# Patent

## Title
Derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones, their preparation processes and their use as medicaments

## Abstract

A method of treating a disorder selected from the group consisting of acromegaly, hypophyseal adenomas, endocrine gastroenteropancreatic tumors 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 the formula




in racemic or enantiomeric form.

## Background
This application is a division of U.S. patent application Ser. No. 10/813,139 filed Mar. 30,2004, now U.S. Pat. No. 7,199,145 which is a division of U.S. patent application Ser. No. 10/048,144 filed Jan. 23, 2002, now U.S. Pat. No. 6,759,415 which is a 371 of PCT/FR00/02164 filed Jul. 28, 2000.


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.
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., Neuroscience 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.
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.
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.
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)




in racemic, enantiomeric form or all combinations of these forms, in which:

    R1 represents a (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O-Z1, (C0-C6)alkyl-C(O)—NH—(CH2)p-Z2 or aryl radical optionally substituted,
    Z1 represents H, a (C1-C6) alkyl, —(CH2)p-aryl radical;
    Z2 represents an amino, (C1-C12)alkylamino, (C3-C8)cycloalkylamino, N,N-di-(C1-C12)alkylamino, NH—C(O)—O—(CH2)p-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-C12)alkyl, (C1-C12)alkenyl, (C3-C8)cycloalkyl, —Y1—(CH2)p-phenyl-(X1)n, —S—(C1-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






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





    Y1 represents O, S, NH or is absent;
    R4 represents (CH2)p-Z4;
    Z4 represents amino, (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)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, (C1-C12)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






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 —(C0-C6)alkyl-C(O)—NH—(CH2)p-Z5,
    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






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, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)p-phenyl-(X1)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-(X1)q, —(CH2)p—C(O)—O—(C1-C6)alkyl, —(CH2)p—C(O)—(C1-C6)alkyl, —O—(CH2)p—NH2, —O—(CH2)p—NH—C1-C6)alkyl, —O—(CH 2)p—N-di-((C1-C6)alkyl) and —((C0-C12))alkyl-(X1)q radicals;

    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, (C1-C12)alkoxy, —S—(C1-C6)alkyl, —(CH2)p-amino, —(CH2)p—NH—(C1-C6)alkyl, —(CH2)p—N-di-((C1-C6)alkyl), —(CH2)p and —(CH2)p—NH—(C3-C6)cycloalkyl radicals;


p each time that it occurs is independently 0 or an integer from 1 to 6;
q each time that it occurs is independently an integer from 1 to 5.
X represents O or S;
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.
According to a preferred variant of the invention, the compounds of general formula (I) are such that R5 represents H.
The compounds of general formula (I) can, if appropriate, contain more than one asymrnetrical 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.
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 (O, 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).
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.
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.
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.
When an arrow emanates from a chemical structure, said arrow indicates the attachment point. For example:




represents the aminoethyl radical.

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:




represents a radical which is attached at any position on the benzene rinag

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

    R1 represents an optionally substituted aryl radical;
    R2 represents H or an alkyl radical;
    R3 represents one of the following radicals:












    R4 represents one of the following radicals:















    R5 represents H or an alkyl radical.


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

    R1 represents the phenyl radical optionally substituted by a halogen atom or a (C1-C12)alkyl, (C1-C12)alkoxy or nitro radical;
    R2 and R5 represent H or alkyl;
    R3 represents H or (CH2)p-Z3;
    Z3 represents (C1-C12)alkyl, (C3-C8)cycloalkyl, Y1-(CH2)p-phenyl-(X1)n, 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






    Y1 represents O, S, NH or is absent;
    R4 represents (CH2)p-Z4;
    Z4 represents amino, (C3-C8)cycloalkyl, (C1-C12)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






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, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)p-phenyl-(X1)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-(X1)q, —(CH2)p—C(O)—O—(C1-C6)alkyl, —(CH2)p—C(O)—(C1-C6)alkyl, —O—(CH2)p—NH2, —O—(CH2)p—NH—(C1-C6)alkyl, —O—(CH2)p—N-di-((C1-C6)alkyl) and —((C0-C12))alkyl-(X1)q radicals;

    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, (C1-C12)alkoxy, —S—(C1-C6)alkyl, —(CH2)p-amino, —(CH2)p—NH—(C1-C6)alkyl, —(CH2)p—N-di-((C1-C6)alkyl), —(CH2)p-phenyl and —(CH2)p—NH—(C3-C6)cycloalkyl radicals;


p each time that it occurs is independently 0 or an integer from 1 to 6;
q each time that it occurs is independently an integer from 1 to 5.
X represents O or S;
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.
More preferentially, the compounds of general formula (I) are such that:

    R1 represents the phenyl radical optionally substituted by a halogen atom or a (C1-C12)alkyl, (C1-C12)alkoxy or nitro radical;
    R2 and R5 represent H or alkyl;
    R3 represents (CH2)p-Z3,
    Z3 representing a (C3-C8)cycloalkyl radical or an optionally substituted radical chosen from the phenyl, naphthyl, furannyl, thiophene, indolyl, pyrrolyl and benzothiophene radicals;
    R4 represents (CH2)p-Z4;
    Z4 representing amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino or amino(C1-C6)alkyl(C3-C6)cycloakyl—(C1-C6)alkyl;
    X represents S;
    p each time that it occurs is independently 0 or an integer from 1 to 6;


m represents 0, 1 or 2; and finally n represents 0 or 1.
Yet more preferentially, the compounds of the present invention are of the compounds:

    
    
        of general sub-formula (I)a represented below:
    
    






in which:

    R′3 represents one of the radicals represented below:






and R′4 represents one of the radicals represented below:





    
    
        of general sub-formula (I)b represented below:
    
    






in which:

    R′3 represents one of the radicals represented below:






and R′4 represents one of the radicals represented below:





    
    
        of general sub-formula (I)c represented below:
    
    






in which:

    R′3 represents one of the radicals represented below:






and R′4 represents one of the radicals represented below:





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).

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




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)

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.

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




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)

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 comprised between 20 and 70° C.
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-diisopropylethylamine.
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):




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.



The following compounds corresponding to general formula (V) are the preferred intermediates:

    - benzyl (2S)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate;
    - benzyl (2R)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate;
    - benzyl (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate;
    - benzyl (2R)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate;
    - benzyl (3R)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate;
    - benzyl (3S)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate.


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.
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.
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, bypophyseal adenomas or endocrinic gastroenteropancreatic tumours including carcinoid syndrome, and gastrointestinal bleeding.
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.
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).
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.
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 U.S. Pat. No. 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.
The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
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.
Preparation of the Compounds of the Invention
Preparation of Imidazolyl Derivatives
General Procedure:
i) Cyclization in order to obtain the imidazole group:
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/H2O (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.




ii) N-substitution on the Imidazole Group:

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.
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.
Preparation of Benzyl (2S)-2-[(Tert-butoycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate




A solution of Boc-L-Asp-OBn (12 g; 37.1 mmol) and cesium carbonate (6.05 g; 0.5 eq.) is stirred for approximately 30 minutes at approximately 20° C. in EtOH/H2O (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, 11H, arom H); 5.95 (d, 1H, NHBoc); 5.21-5.13 (AB, 2H, OCH2Ph, JAB=12 Hz); 4.73 (m, 1H, CH); 3.30 (m, 2H, CH2); 1.42 (s, 9H, (CH3)3C).
MS/LC: calculated MM=421.2; m/z=422.2 (M+H).
The following compounds are prepared in an analogous fashion to the procedure described for benzyl (2S)-2-[(tert-butoxycarbonyl)amino)]-3-(4-phenyl-1H-imidazol-2-yl)propanoate:




Deprotection Stage





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 0° C. and 25° C. for 0.5 to 5 hours.

Preparation of the Dihydrochloride of Benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-amino-propanoate





A flow of dry HCl is passed through a solution of benzyl (3S)-3-(4-phenyl-1H-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, 11H); 5.10 (s, 1H, OCH2Ph); 5.04 (m, 1H, CH); 3.61 (dd, 1H, CH2, 3J=9 Hz, 2J=17.0 Hz); 3.39 (dd, 1H, CH2′, 3J=5.5 Hz, 2J=17.0 Hz).
MS/LC: Calculated MM=321.2; m/z=322.1 (M+H).
The following compounds are prepared in an analogous fashion to the procedure described for the dihydrochloride of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-amino-propanoate.




N-Alkylation Reaction





General procedure: A free amine of formula (a) or (b) is treated with an aldehyde in a 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.

Preparation of Benzyl (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate





Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-1H-imidazol-2yl)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., the 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, CDCl3): 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, 1H, CHNH, 3J=4.5 Hz, 2j=8.5 Hz); 2.98 (m, 1H, CH2CH); 2.88 (m, 1H, CH2CH); 2.17 (m, 1H, CH2); 1.97 (m, 1H, CH2).
MS/LC: Calculated MM=431.2; m/z=432.2 (M+H); m/z=430.8 (M−H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for benzyl (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethy]butanoate:




In the above formulae, R3 represents one of the following radicals:










Preparation of Hydantoins and Thiodydantoins





General Procedure:

An amine of formula (II), 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 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.
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).
Preparation of Certain Non-Commercial Isothiocyanates of General Formula (III):




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.
Preparation of 6-isothiocyanato-N,N-dimethyl-1-hexanamine




Carbon disulphide (8.3 mL, 10 eq) and a solution of N,N-dimethyl-1,6-hexanediamine (2 g, 1 eq) in THF (10 mL) are added successively dropwise to a suspension of N-cyclohexylcarbodiimide N-methyl polystyrene resin (7.8 g, 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 (2.6 g, 93% yield).
NMR 1H, 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).
The following compounds are prepared in an analogous fashion to the procedure described for 6-isothiocyanato-N,N-dimethyl-1-hexanamine:




Preparation of (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2thioxo-4imidazolidinone





4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3ylmethyl)amino]-4(4-phenyl-1H-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 μl). 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 (1H, 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, 2H, CH2CH); 2.74 (m, 1H, CH2); 2.24 (m, 1H, CH2).
MS/LC: Calculated MM=536.2; m/z=537.1 (M+H).
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)-3-(4-nitrophenyl)-5-[2-(4phenyl-1H-imidazol-2-yl)ethyl]2-thioxo-4-imidazolidinone (apart from the final purification by flash chromatography on silica gel which is optional):




In the above formulae, R3 represents one of the following radicals:





and R4 represents one of the following radicals:











Preparation of (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione





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).
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-2yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4imidazolidinedione:




In the above formulae, R3 represents one of the following radicals:




and R4 represents one of the following radicals:








Preparation of Dihydropyrimidine-2,4-diones and 2-thioxo-tetrahydro-4-pyrimidinones





General Procedure:

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




Propylisothiocyanate (25 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3(4phenyl-1H-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, CDCl3): 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, JAB=14.5 Hz); 4.99 (m, 1H, CH); 4.41-4.36 (m, 1H, CH2); 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, 1H, 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).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone (except for the final purification by flash chromatography on silica gel which is optional):




In the above formula, R3 represents one of the following radicals:











and R4 represents one of the following radicals:











Preparation of (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H -imidazol-2-yl)dihydro-2,4(1H,3H)-pyimidinedione





4-methoxyphenylisocyanate (40 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, 1 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, CDCl3): mixture of 2 atropisomers: 9.67-8.96 (2s, 1H, NH); 8.49 (s, 1H, NH); 5.15, 4.36 (AB, 1H, CH2, JAB=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; m/z=492.3 (M+H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2.4(1H,3H)-pyrimidinedione (except for the final purification by flash chromatography on silica gel which is optional):




In the above formula, R3 represents one of the following radicals:




and R4 represents one of the following radicals:










EXAMPLES
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.
Analytical Methods used for the Characterization of the Compounds
The compounds obtained have been characterized according to their retention time (rt) and to their mass spectrometry (MH+).
) Mass Spectrometry
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.
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.).
) High Performance Liquid Chromatography (HPLC)
For the liquid chromatography, an HPLC HP1100 system (Hewlett-Packard) including an in-line degasser, a quatemary pump, a column oven and a diode array UV detector is used.
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.
Elution conditions (i) are used for the characterization of Examples 1 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.


















 









Analyses













Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+
















1
C29H25N5O2








89.6%
6.2
476.2


 


2
C30H27N5O2








91.0%
6.4
490.3


 


3
C30H27N5O3








90.1%
6.2
506.3


 


4
C30H27N5O2S








91.0%
6.6
522.2


 


5
C30H24F3N5O3








83.1%
7.0
560.2


 


6
C32H31N5O2








84.9%
7.0
518.3


 


7
C29H24BrN5O2








81.9%
6.7
556.1


 


8
C29H24ClN5O2








79.1%
6.6
510.2


 


9
C29H24N6O4








87.3%
6.4
521.2


 


10
C35H37N5O2








94.1%
7.3
560.3


 


11
C29H23F2NSO2








96.9%
6.3
512.2


 


12
C30H27N5O2








96.3%
6.4
490.2


 


13
C31H29N5O2








92.0%
6.5
504.2


 


14
C29H31N5O2








85.7%
6.6
482.3


 


15
C26H27N5O2








94.2%
5.9
442.3


 


16
C27H29N5O2








91.7%
6.3
456.3


 


17
C26H25N5O2








96.6%
5.8
440.2


 


18
C28H31N5O2








87.2%
6.6
470.3


 


19
C26H27N5O2








89.1%
6.0
442.2


 


20
C32H31N5O5








80.5%
6.1
566.2


 


21
C25H22N4O2S








92.3%
5.9
443.2


 


22
C26H24N4O2S








90.2%
6.2
457.2


 


23
C26H24N4O3S








92.1%
6.0
473.2


 


24
C26H24N4O2S2








92.8%
6.4
489.2


 


25
C26H21F3N4O3S








87.7%
6.8
527.2


 


26
C28H28N4O2S








87.8%
6.8
485.3


 


27
C25H21BrN4O2S








84.3%
6.5
523.1


 


28
C25H21ClN4O2S








84.9%
6.4
477.2


 


29
C25H21N5O4S








94.0%
6.2
488.2


 


30
C31H34N4O2S








97.2%
7.2
527.3


 


31
C25H20F2N4O2S








96.7%
6.1
479.2


 


32
C26H24N4O2S








95.3%
6.2
457.2


 


33
C27H26N4O2S








93.0%
6.4
471.2


 


34
C25H28N4O2S








88.3%
6.4
449.2


 


35
C22H24N4O2S








90.8%
5.7
409.2


 


36
C23H26N4O2S








91.8%
6.1
423.2


 


37
C22H22N4O2S








97.9%
5.6
407.2


 


38
C24H28N4O2S








84.3%
6.4
437.2


 


39
C22H24N4O2S








87.2%
5.7
409.2


 


40
C28H28N4O5S








92.2%
5.9
533.2


 


41
C28H26N4O3








93.9%
6.1
467.2


 


42
C29H28N4O3








95.8%
6.3
481.3


 


43
C29H28N4O4








93.0%
6.1
497.3


 


44
C29H28N4O3S








94.5%
6.5
513.2


 


45
C29H25F3N4O4








90.4%
6.9
551.2


 


46
C31H32N4O3








87.7%
6.9
509.3


 


47
C28H25BrN4O3








84.2%
6.6
547.1


 


48
C28H25ClN4O3








86.6%
6.5
501.2


 


49
C28H25N5O5








93.9%
6.3
512.2


 


50
C34H38N4O3








98.3%
7.2
551.3


 


51
C28H24F2N4O3








98.0%
6.2
503.2


 


52
C29H28N4O3








94.6%
6.4
481.2


 


53
C30H30N4O3








91.5%
6.4
495.3


 


54
C28H32N4O3








85.8%
6.5
473.3


 


55
C25H28N4O3








89.7%
5.8
433.3


 


56
C26H30N4O3








90.6%
6.2
447.3


 


57
C25H26N4O3








97.1%
5.7
431.2


 


58
C27H32N4O3








75.3%
6.5
461.3


 


59
C25H28N4O3








86.1%
5.9
433.3


 


60
C31H32N4O6








83.5%
6.0
557.2


 


61
C29H29N5O2








92.62%*
5.3
480.3


 


62
C30H31N5O2








93.25%*
5.6
494.3


 


63
C30H31N5O3








94.39%*
5.4
510.3


 


64
C30H31N5O2S








95.36%*
5.8
526.3


 


65
C30H28F3N5O3








89.2%
6.3
564.2


 


66
C32H35N5O2








86.35%*
6.3
522.3


 


67
C29H28BrN5O2








84.14%*
5.9
560.1


 


68
C29H28ClN5O2








85.8%
5.8
514.2


 


69
C29H28N6O4








94.4%
5.6
525.3


 


70
C35H41N5O2








95.76%*
6.8
564.3


 


71
C29H27F2N5O2








96.29%*
5.5
516.3


 


72
C30H31N5O2








97.59%*
5.6
494.3


 


73
C31H33N5O2








94.87%*
5.7
508.3


 


74
C29H35N5O2








87.63%*
5.8
486.3


 


75
C26H31N5O2








87.69%*
5.0
446.3


 


76
C27H33N5O2








86.66%*
5.4
460.3


 


77
C26H29N5O2








93.78%*
4.9
444.3


 


78
C28H35N5O2








85%*
5.8
474.3


 


79
C26H31N5O2








87.49%*
5.0
446.3


 


80
C32H35N5O5








87.6%
5.3
570.3
















 









Analyses













Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+
















81
C28H23N5O2








92%
6.2
462.2


 


82
C29H25N5O2








93%
6.5
476.2


 


83
C29H25N5O3








94%
6.2
492.2


 


84
C29H25N5O2S








92%
6.6
508.2


 


85
C29H22F3N5O3








92%
7.0
546.2


 


86
C31H29N5O2








92%
7.1
504.3


 


87
C28H22BrN5O2








92%
6.8
542.1


 


88
C28H22ClN5O2








92%
6.7
496.2


 


89
C28H22N6O4








82%
6.5
507.2


 


90
C34H35N5O2








92%
7.3
546.3


 


91
C28H21F2N5O2








90%
6.2
498.2


 


92
C31H29N5O5








82%
6.2
552.2


 


93
C29H22F3N5O2








92%
6.9
530.2


 


94
C30H25N5O3








89%
6.1
504.2


 


95
C29H25N5O2








92%
6.4
476.2


 


96
C30H27N5O2








93%
6.6
490.3


 


97
C25H25N5O2








95%
5.9
428.2


 


98
C26H27N5O2








95%
6.3
442.3


 


99
C25H23N5O2








95%
5.8
426.2


 


100
C27H29N5O2








94%
6.6
456.3


 


101
C24H20N4O2S








92%
5.9
429.2


 


102
C25H22N4O2S








91%
6.2
443.2


 


103
C25H22N4O3S








90%
6.0
459.2


 


104
C25H22N4O2S2








87%
6.4
475.2


 


105
C25H19F3N4O3S








89%
6.8
513.2


 


106
C27H26N4O2S








89%
6.9
471.2


 


107
C24H19BrN4O2S








91%
6.5
509.1


 


108
C24H19C1N4O2S








90%
6.4
463.1


 


109
C24H19N5O4S








76%
6.3
474.2


 


110
C30H32N4O2S








90%
7.1
513.3


 


111
C24H18F2N4O2S








82%
6.0
465.2


 


112
C27H26N4O5S








77%
5.8
519.2


 


113
C25H19F3N4O2S








89%
6.7
497.2


 


114
C26H22N4O3S








86%
5.8
471.2


 


115
C25H22N4O2S








85%
6.1
443.2


 


116
C26H24N4O2S








82%
6.3
457.2


 


117
C21H22N4O2S








84%
5.6
395.2


 


118
C22H24N4O2S








93%
5.9
409.2


 


119
C21H20N4O2S








89%
5.4
393.2


 


120
C23H26N4O2S








81%
6.3
423.2


 


121
C27H24N4O3








91%
6.0
453.2


 


122
C28H26N4O3








92%
6.3
467.2


 


123
C28H26N4O4








91%
6.0
483.3


 


124
C28H26N4O3S








88%
6.4
499.2


 


125
C28H23F3N4O4








91%
6.9
537.2


 


126
C30H30N4O3








90%
6.9
495.2


 


127
C27H23BrN4O3








89%
6.6
533.1


 


128
C27H23ClN4O3








91%
6.5
487.2


 


129
C27H23N5O5








75%
6.4
498.2


 


130
C33H36N4O3








90%
7.2
537.3


 


131
C27H22F2N4O3








82%
6.1
489.2


 


132
C30H30N4O6








79%
6.0
543.2


 


133
C28H23F3N4O3








90%
6.8
521.2


 


134
C29H26N4O4








85%
5.9
495.2


 


135
C28H26N4O3








89%
6.2
467.2


 


136
C29H28N4O3








89%
6.4
481.2


 


137
C24H26N4O3








88%
5.7
419.3


 


138
C25H28N4O3








90%
6.1
433.3


 


139
C24H24N4O3








92%
5.6
417.3


 


140
C26H30N4O3








87%
6.4
447.3


 


141
C28H27N5O2








89%
5.1
466.2


 


142
C29H29N5O2








89%
5.5
480.3


 


143
C29H29N5O3








90%
5.2
496.3


 


144
C29H29N5O2S








86%
5.7
512.2


 


145
C29H26F3N5O3








87%
6.2
550.2


 


146
C31H33N5O2








87%
6.2
508.3


 


147
C28H268rNSO2








88%
5.8
546.1


 


148
C28H26ClN5O2








88%
5.7
500.2


 


149
C28H26N6O4








74.76%*
5.6
511.2


 


150
C34H39N5O2








85%
6.7
550.3


 


151
C28H25F2N5O2








81%
5.3
502.2


 


152
C31H33N5O5








79%
5.2
556.3


 


153
C29H26F3N5O2








88%
6.1
534.2


 


154
C30H29N5O3








85%
5.1
508.3


 


155
C29H29N5O2








86%
5.4
480.3


 


156
C30H31N5O2








86%
5.6
494.3


 


157
C25H29N5O2








85%
4.8
432.3


 


158
C26H31N5O2








84%
5.2
446.3


 


159
C25H27N5O2








86%
4.7
430.3


 


160
C27H33N5O2








88%
5.6
460.3
















 









Analyses













Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+
















161
C30H27N5OS








80%
7.1
506.2


 


162
C30H26ClN5OS








83%
7.3
540.2


 


163
C30H25Cl2N5OS








81%
7.7
574.1


 


164
C31H27N5O3S








81%
7.0
550.2


 


165
C30H26FN5OS








82%
7.1
524.3


 


166
C31H29N5OS








81%
7.3
520.3


 


167
C31H28ClN5OS








83%
7.6
554.2


 


168
C33H33N5O3S








80%
7.0
580.3


 


169
C32H31N5OS








78%
7.4
534.3


 


170
C28H25N5O2S








85%
6.7
496.3


 


171
C28H29N5O2S








81%
6.6
500.3


 


172
C28H29N5OS








71%
7.1
484.3


 


173
C29H31N5OS








61%
7.3
498.3


 


174
C30H33N5OS








64%
7.6
512.3


 


175
C29H32N6O2S








84%
5.0
529.3


 


176
C30H34N6O2S








86%
5.0
543.3


 


177
C30H36N6OS








83%
5.2
529.3


 


178
C26H27N5O2S








82%
6.3
474.3


 


179
C27H29N5O2S








80%
6.4
438.3


 


180
C27H29N5OS








74%
7.0
472.3


 


181
C26H24N4OS2








77%
6.9
473.2


 


182
C26H23ClN4OS2








78%
7.1
507.2


 


183
C26H22Cl2N4OS2








84%
7.6
541.1


 


184
C27H24N4O3S2








80%
6.9
517.2


 


185
C26H23FN4OS2








75%
7.0
491.2


 


186
C27H26N4OS2








80%
7.1
487.2


 


187
C27H25ClN4OS2








85%
7.4
521.2


 


188
C29H30N4O3S2








87%
6.8
547.2


 


189
C28H28N4OS2








77%
7.3
501.2


 


190
C24H22N4O2S2








86%
6.5
463.2


 


191
C24H26N4O2S2








58.9% +19.6%
6.4
467.2


 


192
C24H26N4OS2








75%
6.9
451.2


 


193
C25H28N4OS2








77%
7.2
465.2


 


194
C26H30N4OS2








76%
7.5
479.3


 


195
C25H29N5O2S2








81%
4.8
496.3


 


196
C26H31N5O2S2








82%
4.9
510.3


 


197
C26H33N5OS2








71%
5.0
496.3


 


198
C22H24N4O2S2








81%
6.1
441.2


 


199
C23H25N4O2S2








78%
6.2
455.2


 


200
C23H26N4OS2








79%
6.8
551.2


 


201
C29H28N4O2S








80%
7.0
497.3


 


202
C29H27ClN4O2S








81%
7.2
643.2


 


203
C29H26Cl2N4O2S








86%
7.6
677.2


 


204
C30H28N4O4S








82%
7.0
653.2


 


205
C29H27FN4O2S








72%
7.1
627.2


 


206
C30H30N4O2S








83%
7.2
511.3


 


207
C30H29ClN4O2S








87%
7.5
657.2


 


208
C32H34N4O4S








87%
6.9
571.3


 


209
C31H32N4O2S








83%
7.4
637.3


 


210
C27H26N4O3S








87%
6.6
599.2


 


211
C27H30N4O3S








59% +20%
6.5 + 6.6
491.2


 


212
C27H30N4O2S








81%
7.0
475.5


 


213
C28H32N4O2S








82%
7.2
601.2


 


214
C29H34N4O2S








83%
7.5
615.3


 


215
C28H33N5O3S








86%
5.0
520.3


 


216
C29H35N5O3S








86%
5.0
646.3


 


217
C29H37N5O2S








78%
5.1
632.3


 


218
C25H28N4O3S








87%
6.2
577.2


 


219
C26H30N4O3S








80%
6.4
591.3


 


220
C26H30N4O2S








85%
6.9
575.2


 


221
C30H31N5OS








77%
6.5
510.3


 


222
C30H30ClN5OS








66%
6.8
544.3


 


223
C30H29Cl2N5OS








69%
7.3
690.2


 


224
C31H31N5O3S








75%
6.4
666.3


 


225
C30H30FNSOS








52%
6.6
528.5


 


226
C31H33N5OS








82%
6.7
636.3


 


227
C31H32ClN5OS








85%
7.1
670.3


 


228
C33H37N5O3S








82%
6.4
696.3


 


229
C32H35N5OS








66%
7.0
650.3


 


230
C28H29N5O2S








77%
6.1
612.2


 


231
C28H33N5O2S








26% + 48
5.8 + 5.9
616.3


 


232
C28H33N5OS








76%
6.4
600.3


 


233
C29H35N5OS








78%
6.7
614.3


 


234
C30H37N5OS








77%
4.6
645.3


 


235
C29H36N6O2S








85%
4.6
659.4


 


236
C30H38N6O2S








84%
4.8
532.3


 


237
C30H40N5OS








36%
5.5
590.3


 


238
C26H31N5O2S








79%
5.7
492.3


 


239
C27H33N5O2S








69%
6.3
588.3


 


240
C27H33N5OS








78%
6.3
476.3
















 









Analyses














Ex. No.
Formula
m
R1
R2
Purity
rt (min)
[M + H]+

















241
C29H25N5OS
2








93%
6.7
492.2


 


242
C31H27N5O2S
2








87%
6.6
534.2


 


243
C35H37N5OS2
2








68%
7.9
576.3


 


244
C32H31N5OS
2








88%
7.5
534.2


 


245
C29H23F2N5OS
2








92%
6.9
528.2


 


246
C29H24FN5OS
2








92%
6.8
510.2


 


247
C29H22Cl3N5OS
2








82%
7.6
594.1


 


248
C29H23Cl2N5OS
2








86%
7.5
560.1


 


249
C29H22Br3N5OS
2








76%
7.8
725.9


 


250
C31H29N5OS
2








47%
7.1
520.2


 


251
C31H23F6N5OS
2








88%
7.8
628.2


 


252
C30H24F3N5OS
2








90%
7.3
560.2


 


253
C31H29N5O3S
2








86%
6.9
552.2


 


254
C30H27N5O2S
2








93%
6.8
522.2


 


255
C30H27N5OS2
2








88%
7.1
538.2


 


256
C29H24N6O3S
2








92%
6.9
537.2


 


257
C29H24N8OS
2








92%
7.1
533.2


 


258
C31H30N6OS
2








67%
6.7
268.2


 


259
C30H24N6OS
2








82%
6.7
517.2


 


260
C36H31N5O2S
2








85%
7.6
598.2


 


261
C29H29N5OS
2








78%
6.1
248.7


 


262
C31H31N5O2S
2








65%
6.0
269.7


 


263
C35H41N5OS
2








53%
7.5
290.8


 


264
C32H35N5OS
2








82%
7.0
269.8


 


265
C29H27F2N5OS
2








79%
6.4
266.7


 


266
C29H28FN5OS2
2








73%
6.2
257.7


 


267
C29H26Cl3N5OS
2








87%
7.2
299.6


 


268
C29H27Cl2N5OS
2








70%
7.1
282.6


 


269
C29H26Br3N5OS
2








78%
7.3
365.5


 


270
C31H33N5OS2
2








3%
6.6
262.7


 


271
C31H27F6N5OS
2








39%
7.5
316.8


 


272
C30H28F3N5OS
2








64%
6.9
282.7


 


273
C31H33N5O3S
2








78%
6.3
278.7


 


274
C30H31N5O2S
2








45%
6.2
263.7


 


275
C30H31N5OS2
2








66%
6.5
271.7


 


276
C29H28N6O3S
2








67%
6.4
271.2


 


277
C29H28N8OS
2








62%
6.5
269.2


 


278
C31H34N6OS
2








37%
6.1
270.2


 


279
C30H28N6OS
2








49%
6.1
261.3


 


280
C36H35N5O2S
2








73%
7.2
301.8


 


281
C24H20N4OS2
1








89%
6.6
445.1


 


282
C26H22N4O2S2
1








88%
6.6
487.2


 


283
C30H32N4OS2
1








86%
7.9
529.2


 


284
C27H26N4OS2
1








96%
7.5
487.2


 


285
C24H18F2N4OS2
1








93%
6.7
481.1


 


286
C24H19FN4OS2
1








90%
6.8
463.1


 


287
C24H17Cl3N4OS2
1








97%
7.5
547.0


 


288
C24H18Cl2N4OS2
1








90%
7.8
513.1


 


289
C24H17Br3N4OS2
1








92%
7.7
678.9


 


290
C26H24N4OS2
1








87%
7.0
473.2


 


291
C26H18F6N4OS2
1








91%
8.2
581.1


 


292
C25H19F3N4OS2
1








87%
7.5
513.1


 


293
C26H24N4O3S2
1








95%
6.8
505.2


 


294
C25H22N4O2S2
1








92%
6.7
475.1


 


295
C25H22N4OS3
1








89%
7.1
491.1


 


296
C24H19N5O3S2
1








88%
7.0
490.1


 


297
C24H19N7OS2
1








90%
7.1
486.2


 


298
C26H25N5OS2
1








86%
6.6
244.7


 


299
C25H19N5OS2
1








89%
6.8
470.1


 


300
C31H26N4O2S2
1








88%
7.7
551.2


 


301
C27H24N4O2S
1








92%
6.7
459.2


 


302
C29H26N4O3S
1








91%
6.7
511.2


 


303
C33H36N4O2S
1








89%
8.0
553.3


 


304
C30H30N4O2S
1








95%
7.6
511.2


 


305
C27H22F2N4O2S
1








95%
6.8
505.2


 


306
C27H23FN4O2S
1








93%
6.9
487.2


 


307
C27H21Cl3N4O2S
1








93%
7.6
571.1


 


308
C27H22Cl2N4O2S
1








85%
7.9
537.1


 


309
C27H21Br3N4O2S
1








93%
7.8
702.9


 


310
C29H28N4O2S
1








86%
7.1
497.2


 


311
C29H22F6N4O2S
1








93%
8.3
605.2


 


312
C28H23F3N4O2S
1








93%
7.5
537.1


 


313
C29H28N4O4S
1








96%
6.9
529.2


 


314
C28H26N4O3S
1








97%
6.8
499.2


 


315
C28H26N4O2S2
1








84%
7.2
515.2


 


316
C27H23N5O4S
1








88%
7.1
514.2


 


317
C27H23N7O2S
1








94%
7.2
510.2


 


318
C29H29N5O2S
1








89%
6.7
256.7


 


319
C28H23N5O2S
1








90%
6.8
494.2


 


320
C34H30N4O3S
1








89%
7.7
575.2



























Analyses













Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





321
C29H25N5OS








91
7.2
492.2


 


322
C29H24ClN5OS








91
7.5
526.2


 


323
C29H23Cl2N5OS








91
7.9
560.1


 


324
C30H25N5O3S








92
7.0
536.2


 


325
C29H24FN5OS








93
7.3
510.2


 


326
C3OH27N5OS








92
7.4
506.2


 


327
C30H26ClN5OS








91
7.8
540.2


 


328
C32H31N5O3S








90
7.1
566.2


 


329
C31H29N5OS








91
7.6
520.2


 


330
C27H23N5O2S








92
6.8
482.2


 


331
C27H27N5O2S








35 + 51
6.64 + 6.76
486.2


 


332
C27H27N5OS








90
7.2
470.2


 


333
C28H29N5OS








89
7.4
484.3


 


334
C29H31N5OS








90
7.7
498.3


 


335
C28H30N6O2S








94
5.2
258.3


 


336
C29H32N6O2S








93
5.1
265.3


 


353
C24H26N4OS2








84
7.3
451.2


 


354
C25H28N4OS2








86
7.5
465.2


 


355
C24H27N5O2S2








91
5.0
241.7


 


356
C25H29N5O2S2








88
5.0
248.8


 


357
C25H31N5OS2








61
5.1
241.8


 


358
C21H22N4O2S2








88
6.1
427.1


 


359
C22H24N4O2S2








87
6.3
441.1


 


360
C22H24N4OS2








84
6.9
425.2


 


361
C28H26N4O2S








89
7.1
483.2


 


362
C28H25ClN4O2S








89
7.5
517.2


 


363
C28H24Cl2N4O2S








91
7.8
551.1


 


364
C29H26N4O4S








89
7.0
527.2


 


365
C28H25FN4O2S








95
7.2
501.2


 


366
C29H28N4O2S








90
7.3
497.2


 


367
C29H27ClN4O2S








89
7.7
531.2


 


368
C31H32N4O4S








90
7.0
557.2


 


369
C30H30N4O2S








91
7.5
511.2


 


370
C26H24N4O3S








92
6.7
473.2


 


371
C26H28N4O3S








39 + 45
6.44 + 6.56
477.2


 


372
C26H28N4O2S








89
7.1
461.2


 


373
C27H30N4O2S








90
7.3
475.2


 


374
C28H32N4O2S








90
7.6
489.3


 


375
C27H31N5O3S








93
5.1
253.7


 


376
C28H33N5O3S








90
5.1
260.8


 


377
C28H35N5O2S








73
5.3
253.8


 


378
C24H26N4O3S








91
6.2
451.2


 


379
C25H28N4O3S








91
6.4
465.2


 


380
C25H28N4O2S








90
7.0
449.2


 


381
C29H29N5OS








85
6.4
248.7


 


382
C29H28ClN5OS








85
6.9
265.7


 


383
C29H27Cl2N5OS








84
7.3
282.6


 


384
C30H29N5O3S








85
6.3
270.7


 


385
C29H28FN5OS








88
6.5
257.7


 


386
C30H31N5OS








84
6.7
255.6


 


387
C30H30ClN5OS








87
7.2
272.7


 


388
C32H35N5O3S








82
6.4
285.8


 


389
C31H33N5OS








81
6.9
262.7


 


390
C27H27N5O2S








89
5.9
243.7


 


391
C27H31N5O2S








43 + 43
5.68 + 5.86
245.7


 


392
C27H31N5OS








83
6.4
237.7


 


393
C28H33N5OS








83
6.7
244.7


 


394
C29H35N5OS








85
7.0
251.7


 


395
C28H34N6O2S








87
4.6
259.8


 


396
C29H36N6O2S








84
4.6
267.2


 


397
C25H29N5O2S








74
5.4
232.7


 


398
C26H31N5O2S








83
5.6
239.7


 


399
C26H31N5OS








87
6.3
231.8
























Analyses














Ex. No.
Formula
m
R1
R2
Purity
rt (min)
[M + H]+





400
C30H34N6O3S
2








83%
7.8
559.2


 


401
C31H36N6O3S
2








82%
7.9
573.2


 


402
C32H38N6O3S
2








82%
8.0
587.3


 


403
C33H40N6O3S
2








81%
8.3
601.3


 


404
C34H42N6O3S
2








80%
8.5
615.3


 


405
C26H31N5O3S2
2








81%
7.6
526.2


 


406
C27H33N5O3S2
2








83%
7.8
540.2


 


407
C28H35N5O3S2
2








88%
7.9
554.2


 


408
C29H37N5O3S2
2








86%
8.2
568.2


 


409
C30H39N5O3S2
2








86%
8.4
582.3


 


410
C29H35N5O4S
2








87%
7.7
550.3


 


411
C30H37N5O4S
2








87%
7.9
564.3


 


412
C31H39N5O4S
2








92%
8.0
578.3


 


413
C32H41N5O4S
2








89%
8.3
592.3


 


414
C33H43N5O4S
2








88%
8.5
606.3


 


415
C30H38N6O3S
2








83%
7.0
563.3


 


416
C31H40N6O3S
2








85%
7.2
577.3


 


417
C32H42N6O3S
2








88%
7.4
591.3


 


418
C33H44N6O3S
2








88%
7.7
303.3


 


419
C34H46N6O3S
2








88%
7.9
310.4


 


420
C29H32N6O3S
2








78%
7.9
545.2


 


421
C30H34N6O3S
2








81%
8.0
559.2


 


422
C31H36N6O3S
2








84%
8.1
573.3


 


423
C32H38N6O3S
2








82%
8.3
587.3


 


424
C33H40N6O3S
2








86%
8.5
601.3


 


425
C25H29N5O3S2
2








80%
7.7
512.2


 


426
C26H31N5O3S2
2








82%
7.8
526.2


 


427
C27H33N5O3S2
2








87%
7.9
540.2


 


428
C28H35N5O3S2
2








86%
8.2
554.2


 


429
C29H37N5O3S2
2








84%
8.4
568.2


 


430
C28H33N5O4S
2








86%
7.8
536.3


 


431
C29H35N5O4S
2








85%
7.9
550.3


 


432
C30H37N5O4S
2








92%
8.0
564.3


 


433
C31H39N5O4S
2








90%
8.2
578.3


 


434
C32H41N5O4S
2








90%
8.5
592.3


 


435
C29H36N6O3S
2








80%
6.9
549.3


 


436
C30H38N6O3S
2








78%
7.1
563.3


 


437
C31H40N6O3S
2








84%
7.3
577.3


 


438
C32H42N6O3S
2








83%
7.5
296.3


 


439
C33H44N6O3S
2








85%
7.8
303.3


 


440
C25H26N6OS
1








76%
5.4
459.2


 


441
C26H28N6OS
1








61%
5.4
473.3


 


442
C27H30N6OS
1








75%
5.6
244.2


 


443
C28H32N6OS
1








32%
5.7
251.1


 


444
C29H34N6OS
1








59%
5.9
258.3


 


445
C21H23N5OS2
1








78%
5.1
426.2


 


446
C22H25N5OS2
1








79%
5.2
440.2


 


447
C23H27N5OS2
1








84%
5.4
227.6


 


448
C24H29N5OS2
1








84%
5.5
234.7


 


449
C25H31N5OS2
1








83%
5.7
241.7


 


450
C24H27N5O2S
1








88%
5.3
450.2


 


451
C25H29N5O2S
1








96%
5.4
464.2


 


452
C26H31N5O2S
1








90%
5.6
239.7


 


453
C27H33N5O2S
1








90%
5.7
246.7


 


454
C28H35N5O2S
1








91%
5.9
253.7


 


455
C25H30N6OS
1








84%
4.8
232.2


 


456
C26H32N6OS
1








89%
4.9
238.8


 


457
C27H34N6OS
1








86%
5.0
246.1


 


458
C28H36N6OS
1








93%
5.2
252.9


 


459
C29H38N6OS
1








93%
5.4
260.1


 


460
C24H24N6OS
1








68%
5.6
445.2


 


461
C25H26N6OS
1








55%
5.5
459.2


 


462
C26H28N6OS
1








55%
5.6
473.3


 


463
C27H30N6OS
1








48%
5.7
487.3


 


464
C28N32N6OS
1








44%
5.9
501.2


 


465
C20H21N5OS2
1








84%
5.3
412.1


 


466
C21H23N5OS2
1








86%
5.2
426.2


 


467
C22H25N5OS2
1








90%
5.3
440.2


 


468
C23H27N5OS2
1








79%
5.5
227.7


 


469
C24H29N5OS2
1








91%
5.7
234.8


 


470
C23H25N5O2S
1








92%
5.5
436.2


 


471
C24H27N5O2S
1








88%
5.4
450.2


 


472
C25H29N5O2S
1








93%
5.5
464.3


 


473
C26H31N5O2S
1








92%
5.6
478.3


 


474
C27H33N5O2S
1








95%
5.8
246.7


 


475
C24H28N6OS
1








87%
4.9
224.7


 


476
C25H30N6OS
1








80%
4.8
231.9


 


477
C26H32N6OS
1








84%
4.9
238.9


 


478
C27H34N6OS
1








90%
5.0
245.7


 


479
C28H36N6OS
1








91%
5.2
505.3
























Analyses














Ex. No.
Formula
X
R1
R2
Purity
rt (min)
[M + H]+





480
C30H34N6O3S
S








86%
5.4
559.2


 


481
C31H36N6O3S
S








88%
5.5
573.2


 


482
C32H38N6O3S
S








88%
5.5
587.3


 


483
C33H40N6O3S
S








89%
5.7
601.3


 


484
C34H42N6O3S
S








91%
5.8
615.3


 


485
C35H36N5O3S
S








91%
5.6
621.3


 


486
C31H34N6O4S
S








66%
5.6
587.2


 


487
C32H36N6O4S
S








73%
5.6
601.2


 


488
C33H38N6O4S
S








79%
5.7
615.3


 


489
C34H40N6O4S
S








71%
5.9
629.3


 


490
C35H42N6O4S
S








81%
6.0
643.3


 


491
C36H36N6O4S
S








60%
5.8
649.3


 


492
C30H34N6O3S
S








83%
5.4
559.2


 


493
C31H36N6O3S
S








87%
5.5
573.2


 


494
C32H36N6O3S
S








87%
5.5
587.3


 


495
C33H40N6O3S
S








87%
5.7
601.3


 


496
C34H42N6O3S
S








88%
5.8
615.3


 


497
C35H36N6O3S
S








89%
5.6
621.3


 


498
C31H34N6O4S
S








71%
5.6
587.2


 


499
C32H36N6O4S
S








45%
5.6
601.2


 


500
C33H38N6O4S
S








75%
5.7
615.3


 


501
C34H40N6O4S
S








68%
5.9
629.3


 


502
C35H42N6O4S
S








76%
6.0
643.3


 


503
C36H36N6O4S
S








55%
5.8
649.3


 


504
C30H34N6O4
O








88%
4.9
543.3


 


505
C31H36N6O4
O








88%
5.0
557.3


 


506
C32H38N6O4
O








85%
5.0
571.3


 


507
C33H40N6O4
O








86%
5.2
585.3


 


508
C31H34N6O5
O








79%
4.9
571.2


 


509
C32H36N6O5
O








56%
5.0
585.3


 


510
C33H38N6O5
O








77%
5.1
599.3


 


511
C34H40N6O5
O








74%
5.2
613.3


 


512
C30H34N6O4
O








90%
4.9
543.3


 


513
C31H36N6O4
O








90%
5.0
557.3


 


514
C32H38N6O4
O








89%
5.0
571.3


 


515
C33H40N6O4
O








91%
5.2
585.3


 


516
C31H34N6O5
O








76%
4.9
571.2


 


517
C32H36N6O5
O








81%
5.0
585.3


 


518
C33H38N6O5
O








74%
5.1
599.3


 


519
C34H40N6O5
O








75%
5.2
613.3


 


520
C25H26N6OS
S








93%
6.8
459.2


 


521
C26H28N6O5
S








93%
6.6
473.2


 


522
C27H30N6OS
S








90%
6.7
487.2


 


523
C28H32N6OS
S








92%
6.8
501.2


 


524
C29H34N6OS
S








92%
6.9
515.2


 


525
C30H28N6OS
S








89%
6.8
521.2


 


526
C26H26N6O2S
S








63%
7.1
487.2


 


527
C27H28N6O2S
S








87%
6.8
501.2


 


528
C28H30N6O2S
S








85%
6.9
515.2


 


529
C29H32N6O2S
S








79%
7.0
529.2


 


530
C30H34N6O2S
S








91%
7.2
543.2


 


531
C31H28N6O2S
S








80%
7.1
549.2


 


532
C25H26N6OS
S








91%
6.8
459.2


 


533
C26H28N6OS
S








89%
6.6
473.2


 


534
C27H30N6OS
S








93%
6.7
487.2


 


535
C28H32N6OS
S








91%
6.8
501.2


 


536
C29H34N6OS
S








91%
6.9
515.2


 


537
C30H28N6OS
S








87%
6.8
521.2


 


538
C26H26N6O2S
S








90%
7.0
487.2


 


539
C27H28N6O2S
S








61%
6.8
501.2


 


540
C28H30N6O2S
S








87%
6.9
515.2


 


541
C29H32N6O2S
S








83%
7.0
529.2


 


542
C30H34N6O2S
S








93%
7.2
543.2


 


543
C31H28N6O2S
S








76%
7.1
549.2


 


544
C25H26N6O2
O








91%
6.1
443.2


 


545
C26H28N6O2
O








90%
6.1
457.2


 


546
C27H30N6O2
O








87%
6.1
471.2


 


547
C28H32N6O2
O








88%
6.2
485.2


 


548
C26H26N6O3
O








93%
6.2
471.2


 


549
C27H28N6O3
O








91%
6.1
485.2


 


550
C28H30N6O3
O








81%
6.2
499.2


 


551
C29H32N6O3
O








82%
6.3
513.2


 


552
C25H26N6O2
O








91%
6.1
443.2


 


553
C26H28N6O2
O








91%
6.1
457.2


 


554
C27H30N6O2
O








89%
6.1
471.2


 


555
C28H32N6O2
O








91%
6.1
485.2


 


556
C26H26N6O3
O








93%
6.2
471.2


 


557
C27H28N6O3
O








95%
6.1
485.2


 


558
C28H30N6O3
O








85%
6.2
499.2


 


559
C29H32N6O3
O








85%
6.3
513.2


 


560
C24H24N6OS
S








84%
3.6
445.2


 


561
C26H28N6OS
S








92%
3.5
473.3


 


562
C27H30N6OS
S








83%
3.6
487.3


 


563
C28H32N6OS
S








88%
3.7
501.3


 


564
C29H26N6OS
S








59%
3.7
507.2


 


565
C24H24N6O2
O








87%
3.2
429.2


 


566
C25H26N6O2
O








92%
3.1
443.3


 


567
C26H28N6O2
O








97%
3.1
457.3


 


568
C27H30N6O2
O








90%
3.1
471.3


 


569
C24H24N6O2
O








91%
3.1
429.2


 


570
C25H26N6O2
O








97%
3.1
443.3


 


571
C26H28N6O2
O








95%
3.1
457.3


 


572
C27H30N6O2
O








95%
3.2
471.3











































Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





573
C29H25N5OS








93%
6.7
492.2


 


574
C29H24ClN5OS








93%
7.2
526.2


 


575
C29H23Cl2N5OS








93%
7.6
560.1


 


576
C30H27N5OS








94%
7.0
506.2


 


577
C29H24FN5OS








95%
6.9
510.3


 


578
C30H27N5OS








90%
6.9
506.3


 


579
C30H26ClN5OS








92%
7.4
540.2


 


580
C32H31N5O3S








88%
6.4
566.3


 


581
C31H29N5OS








87%
7.1
520.2


 


582
C27H23N5O2S








93%
6.2
482.2


 


583
C27H27N5O2S








38 + 45%
5.6 +5.71
486.3


 


584
C28H30N6O2S








87%
4.6
515.3


 


585
C29H32N6O2S








84%
4.5
529.3


 


586
C29H34N6OS








89%
4.7
515.3


 


587
C25H25N5O2S








90%
5.18 m
460.3


 


588
C26H27N5O2S








87%
5.6
474.3


 


589
C25H22N4OS2








89%
6.7
459.2


 


590
C25H21ClN4OS2








87%
7.2
493.2


 


591
C25H20Cl2N4OS2








90%
7.6
527.1


 


592
C26H24N4OS2








83%
7.0
473.2


 


593
C25H21FN4OS2








88%
6.9
477.2


 


594
C26H24N4OS2








80%
7.0
473.2


 


595
C26H23ClN4OS2








79%
7.4
507.2


 


596
C28H28N4O3S2








82%
6.4
533.2


 


597
C27H26N4OS2








79%
7.2
487.2


 


598
C23H20N4O2S2








80%
6.2
449.2


 


599
C23H24N4O2S2








31 + 32%
5.7 +5.86
453.2


 


600
C24H27N5O2S2








80%
4.3
241.7


 


601
C25H29N5O2S2








81%
4.3
248.8


 


602
C25H31N5OS2








81%
4.5
482.3


 


603
C21H22N4O2S2








79%
5.6
427.1


 


604
C22H24N4O2S2








78%
5.9
441.2


 


605
C28H26N4O2S








89%
6.8
483.2


 


606
C28H25ClN4O2S








90%
7.2
517.2


 


607
C28H24Cl2N4O2S








91%
7.7
551.1


 


608
C29H28N4O2S








88%
7.0
497.3


 


609
C28H25FN4O2S








89%
6.9
501.2


 


610
C29H28N4O2S








87%
7.0
497.3


 


611
C29H27ClN4O2S








90%
7.5
531.2


 


612
C31H32N4O4S








91%
6.5
557.2


 


613
C30H30N4O2S








87%
7.2
511.3


 


614
C26H24N4O3S








89%
6.3
473.2


 


615
C26H28N4O3S








39 + 43%
5.7 +5.85
477.2


 


616
C27H31N5O3S








34%
4.5
506.3


 


617
C28H33N5O3S








79%
4.4
520.3


 


618
C28H35N5O2S








76%
4.6
506.3


 


619
C24H26N4O3S








85%
5.7
451.2


 


620
C25H28N4O3S








84%
5.9
465.2


 


621
C29H29N5OS








89%
5.9
248.8


 


622
C29H28ClN5OS








89%
6.4
265.7


 


623
C29H27Cl2N5OS








93%
6.9
282.7


 


624
C30H31N5OS








90%
6.2
255.8


 


625
C29H28FN5OS








92%
6.1
257.8


 


626
C30H31N5OS








87%
6.2
255.8


 


627
C30H30ClN5OS








90%
6.8
272.7


 


628
C32H35N5O3S








87%
5.6
285.8


 


629
C31H33N5OS








88%
6.4
262.8


 


630
C27H27N5O2S








89%
5.4
243.7


 


631
C27H31N5O2S








31 + 37%
5.26 +5.33
245.6


 


632
C28H34N6O2S








79%
3.7
260.3


 


633
C29H36N6O2S








77%
3.7
267.3


 


634
C29H38N6OS








78%
3.9
260.2


 


635
C25H29N5O2S








80%
4.9
232.7


 


636
C26H31N5O2S








79%
5.0
239.7


 


637
C28H23F3N4O2S








88%
7.4
537.2


 


638
C28H22ClF3N4O2S








90%
7.8
571.1


 


639
C28H21Cl2F3N4O2S








92%
8.3
605.1


 


640
C29H25F3N4O2S








89%
7.6
551.2


 


641
C28H22F4N4O2S








189%
7.5
555.2


 


642
C29H25F3N4O2S








88%
7.7
551.2


 


643
C29H24ClF3N4O2S








90%
8.1
585.1


 


644
C31H29F3N4O4S








92%
7.2
611.2


 


645
C30H27F3N4O2S








86%
7.8
565.2


 


646
C26H21F3N4O3S








88%
7.0
527.2


 


647
C26H25F3N4O3S








44 + 42%
6.59 +6.7
531.2


 


648
C27H28F3N5O3S








81%
5.0
280.8


 


649
C28H30F3N5O3S








82%
5.0
287.8


 


650
C28H32F3N5O2S








86%
5.2
280.8


 


651
C24H23F3N4O3S








90%
6.6
505.2


 


652
C25H25F3N4O3S








88%
6.8
519.2
































Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





653
C29H32N6O3S








88%
6.4
545.3


 


654
C30H34N6O3S








90%
6.3
559.3


 


655
C31H36N6O3S








89%
6.3
573.3


 


656
C32H38N6O3S








91%
6.5
587.3


 


657
C33H40N6O3S








91%
6.8
601.3


 


658
C25H29N5O3S2








78%
6.7
512.3


 


659
C26H31N5O3S2








87%
6.5
526.3


 


660
C27H33N5O3S2








86%
6.6
540.3


 


661
C28H35N5O3S2








84%
6.8
554.3


 


662
C29H37N5O3S2








83%
7.0
568.3


 


663
C28H33N5O4S








83%
6.7
536.3


 


664
C29H35N5O4S








88%
6.6
550.3


 


665
C30H37N5O4S








84%
6.6
564.3


 


666
C31H39N5O4S








86%
6.8
578.3


 


667
C32H41N5O4S








86%
7.0
592.3


 


668
C29H36N6O3S








82%
5.8
549.3


 


669
C30H38N6O3S








80%
5.7
563.3


 


670
C31H40N6O3S








84%
5.8
577.3


 


671
C32H42N6O3S








84%
6.0
591.4


 


672
C33H44N6O3S








84%
6.3
605.4


 


673
C28H30F3N5O4S








82%
7.5
590.3


 


674
C29H32F3N5O4S








81%
7.3
604.3


 


675
C30H34F3N5O4S








84%
7.4
618.3


 


676
C31H36F3N5O4S








86%
7.5
632.3


 


677
C32H38F3N5O4S








88%
7.7
646.3


 


678
C29H34N6O4S








81%
5.8
563.3


 


679
C30H36N6O4S








81%
5.8
577.3


 


680
C31H38N6O4S








82%
5.8
591.3


 


681
C32H40N6O4S








82%
6.0
605.3


 


682
C33H42N6O4S








83%
6.2
619.4














































Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





683
C27H30N6O5S








77%
6.9
551.3


 


684
C28H32N6O5S








75%
6.8
565.3


 


685
C29H34N6O5S








81%
6.9
579.3


 


686
C30H36N6O5S








82%
7.0
593.3


 


687
C31H38N6O5S








82%
7.3
607.3


 


688
C27H37N5O3S








77%
7.5
512.3


 


689
C28H39N5O3S








71%
7.3
526.4


 


690
C29H41N5O3S








76%
7.3
540.3


 


691
C30H43N5O3S








74%
7.5
554.4


 


692
C31H45N5O3S








74%
7.7
568.4


 


693
C24H24N6OS








47%
4.2
445.3


 


694
C25H26N6OS








45%
3.9
459.3


 


695
C26H28N6OS








52%
4.0
473.3


 


696
C27H30N6OS








43%
4.1
487.3


 


697
C28H32N6OS








38%
4.3
501.3


 


698
C20H21N5OS2








78%
4.1
412.2


 


699
C21H23N5OS2








81%
4.0
426.3


 


700
C22H25N5OS2








84%
4.1
440.2


 


701
C23H27N5OS2








86%
4.2
454.3


 


702
C24H29N5OS2








85%
4.3
468.3


 


703
C23H25N5O2S








82%
4.2
436.3


 


704
C24H27N5O2S








84%
4.1
450.3


 


705
C25H29N5O2S








88%
4.2
464.3


 


706
C26H31N5O2S








88%
4.3
478.3


 


707
C27H33N5O2S








87%
4.4
492.3


 


708
C24H28N6OS








80%
3.5
449.3


 


709
C25H30N6OS








83%
3.4
436.3


 


710
C26H32N6OS








84%
3.5
477.3


 


711
C27H34N6OS








84%
3.6
491.3


 


712
C28H36N6OS








85%
3.8
505.3


 


713
C23H22F3N5O2S








83%
4.8
490.3


 


714
C24H24F3N5O2S








84%
4.8
504.2


 


715
C25H26F3N5O2S








88%
4.8
518.2


 


716
C26H28F3N5O2S








91%
4.9
532.2


 


717
C27H30F3N5O2S








90%
5.0
546.2


 


718
C24H26N6O2S








70%
3.6
463.3


 


719
C25H28N6O2S








82%
3.5
477.3


 


720
C26H30N6O2S








83%
3.5
491.3


 


721
C27H32N6O2S








89%
3.7
505.3


 


722
C28H34N6O2S








89%
3.8
519.3


 


723
C22H22N6O3S








81%
4.3
451.2


 


724
C23H24N6O3S








80%
4.3
465.2


 


725
C24H26N6O3S








89%
4.3
479.2


 


726
C25H28N6O3S








86%
4.4
493.3


 


727
C26H30N6O3S








86%
4.5
507.3


 


728
C22H29N5OS








79%
4.8
412.3


 


729
C23H31N5OS








75%
4.6
426.3


 


730
C24H33N5OS








78%
4.6
440.3


 


731
C25H35N5OS








78%
4.7
454.3


 


732
C26H37N5OS








83.8%  
5.0
468.2


































Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





733
C28H24N6OS








45%
4.7
493.2


 


734
C29H26N6OS








57%
4.2
507.3


 


735
C24H21N5OS2








69%
4.7
460.2


 


736
C25H23N5OS2








77%
4.2
474.2


 


737
C27H25N5O2S








73%
4.8
484.3


 


738
C28H27N5O2S








76%
4.3
497.3


 


739
C28H28N6OS








67%
3.9
497.3


 


740
C29H30N6OS








62%
3.6
511.3


 


741
C27H22F3N5O2S








61%
5.7
538.2


 


742
C28H24F3N5O2S








75%
4.9
552.2


 


743
C28H26N6O2S








57%
4.0
511.2


 


744
C29H28N6O2S








60%
3.7
525.3


 


745
C26H22N6O3S








70%
5.0
499.2


 


746
C27H24N6O3S








65%
4.4
513.2


 


747
C26H29N5OS








78%
5.4
460.3


 


748
C27H31N5OS








80%
4.7
474.3


 


749
C34H34N6O3S








86%
6.6
593.3


 


750
C33H32N6O3S








82%
6.5
607.3


 


751
C30H31N5O3S2








77%
6.7
560.2


 


752
C29H29N5O3S2








77%
6.7
574.2


 


753
C33H35N5O4S








81%
6.8
584.3


 


754
C32H33NSO4S








76%
6.7
598.3


 


755
C34H38N6O3S








77%
5.9
597.3


 


756
C33H36N6O3S








74%
5.8
611.3


 


757
C33H32F3N5O4S








76%
7.4
638.3


 


758
C32H30F3N5O4S








74%
7.3
652.3


 


759
C34H36N6O4S








78%
6.1
611.3


 


760
C33H34N6O4S








76%
6.0
625.3


 


761
C32H32N6O5S








74%
6.9
599.2


 


762
C31H30N6O5S








69%
6.8
613.3


 


763
C32H39N5O3S








78%
7.3
560.3


 


764
C31H37N5O3S








74%
7.5
574.3


 


765
C31H34N6O4S








76%
6.9
587.2


 


766
C32H36N6O4S








88%
6.8
601.3


 


767
C33H38N6O4S








81%
6.8
615.3


 


768
C34H40N6O4S








84%
7.0
629.3


 


769
C35H42N6O4S








78%
7.2
643.4


 


770
C36H36N6O4S








83%
6.8
649.3


 


771
C31H34N6O4S








81%
6.9
587.2


 


772
C32H36N6O4S








76%
6.8
601.3


 


773
C33H38N6O4S








82%
6.8
615.3


 


774
C34H40N6O4S








84%
7.0
629.3


 


775
C35H42N6O4S








13%
7.2
643.3


 


776
C36H36N6O4S








71%
6.8
649.3


 


777
C26H26N6O2S








84%
4.4
487.3


 


778
C27H28N6O2S








85%
4.4
501.3


 


779
C28H30N6O2S








65%
4.4
515.3


 


780
C29H32N6O2S








75%
4.6
529.3


 


781
C30H34N6O2S








84%
4.7
543.3


 


782
C31H28N6O2S








82%
4.5
549.3


 


783
C26H26N6O2S








87%
4.4
487.3


 


784
C27H28N6O2S








87%
4.4
501.3


 


785
C28H30N6O2S








83%
4.4
515.3


 


786
C29H32N6O2S








91%
4.5
529.3


 


787
C30H34N6O2S








84%
4.7
543.3


 


788
C31H28N6O2S








79%
4.5
549.3


 


789
C24H24N6OS








42%
4.3
445.3


 


790
C25H26N6OS








72%
4.1
459.3


 


791
C26H28N6OS








87%
4.1
473.4


 


792
C27H30N6OS








88%
4.3
487.4


 


793
C28H32N6OS








92%
4.4
501.4


 


794
C29H26N6OS








78%
4.3
507.3


 


795
C24H24N6OS








46%
4.3
445.3


 


796
C25H26N6OS








71%
4.1
459.3


 


797
C26H28N6OS








93%
4.1
473.4


 


798
C27H30N6OS








94%
4.3
487.4


 


799
C28H32N6OS








86%
4.5
501.4


 


800
C29H26N6OS








77%

507.3


































Ex. No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





801
C30H30N4OS








96%
7.7
495.3


 


802
C30H29ClN4OS








97%
8.1
529.3


 


803
C30H28Cl2N4OS








99%
8.6
563.2


 


804
C31H32N4OS








95%
7.9
509.3


 


805
C30H29FN4OS








96%
7.8
513.3


 


806
C31H32N4OS








93%
7.9
509.3


 


807
C31H31ClN4OS








95%
8.4
543.3


 


808
C33H36N4O3S








93%
7.4
569.3


 


809
C32H34N4OS








94%
8.1
523.3


 


810
C28H28N4O2S








96%
7.2
485.3


 


811
C28H32N4O2S








37 +44%
6.7 + 6.84
489.3


 


812
C29H35N5O2S








88%
5.3
518.3


 


813
C30H37N5O2S








94%
5.3
532.4


 


814
C30H39N5OS








89%
5.4
518.4


 


815
C26H30N4O2S








92%
6.7
463.3


 


816
C27H32N4O2S








91%
6.9
477.3


 


817
C29H27N5O2S








93%
6.0
510.3


 


818
C29H26ClN5O2S








87%
6.5
544.2


 


819
C29H25Cl2N5O2S








74%
6.9
578.2


 


820
C20H29N5O2S








94%
6.2
524.3


 


821
C29H26FN5O2S








94%
6.2
528.3


 


822
C30H29N5O2S








93%
6.3
524.3


 


823
C30H28ClN5O2S








93%
6.7
558.2


 


824
C32H33N5O4S








91%
5.7
584.3


 


825
C31H31N5O2S








89%
6.5
538.3


 


826
C27H25N5O3S








90%
5.5
500.3


 


827
C27H29N5O3S








27% +24
4.99 + 5.1 
504.3


 


828
C28H32N6O3S








85%
3.9
533.3


 


829
C29H34N6O3S








87%
3.9
547.3


 


830
C29H36N6O2S








88%
4.1
533.3


 


831
C25H27N5O3S








92%
4.9
478.3


 


832
C26H29N5O3S








93%
5.1
492.3


 


833
C27H23N5O3S








93%
7.0
498.3


 


834
C27H22ClN5O3S








85%
7.4
532.2


 


835
C27H21Cl2N5O3S








88%
7.8
566.1


 


836
C28H25N5O3S








90%
7.3
512.3


 


837
C27H22FN5O3S








88%
7.1
516.2


 


838
C28H25N5O3S








90%
7.3
512.3


 


839
C28H24ClN5O3S








91%
7.8
546.2


 


840
C30H29N5O5S








92%
6.8
572.2


 


841
C29H27N5O3S








94%
7.5
526.3


 


842
C25H21N5O4S








89%
6.6
488.2


 


843
C25H25N5O4S








46% +45
6.24 + 6.4 
492.3


 


844
C26H28N6O4S








82%
4.6
521.3


 


845
C27H30N6O4S








84%
4.6
535.3


 


846
C27H32N6O3S








76%
4.8
521.3


 


847
C23H23N5O4S








90%
6.1
466.2


 


848
C24H25N5O4S








90%
6.3
480.3


 


849
C24H21N5OS2








87%
6.1
460.2


 


850
C24H20ClN5OS2








53%
6.6
494.1


 


851
C24H19Cl2N5OS2








85%
7.0
528.0


 


852
C25H23N5OS2








79%
6.2
474.1


 


853
C24H20FN5OS2








76%
6.2
478.1


 


854
C25H23N5OS2








74%
6.4
474.1


 


855
C25H22ClN5OS2








82%
6.9
508.1


 


856
C27H27N5O3S2








73%
5.8
534.1


 


857
C26H25N5OS2








74%
6.6
488.1


 


858
C22H19N5O2S2








77%
5.5
450.1


 


859
C22H23N5O2S2








23 +25%
5.2 + 5.33
454.1


 


860
C23H26N6O2S2








78%
3.9
483.2


 


861
C24H28N6O2S2








68%
3.9
497.2


 


862
C24H30N6OS2








59%
4.1
483.2


 


863
C20H21N5O2S2








68%
5.0
428.1


 


864
C21H23N5O2S2








65%
5.3
442.1


 


865
C27H30N4OS








97%
7.4
459.2


 


866
C27H29ClN4OS








98%
7.9
493.2


 


867
C27H28Cl2N4OS








97%
8.4
527.1


 


868
C28H32N4OS








98%
7.6
473.2


 


869
C27H29FN4OS








96%
7.6
477.2


 


870
C28H32N4OS








94%
7.7
473.2


 


871
C28H31ClN4OS








96%
8.3
507.2


 


872
C30H36N4O3S








94%
7.2
533.2


 


873
C29H34N4OS








91%
7.9
487.2


 


874
C25H28N4O2S








95%
6.9
449.2


 


875
C25H32N4O2S








38 + 8%
6.9 + 7.04
453.2


 


876
C26H35N5O2S








94%
5.0
482.2


 


877
C27H37N5O2S








93%
5.0
496.3


 


878
C27H39N5OS








94%
5.2
482.3


 


879
C23H30N4O2S








95%
6.5
427.2


 


880
C24H32N4O2S








97%
6.7
441.2


 


881
C29H27ClN4OS








78%
7.7
515.2


 


882
C29H28N4OS








59%
7.2
481.2


 


883
C21H32N4OS








63%
8.6
617.2


 


884
C31H30N4O2S








61%
7.1
523.2


 


885
C32H34N4OS








60%
7.9
523.3


 


886
C31H33N5OS








28%
6.7
524.2


 


887
C29H27N5O3S








53%
7.6
526.2


 


888
C29H27BrN4OS








68%
7.8
559 1


 


889
C29H26F2N4OS








62%
7.3
517.2


 


890
C29H27N7OS








64%
7.6
522.2


 


891
C30H27N5OS








66%
7.3
506.2


 


892
C20H28N4O3S








62%
7.1
525.2


 


893
C29H26ClN5O3S








55%
7.9
560.1


 


894
C33H36N4OS








59%
8.1
537.3


 


895
C30H30N4OS








67%
7.9
565.2


 


896
C31H32N4OS








57%
7.7
509.2


 


897
C28H24ClN5O2S








64%
6.2
530.1


 


898
C28H25N5O2S








64%
5.6
496.2


 


899
C30H29N5O2S








52%
7.1
632.2


 


900
C30H27N5O3S








57%
5.5
538.2


 


901
C31H31NSO2S








65%
6.4
538.2


 


902
C30H30N6O2S








29%
5.0
539.2


 


903
C28H24N6O4S








51%
6.0
541.2


 


904
C28H24BrN5O2S








72%
6.3
574.0


 


905
C28H23F2N5O2S








66%
5.7
532.2


 


906
C28H24N8O2S








52%
6.1
537.2


 


907
C29H24N6O2S








65%
5.7
521.1


 


908
C29H25N5O4S








66%
5.5
540.1


 


909
C28H23ClN6O4S








55%
6.4
575.1


 


910
C32H33N5O2S








64%
6.6
552.2


 


911
C29H27N5O2S








68%
6.5
580.1


 


912
C30H29N5O2S








68%
6.1
524.2


 


913
C26H20ClN5O3S








60%
7.0
518.1


 


914
C26H21N5O3S








63%
6.6
484.2


 


915
C28H25N5O3S








41%
7.8
620.1


 


916
C28H23N5O4S








51%
6.4
526.1


 


917
C29H27N5O3S








64%
7.3
526.2


 


918
C28H26N6O3S








21%
6.2
527.2


 


919
C26H20N6O5S








27%
6.8
529.1


 


920
C26H20BrN5O3S








61%
7.2
562.0


 


921
C26H19F2N5O3S








55%
6.6
520.1


 


922
C26H20N8O3S








61%
7.0
525.1


 


923
C27H20N6O3S








50%
6.6
509.1


 


924
C27H21N5O5S








68%
6.5
528.1


 


925
C26H19ClN6O5S








44%
7.2
563.1


 


926
C30H29N5O3S








60%
7.5
540.2


 


927
C27H23N5O3S








62%
7.3
568.1


 


928
C28H25N5O3S








60%
7.0
512.2


 


929
C23H18ClN5OS2








28%
6.4
480.1


 


930
C23H19N5OS2








22%
5.8
446.1


 


931
C25H23N5OS2








34%
7.3
582.1


 


932
C25H21N5O2S2








25%
5.7
488.1


 


933
C26H25N5OS2








21%
6.6
488.1


 


934
C25H24N6OS2








13%
5.3
489.1


 


935
C23H18N6O3S2








23%
6.2
491.1


 


936
C23H18BrN5OS2








38%
6.5
524.0


 


937
C23H17F2N5OS2








58%
5.8
482.1


 


938
C23H18N8OS2








28%
6.3
487.1


 


939
C24H18N6OS2








32%
5.9
471.1


 


940
C24H19N5O3S2








23%
5.7
490.1


 


941
C23H17ClN6O3S2








33%
6.7
525.0


 


942
C27H27N5OS2








29%
6.8
502.2


 


943
C24H21N5OS2








35%
6.7
530.1


 


944
C25H23N5OS2








16%
6.3
474.1


 


945
C26H27ClN4OS








61%
7.5
479.2


 


946
C26H28N4OS








54%
7.0
445.2


 


947
C28H32N4OS








61%
8.4
581.1


 


948
C28H30N4O2S








49%
6.9
487.2


 


949
C29H34N4OS








57%
7.7
487.2


 


950
C28H33N5OS








16%
6.4
488.2


 


951
C26H27N5O3S








44%
7.4
490.2


 


952
C26H27BrN4OS








70%
7.6
523.1


 


953
C26H26F2N4OS








61%
7.0
481.2


 


954
C26H27N7OS








66%
7.4
486.2


 


955
C27H27N5OS








68%
7.1
470.2


 


956
C27H28N4O3S








63%
6.9
489.2


 


957
C26H26ClN5O3S








66%
7.7
524.1


 


958
C30H36N4OS








58%
7.9
501.3


 


959
C27H30N4OS








64%
7.7
529.2


 


960
C28H32N4OS








46%
7.5
473.2


















































No.
Formula
R1
R2
Purity
rt (min)
[M + H]+





 961
C30H30N4O3








57%
10.5
495.2


 


 962
C30H27F3N4O2








69%
11.6
533.2


 


 963
C29H28N4O2








69%
10.4
465.2


 


 964
C29H27N5O4








61%
11.0
510.2


 


 965
C30H29ClN4O2








74%
11.6
513.2


 


 966
C32H32N4O4








52%
11.0
537.2


 


 967
C29H27BrN4O2








76%
11.2
543.1


 


 968
C29H27FN4O2








60%
10.7
483.2


 


 969
C29H26Cl2N4O2








68%
11.9
533.1


 


 970
C31H30N4O3








71%
10.3
507.2


 


 971
C30H30N4O2S








72%
10.9
511.2


 


 972
C30H27F3N4O3








77%
11.6
549.2


 


 973
C29H27BrN4O2








66%
11.3
543.1


 


 974
C32H34N4O2








85%
11.5
507.3


 


 975
C29H26F2N4O2








72%
10.8
501.2


 


 976
C32N34N4O5








71%
10.3
555.2


 


 977
C29H27N5O4








72%
8.0
510.2


 


 978
C29H24F3N5O3








70%
9.3
548.2


 


 979
C28H25N5O3








79%
7.8
480.2


 


 980
C28H24N6O5








62%
8.6
525.2


 


 981
C29H26ClN5O3








71%
9.1
528.2


 


 982
C31H29N5O5








65%
8.6
552.2


 


 983
C28H24BrN5O3








82%
8.8
558.1


 


 984
C28H24FN5O3








73%
8.2
498.2


 


 985
C28H23Cl2N5O3








66%
9.5
548.1


 


 986
C30H27N5O4








81%
7.7
522.2


 


 987
C29H27N5O3S








79%
8.4
526.2


 


 988
C29H24F3N5O4








83%
9.3
564.2


 


 989
C28H24BrN5O3








69%
8.8
558.1


 


 990
C31H31N5O3








84%
9.2
522.3


 


 991
C28H23F2N5O3








86%
8.1
516.2


 


 992
C31H31N5O6








60%
7.7
570.2


 


 993
C27H23N5O5








76%
9.5
498.2


 


 994
C27H20F3N5O4








71%
10.7
536.1


 


 995
C26H21N5O4








85%
9.4
488.2


 


 996
C26H20N6O6








56%
10.0
513.2


 


 997
C27H22ClN5O4








77%
10.7
516.1


 


 998
C29H25N5O6








64%
10.2
540.2


 


 999
C26H20BrN5O4








83%
10.4
546.0


 


1000
C26H20FN5O4








74%
9.8
486.2


 


1001
C26H19Cl2N5O4








69%
11.0
536.1


 


1002
C28H23N5O5








81%
9.3
510.2


 


1003
C27H23N5O4S








79%
10.1
514.1


 


1004
C27H20F3N5O5








74%
10.8
552.1


 


1005
C26H20BrN5O4








66%
10.4
546.0


 


1008
C29H27N5O4








84%
10.8
510.2


 


1007
C26H19F2N5O4








76%
9.8
504.1


 


1008
C29H27N5O7








74%
9.3
558.2


 


1009
C24H21N5O3S








60%
8.2
460.1


 


1010
C24H18F3N5O2S








65%
9.5
498.1


 


1011
C23H19N5O2S








77%
8.0
430.1


 


1012
C23H18N6O4S








60%
8.7
475.1


 


1013
C24H20ClN5O2S








62%
9.4
478.1


 


1014
C26H23N5O4S








63%
8.9
502.2


 


1015
C23H18BrN5O2S








79%
9.1
508.0


 


1016
C23H18FN5O2S








63%
8.4
448.1


 


1017
C23H17Cl2N5O2S








54%
9.8
498.1


 


1018
C25H21N5O3S








62%
8.0
472.1


 


1019
C24H21N5O2S2








73%
8.8
476.1


 


1020
C24H18F3N5O3S








70%
9.6
514.1


 


1021
C23H18BrN5O2S








60%
9.2
508.0


 


1022
C26H25N5O2S








74%
9.6
472.2


 


1023
C23H17F2N5O2S








62%
8.3
466.1


 


1024
C26H25N5O5S








64%
8.0
520.1


 


1025
C27H22F2N4O3








76%
9.4
489.2


 


1028
C27H19F5N4O2








77%
10.6
527.1


 


1027
C26H20F2N4O2








87%
9.2
459.2


 


1028
C26H19F2N5O4








79%
9.9
504.1


 


1029
C27H21ClF2N4O2








74%
10.6
507.1


 


1030
C29H24F2N4O4








89%
10.1
531.2


 


1031
C26H19BrF2N4O2








82%
10.3
537.1


 


1032
C26H19F3N4O2








79%
9.7
477.1


 


1033
C26H18Cl2F2N4O2








69%
11.0
527.1


 


1034
C28H22F2N4O3








82%
9.2
501.2


 


1035
C27H22F2N4O2S








76%
9.9
505.1


 


1036
C27H19F5N4O3








83%
10.7
543.1


 


1037
C26H19BrF2N4O2








68%
10.4
537.1


 


1038
C29H26F2N4O2








86%
10.7
501.2


 


1039
C26H18F4N4O2








80%
9.6
495.1


 


1040
C29H26F2N4O5








43%
9.2
549.2







































No.
Formula
R′3
R4
Purity
rt (min)
[M + H]+





1041
C26H33N5OS2








56  
3.69
496.3


 


1042
C29H37N5O2S








74  
3.78
520.3


 


1043
C30H36N6OS








76  
3.77
529.3


 


1044
C31H38N6OS








73  
3.85
543.3


 


1045
C30H39N5OS








63  
4.19
518.3


 


1046
C30H36N6OS








71  
4.01
529.3







































No.
Formula
R′3
R4
Purity
rt (min)
[M + H]+





1047
C27H35N5OS2








69  
3.65
510.3


 


1048
C30H39N5O2S








75  
3.75
534.3


 


1049
C31H42N6OS








71  
3.49
547.3


 


1050
C31H38N6OS








66  
3.74
543.3


 


1051
C31H38N6OS








87  
3.89
543.3







































No.
Formula
R′3
R4
Purity
rt (min)
[M + H]+





1052
C30H36N6OS








 83.38
4.71
529.3


 


1053
C26H33N5OS2








 72.31
4.41
496.3


 


1054
C29H37N5O2S








 71.47
4.5
520.3


 


1055
C30H40N6OS








 62.38
3.86
533.3


 


1056
C25H32N6OS2








25.6
3.9
497.2


 


1057
C28H33F2N5OS








63.2
4.5
526.3


 


1058
C31H41N5OS








 69.01
5.17
532.4


 


1059
C28H34N6O3S








 73.01
4.58
535.3


 


1060
C28H41N5OS








44.6
4.9
496.4


 


1061
C29H34F3N5O2S








80.9
5.1
574.2


 


1062
C30H39N5OS








 58.64
4.91
518.3


 


1063
C36H42N6OS








 54.23
5.3
607.3


 


1064
C28H34BrN5OS








 76.51
4.86
568.2


 


1065
C28H33Cl2N5OS








 74.91
5.03
558.2


 


1066
C29H34F3N5OS








 66.26
4.93
558.2


 


1067
C28H34N6O3S








40  
4.6
535.2


 


1068
C32H37N5OS








73.1
4.9
540.3


 


1069
C29H34N6O5S








55.8
4.58
579.2


 


1070
C34H39N5OS








64.6
5.2
566.3


 


1071
C29H34N6OS








 70.75
4.38
515.3


 


1072
C29H37N5OS








 64.36
4.68
504.3


 


1073
C35H41N5O2S








40.5
5
596.3


 


1074
C31H38N6OS








80.4
4
543.3







































No.
Formula
R′3
R4
Purity
rt (min)
[M + H]+





1075
C26H32N6O3S2








  45.2%
6.1
541.3


 


1076
C27H34N6O3S2








  35.3%
6.3
555.3


 


1077
C28H36N6O3S2








  39.9%
6.5
569.3


 


1078
C30H38N6O3S2








14.9 +22.82%
6.7 +6.76
595.3


 


1079
C32H41N5O3S








  70.3%
7.5
576.4


 


1080
C33H43N5O3S








  71.9%
7.7
590.4


 


1081
C34H45N5O35








  72.7%
7.9
604.4


 


1082
C36H47N5O3S








34.6 +34.7%
8.1 +8.28
630.4


 


1083
C29H33F2N5O3S








  60.6%
6.9
570.3


 


1084
C30H35F2N5O3S








  62.7%
7.1
584.3


 


1085
C31H37F2N5O3S








  65.5%
7.3
598.3


 


1086
C33H39F2N5O3S








33.92% +32.4%
7.5 +4.6
624.3


 


1087
C29H34BrN5O3S








  65.6%
7.3
612.2


 


1088
C30H36BrN5O3S








  68.6%
7.5
626.2


 


1089
C31H38BrN5O3S








  75.2%
7.7
640.3


 


1090
C33H40BrN5O3S








37.14% +37.1%
7.88 +8.0
666.3


 


1091
C29H34BrN5O3S








  71.9%
7.3
612.2


 


1092
C30H36BrN5O3S








  76.2%
7.4
626.2


 


1093
C31H38BrN5O3S








  77.0%
7.6
640.3


 


1094
C33H40BrN5O3S








39.4 +39.64% m
7.8 +8.0
666.3


 


1095
C29H33Cl2N5O3S








  72.1%
7.6
602.2


 


1096
C30H35Cl2N5O3S








  74.9%
7.7
616.3


 


1097
C31H37Cl2N5O35








  76.4%
7.9
630.3


 


1098
C33H39Cl2N5O3S








39.6% +39.16%
8.1 +8.4
656.3


 


1099
C30H34F3N5O3S








  64.3%
7.3
602.3


 


1100
C31H36F3N5O3S








  71.3%
7.5
616.3


 


1101
C32H38F3N5O3S








  71.6%
7.6
630.3


 


1102
C34H40F3N5O3S








34.8 +34.91%
8.0 +7.8
656.4


 


1103
C29H34N6O5S








  63.2%
6.9
579.3


 


1104
C30H36N6O5S








  66.1%
7.1
593.3


 


1105
C31H38N6O5S








  66.1%
7.3
607.3


 


1106
C33H40N6O5S








33.7% +24.4%
7.5 +7.6
633.4


 


1107
C33H37N5O3S








  84.0%
7.2
584.4


 


1108
C34H39N5O3S








  86.3%
7.4
598.4


 


1109
C35H41N5O3S








  86.2%
7.6
612.4


 


1110
C37H43N5O3S








43.1% +43.4%
7.9 +8.12
638.4


 


1111
C36H41N5O4S








  58.2%
7.3
640.4


 


1112
C37H43N5O4S








  61.1%
7.5
654.4


 


1113
C38H45N5O4S








  67.6%
7.7
668.4


 


1114
C40H47N5O4S








  38.1% +38.5%
7.9 +8.1
694.4


 


1115
C21H24N6OS2








  74.0%
3.9
441.2


 


1116
C22H26N6OS2








  80.2%
4.0
455.3


 


1117
C23H28N6OS2








  47.3%
4.2
469.3


 


1118
C25H30N6OS2








18.31% +14%
4.2 +4.3
495.3


 


1119
C27H33N5OS








  76.8%
5.1
476.4


 


1120
C28H35N5OS








  77.9%
5.3
490.4


 


1121
C29H37N5OS








  75.6%
5.4
504.4


 


1122
C31H39N5OS








38.42% +26.7% m
5.5 +5.7
530.4


 


1123
C24H25F2N5OS








  68.1%
4.5
470.3


 


1124
C25H27F2N5OS








  66.9%
4.7
484.3


 


1125
C26H29F2N5OS








  70.0%
4.8
498.3


 


1126
C28H31F2N5OS








  25.0%
4.9
524.3


 


1127
C24H26BrN5OS








  72.7%
4.9
512.2


 


1128
C25H28BrN5OS








  78.5%
5.0
526.2


 


1129
C26H30BrN5OS








  80.2%
5.1
540.2


 


1130
C28H32BrN5OS








39.21% +27%
5.3 +5.4
566.2


 


1131
C24H26BrN5OS








  77.9%
4.9
512.2


 


1132
C25H28BrN5OS








  81.4%
5.0
526.2


 


1133
C26H30BrN5OS








78.25%*
5.1
540.2


 


1134
C26H32BrN5OS








31.02% +27.9
5.2 +5.4
566.2


 


1135
C24H25Cl2N5OS








  79.9%
5.1
502.2


 


1136
C25H27Cl2N5OS








  81.2%
5.2
516.2


 


1137
C26H29Cl2N5OS








  80.1%
5.3
530.2


 


1138
C28H31Cl2N5OS








33.63% +28.8%
5.4 +5.6
556.2


 


1139
C25H26F3N5OS








  73.7%
4.9
502.3


 


1140
C26H28F3N5OS








  80.8%
5.1
516.2


 


1141
C27H30F3N5OS








76.86%*
5.2
530.3


 


1142
C29H32F3N5OS








27.7% +27.3
5.3 +5.4
556.3


 


1143
C24H26N6O3S








  70.7%
4.6
479.3


 


1144
C25H28N6O3S








  72.3%
4.7
493.3


 


1145
C26H30N6O3S








  72.4%
4.8
507.3


 


1146
C28H32N6O3S








27.5% +26.5%
4.9 +5.3
533.3


 


1147
C28H29N5OS








  88.2%
4.8
484.3


 


1148
C29H31N5OS








  89.1%
5.0
498.3


 


1149
C30H33N5OS








  89.9%
5.1
512.3


 


1150
C32H35N5OS








46.67% +31.0
5.3 +5.5
538.3


 


1151
C31H33N5O2S








  46.0%
5.0
540.3


 


1152
C32H35N5O2S








  46.6%
5.1
554.2


 


1153
C33H37N5O2S








  54.2%
5.2
568.3


 


1154
C35H39N5O2S








28 +21%
5.3 +5.5
594.3







































No.
Formula
R′3
R4
Purity
rt (min)
[M + H]+





1155
C29H34N6O5S








82%
6.5
579.3


 


1156
C30H36N6O5S








85%
6.7
593.3


 


1157
C31H38N6O5S








84%
6.9
607.4


 


1158
C33H40N6O5S








42 +42%
7.1 +7.28
633.4


 


1159
C30H34N6O7S








78%
6.5
623.3


 


1160
C30H36N6O7S








82%
6.7
637.3


 


1161
C32H38N6O7S








80%
6.9
651.3


 


1162
C34H40N6O7S








34 +41%
7.1 +7.2
677.4


 


1163
C35H39N5O3S








83%
7.1
610.4


 


1164
C36H41N5O3S








84%
7.3
624.4


 


1165
C37H43N5O3S








85%
7.5
638.4


 


1166
C39H45N5O3S








41 +42%
7.7 +7.9
664.4


 


1167
C33H37N5O3S








91%
6.9
584.4


 


1168
C34H39N5O3S








90%
7.1
598.4


 


1169
C35H41N5O3S








89%
7.3
612.4


 


1170
C37H43N5O3S








41 +42%
7.5 +7.7
638.4


 


1171
C30H34N6O3S








85%
6.4
559.3


 


1172
C31H36N6O3S








87%
6.5
573.3


 


1173
C32H38N6O3S








81%
6.8
587.4


 


1174
C34H40N6O3S








42 +43%
6.9 +7.1
613.4


 


1175
C37H43N5O5S








86%
6.9
670.4


 


1176
C38H45N5O5S








82%
7.1
684.5


 


1177
C39H47N5O5S








86%
7.3
698.5


 


1178
C41H49N5O5S








38.3 +38.4%
7.5 +7.62
724.4


 


1179
C31H39N5O3S








86%
6.9
562.4


 


1180
C32H41N5O3S








87%
7.1
576.4


 


1181
C33H43N5O3S








86%
7.3
590.4


 


1182
C35H45N5O3S








38 +39%
7.5 +7.64
616.4


 


1183
C37H42N6O3S








85%
7.2
651.4


 


1184
C38H44N6O3S








88%
7.3
665.4


 


1185
C39H46N6O3S








88%
7.5
679.4


 


1186
C41H48N6O3S








38.4 +38.5%
7.8 +7.98
705.4


 


1187
C36H39N5O3S








86%
7.2
622.4


 


1188
C37H41N5O3S








87%
7.4
636.4


 


1189
C38H43N5O3S








82%
7.6
650.4


 


1190
C40H45N503S








40.6 +40.9%
7.8 +8.01
676.4


 


1191
C31H36N6O3S








85.41%*
6.8 }


 


1192
C32H38N6O3S








89%
6.8
587.4


 


1193
C33H40N6O3S








90%
7.0
601.4


 


1194
C35H42N6O3S








43.1 +44.5%
7.3 +7.45
627.4


 


1195
C24H26N6O3S








87%
4.3
479.3


 


1196
C25H28N6O3S








92%
4.4
493.3


 


1197
C26H30N6O3S








92%
4.6
507.3


 


1198
C28H32N6O3S








35 +33.9%
4.7 +4.8
533.3


 


1199
C25H26N6O5S








82%
4.3
523.2


 


1200
C26H28N6O5S








86%
4.5
537.3


 


1201
C27H30N6O5S








83%
4.6
551.3


 


1202
C29H32N6O5S








35 +33.9%
4.7 +4.8
577.3


 


1203
C30H31N5OS








88%
4.9
510.3


 


1204
C31H33N5OS








90%
5.0
524.3


 


1205
C32H35N5OS








89%
5.2
538.3


 


1206
C34H37N5OS








43 +31%
5.3 +5.4
564.3


 


1207
C28H29N5OS








92%
4.7
484.3


 


1208
C29H31N5OS








93%
4.8
498.3


 


1209
C30H33N5OS








92%
4.9
512.3


 


1210
C32H35N5OS








43 +30.1%
5.1
538.3


 


1211
C25H26N6OS








87%
4.1
459.3


 


1212
C26H28N6OS








86%
4.2
473.3


 


1213
C27H30N6OS








82%
4.4
487.3


 


1214
C29H32N6OS








40 +36%
4.5 +4.6
513.3


 


1215
C32H35N5O3S








87%
4.8
570.3


 


1216
C33H37N5O3S








84%
4.9
584.3


 


1217
C34H39N5O3S








86%
5.0
598.3


 


1218
C36H41N5O3S








32% +29%
5.2 +5.3
624.4


 


1219
C26H31N5OS








90%
4.6
462.3


 


1220
C27H33N5OS








92%
4.7
476.4


 


1221
C28H35N5OS








91%
4.9
490.4


 


1222
C30H37N5OS








42 +29.9%
5.0 +5.2
516.3


 


1223
C32H34N6OS








80%
5.0
551.3


 


1224
C33H36N6OS








90%
5.1
565.3


 


1225
C34H38N6OS








85%
5.3
579.4


 


1226
C36H40N6OS








37% +27
5.45.6
605.4


 


1227
C31H31N5OS








90%
5.0
522.3


 


1228
C32H33N5OS








91%
5.1
536.3


 


1229
C33H35N5OS








90%
5.2
550.3


 


1230
C35H37N5OS








42% +30.8
5.4 +5.5
576.3


 


1231
C26H28N6OS








68%
4.4
473.4


 


1232
C27H30N6OS








56%
4.5
487.4


 


1233
C28H32N6OS








40%
4.7
613.2


 


1234
C30H34N6OS








40%
4.8
527.4









Pharmacological Properties of the Compounds of the Invention

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 [125I-Tyr11]SRIF-14 to transfected CHO-K1 cells.
The gene of the sst1, receptor of human somatostatin has been cloned in the form of a genomic fragment. A segment PstI-XmnI 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 Bg1II. The resulting DNA fragment is subcloned in the BamHI site of a pCMV-81 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 sst1 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.
The gene of the sst2 receptor of human somatostatin, isolated in the form of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subcloned in a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ. of Chicago). The expression vector of the mammalian 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-K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as selection marker.
The sst3 receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. The expression plasmid in marnmals, pCMV-h3, is constructed by insertion of the NcoI-HindIII fragment of 2.0 Kb in the EcoR1 site of the vector pCMV after modification of the terminations and addition of EcoR1 linkers. A cloned cell line expressing in a stable fashion the sst3 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. 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.
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 NheI-NheI, 456 pb of the non transcribed 5′ region, and 200 pb of the non transcribed 3′ region, cloned in the XbaI/EcoR1 sites of PCMV-HX. A cloned cell line expressing in a stable fashion the sst4 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.
The gene corresponding to the human sst5 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 EcoR1 site of the plasmid pBSSK(+). The insert is recovered in the form of a HindIII-XbaI fragment of 1.2 Kb for subcloning in an expression vector in mammals, pCVM5. A cloned cell line expressing in a stable fashion the sst5 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.
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 minutes at 4° C. The pellet is resuspended in the same buffer and centrifuged at 50000 g for approximately 10 minutes at approximately 4° C. and the membranes in the pellet obtained are stored at −80° C.
The competitive inhibition tests of the bond with [125I-Tyr11]SRIF-14 are carried out in duplicate using 96-well polypropylene plates. The cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-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.
The bound [125I-Tyr ]SRIF-14 is separated from the free [125I-Tyr 11]SRIF-14 by immediate filtration through GFIC 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).
The specific bond is obtained by subtracting the non-specific bond (determined in the presence of 0.1 μM of SRIF-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.
Determination of the agonist or antagonist character of a compound of the present invention is carried out using the test described below.
Functional Test: Inhibition of Production of Intracellular cAMP:
CHO-K1 cells expressing the sub-types of human somatostatin receptors (SRIF-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.
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 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 min at approximately 37 ° C.
The production of cyclic AMP is stimulated by the addition of 1 mM of forskolin (FSK) for 15-30 minutes at approximately 37 ° C.
The inhibitor effect of the somatostatin of an agonist compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10−12 to 10−6 M) and of the compound to be tested (10−10 M to 10−5 M).
The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and of the compound to be tested (1010−10 M to 10−5 M).
The reaction medium is eliminated and 200 ml of 0.1 N HCl are added. The quantity of cAMP is measured by a radioimmunological test (FlashPlate SMP001A kit, New England Nuclear).
Results:
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 Ki being lower than micromolar for certain exemplified compounds, and in particular for the compounds shown in the Tables I and II below.







TABLE I













 









R′3
R′4
Ki









(CH2)3NH2(CH2)4NH2(CH2)5NH2(CH2)6NH2
<1 μM<1 μM<1 μM<1 μM


 






(CH2)3NH2(CH2)4NH2(CH2)5NH2(CH2)6NH2
<1 μM<1 μM<1 μM<1 μM
















TABLE II













 









R′3
R′4
Ki









(CH2)4NH2(CH2)5NH2(CH2)6NH2(CH2)6NMe2
<1 μM<1 μM<1 μM


 






(CH2)5NH2(CH2)6NH2(CH2)6NMe2
<1 μM<1 μM<1 μM


 






(CH2)5NH2(CH2)6NH2(CH2)6NMe2
<1 μM<1 μM<1 μM


 






(CH2)5NH2(CH2)6NH2(CH2)6NMe2
<1 μM<1 μM<1 μM


 






(CH2)5NH2(CH2)6NH2(CH2)6NMe2
<1 μM<1 μM<1 μM


 






(CH2)6NMe2
<1 μM

## Claims

1. A method of treating a disorder selected from the group consisting of acromegaly, hypophyseal adenomas, endocrine gastroenteropancreatic tumors bleeding in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula




in racemic or enantiomeric form,
R1 is selected from the group consisting of (C1-C12) alkyl, (C0-C6)alkyl-C(O)—O-Z1, (C0-C6)alkyl-C(O)—NH—(CH2)p-Z2 and unsubstituted or substituted aryl,
Z1 is selected from the group consisting of H, (C1-C6)alkyl and —(CH2)p-aryl;
Z2 is selected from the group consisting of amino, (C1-C12)alkylamino, (C3-C8)cycloalkylamino, N,N-di-(C1-C12) alkylamino,
NH—C—(O)—O—(CH2)p-phenyl, NH—C(O)—O—(CH2)p—(C1-C6)alkyl, phenyl, naphthyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofuranyl, benzothiophenyl and phthalimidyl, carbocyclic aralkyl selected from the group consisting of benzyl, phenylpropyl and phenylbutyl and heterocyclic aralkyl selected from the group consisting of indolylalkyl and phthalimidoalkyl and unsubstituted or substituted heterocyclic non-aromatic;
R2 is selected from the group consisting of H, (C1-C12) alkyl and aryl optionally substituted;
R3 is H or(CH2)p-Z3;
Z3 is selected from the group consisting of (C1-C12)alkyl, (C1-C12)alkenyl, (C3-C8) cycloalkyl, Y1-(CH2)p-phenyl-(X1)n, —S—(C1-C12)alkyl, S—(C1-C12)alkyl-S—S—(C1-C12) alkyl, and unsubstituted or substituted carbocyclic or heterocyclic aryl;





bis-arylalkyl or



Y1 is O, S, NH or is absent;
R4 is (CH2)p-Z4;
Z4 is selected from the group consisting of amino, (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, amino (C3-C6) cycloalkyl, amino (C1-C6) alkyl (C3-C8) cycloalkyl (C1-C6) alkyl, carbocyclic or heterocyclic aminoaryl, (C1-C12) alkoxy, (C1-C12) alkenyl, N—C(O)O(C1-C6) alkyl, unsubstituted or substituted carbocyclic or heterocyclic aryl, unsubstituted or substituted heterocyclic non-aromatic radical, bis-arylalkyl, di-arylalkyl,





and N (R6)(R7), R6 and R7 taken togetber with the nitrogen atom which they carry form together a heterocycle of 5 to 7 ring members;
R5 is selected from the group consisting of H, —(CH2)p—C(O)—(CH2)p-Z5, —(CH2)p-Z5, —(CH2)p—OZ5 or —(C0-C6)alkyl-C(O)—NH—(CH2)p-Z5,
Z5 is unsubstituted or substituted member selected from the group consisting of —(C1-C12) alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,





it being understood that the above substitutes of Z5 are selected from the group consisting of Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12) alkyl, (C1-C12) alkoxy, —(CH2)p-phenyl-(X1)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-(X1)q, —(CH2)p—C(O)—O—(C1-C6) alkyl, —(CH2)p—C(O)—(C1-C6) alkyl, —O—(CH2)p—NH2, —O—(CH2)p—NH—(C1-C6) alkyl, —O—(CH2)p—N-di((C1-C6) alkyl) and (C0-C12) alkyl-(X1)q;
X1, each time that it occurs, is independently selected from the group consisting of H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12) alkyl, (C1-C12) alkoxy, —S—(C1-C6) alkyl, —(CH2)p-amino, —(CH2)p—NH—(C1-C6) alkyl, —(CH2)p—N-di-((C1-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;
q each time that it occurs is independently an integer from 1 to 5;
X is O or S;
n in the chemical structure is 0;
n in Z3 is 0; and
m is 1, 2 or 3;

or a pharmaceutically acceptable salt of said compound sufficient to treat said disorder.

2. The method of claim 1, wherein
R1 is unsubstituted or substituted aryl;
R2 is H or alkyl;
R3 is selected from the group consisting of










R4 is selected from the group consisting of













R5 is H or alkyl;

or a pharmaceutically acceptable salt of said compound.

3. The method of claim 1, 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-C12) alkyl, (C3-C8) cycloalkyl, Y1-(CH2)p-phenyl-(X1)n, unsubstituted or substituted carbocyclic or heterocyclic aryl, unsubstituted or substituted non-aromatic heterocyclic, bis-arylalkyl, di-arylalkyl,




Y1 represents O, S, NH or is absent;
R4 is (CH2)p-Z4;
Z4 is selected from the group consisting of amino, (C1-C12) alkyl, (C3-C8) cycloalkyl, (C1-C12) alkylamino, N,N-di-(C1-C12) 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,





it being understood that the substituent of substituted phenyl is at least one member of the group consisting of Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12) alkoxy, —(CH2)p-phenyl-(X1)q, —NH—CO—(C1-C6) alkyl, —NH—C(O)—(C1-C6) alkyl, —S—(C1C6) alkyl, —S-phenyl-(X1)q, —O—(CH2)p-phenyl-(X1)q, —(CH2)p—C(O)—O—(C1-C6) alkyl, —(CH2)p—C(O)—(C1-C6) alkyl, —O—(CH2)p—NH2, —O(CH2)p—NH —(C1-C6)alkyl, —O—(CH2)p—N-di-((C1-6) alkyl and (C0-C12) alkyl-(X1)q;
X1, each time that it occurs, is selected from the group consisting of H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, —OCF3, (C1-C12) alkyl, (C1-C12) alkoxy, —S—(C1-C6) alkyl, —(CH2)p-amino, —(CH2)p—NH—(C1-C6) alkyl, —(CH2)p—N-di-((C1-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
q each lime that it occurs is independently an integer from 1 to 5.

4. The method of claim 3, wherein
R1 is phenyl or phenyl substituted by a member selected from the group consisting of halogen, (C1-C12) alkyl, (C1-C12) alkoxy and nitro;
R2 and R5 are H or alkyl;
R3 is (C2)p-Z3,
Z3 is selected from the group Z3 is selected from the group consisting of (C3-C8) cycloalkyl, unsubstituted or substituted phenyl, naphthyl, furanyl, 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-(C1-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, 2 or 3.

5. The method of claim 4 selected from the compounds of formulae




wherein R′3 is selected from




and R′3 is selected from




or a pharmaceutically acceptable salt or said compound.