6.4
509.2

13

1991

6.5
532.2

14

1992

6.8
532.2

15

1993

6.8
532.2

16

1994

6.3
524.2

17

1995

6.2
494.2

18

1996

6.1
494.2

19

1997

6.9
566.1

20

1998

6.4
527.2

[0420]

44

FORMULA 33

1999

Analysis

R1
Tr
[M + H]+

1

2000

6.4
456.1

2

2001

6.2
500.1

3

2002

6.4
500.1

4

2003

6.4
500.1

5

2004

6.1
440.1

6

2005

6.2
458.1

7

2006

6.1
467.1

8

2007

6.2
467.1

9

2008

6.2
490.1

10

2009

6.6
490.1

11

2010

6.1
482.2

12

2011

6.0
452.2

13

2012

5.9
452.2

14

2013

6.7
524.1

15

2014

6.2
485.1

[0421]

45

FORMULA 34

2015

Analysis

R1
Tr
[M + H]+

1

2016

3.9
348.3

2

2017

4.0
382.2

3

2018

4.3
382.2

4

2019

4.1
378.2

5

2020

4.5
416.2

6

2021

5.0
404.3

7

2022

4.0
384.2

8

2023

4.7
432.2

9

2024

4.5
430.2

10

2025

3.9
406.2

11

2026

3.8
354.2

12

2027

3.2
286.3

[0422]

46

FORMULA 35

2028

Analysis

[M +

R1
Tr
H]+

1

2029

3.7
358.2

2

2030

3.9
360.2

3

2031

3.5
399.2

4

2032

4.4
422.2

5

2033

4.7
431.2

6

2034

4.7
433.2

7

2035

5.0
443.2

8

2036

3.8
447.3

9

2037

4.8
451.2

10

2038

4.6
463.2

11

2039

5.2
467.2

12

2040

5.4
468.2

13

2041

4.9
478.2

14

2042

4.6
464.2

15

2043

5.2
467.2

16

2044

3.5
434.2

17

2045

5.3
446.2

18

2046

5.0
478.2

19

2047

3.8
491.2

20

2048

5.5
501.2

21

2049

4.6
502.3

22

2050

5.1
467.2

23

2051

3.8
449.2

24

2052

5.0
428.2

25

2053

5.4
461.2

26

2054

5.4
468.2

27

2055

5.0
491.2

28

2056

4.5
488.2

29

2057

4.0
471.2

30

2058

4.1
451.2

31

2059

5.2
553.3

32

2060

5.6
512.2

33

2061

4.5
463.3

34

2062

4.7
523.3

35

2063

3.8
449.3

36

2064

3.1
458.3

37

2065

4.8
451.2

[0423]

47

FORMULA 36

2066

R1
Tr
[M + H]+

1

2067

3.2
373.3

2

2068

4.8
384.3

3

2069

4.7
392.2

4

2070

4.5
408.2

5

2071

4.8
422.2

6

2072

4.5
452.2

7

2073

3.3
382.2

8

2074

4.4
468.2

9

2075

4.7
437.2

10

2076

4.8
372.3

11

2077

3.2
379.2

12

2078

3.3
393.2

13

2079

3.3
415.2

14

2080

4.4
443.3

15

2081

4.4
453.2

16

2082

5.0
438.2

17

2083

3.9
410.2

18

2084

3.6
414.3

19

2085

4.3
344.3

20

2086

4.6
510.2

21

2087

5.3
454.2

22

2088

3.4
379.2

23

2089

4.8
412.1

24

2090

5.6
482.3

25

2091

5.0
406.2

26

2092

3.3
385.2

27

2093

5.0
426.2

28

2094

4.7
410.2

29

2095

4.8
410.2

30

2096

5.0
426.2

31

2097

5.1
470.2

32

2098

5.1
446.2

33

2099

5.1
446.2

34

2100

3.3
379.2

35

2101

4.6
408.2

36

2102

4.8
412.1

37

2103

4.6
396.2

38

2104

4.5
396.2

39

2105

4.6
396.2

40

2106

3.1
428.3

[0424]

48

FORMULA 37

2107

Analysis

R1
Tr
[M + H]+

1

2108

4.4
388.5

2

2109

4.5
388.3

3

2110

4.2
388.3

4

2111

4.4
402.3

5

2112

4.4
432.3

6

2113

4.2
404.3

7

2114

4.7
418.3

8

2115

4.9
430.5

9

2116

4.6
416.4

10

2117

3.9
418.3

11

2118

4.8
480.2

12

2119

4.5
416.4

13

2120

4.8
419.3

14

2121

4.8
419.3

15

2122

4.7
389.3

[0425]

49

FORMULA 38

2123

Analysis

R1
Tr
[M + H]+

1

2124

5.1
431.2

2

2125

4.4
453.4

3

2126

4.6
377.4

4

2127

4.5
399.3

5

2128

4.5
399.3

6

2129

3.9
339.3

7

2130

4.1
350.4

8

2131

4.5
395.3

9

2132

4.8
399.3

10

2133

4.7
400.3

11

2134

4.5
400.3

12

2135

4.4
400.3

13

2136

4.2
400.3

14

2137

4.3
441.3

15

2138

4.3
441.3

16

2139

4.2
369.3

17

2140

3.9
397.3

18

2141

3.8
350.3

[0426]

50

FORMULA 39

2142

Analysis

R1
Tr
[M + H]+

1

2143

4.5
397.3

2

2144

4.7
397.3

3

2145

4.7
397.3

4

2146

4.6
441.2

5

2147

4.8
441.2

6

2148

4.8
441.2

7

2149

4.3
381.3

8

2150

4.4
381.3

9

2151

4.4
381.3

10

2152

4.3
408.3

11

2153

4.4
408.3

12

2154

4.5
408.3

13

2155

4.7
431.3

14

2156

4.9
431.3

15

2157

5.0
431.3

16

2158

4.4
393.3

17

2159

4.4
393.4

18

2160

4.4
393.3

19

2161

4.3
363.4

20

2162

3.7
406.3

[0427]

51

FORMULA 40

2163

Analysis

R1
Tr
[M + H]+

1

2164

3.6
336.4

2

2165

4.9
420.3

3

2166

4.5
386.4

4

2167

3.5
336.4

5

2168

3.8
336.4

6

2169

4.9
432.3

[0428]

52

FORMULA 41

2170

Analysis

R1
Tr
[M + H]+

1

2171

4.5
335.3

2

2172

4.3
351.3

3

2173

4.2
351.3

4

2174

4.6
353.3

5

2175

4.6
365.3

6

2176

4.6
365.3

7

2177

4.6
365.3

8

2178

4.5
380.3

9

2179

4.6
380.3

10

2180

5.1
403.2

11

2181

4.7
410.3

12

2182

4.9
413.2

13

2183

4.3
341.3

14

2184

4.6
425.3

15

2185

5.4
441.3

16

2186

4.5
353.3

17

2187

4.9
403.3

18

2188

5.3
411.3

19

2189

4.7
415.2

20

2190

5.2
419.3

21

2191

3.9
436.4

22

2192

4.6
383.3

23

2193

5.4
391.4

24

2194

4.9
413.2

25

2195

5.4
457.4

[0429]

53

FORMULA 42

2196

Analysis

R1
Tr
[M + H]+

1

2197

4.7
398.1

2

2198

4.9
398.1

3

2199

4.9
398.1

4

2200

4.7
442.1

5

2201

5.0
442.1

6

2202

5.0
442.1

7

2203

4.7
382.2

8

2204

4.6
400.2

9

2205

4.8
400.2

10

2206

4.7
409.2

11

2207

4.8
409.2

12

2208

5.0
409.2

13

2209

4.8
432.2

14

2210

5.2
432.2

15

2211

5.3
432.2

16

2212

4.7
424.2

17

2213

4.6
394.2

18

2214

4.5
394.2

19

2215

5.2
466.1

20

2216

4.9
427.2

[0430]

54

FORMULA 43

2217

Analysis

[M +

R3
R2
Tr
H]+

1

2218

2219

5.5
374.2

2

2220

2221

5.4
360.2

3

2222

2223

5.4
388.2

4

2224

2225

5.5
416.3

5

2226

2227

5.4
374.2

6

2228

2229

6.1
422.2

7

2230

2231

5.5
388.2

8

2232

2233

5.5
402.2

9

2234

2235

5.5
436.2

10

2236

2237

5.7
436.2

11

2238

2239

2240

2241

5.3
340.3

13

2242

2243

5.4
368.3

14

2244

2245

5.4
396.3

15

2246

2247

5.3
354.3

16

2248

2249

6.0
402.2

17

2250

2251

5.5
368.3

18

2252

2253

5.4
382.3

19

2254

2255

5.5
416.3

20

2256

2257

416.3

[0431]

55

FORMULA 44

2258

Analysis

* = [M +

TFA −

H]−

[M +

R1
R2
Tr
H]+

1

2259

2260

6.0
485.3

2

2261

2262

6.2
485.3

3

2263

2264

6.2
485.3

4

2265

2266

6.1
529.2

5

2267

2268

6.2
529.2

6

2269

2270

6.3
529.2

7

2271

2272

5.9
469.3

8

2273

2274

5.9
469.3

9

2275

2276

5.9
469.3

10

2277

2278

5.8
496.3

11

2279

2280

5.9
496.3

12

2281

2282

6.0
496.3

13

2283

2284

6.2
519.3

14

2285

2286

6.4
519.3

15

2287

2288

6.4
519.3

16

2289

2290

5.9
481.3

17

2291

2292

5.9
481.3

18

2293

2294

5.9
481.3

19

2295

2296

5.8
451.3

20

2297

2298

4.9
494.4

21

2299

2300

6.5
519.2

22

2301

2302

5.7
541.3

23

2303

2304

6.0
465.3

24

2305

2306

5.4
467.3

25

2307

2308

5.9
487.3

26

2309

2310

6.0
485.3

27

2311

2312

6.1
485.3

28

2313

2314

6.2
485.3

29

2315

2316

6.0
529.2

30

2317

2318

6.2
529.2

31

2319

2320

6.2
529.2

32

2321

2322

5.8
469.3

33

2323

2324

5.9
469.3

34

2325

2326

5.9
469.3

35

2327

2328

5.8
496.3

36

2329

2330

5.9
496.3

37

2331

2332

5.9
496.3

38

2333

2334

6.2
519.3

39

2335

2336

6.4
519.3

40

2337

2338

6.4
519.3

41

2339

2340

5.9
481.3

42

2341

2342

5.8
481.3

43

2343

2344

5.8
481.3

44

2345

2346

5.8
563.3*

45

2347

2348

4.8
494.4

46

2349

2350

6.4
519.2

47

2351

2352

5.7
541.3

48

2353

2354

6.0
465.3

49

2355

2356

5.4
467.3

50

2357

2358

6.0
487.3

[0432]

56

FORMULA 45

2359

Analysis

R
Tr
[M + H]+

1

2360

5.9
488.4

2

2361

6.1
488.4

3

2362

5.9
488.4

4

2363

6.0
502.4

5

2364

6.0
502.4

6

2365

6.0
532.4

7

2366

5.7
504.4

8

2367

6.3
518.4

9

2368

6.4
530.4

10

2369

6.2
516.4

11

2370

5.5
518.4

12

2371

6.4
580.3

13

2372

6.1
516.4

14

2373

6.4
519.3

15

2374

6.4
519.3

16

2375

6.3
489.4

[0433]

57

FORMULA 46

2376

Analysis

R1
Tr
[M + H]+

1

2377

6.7
531.3

2

2378

5.9
553.4

3

2379

6.3
477.4

4

2380

6.2
499.3

5

2381

6.2
499.4

6

2382

5.6
439.3

7

2383

5.7
450.4

8

2384

6.2
495.3

9

2385

6.4
499.4

10

2386

6.4
500.4

11

2387

6.2
500.4

12

2388

5.9
500.4

13

2389

5.7
500.4

14

2390

5.9
541.3

15

2391

5.9
541.3

16

2392

5.9
469.3

17

2393

5.5
497.4

18

2394

5.3
450.4

[0434]

58

FORMULA 47

2395

Analysis

R1
Tr
[M + H]+

1

2396

6.2
497.3

2

2397

6.3
497.3

3

2398

6.4
497.3

4

2399

6.2
541.2

5

2400

6.4
541.2

6

2401

6.5
541.2

7

2402

6.0
481.3

8

2403

6.1
481.3

9

2404

6.1
481.3

10

2405

6.0
508.3

11

2406

6.1
508.3

12

2407

6.1
508.3

13

2408

6.4
531.3

14

2409

6.6
531.3

15

2410

6.6
531.3

16

2411

6.1
493.4

17

2412

6.0
493.4

18

2413

6.0
493.4

19

2414

6.0
463.4

20

2415

5.0
506.4

[0435]

59

FORMULA 48

2416

Analysis

R1
R2
Tr
[M + H]+

1

2417

2418

6.9
519.2

2

2419

2420

6.5
541.3

3

2421

2422

6.7
465.3

4

2423

2424

6.3
467.3

5

2425

2426

6.6
487.2

6

2427

2428

7.0
567.0

7

2429

2430

6.7
589.1

8

2431

2432

6.9
513.2

9

2433

2434

6.5
515.1

10

2435

2436

6.8
535.1

11

2437

2438

7.2
534.1

12

2439

2440

6.8
556.2

13

2441

2442

6.8
480.1

14

2443

2444

5.8
482.1

15

2445

2446

6.7
502.1

16

2447

2448

6.3
560.1

17

2449

2450

5.5
582.2

18

2451

2452

5.8
506.3

19

2453

2454

5.1
508.2

20

2455

2456

5.7
528.2

21

2457

2458

6.5
489.1

22

2459

2460

5.7
511.2

23

2461

2462

6.1
435.2

24

2463

2464

5.4
437.2

25

2465

2466

6.0
457.2

[0436]

60

FORMULA 49

2467

Analysis

(min)
[M + H]+

1

2468

6.6
455.2

2

2469

6.6
455.2

3

2470

6.6
455.2

4

2471

6.6
499.2

5

2472

6.7
499.2

6

2473

6.7
499.2

7

2474

6.5
439.2

8

2475

6.5
439.2

9

2476

6.5
439.2

10

2477

6.5
466.2

11

2478

6.5
466.2

12

2479

6.5
466.2

13

2480

6.7
489.2

14

2481

6.7
489.2

15

2482

6.8
489.2

16

2483

6.5
451.3

17

2484

6.5
451.3

18

2485

6.5
451.3

19

2486

6.5
421.3

20

2487

5.8
464.3

[0437]

61

FORMULA 50

2488

Analysis

R1
R2
Tr
[M + H]+

1

2489

2490

6.3
474.3

2

2491

2492

6.3
460.3

3

2493

2494

6.3
488.3

4

2495

2496

6.4
516.3

5

2497

2498

6.3
474.3

6

2499

2500

6.5
522.3

7

2501

2502

6.5
488.3

8

2503

2504

6.4
502.3

9

2505

2506

6.5
536.3

10

2507

2508

6.5
536.3

11

2509

2510

6.2
454.3

12

2511

2512

6.2
440.3

13

2513

2514

6.3
468.3

14

2515

2516

6.4
496.3

15

2517

2518

6.2
454.3

16

2519

2520

6.5
502.3

17

2521

2522

6.4
468.3

18

2523

2524

6.3
482.3

19

2525

2526

6.4
516.3

20

2527

2528

6.4
516.3

[0438]

62

FORMULA 51

2529

Analysis

R1
R2
R3
Tr
[M + H]+

1

2530

2531

2532

5.6
397.2

2

2533

2534

2535

5.9
431.2

3

2536

2537

2538

6.0
431.2

4

2539

2540

2541

5.8
427.2

5

2542

2543

2544

6.3
465.2

6

2545

2546

2547

6.7
453.3

7

2548

2549

2550

5.8
433.2

8

2551

2552

2553

6.4
481.2

9

2554

2555

2556

6.3
479.1

10

2557

2558

2559

5.7
455.2

11

2560

2561

2562

5.4
397.2

12

2563

2564

2565

5.0
431.2

13

2566

2567

2568

5.8
431.2

14

2569

2570

2571

5.5
427.2

15

2572

2573

2574

6.0
465.2

16

2575

2576

2577

6.5
453.3

17

2578

2579

2580

5.5
433.2

18

2581

2582

2583

6.2
481.2

19

2584

2585

2586

6.1
479.1

20

2587

2588

2589

5.5
455.2

21

2590

2591

2592

5.3
406.2

22

2593

2594

2595

5.5
440.1

23

2596

2597

2598

5.7
440.2

24

2599

2600

2601

5.5
436.2

25

2602

2603

2604

6.0
474.2

26

2605

2606

2607

6.4
462.3

27

2608

2609

2610

5.5
442.2

28

2611

2612

2613

6.1
490.2

29

2614

2615

2616

6.0
488.1

30

2617

2618

2619

5.4
464.2

31

2620

2621

2622

5.2
436.2

32

2623

2624

2625

5.4
470.2

33

2626

2627

2628

5.6
470.2

34

2629

2630

2631

5.4
466.2

35

2632

2633

2634

5.9
504.2

36

2635

2636

2637

6.2
492.3

37

2638

2639

2640

5.4
472.2

38

2641

2642

2643

6.0
520.1

39

2644

2645

2646

5.8
518.1

40

2647

2648

2649

5.3
494.2

41

2650

2651

2652

5.2
436.2

42

2653

2654

2655

5.4
470.2

43

2656

2657

2658

5.6
470.2

44

2659

2660

2661

5.4
466.2

45

2662

2663

2664

5.9
504.2

46

2665

2666

2667

6.2
492.3

47

2668

2669

2670

5.4
472.2

48

2671

2672

2673

6.0
520.1

49

2674

2675

2676

5.9
518.1

50

2677

2678

2679

5.3
494.2

51

2680

2681

2682

4.6
386.2

52

2683

2684

2685

4.7
420.2

53

2686

2687

2688

4.9
420.2

54

2689

2690

2691

4.8
416.2

55

2692

2693

2694

5.2
454.2

56

2695

2696

2697

5.6
442.3

57

2698

2699

2700

4.7
422.2

58

2701

2702

2703

5.3
470.2

59

2704

2705

2706

5.2
468.2

60

2707

2708

2709

4.8
444.2

61

2710

2711

2712

4.9
449.2

62

2713

2714

2715

5.0
483.2

63

2716

2717

2718

5.2
483.2

64

2719

2720

2721

5.0
477.2

65

2722

2723

2724

5.4
515.1

66

2725

2726

2727

5.8
503.3

67

2728

2729

2730

4.9
483.2

68

2731

2732

2733

5.5
531.2

69

2734

2735

2736

5.4
531.1

70

2737

2738

2739

4.9
507.2

71

2740

2741

2742

5.3
367.2

72

2743

2744

2745

5.6
401.2

73

2746

2747

2748

5.7
401.1

74

2749

2750

2751

5.5
397.2

75

2752

2753

2754

6.0
435.2

76

2755

2756

2757

6.5
423.3

77

2758

2759

2760

5.5
403.2

78

2761

2762

2763

6.2
451.2

79

2764

2765

2766

6.1
449.1

80

2767

2768

2769

5.4
425.2

[0439]

2770

FORMULA 52

Analysis

R1
R2
Tr
[M + H]+

1

2771

2772

5.9
393.2

2

2773

2774

5.7
409.2

3

2775

2776

5.6
409.2

4

2777

2778

6.0
411.2

5

2779

2780

6.0
423.2

6

2781

2782

6.0
423.2

7

2783

2784

6.0
423.2

8

2785

2786

6.0
438.2

9

2787

2788

6.0
438.2

10

2789

2790

6.5
461.1

11

2791

2792

6.1
468.2

12

2793

2794

6.4
471.1

13

2795

2796

5.8
511.2*

14

2797

2798

5.9
483.3

15

2799

2800

5.9
411.2

16

2801

2802

6.4
461.2

17

2803

2804

6.2
471.1

18

2805

2806

5.5
436.3

19

2807

2808

6.6
477.2

20

2809

2810

4.9
494.3

21

2811

2812

6.0
423.3

22

2813

2814

5.7
439.2

23

2815

2816

5.6
439.2

24

2817

2818

6.1
441.2

25

2819

2820

6.0
453.2

26

2821

2822

5.9
453.2

27

2823

2824

6.0
453.2

28

2825

2826

6.2
468.2

29

2827

2828

6.1
468.2

30

2829

2830

6.7
491.2

31

2831

2832

6.1
498.2

32

2833

2834

6.5
501.1

33

2835

2836

6.0
429.2

34

2837

2838

5.9
513.2

35

2839

2840

6.1
441.2

36

2841

2842

6.6
491.2

37

2843

2844

6.4
501.1

38

2845

2846

5.5
466.3

39

2847

2848

6.7
507.2

40

2849

2850

4.9
524.3

41

2851

2852

5.9
423.2

42

2853

2854

5.6
439.2

43

2855

2856

5.5
439.2

44

2857

2858

6.0
441.2

45

2859

2860

6.0
453.2

46

2861

2862

5.9
453.2

47

2863

2864

6.0
453.2

48

2865

2866

6.1
468.2

49

2867

2868

6.1
468.2

50

2869

2870

6.6
491.1

51

2871

2872

6.2
498.2

52

2873

2874

6.4
501.1

53

2875

2876

5.8
429.2

54

2877

2878

5.8
513.2

55

2879

2880

6.0
441.2

56

2881

2882

6.5
491.2

57

2883

2884

6.3
501.1

58

2885

2886

5.4
466.3

59

2887

2888

6.6
507.2

60

2889

2890

4.9
524.3

61

2891

2892

5.9
423.2

62

2893

2894

5.6
439.2

63

2895

2896

5.5
439.2

64

2897

2898

6.0
441.2

65

2899

2900

6.0
453.2

66

2901

2902

5.9
453.2

67

2903

2904

6.0
453.2

68

2905

2906

6.0
468.2

69

2907

2908

6.0
468.2

70

2909

2910

6.6
491.1

71

2911

2912

6.2
498.2

72

2913

2914

6.4
501.1

73

2915

2916

5.9
429.2

74

2917

2918

5.8
513.3

75

2919

2920

6.0
441.2

76

2921

2922

6.5
491.2

77

2923

2924

6.3
501.1

78

2925

2926

5.4
466.3

79

2927

2928

6.6
507.2

[0440]

2929

FORMULA 53

Analysis

R1
R2
Tr (min)
[M + H]+

1

2930

2931

5.2
416.2

2

2932

2933

5.5
418.1

3

2934

2935

5.0
430.2

4

2936

2937

5.0
457.2

5

2938

2939

5.9
480.2

6

2940

2941

6.1
491.2

7

2942

2943

6.4
501.2

8

2944

2945

4.9
505.2

9

2946

2947

6.3
509.2

10

2948

2949

5.9
521.2

11

2950

2951

6.7
525.2

12

2952

2953

7.0
526.2

13

2954

2955

6.3
536.2

14

2956

2957

5.9
522.2

15

2958

2959

6.7
525.2

16

2960

2961

4.6
492.2

17

2962

2963

6.9
504.2

18

2964

2965

5.4
472.2

19

2966

2967

5.9
506.2

20

2968

2969

6.6
536.2

21

2970

2971

4.9
549.2

22

2972

2973

6.9
559.2

23

2974

2975

6.0
560.2

24

2976

2977

6.7
525.2

25

2978

2979

5.0
507.2

26

2980

2981

6.9
519.2

27

2982

2983

5.0
416.2

28

2984

2985

6.4
549.2

29

2986

2987

5.8
546.2

30

2988

2989

5.5
509.2

31

2990

2991

6.8
611.2

32

2992

2993

7.2
570.2

33

2994

2995

5.8
521.2

34

2996

2997

5.8
581.2

35

2998

2999

5.1
507.2

36

3000

3001

4.2
516.3

37

3002

3003

6.4
509.2

38

3004

3005

6.7
537.2

39

3006

3007

5.1
396.2

40

3008

3009

5.4
398.2

41

3010

3011

5.0
410.2

42

3012

3013

4.9
437.2

43

3014

3015

5.8
460.2

44

3016

3017

6.0
471.3

45

3018

3019

6.4
481.2

46

3020

3021

4.8
485.3

47

3022

3023

6.2
489.2

48

3024

3025

5.8
501.3

49

3026

3027

6.7
505.2

50

3028

3029

6.9
506.3

51

3030

3031

6.2
516.2

52

3032

3033

5.9
502.2

53

3034

3035

6.6
505.2

54

3036

3037

4.5
472.3

55

3038

3039

6.8
484.3

56

3040

3041

5.3
452.3

57

3042

3043

5.8
486.3

58

3044

3045

6.5
516.3

59

3046

3047

4.8
529.2

60

3048

3049

6.9
539.2

61

3050

3051

6.0
540.2

62

3052

3053

6.6
505.2

63

3054

3055

4.9
487.3

64

3056

3057

6.9
499.3

65

3058

3059

4.9
396.2

66

3060

3061

6.3
529.2

67

3062

3063

5.7
526.3

68

3064

3065

5.4
489.2

69

3066

3067

6.7
591.3

70

3068

3069

7.2
550.3

71

3070

3071

5.7
501.3

72

3072

3073

5.7
561.3

73

3074

3075

5.0
487.3

74

3076

3077

4.1
496.4

75

3078

3079

6.3
489.3

76

3080

3081

6.7
517.2

[0441]

3082

FORMULA 54

Analysis

R1
R2
Tr (min)
[M + H]+

1

3083

3084

4.4
431.2

2

3085

3086

6.3
442.2

3

3087

3088

6.1
450.2

4

3089

3090

5.9
466.2

5

3091

3092

6.2
480.2

6

3093

3094

5.9
510.2

7

3095

3096

4.5
440.2

8

3097

3098

5.8
526.2

9

3099

3100

6.1
495.2

10

3101

3102

6.3
430.3

11

3103

3104

4.5
437.2

12

3105

3106

4.5
451.2

13

3107

3108

4.5
473.3

14

3109

3110

5.7
501.3

15

3111

3112

5.8
511.2

16

3113

3114

6.4
496.2

17

3115

3116

5.3
468.2

18

3117

3118

4.7
472.3

19

3119

3120

5.8
402.2

20

3121

3122

5.6
568.2

21

3123

3124

6.8
512.2

22

3125

3126

4.6
437.2

23

3127

3128

6.3
470.2

24

3129

3130

7.0
540.2

25

3131

3132

6.4
464.2

26

3133

3134

4.5
443.3

27

3135

3136

6.5
484.2

28

3137

3138

6.2
468.2

29

3139

3140

6.2
468.2

30

3141

3142

6.5
484.2

31

3143

3144

6.6
528.1

32

3145

3146

6.5
504.2

33

3147

3148

6.5
504.2

34

3149

3150

4.5
437.2

35

3151

3152

6.1
466.2

36

3153

3154

6.2
470.2

37

3155

3156

6.0
454.2

38

3157

3158

6.0
454.2

39

3159

3160

6.0
454.2

40

3161

3162

4.3
486.3

41

3163

3164

4.4
411.3

42

3165

3166

6.3
422.3

43

3167

3168

6.0
430.3

44

3169

3170

5.9
446.2

45

3171

3172

6.2
460.3

46

3173

3174

5.8
490.3

47

3175

3176

4.4
420.3

48

3177

3178

5.7
506.3

49

3179

3180

6.1
475.2

50

3181

3182

6.2
410.3

51

3183

3184

4.4
417.2

52

3185

3186

4.4
431.2

53

3187

3188

4.4
453.3

54

3189

3190

5.7
481.3

55

3191

3192

5.7
491.2

56

3193

3194

6.4
476.3

57

3195

3196

5.2
448.2

58

3197

3198

4.6
452.3

59

3199

3200

5.7
382.3

60

3201

3202

5.5
548.2

61

3203

3204

6.7
492.3

62

3205

3206

4.5
417.2

63

3207

3208

6.2
450.2

64

3209

3210

7.0
520.3

65

3211

3212

6.3
444.3

66

3213

3214

4.4
423.3

67

3215

3216

6.4
464.2

68

3217

3218

6.1
448.2

69

3219

3220

6.2
448.2

70

3221

3222

6.4
464.2

71

3223

3224

6.5
510.1

72

3225

3226

6.5
484.2

73

3227

3228

6.5
484.2

74

3229

3230

4.4
417.2

75

3231

3232

6.0
446.2

76

3233

3234

6.2
450.2

77

3235

3236

6.0
434.2

78

3237

3238

5.9
434.2

79

3239

3240

6.0
434.2

80

3241

3242

4.1
466.3

[0442]

3243

FORMULA 55

Analysis

R1
R2
Tr (min)
[M + H]+

1

3244

3245

6.4
486.2

2

3246

3247

6.6
486.2

3

3248

3249

6.6
486.2

4

3250

3251

6.4
530.1

5

3252

3253

6.7
530.1

6

3254

3255

6.6
530.1

7

3256

3257

6.3
470.2

8

3258

3259

6.3
488.2

9

3260

3261

6.4
488.2

10

3262

3263

6.3
497.2

11

3264

3265

6.4
497.2

12

3266

3267

6.4
497.2

13

3268

3269

6.4
520.2

14

3270

3271

6.8
520.2

15

3272

3273

6.8
520.2

16

3274

3275

6.3
512.2

17

3276

3277

6.2
482.2

18

3278

3279

6.1
482.2

19

3280

3281

6.8
554.1

20

3282

3283

6.4
515.1

21

3284

3285

6.7
534.0

22

3286

3287

6.9
534.0

23

3288

3289

6.8
534.0

24

3290

3291

6.7
578.0

25

3292

3293

6.9
578.0

26

3294

3295

6.9
578.0

27

3296

3297

6.6
518.1

28

3298

3299

6.6
536.1

29

3300

3301

6.7
536.1

30

3302

3303

6.6
545.0

31

3304

3305

6.7
545.0

32

3306

3307

6.7
545.0

33

3308

3309

6.7
568.0

34

3310

3311

7.1
568.0

35

3312

3313

7.1
568.0

36

3314

3315

6.6
560.1

37

3316

3317

6.5
530.1

38

3318

3319

6.4
530.1

39

3320

3321

7.1
602.0

40

3322

3323

6.7
563.0

41

3324

3325

6.6
501.1

42

3326

3327

6.8
501.1

43

3328

3329

6.8
501.1

44

3330

3331

6.7
545.0

45

3332

3333

6.9
545.0

46

3334

3335

6.9
545.0

47

3336

3337

6.5
485.1

48

3338

3339

6.5
503.2

49

3340

3341

6.7
503.2

50

3342

3343

6.6
512.2

51

3344

3345

6.6
512.2

52

3346

3347

6.6
512.2

53

3348

3349

6.7
535.1

54

3350

3351

7.1
535.1

55

3352

3353

7.1
535.1

56

3354

3355

6.4
527.2

57

3356

3357

6.3
497.2

58

3358

3359

6.2
497.2

59

3360

3361

7.2
569.1

60

3362

3363

6.7
530.1

61

3364

3365

5.9
527.2

62

3366

3367

6.2
527.2

63

3368

3369

6.1
527.2

64

3370

3371

5.9
571.1

65

3372

3373

6.3
571.1

66

3374

3375

6.2
571.1

67

3376

3377

5.9
511.3

68

3378

3379

5.8
529.2

69

3380

3381

6.0
529.2

70

3382

3383

5.8
538.2

71

3384

3385

5.9
538.2

72

3386

3387

6.0
538.2

73

3388

3389

6.0
561.2

74

3390

3391

6.4
561.2

75

3392

3393

6.5
561.0

76

3394

3395

5.8
553.3

77

3396

3397

5.7
523.3

78

3398

3399

5.6
523.3

79

3400

3401

6.5
595.2

80

3402

3403

6.0
556.2

[0443]

3404

FORMULA 56

Analysis

R1
R2
Tr (min)
[M + H]+

1

3405

3406

5.6
485.2

2

3407

3408

5.8
485.2

3

3409

3410

6.0
485.2

4

3411

3412

5.8
529.2

5

3413

3414

6.0
529.2

6

3415

3416

6.0
529.2

7

3417

3418

5.5
469.2

8

3419

3420

5.7
469.3

9

3421

3422

5.6
469.2

10

3423

3424

5.5
496.3

11

3425

3426

5.6
496.3

12

3427

3428

5.6
496.3

13

3429

3430

6.0
519.2

14

3431

3432

6.2
519.2

15

3433

3434

6.2
519.2

16

3435

3436

5.5
481.1

17

3437

3438

5.5
481.2

18

3439

3440

5.4
481.2

19

3441

3442

5.4
451.2

20

3443

3444

4.3
494.2

21

3445

3446

6.1
533.1

22

3447

3448

6.1
533.1

23

3449

3450

6.3
533.1

24

3451

3452

6.1
577.0

25

3453

3454

6.3
577.0

26

3455

3456

6.3
577.0

27

3457

3458

5.9
517.1

28

3459

3460

6.0
517.1

29

3461

3462

6.0
517.1

30

3463

3464

5.8
544.1

31

3465

3466

6.0
544.1

32

3467

3468

6.0
544.1

33

3469

3470

6.3
567.1

34

3471

3472

6.5
567.1

35

3473

3474

6.5
567.1

36

3475

3476

5.9
529.1

37

3477

3478

5.9
529.1

38

3479

3480

5.9
529.1

39

3481

3482

5.9
499.1

40

3483

3484

4.7
542.1

41

3485

3486

6.2
500.2

42

3487

3488

6.4
500.2

43

3489

3490

6.9
500.1

44

3491

3492

6.8
544.0

45

3493

3494

7.0
544.0

46

3495

3496

7.0
544.0

47

3497

3498

6.5
484.2

48

3499

3500

6.6
484.2

49

3501

3502

6.6
484.2

50

3503

3504

6.4
511.2

51

3505

3506

6.6
511.2

52

3507

3508

6.6
511.2

53

3509

3510

7.0
534.1

54

3511

3512

7.1
534.1

55

3513

3514

7.2
534.1

56

3515

3516

6.6
496.2

57

3517

3518

6.5
496.2

58

3519

3520

6.5
496.2

59

3521

3522

6.5
466.2

60

3523

3524

5.4
509.2

61

3525

3526

5.8
526.2

62

3527

3528

6.0
526.3

63

3529

3530

6.0
526.3

64

3531

3532

5.9
570.2

65

3533

3534

6.1
570.1

66

3535

3536

6.1
570.1

67

3537

3538

5.6
510.3

68

3539

3540

5.7
510.3

69

3541

3542

5.6
537.2

70

3543

3544

5.7
537.2

71

3545

3546

5.7
537.3

72

3547

3548

6.1
560.2

73

3549

3550

6.2
560.2

74

3551

3552

6.3
560.2

75

3553

3554

5.7
522.3

76

3555

3556

5.6
522.3

77

3557

3558

5.6
522.3

78

3559

3560

5.6
492.3

79

3561

3562

4.7
535.3

[0444]

3563

FORMULA 57

Analysis

R1
R2
Tr (min)
[M + H]+

1

3564

3565

14.4
414.2

2

3566

3567

6.4
418.2

3

3568

3569

11.1
445.3

4

3570

3571

10.8
457.3

5

3572

3573

14.3
462.2

6

3574

3575

14.5
466.1

7

3576

3577

14.5
489.2

8

3578

3579

12.2
519.4

9

3580

3581

10.1
466.1

10

3582

3583

14.8
486.1

11

3584

3585

12.1
459.3

12

3586

3587

14.4
480.1

13

3588

3589

14.8
476.1

14

3590

3591

14.4
442.1

15

3592

3593

14.8
504.1

16

3594

3595

14.7
470.1

17

3596

3597

14.7
574.1

18

3598

3599

15.0
526.2

19

3600

3601

12.0
454.3

20

3602

3603

8.0
529.1

21

3604

3605

14.4
414.2

22

3606

3607

6.3
418.2

23

3608

3609

11.3
445.3

24

3610

3611

10.7
457.3

25

3612

3613

14.3
462.2

26

3614

3615

14.6
466.1

27

3616

3617

14.5
489.2

28

3618

3619

12.2
519.2

29

3620

3621

11.7
466.1

30

3622

3623

14.8
486.1

31

3624

3625

12.0
459.3

32

3626

3627

14.4
480.1

33

3628

3629

14.8
476.2

34

3630

3631

14.4
442.1

35

3632

3633

14.7
504.1

36

3634

3635

14.7
470.1

37

3636

3637

14.7
574.1

38

3638

3639

14.9
526.2

39

3640

3641

11.8
454.3

40

3642

3643

8.5
529.1

41

3644

3645

14.3
394.2

42

3646

3647

6.0
398.2

43

3648

3649

14.2
442.2

44

3650

3651

14.6
446.2

45

3652

3653

14.6
469.2

46

3654

3655

10.7
446.2

47

3656

3657

14.8
466.2

48

3658

3659

11.8
439.3

49

3660

3661

14.4
460.1

50

3662

3663

14.8
456.2

51

3664

3665

14.4
422.1

52

3666

3667

14.8
484.1

53

3668

3669

14.7
450.1

54

3670

3671

14.7
554.1

55

3672

3673

15.0
506.2

56

3674

3675

11.6
434.3

57

3676

3677

8.1
509.1

58

3678

3679

14.4
394.2

59

3680

3681

11.4
398.2

60

3682

3683

14.2
442.2

61

3684

3685

14.6
446.2

62

3686

3687

14.6
469.2

63

3688

3689

11.0
446.2

64

3690

3691

14.8
466.2

65

3692

3693

11.8
439.3

66

3694

3695

14.4
460.2

67

3696

3697

14.8
456.2

68

3698

3699

14.3
422.1

69

3700

3701

14.7
484.2

70

3702

3703

14.6
450.2

71

3704

3705

14.7
554.1

72

3706

3707

14.9
506.2

73

3708

3709

11.7
434.3

74

3710

3711

8.4
509.2

[0445]

69

FORMULA 58

3712

Analysis

R1
R2
Tr (min)
[M + H]+

1

3713

3714

12.9
422.2

2

3715

3716

13.3
456.2

3

3717

3718

12.9
436.2

4

3719

3720

13.6
472.3

5

3721

3722

14.5
514.2

6

3723

3724

14.6
506.3

7

3725

3726

14.2
490.2

8

3727

3728

13.6
494.2

9

3729

3730

13.3
458.2

10

3731

3732

13.3
467.2

11

3733

3734

13.2
438.2

12

3735

3736

13.8
466.2

13

3737

3738

13.9
452.2

14

3739

3740

13.8
488.2

15

3741

3742

14.8
544.2

16

3743

3744

14.3
480.2

17

3745

3746

14.2
472.2

18

3747

3748

14.7
446.3

19

3749

3750

10.4
475.2

20

3751

3752

13.8
496.2

21

3753

3754

13.1
422.2

22

3755

3756

13.4
456.2

23

3757

3758

13.1
436.2

24

3759

3760

13.7
472.3

25

3761

3762

14.7
514.2

26

3763

3764

14.7
506.3

27

3765

3766

14.3
490.2

28

3767

3768

13.7
494.2

29

3769

3770

13.4
458.2

30

3771

3772

13.6
467.2

31

3773

3774

13.3
438.2

32

3775

3776

13.9
466.2

33

3777

3778

13.9
452.2

34

3779

3780

14.0
488.2

35

3781

3782

15.1
544.2

36

3783

3784

14.5
480.2

37

3785

3786

14.2
472.2

38

3787

3788

13.8
496.2

39

3789

3790

13.1
402.2

40

3791

3792

13.6
436.2

41

3793

3794

13.6
452.2

42

3795

3796

14.8
494.2

43

3797

3798

14.9
486.3

44

3799

3800

14.3
470.2

45

3801

3802

13.7
474.3

46

3803

3804

13.4
438.2

47

3805

3806

13.2
418.2

48

3807

3808

13.6
446.2

49

3809

3810

10.0
432.1

50

3811

3812

10.1
468.1

51

3813

3814

14.2
460.2

52

3815

3816

14.0
452.2

53

3817

3818

14.8
426.3

54

3819

3820

10.4
455.3

55

3821

3822

13.9
476.2

56

3823

3824

13.6
436.2

57

3825

3826

14.9
486.3

58

3827

3828

14.4
470.2

59

3829

3830

13.8
474.3

60

3831

3832

13.4
438.2

61

3833

3834

13.3
447.2

62

3835

3836

13.1
418.2

63

3837

3838

13.5
446.2

64

3839

3840

13.5
432.2

65

3841

3842

13.7
468.2

66

3843

3844

14.7
524.2

67

3845

3846

14.3
460.2

68

3847

3848

14.2
452.2

69

3849

3850

13.8
476.2

	Number	Date	Country
Parent	09719457	Jun 2001	US
Child	10771725	Feb 2004	US

	Number	Date	Country
Parent	09096431	Jun 1998	US
Child	09719457	Jun 2001	US

Imidazolyl derivatives

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Provisional Applications (1)

Divisions (1)

Continuations (1)