New derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones, their preparation processes and their use as medicaments

Abstract

The invention concerns compounds for treating pathological conditions or diseases wherein one (or several) somatostatin receptors is (are) involved, corresponding to general formula (I) wherein: R1 represents in particular a carbocyclic or heterocyclic aryl radical optionally substituted or a non-aromatic heterocyclic radical optionally substituted; R2 represents H, alkyl or aryl optionally substituted; R3 represents H or -(CH2)p-Z3, Z3 representing in particular alkyl, cycloalkyl, bis-arylalkyl or di-aryalkyl, -Y1-(CH2)p-phenyl-(X1)n, carbocyclic or heterocyclic aryl optionally substituted, a non-aromatic heterocyclic radical optionally substituted, X1, every time it is present, being independently selected in particular among the radicals H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, -OCF3, alkyl, alkoxy, -S-alkyl, -(CH2)p-NH2, -(CH2)p-NH-alkyl, -(CH2)p-N-dialkyl; Y1 represents O, S, NH or is not present; R4 represents -(CH2)p-Z4, Z4 representing in particular amino, alkylamino, N,N-dialkylamino; R5 represents in particular H or alkyl; X represents O or S; p each time it is present is independently 0 or an integer ranging between 1 and 6; q each time it is present is independently an integer between 1 and 5; n represents 0 or 1; provided that when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.

Description

[0001] The invention relates to new derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones of general formula (I) represented below, their preparation processes and their use as medicaments. These compounds have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to the pharmaceutical compositions containing said compounds and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) somatostatin receptors are involved.

[0002] Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al., Neuiroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.

[0003] The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (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 currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhoea syndrome, diarrhoea associated with AIDS, diarrhoea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumours; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.

[0004] Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumours, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, as well as Alzheimer's disease. Osteoporosis can also be mentioned.

[0005] The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues often have a poor bioavailability by oral route and a low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumours including carcinoid syndrome. The compounds of the present invention correspond to general formula (I) 1

[0006] in racemic, enantiomeric form or all combinations of these forms, in which: R1 represents a (C1-C,2)alkyl, (C0-C6)alkyl-C(O)-O-Z1, (CO-C,)alkyl-C(O)-NH-(CH,)p-Z2 or aryl radical optionally substituted, Z1 represents H, a (C1-C6) alkyl, -(CH2)p-aryl radical; Z2 represents an amino, (C1-C 12)alkylamino, (C3-C8)cycloalkylamino, N,N-di-(C1-C12)alkylamino, NH-C(O)-O-(CH2)-phenyl, NH-C(O)-O-(CH2)p-(C1-C6)alkyl radical, an optionally substituted carbocyclic or heterocyclic aryl radical or an optionally substituted heterocyclic non aromatic radical; R2 represents H, (C1-C12)alkyl or aryl optionally substituted; R3 represents H or (CH2)p-Z3; Z3 represents (C1-C 12)alkyl, (CI-C.2)alkenyl, (C3-C8)cycloalkyl, -Y1-(CH2)p-phenyl- (XII), -S-(Cl1-C12)alkyl, S-(C1-C12)alkyl-S-S-(C1-C12)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, and in particular one of the radicals represented below 2

[0007] an optionally substituted heterocyclic non aromatic radical, a bis-arylalkyl or di-arylalkyl radical or also the radical 3

[0008] Y1 represents O,S, NH or is absent; R4 represents (CH2)p-Z4; Z4 represents amino, (C1-C12)alkyl, (C3-C8)cycloalkyl, (C.-C.2)alkylamino, N,N-di-(C1-Cl2amino(C3-C6)cycloalkyl, amino(C1-C6)alkyl(C3-C6)cycloalkyl(C1-C6)alkyl, carbocyclic or heterocyclic aminoaryl, (C1-Cl2)alkoxy, (C1-C12)alkenyl, N-C(O)O(C1-C6)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below 4

[0009] or also Z4 represents an N(R6)(R7) radical in which R6 and R7 taken together with the nitrogen atom which they carry form together a heterocycle with 5 to 7 members; R5 represents H, -(CH2)p-C(O)-(CH2)p-Z5 -(CH2)p-Z5, -(CH2)p-OZ5 or -(Co-C6)alkyl-C(O

[0010] Z5 representing an optionally substituted radical chosen from the group constituted by the -(C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furannyl, thiophene, isoxazolyl, indolyl radicals, and 5

[0011] it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, -OCF3 (C-CX2)alkyl, (C1-C12)alkoxy, -(CH2)p-phenyl-(X1)q, -NH-CO-(C1+-C6)alkyl, -NH-C(O)O-(C1-C6)alkyl, -S-(Cl-C6)alkyl, -S-phenyl-(X1)q, -O-(CH2)p-phenyl-(X1 )q, (CH2)p-C(O)-(C1-C6)alkyl, -O-(CH2)p-NH23 -O-(CH2)p-NH-(C1-C6)alkyl, -O-(CH2) -N-di-((C -C6)alkyl) and -((CO-C12))alkyl-(X1)q radicals;

[0012] X1, each time that it occurs, is independently chosen from the group constituted by the H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, -OCF3, (C1-C12)alkyl, (C+-C+2)alkoxy, -S- (CH2)p-phenyl and -(CH2)p-NH-(C3-C6)cycloalkyl radicals;

[0013] p each time that it occurs is independently 0 or an integer from I to 6;

[0014] q each time that it occurs is independently an integer from 1 to 5.

[0015] X represents O or S;

[0016] n represents 0 or 1; and finally when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or

[0017] According to a preferred variant of the invention, the compounds of general formula (I) are such that R5 represents H.

[0018] The compounds of general formula (I) can, if appropriate, contain more than one asymmetrical centre. If this happens, the diastereomers or any mixture of diastereomers are also included in the invention. For example, when the compound of general formula (I) has two asymmetrical centres, the invention will include the compounds of general formula (I) of “R,S”, “S,R”, “R,R” and “S,S” configurations, as well as a mixture in whatever proportions of the latter.

[0019] In the present invention, the alkyl radicals can be linear or branched. By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, unless specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system containing at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprise it contains a heteroatom (0, N or S). By aryl, unless specified otherwise, is meant a carbocyclic system comprising at least one aromatic ring. By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom. By heterocyclic non aromatic radical, is meant a heterocyclic system containing no aromatic ring, at least one of the rings comprising said system containing at least one heteroatom (O, N or S).

[0020] By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylamino, alkenyl, alkynyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylmino, alkenyl, alkynyl and aralkyl radicals the alkyl radical of which has the meaning indicated previously.

[0021] By N,N-di-(C1-C12)alkylamino radical, is meant a dialkylamino radical of which the two alkyl radicals substituting the nitrogen atom can have independently 1 to 12 carbon atoms.

[0022] By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By cycloalkyl, is meant in particular the cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexyl and cycloheptanyl radicals. By carbocyclic or heterocyclic aryl, is meant in particular the phenyl, naphthyl, pyridinyl, furannyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl, phthalimidyl radicals. By carbocyclic or heterocyclic aralkyl, is meant in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl radicals.

[0023] When an arrow emanates from a chemical structure, said arrow indicates the attachment point. For example: 6

[0024] represents the aminoethyl radical.

[0025] When an arrow is drawn through a bi- or tricyclic group, said arrow indicates that said bi- or tricyclic group can be attached by any of the available attachment points on any aromatic ring of said group. For example: 7

[0026] represents a radical which is attached at any position on the benzene ring.

[0027] In particular, the compounds of general formula (I) according to the invention can be chosen such that:

[0028] R1 represents an optionally substituted aryl radical;

[0029] R2 represents H or an alkyl radical;

[0030] R3 represents one of the following radicals: 8910

[0031] R4 represents one of the following radicals: 11121314

[0032] R5 represents H or an alkyl radical.

[0033] Preferably, the compounds of general formula (I) are such that:

[0034] R1 represents the phenyl radical optionally substituted by a halogen atom or a (C1-C 2)alkyl, (C1-C12)alkoxy or nitro radical;

[0035] R2 and R5 represent H or alkyl;

[0036] R3 represents H or (CH2)p-Z3;

[0037] Z3 represents (C1-C12)alkyl, (C3-C8)cycloalkyl, YL-(CH2)-phenyl-(X1), an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below 15

[0038] Y1 represents O, S, NH or is absent;

[0039] R4 represents (CH2) -Z4;

[0040] Z4 represents amino, (C3-C8)cycloalkyl, (CI-CI2)alkylamino, N,N-di-(C1-C12)alkylamino, amino(C3-C6)cycloalkyl, amino(C1-C6)alkyl(C3-C6)cycloalkyl(C1-C6)alkyl carbocyclic or heterocyclic aminoaryl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below 16

[0041] it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF3) NO OH, NH2, CN, N3, -OCF3, (C12)alkyl, (C1-C12)alkoxy, -(CH2)p-phenyl-(X 1 )q, -NH-CO-(C1-C6)alkyl, -NH-C(O)O-(C1-C6)alkyl, -S-(C1-C6)alkyl, -S-phenyl-(X1)q, -O-(CH2)p-phenyl-(Xl)q , - (CH2)p-C(O)-O-(C1 -C6)alkyl, -(CH2)p-C(O)-(C1-C6)alkyl, -O-(CH2)p-NH2, -O-(CH2)p- NH-(C-C6)alkyl, -O-(CH2)p-N-di-((C1--C6)alkyl) and -((C0-C12))alkyl-(X 1 )q radicals;

[0042] X1, each time that it occurs, is independently chosen from the group constituted by the H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, -OCF3, (C1-C2)alkyl, (C.-C.2)alkoxy, -S- (C1-C6)alkyl, -(CH2)p-amino, -(CH2)p-NH-(C1-C6)alkyl, -(CH2)p-N-di-((Ci-C6)alkyl), - (CH2)p-phenyl and -(CH2)p-NH-(C3-C6)cycloalkyl radicals;

[0043] p each time that it occurs is independently 0 or an integer from 1 to 6;

[0044] q each time that it occurs is independently an integer from 1 to 5.

[0045] X represents O or S;

[0046] when n represents 0 or 1; and finally when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.

[0047] More preferentially, the compounds of general formula (I) are such that:

[0048] R1 represents the phenyl radical optionally substituted by a halogen atom or a (C1-C12)alkyl, (C1-C12)alkoxy or nitro radical;

[0049] R2- and R5 represent H or alkyl;

[0050] R3 represents (CH2)p-Z3,

[0051] Z3 representing a (C3-C8)cycloalkyl radical or an optionally substituted radical chosen from the phenyl, naphthyl, furannyl, thiophene, indolyl, pyrrolyl and benzothiophene radicals;

[0052] R4 represents (CH2)p-Z4;

[0053] Z4 representing amino, (C2-C 2)alkylamino, N,N-di-(C1-C.2)alkylamino or amino(C1-C6)alkyl(C3-C6)cycloalkyl-(C1-C6)alkyl;

[0054] X represents S;

[0055] p each time that it occurs is independently 0 or an integer from 1 to 6;

[0056] m represents 0, 1 or 2; and finally

[0057] n represents 0 or 1.

[0058] Yet more preferentially, the compounds of the present invention are of the compounds:

[0059] of general sub-formula (I)a represented below: 17

[0060] in which:

[0061] R′3 represents one of the radicals represented below: 18

[0062] and R′4 represents one of the radicals represented below: 19

[0063] -of general sub-formula (I)b represented below: 20

[0064] in which:

[0065] R′3 represents one of the radicals represented below: 21

[0066] and R′4 represents one of the radicals represented below: 22

[0067] - of general sub-formula (I)c represented below: 23

[0068] in which:

[0069] R′3 represents one of the radicals represented below: 24

[0070] and R′4 represents one of the radicals represented below: 25

[0071] The invention relates moreover to the preparation processes for the compounds of general formula (I) described previously (also applicable to the corresponding compounds of general sub-formulae (I)a, (I)b and (I)c).

[0072] The compounds of general formula (I) described previously for which n represents 0 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (II) represented below 26

[0073] in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, with an isocyanate or isothiocyanate of general formula (III)

R4-N=C=X,  (III)

[0074] in which R4 and X have the same meaning as in general formula (I), preferably in the presence of a tertiary base for a duration of approximately 1 to 24 hours and at a temperature preferably comprised between 20 and 60 ° C.

[0075] The compounds of general formula (I) described previously for which n represents 1 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (IV) represented below 27

[0076] in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy,

[0077] with an isocyanate or isothiocyanate of general formula (III)

R4-N=C=X  

[0078] (III)

[0079] in which R4 and X have the same meaning as in general formula (I), preferably in the presence of a tertiary base for a duration of approximately 1 to 48 hours and at a temperature preferably comprised between 20 and 70 ° C.

[0080] For the above processes, the aprotic solvent is preferably polar and can in particular be THF or dichloromethane. The tertiary base will be for example triethylamine or N,N-diisopropylethylaamine.

[0081] Moreover the invention offers new synthesis intermediates which are useful for the preparation of the compounds of general formula (I). These compounds, precursors of the compounds of general formula (II) and (IV), correspond to general formula (V): 28

[0082] in which R1 , R2, R5, m and n have the same meaning as in general formula (I); and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy.

[0083] The following compounds corresponding to general formula (V) are the preferred intermediates: - benzyl (25)-2-amino-3-[(4-phenyl)-IH-imidazol-2-yl]propanoate; - benzyl (2R)-2-amino-3 -[(4-phenyl)- 1 H-imidazol-2-yl]propanoate; - benzyl (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate; - benzyl (2R)-2-amino-4-[(4-phenyl)- 1 H-imidazol-2-yl]butanoate; - benzyl (3R)-3-amino-4-[(4-phenyl)- 1 H-imidazol-2-yl]propanoate; - benzyl (3 S)-3-amino-4-[(4-phenyl)- 1 H-imidazol-2-yl]propanoate.

[0084] A subject of the invention is also, as medicaments, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts. It also relates to the pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat the pathological states or diseases in which one (or more) of the somatostatin receptors are involved.

[0085] In particular, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, dawn phenomena, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding of the esophageal varices, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, diarrhoeas induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, bleeding of grafted vessels, Crohn's disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and in other therapeutic fields, cephaleas including cephalea associated with hypophyseal tumours, pain, inflammatory disorders such as arthritis, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, hyperlipidemia, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, chronic rejection of allografts as well as Alzheimer's disease and finally osteoporosis.

[0086] Preferably, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas or endocrinic gastroenteropancreatic tumours including carcinoid syndrome, and gastrointestinal bleeding.

[0087] By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartarate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate.

[0088] The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to “Pharmaceutical salts”, J Pharm. Sci. 66:1(1977).

[0089] The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

[0090] The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water. The suspensions contain in particular suspensions of sustained release microparticles loaded with active ingredient (in particular microparticles of polylactide-co-glycolide or PLGA - cf. for example the Patents US 3,773,919, EP 52 510 or EP 58 481 or the Patent Application PCT WO 98/47489), which allow the administration of a determined daily dose over a period of several days to several weeks.

[0091] The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.

[0092] The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 10 g according to the type of active compound used. These compounds are prepared according to the following procedures.

[0093] PREPARATION OF THE COMPOUNDS OF THE INVENTION

[0094] PREPARATION OF IMIDAZOLYL DERIVATIVES

[0095] General procedure:

[0096] i) Cyclization in order to obtain the imidazole group:

[0097] An amino acid is converted to its cesium salt using cesium carbonate in a polar solvent such as a DMF/H2O (1:1) or EtOH/H20 (1:1) mixture. An ester is then obtained using an appropriate bromoketone in an aprotic polar solvent such as anhydrous DMF. The cesium bromide formed is eliminated by filtration and ammonium acetate is added in an aprotic solvent having a high boiling temperature such as xylene or toluene or in an acidic aprotic solvent such as acetic acid. The mixture is maintained under reflux using a Dean-Stark trap for 30 minutes to one hour. In the diagram directly below, PG1 is a protective group, preferably a carbamate, such as t-Boc or benzylcarbamate, and PG2 is also a protective group, preferably a benzyl group. 29

[0098] ii) Ni-substitution on the imidazole group:

[0099] If appropriate, the N-substitution on the imidazole group is carried out by the reaction described hereafter for the compounds of general formula (I) for which R5 does not represent H.

[0100] A solution of the intermediate obtained in the preceding stage, an alkylating agent such as an -bromoketone, an -bromoester, an alkyl or aryl bromide, is heated to a temperature of 20 to 80 ° C. for a duration of 2 to 48 hours in the presence of an organic or inorganic base (optionally supported on a resin such as polystyrene resin), in an aprotic solvent such as THF, acetonitrile or DMF.

[0101] Preparation of benzyl (2S)-2-[(tert-butocycarbonyl)amino]-3-(4-phenyl-]H-imidazol-2-yl)propanoate 30

[0102] A solution of Boc-L-Asp-OBn (12 g; 37.1 nmmol) and cesium carbonate (6.05 g; 0.5 eq.) is stirred for approximately 30 minutes at approximately 20° C. in EtOH/H20 (1:1, 7 ml), then concentrated under reduced pressure at approximately 40° C. 25 ml of a solution of 2-bromoacetophenone (7.38 g; 1 eq.) in dry DMF is added to the resulting salt dissolved in 130 ml of dry DMF. The mixture is stirred for approximately 1 hour at approximately 20° C. under an argon atmosphere then concentrated under reduced pressure. Ethyl acetate is added (100 ml) and the mixture filtered, CsBr being washed with ethyl acetate. The filtrate is then concentrated under reduced pressure. A solution of the residue obtained and ammonium acetate (58 g; 20 eq.) in xylene (280 ml) is maintained under reflux for approximately 30 minutes at approximately 140° C.. The excess NH4OAc and water are eliminated using a Dean-Stark trap. The progress of the reaction is monitored by thin layer chromatography (TLC; eluent: ethyl acetate /heptane 1: 1). The mixture is then taken to approximately 20° C. then washed successively with water, a saturated solution of NaHCO3 solution until a basic pH is obtained then with salt water until a neutral pH is obtained. The organic phase is then dried over Na2SO4 and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) yields the expected compound (8.2 g; 52 %). NMR (1H, 400 MHz, CDCl3): 7.64-7.14 (m, l lH, arom H); 5.95 (d, IH, NHBoc); 5.21- 5.13 (AB, 2H, OCH2Ph, JAB =12Hz); 4.73 (m, 1H, CH); 3.30 (m, 2H, CH2); 1.42 ( 9H, (CH3)3C)′MS/LC: calculated MM =421.2; m/z =422.2 (M+H).

[0103] The following compounds are prepared in an analogous fashion to the procedure described for benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-phenyl-lH-imidazol-2-yl)propanoate: 3132

[0104] General procedure: the imidazolyl derivatives protected by N-Boc are treated with an organic or inorganic acid such as trifluoroacetic acid or hydrogen chloride (aqueous or in gaseous form) in an aprotic solvent such as dichloromethane or ethyl acetate at a temperature comprised between 0C and 25° C. for 0.5 to 5 hours.

[0105] Preparation of the dihydrochloride of benzyl (3S)-3-(4-phenyl-]H-imidazol-2-yl)-3-amino-propanoate 33

[0106] A flow of dry HCl is passed through a solution of benzyl (3S)-3-(4-phenyl-IH-imidazol-2-yl)-3-[(tert-butoxycarbonyl)amino propanoate (5 g) in ethyl acetate (120 ml) at 0° C. until the TLC (eluent: 100% ethyl acetate) shows that the starting compound has completely disappeared. The resulting mixture is then evaporated under reduced pressure. Diethylether is added to the solid obtained and the mixture is filtered. The hydrochloride is washed several times with dichloromethane then diethylether and dried under reduced pressure to produce 4.6 g of expected compound (98 % yield). NMR (1H, 400 MHz, DMSOd6): 9.21 (broad s, 2H, NH); 8.03-7.28 (m, arom. H, 1 IH); 5.10 (s, 1H, OCH2Ph); 5.04 (m, 1H, CH); 3.61 (dd, 1H, CH2, 3J =9 Hz, 2J 3.39 (dd, IH, CH2′, 3J =5.5 Hz, 2J =17.0 Hz). MS/LC: Calculated MM =321.2; m/z =322.1 (M+H).

[0107] The following compounds are prepared in an analogous fashion to the procedure described for the dihydrochloride of benzyl (3S)-3-(4-phenyl-lH-imidazol-2-yl)-3- amino-propanoate. 3435

[0108] General procedure: A free amine of formula (a) or (b) is treated with an aldehyde in a 5 protic or aprotic solvent, preferably dichloromethane or tetrahydrofuran, for a duration of 1 to 15 hours at 20-50° C. The resulting imine is then reduced using a reducing agent, preferably sodium triacetoxyborohydride or sodium cyanoborohydride with or without the presence of an acid such as acetic acid, at a temperature comprised between 20 and 50° C. for a duration of 0.2 to 5 hours. The N-alkylated compound is isolated by adding water and extraction followed by flash chromatography on silica gel or by crystallization.

[0109] Preparation of benzyl (2S)-4-(4-phenyl-]H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate 36

[0110] Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-IH-imidazol-2-yl)butanoate in the form of a free base (3.6 g; 1 eq.) in tetrahydrofuran (hereafter THF, 40 ml). The mixture is stirred for 15 hours at approximately 20° C. and diluted by adding 50 ml of tetrahydrofuran. NaBH(OAc)3 (4.73 g; 2 eq.) is then added. After 1 hour of stirring at approximately 20° C.1the reaction is stopped by adding water (40 ml) and ethyl acetate is then added (100 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Flash chromatography purification on silica gel (eluent: ethyl acetate / heptane 9:1) yields the expected compound in the form of a yellow oil (3.08 g; 66 % yield). NMR (1H, 400 MHz, CDCI3): 7.62-7.04 (m, 15H, arom. H, NH); 5.18 (s, 2H, OCH2); 3.87-3.69 (AB, 2H, CH2NH, 2JAB =13 Hz); 3.38 (dd, IH, CHNH, 3J =4.5 Hz, 2J Hz); 2.98 (m, IH, CH2CH); 2.88 (m, 1H, CH2CH); 2.17 (m, IH, CH2); 1.97 (m, 1H, CH2). MS/LC: Calculated MM =431.2; m/z =432.2 (M+H); m/z =430.8 (M-H).

[0111] The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for benzyl (2S)-4-(4-phenyl-IH-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate: 37

[0112] In the above formulae, R3 represents one of the following radicals: 383940

[0113] Qeneral procedure:

[0114] An amine of formula (II), in which m, Ri, R2, R3 and R5 have the same meanings as in general formula (I) and the O-GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or a isothiocyanate of general formula R4-NCX in which R4 has the same meaning as in general formula (I), in the presence or in the absence of a tertiary base such as triethylamine or N,N-diisopropylethylamine, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, at a temperature comprised between approximately 20 and 60° C. and for 1 to 24 hours. The resulting hydantoin or thiohydandoin can be isolated with a yield of 60 to 95 %, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.

[0115] When R4 represents a radical comprising a primary amino termination (for example R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4-NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).

[0116] Preparation of certain non-conmmercial isothiocvanates of Reneral formula (III): 41

[0117] These compounds are prepared as follows: a primary amine of general formula R4-NH2 is treated with a mixture of carbon disulphide and N-cyclohexylcarbodiimide N-methyl polystyrene resin, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, for a duration of 1 hour to 18 hours at 20-50° C. The resulting isothiocyanate is isolated after filtration on frit and evaporation of the filtrate.

[0118] Preparation of 6-isothiocyanato-N,N-dimethyl-1-hexanamine 42

[0119] Carbon disulphide (8.3 mL, 10 eq) and a solution of NN-dimethyl-1,6-hexanediamine (2g, 1 eq) in THF (10 mL) are added successively dropwise to a suspension of N-cyclohexylcarbodiimide N-methyl polystyrene resin (7.8g, 1.1 eq; acquired from Novabiochem, load 1.95 mmol/g) in anhydrous THF (120 mL). The suspension is stirred for 2 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. in order to produce the expected isothiocyanate derivative (2.6g, 93% yield). NMR H, 400 MHz, CDCl3, ): 3.50 (t, 2H); 2.24 (t, 2H), 2.20 (s, 6H), 1.68 (q, 2H), 1.50-1.31 (m, 6H).

[0120] The following compounds are prepared in an analogous fashion to the procedure described for 6-isothiocyanato-N,N-dimethyl-1-hexanamine: 43

[0121] Preparation of (5S)-1-(1H-indol-3-(4nitrophenyl)-5-[2-(4-phenyl-12-thioxo-4-imidazolidinone 44

[0122] 4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(lH-indol-3-ylmethyl)amino]-4-(4-phenyl-IH-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 [tl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84 % yield). NMR (IH, 400 MHz, CDCl3): 8.24-7.09 (m, 17H, arom H, NH); 5.88, 4.64 (AB, 2H, CH2N, 2JAB =15 Hz); 3.38 (dd, 1H, CH, 3J =3.0 Hz, 2J =8.5 Hz); 2.92 (m CH2CH); 2.74 (m, 1H, CH2); 2.24 (m, 1H, CH2). MS/LC: Calculated MM =536.2; m/z =537.1 (M+H).

[0123] The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-I-(IH-indol-3-ylmethyl)-3-(4-nitrophenyl)- 5-[2-(4-phenyl- 1 H-imidazol-2-yl)ethyl]-2-thioxo-4-imidazolidinone (apart from the final purification by flash chromatography on silica gel which is optional): 45

[0124] In the above formulae, R3 represents one of the following radicals: 46

[0125] and R4 represents one of the following radicals: 474849

[0126] Preparation of (5S)-I -(]H-indol-3-ylmethyl)-5-[2-(4-phenyl-]H-imidazol-2-yl)ethyl-3-[3-(trifluoromethyl)phenyl]-2, 4-imidazolidinedione 50

[0127] 3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[( 1H-indol-3-ylmethyl)amino]-4-(4-phenyl- 1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20° C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield). NMR (1H, 400 MHz, CDCl3): 7.75-6.99 (m, 17H, arom H, NH); 5.25, 4.44 (AB, 2H, CH2N, JAB =15 Hz); 3.77 (m, 1H, CH); 2.92 (m, 1H, CH2CH); 2.88 (m, 1H, CH2CH 2.72 (m, 1H, CH2); 2.17 (m, 1H, CH2). MS/LC: Calculated MM =543.2; m/z =544.2 (M+H).

[0128] The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione: 51

[0129] In the above formulae, R3 represents one of the following radicals: 52

[0130] and R4 represents one of the following radicals: 5354

[0131] General procedure:

[0132] An amine of general formula (IV), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the O-GP radical is a parting protective group derived from alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or isothiocyanate R4-NCX in the presence of a tertiary base such as triethylamine or N,N-diisopropylethylamine in an aprotic solvent, preferably THF or dichloromethane, at a temperature comprised between 20 and 70° C. for 1 to 48 hours. The compound obtained can be isolated with a yield of 40 to 90 %, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.

[0133] When R4 represents a radical comprising a primary amino termination (for example R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4-NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).

[0134] Preparation of (6S)-1-(]H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-]H-imidazol-2-yl)-2-thioxotetrahydro-4(]H)-pyrimidinone 55

[0135] Propylisothiocyanate (25 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(lH-indol-3-ylmethyl)amino 3-(4-phenyl-lH-imidazol-2-yl)propanoate (90 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added. The mixture is stirred for 5 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 1 ml of THF and 1 ml of triethylamine are added to the residue. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: ethyl acetate / heptane 8:2) yields the expected compound (72 mg, yield 82%). NMR (1H, 400 MHz, CDCI3): mixture of 2 atropisomers: 8.69-6.45 (m, 12H, H arom, NH); 6.42, 4.89 (AB, 1H, CH2, JAB =14.5 Hz); 5.78, 5.42 (AB, 1H, CH2, JA 14.5 Hz); 4.99 (m, 1H, CH); 4.41-4.36 (m, 1H, CH,); 4.20-4.11 (m, 1H, CH2); 3.49, 2.94 (AB, 1H, CH2CO, JAB=16 Hz); 3.28, 2.80 (AB, 1H, CH2CO, JAB =16 Hz); 1.52 (m, IH, CH2); 1.40 (m, 1H, CH2); 0.76, 0.62 (2m, 3H, CH3). MS/LC: Calculated MM =443.2; m/z =444.2 (M+H).

[0136] The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-I-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-H-imidazol-2-yl)-2-thioxotetrahydro-4(IH)-pyrimidinone (except for the final purification by flash chromatography on silica gel which is optional): 56

[0137] In the above formula, R3 represents one of the following radicals: 575859

[0138] and R4 represents one of the following radicals: 606162

[0139] Preparation of (6S)-b 1-(IH-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-]H-imidazol-2-yl)dihydro-2. 4(1H, 3H)-pyrimidinedione 63

[0140] 4-methoxyphenylisocyanate (40 lil, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, I eq.) in THF (2 ml). The mixture is stirred for 5 hours at a temperature of approximately 20° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 138 mg, 2 eq.) is added. The mixture is stirred for 3 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 2 ml of THF and 2 ml of triethylamine are added to the residue. The mixture is taken to reflux for 24 hours then concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate / heptane 8:2) yields the expected compound (80 mg, yield 74 NMR (1H, 400 MHz, CDCI3): mixture of 2 atropisomers: 9.67-8.96 (2s, 1H, NH); 8.49 (s, H, NH); 5.15, 4.36 (AB, 1H, CH2, J. =15 Hz); 5.08, 4.69 (AB, 1H, CH2, JAB =15 Hz); 4.67, 4.57 (2m, 1H, CH); 3.72 (s, 3H, OCH3); 3.29-2.79 (m, 2H, CH2CO). MS/LC: Calculated MM 491.2; ml/z =492.3 (M+H).

[0141] The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-l-(IH-indol-3-ylmethyl)-3-(4-methoxyphenyl) -6-(4-phenyl- I H-imidazol-2-yl)dihydro-2.4( 1 H,3H)-pyrimidinedione (except for the final purification by flash chromatography on silica gel which is optional): 64

[0142] In the above formula, R3 represents one of the following radicals: 65

[0143] and R4 represents one of the following radicals: 66

[0144] EXAMPLES

[0145] The examples prepared according to the synthesis methods described above are shown in tables below. These examples are presented to illustrate the above procedures and should in no case be considered as limiting the scope of the invention.

[0146] Analytical methods used for the characterization of the compounds

[0147] The compounds obtained have been characterized according to their retention time (rt) and to their mass spectrometry (MH+).

[0148] ) Mass spectrometry

[0149] For the mass spectrometry, a single quadrupole mass spectrometer (Micromass, platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50 % valley.

[0150] Calibration is carried out monthly between the masses 80 and 1000 Da using a calibration mixture of sodium and rubidium iodide in solution in an isopropanol/water mixture (1/1 Vol.).

[0151] ) High performance liquid chromatography (HPLC)

[0152] For the liquid chromatography, an HPLC HP 1100 system (Hewlett-Packard) including an in-line degasser, a quaternary pump, a column oven and a diode array UV detector is used.

[0153] Different elution conditions are used according to the examples:

- Conditions (i):
	Eluants:	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:	5 μl
	Column:	Uptisphere ODS 3 μm 33*4.6 mm i.d.
	Temperature:	40° C.
- Conditions (ii):
	Eluants:	A	water +0.04% trifluoroacetic acid
		B	acetonitrile
T(min)	A %	B %
0	90	10
6	15	85
10	15	85
	Flow rate:	1 ml/min
	Injection:	5 μl
	Column:	Uptisphere ODS 3 μm 50*4.6 mm i.d.
	Temperature:	40° C.

[0154] Elution conditions (i) are used for the characterization of Examples I to 479, 560 to 572 and 733 to 1040. As regards conditions (ii) they are used for Examples 480 to 559, 573 to 732 and 1041 to 1234. The UV detection is carried out at a wavelength of 220 nm for all the examples.

67
	Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
1	C29H25N5O2	68	69	89.6%	6.2	476.2
2	C30H27N5O2	70	71	91.0%	6.4	490.3
3	C30H27N5O3	72	73	90.1%	6.2	506.3
4	C30H27N5O2S	74	75	91.0%	6.6	522.2
5	C30H24F3N5O3	76	77	83.1%	7.0	560.2
6	C32H31N5O2	78	79	84.9%	7.0	518.3
7	C29H24BrN5O2	80	81	81.9%	6.7	556.1
8	C29H24ClN5O2	82	83	79.1%	6.6	510.2
9	C29H24N6O4	84	85	87.3%	6.4	521.2
10	C35H37N5O2	86	87	94.1%	7.3	560.3
11	C29H23F2N5O2	88	89	96.9%	6.3	512.2
12	C30H27N5O2	90	91	96.3%	6.4	490.2
13	C31H29N5O2	92	93	92.0%	6.5	504.2
14	C29H31N5O2	94	95	85.7%	6.6	482.3
15	C26H27N5O2	96	97	94.2%	5.9	442.3
16	C27H29N5O2	98	99	91.7%	6.3	456.3
17	C26H25N5O2	100	101	96.6%	5.8	440.2
18	C28H31N5O2	102	103	87.2%	6.6	470.3
19	C26H27N5O2	104	105	89.1%	6.0	442.2
20	C32H31N5O5	106	107	80.5%	6.1	566.2
21	C25822N4O2S	108	109	92.3%	5.9	443.2
22	C26H24N4O2S	110	111	90.2%	6.2	457.2
23	C26824N4O3S	112	113	92.1%	6.0	473.2
24	C26H24N4O2S2	114	115	92.8%	6.4	489.2
25	C26H21F3N4O3S	116	117	87.7%	6.8	527.2
26	C28H28N4O2S	118	119	87.8%	6.8	485.3
27	C25H21BrN4O2S	120	121	84.3%	6.5	523.1
28	C25H21ClN4O2S	122	123	84.9%	6.4	477.2
29	C25H21N5O4S	124	125	94.0%	6.2	488.2
30	C31H34N4O2S	126	127	97.2%	7.2	527.3
31	C25H20F2N4O2S	128	129	96.7%	6.1	479.2
32	C26H24N4O2S	130	131	95.3%	6.2	457.2
33	C27H26N4O2S	132	133	93.0%	6.4	471.2
34	C25H28N4O2S	134	135	88.3%	6.4	449.2
35	C22H24N4O2S	136	137	90.8%	5.7	409.2
36	C23H26N4O2S	138	139	91.8%	6.1	423.2
37	C22H22N4O2S	140	141	97.9%	5.6	407.2
38	C24H28N4O2S	142	143	84.3%	6.4	437.2
39	C22H24N4O2S	144	145	87.2%	5.7	409.2
40	C28H28N4O5S	146	147	92.2%	5.9	533.2
41	C25H26N4O3	148	149	93.9%	6.1	467.2
42	C29H25N4O3	150	151	95.8%	6.3	461.3
43	C29H28N4O4	152	153	93.0%	6.1	497.3
44	C29H28N4O3S	154	155	94.5%	6.5	513.2
45	C29H25F3N4O4	156	157	90.4%	6.9	551.2
46	C31H32N4O3	158	159	87.7%	6.9	509.3
47	C28H25BrN4O3	160	161	84.2%	6.6	547.1
48	C28H25ClN4O3	162	163	86.6%	6.5	501.2
49	C28H25N5O5	164	165	93.9%	6.3	512.2
50	C34H38N4O3	166	167	98.3%	7.2	551.3
51	C28H24F2N4O3	168	169	98.0%	6.2	503.2
52	C29H28N4O3	170	171	94.6%	6.4	481.2
53	C30H30N4O3	172	173	91.5%	6.4	495.3
54	C28H32N4O3	174	175	85.8%	6.5	473.3
55	C25H28N4O3	176	177	89.7%	5.8	433.3
56	C26H30N4O3	178	179	90.6%	6.2	447.3
57	C25H26N4O3	180	181	97.1%	5.7	431.2
58	C27H32N4O3	182	183	75.3%	6.5	461.3
59	C25H28N4O3	184	185	86.1%	5.9	433.3
60	C31H32N4O6	186	187	83.5%	6.0	557.2
61	C29H29N5O2	188	189	92.62%*	5.3	480.3
62	C30H31N5O2	190	191	93.25%*	5.6	494.3
63	C30H31N5O3	192	193	94.39%*	5.4	510.3
64	C30H31N5O25	194	195	95.36%*	5.8	526.3
65	C30H28F3N5O3	196	197	89.2%	6.3	564.2
66	C32H35N5O2	198	199	86.35%*	6.3	522.3
67	C29H28BrN5O2	200	201	84.14%*	5.9	560.1
68	C29H28ClN5O2	202	203	85.8%	5.8	514.2
69	C29H28N6O4	204	205	94.4%	5.6	525.3
70	C35H41N5O2	206	207	95.76%*	6.8	564.3
71	C29H27F2N5O2	208	209	96.29%*	5.5	516.3
72	C30H31N5O2	210	211	97.59%*	5.6	494.3
73	C31H33N5O2	212	213	94.87%*	5.7	508.3
74	C29H35N5O2	214	215	87.63%*	5.8	486.3
75	C26H31N5O2	216	217	87.69%*	5.0	446.3
76	C27H33N5O2	218	219	86.66%*	5.4	460.3
77	C26H29N5O2	220	221	93.78%*	4.9	444.3
78	C28H35N5O2	222	223	85%*	5.8	474.3
79	C26H31N5O2	224	225	87.49%*	5.0	446.3
80	C32H35N5O5	226	227	87.6%	5.3	570.3
228
	Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
81	C28H23N5O2	229	230	92%	6.2	462.2
82	C29H25N5O2	231	232	93%	6.5	476.2
83	C29H25N5O3	233	234	94%	6.2	492.2
84	C29H25N5O2S	235	236	92%	6.6	508.2
85	C29H22F3N5O3	237	238	92%	7.0	546.2
86	C31H29N5O2	239	240	92%	7.1	504.3
87	C28H22BrN5O2	241	242	92%	6.8	542.1
88	C28H22ClN5O2	243	244	92%	6.7	496.2
89	C28H22N8O4	245	246	82%	6.5	507.2
90	C34H35N5O2	247	248	92%	7.3	546.3
91	C28H21F2N5O2	249	250	90%	6.2	498.2
92	C31H29N5O5	251	252	82%	6.2	552.2
93	C29H22F3N5O2	253	254	92%	6.9	530.2
94	C30H25N5O3	255	256	89%	6.1	504.2
95	C29H25N5O2	257	258	92%	6.4	476.2
96	C30H27N5O2	259	260	93%	6.6	490.3
97	C25H25N5O2	261	262	95%	5.9	428.2
98	C26H27N5O2	263	264	95%	6.3	442.3
99	C25H23N5O2	265	266	95%	5.8	426.2
100	C27H29N5O2	267	268	94%	6.6	456.3
101	C24H20N4O2S	269	270	92%	5.9	429.2
102	C25H22N4O2S	271	272	91%	6.2	443.2
103	C25H22N4O3S	273	274	90%	6.0	459.2
104	C25H22N4O2S2	275	276	87%	6.4	475.2
105	C25H19F3N4O3S	277	278	89%	6.8	513.2
106	C27H26N4O2S	279	280	89%	6.9	471.2
107	C24H19BrN4O2S	281	282	91%	6.5	509.1
108	C24H19ClN4O2S	283	284	90%	6.4	463.1
109	C24H19N5O4S	285	286	76%	6.3	474.2
110	C30H32N4O2S	287	288	90%	7.1	513.3
111	C24H18F2N4O2S	289	290	82%	6.0	465.2
112	C27H26N4O5S	291	292	77%	5.8	519.2
113	C25H19F3N4O2S	293	294	89%	6.7	497.2
114	C26H22N4O3S	295	296	86%	5.8	471.2
115	C25H22N4O2S	297	298	85%	6.1	443.2
116	C26H24N4O2S	299	300	82%	6.3	457.2
117	C21H22N4O2S	301	302	84%	5.6	395.2
118	C22H24N4O2S	303	304	93%	5.9	409.2
119	C21H20N4O2S	305	306	89%	5.4	393.2
120	C23H26N4O2S	307	308	81%	6.3	423.2
121	C27H24N4O3	309	310	91%	6.0	453.2
122	C28H26N4O3	311	312	92%	6.3	467.2
123	C28H26N4O4	313	314	91%	6.0	483.3
124	C28H26N4O3S	315	316	88%	6.4	499.2
125	C28H23F3N4O4	317	318	91%	6.9	537.2
126	C30H30N4O3	319	320	90%	6.9	495.2
127	C27H23BrN4O3	321	322	89%	6.6	533.1
128	C27H23ClN4O3	323	324	91%	6.5	487.2
129	C27H23N5O5	325	326	75%	6.4	498.2
130	C33H36N4O3	327	328	90%	7.2	537.3
131	C27H22F2N4O3	329	330	82%	6.1	489.2
132	C30H30N4O6	331	332	79%	6.0	543.2
133	C28H23F3N4O3	333	334	90%	6.8	521.2
134	C29H26N4O4	335	336	85%	5.9	495.2
135	C28H26N4O3	337	338	89%	6.2	467.2
136	C29H28N4O3	339	340	89%	6.4	481.2
137	C24H25N4O3	341	342	88%	5.7	419.3
138	C25H28N4O3	343	344	90%	6.1	433.3
139	C24H24N4O3	345	346	92%	5.6	417.3
140	C28H30N4O3	347	348	87%	6.4	447.3
141	C28H27N5O2	349	350	89%	5.1	468.2
142	C29H29N5O2	351	352	89%	5.5	480.3
143	C29H29N5O3	353	354	90%	5.2	496.3
144	C29H29N5O2S	355	356	86%	5.7	512.2
145	C29H26F3N5O3	357	358	87%	6.2	550.2
146	C31H33N5O2	359	360	87%	6.2	508.3
147	C28H26BrN5O2	361	362	88%	5.8	546.1
148	C28H26ClN5O2	363	364	88%	5.7	500.2
149	C28H26N6O4	365	366	74.76%*	5.6	511.2
150	C34H39N5O2	367	368	85%	6.7	550.3
151	C28H25F2N5O2	369	370	81%	5.3	502.2
152	C31H33N5O5	371	372	79%	5.2	556.3
153	C29H26F3N5O2	373	374	88%	6.1	534.2
154	C30H29N5O3	375	376	85%	5.1	508.3
155	C29H29N5O2	377	378	86%	5.4	480.3
156	C30H31N5O2	379	380	86%	5.6	494.3
157	C25H29N5O2	381	382	85%	4.8	432.3
158	C26H31N5O2	383	384	84%	5.2	446.3
159	C25H27N5O2	385	386	86%	4.7	430.3
160	C27H33N5O2	387	388	88%	5.6	460.3
389
	Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
161	C30H27N5OS	390	391	80%	7.1	506.2
162	C30H26ClN5OS	392	393	83%	7.3	540.2
163	C30H25Cl2N5OS	394	395	81%	7.7	574.1
164	C31H27N5O3S	396	397	81%	7.0	550.2
165	C30H26FN5OS	398	399	82%	7.1	524.3
166	C31H29N5OS	400	401	81%	7.3	520.3
167	C31H28ClN5OS	402	403	83%	7.6	554.2
168	C33H33N5O3S	404	405	80%	7.0	580.3
169	C32H31N5OS	406	407	78%	7.4	534.3
170	C28H25N5O2S	408	409	85%	6.7	496.3
171	C28H29N5O2S	410	411	81%	6.6	500.3
172	C28H29N5OS	412	413	71%	7.1	484.3
173	C29H31N5OS	414	415	61%	7.3	498.3
174	C30H33N5OS	416	417	64%	7.6	512.3
175	C29H32N6O2S	418	419	84%	5.0	529.3
176	C30H34N6O2S	420	421	86%	5.0	543.3
177	C30H36N6OS	422	423	83%	5.2	529.3
178	C26H27N5O2S	424	425	82%	6.3	474.3
179	C27H29N5O2S	426	427	80%	6.4	488.3
180	C27H29N5OS	428	429	74%	7.0	472.3
181	C26H24N4OS2	430	431	77%	6.9	473.2
182	C26H23ClN4OS2	432	433	78%	7.1	507.2
183	C26H22Cl2N4OS2	434	435	84%	7.8	541.1
184	C27H24N4O3S2	436	437	80%	6.9	517.2
185	C28H23FN4OS2	438	439	75%	7.0	491.2
186	C27H26N4OS2	440	441	80%	7.1	487.2
187	C27H25ClN4OS2	442	443	85%	7.4	521.2
188	C29H30N4O3S2	444	445	87%	6.8	547.2
189	C28H28N4OS2	446	447	77%	7.3	501.2
190	C24H22N4O2S2	448	449	86%	6.5	463.2
191	C24H26N4O2S2	450	451	58.9% + 19.6%	64	467.2
192	C24H26N4OS2	452	453	75%	6.9	451.2
193	C25H28N4OS2	454	455	77%	7.2	465.2
194	C26H30N4OS2	456	457	76%	7.5	479.3
195	C25H29N5O2S2	458	459	81%	4.8	496.3
196	C26H31N5O2S2	460	461	82%	4.9	510.3
197	C26H33N5OS2	462	463	71%	5.0	496.3
198	C22H24N4O2S2	464	465	81%	6.1	441.2
199	C23H26N4O2S2	466	467	78%	6.2	455.2
200	C23H26N4OS2	468	469	79%	6.8	551.2
201	C29H28N4O2S	470	471	80%	7.0	497.3
202	C29H27ClN4O2S	472	473	81%	7.2	643.2
203	C29H26Cl2N4O2S	474	475	86%	7.6	677.2
204	C30H28N4O4S	476	477	82%	7.0	653.2
205	C29H27FN4O2S	478	479	72%	7.1	627.2
206	C30H30N4O2S	480	481	83%	7.2	511.3
207	C30H29ClN4O2S	482	483	87%	7.5	657.2
208	C32H34N4O4S	484	485	87%	6.9	571.3
209	C31H32N4O2S	486	487	83%	7.4	637.3
210	C27H26N4O3S	488	489	87%	6.6	599.2
211	C27H30N4O3S	490	491	59% +  20%	6.5 + 6.6	491.2
212	C27H30N4O2S	492	493	81%	7.0	475.5
213	C28H32N4O2S	494	495	82%	7.2	601.2
214	C29H34N4O2S	496	497	83%	7.5	615.3
215	C28H33N5O3S	498	499	86%	5.0	520.3
216	C29H35N5O3S	500	501	86%	5.0	646.3
217	C29H37N5O2S	502	503	78%	5.1	632.3
218	C25H28N4O3S	504	505	87%	6.2	577.2
219	C26H30N4O33	506	507	80%	6.4	591.3
220	C26H30N4O2S	508	509	85%	6.9	575.2
221	C30H31N5OS	510	511	77%	6.5	510.3
222	C30H30ClN5OS	512	513	66%	6.8	544.3
223	C30H29Cl2N5OS	514	515	69%	7.3	690.2
224	C31H31N5O3S	516	517	75%	6.4	666.3
225	C30H30FN5OS	518	519	52%	6.6	528.5
226	C31H33N5OS	520	521	82%	6.7	636.3
227	C31H32ClN5OS	522	523	85%	7.1	670.3
228	C33H37N5O3S	524	525	82%	6.4	696.3
229	C32H35N5OS	526	527	66%	7.0	650.3
230	C28H29N5O2S	528	529	77%	6.1	612.2
231	C28H33N5O2S	530	531	25% +48	5.8 + 5.9	616.3
232	C28H33N5OS	532	533	76%	6.4	600.3
233	C29H35N5OS	534	535	78%	6.7	614.3
234	C30H37N5OS	536	537	77%	4.6	645.3
235	C29H36N6O2S	538	539	85%	4.6	659.4
236	C30H38N6O2S	540	541	84%	4.8	532.3
237	C30H40N6OS	542	543	36%	5.5	590.3
238	C26H31N5O2S	544	545	79%	5.7	492.3
239	C27H33N5O2S	546	547	69%	6.3	588.3
240	C27H33N5OS	548	549	78%	6.3	476.3
550
	Analyses
Ex. No.	Formula	m	R1	R2	Purity	rt (min)	[M + H]+
241	C29H25N5OS	2	551	552	93%	6.7	492.2
242	C31H27N5O2S	2	553	554	87%	6.6	534.2
243	C35H37N5OS	2	555	556	68%	7.9	576.3
244	C32H31N5OS	2	557	558	88%	7.5	534.2
245	C29H23F2N5OS	2	559	560	92%	6.9	528.2
246	C29H24FN5OS	2	561	562	92%	6.8	510.2
247	C29H22Cl3N5OS	2	563	564	82%	7.6	594.1
248	C29H23Cl2N5OS	2	565	566	86%	7.5	560.1
249	C29H22Br3N5OS	2	567	568	76%	7.8	725.9
250	C31H29N5OS	2	569	570	47%	7.1	520.2
251	C31H23F6N5OS	2	571	572	88%	7.8	628.2
252	C30H24F3N5OS	2	573	574	90%	7.3	560.2
253	C31H29N5O3S	2	575	576	86%	69	552.2
254	C30H27N5O2S	2	577	578	93%	68	522.2
255	C30H27N5OS2	2	579	580	88%	7.1	538.2
256	C29H24N6O3S	2	581	582	92%	6.9	537.2
257	C29H24N8OS2	2	583	584	92%	7.1	533.2
258	C31H30N6OS	2	585	586	67%	6.7	268.2
259	C30H24N6OS	2	587	588	82%	6.7	517.2
260	C36H31N5O2S	2	589	590	86%	7.6	598.2
261	C29H29N5OS	2	591	592	78%	6.1	248.7
262	C31H31N5O2S	2	593	594	65%	6.0	269.7
263	C35H41N5OS	2	595	596	53%	7.5	290.8
264	C32H35N5OS	2	597	598	82%	7.0	269.8
265	C29H27F2N5OS	2	599	600	79%	6.4	266.7
266	C29H28FNSOS	2	601	602	73%	6.2	257.7
267	C29H26Cl3N5OS	2	603	604	87%	7.2	299.6
268	C29H27Cl2N5OS	2	605	606	70%	7.1	282.6
269	C29H26Br3N5OS	2	607	608	78%	7.3	365.5
270	C31H33N5OS	2	609	610	3%	6.6	262.7
271	C31H27F6N5OS	2	611	612	39%	7.5	316.8
272	C30H28F3N5OS	2	613	614	64%	6.9	282.7
273	C31H33N5O3S	2	615	616	78%	6.3	278.7
274	C30H31N5O2S	2	617	618	45%	6.2	263.7
275	C30H31N5OS2	2	619	620	66%	6.5	271.7
276	C29H28N6O3S	2	621	622	67%	6.4	271.2
277	C29H28N8OS	2	623	624	62%	6.5	269.2
278	C31H34N6OS	2	625	626	37%	6.1	270.2
279	C30H28N6OS	2	627	628	49%	6.1	261.3
280	C36H35N5O2S	2	629	630	73%	7.2	301.8
281	C24H20N4OS2	1	631	632	89%	6.6	445.1
282	C26H22N4O2S2	1	633	634	88%	6.6	487.2
283	C30H32N4OS2	1	635	636	86%	7.9	529.2
284	C27H26N4OS2	1	637	638	96%	7.5	487.2
285	C24H18F2N4OS2	1	639	640	93%	6.7	481.1
286	C24H19FN4OS2	1	641	642	90%	6.8	463.1
287	C24H17Cl3N4OS2	1	643	644	97%	7.5	547.0
288	C24H18Cl2N4OS2	1	645	646	90%	7.8	513.1
289	C24H17Br3N4OS2	1	647	648	92%	7.7	678.9
290	C26H24N4OS2	1	649	650	87%	7.0	473.2
291	C26H18F6N4OS2	1	651	652	91%	8.2	581.1
292	C25H19F3N4OS2	1	653	654	87%	7.5	513.1
293	C26H24N4O3S2	1	655	656	95%	6.8	505.2
294	C25H22N4O2S2	1	657	658	92%	6.7	475.1
295	C25H22N4OS3	1	659	660	89%	7.1	491.1
296	C24H19N5O3S2	1	661	662	88%	7.0	490.1
297	C24H19N7OS2	1	663	664	90%	7.1	486.2
298	C26H25N5OS2	1	665	666	86%	6.8	244.7
299	C25H19N5OS2	1	667	668	89%	6.8	470.1
300	C31H26N4O2S2	1	669	670	88%	7.7	551.2
301	C27H24N4O2S	1	671	672	92%	6.7	469.2
302	C29H26N4O3S	1	673	674	91%	6.7	511.2
303	C33H36N4O2S	1	675	676	89%	8.0	553.3
304	C30H30N4O2S	1	677	678	95%	7.6	511.2
305	C27H22F2N4O2S	1	679	680	95%	6.8	505.2
306	C27H23FN4O2S	1	681	682	93%	6.9	487.2
307	C27H21Cl3N4O2S	1	683	684	93%	7.6	571.1
308	C27H22Cl2N4O2S	1	685	686	85%	7.9	537.1
309	C27H21Br3N4O2S	1	687	688	93%	7.8	702.9
310	C29H28N4O2S	1	689	690	86%	7.1	497.2
311	C29H22F6N4O2S	1	691	692	93%	8.3	605.2
312	C28H23F3N4O2S	1	693	694	93%	7.5	537.1
313	C29H28N4O4S	1	695	696	96%	6.9	529.2
314	C28H26N4O3S	1	697	698	97%	6.8	499.2
315	C28H26N4O2S2	1	699	700	84%	7.2	515.2
316	C27H23N5O4S	1	701	702	88%	7.1	514.2
317	C27H23N7O2S	1	703	704	94%	7.2	510.2
318	C29H29N5O2S	1	705	706	89%	6.7	256.7
319	C28H23N5O2S	1	707	708	90%	6.8	494.2
320	C34H30N4O3S	1	709	710	89%	7.7	575.2
711
	Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
321	C29H25N5OS	712	713	91	7.2	492.2
322	C29H24ClN5OS	714	715	91	7.5	526.2
323	C29H23Cl2N5OS	716	717	91	7.9	560.1
324	C30H25N5O3S	718	719	92	7.0	536.2
325	C29H24FN5OS	720	721	93	7.3	510.2
326	C30H27N5OS	722	723	92	7.4	506.2
327	C30H26ClN5OS	724	725	91	7.8	540.2
328	C32H31N5O3S	726	727	90	7.1	566.2
329	C31H29N5OS	728	729	91	7.6	520.2
330	C27H23N5O2S	730	731	92	6.8	482.2
331	C27H27N5O2S	732	733	35 + 51	6.64 + 6.76	486.2
332	C27H27N5OS	734	735	90	7.2	470.2
333	C28H29N5OS	736	737	89	7.4	484.3
334	C29H31N5OS	738	739	90	7.7	498.3
335	C28H30N6O2S	740	741	94	5.2	258.3
336	C29H32N6O2S	742	743	93	5.1	265.3

[0155]

744
	Analyses
	Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
	337	C29H34N6OS	745	746	85	5.3	258.3
	338	C25H25N5O2S	747	748	92	6.4	460.2
	339	C26H27N5O2S	749	750	92	6.5	474.2
	340	C26H27N5OS	751	752	91	7.1	458.2
	341	C25H22N4OS2	753	754	90	7.0	459.2
	342	C25H21ClN4OS2	755	756	89	7.4	493.1
	343	C25H20Cl2N4OS2	757	758	92	7.7	527.1
	344	C26H22N4O3S2	759	760	88	6.9	503.2
	345	C25H21FN4OS2	761	762	91	7.1	477.2
	346	C26H24N4OS2	763	764	89	7.3	473.2
	347	C26H23ClN4OS2	765	766	91	7.7	507.1
	348	C28H28N4O3S2	767	768	88	6.9	533.2
	349	C27H26N4OS2	769	770	85	7.5	487.2
	350	C23H20N4O2S2	771	772	93	6.6	449.1
	351	C23H24N4O2S2	773	774	36 + 50	6.34 + 6.46	453.2
	352	C23H24N4OS2	775	776	87	7.0	437.2
	353	C24H26N4OS2	777	778	84	7.3	451.2
	354	C25H28N4OS2	779	780	86	7.5	465.2
	355	C24H27N5O2S2	781	782	91	5.0	241.7
	356	C25H29N5O2S2	783	784	88	5.0	248.8
	357	C25H31N5OS2	785	786	61	5.1	241.8
	358	C21H22N4O2S2	787	788	88	6.1	427.1
	359	C22H24N4O2S2	789	790	87	6.3	441.1
	360	C22H24N4OS2	791	792	84	6.9	425.2
	361	C28H26N4O2S	793	794	89	7.1	483.2
	362	C28H25ClN4O2S	795	796	89	7.5	517.2
	363	C28H24Cl2N4O2S	797	798	91	7.8	551.1
	364	C29H26N4O4S	799	800	89	7.0	527.2
	365	C28H25FN4O2S	801	802	95	7.2	501.2
	366	C29H28N4O2S	803	804	90	7.3	497.2
	367	C29H27ClN4O2S	805	806	89	7.7	531.2
	368	C31H32N4O4S	807	808	90	7.0	557.2
	369	C30H30N4O2S	809	810	91	7.5	511.2
	370	C26H24N4O3S	811	812	92	6.7	473.2
	371	C26H28N4O3S	813	814	39 + 45	6.44 + 6.56	477.2
	372	C26H28N4O2S	815	816	89	7.1	461.2
	373	C27H30N4O2S	817	818	90	7.3	475.2
	374	C28H32N4O2S	819	820	90	7.6	489.3
	375	C27H31N5O3S	821	822	93	5.1	253.7
	376	C28H33N5O3S	823	824	90	5.1	260.8
	377	C28H35N5O2S	825	826	73	5.3	253.8
	378	C24H26N4O3S	827	828	91	6.2	451.2
	379	C25H28N4O3S	829	830	91	6.4	465.2
	380	C25H28N4O2S	831	832	90	7.0	449.2
	381	C29H29N5OS	833	834	85	6.4	248.7
	382	C29H28ClN5OS	835	836	85	6.9	265.7
	383	C29H27Cl2N5OS	837	838	84	7.3	282.6
	384	C30H29N5O3S	839	840	85	6.3	270.7
	385	C29H28FN5OS	841	842	88	6.5	257.7
	386	C30H31N5OS	843	844	84	6.7	255.6
	387	C30H30ClN5OS	845	846	87	7.2	272.7
	388	C32H35N5O3S	847	848	82	6.4	285.8
	389	C31H33N5OS	849	850	81	6.9	262.7
	390	C27H27N5O2S	851	852	89	5.9	243.7
	391	C27H31N5O2S	853	854	43 + 43	5.68 + 5.86	245.7
	392	C27H31N5OS	855	856	83	6.4	237.7
	393	C28H33N5OS	857	858	83	6.7	244.7
	394	C29H35N5OS	859	860	85	7.0	251.7
	395	C28H34N6O2S	861	862	87	4.6	259.8
	396	C29H36N6O2S	863	864	84	4.6	267.2
	397	C25H29N5O2S	865	866	74	5.4	232.7
	398	C26H31N5O2S	867	868	83	5.6	239.7
	399	C26H31N5OS	869	870	87	6.3	231.8
871
	Analyses
Ex. No.	Formula	m	R1	R2	Purity	rt (min)	[M + H]+
400	C30H34N6O3S	2	872	873	83%	7.8	559.2
401	C31H36N6O3S	2	874	875	82%	7.9	573.2
402	C32H38N6O3S	2	876	877	82%	8.0	587.3
403	C33H40N6O3S	2	878	879	81%	8.3	601.3
404	C34H42N6O3S	2	880	881	80%	8.5	615.3
405	C26H31N5O3S2	2	882	883	81%	7.6	526.2
406	C27H33N5O3S2	2	884	885	83%	7.8	540.2
407	C28H35N5O3S2	2	886	887	88%	7.9	554.2
408	C29H37N5O3S2	2	888	889	86%	8.2	568.2
409	C30H39N5O3S2	2	890	891	86%	8.4	582.3
410	C29H35N5O4S	2	892	893	87%	7.7	550.3
411	C30H37N5O4S	2	894	895	87%	7.9	564.3
412	C31H39N5O4S	2	896	897	92%	8.0	578.3
413	C32H41N5O4S	2	898	899	89%	8.3	592.3
414	C33H43N5O4S	2	900	901	88%	8.5	606.3
415	C30H38N6O3S	2	902	903	83%	7.0	563.3
416	C31H40N6O3S	2	904	905	85%	7.2	577.3
417	C32H42N6O3S	2	906	907	88%	7.4	591.3
418	C33H44N6O3S	2	908	909	88%	7.7	303.3
419	C34H46N6O3S	2	910	911	88%	7.9	310.4
420	C29H32N6O3S	2	912	913	78%	7.9	545.2
421	C30H34N6O3S	2	914	915	81%	8.0	559.2
422	C31H36N6O3S	2	916	917	84%	8.1	573.3
423	C32H38N6O3S	2	918	919	82%	8.3	587.3
424	C33H40N6O3S	2	920	921	86%	8.5	601.3
425	C25H29N5O3S2	2	922	923	80%	7.7	512.2
426	C26H31N5O3S2	2	924	925	82%	7.8	526.2
427	C27H33N5O3S2	2	926	927	87%	7.9	540.2
428	C28H35N5O3S2	2	928	929	86%	8.2	554.2
429	C29H37N5O3S2	2	930	931	84%	8.4	568.2
430	C28H33N5O4S	2	932	933	86%	7.8	536.3
431	C29H35N5O4S	2	934	935	85%	7.9	550.3
432	C30H37N5O4S	2	936	937	92%	8.0	564.3
433	C31H39N5O4S	2	938	939	90%	8.2	578.3
434	C32H41N5O4S	2	940	941	90%	8.5	592.3
435	C29H36N6O3S	2	942	943	80%	6.9	549.3
436	C30H38N6O3S	2	944	945	78%	7.1	563.3
437	C31H40N6O3S	2	946	947	84%	7.3	577.3
438	C32H42N6O3S	2	948	949	83%	7.5	296.3
439	C33H44N6O3S	2	950	951	85%	7.8	303.3
440	C25H26N6OS	1	952	953	76%	5.4	459.2
441	C26H28N6OS	1	954	955	61%	5.4	473.3
442	C27H30N6OS	1	956	957	75%	5.6	244.2
443	C28H32N6OS	1	958	959	32%	5.7	251.1
444	C29H34N6OS	1	960	961	59%	5.9	258.3
445	C21H23N5OS2	1	962	963	78%	5.1	426.2
446	C22H25N5OS2	1	964	965	79%	5.2	440.2
447	C23H27N5OS2	1	966	967	84%	5.4	227.6
448	C24H29N5OS2	1	968	969	84%	5.5	234.7
449	C25H31N5OS2	1	970	971	83%	5.7	241.7
450	C24H27N5O2S	1	972	973	88%	5.3	450.2
451	C25H29N5O2S	1	974	975	96%	5.4	464.2
452	C26H31N5O2S	1	976	977	90%	5.6	239.7
453	C27H33N5O2S	1	978	979	90%	5.7	246.7
454	C28H35N5O2S	1	980	981	91%	5.9	253.7
455	C25H30N6OS	1	982	983	84%	4.8	232.2
456	C26H32N6OS	1	984	985	89%	4.9	238.8
457	C27H34N6OS	1	986	987	86%	5.0	246.1
458	C28H36N6OS	1	988	989	93%	5.2	252.9
459	C29H38N6OS	1	990	991	93%	5.4	260.1
460	C24H24N6OS	1	992	993	68%	5.6	445.2
461	C25H26N6OS	1	994	995	55%	5.5	459.2
462	C26H28N6OS	1	996	997	55%	5.6	473.3
463	C27H30N6OS	1	998	999	48%	5.7	487.3
464	C28H32N6OS	1	1000	1001	44%	5.9	501.2
465	C20H21N5OS2	1	1002	1003	84%	5.3	412.1
466	C21H23N5OS2	1	1004	1005	86%	5.2	426.2
467	C22H25N5OS2	1	1006	1007	90%	5.3	440.2
468	C23H27N5OS2	1	1008	1009	79%	5.5	227.7
469	C24H29N5OS2	1	1010	1011	91%	5.7	234.8
470	C23H25N5O2S	1	1012	1013	92%	5.5	436.2
471	C24H27N5O2S	1	1014	1015	88%	5.4	450.2
472	C25H29N5O2S	1	1016	1017	93%	5.5	464.3
473	C26H31N5O2S	1	1018	1019	92%	5.6	478.3
474	C27H33N5O2S	1	1020	1021	95%	5.8	246.7
475	C24H28N6OS	1	1022	1023	87%	4.9	224.7
476	C25H30N6OS	1	1024	1025	80%	4.8	231.9
477	C26H32N6OS	1	1026	1027	84%	4.9	238.9
478	C27H34N6OS	1	1028	1029	90%	5.0	245.7
479	C28H36N6OS	1	1030	1031	91%	5.2	505.3
1032
	Analyses
Ex. No.	Formula	X	R1	R2	Purity	rt (min)	[M + H]+
480	C30H34N6O3S	S	1033	1034	86%	5.4	559.2
481	C31H36N6O3S	S	1035	1036	88%	5.5	573.2
482	C32H38N6O3S	S	1037	1038	88%	5.5	587.3
483	C33H40N6O3S	S	1039	1040	89%	5.7	601.3
484	C34H42N6O3S	S	1041	1042	91%	5.8	615.3
485	C35H36N6O3S	S	1043	1044	91%	5.6	621.3
486	C31H34N6O4S	S	1045	1046	56%	5.6	587.2
487	C32H36N6O4S	S	1047	1048	73%	5.6	601.2
488	C33H38N6O4S	S	1049	1050	79%	5.7	615.3
489	C34H40N6O4S	S	1051	1052	71%	5.9	629.3
490	C35H42N6O4S	S	1053	1054	81%	6.0	643.3
491	C36H36N6O4S	S	1055	1056	60%	5.8	649.3
492	C30H34N6O3S	S	1057	1058	83%	5.4	559.2
493	C31H36N6O3S	S	1059	1060	87%	5.5	573.2
494	C32H38N6O3S	S	1061	1062	87%	5.5	587.3
495	C33H40N6O3S	S	1063	1064	87%	5.7	601.3
496	C34H42N6O3S	S	1065	1066	88%	5.8	615.3
497	C35H36N6O3S	S	1067	1068	89%	5.6	621.3
498	C31H34N6O4S	S	1069	1070	71%	5.6	587.2
499	C32H36N6O4S	S	1071	1072	45%	5.6	601.2
500	C33H38N6O4S	S	1073	1074	75%	5.7	615.3
501	C34H40N6O4S	S	1075	1076	68%	5.9	629.3
502	C35H42N6O4S	S	1077	1078	76%	6.0	643.3
503	C36H36N6O4S	S	1079	1080	55%	5.8	649.3
504	C30H34N6O4	O	1081	1082	88%	4.9	543.3
505	C31H36N6O4	O	1083	1084	88%	5.0	557.3
506	C32H38N6O4	O	1085	1086	85%	5.0	571.3
507	C33H40N6O4	O	1087	1088	86%	5.2	585.3
508	C31H34N6O5	O	1089	1090	79%	4.9	571.2
509	C32H36N6O5	O	1091	1092	56%	5.0	585.3
510	C33H38N6O5	O	1093	1094	77%	5.1	599.3
511	C34H40N6O5	O	1095	1096	74%	5.2	613.3
512	C30H34N6O4	O	1097	1098	90%	4.9	543.3
513	C31H36N6O4	O	1099	1100	90%	5.0	557.3
514	C32H38N6O4	O	1101	1102	89%	5.0	571.3
515	C33H40N6O4	O	1103	1104	91%	5.2	585.3
516	C31H34N6O5	O	1105	1106	76%	4.9	571.2
517	C32H36N6O5	O	1107	1108	81%	5.0	585.3
518	C33H38N6O5	O	1109	1110	74%	5.1	599.3
519	C34H40N6O5	O	1111	1112	75%	5.2	613.3
520	C25H26N6OS	S	1113	1114	93%	6.8	459.2
521	C26H28N6OS	S	1115	1116	93%	6.6	473.2
522	C27H30N6OS	S	1117	1118	90%	6.7	487.2
523	C28H32N6OS	S	1119	1120	92%	6.8	501.2
524	C29H34N6OS	S	1121	1122	92.%	6.9	515.2
525	C30H28N6OS	S	1123	1124	89%	6.8	521.2
526	C26H26N6O2S	S	1125	1126	63%	7.1	487.2
527	C27H28N6O2S	S	1127	1128	87%	6.8	501.2
528	C28H30N6O2S	S	1129	1130	85%	6.9	515.2
529	C29H32N6O2S	S	1131	1132	79%	7.0	529.2
530	C30H34N6O2S	S	1133	1134	91%	7.2	543.2
531	C31H28N6O2S	S	1135	1136	80%	7.1	549.2
532	C25H26N6OS	S	1137	1138	91%	6.8	459.2
533	C26H28N6OS	S	1139	1140	89%	6.6	473.2
534	C27H30N6OS	S	1141	1142	93%	6.7	487.2
535	C28H32N6OS	S	1143	1144	91%	6.8	501.2
536	C29H34N6OS	S	1145	1146	91%	6.9	515.2
537	C30H28N6OS	S	1147	1148	87%	6.8	521.2
538	C26H26N6O2S	S	1149	1150	90%	7.0	487.2
539	C27H28N6O2S	S	1151	1152	61%	6.8	501.2
540	C28H30N6O2S	S	1153	1154	87%	6.9	515.2
541	C29H32N6O2S	S	1155	1156	83%	7.0	529.2
542	C30H34N6O2S	S	1157	1158	93%	7.2	543.2
543	C31H28N6O2S	S	1159	1160	76%	7.1	549.2
544	C25H26N6O2	O	1161	1162	91%	6.1	443.2
545	C26H28N6O2	O	1163	1164	90%	6.1	457.2
546	C27H30N6O2	O	1165	1166	87%	6.1	471.2
547	C28H32N6O2	O	1167	1168	88%	6.2	485.2
548	C26H26N6O3	O	1169	1170	93%	6.2	471.2
549	C27H28N6O3	O	1171	1172	91%	6.1	485.2
550	C28H30N6O3	O	1173	1174	81%	6.2	499.2
551	C29H32N6O3	O	1175	1176	82%	6.3	513.2
552	C25H26N6O2	O	1177	1178	91%	6.1	443.2
553	C26H28N6O2	O	1179	1180	91%	6.1	457.2
554	C27H30N6O2	O	1181	1182	89%	6.1	471.2
555	C28H32N6O2	O	1183	1184	91%	6.1	485.2
556	C26H26N6O3	O	1185	1186	93%	6.2	471.2
557	C27H28N6O3	O	1187	1188	95%	6.1	485.2
558	C28H30N6O3	O	1189	1190	85%	6.2	499.2
559	C29H32N6O3	O	1191	1192	85%	6.3	513.2
560	C24H24N6OS	S	1193	1194	84%	3.6	445.2
561	C26H28N6OS	S	1195	1196	92%	3.5	473.3
562	C27H30N6OS	S	1197	1198	83%	3.6	487.3
563	C28H32N6OS	S	1199	1200	88%	3.7	501.3
564	C29H26N6OS	S	1201	1202	59%	3.7	507.2
565	C24H24N6O2	O	1203	1204	87%	3.2	429.2
566	C25H26N6O2	O	1205	1206	92%	3.1	443.3
567	C26H28N6O2	O	1207	1208	97%	3.1	457.3
568	C27H30N6O2	O	1209	1210	90%	3.1	471.3
569	C24H24N6O2	O	1211	1212	91%	3.1	429.2
570	C25H26N6O2	O	1213	1214	97%	3.1	443.3
571	C26H28N6O2	O	1215	1216	95%	3.1	457.3
572	C27H30N6O2	O	1217	1218	95%	3.2	471.3
1219
Ex.				Analyses
No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
573	C29H25N5OS	1220	1221	93%	6.7	492.2
574	C29H24ClN5OS	1222	1223	93%	7.2	526.2
575	C29H23Cl2N5OS	1224	1225	93%	7.6	560.1
576	C30H27N5OS	1226	1227	94%	7.0	506.2
577	C29H24FN5OS	1228	1229	95%	6.9	510.3
578	C30H27N5OS	1230	1231	90%	6.9	506.3
579	C30H26ClN5OS	1232	1233	92%	7.4	540.2
580	C32H31N5O3S	1234	1235	88%	6.4	566.3
581	C31H29N5OS	1236	1237	87%	7.1	520.2
582	C27H23N5O2S	1238	1239	93%	6.2	482.2
583	C27H27N5O2S	1240	1241	38 + 45%	5.6 + 5.71	486.3
584	C28H30N6O2S	1242	1243	87%	4.6	515.3
585	C29H32N6O2S	1244	1245	84%	4.5	529.3
586	C29H34N6OS	1246	1247	89%	4.7	515.3
587	C25H25N5O2S	1248	1249	90%	5.18 m	460.3
588	C26H27N5O2S	1250	1251	87%	5.6	474.3
589	C25H22N4OS2	1252	1253	89%	6.7	459.2
590	C25H21ClN4OS2	1254	1255	87%	7.2	493.2
591	C25H20Cl2N4OS2	1256	1257	90%	7.6	527.1
592	C26H24N4OS2	1258	1259	83%	7.0	473.2
593	C25H21FN4OS2	1260	1261	88%	6.9	477.2
594	C26H24N4OS2	1262	1263	80%	7.0	473.2
595	C26H23ClN4OS2	1264	1265	79%	7.4	507.2
596	C28H28N4O3S2	1266	1267	82%	6.4	533.2
597	C27H26N4OS2	1268	1269	79%	7.2	487.2
598	C23H20N4O2S2	1270	1271	80%	6.2	449.2
599	C23H24N4O2S2	1272	1273	31 + 32%	5.7 + 5.86	453.2
600	C24H27N5O2S2	1274	1275	80%	4.3	241.7
601	C25H29N5O2S2	1276	1277	81%	4.3	248.8
602	C25H31N5OS2	1278	1279	81%	4.5	482.3
603	C21H22N4O2S2	1280	1281	79%	5.6	427.1
604	C22H24N4O2S2	1282	1283	78%	5.9	441.2
605	C28H26N4O2S	1284	1285	89%	6.8	483.2
606	C28H25ClN4O2S	1286	1287	90%	7.2	517.2
607	C28H24Cl2N4O2S	1288	1289	91%	7.7	551.1
608	C29H28N4O2S	1290	1291	88%	7.0	497.3
609	C28H25FN4O2S	1292	1293	89%	6.9	501.2
610	C29H28N4O2S	1294	1295	87%	7.0	497.3
611	C29H27ClN4O2S	1296	1297	90%	7.5	531.2
612	C31H32N4O4S	1298	1299	91%	6.5	557.2
613	C30H30N4O2S	1300	1301	87%	7.2	511.3
614	C26H24N4O3S	1302	1303	89%	6.3	473.2
615	C26H28N4O3S	1304	1305	39 + 43%	5.7 + 5.85	477.2
616	C27H31N5O3S	1306	1307	34%	4.5	506.3
617	C28H33N5O3S	1308	1309	79%	4.4	520.3
618	C28H35N5O2S	1310	1311	76%	4.6	506.3
619	C24H26N4O3S	1312	1313	85%	5.7	451.2
620	C25H28N4O3S	1314	1315	84%	5.9	465.2
621	C29H29N5OS	1316	1317	89%	5.9	248.8
622	C29H28ClN5OS	1318	1319	89%	6.4	265.7
623	C29H27Cl2N5OS	1320	1321	93%	6.9	282.7
624	C30H31N5OS	1322	1323	90%	6.2	255.8
625	C29H28FN5OS	1324	1325	92%	6.1	257.8
626	C30H31N5OS	1326	1327	87%	6.2	255.8
627	C30H30ClN5OS	1328	1329	90%	6.8	272.7
628	C32H35N5O3S	1330	1331	87%	5.6	285.8
629	C31H33N5OS	1332	1333	88%	6.4	262.8
630	C27H27N5O2S	1334	1335	89%	5.4	243.7
631	C27H31N5O2S	1336	1337	31 + 37%	5.26 + 5.33	245.6
632	C28H34N6O2S	1338	1339	79%	3.7	260.3
633	C29H36N6O2S	1340	1341	77%	3.7	267.3
634	C29H38N6OS	1342	1343	78%	3.9	260.2
635	C25H29N5O2S	1344	1345	80%	4.9	232.7
636	C26H31N5O2S	1346	1347	79%	5.0	239.7
637	C28H23F3N4O2S	1348	1349	88%	7.4	537.2
638	C28H22ClF3N4O2S	1350	1351	90%	7.8	571.1
639	C28H21Cl2F3N4O2S	1352	1353	92%	8.3	605.1
640	C29H25F3N4O2S	1354	1355	89%	7.6	551.2
641	C28H22F4N4O2S	1356	1357	89%	7.5	555.2
642	C29H25F3N4O2S	1358	1359	88%	7.7	551.2
643	C29H24ClF3N4O2S	1360	1361	90%	8.1	585.1
644	C31H29F3N4O4S	1362	1363	92%	7.2	611.2
645	C30H27F3N4O2S	1364	1365	86%	7.8	565.2
646	C26H21F3N4O3S	1366	1367	88%	7.0	527.2
647	C26H25F3N4O3S	1368	1369	44 + 42%	6.59 + 6.7	531.2
648	C27H28F3N5O3S	1370	1371	81%	5.0	280.8
649	C28H30F3N5O3S	1372	1373	82%	5.0	287.8
650	C28H32F3N5O2S	1374	1375	86%	5.2	280.8
651	C24H23F3N4O3S	1376	1377	90%	6.6	505.2
652	C25H25F3N4O3S	1378	1379	88%	6.8	519.2
1380
Ex.				Analyses
No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
653	C29H32N6O3S	1381	1382	88%	6.4	545.3
654	C30H34N6O3S	1383	1384	90%	6.3	559.3
655	C31H36N6O3S	1385	1386	89%	6.3	573.3
656	C32H38N6O3S	1387	1388	91%	6.5	587.3
657	C33H40N6O3S	1389	1390	91%	6.8	601.3
658	C25H29N5O3S2	1391	1392	78%	6.7	512.3
659	C26H31N5O3S2	1393	1394	87%	6.5	526.3
660	C27H33N5O3S2	1395	1396	86%	6.6	540.3
661	C28H35N5O3S2	1397	1398	84%	6.8	554.3
662	C29H37N5O3S2	1399	1400	83%	7.0	568.3
663	C28H33N5O4S	1401	1402	83%	6.7	536.3
664	C29H35N5O4S	1403	1404	88%	6.6	550.3
665	C30H37N5O4S	1405	1406	84%	6.6	564.3
666	C31H39N5O4S	1407	1408	86%	6.8	578.3
667	C32H41N5O4S	1409	1410	86%	7.0	592.3
668	C29H36N6O3S	1411	1412	82%	5.8	549.3
669	C30H38N6O3S	1413	1414	80%	5.7	563.3
670	C31H40N6O3S	1415	1416	84%	5.8	577.3
671	C32H42N6O3S	1417	1418	84%	6.0	591.4
672	C33H44N6O3S	1419	1420	84%	6.3	605.4
673	C28H30F3N5O4S	1421	1422	82%	7.5	590.3
674	C29H32F3N5O4S	1423	1424	81%	7.3	604.3
675	C30H34F3N5O4S	1425	1426	84%	7.4	618.3
676	C31H36F3N5O4S	1427	1428	86%	7.5	632.3
677	C32H38F3N5O4S	1429	1430	88%	7.7	646.3
678	C29H34N6O4S	1431	1432	81%	5.8	563.3
679	C30H36N6O4S	1433	1434	81%	5.8	577.3
680	C31H38N6O4S	1435	1436	82%	5.8	591.3
681	C32H40N6O4S	1437	1438	82%	6.0	605.3
682	C33H42N6O4S	1439	1440	83%	6.2	619.4

[0156]

	1441
		Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
683	C27H30N6O5S	1442	1443	77%	6.9	551.3
684	C28H32N6O5S	1444	1445	75%	6.8	565.3
685	C29H34N6O5S	1446	1447	81%	6.9	579.3
686	C30H36N6O5S	1448	1449	82%	7.0	593.3
687	C31H38N6O5S	1450	1451	82%	7.3	607.3
688	C27H37N5O3S	1452	1453	77%	7.5	512.3
689	C28H39N5O3S	1454	1455	71%	7.3	526.4
690	C29H41N5O3S	1456	1457	78%	7.3	540.3
691	C30H43N5O3S	1458	1459	74%	7.5	554.4
692	C31H45N5O3S	1460	1461	74%	7.7	568.4
693	C24H24N6OS	1462	1463	47%	4.2	445.3
694	C25H26N6OS	1464	1465	45%	3.9	459.3
695	C26H28N6OS	1466	1467	52%	4.0	473.3
696	C27H30N6OS	1468	1469	43%	4.1	487.3
697	C28H32N6OS	1470	1471	38%	4.3	501.3
698	C20H21N5OS2	1472	1473	78%	4.1	412.2
699	C21H23N5OS2	1474	1475	81%	4.0	426.3
700	C22H25N5OS2	1476	1477	84%	4.1	440.2
701	C23H27N5OS2	1478	1479	86%	4.2	454.3
702	C24H29N5OS2	1480	1481	85%	4.3	468.3
703	C23H25N5O2S	1482	1483	82%	4.2	436.3
704	C24H27N5O2S	1484	1485	84%	4.1	450.3
705	G25H29N5O2S	1486	1487	88%	4.2	464.3
706	C26H31N5O2S	1488	1489	88%	4.3	478.3
707	C27H33N5O2S	1490	1491	87%	4.4	492.3
708	C24H28N6OS	1492	1493	80%	3.5	449.3
709	C25H30N6OS	1494	1495	83%	3.4	436.3
710	C26H32N6OS	1496	1497	84%	3.5	477.3
711	C27H34N6OS	1498	1499	84%	3.6	491.3
712	C28H36N6OS	1500	1501	85%	3.8	505.3
713	C23H22F3N5O25	1502	1503	83%	4.8	490.3
714	C24H24F3N5O2S	1504	1505	84%	4.8	504.2
715	C25H26F3N5O2S	1506	1507	88%	4.8	518.2
716	C25H28F3N5O2S	1508	1509	91%	4.9	532.2
717	C27H30F3N5O2S	1510	1511	90%	5.0	548.2
718	C24H26N6O2S	1512	1513	70%	3.6	463.3
719	C25H28N6O2S	1514	1515	82%	3.5	477.3
720	C26H30N6O2S	1516	1517	83%	3.5	491.3
721	C27H32N6O2S	1518	1519	89%	3.7	505.3
722	C28H34N6O2S	1520	1521	89%	3.8	519.3
723	C22H22N6O3S	1522	1523	81%	4.3	451.2
724	C23H24N6O3S	1524	1525	80%	4.3	465.2
725	C24H26N6O3S	1526	1527	89%	4.3	479.2
726	C25H28N6O3S	1528	1529	86%	4.4	493.3
727	C26H30N6O3S	1530	1531	86%	4.5	507.3
728	C22H29N5OS	1532	1533	79%	4.8	412.3
729	C23H31N5OS	1534	1535	75%	4.6	426.3
730	C24H33N5OS	1536	1537	78%	4.6	440.3
731	C25H35N5OS	1538	1539	78%	4.7	454.3
732	C26H37N5OS	1540	1541	83.8%	5.0	468.2
	1542
		Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
733	C28H24N6OS	1543	1544	45%	4.7	493.2
734	C29H26N6OS	1545	1546	57%	4.2	507.3
735	C24H21N5OS2	1547	1548	69%	4.7	460.2
736	C25H23N5O62	1549	1550	77%	4.2	474.2
737	C27H25N5O2S	1551	1552	73%	4.8	484.3
738	C28H27N5O2S	1553	1554	76%	4.3	497.3
739	C2BH2BN6OS	1555	1556	67%	3.9	497.3
740	C29H30N6OS	1557	1558	62%	3.6	511.3
741	C27H22F3N5O2S	1559	1560	61%	5.7	538.2
742	C28H24F3N5O2S	1561	1562	75%	4.9	552.2
743	C28H26N6O2S	1563	1564	57%	4.0	511.2
744	C29H28N6O2S	1565	1566	60%	3.7	525.3
745	C26H22N6O3S	1567	1568	70%	5.0	499.2
746	C27H24N6O3S	1569	1570	65%	4.4	513.2
747	C26H29N5OS	1571	1572	78%	5.4	460.3
748	C27H31N5OS	1573	1574	80%	4.7	474.3
749	C34H34N6O3S	1575	1576	86%	6.6	593.3
750	C33H32N6O3S	1577	1578	82%	6.5	607.3
751	C30H31N5O3S2	1579	1580	77%	6.7	560.2
752	C29H29N5O3S2	1581	1582	77%	6.7	574.2
753	C33H35N5O4S	1583	1584	81%	6.8	584.3
754	C32H33N5O4S	1585	1586	76%	6.7	598.3
755	C34H38N6O3S	1587	1588	77%	5.9	597.3
756	C33H36N6O3S	1589	1590	74%	5.8	611.3
757	C33H32F3N5O4S	1591	1592	76%	7.4	636.3
758	C32H30F3N5O4S	1593	1594	74%	7.3	652.3
759	C34H36N6O4S	1595	1596	78%	6.1	611.3
760	C33H34N6O4S	1597	1598	76%	6.0	625.3
761	C32H32N6O5S	1599	1600	74%	6.9	599.2
762	C31H30N6O5S	1601	1602	69%	6.8	613.3
763	C32H39N5O3S	1603	1604	78%	7.3	560.3
764	C31H37N5O3S	1605	1606	74%	7.5	574.3
765	C31H34N6O4S	1607	1608	76%	6.9	587.2
766	C32H36N6O4S	1609	1610	86%	6.8	601.3
767	C33H38N6O4S	1611	1612	81%	6.8	615.3
768	C34H40N6O4S	1613	1614	84%	7.0	629.3
769	C35H42N6O4S	1615	1616	78%	7.2	643.4
770	C36H36N6O4S	1617	1618	83%	6.8	649.3
771	C31H34N6O4S	1619	1620	81%	6.9	587.2
772	C32H36N6O4S	1621	1622	76%	6.8	601.3
773	C33H38N6O4S	1623	1624	82%	6.8	615.3
774	C34H40N6O4S	1625	1626	84%	7.0	629.3
775	C35H42N6O4S	1627	1628	73%	7.2	643.3
776	C36H36N6O4S	1629	1630	71%	6.8	649.3
777	C26H26N6O2S	1631	1632	84%	4.4	487.3
778	C27H28N6O2S	1633	1634	85%	4.4	501.3
779	C28H30N6O2S	1635	1636	65%	4.4	515.3
780	C29H32N6O2S	1637	1638	75%	4.6	529.3
781	C30H34N6O2S	1639	1640	84%	4.7	543.3
782	C31H28N6O2S	1641	1642	82%	4.5	549.3
783	C26H26N6O2S	1643	1644	87%	4.4	487.3
784	C27H28N6O2S	1645	1646	87%	4.4	501.3
785	C28H30N6O2S	1647	1648	83%	4.4	515.3
786	C29H32N8O2S	1649	1650	91%	4.5	529.3
787	C30H34N8O2S	1651	1652	84%	4.7	543.3
788	C31H28N6O2S	1653	1654	79%	4.5	549.3
789	C24H24N6OS	1655	1656	42%	4.3	445.3
790	C25H26N6OS	1657	1658	72%	4.1	459.3
791	C26H28N6OS	1659	1660	87%	4.1	473.4
792	C27H30N6OS	1661	1662	88%	4.3	487.4
793	C28H32N6OS	1663	1664	92%	4.4	501.4
794	C29H26N6OS	1665	1666	78%	4.3	507.3
795	C24H24N6OS	1667	1668	46%	4.3	445.3
796	C25H26N6OS	1669	1670	71%	4.1	459.3
797	C26H28N6OS	1671	1672	93%	4.1	473.4
798	C27H30N6OS	1673	1674	94%	4.3	487.4
799	C28H32N6OS	1675	1676	86%	4.5	501.4
800	C29H26N6OS	1677	1678	77%		507.3
	1679
		Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
801	C30H30N4OS	1680	1681	96%	7.7	495.3
802	C30H29ClN4OS	1682	1683	97%	8.1	529.3
803	C30H28Cl2N4OS	1684	1685	99%	8.6	563.2
804	C31H32N4OS	1686	1687	95%	7.9	509.3
805	C30H29FN4OS	1688	1689	96%	7.8	513.3
806	C31H32N4OS	1690	1691	93%	7.9	509.3
807	C31H31ClN4OS	1692	1693	95%	8.4	543.3
808	C33H36N4O3S	1694	1695	93%	7.4	569.3
809	C32H34N4OS	1696	1697	94%	8.1	523.3
810	C28H28N4O2S	1698	1699	96%	7.2	485.3
811	C28H32N4O2S	1700	1701	37 + 44%	6.7 + 6.84	489.3
812	C29H35N5O2S	1702	1703	88%	5.3	518.3
813	C30H37N5O2S	1704	1705	94%	5.3	532.4
814	C30H39N5OS	1706	1707	89%	5.4	518.4
815	C28H30N4O2S	1708	1709	92%	6.7	463.3
816	C27H32N4O2S	1710	1711	91%	6.9	477.3
817	C29H27N5O2S	1712	1713	93%	6.0	510.3
818	C29H26ClN5O2S	1714	1715	87%	6.5	544.2
819	C29H25Cl2NSO2S	1716	1717	74%	6.9	578.2
820	C30H29N5O2S	1718	1719	94%	6.2	524.3
621	C29H26FN5O2S	1720	1721	94%	6.2	528.3
822	C30H29N5O2S	1722	1723	93%	6.3	524.3
823	C30H28ClN5O2S	1724	1725	93%	6.7	558.2
824	C32H33N5O4S	1726	1727	91%	5.7	584.3
825	C31H31N5O2S	1728	1729	89%	6.5	538.3
826	C27H25N5O3S	1730	1731	90%	5.5	500.3
827	C27H29N5O3S	1732	1733	27% + 24	4, 99 + 5, 1	504.3
828	C28H32N6O3S	1734	1735	85%	3.9	533.3
829	C29H34N6O3S	1736	1737	87%	3.9	547.3
830	C29H36N6O2S	1738	1739	88%	4.1	533.3
831	C25H27N5O3S	1740	1741	92%	4.9	478.3
832	C26H29N5O3S	1742	1743	93%	5.1	492.3
833	C27H23N5O3S	1744	1745	93%	7.0	498.3
834	C27H22ClN5O3S	1746	1747	85%	7.4	532.2
835	C27H21Cl2N5O3S	1748	1749	88%	7.8	566.1
836	C28H25N5O3S	1750	1751	98%	7.3	512.3
837	C27H22FN5O3S	1752	1753	88%	7.1	516.2
838	C28H25N5O3S	1754	1755	90%	7.3	512.3
839	C28H24CN5O3S	1756	1757	91%	7.8	546.2
840	C30H29N5O5S	1758	1759	92%	6.8	572.2
841	C29H27N5O3S	1760	1761	94%	7.5	526.3
842	C25H21N5O4S	1762	1763	89%	6.6	488.2
843	C25H25N5O4S	1764	1765	46% + 46	6.24 + 6.4	492.3
844	C26H28N8O4S	1766	1767	82%	4.6	521.3
845	C27H30N6O4S	1768	1769	84%	4.6	535.3
846	C27H32N6O3S	1770	1771	76%	4.8	521.3
847	C23H23N5O4S	1772	1773	90%	6.1	466.2
848	C24H25N5O4S	1774	1775	90%	6.3	480.3
849	C24H21N5OS2	1776	1777	87%	6.1	460.2
850	C24H20ClN5OS2	1778	1779	53%	6.6	494.1
851	C24H19Cl2N5OS2	1780	1781	85%	7.0	528.0
852	C25H23N5OS2	1782	1783	79%	6.2	474.1
853	C24H20FNSOS2	1784	1785	76%	6.2	478.1
854	C25H23N5OS2	1786	1787	74%	6.4	474.1
855	C25H22ClN5OS2	1788	1789	82%	6.9	508.1
856	C27H27N5O3S2	1790	1791	73%	5.8	534.1
857	C26H25N5OS2	1792	1793	74%	6.6	488.1
858	C22H19N5O2S2	1794	1795	77%	5.5	450.1
859	C22H23N5O2S2	1796	1797	23 + 25%	5.2 + 5.33	454.1
860	C23H26N8O2S2	1798	1799	78%	3.9	483.2
861	C24H28N6O2S2	1800	1801	68%	3.9	497.2
862	C24H30N6OS2	1802	1803	59%	4.1	483.2
863	C20H21N5O2S2	1804	1805	68%	5.0	428.1
864	C21H23N5O2S2	1806	1807	65%	5.3	442.1
865	C27H30N4OS	1808	1809	97%	7.4	459.2
866	C27H29ClN4OS	1810	1811	98%	7.9	493.2
867	C27H28Cl2N4OS	1812	1813	97%	8.4	527.1
868	C28H32N4OS	1814	1815	98%	7.6	473.2
869	C27H29FN4OS	1816	1817	96%	7.6	477.2
870	C28H32N4OS	1818	1819	94%	7.7	473.2
871	C28H31ClN4OS	1820	1821	96%	8.3	507.2
872	C30H36N4O3S	1822	1823	94%	7.2	533.2
873	C29H34N4OS	1824	1825	91%	7.9	487.2
874	C25H28N4O2S	1826	1827	95%	6.9	449.2
875	C25H32N4O2S	1828	1829	38 + 8%	6.9 + 7.04	453.2
876	C26H35N5O2S	1830	1831	94%	5.0	482.2
877	C27H37N5O2S	1832	1833	93%	5.0	496.3
078	C27H39N5OS	1834	1835	94%	5.2	482.3
879	C23H30N4O2S	1836	1837	95%	6.5	427.2
880	C24H32N4O2S	1838	1839	97%	6.7	441.2
881	C29H27ClN4OS	1840	1841	78%	7.7	515.2
882	C29H28N4OS	1842	1843	59%	7.2	481.2
883	C31H32N4OS	1844	1845	63%	8.6	617.2
884	C31H30N4O2S	1846	1847	61%	7.1	523.2
885	C32H34N4OS	1848	1849	60%	7.9	523.3
886	C31H33N5OS	1850	1851	28%	6.7	524.2
887	C29H27N5O3S	1852	1853	53%	7.6	526.2
888	C29H27BrN4OS	1854	1855	68%	7.8	559.1
889	C29H26F2N4OS	1856	1857	62%	7.3	517.2
890	C29H27N7OS	1858	1859	64%	7.8	522.2
891	C30H27NSOS	1860	1861	66%	7.3	506.2
892	C30H28N4O3S	1862	1863	62%	7.1	525.2
893	C29H26ClN5O3S	1864	1865	55%	7.9	560.1
894	C33H36N4OS	1866	1867	59%	8.1	537.3
895	C30H30N4OS	1868	1869	67%	7.9	565.2
896	C31H32N4OS	1870	1871	57%	7.7	509.2
897	C28H24ClN5O2S	1872	1873	64%	6.2	530.1
898	C28H25N5O2S	1874	1875	64%	5.6	496.2
899	C30H29N5O2S	1876	1877	52%	7.1	632.2
900	C30H27N5O3S	1878	1879	57%	5.5	538.2
901	C31H31N5O2S	1880	1881	65%	6.4	538.2
902	C30H30N6O2S	1882	1883	29%	5.0	539.2
903	C28H24N6O4S	1884	1885	51%	6.0	541.2
904	C28H24BrN5O2S	1886	1887	72%	6.3	574.0
905	C28H23F2N5O2S	1888	1889	66%	5.7	532.2
906	C28H24N8O2S	1890	1891	52%	6.1	537.2
907	C29H24N6O2S	1892	1893	65%	5.7	521.1
908	C29H25N5O4S	1894	1895	66%	5.5	540.1
909	C28H23ClN6O4S	1896	1897	55%	6.4	575.1
910	C32H33N5O2S	1898	1899	64%	6.6	552.2
911	C29H27N5O2S	1900	1901	68%	6.5	580.1
912	C30H29N5O2S	1902	1903	68%	6.1	524.2
913	C26H20ClN5O3S	1904	1905	60%	7.0	518.1
914	C26H21N5O3S	1906	1907	63%	6.6	484.2
915	C28H25N5O3S	1908	1909	41%	7.8	620.1
916	C28H23N5O4S	1910	1911	51%	6.4	526.1
917	C29H27N5O3S	1912	1913	64%	7.3	526.2
918	C25H26N6O3S	1914	1915	21%	6.2	527.2
919	C26H20N6O5S	1916	1917	27%	6.8	529.1
920	C26H20BrN5O3S	1918	1919	61%	7.2	562.0
921	C26H19F2N5O3S	1920	1921	55%	6.6	520.1
922	C26H20N8O3S	1922	1923	61%	7.0	525.1
923	C27H20N8O3S	1924	1925	50%	6.6	509.1
924	C27H21N5O5S	1926	1927	68%	6.5	528.1
925	C26H19ClN6O5S	1928	1929	44%	7.2	563.1
926	C30H29N5O3S	1930	1931	60%	7.5	540.2
927	C27H23N5O3S	1932	1933	62%	7.3	568.1
928	C28H25N5O3S	1934	1935	60%	7.0	512.2
929	C23H18ClN5OS2	1936	1937	28%	6.4	480.1
930	C23H19N5OS2	1938	1939	22%	5.5	448.1
931	C25H23N5OS2	1940	1941	34%	7.3	582.1
932	C25H21N5O2S2	1942	1943	25%	5.7	488.1
933	C26H25N5OS2	1944	1945	21%	6.6	488.1
934	C25H24N6OS2	1946	1947	13%	5.3	489.1
935	C23H18N6O3S2	1948	1949	23%	6.2	491.1
936	C23H18BrN5OS2	1950	1951	38%	6.5	524.0
937	C23H17F2N5OS2	1952	1953	58%	5.8	482.1
938	C23H18N8OS2	1954	1955	28%	8.3	487.1
939	C24H18N6OS2	1956	1957	32%	5.9	471.1
940	C24H19N5O3S2	1958	1959	23%	5.7	490.1
941	C23H17ClN6O3	1960	1961	33%	6.7	525.0
942	C27H27N5OS2	1962	1963	29%	6.8	502.2
943	C24H21N5OS2	1964	1965	35%	6.7	530.1
944	C25H23N5OS2	1966	1967	16%	6.3	474.1
945	C26H27ClN4OS	1968	1969	61%	7.5	479.2
946	C26H28N4OS	1970	1971	54%	7.0	445.2
947	C28H32N4OS	1972	1973	61%	8.4	581.1
948	C28H30N4O2S	1974	1975	49%	6.9	487.2
949	C29H34N4OS	1976	1977	57%	7.7	487.2
950	C28H33N5OS	1978	1979	16%	6.4	488.2
951	C26H27N5O3S	1980	1981	44%	7.4	490.2
952	C26H27BrN4OS	1982	1983	70%	7.6	523.1
953	C26H26F2N4OS	1984	1985	61%	7.0	481.2
954	C26H27N7OS	1986	1987	66%	7.4	486.2
955	C27H27N5OS	1988	1989	68%	7.1	470.2
956	C27H28N4O3S	1990	1991	63%	6.9	489.2
957	C26H26ClN5O3S	1992	1993	66%	7.7	524.1
958	C30H36N4OS	1994	1995	58%	7.9	501.3
959	C27H30N4OS	1996	1997	64%	7.7	529.2
960	C28H32N4OS	1998	1999	46%	7.5	473.2
	2000
		Analyses
Ex. No.	Formula	R1	R2	Purity	rt (min)	[M + H]+
961	C30H30N4O3	2001	2002	57%	10.5	495.2
962	C30H27F3N4O2	2003	2004	69%	11.6	533.2
963	C29H28N4O2	2005	2006	69%	10.4	465.2
964	C29H27N5O4	2007	2008	61%	11.0	510.2
965	C30H29ClN4O2	2009	2010	74%	11.6	513.2
966	C32H32N4O4	2011	2012	52%	11.0	537.2
967	C29H27BrN4O2	2013	2014	76%	11.2	543.1
965	C29H27FN4O2	2015	2016	60%	10.7	483.2
969	C29H26Cl2N4O2	2017	2018	68%	11.9	533.1
970	C31H30N4O3	2019	2020	71%	10.3	507.2
971	C30H30N4O2S	2021	2022	72%	10.9	511.2
972	C30H27F3N4O3	2023	2024	77%	11.6	549.2
973	C29H27BrN4O2	2025	2026	66%	11.3	543.1
974	C32H34N4O2	2027	2028	85%	11.5	507.3
975	C29H26F2N4O2	2029	2030	72%	10.8	501.2
976	C32H34N4O5	2031	2032	71%	10.3	555.2
977	C29H27N504	2033	2034	72%	8.0	510.2
978	C29H24F3N5O3	2035	2036	70%	9.3	548.2
979	C28H25N5O3	2037	2038	79%	7.8	480.2
980	C28H24N6O5	2039	2040	62%	8.6	525.2
981	C29H26CN5O3	2041	2042	71%	9.1	528.2
982	C31H29N5O5	2043	2044	65%	8.6	552.2
983	C28H24BrN5O3	2045	2046	82%	8.8	558.1
984	C28H24FN5O3	2047	2048	73%	8.2	498.2
985	C28H23Cl2N5O3	2049	2050	66%	9.5	548.1
986	C30H27N5O4	2051	2052	81%	7.7	522.2
987	C29H27N5O3S	2053	2054	79%	8.4	526.2
988	C29H24F3N5O4	2055	2056	83%	9.3	564.2
989	C28H24BrN5O3	2057	2058	69%	8.8	558.1
990	C31H31N5O3	2059	2060	84%	9.2	522.3
991	C28H23F2N5O3	2061	2062	86%	8.1	516.2
992	C31H31N5O6	2063	2064	60%	7.7	570.2
993	C27H23N5O5	2065	2066	76%	9.5	498.2
994	C27H20F3N5O4	2067	2068	71%	10.7	536.1
995	C26H21N5O4	2069	2070	85%	9.4	468.2
996	C26H20N6O6	2071	2072	56%	10.0	513.2
997	C27H22ClN5O4	2073	2074	77%	10.7	516.1
998	C29H25N5O6	2075	2076	64%	10.2	540.2
999	C28H20BrN5O4	2077	2078	83%	10.4	546.0
1000	C26H20FN5O4	2079	2080	74%	9.8	486.2
1001	C26H19Cl2N5O4	2081	2082	69%	11.0	536.1
1002	C28H23N5O5	2083	2084	81%	9.3	510.2
1003	C27H23N5O4S	2085	2086	79%	10.1	514 1
1004	C27H20F3N5O5	2087	2088	74%	10.8	552.1
1005	C26H20BrN5O4	2089	2090	66%	10.4	546.0

[0157]

	2091
		Analyses
Ex.						[M +
No.	Formula	R1	R2	Purity	rt (min)	H]+
1006	C29H27N5O4	2092	2093	84%	10.8	510.2
1007	C26H19F2N5O4	2094	2095	76%	9.8	504.1
1008	C29H27N5O7	2096	2097	74%	9.3	558.2
1009	C24H21N5O3S	2098	2099	60%	8.2	460.1
1010	C24H18F3N5O2S	2100	2101	65%	9.5	498.1
1011	C23H19N5O2S	2102	2103	77%	8.0	430.1
1012	C23H18N6O4S	2104	2105	60%	8.7	475.1
1013	C24H20ClN5O2S	2106	2107	62%	9.4	478.1
1014	C26H23N5O4S	2108	2109	63%	8.9	502.2
1015	C23H18BrN5O2S	2110	2111	79%	9.1	508.0
1016	C23H18FN5O2S	2112	2113	63%	8.4	448.1
1017	C23H17Cl2N5O2S	2114	2115	54%	9.8	498.1
1018	C25H21N5O3S	2116	2117	82%	8.0	472.1
1019	C24H21N5O2S2	2118	2119	73%	8.8	476.1
1020	C24H18F3N5O3S	2120	2121	70%	9.6	514.1
1021	C23H18BrNSO2S	2122	2123	60%	9.2	508.0
1022	C26H25N5O2S	2124	2125	74%	9.6	472.2
1023	C23H17F2N5O2S	2126	2127	62%	8.3	466.1
1024	C26H25N5O5S	2128	2129	64%	8.0	520.1
1025	C27H22F2N4O3	2130	2131	76%	9.4	489.2
1026	C27H19F5N4O2	2132	2133	77%	10.6	527.1
1027	C26H20F2N4O2	2134	2135	87%	9.2	459.2
1028	C26H19F2N5O4	2136	2137	79%	9.9	504.1
1029	C27H21ClF2N4O2	2138	2139	74%	10.6	507.1
1030	C29H24F2N4O4	2140	2141	89%	10.1	531.2
1031	C26H19BrF2N4O2	2142	2143	82%	10.3	537.1
1032	C26H19F3N4O2	2144	2145	79%	9.7	477.1
1033	C26H18Cl2F2N4O2	2146	2147	69%	11.0	527.1
1034	C28H22F2N4O3 2148	2149	82%	9.2	501.2
1035	C27H22F2N4O2S	2150	2151	76%	9.9	505.1
1036	C27H19F5N4O3	2152	2153	83%	10.7	543.1
1037	C26N19BrF2N4O2	2154	2155	68%	10.4	537.1
1038	C29H26F2N4O2	2156	2157	86%	10.7	501.2
1039	C26H18F4N4O2	2158	2159	80%	9.6	495.1
1040	C29H26F2N4O5	2160	2161	43%	9.2	549.2
	2162
		Analyses
Ex.						[M +
No.	Formula	R1	R2	Purity	rt (min)	H]+
1041	C26 H33 N5 O S2	2163	2164	56	3.69	496.3
1042	C29 H37 N5 O2 S	2165	2166	74	3.78	520.3
1043	C30 H36 N6 O S	2167	2168	76	3.77	529.3
1044	C31 H38 N6 O S	2169	2170	73	3.85	543.3
1045	C30 H39 N5 O S	2171	2172	63	4.19	518.3
1046	C30 H36 N6 O S	2173	2174	71	4.01	529.3
	2175
		Analyses
Ex.						[M +
No.	Formula	R1	R2	Purity	rt (min)	H]+
1047	C27 H35 N5 O S2	2176	2177	69	3.65	510.3
1048	C30 H39 N5 O2 S	2178	2179	75	3.75	5343
1049	C31 H42 N6 O S	2180	2181	71	3.49	547.3
1050	C31 H38 N6 O S	2182	2183	86	3.74	543.3
1051	C31 H38 N6 O S	2184	2185	87	3.89	543.3
	2186
		Analyses
Ex.						[M +
No.	Formula	R1	R2	Purity	rt (min)	H]+
1052	C30 H36 N6 O S	2187	2188	83.38	4.71	529.3
1053	C26 H33 N5 O S2	2189	2190	72.31	4.41	496.3
1054	C29 H37 N5 O2 S	2191	2192	71.47	4.5	520.3
1055	C30 H40 N6 O S	2193	2194	62.38	3.86	533.3
1056	C25 H32 N6 O S2	2195	2196	25.6	3.9	497.2
1057	C28 H33 F2 N5 O S	2197	2198	63.2	4.5	526.3
1058	C31 H41 N5 O S	2199	2200	69.01	5.17	532.4
1059	C28 H34 N6 O3 S	2201	2202	73.01	4.58	535.3
1060	C28 H41 N5 O S	2203	2204	44.6	4.9	496.4
1061	C29 H34 F3 N5 O2 S	2205	2206	80.9	5.1	574.2
1062	C30 H39 N5 O S	2207	2208	58.84	4.91	518.3
1063	C36 H42 N6 O S	2209	2210	54.23	5.3	607.3
1064	C28 H34 Br N5 O S	2211	2212	76.51	4.86	568.2
1065	C28 H33 Cl2 N5 O S	2213	2214	74.91	5.03	558.2
1066	C29 H34 F3 N5 O S	2215	2216	66.26	4.93	558.2
1067	C28 H34 N6 O3 S	2217	2218	40	4.6	535.2
1068	C32 H37 N5 O S	2219	2220	73.1	4.9	540.3
1069	C29 H34 N6 O5 S	2221	2222	55.8	4.58	579.2
1070	C34 H39 N5 O S	2223	2224	64.6	5.2	566.3
1071	C29 H34 N6 O S	2225	2226	70.75	4.38	515.3
1072	C29 H37 N5 O S	2227	2228	64.36	4.68	504.3
1073	C35 H41 N5 O2 S	2229	2230	40.5	5	596.3
1074	C31 H38 N6 O S	2231	2232	80.4	4	543.3
	2233
		Analyses
Ex.						[M +
No.	Formula	R1	R2	Purity	rt (min)	H]+
1075	C26H32N6O3S2	2234	2235	45.2%	6.1	541.3
1076	C27H34N6O3S2	2236	2237	35.3%	6.3	555.3
1077	C28H36N6O3S2	2238	2239	39.9%	6.5	569.3
1078	C30H38N6O3S2	2240	2241	14.9 +22.82%	6, 7 +6, 76	595.3
1079	C32H41N5O3S	2242	2243	70.3%	7.5	576.4
1080	C33H43N5O3S	2244	2245	71.9%	7.7	590.4
1081	C34H45N5O3S	2246	2247	72.7%	7.9	604.4
1082	C36H47N5O3S	2248	2249	34.6 +34.7%	8.1 +8.28	630.4
1083	C29H33F2N5O3S	2250	2251	60.6%	6.9	570.3
1084	C30H35F2N5O3S	2252	2253	62.7%	7.1	584.3
1085	C31H37F2N5O3S	2254	2255	65.5%	7.3	598.3
1086	C33H39F2N5O3S	2256	2257	33.92% +32.4%	7.5 +4.6	624.3
1087	C29H34BrN5O3S	2258	2259	65.6%	7.3	612.2
1088	C30H36BrN5O3S	2260	2261	68.6%	7.5	626.2
1089	C31H38BrN5O3S	2262	2263	75.2%	7.7	640.3
1090	C33H40BrN5O3S	2264	2265	37.14% +37.1%	7.88 +8.0	666.3
1091	C29H34BrN5O3S	2266	2267	71.9%	7.3	612.2
1092	C30H38BrN5O3S	2268	2269	76.2%	7.4	626.2
1093	C31H38BrN5O3S	2270	2271	77.0%	7.6	640.3
1094	C33H40BrN5O3S	2272	2273	39.4 +39.64% m	7.8 +8.0	666.3
1095	C29H33Cl2N5O3S	2274	2275	72.1%	7.6	602.2
1096	C30H35Cl2N5O3S	2276	2277	74.9%	7.7	616.3
1097	C31H37Cl2N5O3S	2278	2279	76.4%	7.9	630.3
1098	C33H39Cl2N5O3S	2280	2281	39.6% +39.16%	8.1 +8.4	656.3
1099	C30H34F3N5O3S	2282	2283	64.3%	7.3	602.3
1100	C31H36F3N5O3S	2284	2285	71.3%	7.5	616.3
1101	C32H38F3N5O3S	2286	2287	71.6%	7.6	630.3
1102	C34H40F3N5O3S	2288	2289	34.8 +34.91%	8.0 +7.8	656.4
1103	C29H34N6O5S	2290	2291	63.2%	6.9	579.3
1104	C30H36N6O5S	2292	2293	66.1%	7.1	593.3
1105	C31H38N6O5S	2294	2295	66.1%	7.3	607.3
1106	C33H40N6O5S	2296	2297	33.7% +24.4%	7.5 +7.6	633.4
1107	C33H37N5O3S	2298	2299	84.0%	7.2	584.4
1108	C34H39N5O3S	2300	2301	86.3%	7.4	598.4
1109	C35H41N5O3S	2302	2303	88.2%	7.6	812.4
1110	C37H43N5O3S	2304	2305	43.1% +43.4%	7.9 +8.12	638.4
1111	C36H41N5O4S	2306	2307	58.2%	7.3	640.4
1112	C37H43N5O4S	2308	2309	61.1%	7.5	654.4
1113	C38H45N5O4S	2310	2311	67.6%	7.7	668.4
1114	C40H47N5O4S	2312	2313	38.1% +38.5%	7.9 +8.1	694.4
1115	C21H24N6OS2	2314	2315	74.0%	3.9	441.2
1116	C22H26N6OS2	2316	2317	80.2%	4.0	455.3
1117	C23H28N6OS2	2318	2319	47.3%	4.2	469.3
1118	C25H30N6OS2	2320	2321	18.31% +14%	4.2 +4.3	495.3
1119	C27H33N5OS	2322	2323	76.8%	5.1	476.4
1120	C28H35N5OS	2324	2325	77.9%	5.3	490.4
1121	C29H37N5OS	2326	2327	75.6%	5.4	504.4
1122	C31H39N5OS	2328	2329	38.42% +26.7% m	5.5 +5.7	530.4
1123	C24H25F2N5OS	2330	2331	68.1%	4.5	470.3
1124	C25H27F2N5OS	2332	2333	66.9%	4.7	484.3
1125	C26H29F2N5OS	2334	2335	70.0%	4.8	498.3
1126	C25H31F2N5OS	2336	2337	25.0%	4.9	524.3
1127	C24H26BrN5OS	2338	2339	72.7%	4.9	512.2
1128	C25H28BrN5OS	2340	2341	78.5%	5.0	526.2
1129	C26H30BrN5OS	2342	2343	80.2%	5.1	540.2
1130	C28H32BrN5OS	2344	2345	39.21% +27%	5.3 +5.4	568.2
1131	C24H26BrN5OS	2346	2347	77.9%	4.9	512.2
1132	C25H28BrN5OS	2348	2349	81.4%	5.0	526.2
1133	C26H30BrN5OS	2350	2351	78.25%	5.1	540.2
1134	C28H32BrN5OS	2352	2353	31.02% +27.9	5.2 +5.4	566.2
1135	C24H25Cl2N5OS	2354	2355	79.9%	5.1	502.2
1136	C25H27Cl2N5OS	2356	2357	81.2%	5.2	516.2
1137	C26H29Cl2N5OS	2358	2359	80.1%	5.3	530.2
1138	C28H31Cl2N5OS	2360	2361	33.63% +28.8%	5.4 +5.6	556.2
1139	C25H26F3N5OS	2362	2363	73.7%	4.9	502.3
1140	C26H28F3N5OS	2364	2365	80.8%	5.1	516.2
1141	C27H30F3N5OS	2366	2367	76.86%	5.2	530.3
1142	C29H32F3N5OS	2368	2369	27.7% +27.3	5.3 +5.4	556.3
1143	C24H26N6O3S	2370	2371	70.7%	4.6	479.3
1144	C25H28N6O3S	2372	2373	72.3%	4.7	493.3
1145	C26H30N6O3S	2374	2375	72.4%	4.8	507.3
1146	C28H32N6O3S	2376	2377	27.5% +26.5%	4.9 +5.3	533.3
1147	C28H29N5OS	2378	2379	88.2%	4.8	484.3
1148	C29H31N5OS	2380	2381	89.1%	5.0	498.3
1149	C30H33N5OS	2382	2383	89.9%	5.1	512.3
1150	C32H35N5OS	2384	2385	46.67% +31.0	5.3 +5.5	538.3
1151	C31H33N5O2S	2386	2387	46.0%	5.0	540.3
1152	C32H35N5O2S	2388	2389	46.6%	5.1	554.2
1153	C33H37N5O2S	2390	2391	54.2%	5.2	568.3
1154	C35H39N5O2S	2392	2393	28 + 21%	5.3 +5.5	594.3
	2394
		Analyses
Ex.						[M +
No.	Formula	R1	R2	Purity	rt (min)	H]+
1155	C29H34N6O5S	2395	2396	82%	6.5	579.3
1156	C30H36N6O5S	2397	2398	85%	6.7	593.3
1157	C31H38N6O53	2399	2400	84%	6.9	607.4
1158	C33H40N6O5S	2401	2402	42 +42%	7.1 +7.28	633.4
1159	C30H34N6O7S	2403	2404	78%	6.5	623.3
1160	C30H36N6O7S	2405	2406	82%	6.7	637.3
1161	C32H38N6O7S	2407	2408	80%	6.9	651.3
1162	C34H40N6O7S	2409	2410	34 + 41%	7.1 +7.2	677.4
1163	C35H39N5O3S	2411	2412	83%	7.1	610.4
1164	C36H41N5O3S	2413	2414	84%	7.3	624.4
1165	C37H43N5O3S	2415	2416	85%	7.5	638.4
1166	C39H45N5O3S	2417	2418	41 + 42%	7.7 +7.9	664.4
1167	C33H37N5O3S	2419	2420	91%	6.9	584.4
1168	C34H39N5O3S	2421	2422	90%	7.1	598.4
1169	C35H41N5O3S	2423	2424	89%	7.3	612.4
1170	C37H43N5O3S	2425	2426	41 + 42%	7.5 +7.7	638.4
1171	C30H34N6O3S	2427	2428	85%	6.4	559.3
1172	C31H36N6O3S	2429	2430	87%	6.5	573.3
1173	C32H38N6O3S	2431	2432	81%	6.8	587.4
1174	C34H40N6O3S	2433	2434	42 + 43%	6.9 +7.1	613.4
1175	C37H43N5O5S	2435	2436	86%	6.9	670.4
1176	C38H45N5O5S	2437	2438	82%	7.1	684.5
1177	C39H47N5O5S	2439	2440	86%	7.3	698.5
1178	C41H49N5O5S	2441	2442	38.3 +38.4%	7.5 +7.62	724.4
1179	C31H39N5O3S	2443	2444	86%	6.9	562.4
1180	C32H41N5O3S	2445	2446	87%	7.1	576.4
1181	C33H43N5O3S	2447	2448	86%	7.3	590.4
1182	C35H45N5O3S	2449	2450	38 + 39%	7.5 +7.64	616.4
1183	C37H42N6O3S	2451	2452	85%	7.2	651.4
1184	C38H44N6O3S	2453	2454	88%	7.3	665.4
1185	C39H46N6O3S	2455	2456	88%	7.5	679.4
1186	C41H48N6O3S	2457	2458	38.4 +38.5%	7.8 +7.98	705.4
1187	C36H39N5O3S	2459	2460	86%	7.2	622.4
1188	C37H41N5O3S	2461	2462	87%	7.4	636.4
1189	C38H43N5O3S	2463	2464	82%	7.6	650.4
1190	C40H45N5O3S	2465	2466	40.6 +40.9%	7.8 +8.01	676.4
1191	C31H36N6O3S	2467	2468	85.41%	6.6	573.3
1192	C32H38N6O3S	2469	2470	89%	6.8	587.4
1193	C33H40N6O3S	2471	2472	90%	7.0	601.4
1194	C35H42N6O3S	2473	2474	43.1 +44.5%	7.3 +7.45	627.4
1195	C24H26N6O3S	2475	2476	87%	4.3	479.3
1196	C25H28N6O3S	2477	2478	92%	4.4	493.3
1197	C26H30N6O3S	2479	2480	92%	4.6	507.3
1198	C28H32N6O3S	2481	2482	35 +33.9%	4.7 +4.8	533.3
1199	C25H26N6O5S	2483	2484	82%	4.3	523.2
1200	C26H28N6O5S	2485	2486	86%	4.5	537.3
1201	C27H30N6O5S	2487	2488	83%	4.5	551.3
1202	C29H32N6O5S	2489	2490	35 +33.9%	4.7 +4.8	577.3
1203	C30H31N5OS	2491	2492	88%	4.9	510.3
1204	C31H33N5OS	2493	2494	99%	5.0	524.3
1205	C32H35N5OS	2495	2496	89%	5.2	538.3
1206	C34H37N5OS	2497	2498	43 + 31%	5.3 +5.4	564.3
1207	C28H29N5OS	2499	2500	92%	4.7	484.3
1208	C29H31N5OS	2501	2502	93%	4.8	498.3
1209	C30H33N5OS	2503	2504	92%	4.9	512.3
1210	C32H35N5OS	2505	2506	43 +30.1%	5.1	538.3
1211	C25H26N6OS	2507	2508	87%	4.1	459.3
1212	C28H28N6OS	2509	2510	86%	4.2	473.3
1213	C27H30N6OS	2511	2512	82%	4.4	487.3
1214	C29H32N6OS	2513	2514	40 + 36%	4.5 +4.6	513.3
1215	C32H35N5O3S	2515	2516	87%	4.8	570.3
1216	C33H37N5O3S	2517	2518	84%	4.9	584.3
1217	C34H39N5O3S	2519	2520	86%	5.0	598.3
1218	C36H41N5O3S	2521	2522	32% +29%	5.2 +5.3	624.4
1219	C26H31N5OS	2523	2524	90%	4.6	462.3
1220	C27H33N5OS	2525	2526	92%	4.7	476.4
1221	C28H35N5OS	2527	2528	91%	4.9	490.4
1222	C30H37N5OS	2529	2530	42 +29.9%	5.0 +5.2	516.3
1223	C32H34N6OS	2531	2532	80%	5.0	551.3
1224	C33H36N6OS	2533	2534	90%	5.1	565.3
1225	C34H36N6OS	2535	2536	85%	5.3	579.4
1226	C36H40N6OS	2537	2538	37% + 27	5.45.6	605.4
1227	C31H31N5OS	2539	2540	90%	5.0	522.3
1228	C32H33N5OS	2541	2542	91%	5.1	536.3
1229	C33H35N5OS	2543	2544	90%	5.2	550.3
1230	C35H37N5OS	2545	2546	42% +30.8	5.4 +5.5	576.3
1231	C26H28N6OS	2547	2548	68%	4.4	473.4
1232	C27H30N6OS	2549	2550	56%	4.5	487.4
1233	C28H32N6OS	2551	2552	40%	4.7	613.2
1234	C30H34N6OS	2553	2554	40%	4.8	527.4

[0158] PHARMACOLOGICAL PROPERTIES OF THE COMPOUNDS OF THE INVENTION

[0159] The compounds of the present invention can and have been tested as regards their affinity for different sub-types of somatostatin receptors according to the procedures described below. Study of the affinity for the sub-types of human somatostatin receptors: The affinity of a compound of the invention for sub-types of somatostatin receptors 1 to 5 (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measurement of the inhibition of the bond of [25I-Tyr"]SR1 F-14 to transfected CHO-KI cells. The gene of the sst, receptor of human somatostatin has been cloned in the form of a genomic fragment. A segment PstI-XrnnI of 1.5 Kb containing 100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region in totality, and 230 bp of the non transcribed 3′ region is modified by the addition of the linker BglII. The resulting DNA fragment is subcloned in the BamHil site of a pCMV-8 1 in order to produce the expression plasmid in mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cell line expressing in a stable fashion the sst, receptor is obtained by transfection in CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

[0160] The gene of the sst2 receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindlII and subcloned in a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ. of Chicago). The expression vector of the marmnaliari cells is constructed by inserting the BamHl-HindlI fragment of 1.7 Kb in endonuclease restriction sites compatible with the plasmid pCMV5. A cloned cell line is obtained by transfection in CHO-KI cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as selection marker.

[0161] The sst3 receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a BamHI/HindlII fragment of 2.4 Kb. The expression plasmid in mammals, pCMV-h3, is constructed by insertion of the NcoI-HindlII fragment of 2.0 Kb in the EcoR1 site of the vector pCMV after modification of the terminations and addition of EcoRl linkers. A cloned cell line expressing in a stable fashion the sst3 receptor is obtained by transfection in CHO-KI cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. Cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

[0162] The expression plasmid of the human sst4 receptor, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst4 receptor of 1.4 Kb NAhel-Nhel, 456 pb of the non transcribed 5′ region, and 200 pb of the non transcribed 3′ region, cloned in the XbaI/EcoRl sites of PCMV- HX. A cloned cell line expressing in a stable fashion the sst4 receptor is obtained by transfection in CHO-KI cells (ATCC) by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

[0163] The gene corresponding to the human sst. receptor, obtained by the PCR method using a genomic clone as probe, was provided by Dr. Graeme Bell (Univ. Chicago). The resulting PCR fragment of 1.2 Kb contains 21 base pairs of the non transcribed 5′region, the coding region in totality, and 55 pb of the non transcribed 3′ region. The clone is inserted in an EcoRl site of the plasmid pBSSK(+). The insert is recovered in the form of a Hindll-Xbal fragment of 1.2 Kb for subcloning in an expression vector in mammals, pCVM5. A cloned cell line expressing in a stable fashion the sstS receptor is obtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphate co- precipitation method. The plasmid pRSV-neo (ATCC) is included as selection marker. The cloned cell lines were selected in an RPMI 1640 medium containing 0.5 mg/ml of G418 (Gibco), followed by circular cloning and multiplication in culture.

[0164] The CHO-K1 cells which express in a stable fashion the human sst receptors are cultured in an RPMI 1640 medium containing 10% of foetal calf serum and 0.4 mg/ml of geneticin. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for approximately 5 minutes at approximately 4° C. The pellet is resuspended in Tris 50 mM at pH 7.4 and centrifuged twice at 500 g for approximately 5 minutes at approximately 4° C. The cells are lysed by sonication and centrifuged at 39000 g for approximately 10 minlutes at 4° C. The pelleL is resuspended in the same buffer and centrifuged at 50000 g for approximately IO minutes at approximately 4° C. and the membranes in the pellet obtained are stored at −80° C.

[0165] The competitive inhibition tests of the bond with [251-Tyr11]SR1 F-14 are carried out in duplicate using 96-well polypropylene plates. The cell membranes (10 jig protein/well) are incubated with [125-Tyr ]SR1 F-14 (0.05 nM) for approximately 60 min. at approximately 37 ° C. in a 50 mM HEPES buffer (pH 7.4) containing BSA 0.2 %, MgCl2 5 mM, Trasylol 200 KIU/ml, bacitricin 0.02 mg/ml, phenylmethylsulphonyl fluoride 0.02 mg/ml. 125 11 125 11 The bound [ I-Tyr ]SR1 F-14 is separated from the free [ I-Tyr ]SR1 F-14 by immediate filtration through GF/C glass fibre filter plates (Unifilter, Packard) pre- impregnated with 0.1 % of polyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filters are washed with 50 mM HEPES buffer at approximately 0-4 ° C. for approximately 4 seconds and their radioactivity is determined using a counter (Packard Top Count).

[0166] The specific bond is obtained by subtracting the non-specific bond (determined in the presence of 0.1 liM of SR1 F-14) from the total bond. The data relative to the bond are analyzed by computer-aided non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) are determined.

[0167] Determination of the agonist or antagonist character of a compound of the present invention is carried out using the test described below.

[0168] Functional test: Inhibition ofproduction of intracellular cAMP:

[0169] CHO-K1 cells expressing the sub-types of human somatostatin receptors (SR1 F-14) are cultured in 24-well plates in an RPMI 1640 medium with 10% of foetal calf serum and 0.4 mg/ml of geneticin. The medium is changed the day preceding the experiment.

[0170] The cells at a rate of 105 cells/well are washed twice with 0.5 ml of new RPMI medium comprising 0.2 % BSA completed by 0.5 niM of 3-isobutyl-l-methylxanthine (IBMX) and incubated for approximately 5 min at approximately 37 ° C.

[0171] The production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (FSK) for 15-30 minutes at approximately 37 ° C.

[0172] The inhibitor effect of the somatostatin of an agonist compound is measured by the simultaneous addition of FSK (I uM), SR1 F-14 (10 M to 10 M) and of the compound to be tested (10 M to 10 M).

[0173] The antagonist effect of a compound is measured by the simultaneous addition of FSK (I1gM), SR1 F-14 (I to 10 nM) and of the compound to be tested (10 M to 10 M).

[0174] The reaction medium is eliminated and 200 ml of 0.1 N HC1 are added. The quantity of cAMP is measured by a radioirnmunological test (FlashPlate SMPOOIA kit, New England Nuclear).

[0175] Results:

[0176] The tests carried out according to the protocols described above have demonstrated that the compounds of general formula (I) defined in the present Application have a good affinity for at least one of the sub-types of somatostatin receptors, the inhibition constant K1 being lower than micromolar for certain exemplified compounds, and in particular for the compounds shown in the Tables I and II below.

TABLE I
2555
	R′3	R′4	Ki
	2556	(CH2)3NH2(CH2)4NH2(CH2)5NH2(CH2)6NH2	<1 μM <1 μM <1 μM <1 μM
	2557	(CH2)3NH2(CH2)4NH2(CH2)5NH2(CH2)6NH2	<1 μM <1 μM <1 μM <1 μM

[0177]

TABLE II
R′3	R′4	Ki
2558	(CH2)4NH2(CH2)5NH2(CH2)6NH2(CH2)6NMe2	<1 μM <1 μM <1 μM
2559	(CH2)5NH2(CH2)6NH2(CH2)6NMe2	<1 μM <1 μM <1 μM
2560	(CH2)5NH2(CH2)6NH2(CH2)6NMe2	<1 μM <1 μM <1 μM
2561	(CH2)5NH2(CH2)6NH2(CH2)6NMe2	<1 μM <1 μM <1 μM
2562	(CH2)5NH2(CH2)6NH2(CH2)6NMe2	<1 μM <1 μM <1 μM
2563	(CH2)6NMe2	<1 μM <1 μM <1 μM

Claims

1-14. (canceled)

15. A compound of the formula

16. A compound of claim 15, wherein R1 is unsubstituted or substituted aryl; R2 is H or alkyl; R3 is selected from the group consisting of 256725682569R4 is selected from the group consisting of 2570257125722573R5 is H or alkyl; or a pharmaceutically acceptable salt of said compound.

17. A compound of claim 15, wherein R1 is unsubstituted phenyl or phenyl substituted with a member of the group consisting of halogen, (C1-C12) alkyl, (C1-C12) alkoxy and nitro; R2 and R5 are H or alkyl; R3 is H or (CH2)p-Z3; Z3 is selected from the group consisting of (C1-C]2) alkyl, (C3-C8) cycloalkyl, Y1-(CH2)p-phenyl-(X I),, unsubstituted or substituted carbocyclic or heterocyclic aryl, or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl, 2574Y1 is 0, S, NY or is absent; R4 is (CH2)p-Z4; Z4 is selected from the group consisting of amino, (C1-C12) alkyl, (C3-C8) cycloalkyl, (C I-C 12) alkylamino, N,N-di-(C I-C 12) alkylamino, amino (C3-C6) cycloalkyl, amino (C1-C6) alkyl (C3-C8) cycloalkyl (C1-C6) alkyl, carbocyclic or heterocyclic aminoaryl, an unsubstituted or substituted carbocyclic and heterocyclic aryl, unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl, 2575it being understood that the substituents or substituted phenyl is at least one member of the group consisting of Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, -OCF3, (C1-C2) alkoxy, -(CH2)p-phenyl-(X11)q, -NH-CO-(C1-C6) alkyl, -NH-C(O)o-(C1-C6) alkyl, -S-(C1-C6) alkyl, -S-phenyl-(X 1 )q, -O-(CH2)p-phenyl-(X 1 )q, -(CH2),-C(O)-O-(C1-C6) alkyl, -(CH2)p- C(O)-(C1-C6) alkyl, -O-(CH2),-NH2, -OO(CH2),-NH-(C1-C6) alkyl, -O-(CH2)p-N-di-((Cl- C6) alkyl and -{(C0-C12) alkyl-(Xl)q; X1, each time that it occurs, is selected from the group consisting of H, C 1, F, Br, I, CF3, NO2, OH, NH2, CN, N3, -OCF3, (C1-C2) alkyl, (C+-C]2) alkoxy, -S-(C+-C6) alkyl, -CH2)p-amino, -(CH2)p-NH-(C1-C6) alkyl, -(CH2)p-N-di-((C -C6) alkyl), -(CH2)p-phenyl and {CH2)p-NH-(C3-C6) cycloalkyl; p each time that it occurs is independently an integer from 0 to 6; and 1 each time that it occurs is independently an integer from 1 to 5.

18. A compound of claim 17, wherein R1 is phenyl or phenyl substituted by a member selected from the group consisting of halogen, (C1-C]2) alkyl, (C1-C12) alkoxy and nitro; R2 and R5 are H or alkyl; R3 is (CH2)p-Z3, Z3 is selected from the group consisting of (C3-C8) cycloalkyl, unsubstituted or substituted phenyl, naphthyl, flirannyl, thiophene, indolyl, pyrrolyl and benzothiophene; R4 is (CH2)p-Z4; Z4 is selected from the group consisting of amino, (C1-C12) alkylamino, N,N-di-(C1-C12) alkylamino and amino (C1-C6) alkyl (C3-C6) cycloalkyl-(Ci-C6) alkyl; X is S; p each time that it occurs is independently an integer from 0 to 6; n is 0; and m is 1,2or3.

19. A compound of claim 18 selected from the compounds of formulae

20. A process for the preparation of a compound of claim 15 in which n is 0, comprising reacting a compound of the formula

21. A compound of claim 15, wherein Z3 is selected from the group consisting of

22. The process of claim 20 wherein the protective parting group is an alcohol derived from the group consisting of benzyl alcohol, methanol and tert.-butanol

23. A composition for treating disorders selected from acromegaly, hypophyseal adenomas, endocrine gastroenteropancreatic tumours including carcinoid syndrome and gastrointestinal bleeding comprising an effective amount of a compound of claim 15 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

24. A method of treating disorders selected from acromegaly, hypophyseal adenomas, endocrine gastroenteropancreatic tumours including carcinoid syndrome and gastrointestinal bleeding in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of claim 15 or of a pharmaceutically acceptable salt thereof sufficient to treat said disorder.

25. A compound of claim 15 wherein carbocyclic aryl and heterocyclic are selected from the group consisting of phenyl, naphthyl, pyridinyl, furannyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl and phthalimidyl and carbocyclic aralkyl and heterocyclic aralkyl are selected from the group consisting of benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl and phthalimidoalkyl.