Condensing dicyclic nitrogen containing heterocycles, which have dgat inhibiting action

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

 

This application claims priority of the provisional application U.S. serial No. 60/428600, filed November 22, 2002, the contents of which are incorporated in this description by reference.

Triglycerides are the main form of energy conservation in eukaryotes. Violations or neustoichivosti triglyceride metabolism entail the pathogenesis or increased risk of obesity, syndrome of insulin resistance and diabetes type II disease nonalcoholic fatty infiltration of the liver and coronary heart disease (see Lewis, et al., Endocrine Reviews (2002) 23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:111). Additionally, hypertriglyceridemia is often harmful consequence of cancer therapy (see Bast, et al. Cancer Medicine, 5thEd. (2000) B.C. Decker, Hamilton, Ontario, CA).

A key enzyme in the synthesis of triglycerides is an acyl CoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal enzyme that is widely expressed in mammalian tissues and which catalyzes the compound 1,2-diacylglycerol and fatty acyl CoA to form triglycerides in endoplasmic reticulum (review made by Chen and Farese, Trends Cardiovasc. Med. (2000) 10:188 and Farese, et al., Curr. Opin. Lipidol. (2000) 11:229). Initially it was assumed that DGAT uniquely regulates catalysis final stage of acylation of diacylglycerol to the triglyceride in two main ways of synthesis of triglycerides in the way of glycerol phosphate and the MOT monoacylglycerides. Because triglycerides are considered vital and as their synthesis, as expected, is the only mechanism, the inhibition of the synthesis of triglycerides via inhibition of DGAT activity was not widely investigated.

Genes encoding mouse DGAT1 and related homologues ARGP1 and ARGP2 man, now cloned and characterized (Cases et al., Proc. Natl. Acad. Sci. (1998) 95:13018; Oelkers et al., J. Biol. Chem. (1998) 273:26765). The gene for mouse DGAT1 used to create mice with embossed DGAT, in order to better explain the function of the DGAT gene. It was unexpectedly found that mice unable to Express a functional enzyme DGAT, (mouse Dgat-/-) are viable and can even synthesize triglycerides, showing that in the synthesis of triglycerides contribute many catalytic mechanisms (Smith, et al., Nature Genetics (2000) 25:87). Other enzymes that catalyze the synthesis of triglycerides, for example, DGAT2 and diacylglycerides, also identified (Buhman, J. Biol. Chem., above and Cases, et al., J. Biol. Chem. (2001) 276:38870).

It is noteworthy that the mouse Dgat-/- resistant to caused by diet, obesity and remain skinny. Even when they are fed food with high fat content (21% fat), mouse Dgat-/- save weight compared with mice that provide a proper diet (4% fat) and which have lower overall levels of triglycerides in the body. Resistance to coirini in mice Dgat-/- is not a consequence of reduced calorie intake, as a result of increased energy expenditure and reduced insulin resistance and leptin (Smith, et al., Nature Genetics, above; Chen and Farese, Trends Cardiovasc. Med., above; and Chen, et al., J. Clin. Invest. (2002) 109:1049). Additionally, mouse Dgat-/- have a lower degree of assimilation of triglycerides (Buhman et al., J. Biol. Chem. (2002) 277:25474). In addition to improved triglyceride metabolism mouse Dgat-/- have also improved glucose metabolism with lower levels of glucose and insulin after glucose load compared with wild-type mice (Chen and Farese, Trends Cardiovasc. Med., above).

The discovery of the fact that many enzymes contribute to the catalysis of the synthesis of triglyceride from diacylglycerol, is significant as it represents an opportunity to modulate one catalytic mechanism specified biochemical reactions in order to achieve therapeutic outcomes for individual with minimal harmful side effects. It was found that compounds that inhibit the conversion of diacylglycerol in the triglyceride, for example, specific inhibition activity homologue of human DGAT1, applicable to reduce the concentrations in the body and absorption of triglycerides for therapeutic counteract the pathogenic effects caused by abnormal metabolism of triglycerides, obesity, syndrome of insulin resistance is diabetes clinical diabetes type II congestive heart failure and atherosclerosis and the effects of cancer treatment.

Due to the constant increase in the prevalence of obesity, type II diabetes, heart disease and cancer in society around the world there is an urgent need to develop new therapeutic agents for the effective treatment and prevention of these diseases. Therefore, there is interest in developing compounds that can strongly and specifically to modulate only the catalytic mechanism of the enzymatic conversion of diacylglycerol in the triglyceride. Particular perspective are compounds that specifically inhibit the catalytic activity of DGAT1 and other homologues in mammals.

This invention relates to a condensed bicyclic nitrogen-containing heterocyclic compounds, which are applicable for the treatment or prevention of conditions and disorders associated with DGAT in animals, especially in humans.

Basically, the compounds of this invention represented by formula (I):

I

or their pharmaceutically acceptable salt, prodrug or stereoisomer, where X is C(R1or N; Y means C(R1), C(R2)(R2), N or N(R2), and Z denotes O or S. L1means of communication, (C1-C4 )alkylene, (C2-C4)albaniles, O or N(Ra)C(O), and W1means substituted or unsubstituted group selected from cyclo(C3-C8)alkyl, heterocycle(C3-C8)alkyl, aryl and heteroaryl. m denotes 0 or 1, indicating the presence (m=1) or absence (m=0) an additional part of the molecule, L2-W2. For those cases where m is 1, L2means a bond, O, (C1-C4)alkylene, (C2-C4)albaniles, (C1-C4)heteroalkyl or N(Ra)C(O), and W2means substituted or unsubstituted group selected from cyclo(C3-C8)alkyl, heterocycle(C3-C8)alkyl, aryl and heteroaryl.

Other substituents, R1-R7and Raand Rbhave the following meanings: each R1independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, fluorine(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, C(O)Ra, CO2Raand C(O)NRaRb; each R2independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, fluorine(C1-C8)alkyl, C(O)Ra, CO2RaC(O)NRaRb, aryl and aryl(C1-C4)alkyl; R3and R4independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl is, (C2-C8)quinil, C(O)Ra, CO2RaC(O)NRaRband (C1-C4)alkylen-ORa; R5and R6independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, C(O)Raand CO2Ra; R7selected from H, (C1-C8)alkyl, halogen(C1-C4)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, C(O)Ra, ORaand NRaRband each Raand Rbindependently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, fluorine(C1-C8)alkyl, aryl and aryl(C1-C4)alkyl.

The dotted line indicates a possible link. In other possible embodiments, R3and R4can be combined to form a 3-, 4-, 5 - or 6-membered spirocerca; R2, R3or R4can be combined with W1education5-, 6 - or 7-membered condensed ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S; R5and R6can be combined with the nitrogen atom to which each is attached, with the formation of 5-, 6 - or 7-membered ring; when X is C(R1), R5or R6can be combined with R1with the formation of 5-, 6 - or 7-membered condensed ring containing the nitrogen atom to which R 5or R6attached; when X is C(R1), R7can be combined with R1with the formation of 5-, 6 - or 7-membered condensed ring; R2or R1when present as part of Y, can be combined with R5with the formation of 5 - or 6-membered ring with the nitrogen atom to which R5attached, optionally bearing oxoprop; and when m is 1 and L2means of communication, Deputy for W2can be combined with the Deputy on W1with the formation of 5-, 6 - or 7-membered ring condensed with W1and forming spinosissima or condensed with W2where the ring is saturated or unsaturated and has 0, 1 or 2 heteroatoms selected from N, O and S as ring members.

Among these compounds of the formula I compound is other than

where R8means H, NO2, Cl, methoxy, methyl or phenyl.

If not indicated otherwise, the compounds represented by the specified formula is meant to include all their pharmaceutically acceptable salts, prodrugs or stereoisomers.

This invention also relates to pharmaceutical compositions containing a compound according to the invention, pharmaceutically acceptable carrier or excipient.

This invention also relates to a method cured the I or prevention of a condition or disorder, selected from the group consisting of obesity, diabetes, anorexia nervosa, bulimia nervosa, hodonice, syndrome X, metabolic syndrome, insulin resistance, hyperglycemia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, disease nonalcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, and vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and cancer of the ovary, containing an introduction to the subject, if necessary, that therapeutically effective amounts of compounds according to the invention. For this method and the methods proposed below, the connection according to the invention will be, in some embodiments, be administered in combination with a second therapeutic agent.

This invention also relates to a method of treatment or prophylaxis status is of any and disorders, associated with DGAT, containing an introduction to the subject, if necessary, that therapeutically effective amounts of compounds according to the invention.

The invention additionally relates to a method of treatment or prevention of conditions and disorders mediated by DGAT, containing an introduction to the subject, if necessary, that therapeutically effective amounts of compounds according to the invention.

The invention additionally relates to methods of modulating DGAT containing the contacting cells with a compound according to the invention.

DETAILED description of the INVENTION

Abbreviations and definitions

The terms "treat", "treatment" and "treatment" refer to a method of alleviating or eliminating the disease and/or its attendant symptoms.

The terms "prevent", "preventing" and "prevention" refer to the prevention of the onset of the disease and/or concomitant symptoms or exclusion of acquisition subject to the disease. Used here, the terms "prevent", "preventing" and "prevention" include also delay the onset and/or its attendant symptoms and decrease for the subject's risk of acquiring the disease.

The term "therapeutically effective amount" refers to that amount of the compound that is sufficient to prevent development of or to clothe treatment to some extent one or more symptoms of the condition or disease, which is subjected to the treatment.

Used herein, the term "diabetes" refers to diabetes mellitus type I (initial juvenile diabetes, insulin-dependent diabetes mellitus or IDDM) or diabetes mellitus type II (non-insulin-dependent diabetes mellitus or NIDDM), preferably for diabetes II.

Used herein, the term "syndrome X" refers to a collection of anomalies, including hyperinsulinemia, obesity, elevated levels of triglycerides, uric acid, fibrinogen, LDL particles of low density and inhibitor 1, plasminogen activator (PAI-1), and lower levels of HDL cholesterol. Syndrome X optional covers metabolic syndrome.

Used herein, the term "obesity" refers to excessive accumulation of body fat. Obesity can be genetic, environmental (e.g., energy spent less than consumption) and regulatory determinants. Obesity includes exogenous, hyperinsulinemia, giperplasticeski, hypothyroid, hypothalamic, symptomatic infantile, Verkhnekamskoe associated with food, hypogonadal, simple and Central obesity, hypophyseal adiposity and hyperphagia. Metabolic disorders such as hyperlipidemia and diabetes, and cardiovascular disorders such as hypertension and coronary artery disease, usually is associated with obesity.

The term "modulate" refers to the ability of the compound to increase or decrease the function or activity of DGAT. The term "modulation"is used here in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism activity associated with DGAT. The DGAT inhibitors are compounds that, for example, compel partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desencibiliziruta or down-regulate signal transduction. Activators DGAT are compounds that, for example, induce, stimulate, increase, open, activate, facilitate, enhance activation, sensibiliser or up-regulate signal transduction.

Used herein, the term "composition" includes a product containing specific ingredients in specific amounts, as well as any product which is directly or indirectly the result of a combination of specific ingredients in specific amounts. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with other ingredients of the composition and harmless to their recipient.

The definition of "subject" includes animals such as mammals, including, but not limited to, p is Ipatov (for example, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is the man.

The term "DGAT" refers to acyl-CoA:the diacylglycerol acyltransferase or her option, if not precisely defined otherwise. Options DGAT include proteins, essentially homologous native DGAT, i.e. proteins having one or more naturally occurring or not naturally occurring deletions, insertions or substitutions of amino acids (for example, derivatives of DGAT, homologs and fragments). Amino acid sequence variants of DGAT, preferably at least about 80% identical to native DGAT, more preferably at least about 90% identical and most preferably at least about 95% identical.

Used herein, the term "associated with DGAT condition or disorder" refers to a condition or disorder associated with inappropriate, e.g., greater or lesser than normal, DGAT activity and at least partially responsible for the modulation of DGAT or amenable to its influence (e.g., inhibitor or antagonist DGAT results in some improvement in at least some patients). Inadequate functional activity of DGAT may receive as a result of DGAT expression in the cells is Oh, that normally does not Express DGAT, low DGAT expression or increased expression of DGAT. Associated with DGAT condition or disorder may include mediated by DGAT condition or disorder.

Used herein, the term "mediated by DGAT condition or disorder" and the like refers to a condition or disorder characterized by inappropriate, e.g., greater or lesser than normal, DGAT activity. Mediated by DGAT condition or disorder may be completely or partially mediated by inappropriate activity of DGAT. However, mediated by DGAT condition or disorder is so, in which modulation of DGAT lead to some impact on the main condition or disease (e.g., inhibitor or antagonist DGAT results in some improvement in at least some patients).

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear or branched chain, or cyclic hydrocarbon radical or a combination thereof, it is fully saturated, having the specified number of carbon atoms (for example, C1-C8means from one to eight carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl is, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentile, n-hexyl, n-heptyl, n-Attila and the like.

The term "alkenyl", by itself or as part of another substituent, means a linear or branched chain, or cyclic hydrocarbon radical, or a combination thereof, which may be mono - or polyunsaturated, having the specified number of carbon atoms (for example, C2-C8means from two to eight carbon atoms) and one or more double bonds. Examples alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and their higher homologs and isomers.

The term "quinil", by itself or as part of another substituent, means a linear or branched chain, or cyclic hydrocarbon radical, or a combination thereof, which may be mono - or polyunsaturated, having the specified number of carbon atoms (for example, C2-C8means from two to eight carbon atoms) and one or more triple bonds. Examples etkinlik groups include ethinyl, 1 - and 3-PROPYNYL, 3-butynyl and their higher homologs and isomers.

The term "alkylene", by itself or as part of another substituent means a divalent radical derived from alkyl as, for example, -CH2CH2CH2CH2-. Usually the group of alkyl (or al who Elena) will have from 1 to 24 carbon atoms, with the group having 10 or less carbon atoms, are preferred in this invention. "Lower alkyl" or "lower alkylene" means the group of alkyl or alkylene with a shorter chain, generally having eight or less carbon atoms. Similarly, "albaniles and akinyan" refers to unsaturated versions of alkylene having at least one double bond or triple bond, respectively. For example, "albaniles" means the inclusion of the-CH2CH=CHCH2-while akinyan" means the inclusion of the-CH2C≡CCH2-.

The terms "alkoxy", "alkylamino and alkylthio" (or dialkoxy) are used in their ordinary sense and refer to those alkyl groups that are attached to the rest of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively.

The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of a specified number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, where the atoms of nitrogen and sulfur may not necessarily be oxidized and the nitrogen heteroatom may not necessarily be quaternity. Heteroatom(s) O, N and S may be located at any internal polariseerumine group. Heteroatom Si can be located at any position heteroalkyl group, including the position at which the alkyl group attached to the rest of the molecule. Examples include-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3and-CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive as, for example, -CH2-NH-OCH3and-CH2-O-Si(CH3)3.

Similarly, the term "heteroalkyl", by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as, for example, -CH2-CH2-S-CH2CH2- and-CH2-S-CH2-CH2-NH-CH2-. In groups of heteroalkyl heteroatoms can also occupy either or both ends of the chain (for example, alkylene, alkylenedioxy, alkylamino, alkylenediamine and the like). Additionally, for cross-linking groups alkylene and heteroalkyl no orientation of the linking groups is not assumed.

The terms "cycloalkyl and heteroseksualci", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteros who of alkyl", respectively. Accordingly, cycloalkene the group has the indicated number of carbon atoms (for example, C3-C8means from three to eight carbon atoms) and may also have one or two double bonds. Heterocytolysine group consists of the specified number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and the atoms of nitrogen and sulfur may not necessarily be oxidized and the nitrogen heteroatom may not necessarily be quaternity. Additionally for geterotsiklicheskie, heteroatom can occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of geterotsiklicheskie include 1-(1,2,5,6-tetrahydropyridine), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothieno-2-yl, tetrahydrothieno-3-yl, 1-piperazinil, 2-piperazinil and the like.

The term "halogen", alone or as part of another substituent, means, unless otherwise stated, a fluorine atom, chlorine, bromine or iodine. Additionally, terms such as "halogenated", meaning that they include alkyl substituted by halogen atoms, which may be the same or different, within their number is from one to (2m'+1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "halogen(C1-C4)alkyl" means that it includes trifluoromethyl, 2,2,2-triptorelin, 4-chlorobutyl, 3-bromopropyl and the like. Thus, the term "halogenated" includes monohalogenated (alkyl, substituted by one halogen atom) and POLYHALOGENATED (alkyl substituted by halogen atoms within their number from two to (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group). The term "perhalogenated" means, unless otherwise stated, alkyl, substituted (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "pagelogin(C1-C4)alkyl" means that it includes trifluoromethyl, pentachloride, 1,1,1-Cryptor-2-bromo-2-chloroethyl, and the like. The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon Deputy, which may be a single ring or multiple rings (up to three rings)which are condensed together or covalently crosslinked. Non-restrictive examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1,2,3,4-tetrahydronaphthalen.

The term "heteroaryl" refers to aryl groups (or rings)that contain from one to four heteroatoms selected from N, O and S, where the atoms AZ is the one and sulfur optionally oxidized and the nitrogen heteroatoms optional quaternity. Heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-restrictive examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4 pirimidil, 5-benzothiazolyl, purines, 2-benzimidazolyl, 5-indolyl, 1-ethanolic, 5-ethanolic, 2-honokalani, 5-honokalani, 3-chinolin and 6-chinolin. For brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, arylthiols, arylalkyl) includes ring and aryl and heteroaryl defined above. So, it is understood that the term "arylalkyl" includes those radicals in which an aryl group is attached to alkalino group (such as benzyl, phenethyl, pyridylmethyl and the like)including those alkyl groups in which a carbon atom (for example, MEDIENGRUPPE) substituted, for example, an oxygen atom (for example, phenoxymethyl, 2-pyridyloxy, 3-(1-naphthyloxy)propyl, and the like). Each of the above terms (e.g., "alkyl," "heteroalkyl", "aryl" and "heteroaryl"), as implied, includes both substituted and unsubstituted forms of the indicated is adikal. Preferred substituents for each type of radical are presented below.

Substituents for the alkyl radicals and heteroalkyl (as well as those groups referred to as alkylene, alkenyl, heteroalkyl, heteroalkyl, quinil, cycloalkyl, heteroseksualci, cycloalkenyl and geteroseksualen) can be a variety of groups selected from-OR',=O, =NR', =H,-OR', -NR'r R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)R NR'r", -NR"C(O)R', -NR'-C(O)NR"R"', -NR'-SO2NR"R"', -NR"'CO2R', -NH-C(NH2)=NH, -NR'r C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'r R", -NR"SO2R',- CN and-NO2within their number from zero to three, with those groups having zero, one or two Deputy, is particularly preferred. R', R" and R"each independently refer to hydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, the unsubstituted aryl, aryl substituted by one to three halogen atoms, the unsubstituted alkyl, alkoxy or dialkoxy or aryl(C1-C4)alkalino group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom with the formation of 5-, 6 - or 7-membered ring. For example, -NR'r R", as implied, includes 1-pyrrolidinyl and 4-morpholinyl. Additionally, these substituents may be attached to the alkyl group (or alkylene, cycloalkyl and the like) through the spacer (the separation group) from one to four carbon atoms, usually represented as a methylene group or branched unsubstituted alkylene (for example, -CH2CH2- , and-CH(CH3)CH2), Alcanena or albinyana. Typically, the alkyl or heteroalkyl group will have from zero to three substituents, and such groups having two or less substituents, preferred in this invention. More preferably, the alkyl or heterouncinata be unsubstituted or monosubstituted. Most preferably, the alkyl - or heterouncinata is unsubstituted. From the discussion above substituents specialist should understand, the term "alkyl" is intended to include groups such as trihalomethyl (e.g.,- CF3and-CH2CF3).

Preferred substituents for the alkyl radicals and heteroalkyl selected from-OR', =O, -R NR'r", -SR', halogen, -SiR'R"R"', -OC(OR', -C(O)R', -CO2R', -CONR'R", -OC(O)R NR'r", -NR"C(O)R', -NR"CO2R', -NR'-SO2NR"R"', -S(O)R', -SO2R', -SO2NR'r R", -NR"SO2R', -CN and-NO2where R' and R" have the meanings specified above. More preferred substituents selected from-OR', =O, -NR'r R", halogen, -OC(O)R', -CO2R', -CONR'R", -OC(O)R NR'r", -NR"C(O)R', -NR"CO2R', -NR'-SONR"R"', -SO2R', -SO2NR'r R", -NR"SO2R, -CN and-NO2. Additionally, each of the preferred and additionally preferred substituents can be attached to the alkyl group is e (or alkylene, cycloalkyl and the like) through spacer elements group of one to four carbon atoms, usually represented as methylene groups or branched unsubstituted alkylene.

Similarly, substituents for the aryl groups and heteroaryl are varied and selected from halogen, -OR', -OC(O)R', -NR'r R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)R NR'r", -NR"C(O)R', -NR"CO2R', -NR'-C(O)NR"R"', -NR'-SO2NR"R"', -NH-C(NH2)=NH, -NR'r C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'r R", -NR"SO2R', -N3, -CH(Ph)2, PERFLUORO(C1-C4)alkoxy, and PERFLUORO(C1-C4)alkyl, within their number from zero to the total number of open valences on aromatic ring system; and where R', R" and R"' are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl. When the aryl group is 1,2,3,4-tetrahydronaphthalen, it can be replaced by a substituted or unsubstituted (C3-C7)spirocyclohexane group. (C3-C7)spiratically group may be substituted in the same manner as defined here for the "cycloalkyl". Typically, the aryl or heteroaryl group will have from zero to three substituents, and these groups having two or less replaces the lei, preferred in this invention. In one embodiment of the invention, the aryl group or heteroaryl will be unsubstituted or monosubstituted. In another embodiment, the aryl group or heteroaryl are unsubstituted. When they are substituted, the above substituents can be attached to the aryl or heteroaryl group via a spacer from one to four carbon atoms, usually represented as methylene groups or branched unsubstituted alkylene (for example, -CH2CH2- , and-CH(CH3)CH2-).

Preferred substituents for aryl groups and heteroaryl selected from halogen, -OR', -OC(O)R', -NR'r R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)R NR'r", -NR"C(O)R', -S(O)R', -SO2R', -SO2NR'r R", -NR"SO2R', -N3, -CH(Ph)2, PERFLUORO(C1-C4)alkoxy, and PERFLUORO(C1-C4)alkyl, where R' and R" have the meanings specified above. More preferred substituents selected from halogen, -OR', -OC(O)R', -NR'r R", -R', -CN, -NO2, -CO2R', -CONR'R", -NR"C(O)R', -SO2R', -SO2NR'r R", -NR"SO2R', PERFLUORO(C1-C4)alkoxy, and PERFLUORO(C1-C4)alkyl. As indicated above, the above optional substituents attached to the aryl or heteroaryl part of the molecule via a spacer group of one to four methylene groups.

It should be understood that the Deputy-CO2H used here, which incorporates both bioisosteric replacement such as

,,,,,,,,,,,,,,,,,

and things like that. See, for example. The Practice of Medicinal Chemistry; Wermuth, C.G., Ed.; Academic Press: New York, 1996; p.203.

Two of the substituents on adjacent atoms of the aryl ring or heteroaryl optionally can be substituted by the Deputy of the formula

-T-C(O)-(CH2)q-U, where T and U independently mean-NH-, -O-, -CH2or ordinary communication, and q denotes an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring or heteroaryl optionally can be substituted by the Deputy of the formula-A-(CH2)r-B-, where a and b independently denote-CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single links formed so new rings optionally may be the substituted double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring or heteroaryl optionally can be substituted by the Deputy of the formula -(CH2)s-X-(CH2)t-, where s and t independently denote integers from 0 to 3, and X is-O-, -NR'-, -S-, -S(O)-, -S(O)2-, or-S(O)2NR'-. The substituent R' in-NR'- and-S(O)2NR'is selected from hydrogen or unsubstituted (C1-C6)alkyl.

Used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The term "pharmaceutically acceptable salts" means salts of the active compounds, which are obtained from relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of this invention contain relatively acidic group, a salt additive with the base can be obtained by contacting such compounds in the form of the free acid with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable additive salts with base include salts of sodium, potassium, calcium, ammonium, organic amino, or magnesium, or a similar salt. When the compounds of this invention contain groups regarding the main character,additive salts with an acid can be obtained by contacting such compounds in the free base form with a sufficient amount of the desired acid, either undiluted or in a suitable inert solvent. Examples of pharmaceutically acceptable additive salts with an acid include those derived from inorganic acids, such as chloromethane, Hydrobromic, nitric, carbonic, monohydrochloride, phosphoric, managerfactory, dihydrotestorone, sulfur, monohydrogen, iodomethane or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids, such as acetic, propionic, somalina, maleic, malonic, benzoic, succinic, subernova, fumaric, almond, phthalic, benzolsulfonat, p-toluensulfonate, citric, tartaric, methanesulfonate and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge, S.M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Some specific compounds of this invention contain groups and the main character, and acid that allows you to make connections in additive salt or a base or acid.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound usual obrazovka connection form differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other aspects of salt is equivalent to the parent form of the compound for the purposes of this invention.

In addition to salt forms, the present invention relates to compounds that are in proletarienne form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under the influence of physiological conditions, giving compounds according to this invention. Additionally, prodrugs can be converted into compounds according to this invention by chemical or biochemical methods in an environment in and ex vivo. For example, prodrugs can be slowly converted to compounds according to this invention, when they are placed in the reservoir of the patch for percutaneous injection with a suitable enzyme or chemical reagent.

It should be understood that when the connection according to the invention contains one or more asymmetric carbon atoms (optical centers) or double bonds, the invention includes the individual stereoisomers and geometric isomers, and mixtures thereof. For example, when m=1 and W2means substituted cyclo(C3-C8)alkyl (e.g., A.4 below), it is assumed that the 1,4-CIS - and TRANS-isomers and racemates are within the scope of the invention.

A.4

Some compounds in this invention can exist in resolutiony forms, as well as in solvated forms, including hydrated forms. Usually solvated forms are equivalent nonsolvated forms and, of course, must be included in the scope of this invention. Some compounds in this invention can exist in multiple crystalline or amorphous forms. Usually, all physical forms are equivalent for the uses proposed by this invention and, of course, must be within the scope of this invention.

Compounds according to this invention may also contain unnatural relative share of nuclear isotopes of one or more of the atoms that constitute such compounds. For example, the compounds can be in the state of radioactive isotopes, such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds according to this invention, radioactive or not, must be included in the scope of this invention.

Connections

In one aspect, this invention relates to compounds of formula (I):

I

or their pharmaceutically acceptable salts, prodrugs or stereoisomers. In this formula X is C(R1or N; Y is appoints C(R 1), C(R2)(R2), N or N(R2), and Z denotes O or S.

Turning then to the substituents on the bicyclic heteroaromatic nucleus, L1means of communication, (C1-C4)alkylene, (C2-C4)albaniles, O or N(Ra)C(O), and W1means substituted or unsubstituted group selected from cyclo(C3-C8)alkyl, heterocycle(C3-C8)alkyl, aryl and heteroaryl. m denotes 0 or 1, indicating the presence (m=1) or absence (m=0) an additional part of the molecule, L2-W2. For those cases in which m=1, L2means a bond, O, (C1-C4)alkylene, (C2-C4)albaniles, (C1-C4)heteroalkyl or N(Ra)C(O); and W2means substituted or unsubstituted group selected from cyclo(C3-C8)alkyl, heterocycle(C3-C8)alkyl, aryl and heteroaryl. When m=1 and L2means of communication, Deputy for W2can be combined with the Deputy on W1with the formation of 5-, 6 - or 7-membered ring condensed with W1and forming spinosissima or condensed with W2where the ring is saturated or unsaturated and has 0, 1 or 2 heteroatoms selected from N, O and S as ring members. Substituents for each of the W1and W2can be selected from the substituents listed in the definition above, as well as the C-mentioned substituents for various specific options below.

Other substituents, R1-R7and Raand Rbhave the following meanings: each R1independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, fluorine(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, C(O)Ra, CO2Raand C(O)NRaRb; each R2independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, fluorine(C1-C8)alkyl, C(O)Ra, CO2RaC(O)NRaRb, aryl and aryl(C1-C4)alkyl; R3and R4independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, C(O)Ra, CO2RaC(O)NRaRband (C1-C4)alkylen-ORa; R5and R6independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, C(O)Raand CO2Ra; R7selected from H, (C1-C8)alkyl, halogen(C1-C4)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, C(O)Ra, ORaand NRaRb; and each Raand Rbindependently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil, fluorine(C1-C8)alkyl, aryl and aryl(C1-C4)alkyl.

3and R4can be combined to form a 3-, 4-, 5 - or 6-membered spirocerca; R2, R3or R4can be combined with W1with the formation of 5-, 6 - or 7-membered condensed ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S; R5and R6can be combined with the nitrogen atom to which each is attached, with the formation of 5-, 6 - or 7-membered ring; R2or R1when present as part of Y, can be combined with R5with the formation of 5 - or 6-membered ring with the nitrogen atom to which R5attached, optionally bearing oxoprop; when X is C(R1), R5or R6can be combined with R1with the formation of 5-, 6 - or 7-membered condensed ring containing the nitrogen atom to which R5or R6attached; and when X is C(R1), R7can be combined with R1with the formation of 5-, 6 - or 7-membered condensed ring.

In preferred embodiments, R1and R2each independently represent H or (C1-C8)alkyl; R3and R4each independently represent H or (C1-C4)alkyl; R5and R6each represent H, (C1-C4)alkyl, or are combined with the nitrogen atom to which each is attached, with images is of a 5 - or 6-membered ring (for example, ring pyrrolidine or piperidine); and R7means H, (C1-C8)alkyl or halo(C1-C4)alkyl.

Among these compounds of formula (I), the compound is other than

where R8means H, NO2, Cl, methoxy, methyl or phenyl.

In the formula (I) above, some groups of preferred options.

In one group of preferred options X is N. more preferably, X is N and Z signifies O. In this group of variants, L1means is preferably a bond, and W1means substituted or unsubstituted group selected from benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C4-C7)cycloalkane, (C5-C7)cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane. Even more preferably, W1means substituted or unsubstituted group selected from benzene, pyridine, thiophene, (C4-C7)cycloalkane, 1,2,3,4-tetrahydronaphthalene and indane. For those cases in which W1means substituted benzene, the substituents (Rcbelow), other than L2-W2preferably selected from halogen (including F, Cl, Br and I), Rc1, ORc1N(Rc1)2, SRc1, NO2CN, (C1-C8)halogenoalkane and (C1-C8)halogenoalkane, where each g is the PAP R c1independent means H, (C1-C8)alkyl, (C2-C8)alkenyl or (C2-C8)quinil, and optionally, two groups of Rc1attached to a common nitrogen atom, combined with the formation of five - or six-membered ring. Optionally substituted benzene preferably will have from one to four substituents, preferably one or two substituent, and most preferably one Deputy. Substituents for each of the W1and W2can be selected from the substituents listed in the definition above, and the substituents mentioned for different specific options below.

In one group specific options subscript m=0 and L1means communication. Even more preferably, W1selected from substituted or unsubstituted benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C4-C7)cycloalkane, (C5-C7)cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane. Even more preferably W1means substituted or unsubstituted group selected from benzene, pyridine, thiophene, (C4-C7)cycloalkane, 1,2,3,4-tetrahydronaphthalene and indane. Further preferred are variants represented by formulas Ia, Ib, Ic, Id, Ie, If and Ig below:

where n means an integer from 0 to 4 and each Rcmeans the Deputy, independently selected from halogen (including F, Cl, Br and I), Rc1, ORc1N(Rc1)2, SRc1, NO2CN, (C1-C8)halogenoalkane and (C1-C8)halogenoalkane, where each group Rc1independently mean H, (C1-C8)alkyl, (C2-C8)alkenyl or (C2-C8)quinil and, when Rcmeans N(Rc1)2two groups of Rc1can be combined with the formation of five - or six-membered ring. Optional, If and Ig, the two groups Rc1can be combined to form a 3-, 4-, 5-, 6 - or 7-membered optionally substituted spirocycles rings. The remaining substituents have the meanings mentioned above in respect of General formula I.

In the related group-specific variants X is N, Z denotes O, L1preferably means a bond, W1means substituted or unsubstituted group selected from benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C4-C7)cycloalkane, (C5-C7)cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane, and m=1. In this group of options L2preferably means a bond, O, or (C1-C4)heteroalkyl (e.g.,- OCH2 -, -OCH2CH2-, -NHCH2-) and W2means substituted or unsubstituted group selected from benzene, pyridine and (C4-C7)cycloalkane.

In one group of particularly preferred options compound selected from the group:

where n means an integer from 0 to 4 and each Rcmeans the Deputy, independently selected from halogen (including F, Cl, Br and I), Rc1, ORc1N(Rc1)2, SRc1, NO2CN, (C1-C8)halogenoalkane and (C1-C8)halogenoalkane, where each group Rc1independently mean H, (C1-C8)alkyl, (C2-C8)alkenyl or (C2-C8)quinil, and, optionally, two groups of Rc1attached to a common nitrogen atom, combined with the formation of five - or six-membered ring. Additionally, p is an integer from 0 to 4, more preferably 0, 1 or 2, and each Rdmeans the Deputy, independently selected from halogen (including F, Cl, Br and I), Rd1, ORd1N(Rd1)2, -(CH2)t-S(O)uRe, NO2CN, (C1-C8)halogenoalkane, (C1-C8)halogenoalkane, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -C(O)CO2Re, -(CH2)t-CO2R e, -(CH2)t-C(O)Re, -(CH2)t-C(O)NReRf, -(CH2)t-NHSO2Re, -(CH2)t-SO2NReRf, -(CH2)t-NReRf, -(CH2)t-ORe, -(CH2)t-NHSO2NHCO2Re, -(CH2)t-NHSO2NReRf, -(CH2)t-CONHSO2Re, -(CH2)t-W3, -(CH2)t-NHCO2Re, -(CH2)t-NRfCORe, -(CH2)t-NHCONReRfand -(CH2)t-NHCO-(CH2)t-OCORewhere t in each case means an integer from 0 to 8, u represents an integer from 0 to 2, Rd1selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil and (C3-C8)cycloalkyl, where the aliphatic portion of the optionally substituted by OH, CO2H, NH2, CONH2, phenyl, halogen, halogen(C1-C4)- alkyl and CO2Rgand, optionally, two groups of Rd1attached to a common nitrogen atom, combined with the formation of five - or six-membered ring; and where each Reand Rfindependently denotes H, or (C1-C8)alkyl, or when they are attached to a common nitrogen atom, they merged to form a 5 - or 6-membered ring, or optionally selected from the

and DG is any alkyl part in R eand Rfoptionally substituted by the Deputy, is selected from OH, COOH, NH2, CONH2, phenyl, dialkylamino and COORgwhere Rgmeans (C1-C4)alkyl; and W3selected from the

where each Riand each Rjindependently selected from H, OH, COOH, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C4)alkyl and COO(C1-C4)alkyl, where the aliphatic part are unsubstituted or optionally substituted with halogen.

In some embodiments, the substituents Rdselected from halogen (including F, Cl, Br and I), Rd1, ORd1N(Rd1)2, SRd1, NO2CN, (C1-C8)halogenoalkane, (C1-C8)halogenoalkane, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, (C1-C8)alkylene-CO2ReC(O)Re, CO2Re, -CH2-CO2Re, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Re, -C(O)NReRf, -CH2C(O)NReRf, -CH2CH2CONReRf, -NHSO2Re, -CH2NHSO2Re, -CH2CH2NHSO 2Re, -CH2SO2NReRf, -CH2CH2SO2NReRf, -CH2OH, -CH2NReRfCH2CH2OH, -CH2C(CH3)2OH, -CH2-W3, -CH2CH2-W3and-C(O)CO2Rewhere each Rd1, Re, Rfand W3have the meanings specified above in respect of formula Ih, Ii, Ij and Ik, and the remaining substituents have the meanings mentioned above in respect of General formula I.

In other preferred embodiments, the compound has a formula selected from the

where each of R2, R3, R4, R5, R6, R7and Rcand n have the meanings specified above in respect to formulae Ia-Ik. q denotes an integer from 0 to 3, more preferably 0 or 1. s denotes an integer from 0 to 4, more preferably 0, 1 or 2, and each Rhmeans the Deputy, independently selected from oxo, halogen (including F, Cl, Br and I), Rh1, ORh1N(Rh1)2, -(CH2)t-S(O)uRe, NO2CN, (C1-C8)halogenoalkane, (C1-C8)halogenoalkane, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -C(O)CO2Re, =CH-CONReRf, =CH-CO2Re, -(CH2)t-CO2 e, -(CH2)t-C(O)Re, -(CH2)t-C(O)NReRf, -(CH2)t-NHSO2Re, -(CH2)t-SO2NReRf, -(CH2)t-NReRf, -(CH2)t-ORe, -(CH2)t-NHSO2NHCO2Re, -(CH2)t-NHSO2NReRf, -(CH2)t-CONHSO2Re, -(CH2)t-W3, -(CH2)t-NHCO2Re, -(CH2)t-NRfCORe, -(CH2)t-NHCONReRfand -(CH2)t-NHCO-(CH2)t-OCORewhere t in each case means an integer from 0 to 8, u represents an integer from 0 to 2, Rh1selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)quinil and (C3-C8)cycloalkyl, where the aliphatic portion of the optionally substituted by OH, CO2H, NH2, CONH2, phenyl, halogen, halogen(C1-C4)- alkyl and CO2Rgand optional two groups of Rh1attached to a common nitrogen atom, combined with the formation of five - or six-membered ring, or a group Rhand Rh1can be combined to form a 3-, 4-, 5 - or 6-membered Spiro - or condensed ring having zero to two heteroatoms selected from N, O and S; and where each Reand Rfindependently denotes H, or (C1-C8)is lkyl or being attached to a common nitrogen atom, they merged to form a 5 - or 6-membered ring, or, optionally, selected from

and where any alkyl part in Reand Rfoptionally substituted by the Deputy, is selected from OH, COOH, NH2, CONH2, phenyl, dialkylamino and COORgwhere Rgmeans (C1-C4)alkyl; and W3selected from the

where each Riand each Rjindependently selected from H, OH, COOH, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C4)alkyl and COO(C1-C4)alkyl, where the aliphatic part are unsubstituted or optionally substituted with halogen.

In some embodiments, the substituents Rhselected from oxo, halogen (including F, Cl, Br and I), Rh1, ORh1N(Rh1)2, SRh1, NO2CN, (C1-C8)halogenoalkane, (C1-C8)halogenoalkane, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, (C1-C8)alkylene-CO2ReC(O)Re, CO2Re, =CH-CONReRf, =CH-CO2Re, -CH2 -CO2Re, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Re, -C(O)NReRf, -CH2C(O)NReRf, -CH2CH2CONReRf, -NHSO2Re, -CH2NHSO2Re, -CH2CH2NHSO2Re, -CH2SO2NReRf, -CH2CH2SO2NReRf, -CH2OH, -CH2NReRfCH2CH2OH, -CH2C(CH3)2OH, -CH2-W3, -CH2CH2-W3and-C(O)CO2Rewhere Rh1, Re, Rfand W3have the meanings specified above in respect of formula Il, Im, In, Io, Ip, and Iq, and the remaining substituents have the meanings mentioned above in respect of General formula I.

In some embodiments, each of the formulas from Ia to Iq, R2(when present) means H or (C1-C8)alkyl; R3and R4each independently represent H, (C1-C4)alkyl, or combined to form a 3-, 4-, 5 - or 6-membered spirocycles ring; R5and R6each represent H, (C1-C4)alkyl, or are combined with the nitrogen atom to which each is attached with the formation of 5 - or 6-membered ring (e.g. ring pyrrolidine or piperidine); and R7means H, (C1-C8)alkyl or halo(C1-C4)alkyl. Additionally, prepact the tion to the options in which the subscript n=0, q=1 and s=1. In a particularly preferred group of options, the compound has the formula Il, Im or In, and Rhmeans the Deputy, having the formula C(O)Re, CO2Re, =CH-CO2Re, -CH2-CO2Re, -CH2NHCORe, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Re, -C(O)NReRf, =CH-CONReRf, -CH2C(O)NReRf, -CH2CH2C(O)NReRf, -CH2CH2NHCO2Re, -CH2NHCO2Re, -NHSO2Re, -CH2NHSO2Re, -CH2CH2NHSO2Re, -CH2SO2NReRf, -CH2CH2SO2NReRf, -CH2OH, -CH2NReRf, -CH2CH2OH, -CH2C(CH3)2OH, -CH2-W3, -CH2CH2-W3, -C(O)CO2Reor-CH2-C(CF3)2-OH. In an additional group of preferred options, the compounds have the formula Il in which R3and R4independently denote H or unsubstituted (C1-C4)alkyl; R5and R6independently denote H or unsubstituted (C1-C4)alkyl; R7selected from H, unsubstituted (C1-C4)alkyl or halo(C1-C4)alkyl; n is 0, 1 or 2, and Rcselected from fluorine, chlorine, bromine, qi is but bromide, trifloromethyl and nitro; Rhselected from CO2Re, =CH-CO2Re, -CH2-CO2Re, -CH2NHCORe, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Re, -C(O)NReRf, =CH-CONReRf, -CH2C(O)NReRf, -CH2CH2C(O)NReRf, -CH2CH2NHCO2Re, -CH2NHCO2Re, -CH2NReRf, -CH2-W3and-CH2CH2-W3; where each Reand Rfmeans H or (C1-C4)alkyl, optionally substituted Deputy selected from OH, COOH, NH2, CONH2, phenyl, dialkylamino and COORgwhere Rgmeans (C1-C4)alkyl; and where W3selected from the

where Riand Rjeach independently selected from H and (C1-C4)alkyl.

In another group of preferred options of the compounds represented by formulas from Ir to Iy.

where each of R3, R4, R5, R6, R7and Rcand n have the meanings specified above in respect to formulae Ia-Ik. q denotes an integer from 0 to 3, more preferably 0 or 1. s denotes an integer from 0 to 4, more preferably 0, 1 or 2, and each Rhoznacza the t Deputy, independently selected from the groups specified above for formula Il, Im, In, Io, Ip, and Iq. Preferred groups for Rhare those specified above as preferred groups for formula Il, Im, In, Io, Ip, and Iq.

In preferred embodiments, R3and R4each independently represent H, (C1-C4)alkyl, or combined to form a 3-, 4-, 5 - or 6-membered spirocycles ring; R5and R6each represent H, (C1-C4)alkyl, or are combined with the nitrogen atom to which each is attached, with the formation of 5 - or 6-membered ring (e.g. ring pyrrolidine or piperidine); and R7means H, (C1-C8)alkyl or halo(C1-C4)alkyl. Still further preferred are those cases in which n=0, q=1 and s=1. In a particularly preferred group of options Rhmeans the Deputy, having the formula C(O)Re, CO2Re, =CH-CO2Re, -CH2-CO2Re, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Re, -C(O)NReRf, =CH-CONReRf, -CH2C(O)NReRf, -CH2CH2C(O)NReRf, -CH2CH2NHCO2Re, -CH2NHCO2Re, -NHSO2Re, -CH2NHSO2Re, -CH2CH2NHSO2Re, -CH2SO2NRe Rf, -CH2CH2SO2NReRf, -CH2OH, -CH2NReRf, -CH2CH2OH, -CH2C(CH3)2OH, -CH2-W3, -CH2CH2-W3, -C(O)CO2Reor-CH2-C(CF3)2-OH, where each Re, Rfand W3have the values specified above.

In a particularly preferred group of variants compounds have the formula Iw.4, where the substituents have the meanings mentioned above in respect of General formula I, and preferably selected from the preferred groups described formulas from Ir to Iy.

More preferably, the compounds of formula Iw.4 are those in which R3and R4independently denote H or unsubstituted (C1-C4)alkyl; R5and R6independently denote H or unsubstituted (C1-C4)alkyl; R7selected from H, unsubstituted (C1-C4)alkyl or halo(C1-C4)alkyl; n is 0, 1 or 2, and Rcselected from fluorine, chlorine, bromine, cyano, methyl, trifloromethyl and nitro; Rhselected from CO2Re, =CH-CO2Re, -CH2-CO2Re, -CH2NHCORe, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Re, -C(O)NReRf, =CH-CONReRf, -CH2C(O)NReRf , -CH2CH2C(O)NReRf, -CH2CH2NHCO2Re, -CH2NHCO2Re, -CH2NReRf, -CH2-W3and-CH2CH2-W3; where each Reand Rfmeans H or (C1-C4)alkyl, optionally substituted Deputy selected from OH, COOH, NH2, CONH2, phenyl, dialkylamino and COORgwhere Rgmeans (C1-C4)alkyl; and where W3selected from the

where Riand Rjeach independently selected from H and unsubstituted (C1-C4)alkyl.

In another particularly preferred group of variants of the compounds represented by formulas Il.4 and Ig.4:

where each of the substituents have the values and preferred groups described above for formulas from Ir to Iy.

More preferred compounds of this invention are those specified in the examples below and in addition are shown in tables 1-10.

In one particularly preferred group of variants of the compounds selected from the

Obtaining compounds

Compounds according to this invention can be produced from commercially available IP is adnych materials and using conventional technologies of synthesis, well-known experts in this field. Below, in General terms, the scheme of reactions suitable for obtaining such compounds. Additional examples can be found in the accompanying examples.

Scheme 1

As shown in scheme 1, the compounds of this invention where X represents N, Y represents N and Z denotes O, can be obtained from suitably substituted pyrimidine (ii) and substituted ketone (i), where LG denotes a leaving group such as halogen atom, toluensulfonate, methanesulfonate or triftorbyenzola. Condensation of i and ii in an organic solvent or mixture of solvents (including water mixture) in the presence or in the absence of acid (such as HCl) or base (e.g., NaHCO3) gives, after final processing, the compound of formula iii. Recovery iii reducing agent, such as, for example, sodium borohydride, lithium borohydride, triacetoxyborohydride sodium, gives still other compounds according to this invention, illustrated as iv in scheme 2.

Scheme 2

Scheme 3a-3i explain several ways to obtain the intermediate compounds of General structure i. Scheme 3a a derivative of benzene, such as 4-phenylcyclohexanone (v), functionalitywith to introduce the desired substituents on the cyclohexane ring. In the shown example the reaction Horner-Emmons or similar reaction the Wittig use, to enter the group α,βunsaturated complex ester, receiving compound vi (for example, reaction with a suitable phosphonate in the presence of a base such as sodium hydride in a solvent such as DMF or THF). Catalytic hydrogenation of compound vi by using, for example, palladium or platinum catalyst in a relatively polar solvent such as THF, methanol or an aqueous mixture containing an alcohol or THF as co-solvent, for example, used to restore the double bond, receiving the connection vii. The reaction of acylation Friedel-craft will then use to attach halogenoacetyl group to the phenyl ring of compound vii, forming the functionalized acetophenone (ix). Preferably, the leaving group in this sequence is Cl or Br. Suitable Lewis acid acylation include, for example, AlCl3, AlBr3, BCl3, TiCl4and the like; suitable solvents are well known and include CS2, nitrobenzene, dichloromethane and the like solvents, which are erections.possible in respect of reagents used and Lewis acids. Professionals need to take into account that there are also other methods of synthesis for the preparation of such intermediates, such as, for example, acylation metallizovannyh aromatic with the joining, such as ability or aryl-Grignard reagent, for example, allermuir agent such as N-methyl-N-methoxime (commonly referred to as Weinreb amide) derived Chloroacetic acid (see, for example, Nahm and Weinreb (1981) Tetrahedron Lett. 22:3815-3818) or suitable complex acylovir. Such methods provide an approach to other isomers of these functionalized derivatives of acetophenone.

Scheme 3a

Alternatively, compound vii can be alkylated by treatment with a base, such as diisopropylamide lithium or hexamethyldisilazide lithium in a suitable solvent, such as THF, followed by reaction with an alkylating agent such as alkylhalogenide, alkyl methanesulfonate, alkyl-triftorbyenzola or alkyl-toluensulfonate, to obtain the intermediate compound x (Scheme 3b). If desirable, the sequence can be repeated to obtain the intermediate compounds of General formula xi. The acylation of compound xi can be carried out as described above to obtain compound xii.

Scheme 3b

Similar approaches can be used to obtain other functionalized derivatives of acetophenone (see figure 3c). For example, 4-phenylcyclohexanone (v) can be converted into aldehyde in two herds and, when using the Wittig reaction with ethoxymethyleneamino in a suitable solvent, such as THF, DME or dioxane, to obtain a connection xiv, for example, with subsequent mild acid hydrolysis. Specified aldehyde can be converted to α,β-unsaturated ester by reaction with Wittig (carbomethoxy)methyltriphenylphosphonium in a suitable solvent. If desirable, the double bond can be restored by catalytic hydrogenation using palladium-on-carbon, for example, to obtain the compound xv. Suitable solvents for these reactions include hydrogenation ethanol or ethyl acetate. The acylation of compound xv to obtain a functionalized derivative of acetophenone (xvi) can be carried out as described above for the acylation of compound vii.

Diagram 3c

Diagram 3d illustrates the synthesis of other functionalized derivatives of acetophenone of General formula i, suitable for the synthesis of compounds according to this invention.

Diagram 3d

In scheme 3d phenyl group is injected with, for example, phenyl-Grignard reagent or finelite to obtain compound xiii. The functional group of carboxylic acid can be etherification in a hundred is at standard conditions, to obtain a connection of the nineteenth and the dehydration can be carried out using an acid catalyst such as acetic acid, chloromethane acid or triperoxonane acid, in a suitable solvent, such as chloroform or toluene, to obtain the compound xx. The restoration of the double bond of the cyclohexene can be carried out under conditions of catalytic hydrogenation usually using palladium as a catalyst, to obtain a compound xxi. This restoration gives a mixture of isomers (receive and CIS - and TRANS-disubstituted cyclohexane); if desirable, they can be separated or balanced using a base such as an alkoxide or DBU in methanol or toluene, to obtain, mainly, more thermodynamically stable TRANS-disubstituted isomer. The acylation of compound xxi to obtain functionalized acetophenone xxii is carried out, as described above.

Compounds according to this invention, which contain a heterocyclic ring W2can be synthesized by a similar sequence of reactions, provided that the heterocyclic ring is stable under the reaction conditions for the acylation. For example, the connection, where W2means acylated piperidine, can be synthesized in this way using functionality is consistent derivative of acetophenone, such as obtained by the sequence of reactions shown in scheme 3e. In this sequence, 4-hydroxy-4-phenylpiperidine (xxiii) alkylate, sulfonylurea or acelerou on the nitrogen atom using reagents and conditions known in the art (for example, by acylation diethyloxalate or heterocalixarenes in the presence of a mild base, such as triethylamine or pyridine)to obtain compound xxiv. N-functionalized (for example, N-acylated) connection then dehydration and restore catalytically as described above in scheme 3d, to obtain the amide oxalate 4 phenylpiperidine (xxv). This compound is then acelerou as described above to obtain the appropriate functionalityand derivatives of acetophenone (xxvi).

Scheme 3e

Similarly, phenylpiperazin xxvii can be alkylated, sulfonylureas or allerban on the nitrogen atom, to obtain N-functionalized compound xxviii, which, in turn, can be allyawan, as described previously, to obtain a functionalized derivative of acetophenone xxix.

Scheme 3f

Other compounds according to this invention, having a heterocycle as W2can be obtained by joining heterocyclic the koi group acetophenone, then halogenoalkanes of acetophenone α-the carbon atom to obtain a compound of General formula i, as shown in figure 3g. In this sequence, the compound 4-fortetienne (xxiv) are synthesized by acylation of fervently in typical conditions of the Friedel-craft, as described above. Then 4-vorgruppe subjected to aromatic nucleophilic substitution reactions; in the scheme it replaces the group of substituted piperidine derivatives by reacting with the nucleophilic piperidine in a polar aprotic solvent such as DMSO or DMF. Funktsionalizirovannyi on the carbon atom bearing R3and R4to obtain compounds xxvi can be carried out using, for example, bromine (Br2) or chlorine (Cl2) in a polar solvent such as DME or ethyl acetate, in the presence of an acid catalyst such as acetic acid or Hydrobromic acid.

Scheme 3g

Specific functionalityand derivatives of acetophenone, suitable for producing compounds according to this invention, where L1means of communication, can be obtained from the substituted acetophenone, especially when R3and R4are identical groups, as shown in figure 3h. For example, acetophenone, substituted-L2-W2(xxxiii)can be alkylated with alkylating agent, is how methyliodide, ethylbromide or other similar alkylating agent in the presence of a base, such as diisopropylamide lithium hexamethyldisilazide lithium or sodium hydride and a solvent such as DMF, DME, THF or toluene. This gives acetophenone, where R3and R4are the same. This acetophenone can then be galogenidov, as described above in scheme 3g to get the functionalized acetophenone of General formula i, which is subjected to condensation with substituted pyrimidines, as shown in scheme 1, to obtain the compounds according to this invention.

Scheme 3h

The preparation of the compounds according to the invention, which contain a heterocyclic ring W1can be synthesized using similar procedures, which are outlined in the diagram 3g. For example, substituted or unsubstituted a heterocycle xxxvi, such as furan, thiophene, pyrrole, oxazole, thiazole, imidazole or thiadiazole may be metallicafan lithium, for example, using utility or diisopropylamide lithium in a suitable solvent, such as THF, DME or dioxane. Metilirovannye varieties can be subjected to the reaction, for example, amidon, such as dimethylamide or N-methyl-N-methoxime to obtain acylated heterocycle xxxvii, which, in turn, MoE is et to be galogenidov, as described above, to obtain a functionalized derivative of acetophenone of General formula xxxviii. In this sequence substituted or unsubstituted benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole or benzothiadiazole (xxxix) can be metallicafan lithium and allerban to get the connection xl, which, in turn, can be galogenirovannami, as described previously. The specialist must take into account that other heterocycles can also be used in such transformations.

Scheme 3i

As shown in scheme 4, compounds of General formula iv with a substituted phenyl ring as W1 and substituted cyclohexane ring as L2-W2 (e.g., xlii)can be obtained from these substituted derivatives of acetophenone such ix.

Scheme 4

Compounds such as xlii, can be used to obtain other compounds of this invention, for example, hydrolysis of ethyl ether complex, to obtain a connection carboxylic acid xliii (scheme 5). Hydrolysis of ester can be carried out in most solvents, which dissolve the compound xlii and at least partially mixed with water, by treatment of a solution of the compound xlii aqueous base, such as hydroxide is the atrium or potassium hydroxide, for example. Carboxylic acid, in turn, can be converted into other groups, such as amide, by methods well known to the ordinary expert. For example, the carboxylic acid can be activated by condensation with different reagents mates, including hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSu), for example, with the use of dicyclohexylcarbodiimide (DCC) or similar carbodiimide reagent or a wide variety of reagents, such as those developed for the formation of peptide bonds. Conditions for such reactions are well known in the art. The activated intermediate connection, HOBt ester or HOSu, for example, can then be condensed with a wide variety of nucleophiles, such as amines, alcohols and thiols. Figure 5 shows the transformation of compounds of formula xlii in amide (xliv) on the specified sequence using ammonia as the nucleophile.

Scheme 5

Dehydration of amide xliv to nitrile (xlv) can be implemented in a variety of ways. Cm. scheme 5 above. The phosphorus pentoxide is the most common reagent degidrirovaniya for the specified reaction, but many other well-known specialists. Nitrile, in turn, can be converted into other groups, such as tetrazole (xlvi), ways well known to the ordinary expert. For example, the interaction of the nitrile with an azide such as sodium azide, lithium azide or attestation acid, in a solvent such as DMF or water, will perform this conversion.

Scheme 6a and 6b explain one approach to obtaining the compounds of formula I in which W1means the group of phenylene having additional substituents other than the L2-W2. As shown in scheme 6a, the intermediate bromoacetophenone xlvii can be nitrified in standard conditions (nitric acid, sulphuric acid in solvents such as chloroform, methylene chloride, acetic acid, or without dilution)to get xlviii. The restoration of the nitro group is carried dibromononane to get xlix, using catalytic hydrogenation or SnCl2(usually in an alcohol solvent). Substitution of chloride amino group is performed with the use of copper chloride in the presence of a suitable nitrite (for example, tert-butylnitrite, sodium nitrite) and solvent, to obtain the intermediate compounds such as l. Bromine can be re-introduced, providing a connection li, using standard conditions, the synthesized (for example, HBr/HOAc, Br2/N-bromosuccinimide or CuBr2). Alternatively, the connection xlvii can be directly chlorinated to obtain a connection li, using standard reagents (for example, sulfurylchloride, Cl2or N-chlorosuccinimide) and the conditions known to the expert.

Scheme 6a

Scheme 6b explains the improvement of intermediate compounds, such as xlix other substituted compounds. For example, the compounds of formula lii (where X10means (F) can be obtained from compound xlix using fluorination reagents, such as tetrafluoroborate microzone, DAST, HF or CsF (usually in solvents such as toluene, benzene, methylene chloride or dichloroethane). Subsequent bromination of compounds lii for connection liii can be carried out according to known methods. The transformation or compounds of li, or liii in the target compounds of formula liv is performed via condensation with a suitably substituted pyrimidine (see example 1).

Scheme 6b

As shown in scheme 7, compounds according to this invention, where X represents N, Y represents CH, Z denotes O and W1means substituted or unsubstituted aryl or heteroaryl, can be obtained from suitably substituted pyrimidine lv (where A denotes halogen, such as, Br, I or triflate or other suitable Deputy, known to specialists), and substituted or unsubstituted derivative of the aryl or heteroaryl lvi (where M means B(OR ), Sn(R3or other suitable metal known in the art), for example, catalyzed by palladium reaction cross combination. Professionals should also take into account that a and M can be used interchangeably.

Scheme 7

Scheme 8 illustrates the method of obtaining the intermediate compounds of General structure lv. Condensation pyrimidine lviii connection lvii in a suitable solvent, such as acetic acid, gives compound lix. The transformation of the hydroxy-group into a leaving group, e.g. chloride or bromide, for example, with phosphorus oxychloride or oxybromide phosphorus, respectively, accompanied by displacement of the leaving group suitably substituted amine to obtain the compound lv.

Scheme 8

Compounds

In another aspect this invention relates to pharmaceutical compositions for modulating the activity of DGAT in humans and animals, the compositions will usually contain the compound of formula I and pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions for administration of the compounds according to this invention can typically be represented in a uniform dosage form and may be prepared by any means well known in pharmacy. All methods include the stage of merge is of the active ingredient with the carrier, which is formed by one or more accessory ingredients. Typically, the pharmaceutical compositions are prepared homogeneous and close Association the active ingredient with liquid carriers or finely ground solid carriers or both and then, if necessary, by giving the desired product form. In the pharmaceutical composition the active target compound is administered in a quantity sufficient to obtain the desired effect on the course of the disease or condition.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, in the form of tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the production of pharmaceutical compositions. Such compositions can contain one or more agents selected from podslushivala, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically classy and acceptable to the taste of the drugs. Tablets contain the active ingredient in a mixture with other non-toxic pharmaceutically acceptable excipient and, which are suitable for the manufacture of tablets. Such fillers can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or gum acacia, and lubricating agents, e.g. magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known technologies to delay disintegration and absorption in the digestive tract and thereby provide a prolonged action over a longer period. For example, there may be used the material for a time delay, such as glycerylmonostearate or glycerylmonostearate. They can also be coated by the techniques described in U.S. patent No. 4256108, 4166452 and 4256874 to get the osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water is whether oily environment, for example, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in a mixture with excipients suitable for the preparation of aqueous suspensions. Such fillers are suspendresume agents, for example, sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum acacia; dispersing or wetting agents can be found in the nature of phosphated, for example, lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene stearate, or products consensii of ethylene oxide with long chain aliphatic alcohols, for example, heptadecafluorooctane, or products consensii of ethylene oxide with partial esters derived from fatty acids and exit, such as monooleate of polyoxyethylenesorbitan, or products consensii of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, for example, monooleate polyethylene-sorbitan. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, n-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more podslushivaet the x agents such as sucrose or saccharin.

Oily suspensions may be prepared by suspendirovanie active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyloxy alcohol. Sweetening agents such as those described above, and flavoring agents may be added to provide acceptable taste oral drug. These compounds may be protected from damage by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspendida agents are those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be submitted.

The pharmaceutical compositions according to the present invention can also be in the form of emulsions of the type oil-in-water. The oil phase may is be vegetable oil, for example, olive oil or peanut oil, or mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or tragacanth gum, naturally occurring phosphatides, for example soy, lecithin, and esters or partial esters derived from fatty acids and anhydrides of exit, for example, monooleate sorbitan, and condensation products of these partial esters with ethylene oxide, for example, monooleate polyoxyethylene-sorbitane. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs can be prepared with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain a demulsifier, a preservative and flavoring and coloring agents.

The pharmaceutical compositions can be in the form of a sterile aqueous or oily suspension for injection. Such suspension may be prepared according to known techniques using suitable dispersing or wetting agents and suspendida agents which have been mentioned above. A sterile preparation for injection may also be a sterile solution or suspension for injection in a non-toxic parenterally in memom diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents can be used water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as solvent or suspendida environment. For this purpose, can be used with any soft non-volatile oil containing synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of compositions for injection.

Compounds according to this invention can also be introduced in the form of suppositories for rectal administration of medication. These compounds may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For local applications use the patches, creams, ointments, jellies, solutions or suspensions, etc. containing compounds according to this invention. As used herein, topical application involves the inclusion of the application of the wash and rinse for the mouth.

Pharmaceutical composition and method according to this invention can more the tion to contain other therapeutically active compounds, as noted here, which are usually applied for the treatment of the above-mentioned pathological conditions.

Applications

In another aspect, the invention relates to a method of applying a compound or composition according to the invention for the treatment or prevention of a disease or condition associated with DGAT. Diseases and conditions associated with lipid metabolism and cell proliferation, and their complications can be treated by the proposed compounds and compositions. In one group, variants, diseases and conditions, including chronic diseases, of humans or other representatives who may be subjected to treatment with inhibitors of DGAT function, include, but are not limited to, metabolic disorders such as obesity, diabetes, anorexia nervosa, bulimia, homosocial, syndrome X, insulin resistance, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia and disease nonalcoholic fatty infiltration of the liver; cardiovascular diseases such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina, hypertension, hypotension, stroke, ischemia, isemi the mini-reperfusion injury, aneurysm, restenosis, and vascular stenosis; pathological lesions, such as solid tumors, skin cancer, melanoma, lymphoma and varieties of endothelial cancer, for example breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the digestive tract (for example, esophageal cancer and pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer, and other diseases and conditions that are sensitive to modulation of DGAT function or amenable to its influence.

Methods according to this invention typically involve the administration to a subject in need of treatment an effective amount of the compounds of formula (I). Dose, frequency and timing of this introduction will depend largely on the selected therapeutic agent, the nature of the condition which requires treatment, the condition of the subject, including age, weight and the presence of other conditions or disorders of the input part and the decision of the attending physician. Preferably, the compositions and compounds according to the invention and their pharmaceutically acceptable salts are administered orally, parenteral or local way. Usually the connection is injected in doses ranging from about 2 mg up to about 2000 mg per day, although the changes necessarily the Udut depending as noted above, the target disease, the patient and route of administration. The preferred dose administered orally in the range from about 0.05 mg/kg to about 20 mg/kg, more preferably in the range from about 0.05 mg/kg to about 2 mg/kg, most preferably in the range from about 0.05 mg/kg to about 0.2 mg/kg of body weight per day. The dose used for local administration, of course, will depend on the size of the area requiring treatment.

Combination therapy with an additional active agents

The invention additionally relates to a method of applying a compound or composition according to the invention in combination with one or more additional active agents depending on the desired target therapy (see for example, Turner, N. et al. Prog. Drug Res. (1998) 51: 33-94; Haffner, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Some studies are devoted to the use of the methods of combination therapy agents for oral administration (see, for example, Mahler, R., J. Clin. Endocrinol. Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, C. W. (ed.), Current Therapy in Endocrinology and Metabolism, 6thEdition (Mosby - Year Book, Inc., St. Louis, MO 1997); Chiasson, J. et al., Ann. Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin. Ther. (1997) 19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. et al., Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol. (1998) 82 (12A): 3U-17U).

In particular, the above-mentioned studies which have the correction of diabetes and hyperlipidemia can be further improved in many cases by adding a second agent to therapeutic regime. Combination therapy involves the introduction of a single pharmaceutical dosage composition which contains a compound having the General structural formula I, and one or more additional active agents, as well as the introduction of the compounds of formula I and each active agent in its own separate pharmaceutical dosage formulation. For example, the compound of formula I and an inhibitor of HMG-CoA reductase can be entered together in a single dosage composition for oral administration such as tablet or capsule, or each agent can be introduced in a separate dosage formulations for oral administration. When using separate dosage formulations, the compound of formula I and one or more additional active agents can be introduced essentially in one and the same time (i.e. simultaneously or separately in alternating moments of time (i.e. sequentially). It is implied that combination therapy contains all of the specified modes.

An example of combination therapy that modulates (prevents start of the symptoms or complications associated with) atherosclerosis, provides for the introduction of connection forms the crystals I in combination with one or more of the following active agents: an antihyperlipidemic agent; the agent that increases the levels of plasma HDL; antihypercholesterolemic agent, such as an inhibitor of the biosynthesis of cholesterol, for example, the inhibitor hydroxymethylglutaryl(HMG)CoA reductase inhibitor (also related to the statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin), an inhibitor synthase HMG-CoA, an inhibitor of squalene-epoxidase or inhibitor of squalene synthetase (also known as an inhibitor of squalene synthase); inhibitor of acyl-coenzyme a cholesterol acyltransferase (ACAT), such as melinamide; probucol; nicotinic acid and its salts and Niacinamide; inhibitor of cholesterol absorption, such as β-sitosterol; anion-exchange resin that binds bile acids, such as cholestyramine, colestipol or dialkylaminoalkyl-derived transverse cross-linked dextran; an inductor receptor LDL (low density lipoprotein); fibrates, such as clofibrate, bezafibrat, fenofibrate, and gemfibrozil; vitamin B6(also known as pyridoxine) and its pharmaceutically acceptable salts such as HCl salt; vitamin B12(also known as cyanocobalamin); vitamin B3(also known as nicotinic acid and Niacinamide, supra); anti-oxidant vitamins such as vitamin C and E and beta carotene; beta-blocker; an antagonist of angiotensin II; angiotensin-converting enzyme and inhibitor AGR the delegation of platelets, such as receptor antagonists of fibrinogen (e.g., antagonists of glycoprotein fibrinogen receptor IIb/IIIa) and aspirin. As noted above, the compounds of formula I can be introduced in combination with more than one additional active agent, for example, the combination of the compounds of formula I with an inhibitor of HMG-CoA reductase (e.g., lovastatin, simvastatin and pravastatin) and aspirin, or a compound of formula I with an inhibitor of HMG-CoA reductase and β-blocker.

Another example of combination therapy can be considered for the treatment of obesity or related to obesity disorders, where the compounds of formula I can be effectively used in combination with, for example, phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine, dexfenfluramine, fentermina, agents-agonists β3-adrenergic receptors; sibutramine, gastrointestinal lipase inhibitors (such as orlistat) and latinae. Other agents used in the treatment of obesity or related to obesity disorders, can be used in combination with compounds of formula I, including, for example, neuropeptide Y, enterostatin, cholecytokinin, bombezin, Amylin, receptors of histamine H3the receptors of dopamine D2the melanocyte-stimulating hormone, factor release corticotropin, Galanin and gamma and anomalina acid (GABA).

Another example of combination therapy can be considered for modulating diabetes (or treating diabetes and its related symptoms, complications, and disorders), where the compounds of formula I can be effectively used in combination with, for example, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, gliburid, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as Metformin), preparations of thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone and rosiglitazone); dehydroepiandrosterone (also referred to as as DHEA or its conjugated ester sulfate, DHEA-SO4); antiglucocorticoids; inhibitors of TNFα; inhibitors α-glucosidase (such as acarbose, miglitol and voglibose), pramlintide (a synthetic analogue of Amylin hormone human), other agents that stimulate insulin secretion (such as Repaglinide, gaidon and nateglinide), insulin, as well as the active agents discussed above for treating atherosclerosis.

Still another example of combination therapy can be considered for modulating hyperlipidemia (treatment of hyperlipidemia and its related complications), where the compounds of formula I can be effectively used in combination, for example, statins such as fluvastatin, lovastatin, pravastatin sludge is simvastatin), resins that bind bile acids (such as colestipol or cholestyramine), nicotinic acid, probucol, beta carotene, vitamin E or vitamin C.

In accordance with this invention, therapeutically effective amounts of compounds of formula I can be used for the preparation of a pharmaceutical composition suitable for treating diabetes, treating hyperlipidemia, treating hyperuricemia, obesity, lower levels of triglycerides, lower cholesterol levels, increased levels of plasma high density lipoprotein, and for treating, preventing or reducing the risk of developing atherosclerosis.

An additional example of combination therapy can be considered for modulating dermatological conditions where the compounds of formula I can be effectively used in combination, for example, with means for the treatment of acne (e.g., isotretinoin, doxycycline, tetracycline, salicylate) and means to ensure sebrango dermatitis (antifungal agents such as climbazole, ketoconazole). Moreover, the compounds of formula I can be effectively used to enhance percutaneous drug delivery, applied topically in the form of a patch, lotion, jelly, cream, etc.

Another example of combination therapy can be considered for Les is is possible disease nonalcoholic fatty infiltration of the liver (NAFLD), where the compounds of formula I can be effectively used in combination with hepatoprotective agents, such as ursodeoxycholic acid and betaine.

Additionally, an effective amount of the compounds of formula I and a therapeutically effective amount of one or more active agents selected from the group consisting of such agents, as antihyperlipidemic agent; an agent that increases the levels of plasma HDL; antihypercholesterolemic agent, such as an inhibitor of the biosynthesis of cholesterol, for example, an inhibitor of HMG-CoA reductase, inhibitor synthase HMG-CoA, an inhibitor of squalene-epoxidase or inhibitor of squalene synthetase (also known as an inhibitor of squalene synthase); inhibitor of acyl-coenzyme a cholesterol-acyltransferase; probucol; nicotinic acid and its salts; Niacinamide; inhibitor of cholesterol absorption; anion-exchange resin that binds bile acids; inductor receptor low-density lipoprotein; clofibrate, fenofibrate, and gemfibrozil; vitamin B6and its pharmaceutically acceptable salt; vitamin B12; antioxidant vitamin; β-blocker; an antagonist of angiotensin II; angiotensin-converting enzyme; inhibitor of platelet aggregation; receptor antagonist of fibrinogen; aspirin; fenteramine; agonists β3adrenergic receptor; sulfanilic the guilt, biguanides, inhibitors α-glucosidase, other agents that stimulate insulin secretion; insulin and hepatoprotective agent, can be used together for the preparation of a pharmaceutical composition applicable for the above treatment methods.

EXAMPLES

Range1H-NMR were recorded on a NMR spectrometer Varian Gemini 400 MHz, Jeol Alpha 300 MHz, Bruker DPX 300 MHz Varian Mercury 400 MHz or Bruker Avance 500 MHz. Indicative peaks are tabulated, and they usually include the number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, Quartet; m, multiplet; users, broadened singlet) and a constant (constant) binding in Hertz. IR spectrum was recorded on a spectrometer Perkin Elmer 1600 FT-IR or a Perkin Elmer Spectrum One FT-IR. The results of mass spectrometry are presented as the ratio of mass-to-charge, accompanied by a relative totality of each ion (in parentheses). Starting materials in the examples of synthesis below or available from commercial sources such as Aldrich Chemical Co., Milwaukee, Wisconsin, USA, or by procedures described in the literature. Abbreviations used in the examples below, have their generally accepted in the chemical literature values. For example, THF (tetrahydrofuran), Et2O (simple diethyl ether), MeOH (methanol), LDA (diisopropylamide lithium), MeCN (acetonitrile), DMAP (4-dimethylaminopyridine), WSC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), HOBt (1-hydroxine striatal), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DME (1,2-dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), AcOH (acetic acid) and AcOEt (ethyl acetate). Other common abbreviations are used herein: for example, a methyl group is often referred to as the unlabeled end "communication", according to the accepted practice.

Example 1

This example explains the connection is indicated by Example 1.

To a suspension of 4,5-diamino-6-hydroxypyrimidine (1.0 g, to 7.93 mmol) and 4-bromophenethylamine (2.2 g, to 7.93 mmol) in EtOH (20 ml) is added NaHCO3(666 mg, of 7.93 mmol) and the mixture stirred for 1.5 h at 80°C. After cooling, the reaction mixture was concentrated and the residue diluted with CHCl3(40 ml). After filtering off the insoluble material, the filtrate concentrated. The residue is triturated with toluene, obtaining the desired compound of Example 1 (840 mg) as a pale yellow crystal, so pl.: >200°C. IR (cm-1): 3291, 3145, 1634, 1586, MS (ESI+): 305, 307 (100),1H NMR (DMSO-d6, 400 MHz): 5,44 (s, 2H), 7,10 (users, 2H), 7,69 (d, 2H, J=8.6 Hz), to 7.93 (s, 1H), 8,03 (d, 2H, J=8.6 Hz).

Examples 1-2 to 1-37:

Compounds shown in table 1, receive the same manner as in example 1.

Example 2

This example explains the connection is indicated by Example 2.

a)

When 0°C to a solution of triethylphosphine the Tata (2,6 ml, 12,91 mmol) in DMF (5.5 ml) is added in portions sodium hydride (60% in oil, 517 mg, 12,91 mmol) and the reaction mixture was stirred at room temperature for 30 minutes, Add a solution of 4-phenylcyclohexanone in DMF (2.0 ml). After stirring for 0.5 h the mixture was poured into 5% aqueous solution of KHSO4(10 ml) and extracted with a simple diethyl ether (10 ml). The organic layer is washed successively with water (5 ml) and saturated salt solution (5 ml), dried over MgSO4and concentrate. The residue is purified column chromatography (hexane/AcOEt=7/1)to give compound 2 (2.0 g) as a colourless oil.

b)

To a stirred solution of compound 2 (500 mg, 2.05 mmol) in EtOH (5 ml) is added 10% Pd/C (50 mg). The mixture is stirred at room temperature for 1 h under atmospheric pressure of hydrogen. The catalyst was removed by filtration and the filtrate concentrated in vacuum to give crude compound 3 (491 mg) as a colourless oil, which was used for next reaction without further purification.

c)

When 0°C to a solution of compound 3 (271 mg, 1.10 mmol) in CH2Cl2(1,4 ml) add portions of anhydrous AlCl3(440 mg, 3,30 mmol) and then added dropwise 2-bromoisobutyrate (0,14 ml, 1.10 mmol). After stirring for 1 h at 0°C the mixture was poured into the remote control with ice and extracted with CHCl 3(5 ml). The combined organic layer is washed sequentially with saturated NaHCO3(5 ml) and saturated salt solution (5 ml), dried over MgSO4and concentrate. The residue is purified column chromatography (hexane/AcOEt=7/1)to give compound 4 (402 mg) as a colourless oil.

d)

4,5-Diamino-6-hydroxypyrimidine (63,1 mg, 0.50 mmol) is mixed with 1H. aqueous HCl (to 0.50 ml, 0.50 mmol), water (2 ml) and EtOH (2 ml) and compound 4 (395 mg, 1.00 mmol) in EtOH (2 ml). The reaction mixture is refluxed (105° (C) within 12 hours, the Reaction mixture was concentrated to half volume. The residue was adjusted to pH 9-10 2n. aqueous solution of NaOH. The resulting mixture was extracted with AcOEt (5 ml). The aqueous layer was adjusted to pH 3-4 with 10% aqueous citric acid, extracted with AcOEt (5 ml). The organic layer was washed with water (5 ml) and saturated salt solution (5 ml), dried over MgSO4. Evaporation of the solvent gives the crude compound of Example 2 (54 mg, mixture of CIS - and TRANS-isomers). The first organic layer washed with water (5 ml) and saturated salt solution (5 ml), dried over MgSO4. Evaporation of the solvent gives the crude compound 5 (126 g, mixture of CIS - and TRANS-isomers), which is used for the next reaction without further purification. To a solution of crude compound 5 in EtOH (1.2 ml), THF (1.8 ml) and water (1.2 ml) is added 2n. an aqueous solution of NaOH(0.45 ml) after stirring at 40° C for 4 h, the Reaction mixture was concentrated to half volume and added to water (2 ml) and washed with AcOEt (2 ml). The aqueous layer was adjusted to pH 3-4 with 10% aqueous citric acid and extracted with AcOEt (5 ml). The organic layer was washed with water (5 ml) and saturated salt solution (5 ml), dried over MgSO4. Evaporation of solvent gives a white solid (113 mg). White solid (113 mg) and the crude compound of Example 2 (54 mg) are combined and subjected to recrystallization from EtOH, receiving the compound of Example 2 (92 mg, TRANS-isomer) as a white crystal, so pl.: >270°C. IR (cm-1): 3320, 2929, 1702, 1601, MS (ESI+): 395 (100).1H NMR (DMSO-d6, 300 MHz): 1,10-of 1.16 (m, 2H), 1,45-of 1.84 (m, 13H), of 2.15 (d, 2H, J=6.0 Hz), of 2.54 (m, 1H), 6,97 (users, 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,94 (s, 1H), 11,95 (users, 1H),

Example 2-2:

To a solution of compound of Example 2 (80 mg, 0.20 mmol) in DMF (2.4 ml) is added HOBt-H2On (34,2 mg, 0.22 mmol), EDC-HCl (42,8 mg, 0.22 mmol) and 28% aqueous ammonia solution (0.04 ml, 0.81 mmol). The reaction mixture was stirred at room temperature for 70 hours, the Mixture was poured into saturated aqueous solution of NaHCO3and extracted with AcOEt (3 ml). The organic layer is washed successively with water (3 ml × 2), saturated NaHCO3(3 ml) and saturated salt solution (3 ml), dried over MgSO4. Evaporation of solvent gives a white solid (69,5 mg). Tortoiseshell suspended with EtOH, receiving a connection Example 2-2 (48,2 mg) as a white crystal, so pl.: 224-226°C. IR (cm-1): 3348, 2923, 1672, 1604. MS (ESI+): 394 (100).1H NMR (DMSO-d6, 400 MHz): 1,03-1,22 (m, 8H), 1,4-1,49 (m, 2H), 1.70 to to 1.82 (m, 5H), and 2.14 (d, 2H, J=6.9 Hz), of 2.54 (m, 1H), 4,11 (users, 1H), 5,27 (users, 1H), 6,23 (users, 2H), 7,25 (d, 2H, J=8.0 Hz), was 7.36 (d, 2H, J=8.0 Hz,), to 7.61 (s, 1H), 11,75 (users, 1H).

Example 2-3:

When 0°C to a solution of compound of Example 2 (120 mg, 0.30 mmol) in THF (3.6 ml) and MeOH (3.6 ml) is added by portions NaBH4(194 mg, a 4.86 mmol) and the reaction mixture stirred at 0°C for 20 h 2H. an aqueous solution of NaOH (0,46 ml of 0.91 mmol) is added and stirred for 30 min at 60°C. the Reaction mixture was concentrated to half volume. The residue added to water (3 ml) and washed with AcOEt (3 ml). The aqueous layer was adjusted to pH 3-4 with 10% aqueous citric acid solution, extracted with AcOEt (5 ml). The organic layer was washed with water (5 ml) and saturated salt solution (5 ml), dried over MgSO4. Evaporation of solvent gives a white solid (150 mg). The solid is subjected to recrystallization from EtOH, receiving a connection Example 2-3 (97 mg) as a white crystal, TPL: 274-279°C (decomposes). IR (cm-1): 3414, 2927, 1650, 1595. MS (ESI+): 397 (100).1H NMR (DMSO-d6, 300 MHz): 1,02-1,17 (m, 2H), 1,40-of 1.53 (m, 2H), 1.61 of (s, 6H), 1,66-to 1.87 (m, 5H), to 1.98 (d, 2H, J=7,1 Hz), 2,53 (m, 1H), 6,67 (users, 1H), 6.89 in (users, 2H), 7,21 (users, 1H), 7,30 (d, 2H, J=8.1 Hz), 7,63 (d, 2H, J=8,1 G IS), 7,94 (s, 1H).

Example 2-4:

a)

To a stirred suspension of chloride methoxybutyrophenone (3,14 g, 9.2 mmol) in THF (8 ml) is added tert-piperonyl potassium (516 mg, 4.6 mmol) in an atmosphere of Ar. After 1 h the solution was added 4-phenylcyclohexanone (1) (400 mg, 2.3 mmol). The mixture is stirred for 1 h at room temperature, then heated overnight at 70°C. After cooling, the reaction mixture was poured into saturated NaHCO3(40 ml) and extracted with simple ether (50 ml). The organic extract was washed with water (40 ml) and saturated salt solution (40 ml) and dried over Na2SO4and the solvent is removed, give crude compound 7 (2,19 g), which is used in the next stage without additional purification.

b)

The crude compound 7 (2,19 g) is mixed with 80% aqueous AcOH solution (25 ml) and heated at 70°C for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure. The residue is purified column chromatography (hexane/AcOEt=20/1)to give compound 8 (395 mg) as a colourless oil.

c)

To a stirred solution of compound 8 (383 mg, 2.03 mmol) in toluene (20 ml) is added DBU (365 μl, of 2.44 mmol) and the mixture is heated at 80°C for 5 h in an atmosphere of Ar. Then to the reaction mixture add meth is l(triphenylphosphonium) acetate (1.2 g, of 3.05 mmol) and the mixture is stirred over night at 100°C. After cooling, the reaction mixture is washed with 5% KHSO4(10 ml), saturated NaHCO3(10 ml) and saturated salt solution (10 ml) and the organic layer dried over Na2SO4and concentrate. The residue is purified column chromatography (hexane/AcOEt=20/1)to give compound 9 (474 mg) as a colourless oil.

d)

A suspension of 10% palladium-on-coal (50 mg) in a solution of the compound (9) (474 mg, 1.94 mmol) in EtOH (15 ml) hydronaut under atmospheric pressure of hydrogen overnight at room temperature. The reaction mixture is filtered and the filtrate is concentrated and receiving connection 10 (436 mg) as a colourless oil which is sufficiently pure for use in the next stage without additional purification.

e)

Analogously to example 2, based on the connection 10 in the amount of 436 mg (1.94 mmol), get a connection Example 2-4 (231 mg) as a colorless crystal, so pl.: >250°C. IR (cm-1): 3310, 2922, 1702, 1611. MS (ESI+): 409 (100).1H NMR (DMSO-d6, 400 MHz): 1,04-of 1.09 (m, 2H), USD 1.43 (m, 1H), 1,43 of 1.50 (m, 4H), to 1.60 (s, 6H), 1,83 (userd, 4H, J=11,4 Hz in), 2.25 (t, 2H, J=7,7 Hz)of 2.50 (m, 1H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H), 11,84 (users, 1H).

Example 2-5:

Analogously to Example 2-2, based on the connection PR is a measure 2-4 in the amount of 50 mg (0.12 mmol), get a connection Example 2-5 (41 mg) as a colorless crystal, so pl.: 244-246°C. IR (cm-1): 3357, 2920, 1696, 1602. MS (ESI+): 408 (100).1H NMR (DMSO-d6, 400 MHz): 1,04-1,08 (m, 2H), 1,29 (m, 1H), 1,40-1,49 (m, 4H), to 1.60 (s, 6H), 1,83 (userd, 4H, J=10,2 Hz), is 2.09 (t, 2H, J=7.4 Hz), 2,50 (m, 1H), 6,60 (users, 1H), 6,88 (users, 2H), 7,20 (users, 1H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H).

Example 2-6:

Analogously to Example 2-3, based on the compound of Example 2-4 in the amount of 38 mg (0.09 mmol), get a connection Example 2-6 (19 mg) as a colorless crystal, so pl.: >250°C. IR (cm-1): 3348, 2922, 1638, 1595. MS (ESI+): 411 (100).1H NMR (DMSO-d6, 400 MHz): 1,04-of 1.09 (m, 2H), only 1.08 (s, 3H), 1,22 (s, 3H), 1,32 (m, 1H), USD 1.43 to 1.48 (m, 4H), 1,83 (userd, 4H, J=10,7 Hz), 2,24 (t, 2H, J=7,7 Hz)of 2.50 (m, 1H), 4,11 (s, 1H), 5,26 (s, 1H), 6.22 per (users, 2H), of 7.23 (d, 2H, J=8.1 Hz), 7,35 (d, 2H, J=8.1 Hz), a 7.62 (s, 1H), 11,73 (users, 1H).

Example 2-7:

a)

Compound 11 (3 ml, 18,82 mmol) and 30 ml of ethanol and NaOH solution is stirred together at room temperature for 3 hours the Solvent then removed in vacuo and add 12 ml of 2M HCl solution. The aqueous layer was extracted with 25 ml of AcOEt and the extract is washed with saturated salt solution, dried over MgSO4and concentrated in vacuo give crude compound 12, which is used for the next reaction without further purification.

b)

To peremeshivaemogo crude compound 12 (of 1.594 g, approximately, 11,21 mmol) in 15 ml THF added to 1.0 M PhMgBr (24,7 ml of 24.7 mmol) at 0°C and stirred for 30 minutes After adding 10 ml of water, the mixture acidified with 1M HCl solution. The aqueous layer was extracted with 30 ml of AcOEt and the extract is washed with saturated salt solution, dried over MgSO4and concentrated in vacuo give crude compound 13, which is used for the next reaction without further purification.

c)

To a stirred suspension of crude compound 13 and K2CO3(2,01 g, 14.5 mmol) in 10 ml DMF added MeI (0,98 ml, 15.7 mmol) and stirred for 3 hours After adding 15 ml of water, the aqueous layer was extracted with 25 ml of AcOEt and the extract is washed with water and saturated salt solution, dried over MgSO4and concentrated in vacuo give crude compound 14, which is used for the next reaction without further purification.

d)

The crude compound 14, 15 ml of CHCl3, triperoxonane acid (3,02 ml, to 39.4 mmol) and triethylsilane (3,02 ml of 22.5 mmol) is stirred together at 65°C for 5.5 h After adding 25 ml of water the organic layer is separated, washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (hexane/AcOEt=10/1)to give compound 15 (1.5 g) as pale yellow is the asle.

e)

To a stirred solution of compound 15 (1.5 g, 6,94 mmol) in 15 ml MeOH added 10% Pd/C (240 mg). The mixture is stirred at room temperature for 5 hours under atmospheric pressure of hydrogen. The catalyst was removed by filtration and the filtrate concentrated in vacuum to give crude compound 16, which is used for the next reaction without further purification.

f)

The crude compound 16 and 10 ml of MeOH and 28% MeONa (1.5 ml, 7,3 mmol, solution in methanol) is stirred together at 70°C for a period of 7.5 hours After adding water (30 ml) the aqueous layer was extracted with 40 ml of AcOEt and the extract is washed with water and saturated salt solution, dried over MgSO4and concentrated in vacuo give crude compound 17 in the form of a mixture of diastereoisomers (ratio 4:1), which is used for the next reaction without further purification.

g)

Analogously to Examples 2-c and 2-d), based on the connection 17 in the amount of 69 mg (0.55 mmol), get a connection Example 2-7 (54 mg) as a colorless crystal, so pl.: >250°C. IR (cm-1): 3328, 2931, 1704, 1615. MS (ESI+): 381 (100).1H NMR (DMSO-d6, 400 MHz): 1,40 is 1.58 (m, 4H), to 1.61 (s, 6H), 1,82-of 1.92 (m, 2H), 1,97-of 2.08 (m, 2H), 2,24-of 2.36 (m, 1H), 2,52-2,61 (m, 1H), 6,91 (users, 2H), 7,31 (d, 2H, J=8.6 Hz), the 7.65 (d, 2H, J=8.6 Hz), 7,95 (s, 1H), 11,92 (users, 1H).

Examples 2-8 to 2-268:

Connections on Azania in table 2, get in the same way as in examples 2 to 2-7.

Example 3

a)

To a stirred solution of 4-hydroxy-4-phenylpiperidine (18) (1,00 g, 5,64 mmol) and Et3N (0,94 ml, 6,77 mmol) in 10 ml of CHCl3add ethyl-oxalicacid (0.63 ml, 5,64 mmol) at 0°C and stirred for 1 h After adding 10 ml of water the organic layer is separated, dried over MgSO4and concentrated in vacuo give crude compound 19, which is used for the next reaction without further purification.

b)

The crude compound 19, 10 ml of CHCl3, triperoxonane acid (1,52 ml of 19.7 mmol) and triethylsilane (of 1.52 ml, 11.3 mmol) is stirred together at 65°C for 1.5 hours After adding 15 ml of water the organic layer is separated, washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (hexane/AcOEt=9/1)to give compound 20 (1,38 g) as a pale yellow oil.

c)

To a stirred solution of compound 20 (1,38 g, 5,32 mmol) in 8 ml of MeOH added 10% Pd/C (200 mg). The mixture is stirred at room temperature for 5 hours under atmospheric pressure of hydrogen. The catalyst was removed by filtration and the filtrate concentrated in vacuum to give crude compound 21 to the e used for the next reaction without further purification.

d)

Analogously to examples 2-c and 2-d), based on the connection 21 in the amount of 58 mg (0.46 mmol), get a connection Example 3 (20 mg) as a colorless crystal, so pl.: to 188.8-190,9°C, IR (cm-1): 1618, 1460, 1440. MS (ESI+): 410 (100).1H NMR (DMSO-d6, 400 MHz): 1,46-to 1.67 (m, 2H), and 1.6 (s, 6H), 1,81-of 1.94 (m, 2H), 2,72 are 2.98 (m, 2H), 3,21-to 3.34 (m, 1H), 3,63-3,71 (m, 1H), 4,34-to 4.46 (m, 1H), 6,98 (users, 2H), 7,33 (d, 2H, J=8,4 Hz), to 7.67 (d, 2H, J=8.4 and Hz), 7,95 (s, 1H).

Example 3-2 to 3-3:

Compounds shown in table 3, receive the same manner as in example 3.

Example 4

a)

Torbenson (1,78 ml, 18,96 mmol), aluminum chloride (2,53 g, 18,96 mmol) and isobutylene (1.0 ml, 9,48 mmol) is mixed in an Ar atmosphere and the mixture is stirred at room temperature for 1 h, the Reaction mixture was poured into ice water with stirring and extracted with simple ether (50 ml). The organic extract was washed with saturated NaHCO3(30 ml) and saturated salt solution (30 ml) and dried over Na2SO4and the solvent is removed, receiving the connection 23 (1.47 g) as a colourless oil which is sufficiently pure for use in the next stage without additional purification.

b)

To a solution of compound 23 (50 mg, 0.30 mmol) in DMSO (0.5 ml) is added piperidine (119 μl, 1.2 mmol) and the mixture is heated at 140°C is for 5 h in an atmosphere of Ar. After cooling, the reaction mixture is diluted with simple ether (10 ml) and washed with 5% KHSO4(10 ml), water (10 ml) and saturated salt solution (10 ml). The organic layer is dried over Na2SO4and the solvent is removed, receiving the connection 24 (65 mg) as a colourless oil which is sufficiently pure for use in the next stage without additional purification.

c)

To a solution of compound 24 (64 mg, 0.28 mmol) in DME (1 ml) add 25% HBr-AcOH (100 μl, 0.31 mmol) and Br2(a 15.7 μl, 0.31 mmol) successively and the mixture is stirred at room temperature for 30 minutes To the reaction mixture of 4,5-diamino-6-hydroxypyrimidine (17.5 mg, 0.14 mmol), 1H. HCl (140 μl, 0.14 mmol), EtOH (1 ml) and water (1 ml) and the mixture refluxed overnight. After cooling, the EtOH is removed under reduced pressure and the residue was diluted with AcOEt (10 ml) and washed with 1N. NaOH (10 ml) and saturated salt solution (10 ml). The organic layer is dried over Na2SO4and concentrate. The residue is purified by thin-layer chromatography, using as eluent CHCl3-MeOH (9:1)to give compound of Example 4 (40 mg) as a pale yellow crystal, so pl.: 191-193°C. IR (cm-1): 3318, 2933, 1606, 158. MS (ESI+): 338 (100).1H NMR (DMSO-d6, 400 MHz): 1,58-of 1.62 (m, 6H), of 1.62 (s, 6H), 3,26 (users, 4H), 6,79 (users, 2H), 7,29 (d, 2H, J=9.0 Hz), 7,63 (d, 2H, J=9.0 Hz), to $ 7.91 (s, H).

Example 4-2 to 4-7:

Compounds shown in table 4, receive the same manner as in example 4.

Example 5

a)

3-Chloracetophenone (0.5 ml, of 3.85 mmol), powdered KOH (2.16 g, a 38.5 mmol), 18-crown-6 (102 mg, 0,385 mmol), methyliodide (1,92 ml, for 30.8 mmol) and 12 ml of toluene is stirred together at room temperature for 3 days. After adding 30 ml of water, the aqueous layer was extracted with 20 ml of AcOEt and the extract is washed with saturated salt solution, dried over MgSO4and concentrated in vacuo give crude compound 27, which is used for the next reaction without further purification.

b)

Analogously to Example 4, based on the connection 27 in the amount of 60 mg (0.47 mmol), get a connection Example 5 (40 mg) as a colorless crystal, so pl.: 117,2-133,4°C. IR (cm-1): 1639, 1583, 1468. MS (ESI+): 289 (100).1H NMR (DMSO-d6, 400 MHz): 1,60 (s, 6H), 7,01 (users, 2H), of 7.48 (t, 1H, J=5,9 Hz), 7,55 (DDD, 1H, J=5,9, 1,3, 0.8 Hz), to 7.67 (DDD, 1H, J=5,9, 1,3, 0.8 Hz), 7,76 (t, 1H, J=1.3 Hz), of 7.97 (s, 1H).

Example 5-2 to 5-3:

Compounds shown in table 5, receive the same manner as in example 5.

Example 6

a)

To a stirred solution of compound 22 (20,0 g, to 54.5 mmol) in 160 ml of CHCl3added dropwise 96% sulfuric acid (12.1 ml, 218 mmol) and 60% nitric acid (4,56 ml, 9.9 mmol) at 0° C and stirred at the same temperature for 30 minutes the Reaction mixture was then poured into crushed ice (150 g). The organic layer was washed with water (50 ml) and saturated salt solution (50 ml), dried over MgSO4and concentrated in vacuo. The residue is purified by crystallization from a mixture of AcOEt/heptane (1/2, 120 ml)to give compound 28 (18,4 g) as a pale yellow crystal.

To a stirred suspension of Zn (15.9 g, 218 mmol) in 150 ml of acetic acid compound 28 (15.0 g, of 36.4 mmol) is added by portions at 0°and stirred at room temperature for 1 h, then stirred at 60°in the next 30 minutes the Mixture is cooled to ambient temperature, filtered and the filtrate concentrated in vacuo. To the residue add AcOEt (150 ml), washed with water (50 ml) and saturated salt solution (50 ml), dried over MgSO4and concentrated in vacuo. The residue is purified by crystallization from EtOH/H2O (3/1, 50 ml)to give compound 29 (9,36 g) as a white crystal.

To a stirred suspension of copper chloride(II) (6,30 g of 44.5 mmol) in 135 ml of acetone added tert-butylnitrite (5,88 ml of 44.5 mmol) at 0°With, then add the connection portions 29 (9.00 g, 29.7 mmol) and stirred at the same temperature for 2 hours

The mixture is then stirred at room temperature during the course the e 1 o'clock After adding 2n. HCl, the mixture is extracted with AcOEt (100 ml). The extract is washed successively 1H. HCl (50 ml), water (50 ml) and saturated salt solution (50 ml), dried over MgSO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (CHCl3/AcOEt=10/l˜4/1)to give compound 30 (7,40 g) as a pale yellow crystal.

To a stirred solution of compound 30 (100 mg, 0.31 mmol) in 1 ml DME add 25% solution of HBr-Asón (89 ml, 0,372 mmol) and bromine (19 ml of 0.37 mmol) at 0°C and stirred for 7 h at room temperature. After addition of water the mixture is extracted with AcOEt, the organic layer washed with water and saturated salt solution, dried over MgSO4. Evaporation of the solvent gives the crude compound 31 (112 mg) as a pale yellow solid, which was used for next reaction without further purification.

To a solution of compound 31 (461 mg, 1.07 mmol) in EtOH (4 ml) add dihydrochloride 4,5-diamino-6-hydroxy-2-methylpyrimidine (457 mg, 2.14 mmol) and water (1.3 ml) and refluxed for 12 hours After cooling, the reaction mixture was added 4n. NaOH (2.5 ml, 10.0 mmol) and refluxed for 1 h, After cooling, the reaction mixture is brought to pH 4 with 4n. HCl and stirred for 1 h the Precipitated solid is collected what filtrowanie, washed with water and dried in vacuum, obtaining the compound of Example 6 (354 mg) as an orange solid.

As an alternative preparation of compound 31: To a stirred solution of compound 22 (100 mg, 0,272 mmol) in sulfurylchloride (0,219 ml of 2.72 mmol) is added aluminum chloride (127 mg, 0,953 mmol) and a catalytic amount S2Cl2when 0°C and stirred for 2 h, the Reaction mixture was then poured into ice water (30 g) and extracted with AcOEt (30 ml). The organic layer was washed with water (20 ml), saturated salt solution (20 ml), dried over MgSO4. Evaporation of the solvent yields the following reaction above without additional purification.

Example 6-9:

a)

To a suspension of compound 29 (1.0 g, 3,29 mmol) in 15 ml of toluene added tetrafluoroborate microzone (462 mg, 3.95 mmol) in an argon atmosphere at 0°C. After stirring for 30 min at 0°C the mixture is heated to 120°C and stirred for 1 h After cooling, the solution was diluted with AcOEt and the organic layer washed with water, dried over Na2SO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (AcOEt/CHCl3/hexane=1/1/1)to give compound 32 (381 mg) as a pale yellow crystal.

b)

To pen MachineName to a solution of compound 32 (381 mg, to 1.24 mmol) in 4 ml DME add 25% solution of HBr-AcOH (356 ml, 1,49 mmol) and bromine (76 ml, 1,49 mmol) at 0°C and stirred for 5 min at 0°C and for 30 min at room temperature. After addition of water the mixture is extracted with AcOEt, the organic layer was washed with saturated salt solution, dried over Na2SO4. Evaporation of the solvent gives the crude compound 33 (454 mg) as a pale yellow solid, which was used for next reaction without further purification.

c)

To a solution of compound 33 (454 mg, 1.18 mmol) in EtOH (6 ml) add dihydrochloride 4,5-diamino-6-hydroxy-2-methylpyrimidine (502 mg, 2.36 mmol) and water (2 ml) and refluxed for 12 hours, After cooling, to the reaction mixture are added 2n. NaOH (5,9 ml of 11.8 mmol) and refluxed for 3 hours After cooling, the reaction mixture is brought to pH 4 2n. HCl and stirred for 1 h the Precipitated solid is collected by filtration, washed with water and dried in vacuum, obtaining the compound of Example 6-9 (477 mg) as a pale yellow solid.

Example 6-2 to 6-25:

Compounds shown in table 6, receive the same manner as in examples 6 and 6-9.

Example 7

a)

To a stirred mixture of AlCl3(6,41 g, 48.1 mmol) in 30 ml of CH2Cl 2add ethyl-oxalicacid (1,58 ml of 14.2 mmol) and compound 34 (3.0 g, of 14.2 mmol) at 0°C and stirred at 0° ˜ to room temperature for 2 h Then the reaction mixture was poured into ice, 10 ml of AcOEt is added to the mixture and concentrated HCl added until suspended until the solution is clear. The organic layer is separated and concentrated in vacuo. The residue is purified column chromatography on silica gel (hexane/AcOEt=3/1˜1/1)to give compound 35 (3,36 g) as a white solid.

A mixture of compound 35 (3,36 g, 10.5 mmol) and KOH (2.0 g, 35.8 mmol) and N2H4·H2O (1,38 ml, 28.5 mmol) in three(etilenglikole) (30 ml) was stirred at 175°C for 1 h After cooling to room temperature, add 2n. HCl (30 ml, 60 mmol) and water (40 ml) and the precipitated solid is collected by filtration, receiving the connection 36 (2.58 g) as a pale yellow solid.

To a stirred mixture of compound 36 (to 2.57 g, 9.3 mmol) in 30 ml Meon add SOCl2(1.7 ml, with 23.3 mmol) at 0°and stirred at room temperature for 4 h, the Reaction mixture was concentrated in vacuo, then the residue purified column chromatography on silica gel (hexane/AcOEt=5/1˜3/1)to give compound 37 (2,13 g) as white solid is th substance.

d)

A mixture of compound 37 (2,13 g, 7.0 mmol) and diethylacetal N,N-dimethylformamide (6.8 ml, and 39.7 mmol) is stirred 130°C for 3 days. Then add toluene (20 ml) and the reaction mixture was concentrated in vacuo, to give crude compound 38, which is then used for the next reaction without further purification.

e)

A mixture of compound 38 (raw, 7.0 mmol) and 4,6-dihydroxy-2-methylpyrimidine (883 mg, 7.0 mmol) in AcOH (20 ml) was stirred at 110°C for 4 h Then the reaction mixture was concentrated in vacuo, add EtOH (10 ml) and water (8 ml) and the precipitated solid is collected by filtration, receiving the connection 39 (1.12 g) as a brown solid.

f)

A mixture of compound 39 (200 mg, 0.49 mmol) and POCl3(1 ml) was stirred at 90°C for 3 h Then the reaction mixture was poured into ice and the product extracted with AcOEt (3 ml) and the organic layer washed successively with water (2 ml) and saturated salt solution (2 ml). The organic layer is dried over MgSO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (hexane/AcOEt=2/1)to give compound 40 (174 mg) as an orange solid.

g)

A mixture of compound 40 (124 mg, 0.30 mmol) and 4n. aOH (0,41 ml, of 1.65 mmol) in MeOH (5 ml) was stirred at room temperature for 19 h and then stirred at 60°C for 2.5 hours After cooling to room temperature, add 2n. HCl (2 ml, 4 mmol) and water (10 ml) and the precipitated solid is collected by filtration, receiving the connection 41 (100 mg) as a pale yellow solid.

h)

To a stirred solution of 0.93 M MeMgBr in THF (1.2 ml, 1.12 mmol) is added suspended solution of compound 41 (100 mg, 0.23 mmol) in THF (1.5 ml) and stirred at room temperature for 3 hours After adding water (1 ml) and 2n. HCl (2 ml) and the product extracted with AcOEt (3 ml) and the organic layer is then washed with a saturated solution of salt (2 ml). The organic layer is dried over MgSO4and concentrated in vacuo give crude compound 42, which is then used for the next reaction without further purification.

i)

A mixture of compound 42 (raw, 0.23 mmol) and AcOH (2 ml) was stirred at 100°C for 40 min After cooling to room temperature, to the reaction mixture are added water (3 ml) and the product extracted with AcOEt (3 ml), then the organic layer is washed successively with water (2 ml) and saturated salt solution (2 ml). The organic layer is dried over MgSO4and concentrated in vacuo. The residue is purified column chromium is ografia on silica gel (CHCl 3/MeOH=40/1˜20/1)to give compound 43 (54 mg) as an orange solid.

To a stirred suspension of compound 43 (52 mg, 0.12 mmol) and K2COC(50 mg, and 0.37 mmol) in DMF (1.5 ml) is added Me (0,023 ml of 0.37 mmol) and the mixture is stirred at room temperature for 3 hours After adding water (3 ml) and the product extracted with AcOEt (3 ml) and the organic layer washed successively with water (2 ml) and saturated salt solution (2 ml). The organic layer is dried over MgSO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (hexane/AcOEt=4/1)to give compound 44 (46 mg) as a white solid.

To a stirred solution of compound 44 (134 mg, 0.30 mmol) in toluene (4 ml) add benzophenone (0,255 ml of 1.52 mmol) and Pd(OAc)2 (14 mg, 0.061 mmol) and (S)-(-)-BINAP (57 mg, 0,091 mmol) and CCCOC(198 mg, 0.61 mmol) and the mixture was stirred at 110°C for 23 hours After addition of water (3 ml) and the product extracted with AcOEt (3 ml) and the organic layer is then washed with a saturated solution of salt (2 ml). The organic layer is dried over MgSO4and concentrated in vacuo. The residue is purified column chromatography on silica gel (hexane/AcOEt=4/1˜2/1)to give compound 45 (88 mg) as a yellow solid.

To a stirred solution of compound 45 (85 mg, 0,145 mmol) in THF (2 ml) is added concentrated HCl (0,050 ml) and the mixture is stirred at room temperature for 1 h After addition of 4n. NaOH (0,14 ml) and the product extracted with AcOEt (5 ml) and the organic layer washed successively with water (4 ml) and saturated salt solution (4 ml). The organic layer was concentrated in vacuo, the resulting residue is purified column chromatography on silica gel (CHCl3/Meon=50/1)to give compound 46 (57 mg) as a yellow solid.

To a stirred mixture of compound 46 (55 mg, 0.13 mmol) in a mixed solvent (2 ml THF and 3 ml of Meon) type 1H. NaOH (of 0.43 ml, 0.43 mmol) and the mixture was stirred at 80°C for 4 h Then the reaction mixture was concentrated in vacuo, 2n. HCl (0.25 ml, 0.5 mmol) and EtOH (1 ml) is added to the mixture and the precipitated solid is collected by filtration, obtaining the compound of Example 7 (38 mg) as a pale yellow solid.

Example 7-4:

The connection 49.The mixture of compounds 47 (10.0 g, of 89.2 mmol) and 48 (14.5 g, of 89.2 mmol) in AcOH (100 ml) is heated at 100°C for 24 hours the Solvent is removed in vacuo and the resulting brown residue purified flash chromatography (silica gel, 4% MeOH/CH2Cl2)to give compound 49 as a yellow is th solids (12,04 g). 1H NMR (DMSO-d6) δ 8,02 (s, 1H), of 6.71 (s, 1H), 1,53 (s, 6H). Mass spectrum (ESI+) m/e=257 and 259 (M+1).

The connection 50.A solution of compound 49 (2,13 g, 8,29 mmol) in POCl3(10 ml) is heated at 100°C for 1 h, cooled to room temperature and poured on ice. The resulting solution was extracted with EtOAc (3 × 75 ml). The organic layers are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, obtaining compound 50 as a yellow oil (2.28 g).1H NMR (DMSO-d6) δ 8,49 (s, 1H), 7,00 (s, 1H), 1,64 (s, 6H). Mass spectrum (ESI+) m/e=275, 277 and 279 (M+1).

The connection 51.Diisopropylethylamine (1.9 ml, 10.9 mmol) are added to a solution of compound 50 (2.0 g, 7,26 mmol) and 4-methoxybenzylamine and 2.83 ml, and 21.8 mmol) in THF (20 ml). The reaction mixture is heated to boiling under reflux for 16 h, cooled to room temperature, diluted with water (20 ml) and extracted with EtOAc (3 × 75 ml). The organic layers are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving a yellow solid. Purification with flash chromatography (silica gel, 50% EtOAc/hexane) gives compound 51 as not quite white solid (2.14 g).1H NMR (DMSO-d6) δ with 8.05 (s, 1H), 7,79 (m, 1H), 7,21 (d, J=8.7 Hz, 2H), was 7.08 (s, 1H), 6.87 in (d, J=8.7 Hz, 2H), 4,50 (d, J=5.7 Hz, 2H), 3,71 (s, 3H), of 1.50 (s, 6H). Mass spectrum (ESI+) m/e=376 and 378 (M+1)./p>

The connection 52.A solution of compound 51 (620 mg, of 1.65 mmol) in TFA (20 ml) is heated at 50°C for 7 hours, the Solvent is removed in vacuum and the oil obtained is dissolved in EtOAc (30 ml), washed with saturated aqueous NaHCO3(2 × 50 ml), saturated salt solution, dried (MgSO4), filtered and concentrated in vacuo, receiving a yellow solid. The solid is subjected to sonication in Et2O (5 ml) and collected by vacuum filtration, receiving the connection 52 in the form of not-quite-white solid (388 mg).1H NMR (DMSO-d6) δ of 7.97 (s, 1H), 7,10 (s, 1H), 7,00 (s, 2H), of 1.52 (s, 6H). Mass spectrum (ESI+) m/e=256 and 258 (M+1).

The connection 54.60% suspension of NaH (211 mg, 5,23 mmol) in mineral oil is added to a solution of compound 53 (1.0 g, of 5.26 mmol) in anhydrous THF (25 ml) at 0°C in nitrogen atmosphere. In a separate flask trimethylphosphate (1,02 ml of 6.31 mmol) are added to a suspension of NaH (315 mg, 7,88 mmol) in anhydrous THF (25 ml) at 0°C in nitrogen atmosphere. After 15 min the two mixture warmed to room temperature and stirred for 30 minutes, the Solution containing the ketone, are added to a solution of phosphonate through the cannula. The reaction mixture was stirred at room temperature for 5 h, quenched with water (50 ml) and extracted with EtOAc (3 × 50 ml). The organic layers are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and will contentresult in vacuum, receiving compound 54 as a white solid (1.25 g).1H NMR (DMSO-d6) δ 9,12 (s, 1H), 7,01 (d, J=8,4 Hz, 2H), 6,66 (d, J=8,4 Hz, 2H), 5,70 (s, 1H), 3,82 (m, 1H), 3,62 (s, 3H), 2,70 (m, 1H), 2,33 (m, 2H), 2,01 (m, 1H), 1,92 (m, 2H), 1,47 (m, 2H). Mass spectrum (ESI+) m/e=247 (M+1).

The connection 55.A mixture of compound 54 (5,18 g, 21,0 mmol) and 10% Pd/C (500 mg) in EtOAc (150 ml) was stirred at room temperature in hydrogen atmosphere for 20 hours, the Reaction mixture was filtered through celite and concentrated in vacuo, receiving a yellow solid. Recrystallization from EtOAc (6 ml) gives compound 55 in the form of colorless prisms with TRANS/CIS-ratio of 20:1 (2,96 g).1H NMR (DMSO-d6) δ the remaining 9.08 (s, 1H), 6,99 (d, J=8.5 Hz, 2H), 6,65 (d, J=8.5 Hz, 2H), 3,60 (s, 3H), of 2.33 (dt, J=3.0 and 12.1 Hz, 1H), 2,23 (d, J=6,9 Hz, 2H), of 1.75 (m, 5H), to 1.38 (m, 2H), 1,11 (m, 2H). Mass spectrum (ESI+) m/e=249 (M+1).

The connection 56.The triethylamine (421 μl, to 3.02 mmol) is added dropwise to a solution of compound 55 (500 mg, 2.02 mmol) and triftormetilfullerenov anhydride (424 μl, 2,52 mmol) in anhydrous CH2Cl2(20 ml) at 0°C in nitrogen atmosphere. The reaction mixture is heated to room temperature and stirred for 4.5 h, then poured into water (30 ml) and the layers separated. The organic layers are combined, washed with saturated aqueous NaHCO3, a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving the connection 56 in the form of not quite white solid substances is a (765 mg). 1H NMR (DMSO-d6) δ 7,42 (d, J=8.7 Hz, 2H), 7,38 (d, J=8.7 Hz, 2H), 3,60 (s, 3H), 2.57 m (m, 1H), 2,25 (d, J=6.6 Hz, 2H), 1,79 (m, 5H), of 1.47 (m, 2H), 1.14 in (m, 2H). Mass spectrum (ESI+) m/e=381 (M+1).

The connection 57.In a 50 ml round-bottom flask is charged with compound 56 (1.35 g, 3,55 mmol), KOAc (1,05 g, 10.6 mmol), bis(pinacolato)LIBOR (991 mg, 3.90 mmol), PdCl2(dppf) (87 mg, 0,107 mmol) and dppf (59 mg, 0,107 mmol). The flask is then filled with nitrogen and vacuum three times. Anhydrous dioxane (25 ml) is added and the reaction mixture is heated at 80°C for 17 h, the Reaction mixture was cooled to room temperature, diluted with EtOAc (50 ml), washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, obtaining a brown oil. Purification with flash chromatography (silica gel, 15% EtOAc/hexane) gives compound 57 as a white solid (914 mg).1H NMR (DMSO-d6) δ to 7.59 (d, J=7.8 Hz, 2H), 7,24 (d, J=7.9 Hz, 2H), 3,60 (s, 3H), of 2.45 (m, 1H), 2,25 (d, J=6,8 Hz, 2H), 1,78 (m, 5H), of 1.46 (m, 2H), 1.28 (in s, 12H), 1.14 in (m, 2H). Mass spectrum (ESI+) m/e=359 (M+1).

The connection 58.A mixture of compound 52 (1.12 g, of 4.38 mmol), 57 (2.0 g, to 6.57 mmol), PdCl2(dppf) (107 mg, 0,132 mmol) and 2 M aqueous Na2CO3(11 ml) in DMF (30 ml) is heated at 80°C in nitrogen atmosphere for 24 hours the Solution was diluted with water (75 ml) and the precipitate collected by vacuum filtration, getting not quite white solid. Purification with flash chromatography (silica gel, 5% MeOH/CH2/sub> Cl2) gives compound 58 as a white solid (1,09 g).1H NMR (DMSO-d6) δ to 7.95 (s, 1H), 7,29 (d, J=8.0 Hz, 2H), 7,24 (d, J=8.1 Hz, 2H), 6,86 (s, 2H), to 6.57 (s, 1H), 3,61 (s, 3H), 2,47 (m, 1H), 2,25 (d, J=6,7 Hz, 2H), 1,79 (m, 5H)and 1.51 (s, 6H), of 1.44 (m, 2H), 1,16 (m, 2H). Mass spectrum (ESI+) m/e=408,5 (M+1).

Example 7-4.A solution of compound 58 (130 mg, 0,319 mmol) in MeOH (12 ml) and 10% aqueous LiOH (4 ml) is heated at 100°C for 4 h MeOH removed in vacuo and the resulting aqueous solution is acidified with 1N. HCl to pH 4. The precipitate is collected by vacuum filtration, obtaining the compound of Example 7-4 in the form of not-quite-white solid (111 mg).1H NMR (DMSO-d6) δ of 8.09 (s, 1H), 7,33 (users, 2H), 7,30 (d, J=8.1 Hz, 2H), 7,26 (d, J=8.1 Hz, 2H), is 6.61 (s, 1H), 2,47 (m, 1H), 2,15 (d, J=6,9 Hz, 2H), equal to 1.82 (m, 4H), of 1.74 (m, 1H), 1.55V (s, 6H)and 1.51 (m, 2H), 1,13 (m, 2H). Mass spectrum (ESI+) m/e=394 (M+1).

Example 7-5:

The connection 60.In a 100 ml round bottom flask is charged with compound 59 (2,54 g, 7,58 mmol), bis(pinacolato)LIBOR (2,41 g, 9.47 mmol), KOAc (2,23 g, 22.7 mmol), PdCl2(dppf) (186 mg, 0,227 mmol) and dppf (126 mg, 0,227 mmol). The flask is then filled with nitrogen and vacuum three times. Anhydrous dioxane (70 ml) is added and the reaction mixture is heated at 80°C for 17 h, the Reaction mixture was diluted with EtOAc (75 ml) and washed with water, saturated salt solution, dried (MgSO4), filtered and concentrated in vacuo, obtaining a brown oil. Clean the lash-chromatography (silica gel, 5% EtOAc/hexane) gives compound 60 as a white solid (2,02 g).1H NMR (DMSO-d6) δ 7,52 (s, 1H), 7,47 (d, J=7,6 Hz, 1H), 7,18 (d, J=7.5 Hz, 1H), 5,74 (s, 1H), 3,71 (m, 1H), 3,62 (s, 3H), 2,89 (t, J=7.4 Hz, 2H), 2,41 (m, 1H), 2,32 (m, 1H), 2,13 (m, 3H), of 1.66 (m, 4H), 1.28 (in with, 12H). Mass spectrum (ESI+) m/e=383 (M+1).

The connection 61.A mixture of compound 60 (2,02 g, 5,28 mmol) and 10% Pd/C (562 mg) in MeOH (50 ml) was stirred at room temperature in an atmosphere of hydrogen for 21 hours, the Reaction mixture was filtered through celite and concentrated in vacuo, obtaining a colorless oil. Crystallization from MeOH followed by recrystallization from CH2Cl2with the diffusion of MeOH gives compound 61 in the form of white needle-shaped crystals, with the ratio of TRANS/CIS 20:1 (600 mg).1H NMR (DMSO-d6) δ of 7.70 (s, 1H), 7,68 (d, J=7.7 Hz, 1H), 7,18 (d, J=7.5 Hz, 1H), 3,71 (s, 3H), 2,90 (t, J=7,3 Hz, 2H), to 2.29 (d, J=7,0 Hz, 2H), 1,99 (t, J=7.4 Hz, 2H), 1,90 (m, 1H), 1,76 (m, 2H), by 1.68 (m, 2H), to 1.60 (m, 2H), of 1.35 (s, 12H), 1,25 (m, 2H). Mass spectrum (ESI+) m/e=385 (M+1).

The connection 62.A mixture of compound 52 (100 mg, 0,391 mmol), compound 61 (150 mg, 0,391 mmol), Pd(PPh3)4(23 mg, at 0.020 mmol) and 2 M aqueous Na2CO3(1 ml) in DMF (10 ml) is heated at 80°C for 3.5 h, the Reaction mixture was diluted with EtOAc (75 ml), washed with water (3 × 50 ml), saturated salt solution, dried (MgSO4), filtered and concentrated in vacuo, receiving a yellow solid. Purification with flash chromatography (silica gel, 5% MeOH/CH2Cl 2) gives compound 62 as a white solid (103 mg).1H NMR (DMSO-d6) δ to 7.95 (s, 1H), 7,18 (m, 3H), at 6.84 (s, 2H), 6,56 (s, 1H), 3,61 (s, 3H), 2,85 (t, J=7,3 Hz, 2H), 2,28 (d, J=7,0 Hz, 2H), 1,95 (t, J=7,3 Hz, 2H), 1,79 (m, 1H), 1,65 (m, 5H)and 1.51 (s, 6H), 1,49 (m, 1H), 1,23 (m, 2H). Mass spectrum (ESI+) m/e=434 (M+1).

Example 7-5.A solution of compound 62 (103 mg, 0,238 mmol) in MeOH (9 ml) and 10% aqueous LiOH (3 ml) is heated at 100°C for 2 h MeOH removed in vacuo and the resulting aqueous layer acidified with 1N. HCl to pH 1. The precipitate is collected by vacuum filtration, obtaining the compound of Example 7-5 in the form of not-quite-white solid (73 mg).1H NMR (DMSO-d6) δ to 8.14 (s, 1H), 7,50 (users, 2H), 7,20 (m, 3H), of 6.61 (s, 1H), 2,86 (t, J=7.2 Hz, 2H), 2,17 (d, J=6,8 Hz, 2H), 1,96 (t, J=7,3 Hz, 2H), 1,71 (m, 1H), 1,67 (m, 2H), and 1.63 (m, 3H), and 1.56 (s, 6H), 1,50 (m, 2H), 1,22 (m, 2H). Mass spectrum (ESI+) m/e=420 (M+1).

Compounds shown in table 7, get in the same way as in Examples 7, 7-4 and 7-5.

Example 8

Stage (A), (B) and (C).In in a flame dried 1-l 3-necked round bottom flask, equipped with magnetic stirrer, irrigation condenser and addition funnel, was placed magnesium turnings (1.1 EQ., 8.8 g) and simple diethyl ether (60 ml) under nitrogen atmosphere. The solution is simple diethyl ether 1-bromo-3-phenylpropane (322,4 mmol, 65,5 g) is added via addition funnel with such speed, that under arrivati calm boiling under reflux while adding about 1 hour 10 minutes In the beginning add enter some particles of iodine to initiate the reaction. After complete addition of the bromide, the reaction mixture is heated to boiling under reflux for 1 h, allow to cool to room temperature and optionally cooled in a bath with ice. The solution monoelemental 1,4-cyclohexandione (1 EQ., 51,91 g) in THF (100 ml) is added slowly to a cooled ice mixture through an addition funnel with stirring for 1 h 30 min the Mixture was continuously stirred for 30 min in a bath with ice and over night at ambient temperature. The reaction mixture is pre-cooled in a bath with ice and add a mixture of ice and 4h. aqueous HCl. The mixture is stirred until dissolved all the magnesium, the layers separated and the aqueous layer was extracted with simple diethyl ether (2×). The combined organic substance is washed with saturated salt solution until neutral, dried over anhydrous sodium sulfate and concentrated in vacuo. The remainder is taken to the next stage, where it is subjected to hydrolysis in boiling under reflux the mixture with MeOH (400 ml) and 3n. water (H2SO4(100 ml) for 6 hours the Reaction mixture is cooled, concentrated in vacuo, diluted with water with ice and extracted with EtOAc (2×). The combined organic substance was washed with a saturated solution with the and (2× ), dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography (EtOAc/hexane, 35/65) of the residue gives the desired hydroxyketone 64 (30 g).1H NMR (CDCl3) δ 1,45 (users, 1H), 1,59-to 1.63 (m, 2H), 1,73 of-1.83 (m, 4H), 1.93 and-of 1.97 (m, 2H), 2,20-of 2.28 (m, 2H), 2,65 was 2.76 (m, 4H), 7,19-7,24 (m, 3H), 7,28-7,33 (m, 2H). Mass spectrum (CI+) m/e=215,1 (M+1).

Stage (D). In a flame dried odnogolosy round bottom flask in a bath with ice placed NaH (60% dispersion in mineral oil) (1 EQ., 0.66 g) and then uploading THF (20 ml) under nitrogen atmosphere. To this is added dropwise trimethylphosphate (1 EQ., 2,89 g/2,75 ml) with a syringe. When the evolution of hydrogen is complete, the solution hydroxyketone 64 (15,5 mmol, 3.33 g) in THF (40 ml) is slowly injected through an addition funnel. The reaction mixture was stirred at ambient temperature overnight. The reaction is quenched with saturated aqueous NH4Cl, then with water, and extracted with EtOAc (2×). The combined organic substance was washed with a saturated solution of salt (2×), dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography of the residue (EtOAc/hexane, 30/70) gives the desired hydroxyacrylates (3.5 g).1H NMR (CDCl3) δ to 1.16 (s, 1H), 1,29 (t, J=7,1 Hz, 3H), 1,51-to 1.61 (m, 4H), 1,70-1,80 (m, 4H), 2,10-and 2.14 (m, 1H), 2,43 at 2.59 (m, 2H), 2,65 (t, J=7.5 Hz, 2H), 3.46 in-3,50 (m, 1H), 4,16 (kV, J=7,1 Hz, 2H), 5,65 (s, 1H), 7,19-7,22 (m, 3H), 7,28-to 7.32 (m, 2H).

Stage (E). Received hydro is diacrylate (15,5 mmol) hydronaut over palladium (10% on coal) (10 mol.%) in EtOAc (60 ml), using gaseous hydrogen at atmospheric pressure for 10 hours with Pd/C is filtered by a layer of celite and the filtrate concentrated in vacuo. The resulting product contains a mixture of two conformers (ratio 3:1) desirable tertiary hydroxyl of ester 65, which is shared by column chromatography (EtOAc/hexane, 20/80) and characterized by the following spectral data. In practice, a mixture of conformers additionally receive without separation.1H NMR (major conformer, CDCl3) δ of 1.06 (s, 1H), 1.27mm (t, J=7,1 Hz, 3H), 1,33-of 1.42 (m, 4H), 1,46-is 1.51 (m, 2H), 1,55-of 1.66 (m, 4H), by 1.68 to 1.76 (m, 3H), of 2.23 (d, J=7,0 Hz, 2H), 2.63 in (t, J=7,6 Hz, 2H), 4,14 (kV, J=7,1 Hz, 2H), 7.18 in-7.23 percent (m, 3H), 7,28-to 7.32 (m, 2H). Mass spectrum (CI+) m/e=287,1 (M+1);1H NMR (small conformer, CDCl3) δ 1,07-of 1.15 (m, 2H), 1,22 (s, 1H), 1.27mm (t, J=7,1 Hz, 3H), 1,39-of 1.44 (m, 2H), 1,54 is 1.58 (m, 2H), 1,67 is 1.75 (m, 6H), of 1.88 (m, 1H), 2,22 (d, J=7,1 Hz, 2H), 2,65 (t, J=7,6 Hz, 2H), 4,14 (kV, J=7,1 Hz, 2H), 7.18 in-7,22 (m, 3H), 7,29-to 7.32 (m, 2H). Mass spectrum (CI+) m/e=287,1 (M+1).

Stage (F), (G) and (H). In a flame dried 50-ml odnogolosy round bottom flask in a bath with a mixture of ice and salt is placed AlCl3(2.5 EQ., 1,43 g), followed by adding dropwise 2-bromoisobutyrate (2 EQ., 2,01 g/1.08 ml) in nitrogen atmosphere. The mixture is stirred for about 5 min and injected CH2Cl2(8 ml). After another 5 min is added dropwise a solution of CH2Cl2(20 ml) mixture of conformers tertiary hydroxyl complex E. the Ira 65 (4.3 mmol, of 1.23 g). The reaction mixture was continuously stirred in a bath of ice and salt for 1 hour, a Mixture of ice and 2n. aqueous HCl is added and the mixture is stirred until everything was dissolved, and extracted with CH2Cl2(2×). The combined organic substance is washed with saturated salt solution (3×), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue contains mainly two acylated regioisomer in respect of from about 4 to 1, which is subjected to cyclization with hemisulfate 4,5-diamino-6-hydroxypyrimidine (0.5 EQ., 0,63 g) in the presence of 2n. aqueous HCl (2.2 EQ., 4 ml) in a mixture of 3:1 EtOH-H2O (40 ml). The mixture is refluxed for about 12 hours the Mixture is cooled, diluted with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic substances washed with saturated aqueous NH4Cl (2×), dried over anhydrous sodium sulfate and concentrated in vacuo. The product is subjected to hydrolysis LiOH·H2O (5 EQ., 0.73 g) in a mixture of 3:1 MeOH-H2O (20 ml). By the same processing, which is used at the previous stage cyclization receive a mixture of two major regioisomers (67). The main isomer) (1.2 g) is obtained by recrystallization (EtOAc/CH2Cl2/MeOH). The desired isomer (Example 8) (200 mg) receive preparative HPLC mother liquor.1H NMR (CDCl3) (single conforme is, TRANS-) δ 1,35 was 1.43 (m, 2H), 1,69-of 1.88 (m, 16 H)a 1.96 (m, 1H), 2,36 (d, J=7,0 Hz, 2H), and 2.83 (t, J=6.0 Hz, 2H), 7,34 (d, J=1.6 Hz, 1H), 7,42 (DD, J=8,4, and 1.6 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H), 8,16 (s, 1H). Mass spectrum (CI+) m/e=435,2 (M+1).

Example 8-2:

Connection 69.Trimethylphosphate (10,36 ml, 64,0 mmol) are added to a suspension of NaH in anhydrous THF (500 ml) at 0°C in nitrogen atmosphere. After 30 min at 0°C a solution of mono-atelectasia 1,4-cyclohexandione (10.0 g, 64,0 mmol) in anhydrous THF (50 ml) added via cannula. The reaction mixture is heated to ambient temperature and stirred for 12 hours the Reaction is quenched with water and the THF removed in vacuo. The aqueous layer was extracted with EtOAc and the organic layers combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving the connection 68 in the form of a colorless oil. 10% Pd/C are added to a solution of compound 68 in 95% EtOH (200 ml). The reaction mixture was stirred in an atmosphere of hydrogen for 20 h, filtered through celite and concentrated in vacuo, obtaining a colorless oil. Monohydrate p-toluensulfonate acid (1,21 g, 6,40 mmol) are added to a solution of the oil in acetone (200 ml) and water (50 ml) and the reaction mixture is heated to boiling under reflux for 24 hours, the Acetone is removed in vacuo and the aqueous solution extracted with EtOAc. The organic layers are combined, washed the feast upon the s ' solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving the connection 69 in the form of a colourless liquid (5,86 g).1H NMR (CDCl3) δ of 1.46 (m, 2H), 2,08 (m, 2H), 2,25 is 2.33 (m, 3H), is 2.37 (m, 4H), 3,68 (s, 3H). Mass spectrum (ESI+) m/e=RUB 171.1 (M+H).

The connection 70.Chloride Isopropylamine (25,5 ml of 51.0 mmol) is added via syringe to a solution of 4-bromo-3-methylbenzonitrile (5.0 g, 25.5 mmol) in anhydrous Et2O (50 ml) at 0°C in nitrogen atmosphere. The reaction mixture is heated to boiling under reflux for 12 hours, the Reaction mixture was cooled to 0°C and quenched with 6 N. HCl. After stirring at ambient temperature for 12 h, the layers separated and the aqueous solution extracted with EtOAc. The organic extracts are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, obtaining a brown oil. Flash chromatography (silica gel, 2% EtOAC/hexane) gives compound 70 as a colorless oil (3,69 g).1H NMR (DMSO-d6) δ a 1.08 (d, J=6.8 Hz, 6H), is 2.41 (s, 3H), 3,62 (m, 1H), 7,68 (d, J=8,4 Hz, 1H), 7,73 (d, J=8,3 Hz, 1H), 7,92 (s, 1H). Mass spectrum (ESI+) m/e=241,1 and 243,1 (M+H).

Connection 71.Monohydrate p-toluensulfonate acid (360 mg, 1,89 mmol) are added to a solution of compound 70 (of 4.57 g of 18.9 mmol) and ethylene glycol (8,45 ml, 0,152 mol) in benzene (50 ml). The reaction mixture is heated to boiling under reflux for 20 h, at the same time is dalee water using traps Dean-stark. The solution was washed with saturated aqueous NaHCO3, a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, obtaining a colorless oil. Flash chromatography (silica gel, 2% EtOAc/hexane) gives compound 71 as a colourless oil (a 4.86 g).1H NMR (DMSO-d6) δ of 0.79 (d, J=6.8 Hz, 6H), 2,03 (m, 1H), 2,34 (s, 3H), 3,63 (m, 2H), 3,92 (m, 2H), 7,07 (DD, J=2.2 and 8.2 Hz, 1H), 7,30 (d, J=2.1 Hz, 1H), 7,52 (d, J=8,2 Hz, 1H). Mass spectrum (ESI+) m/e=285,0 and 287,1 (M+H).

The connection 72.n-BuLi (5,4 ml, 13.5 mmol) are added to a solution of compound 71 (3.50 g, 12.3 mmol) in anhydrous THF (20 ml) at -78°C. the Solution was stirred at -78°C for 30 min and added to a solution of compound 69 (2.30 g, 13.5 mmol) in anhydrous THF (20 ml) at -78°C. the Reaction mixture is heated to ambient temperature and stirred for 12 hours the Reaction is quenched with saturated aqueous NH4Cl and the layers separated. The aqueous layer was extracted with EtOAc and the organic extracts are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving a yellow oil. Flash chromatography (silica gel, 15% EtOAc/hexane) gives compound 72 in the form of a colorless oil as a mixture of CIS - and TRANS-isomers (2.24 g).1H NMR (CDCl3) δ to 0.88 (d, J=6.8 Hz, 6H), to 0.88 (d, J=6.8 Hz, 6H), 1.60-to 2,40 (m, 24H), 2,60 (s, 3H), 2,62 (s, 3H), 3,66 (s, 3H), 3,68 (s, 3H), of 3.75 (m, 4H), 3,98 (m, 4H), 7,15-7,26 (m, 4H), 7,33 (m, 2H). Mass spectrum (ESI+) m/e=359,2 ([M-H2O]+H).

With the unity 73. A solution of NBS (260 mg, of 1.46 mmol) and compound 72 (500 mg, of 1.33 mmol) in benzene (100 ml) is heated at the boil under reflux for 24 hours, the Reaction mixture was cooled to ambient temperature, washed with water, saturated salt solution, dried (MgSO4), filtered and concentrated in vacuo, obtaining a brown oil. Flash chromatography (silica gel, 10% EtOAc/hexane) gives compound 73 as a yellow oil as a mixture of CIS - and TRANS-isomers (187 mg).1H NMR (DMSO-d6) δ to 0.88 (d, J=6.8 Hz, 6H), to 0.89 (d, J=6.8 Hz, 6H), 1,54 is 2.10 (m, 20H) 2,28 (d, J=7,0 Hz, 2H), 2,43 (d, J=7,3 Hz, 2H), 3,68 (s, 3H), 3,70 (s, 3H), 3,76 (m, 4H), of 3.97 (m, 4H), 5,02 (s, 2H), to 5.03 (s, 2H), 7,00 (d, J=7.8 Hz, 1H), 7,22 (m, 3H), 7,28 (m, 2H). Mass spectrum (ESI+) m/e=375,1 (M+H).

The connection 74.A solution of compound 73 (450 mg, 1.20 mmol) and monohydrate p-toluensulfonate acid (23,0 mg, 0,120 mmol) in acetone (25 ml) and water (5 ml) is heated at the boil under reflux for 24 hours, the Acetone is removed in vacuo and the aqueous solution extracted with EtOAc. The organic layers are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving a yellow oil as a mixture of CIS - and TRANS-isomers (366 mg).1H NMR (DMSO-d6) δ of 1.09 (d, J=6.8 Hz, 6H), of 1.09 (d, J=6.8 Hz, 6H), 1,40 of-1.83 (m, 18H) to 2.25 (d, J=7,0 Hz, 2H), 2,53 (d, J=7,4 Hz, 2H)and 3.59 (s, 3H), of 3.60 (s, 3H), 3,63 (m, 2H), to 4.98 (s, 4H), 7,38 (d, J=7.9 Hz, 1H), 7,60 (d, J=7.9 Hz, 1H), 7,87 (m, 4H). Mass spectrum (ESI+) m/e=331,2 (M+H).

With the ect connection 74 (400 mg, to 1.21 mmol) and CuBr2(811 mg, 3.63 mmol) in CHCl3(25 ml) and EtOAc (25 ml) is heated at the boil under reflux for 5 hours the Solvent is removed in vacuo and the residue partitioned between EtOAc and water. The layers are separated and the aqueous solution extracted with EtOAc. The organic layers are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, obtaining compound 75 as a yellow oil. Hemisulfate 4,5-diamino-6-hydroxypyrimidine (170 mg, 0,486 mmol) and 2n. HCl (535 μl, 1.07 mmol) are added to a solution of compound 75 (398 mg, 0,972 mmol) in EtOH (18 ml) and water (6 ml). The reaction mixture is heated to boiling under reflux for 23 h and quenched with saturated aqueous NH4Cl. The solution is extracted with EtOAc and the organic layers combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, receiving the connection 76 in the form of an orange foam (360 mg). The monohydrate of lithium hydroxide (173 mg, 4,12 mmol) are added to a solution of compound 76 (360 mg, 0,825 mmol) in MeOH (18 ml) and water (6 ml). The reaction mixture is heated to boiling under reflux for 18 h and quenched with NH4Cl. The solution is acidified with HCl and extracted with EtOAc. The organic layers are combined, washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated in vacuo, obtaining the compound of Example 8-2 in the form of the same is also solid (146 mg) as a mixture of CIS - and TRANS-isomers, shared by HPLC with reversed phase.1H NMR (major isomer, DMSO-d6) δ 1,50 (m, 5H), to 1.61 (s, 6H), is 1.82 (m, 4H), 2.40 a (d, J=7,3 Hz, 2H), equal to 4.97 (s, 2H), 7,53 (d, J=7.9 Hz, 1H), 7,60 (d, J=8.0 Hz, 1H), 7.62mm (s, 1H), 7,99 (s, 1 H). Mass spectrum (CI+) m/e=423,2 (M+1).1H NMR (small isomer, DMSO-d6) δ of 1.40 (m, 2H), 1,60 (s, 6H), of 1.64 (m, 4H), of 1.75 (m, 3H), of 2.15 (d, J=6,9 Hz, 2H), equal to 4.97 (s, 2H), 7,30 (d, J=8.5 Hz, 1H), to 7.61 (m, 2H), 7,98 (s, 1H). Mass spectrum (CI+) m/e=423,2 (M+1).

Example 8-3:

The connection 78.To a stirred suspension of tert-butoxide potassium (16.2 g, 142 mmol) in 1,4-dioxane (300 ml) is added chloride (methoxymethyl)triphenylphosphine (48,5 g, 142 mmol) at room temperature in an atmosphere of N2. After stirring for 2 h, 5-bromoindene (77,13 g of 61.6 mmol) in dioxane (170 ml) is added to the solution at room temperature in an atmosphere of N2. The mixture is stirred for 2 h at room temperature, poured into water (500 ml) and extracted with EtOAc (500 ml). The organic layer is separated, washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo. To the residue add hexane:EtOAc (2:1 (500 ml)). The mixture is stirred at room temperature, filtered and the precipitate washed with 2× hexane:EtOAc (2:1 (500 ml)). The filtrate was concentrated in vacuo and the residue is distilled (700 mm Torr at 145-150° (C)receiving Obedinenie 78 in the form of a light yellow solid, CIS - and TRANS-mixture (14.5 g).1H NMR (CDCl3) δ 2,70 is 2.80 (m, 2H, major and minor isomers), 2,94-3,00 (m, 2H, major and minor isomers in), 3.75 (s, 3H, major and minor isomers), of 6.20 (t, J=1.8 Hz, 1H, only a small isomer), of 6.65 (t, J=2,6 Hz, 1H, main isomer), 7,12 (d, J=8,2 Hz, 1H, main isomer), 7,22-7,34 (m, 2H,, major and minor isomers), to 7.68 (d, J=8,2 Hz, 1H, only a small isomer).

Connection 79.To a stirred solution of compound 78 (14.5 g, of 60.8 mmol) in toluene (60 ml) was added methyl vinyl ketone are (6,0 ml, 68 mmol) and monohydrate p-toluensulfonate acid (1.2 g, 6.3 mmol) at room temperature. The mixture is heated at 100°C for 18 h in an atmosphere of N2allow to cool to room temperature and poured into saturated aqueous solution of NaHCO3(200 ml). The organic layer is separated and washed with a saturated solution of salt. The aqueous layer was extracted with EtOAc and the organic layer is separated and washed with a saturated solution of salt. The organic layer is dried over Na2SO4and concentrated in vacuo. The residue is subjected to recrystallization from EtOH:H2O (2:1 (ml)), filtered and dried in vacuum at 60°C, receiving the connection 79 in the form of a pale yellow solid (9,90 g).1H NMR (CDCl3) δ 2,09-of 2.24 (m, 3H), 2,29 of-2.32 (m, 1H), 2,54 (DD, J=7,2, 6.3 Hz, 2H), 2,99-of 3.12 (m, 2H), 6,10 (d, J=10.1 Hz, 1H), 6,76 (d, J=10.1 Hz, 1H), 6,99 (d, J=8,1 Hz, 1H), 7,35 (d, J=8,1 Hz, 1H), 7,44 (s, 1H).

The connection 80.To paramesh is applied to the solution of compound 79 (153,4 g, 0,55 M) in acetic acid (3.7 liters) is added 10% Pd/C (30 g). The mixture is stirred in hydrogen atmosphere for 4 h and filtered through silica gel (washing with acetic acid, and then DCM). The filtrate was concentrated in vacuo, receiving the connection 80 in the form of a white solid (150,51 g).1H NMR (CDCl3) δ 1,90-of 1.97 (m, 2H), 2,02-2,12 (m, 2H), and 2.26 (t, J=7,3 Hz, 2H), 2,43-2,61 (m, 4H), 3,01 (t, J=7,3 Hz, 2H),? 7.04 baby mortality (d, J=8,1 Hz, 1H), 7,32-7,35 (m, 1H), 7,40 (s, 1H).

The connection 59.To a stirred solution of trimethylphosphate (116,45 g, 640 mmol) in anhydrous THF (2.2 l) in the atmosphere N2when 0°C add portions within 7 min sodium hydride (25,6 g 60% dispersion in mineral oil, 640 mmol). The mixture was stirred at 0oC for 30 min and allow to warm to room temperature over 30 minutes a Solution of compound 80 (149 g, 533 mmol) in anhydrous THF (375 ml) added dropwise within 10 minutes the Mixture is stirred at room temperature for 90 min and add saturated aqueous NH4Cl (500 ml). The mixture is stirred for 5 min and concentrated in vacuo to remove THF. The aqueous phase is washed with simple diethyl ether (1 l and 500 ml). The combined organic fractions washed with a saturated solution of salt, dried (MgSO4) and concentrated in vacuo. Rubbing the obtained oily residue gives a white solid which is collected by filtration and washed the hexane, receiving a connection 59 (62,0 g). The mother liquid was concentrated in vacuo and the residue is subjected to recrystallization from a mixture of EtOAc/hexane at 0oC, receiving additional connection 59 (38,3 g). Additional three repetitions of this method recrystallization additionally give compound 59 (40,5 g).1H NMR (CDCl3) δ 1,68-of 1.78 (m, 4H), 2,11-of 2.21 (m, 3H), 2,31 is 2.46 (m, 2H), 2.95 points (t, J=7.4 Hz, 2H), of 3.73 (s, 3H), 3,82-a 3.87 (m, 2H), 5,73 (s, 1H), 6,99 (d, J=8.0 Hz, 2H), 7,29-7,32 (m, 1H), 7,37 (s, 1H).

Connection 82a.In a 5 l 3-necked round bottom flask containing compound 59 (140 g, 418 mmol), type Et3N (280 ml, 2.03 mol), benzyl alcohol (420 ml, 4,06 mmol) and toluene (1.4 l). The resulting solution was rinsed CO for 5 min before adding Pd(PPh3)4(9,34 g, 8 mmol). The reaction mixture is heated to 90oC for 8 h with aeration CO. The mixture is stirred in a bath with ice for 30 min and filtered and the precipitate washed with EtOAc. The filtrate is washed with water, saturated salt solution and dried over sodium sulfate. The solvents and excess benzyl alcohol is removed in vacuo. The residue is dissolved in DCM (50 ml) and hexane (50 ml) and filtered through a funnel filled with silica gel (500 g). The gasket washed with hexane/EtOAc (gradient elution: 9/1 to 1/1). Concentration in vacuo gives compound 81 as a yellow oil (160 g). Compound 81 was dissolved in EtOH (12 l) and added Pd on carbon (1%, 20 g). The mixture is stirred in hydrogen atmosphere for 2 days, filtered through the gasket from celite and concentrated in vacuo, getting a white solid (120 g). To the crude product added EtOAc (200 ml) and the mixture is heated to boiling under reflux for 1 min and filtered. The filtrate is again heated to boiling under reflux and slowly add hexane. The mixture is cooled slowly to room temperature, obtaining a white crystalline solid, which is collected by filtration (44 g of TRANS-isomer 82a). Uterine fluid concentrate, and recrystallization from a mixture of EtOAc:hexane gives additional 16 g of compound 82a.1H NMR (CDCl3) δ 1,23-of 1.27 (m, 2H), 1,59-1,90 (m, 7H), 2,03 (t, J=7.4 Hz, 2H), 2,28 (d, J=7,0 Hz, 2H), 2,93 (t, J=7.4 Hz, 2H), 3,70 (s, 3H), 7,21 (d, J=7.9 Hz, 1H), to 7.93 (s, 1H), 7,95 (d, J=7.9 Hz, 1H). Mass spectrum (ESI+) m/e=303 (M+1).

Connection 83.DMF (200 μl) are added to a solution of compound 82a (57,23 g, 0,189 mol) and oxalicacid (to 19.8 ml, 0,227 mol) in CH2Cl2(500 ml) at 0°C in nitrogen atmosphere. The reaction mixture was stirred at 0°C for 15 min and at room temperature for 3 hours the Solvent is removed in vacuum, obtaining the acid chloride of the acid in the form of not-quite-white solid (60,3 g). In a three-neck 2 l round bottom flask is charged with CuCN (4,19 g, 46.8 mmol) and anhydrous THF (500 ml) and cooled to 25° C. To this stirred suspension is added 2 M solution of chloride Isopropylamine (46,8 ml of 93.5 mmol in THF) dropwise, maintaining the internal temperature between -25 -22°C. To this solution was added a solution of carboxylic acid (getting above) (10 g, and 31.2 mmol) in anhydrous THF (50 ml) dropwise, maintaining an internal temperature between -20 and -17°C. the Reaction mixture is stirred at -15°C for 1 h and quenched with 10% NH4OH in a saturated aqueous NH4Cl (300 ml). This solution is heated to room temperature and the layers separated. The organic layer is washed with 10% NH4OH in a saturated aqueous NH4Cl (2 × 300 ml), saturated salt solution (1 × 300 ml), dried (MgSO4), filtered and concentrated in vacuo, obtaining compound 83 as not quite white solid (10,08 g).1H NMR (CDCl3) δ 7,83 (m, 2H), 7,22 (d, J=8,4 Hz, 1H), and 3.72 (s, 3H), 3,54-to 3.58 (m, 1H), equal to 2.94 (t, J=7.4 Hz, 2H), 2,30 (d, J=7,0 Hz, 2H), 2,04 (t, J=7.4 Hz, 2H), 1,92 (m, 1H), 1,78 (m, 2H), 1,69-of 1.64 (m, 4H), 1,28 (m, 2H), 1,23 (d, J=6.8 Hz, 6H). Mass spectrum (ESI+) m/e=329 (M+1).

The connection 84.A solution of compound 83 (5 g, of 15.2 mmol) in EtOAc (100 ml) and chloroform (100 ml) is treated with CuBr2(10 g, with 44.8 mmol) and the mixture heated to boiling under reflux for 8 h before cooling to room temperature. The reaction mixture was filtered and washed with EtOAc. The filtrate is washed with water, saturated salt solution and su is at over sodium sulfate. The solvents are removed in vacuo and add hexane (20 ml). White solid 84 receive under stirring and collected by filtration (5 g). Additional connection 84 (0,76 g) is obtained by crystallization from the mother liquor at 0oC.1H NMR (CDCl3) δ 1,25-of 1.28 (m, 2H), 1,61-of 1.92 (m, 7H), 2,03-to 2.06 (m, 8H), to 2.29 (d, J=7,0 Hz, 2H), equal to 2.94 (t, J=7.4 Hz, 2H), and 3.72 (s, 3H), 7,19 (d, J=8.0 Hz, 1H), to 7.99 (s, 1H), with 8.05 (d, J=8.0 Hz, 1H). Mass spectrum (ESI+) m/e=407 and 409 (M+1).

Connection 86.To compound 84 (0.5 g, of 1.23 mmol) and 4,5-diamino-6-hydroxy-2-cryptomaterial (compound 85, J.A. Barone et al., J. Med. Chem., 1969, 6, 39; P.D. Landauer et al., J. Chem. Soc. 1953, 3721) (0.26 g, of 1.34 mmol) is added methanol (13 ml), 2n. HCl (2 ml) and water (5 ml). The mixture is heated at the boil under reflux for 24 h, cooled and concentrated in vacuo. To the residue is added water (10 ml) and the precipitate collected by filtration, washed with pentane and dried in vacuum, obtaining a connection 86 (375 mg) as a white solid.1H NMR (DMSO-d6) δ 1,18-of 1.27 (m, 2H), 1,48 is 1.86 (m, 13H), to 1.98 (t, J=7,3 Hz, 2H), 2,28 (d, J=7.2 Hz, 2H), 2,89 (t, J=7,1 Hz, 2H), 3,61 (s, 3H), 7,28 (d, J=8.0 Hz, 1H), 7,53 (d, J=8.0 Hz, 1H), 7,58 (s, 1H).

Example 8-3.To a stirred solution of compound 86 (100 mg, 0,199 mmol) in DMF (1 ml) is added anhydrous lithium iodide (670 mg, 5 mmol). The mixture is heated at 125-130oC for 24 h and poured into water (20 ml). The precipitate is collected by filtration and washed in the DOI. The residue is subjected to recrystallization from ethanol, obtaining the compound of Example 8-3 (70 mg) as a white solid.1H NMR (DMSO-d6) δ 1,17-of 1.26 (m, 2H), 1,48-to 1.82 (m, 16H), to 1.98 (t, J=7.4 Hz, 2H), 2,18 (d, J=6,8 Hz, 2H), 2,90 (t, J=7.2 Hz, 2H), 7,28 (d, J=8,1 Hz, 1H), 7,37 (users, 1H), 7,53 (d, J=8,1 Hz, 1H), 7,58 (s, 1H), 7,80 (users, 1H), 12,05 (users, 1H).

Example 8-4:

Connection 89.In dry odnogolosy a round bottom flask of 500 ml download inden 87 (8,91 g, 76,65 mmol) and THF (60 ml). The solution is stirred and cooled in a bath with ice. To the flask was added lithium bis(trimethylsilyl)amide (153,3 ml, 1.0 M in THF, 153,3 mmol) via syringe over a period of 30 minutes the resulting mixture was stirred at 0°C for 30 min and transferred by cannula to a stirred solution of dibromoethane 88 (20,0 g, 66,23 mmol) in THF at 0°C within 30 minutes After the addition, the reaction mixture was stirred for 2 h at 0°C and 30 min at room temperature. The solvent is evaporated in vacuo and the residue purified by chromatography on silica gel (hexane/EtOAc 25/1 to 15/1; gradient elution)to give compound 89 (15.0 g) as light yellow crystals.1H NMR (CDCl3) δ 1,43 (d, J=13.5 Hz, 2H), 1,88 of 1.99 (m, 4H), 2,20 (d, J=4.0 a, 13,0 Hz, 2H), 4,06 (s, 4H), 6,78 (d, J=6.0 Hz, 1H), 6,85 (d, J=6.0 Hz, 1H), 7,20-7,27 (m, 2H), 7,34 (d, J=7.5 Hz, 1H), 7,42 (d, J=7.5 Hz,, 1H). MA is with spectrum (ESI+) m/e=243 (M ++1).

The connection 90.To a solution of compound 89 (15.0 g, 62 mmol) in MeOH (350 ml) is added 3 M H2SO4(60 ml). The reaction mixture is heated to boiling under reflux for 7 h under nitrogen atmosphere. The mixture is cooled to room temperature and the MeOH removed in vacuo. The mixture is diluted with water with ice and extracted with EtOAc (100 ml × 3), washed with water (25 ml × 2) and saturated salt solution (20 ml) and dried over MgSO4. Concentration in vacuo gives the crude product, which was purified column chromatography on silica gel (hexane/EtOAc 20/1)to give compound 90 (10.0 g) as a white solid.1H NMR (CDCl3) δ to 1.76 (m, 2H), 2,34 (m, 2H), 2,68 (m, 4H), of 6.90 (d, J=6.0 Hz, 1H), 6,95 (d, J=6.0 Hz, 1H), 7,25-7,51 (m, 4H). Mass spectrum (ESI+) m/e=199 (M+1).

Connection 91.A suspension of NaH (60% dispersion in mineral oil) (2,45 g, 61,25 mmol) in THF (200 ml) in a pre-dried flask of 500 ml, cooled to 0°C in nitrogen atmosphere. To the flask was added a solution of triethyl 2-phosphonopropionic (14,60 g, 61,25 mmol) in THF (10 ml) dropwise at 0°C for 15 minutes the Mixture is stirred at 0°C for 15 min and a solution of compound 90 (7,8 g, 39,20 mmol) in THF (50 ml) is added via addition funnel dropwise over 25 minutes After the addition the mixture is stirred at room temperature overnight. The reaction is quenched with aqueous saturated solution of NH4Cl and e is stragiht EtOAc, washed with water and saturated salt solution and dried over MgSO4. Evaporation of the solvent gives the crude product, which was purified column chromatography on silica gel (hexane/EtOAc 20/1)to give compound 91 (10.0 g) as a white solid.1H NMR (CDCl3) δ to 1.35 (t, J=7,1 Hz, 3H), 1,50-1,60 (m, 2H), up to 1.98 (s, 3H), 1,95-2,05 (m, 2H), 2,25-2,48 (m, 2H), 2,75-2,90 (m, 1H), 3,10-of 3.25 (m, 1H), 4,25 (kV, J=7,1 Hz, 2H), for 6.81 (d, J=5.7 Hz, 1H), 6,93 (d, J=5,7 Hz, 1H), 7,20 was 7.36 (m, 4H).

The connection 92.Compound 91 (5.6 g, of 19.72 mmol) dissolved in EtOAc (60 ml) and hydronaut over palladium (10% on coal), using gaseous hydrogen at atmospheric pressure for 24 hours the Mixture is filtered through celite and the filtrate was concentrated in vacuo, obtaining the product 92 (5,4 g) as a colourless oil, which was used directly in the next reaction without further purification.1H NMR (CDCl3) δ of 1.18 (d, J=7,0 Hz, 3H), of 1.30 (t, J=7,1 Hz, 3H), 1,61-of 1.85 (m, 9H), to 1.98 (t, J=7.5 Hz, 2H), 2,31 (m, 1H), 2,89 (t, J=7.4 Hz, 2H), 4,14-4,19 (m, 2H), 7,05-7,20 (m, 4H).

Connection 93.Compound 92 (2,63 g of 9.21 mmol) dissolved in MeOH/THF/H2O (40 ml, 5/2/1). To the above solution add monohydrate of lithium hydroxide (1,93 g, 46,0 mmol) and the mixture was stirred at 50°C during the night. MeOH is removed in vacuo and the reaction mixture is acidified with 2n. HCl. The mixture is extracted with EtOAc (25 ml × 3), washed with water, saturated salt solution and dried over MgSO4. Evaporation RA is the solvent gives the crude product, which is purified column chromatography on silica gel (hexane/EtOAc 8/1)to give compound 93 (2.38 g) as a white solid1H NMR (CDCl3) δ 1,24 (d, J=7,02 Hz, 3H), 1,61-of 1.85 (m, 10H), 1,95-2,0 (m, 2H), 2.3 to 2.4 (m, 1H), 2,88 of 2.92 (m, 2H), 7,05-7,20 (m, 4H). Mass spectrum (ESI+) m/e=258 (M).

Connection 94a and 94b.To connect 93 (2.2 g, 8,53 mmol) in CH2Cl2when 0°C in an atmosphere of nitrogen was added (COCl)2(of 0.82 ml, 9,38 mmol) and a drop of DMF. The reaction mixture was stirred at 0°C for 1 h To this solution of the resulting carboxylic acid is added a solution of (S)-(-)-4-benzyl-2-oxazolidinone (1.66 g, 9,37 mmol), DMAP (1,09 g of 8.92 mmol) and triethylamine (of 1.88 ml, 13,49 mmol) in CH2Cl2dropwise at 0°C in nitrogen atmosphere. After the addition the mixture is stirred at room temperature for 2 hours the Reaction is quenched by addition of saturated aqueous NH4Cl, extracted with EtOAc (25 ml × 3), washed with water (10 ml × 2), saturated salt solution and dried over MgSO4. Concentration in vacuo gives the crude product, which was purified column chromatography on silica gel (hexane/EtOAc 19/1 to 10/1)to give compound 94a (926 mg) and 94b (1.27 g). NB: stereochemical distribution of compounds 94a and 94b is random. Connection 94a:1H NMR (CDCl3) δ of 1.26 (d, J=6.9 Hz, 3H), 1.61 of and 1.80 (m, 2H), 1,80-of 1.95 (m, 7H), 1,99 (t, J=7,3 Hz, 2H), 2,80 (DD, J=9,6, J=13.3 Hz, 1H), only 2.91 (t, J=7.4 Hz, 2H), to 3.33 (DD, J=3.2, and 13.3 Hz, 1H), ,71-3,75 (m, 1H), 4,15-to 4.23 (m, 2H), 4,70-4,78 (m, 1H), 7,05-7,37 (m, 9H). Mass spectrum (ESI+) m/e=418 (M+1). [α]26=+54,85 (c=0,60, CH2Cl2). Compound 94b:1H NMR (CDCl3) δ to 1.21 (d, J=6.9 Hz, 3H), 1,25-of 1.95 (m, 9H), for 2.01 (t, J=7.4 Hz, 2H), 2,75 (m, 1H), 2,90 (t, J=7,3 Hz, 2H), 3,32-to 3.41 (m, 1H), of 3.73-of 3.78 (m, 1H), 4,12-4,22 (m, 2H), 4,73-of 4.77 (m, 1H), 7,05-7,39 (m, 9H). Mass spectrum (ESI+) m/e=418 (M+1). [α]26=+10,12 (c=0,60, CH2Cl2)

Connection 95a.To a stirred solution of compound 94a (900 mg, of 2.16 mmol) in THF (30 ml) and H2O (10 ml) add H2O2(30%, 1.8 ml of 17.7 mmol) and the monohydrate of lithium hydroxide (360 mg, 8,55 mmol) at 0°C. the Reaction mixture was allowed to warm to room temperature overnight and quenched with saturated aqueous Na2SO3and acidified with 10% HCl. The mixture is extracted with EtOAc (15 ml × 3), washed with water (5 ml × 2), saturated salt solution and dried over MgSO4. Concentration in vacuo gives the crude product, which was purified column chromatography on silica gel (hexane/EtOAc 8/1)to give compound 95a (500 mg) as a white solid.1H NMR (CDCl3) δ 1,24 (d, J=7,0 Hz, 3H), 1,61-of 1.85 (m, 10H), 1,95-2,0 (m, 2H), 2,30-to 2.40 (m, 1H), 2,88 of 2.92 (m, 2H), 7,05-7,20 (m, 4H). Mass spectrum (ESI+) m/e=258 (M).

Connection 95b.Connection 95b (ent-95a) is produced from compound 94b just as described for the conversion of compound 94a 95a in above.

Example 8-4.To a suspension of anhydrous AlCl3(484 mg, 3.63 mmol) in CHsub> 2Cl2(5 ml) is added 2-bromoisobutyrate (of 0.21 ml, 1.70 mmol) dropwise at 0°C in nitrogen atmosphere. The mixture is then stirred for 5 min, a solution of compound 95a (376 mg, of 1.46 mmol) in CH2Cl2(20 ml) is added dropwise. After stirring at 0°C for 1 h the mixture was poured into ice water and extracted with CH2Cl2(15 ml × 3). The combined organic layer is washed successively with water, saturated NaHCO3and saturated salt solution, dried over MgSO4and concentrated in vacuo. To the residue add 2-methyl-4,5-diamino-6-hydroxypyrimidine (PD Landauer et al., J. Chem. Soc. 1953, 3721) (250 mg, 1.54 mmol), 1H. HCl (5 ml, 5 mmol), water (5 ml) and EtOH (25 ml). The reaction mixture is heated to boiling under reflux overnight. The reaction mixture is cooled to room temperature and EtOH is removed by evaporation. The residue was diluted with saturated aqueous NH4Cl and extracted with EtOAc (15 ml × 3). The combined organic layer is washed successively with water and saturated salt solution, dried over MgSO4and concentrated in vacuo. To the residue add MeOH/THF/H2O (15 ml, 1/1/1) and the monohydrate of lithium hydroxide (200 mg, 4.77 mmol) and the mixture was stirred at 45°C for 40 h MeOH removed in vacuo and the residue acidified with 2n. HCl. This mixture is extracted with EtOAc (15 ml × 3), washed with water, saturated solution of the m salt and dried over MgSO 4. Concentration in vacuo gives the crude product, which was purified HPLC (reversed phase), obtaining the compound of Example 8-4 (65,6 mg) as a white solid.1H NMR (DMSO-d6) δ of 1.07 (d, J=7,0 Hz, 3H), 1,15-1,35 (m, 1H), 1,50-of 1.81 (m, 6H), and 1.63 (s, 6H), to 1.96 (t, J=7.5 Hz, 2H), of 2.21 (m, 1H), 2,34 (s, 3H), 2,45 is 2.55 (m, 2H), 2,88 (t, J=7.5 Hz, 2H), 7,25 (m, 1H), 7,51-7,54 (m, 4H), 12,0 (users, 1H). Mass spectrum (ESI+) m/e=449 (M+1).

Example 8-5.Connection Example 8-5 (ent-Example 8-4) get like getting a connection Example 8-4 95a of the above.

Example 8-6:

This connection will receive the same manner as in example 8.1H NMR (DMSO-d6) δ 1,14-of 1.23 (m, 2H), 1,47 and 1.80 (m, 15H), a 1.96 (t, J=7,3 Hz, 2H), 2,15 (d, J=7,0 Hz, 2H), 2,32 (s, 3H), 2,87 (t, J=7,3 Hz, 2H), 7,10 (with, of user., 2H), 7,24 (d, J=7.8 Hz, 1H), 7,43-to 7.50 (m, 2H).

Example 8-7:

This connection will receive the same manner as in example 8.1H NMR (DMSO-d6) δ 1,39-of 1.45 (m, 2H), 1,47-of 1.55 (m, 2H), 1,60-1,75 m, 10H), was 1.94 (t, J=7.2 Hz, 2H), 2,03 (m, 1H), 2,38 (d, J=7,3 Hz, 2H), 2,87 (t, J=7,3 Hz, 2H), 7,35 (with, of user., 1H), 7,44 (d, J=8.0 Hz, 1H), 7,52 (d, J=8.0 Hz, 1H), EUR 7.57 (s, 1H), to 7.77 (s, user., 1H).

Example 9

Connection 97.Connection 96 is obtained from 4-phenylcyclohexanone and triethyltetramine just as described for the conversion of compound 1 in 2 (Example 2). Compound 97 was obtained from 96 under the GHP to as described for the conversion of 2 into 3 (Example 2).

Connection 98.To a stirred solution of compound 97 (2.86 g, 11 mmol) in methanol (83 ml) is added lithium hydroxide (2,62 g, 110 mmol) in water (28 ml). The mixture is heated at the boil under reflux for 2 hours and allow to cool to room temperature and the methanol removed in vacuo. The aqueous solution was washed with simple diethyl ether, acidified with 1N. HCl to pH 1 and extracted with a simple diethyl ether (3×). The combined organic substance is dried (MgSO4), filtered and concentrated in vacuo, obtaining compound 98 (2,31 g) as a white solid.1H NMR (CDCl3) δ of 1.23 (d, J=7.2 Hz, 3H), of 1.29 and 1.33 (m, 2H), 1,42-to 1.59 (m, 2H), was 1.69 and 1.80 (m, 2H), 1.85 to 2,00 (m, 3H), 2,30-2,39 (m, 1H), 2,45-2,60 (m, 1H), 7,21-7,34 (m, 5H).

Connection 99a and 99b.To a stirred solution of compound 98 (13.5 g, to 58.1 mmol) in DCM (225 ml) is added 3 drops of DMF. The mixture is cooled to 0oC and oxalicacid (5,58 ml, 63,91 mmol) is added dropwise. The mixture is stirred at room temperature for 2 h and added dropwise in a separate vessel, stereosushi (S)-4-benzyl-2-oxazolidinone (10,81 g, 61 mmol), DMAP (7,1 g, to 58.1 mmol), Et3N (20,24 ml, 145,3 mmol) and DCM (100 ml) at 0oC. the Mixture was allowed to warm to room temperature and stirred at room temperature for 12 hours, Add water (300 ml). The organic layer is separated and washed the Ute 1H. HCl (200 ml), saturated aqueous sodium bicarbonate (200 ml) and saturated salt solution and dried (MgSO4), filtered and concentrated in vacuo. The residue is purified flash chromatography (silica gel 5-40% EtOAc in hexane,gradient elution)to give compound 99a (11,48 g) as white crystals and compound 99b (10,75 g) as a white foam. NB: stereochemical distribution of compounds 99a and 99b is random. Connection 99a:1H NMR (CDCl3) δ 1,17 is 1.34 (m, 5H), 1,45 is 2.01 (m, 7H), 2,49 (TT, J=12.3 Hz, J=3.5 Hz, 1H), 2,81 (DD, J=9.6 Hz, J=13,2 Hz, 1H), 3,33 (DD, J=3.2 Hz, J=a 13.4 Hz, 1H), 3,74 (Queen, J=7,0 Hz, 1H), 4,19-of 4.25 (m, 2H), 4,70 was 4.76 (m, 1H), 7,19-7,39 (m, 10H). Connection 99b:1H NMR (CDCl3) δ to 1.21 (d, J=6.9 Hz, 3H), 1,25-2,02 (m, 9H), of 2.51 (TT, J=12.1 Hz, J=3,4 Hz, 1H), 2,74 (DD, J=10.0 Hz, J=13,2 Hz, 1H), 3,40 (DD, J=3,4 Hz, J=13,2 Hz, 1H), 3,78 (Queen, J=6,8 Hz, 1H), 4,12-is 4.21 (m, 2H), 4.72 in-rate 4.79 (m, 1H), 7,19-7,39 (m, 10H).

Connection 100a.To a stirred solution of compound 99a (10,48 g, 26.8 mmol) in THF (400 ml) and water (125 ml) at 0°C add lithium hydroxide (1.28 g, 53.6 mmol) and 3% hydrogen peroxide (to 10.7 ml). The mixture was stirred at 0°C for 75 min and an aqueous solution of sodium sulfite (14,75 g in 80 ml water) is added, followed by addition of 0.5 M aqueous sodium bicarbonate (270 ml). The aqueous layer was washed with DCM and acidified with 5 N. HCl to pH 1 and extracted with EtOAc. The ethyl acetate layer is dried (MgSO4), filtered and concentrated in vacuo, receiving the connection 100a (1 g) as white is th solids.

Additional material can be obtained from the DCM layer.1H NMR (CDCl3) δ 1,22 (d, J=7.2 Hz, 3H), of 1.23 and 1.33 (m, 2H), 1,50-of 1.56 (m, 2H), 1,58-of 1.65 (m, 1H), 1,87 is 2.01 (m, 4H), 2,38 (Queen, J=6,8 Hz, 1H), 2,50 (TT, J=3.2 Hz, J=12.0 Hz, 1H), 7.18 in-7,33 (m, 5H).

Connection 100b.Connection 100b (ent-100a) is produced from compound 99b like getting a connection 100a 99a of the above.

Connection 101a.Connection 101a get from 100a is similar as described for the conversion of compound 3 in 4 (Example 2).1H NMR (CDCl3) δ of 1.23 (d, J=7.2 Hz, 3H), of 1.29 and 1.33 (m, 2H), 1,42-to 1.59 (m, 2H), was 1.69 and 1.80 (m, 2H), 1.85 to 2,00 (m, 3H), 2,30-2,39 (m, 1H), 2,45-2,60 (m, 1H), 7,21-7,34 (m, 5H).

Connection 101b.Compound 101b (ent-101a) is produced from compound 100b is similar to obtaining connection 101a of the above 100a.

Example 9.The compound of Example 9 is obtained from 101a and 4,5-diamino-6-hydroxy-2-methylpyrimidine (P.D. Landauer et al., J. Chem. Soc., 1953, 3721.) just as described for the conversion of compound 4 to compound of Example 2.1H NMR (CDCl3) δ 1,24 (d, J=6.8 Hz, 3H), between 1.25-1.30 (m, 2H), 1,48-to 1.59 (m, 3H), 1,71 (s, 6H), 1.91 a is 2.00 (m, 4H), a 2.36-2.40 a (m, 1H), 2,46 (s, 3H), of 2.51-2.57 m (m, 1H), 7,27 (d, J=8,4 Hz, 2H), 7,55 (d, J=8,4 Hz, 2H). Mass spectrum (ESI+) m/e=423,3 (M+1).

Example 9-2.The compound of Example 9-2 (ent-Example 9) is produced from compound 101b is similar to obtaining compounds of Example 9 from 101a above.

Example 9-3:

This connection will receive the same manner as in example 9.1H NMR (DMSO-d6) ; of 1.10-1.20 (m, 2H), 1,42-1,90 (m, 13H), 2,17 (d, J=6,8 Hz, 2H), 2,45-2,60 (m, 1H), 7,34 (d, J=8 Hz, 2H), was 7.36 (users, 1H), 7,71 (d, J=8 Hz, 2H), 7,74 (users, 1H), 12,04 (users, 1H).

Compounds shown in table 10, is obtained by combination of the methods described above.

Table 1
New example No.MastrocolaTPLNMR (δ)Solvent
1>2005,44(8, 2H), 7,10 (users, 2H), 7,69 (d, 2H, J=8.6 Hz), to 7.93 (s, 1H), 8,03 (d, 2H, J=8.6 Hz)DMSO-d6, 400 MHz
1-2>2205,46 (s, 2H), 7,08 (users, 2H), 7,35 (t, 2H, J=7.5 Hz), 7,94(s, 1H), 8,15-8,19 (m, 2H)DMSO-d6, 400 MHz
1-3>2205,46 (s, 2H), 7,12 (users, 2H), EUR 7.57 (d, 2H, J=6.0 Hz), 7,94 (s, 1H), 8,13 (d, 2H, J=9.0 Hz)DMSO-d6, 400 MHz
1-4217-2192,39 (s, 3H), 5,43 (s, 2H), 7,03 (users, 2H), 7,32 (d, 2H, J=6.0 Hz), to 7.93 (s, 1H), to 7.99 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-5 with 5.22 (s, 2H), 7,02 (users, 2H), 7,45 (t, 1H, J=6.0 Hz), 7,53 (t, 1H, J=4.5 Hz), to 7.64 (d, 1H, J=6.0 Hz), 7,76 (d, 1H, J=6.0 Hz), to 7.99 (s, 1H)DMSO-d6, 400 MHz
1-6206 decomp.to 1.14 (t, 6H, J=6.0 Hz), 3,44 (q, 4H, J=5.0 Hz), of 5.34 (s, 2H), 6,72 (d, 2H, J=6.0 Hz), 6,84 (users, 2H), 7,88 (s, 1H), of 7.90 (d, 2H, J=9.0 Hz)DMSO-d6, 400 MHz
1-7>220the 5.45 (s, 2H), 7,19 (users, 2H), 7,46 (t, 1H, J=6.0 Hz), 7,72 (d, 1H, J=6.0 Hz), 7,95 (s, 1H), 8,01 (d, 1H, J=6.0 Hz), 8,39 (s, 1H)DMSO-d6, 400 MHz
1-8>220the 5.51 (s, 2H), 7,19 (users,2H), 7,86 (d, 2H, J=6.0 Hz), of 7.96 (s, 1H), 8.30 to (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-9176-178of 1.23 (d, 6H, J=6.0 Hz), 2.93 which is 3.00 (m, 1H), 5,42 (s, 2H), 7,01 (users, 2H), was 7.36 (d, 2H, J=6.0 Hz), 7,92 (s, 1H), to 7.99 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-10222-224of 1.33 (d, 3H, J=6.0 Hz), 5,98 (kV, 1H, J=6.0 Hz), 7,14 (users, 2H), 7,69 (d, 2H, J=6.0 Hz), 7,95 (s, 1H), 8,09 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-11 >2505,49 (s, 2H), 7,08 (users, 2H), 7,39-the 7.43 (m, 1H), 7,49-7,52 (m, 2H), 7,76-7,81 (m, 4H), to 7.93 (s, 1H), 8,18 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-12191-193of 3.84 (s, 3H), of 5.40 (s, 2H), 6,98 (users, 2H), 7,03 (d, 2H, J=6.0 Hz), of 7.90 (s, 1H), with 8.05 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-13>2505,52 (s, 2H), 7,25 (users, 2H), of 7.96 (s, 1H), 8.30 to (d, 2H, J=6.0 Hz), a 8.34 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-14>220of 2.25 (s, 3H), of 5.40 (s, 2H), 7,05 (users, 2H), of 7.70 (d, 2H, J=9.0 Hz), 8,03 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
1-1575-77of 5.05 (s, 2H), 5,58 (users, 2H), the 6.06 (DD, 1H, J=1,1, 8.0 Hz), 6,32 (DD, 1H, J=1,1, 8.0 Hz), 6,85 (t, 1H, J=8.0 Hz), 7,69 (d, 2H, J=8.6 Hz), of 8.04 (d, 2H, J=8.6 Hz)DMSO-d6, 300 MHz
1-16215to 5.56 (s, 2H), 7,22 (user., 2H), 7,51-of 7.55 (m, 1H), 7.95 is-8,00 (m, 2H), charged 8.52-8,55 (m, 1H), 8,65-8,67 (m, 1H)DMSO-d6, 300 MHz
1-17>2205,49 (s, 2H), 7,21 (ush the D.C, 2H), 7,51-of 7.55 (m, 1H), 7,94 (s, 1H), 8,44-8,48 (m, 1H), 8,68-to 8.70 (m, 1H), 9,27 (s, 1H)DMSO-d6, 300 MHz
1-18>220of 5.48 (s, 2H), 7,28 (user., 2H), of 7.96 (s, 1H), 8,01 (d, 2H, J=6.0 Hz), 8,73 (d, 2H, J=6.0 Hz)DMSO-d6, 300 MHz
1-19191-193to 1.21 (t, 3H, J=7.5 Hz), 2,68 (q, 2H, J=7.0 Hz), 5,43 (s, 2H), 7,07 (users, 2H), 7,34 (d, 2H, J=9.0 Hz), 7,92 (s, 1H), 8,01 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
1-20189-192of 0.90 (t, 3H, J=7.5 Hz), 1.56 to its 1.68 (m, 2H), 2,60-to 2.65 (m, 2H), 5,43 (s, 2H), 7,07 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), 7,92 (s, 1H), 8,01 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
1-21183-186of 0.91 (t, 3H, J=7.5 Hz), of 1.27 to 1.37 (m, 2H), 1,53-to 1.63 (m, 2H), 2,62-to 2.67 (m, 2H), 5,43 (s, 2H), 7,08 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), 7,92 (s, 1H), 8,00 (d, 2H, J=9.0 Hz)DMSO-d6, 400 MHz
1-221421,14-of 1.45 (m, 5H), 1,61-of 1.85 (m, 5H), 2,23-of 2.30 (m, 1H), 4,89 (s, 2H), 6,74 (users, 2H), 7,87 (s, 1H)DMSO-d6, 400 MHz
1-23209-212vs. 5.47 (s, 2H), 7,17 (ush the D.C, 2H), 7,49 (d, 2H, J=6.0 Hz), 7,94 (s, 1H), they were 8.22 (d, 2H, J=6.0 Hz)DMSO-d6, 300 MHz
1-24to 5.35 (s, 2H), 6,95 (users, 2H), 7,35 (d, 2H, J=6.0 Hz), 7,52 (d, 2H, J=3.0 Hz), 7,92 (s, 1H)DMSO-d6, 300 MHz
1-25219-2211,23-is 1.51 (m, 5H), 1,69-of 1.85 (m, 5H), to 2.55 2.63 in (m, 1H), 5,43 (s, 2H), 7,06 (users, 2H), 7,92 (s, 1H), 8,00 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
1-26>220the 5.25 (s, 2H), 6,24 (users, 2H), 6,55 (users, 2H), 7,63 (d, 2H, J=12.0 Hz), 7,92 (d, 2H, J=12.0 Hz)DMSO-d6, 400 MHz
1-27>220the 5.45 (s, 2H), 7,29 (users, 2H), to 7.77 (d, 1H, J=9.0 Hz), 7,94 (s, 1H), 8,02 (d, 1H, J=9.0 Hz), 8,46 (s, 1H)DMSO-d6, 300 MHz
1-28218-220with 5.22 (s, 2H), 7,17 (users, 2H), EUR 7.57-of 7.60 (m, 1H), 7,75-7,79 (m, 2H), to 7.99 (s, 1H)DMSO-d6, 300 MHz
1-29>220to 5.35 (s, 2H), 7,18 (users, 2H), 7,65 (d, 2H, J=9.0 Hz), 7,92 (d, 2H, J=6.0 Hz), 10,67 (users, 1H)DMSO-d6, 400 MHz
1- 30>220totaling 3.04 (s, 6H), at 5.27 (s, 2H), 6.73 x (users, 2H), 7,63 (d, 2H, J=6.0 Hz), 7,94 (d, 2H, J=6.0 Hz)DMSO-d6, 400 MHz
1-31190-192of 5.17 (s, 2H), 8,01 (s, 1H)DMSO-d6, 300 MHz
1-32>2004,07 (DD, 1H, J=7,6 and 10.7 Hz), 4,33 (DD, 1H, J=1,6 and 10.7 Hz), 4,48 (m, 1H), 5,19 (users, 1H), 6,27 (users, 2H), 7,40 (d, 2H, J=8.6 Hz), 7,58 (s, 1H), 7,60 (d, 2H, J=8.6 Hz),DMSO-d6, 400 MHz
1-330,99 (d, 3H, J=6.0 Hz), 4,54 (users, 2H), are 5.36 (user., 1H), 6,36 (user., 2H), 7,28 (d, 2H, J=6.0 Hz), 7,58 (d, 2H, J=9.0 Hz), the 7.65 (s, 1H)DMSO-d6, 300 MHz
1-34232-233of 2.16 (s, 3H), 4,03-4,08 (m, 1H), 4,29-4,32 (m, 1H), 4,42 is 4.45 (m, 1H), 4,99 (users, 1H), to 6.19 (users, 2H), 7,40 (d, 2H, J=6.0 Hz), to 7.59 (d, 2H, J=9.0 Hz)DMSO-d6, 400 MHz
1-35>2204,56-to 4.73 (m, 2H), 5,46-5,49 (m, 1H), 7,26 (d, 2H, J=9.0 Hz), 7,60 (d, 2H, J=9.0 Hz), 8,30 (s, 1H), 11,94 (users, 1H)DMSO-d6, 300 MHz
1-36 198-2004.09 to to 4.15 (m, 1H), 4,34-to 4.38 (m, 1H), 4,54 (users, 1H), 5,23 (users, 1H), 6.35mm (users, 2H), 7,45 (d, 1H, J=12.0 Hz), 7,63 (s, 1H), 7,69 (d, 1H, J=9.0 Hz), 7,74 (s, 1H)DMSO-d6, 300 MHz
1-37>220as 4.02-4.09 to (m, 1H), 4,34-to 4.38 (m, 1H), 4,80 (users, 1H), 5,28 (users, 1H), 6.35mm (users, 2H), 7,51 (s, 2H), to 7.64 (s, 1H), of 7.70 (s, 1H)DMSO-d6, 300 MHz

Table 2
New example No.MastrocolaTPLNMR (δ)Dissolve ritel
2>2701,07-to 1.21 (m, 2H), 1,42-of 1.84 (m, 13H), of 2.15 (d, 2H, J=6.0 Hz), 2,53-of 2.56 (m, 1H), 6,97 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), 7,95 (s, 1H), 11,96 (users, 1H)DMSO-d6, 300 MHz
2-2224-2261,02-1,17 (m, 2H), 1,4-of 1.53 (m, 2H), 1.61 of (s, 6H), 1,66-to 1.87 (m, 5H), to 1.98 (d, 2H, J=7,12 Hz), 2,53 (m, 1H), 6,67 (user., 1H), 6.89 in (user., 2H), 7,21 (user., 1H), and 7.3 (d, 2H,J=8,12 Hz), 7,63 (d, 2H, J=8,12 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-3273-2791,03-1,22 (m, 8H), 1,4-1,49 (m, 2H), 1,7-to 1.82 (m, 5H), 214 (d, 2H, J=6,93 Hz)to 2.54 (m, 1H), 4,11 (user., 1H), 5,27 (user., 1H), 6,23 (user., 2H), 7,25 (d, 2H, J=8,07 Hz), was 7.36 (d, 2H,J=8,04 Hz), to 7.61 (s, 1H), 11,75 (user., 1H)DMSO-d6, 300 MHz
2-4>2501,04-of 1.09 (m, 2H), USD 1.43 (m, 1H), 1,43 of 1.50 (m, 4H), to 1.60 (s, 6H), 1,83 (userd, 4H, J=11,4 Hz in), 2.25 (t, 2H, j=7,7 Hz)of 2.50 (m, 1H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H), 11,84 (users, 1H)DMSO-d6, 400 MHz
2-5244-2461,04-1,08 (m, 2H), 1,29 (m, 1H), 1,40-1,49 (m, 4H), to 1.60 (s, 6H), 1,83 (userd, 4H, J=10,2 Hz), is 2.09 (t, 2H, j=7.4 Hz), 2,50 (m, 1H), 6,60 (users, 1H), 6,88 (users, 2H), 7,20 (users, 1H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-6>2501,04-of 1.09 (m, 2H), only 1.08 (s, 3H), 1,22 (s, 3H), 1,32 (m, 1H), USD 1.43 to 1.48 (m, 4H), 1,83 (userd, 4H, J=10,7 Hz), 2,24 (t, 2H, J=7,7 Hz)of 2.50 (m, 1H), 4,11 (s, 1H), 5,26 (s, 1H), 6.22 per (users, 2H), 7.23 percent (d, 2H, J=8,1 Hz), 7,35 (d, 2H, J=8.1 Hz), a 7.62 (s, 1H), 11,73 (users, 1H)DMSO-d6, 400 MHz
2-7>2501,42-of 1.55 (m, 4H), to 1.60 (s, 6H), 1,81 is 1.91 (m, 2H), 1,95-to 2.06 (m, 2H), 2,23 is 2.33 (m, 1H), 2,52-2,60 (m, 1H), 6.90 to (user., 2H), 7,30 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-8 >220of 1.07 (s, 3H), of 1.23 (s,3H), 4,17 (users, 1H), 5,31 (users, 1H), 6,26 (users, 2H), 7,35-7,47 (m, 5H), 7,63 (s, 1H)DMSO-d6, 300 MHz
2-9189-190to 1.60 (s, 6H), 6,93 (users, 2H), 7,44 is 7.50 (m, 3H), 7,69-7,71 (m, 2H), of 7.96 (s, 1H)DMSO-d6, 400 MHz
2-10201-203to 1.60 (s, 6H), 7,03 (users, 2H), 7,65 (d, 2H, J=9.0 Hz), of 7.70 (d, 2H, J=9.0 Hz), of 7.96 (s, 1H)DMSO-d6, 300 MHz
2-11>220to 1.22 (s, 3H), of 1.47 (s, 3H), 5,38 (s, 2H), 6,99 (d, 2H, J=6.0 Hz), 7,55 (d, 2H, J=6.0 Hz), 8,35 (s, 1H), 11,94 (users, 1H)DMSO-d6, 400 MHz
2-12>220of 1.05 (s, 3H), of 1.23 (s, 3H), 4,20 (users, 1H), 5,33 (users, 1H), 6,26 (users, 2H), 7,40 (d, 2H, J=9.0 Hz), 7,60 (d, 2H, J=6.0 Hz), 7,63 (s, 1H)DMSO-d6, 300 MHz
2-13184-1861,79 is 1.86 (m, 2H), 2,01-of 2.08 (m, 1H), 2,13-2,19 (m, 1H), 7,05 (users, 2H), to 7.61 (d, 2H, J=6.0 Hz), 7,66 (d, 2H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-14/img> 226-2331,29 to 1.76 (m, 4H), 4,37 (users, 1H), 5,51 (users, 1H), 6,23 (users, 2H), 7,27 (d, 2H, J=6.0 Hz), 7,55 (d, 2H, J=6.0 Hz), 7,63 (s, 1H)DMSO-d6, 300 MHz

2-15210-211to 1.60 (s, 6H), 7,05 (users, 2H), 7,52 (d, 2H, J=9.0 Hz), to 7.77 (d, 2H, J=9.0 Hz), of 7.96 (s, 1H)DMSO-d6, 300 MHz
2-16161-162to 1.60 (s, 6H), a 2.36 (s, 3H), 6,97 (users, 2H), 7,27 (d, 2H, J=9.0 Hz), 7,63 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-17189-190to 1.60 (s, 6H), 7,01 (users, 2H), 7,29 (DD, 2H, J=9,0, 9.0 Hz), 7,81 (DD, 2H, J=9,0, 9.0 Hz), of 7.96 (s, 1H)DMSO-d6, 300 MHz
2-18186-187to 1.21 to 1.47 (m, 5H), to 1.60 (s, 6H), 1.70 to to 1.82 (m, 5H), 2,54-of 2.58 (m, 1H), 6.89 in (users,2H), 7,29 (d, 2H, J=6.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-19>230of 1.05 (s, 3H), of 1.23 (s, 3H), 4,21 (users, 1H), 5,33 (users, 1H), 6,28 (users, 2H), 7,46 (s, 4H), 7,63 (s, 1H)DMSO-d6, 300 MHz
2-20 >230of 1.06 (s, 3H), 1,21 (s,3H), 2,31 (s, 3H), 4,12 (users, 1H), 5,26 (users, 1H), 6,27 (users, 2H), 7,20 (d, 2H, J=6.0 Hz), 7,34 (d, 2H, J=9.0 Hz), a 7.62 (s, 1H)DMSO-d6, 300 MHz
2-21>230of 1.06 (s, 3H), of 1.23 (s, 3H), 4,20 (users, 1H), 5,28 (users, 1H), 6.22 per (users, 2H), 7,22 (DD, 2H, J=6,0, 6,0 Hz), of 7.48 (DD, 2H, J=6,0, 6,0 Hz), 7,63 (s, 1H)DMSO-d6, 400 MHz
2-22>230a 1.08 (s, 3H), 1,22 (s, 3H), 1,26 of 1.46 (m, 5H), 1,69 of-1.83 (m, 5H), 2,47-of 2.54 (m, 1H), 4,11 (users, 1H), 5,28 (users, 1H), 6,25 (users, 2H), 7,25 (d, 2H, J=9.0 Hz), 7,37 (d, 2H, J=9.0 Hz), to 7.61 (s, 1H)DMSO-d6, 300 MHz
2-23183-184to 1.61 (s,6H), 3,82 (s, 3H), 6.87 in (users, 2H), 6,99 (d, 2H, J=6.0 Hz), 7,71 (d, 2H, J=6.0 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-24225-226of 1.06 (s, 3H), 1,21 (s, 3H), 3,76 (s, 3H), 4,11 (users, 1H), 5,23 (users, 1H) 6,26 (users, 2H), of 6.96 (d, 2H, J=9.0 Hz), 7,38 (d, 2H, J=9.0 Hz), a 7.62 (s, 1H)DMSO-d6, 300 MHz
2-25245-246to 1.60 (s, 6H), PC 6.82 (d,2H, J=9.0 Hz), 6,91 (users, 2H), a 7.62 (d, 2H, J=6.0 Hz), to 7.93 (s, 1H), 9,94 (s, 1H)D. the CO-d6, 300 MHz
2-26226-227 of1,19 of 1.46 (m, 5H), was 1.58 (s, 6H), 1,69-to 1.82 (m, 5H), of 2.25 (s, 3H), 2,52-of 2.58 (m, 1H), 6,86 (users, 2H), 7,29 (d, 2H, J=9.0 Hz), 7,63 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
2-27218-219of 1.66 (s, 6H), 7,02 (users, 2H), 7,39-7,53 (m, 3H), 7,73-to 7.77 (m, 4H), 7,83-7,86 (m, 2H), of 7.97 (s, 1H)DMSO-d6, 300 MHz
2-28>250of 1.65 (s, 6H), 6,97 (users, 2H), to 7.77 (d, 2H, J=3.0 Hz), 7,88 (s, 4H), of 7.97 (s, 1H), 8,68 (d, 2H, J=3.0 Hz)DMSO-d6, 300 MHz
2-29231-232of 1.66 (s, 6H), 7,02 (users, 2H), 7,51-of 7.55 (m, 1H), 7,83 (d, 2H, J=9.0 Hz), 7,88 (d, 2H, J=9.0 Hz), 7,98 (s, 1H), 8,14-8,18 (m, 1H), 8,61-8,63 (m, 1H), 8,97-8,98 (m, 1H)DMSO-d6, 300 MHz
2-30210-211of 1.65 (s, 6H), 2,96 (s, 6H), 6,83 (d, 2H, J=9.0 Hz), 6,99 (users, 2H), 7,60 (d, 2H, J=6.0 Hz), to 7.67 (d, 2H, J=6.0 Hz), 7,78 (d, 2H, J=9.0 Hz), of 7.96 (s, 1H)DMSO-d6, 300 MHz

td align="center"> 157-160
2-31>240to 1.61 (s, 6N), 1,89 and 2.13 (m, 4H), 2.26 and-2,4 (m, 2H), 2,55-2,62 (m, 2H), 3,09-3,17 (m, 1H), 6,97 (users, 2H), 7,39 (d, 2H, J=9.0 Hz), to 7.68 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-32174-1751,26 is 1.58 (m, 7H), to 1.61 (s, 6H), of 1.70 to 1.76 (m, 2H), 1,92 is 1.96 (m, 2H), 6,86 (users, 2H), 6,97 (d, 2H, J=8.0 Hz), to 7.68 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-33185-186of 0.91 (t, 3H, J=8.0 Hz), 1,57-of 1.66 (m, 2H), 1,60 (s, 6H), 2,61 (t, 2H, J=8.0 Hz), 6.89 in (user., 2H), 7,27 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-34220-220of 1.33 (s, 9H), to 1.67 (s, 6H), 7,49 (d, 2H, J=8.0 Hz), 7,58 (user., 2H), of 7.70 (d, 2H, J=8.0 Hz), 8,15 (s, 1H)DMSO-d6, 400 MHz
2-35135-136to 1.21 (t, 3H, J=7.0 Hz), to 1.60 (s, 6H), to 2.66 (q, 2H, J=7.0 Hz), 6.90 to (user., 2H), 7,29 (d, 2H, J=8.0 Hz), to 7.64 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-36175-179of 1.23 (d, 6H, J=8.0 Hz), to 1.61 (s, 6H), 2.91 in are 2.98 (m, 1H), 6.89 in (user., 2H), 7,32 (d, 2H, J=8.0 Hz), to 7.64 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-37of 0.91 (t, 3H, J=8.0 Hz), 1,27-of 1.36 (m, 2H), 1,54-to 1.61 (m, 2H), 1,60 (s, 6H), 2.63 in (t, 2H, J=8.0 Hz), 6.90 to (user., 2H), 7,27 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-38189-190of 1.35 (t, 3H, J=6.0 Hz), to 1.61 (s, 6H), 4,10 (q, 2H, J=6,7 Hz), 6.87 in (users, 2H), 6,97 (d, 2H, J=8.0 Hz), of 7.70 (d, 2H, J=12.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-39207-208to 1.21 (t, 3H,J=7.5 Hz), 1,49 was 1.69 (m, 8H), 1.93 and-of 2.08 (m, 3H), 2,33 at 2.45 (m, 2H), 2,84-to 2.94 (m, 1H), 3,85-3,90 (m, 1H), 4.09 to (q, 2H, J=7.0 Hz), 5,72 (s, 1H), 6,97 (users, 2H), 7,33 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-40>2501,46-to 1.63 (m, 8H), 1,97-2,04 (m, 3H), 2,32-of 2.38 (m, 2H), 2,84-to 2.94 (m, 1H), 3,85-3,90 (m, 1H), 5,64 (s, 1H), 6.90 to (users, 2H), 7,32 (d, 2H, J=8.0 Hz), to 7.64 (d, 2H, J=8.0 Hz), 7,94 (s, 1H), 11,80 (users, 1H)DMSO-d6, 400 MHz
2-41201-209of 0.93 (d, 3H, J=6.5 Hz), 1,03 is 1.13 (m, 2H), 1,39-of 1.57 (m, 3H), of 1.62 (s, 6H), 1,76-to 1.87 (m, 4H), 2,49-of 2.58 (m, 1H), 6,91 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), 7,76 (d, 2H, J=8,4 Hz), 7,98 (s, 1H)DMSO-d6, 400 MHz
2-42226-227 ofto 1.60 (s, 6H), 1,6-of 1.74 (m, 2H), 1,89-of 2.16 (m, 6H), 2,75-of 2.81 (m, 1H), 6.90 to (users, 2H), 7,33 (d, 2H, J=8.0 Hz), 7,66 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-43246-248of 1.23 and 1.35 (m, 2H), 1,43-of 1.56 (m, 2H), 1,60 (s, 6H), 1,75-of 1.81 (m, 2H), 1,90 is 1.96 (m,2H), 2,46-of 2.54 (m, 1H), 4,60 (d, 1H, J=6.0 Hz), 6,97 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-441,40-1,60 (m, 2H), 1,60 (s, 6H), 1,90-2,00 (m, 3H), 2,25-to 2.40 (m, 2H), 2,85 (s, 3H), of 3.00 (s, 3H), of 3.13 (m, 1H), of 5.89 (s, 1H), 6.90 to (users, 2H), 7,31 (d, 2H, J=8,3 Hz), to 7.64 (d, 2H, J=8,3 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz

2-45142-1441,40-1,60 (m, 2H), 1,60 (s, 6H), 1,90-2,00 (m, 3H), 2,25-to 2.40 (m, 2H), 2,80 (m, 1H), 4,13 (m, 1H), 4,30 (d, 2H, J=6.0 Hz), of 5.89 (s, 1H), 6.90 to (users, 2H), 7,20-7,33 (m, 6H), to 7.64 (d, 2H, J=8,3 Hz), 7,94 (s, 1H), 8,30 (ushort, 1H, J=6.0 Hz)DMSO-d6, 400 MHz
2-461,45-of 1.57 (m,2H), 1,60 (s, 6H), 1,84 is 2.00 (m, 3H), 2,23-of 2.36 (m, 2H), 2,75-2,89 (m, 1H), 5,67 (s, 1H), 6,77 (users, 1H), 6,97 (users, 2H), 7,26 (users, 1H), 7,32 (d, 2H, J=9.0 Hz), 7,66 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-47 229-230of 1.03 (t, 3H, J=7.5 Hz), 1,45 is 1.58 (m, 3H), 1,60 (s, 6H), 1,81 of-2.32 (m, 5H), 2,73-2,89 (m, 1H), 3,05-3,14 (m, 2H), 5,65 (s, 1H), 6,97 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=6.0 Hz), 7,80-to 7.84 (m, 1H), to 7.95 (s, 1H)DMSO-d6, 300 MHz
2-481,45 is 1.58 (m, 3H), 1,60 (s, 6H), 1,84-2,02 (m, 3H), 2,22-of 2.36 (m, 2H), 2,80-2,89 (m, 1H), 3,12-3,19 (m, 2H), 3,38-of 3.43 (m, 2H), 4,07-4,14 (m, 0,5H), 4,65-4,70 (m, 0,5H), of 5.68 (s, 1H), 6,97 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), to 7.84 (t, 1H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-490,88-of 1.09 (m, 2H), 1,27-to 1.59 (m, 3H), by 1.68 (s, 6H), 1,78-of 1.88 (m, 4H), 2,33-2,47 (m, 1H), 2,63-by 2.73 (m, 2H), 2.77-to is 2.88 (m, 2H), is 3.08 (t, 2H, J=7,0 Hz), and 4.68 (s, 2H), 6,99 (t, 1H, J=5.8 Hz), 7,11 (d, 2H, J=8,3 Hz), 7,26 (s, 2H), 7,43 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-501,41 is 1.60 (m, 2H), 1,60 (s, 6H), 1.91 a-2,03 (m, 3H), 2,16-to 2.42 (m, 9H), 2,79-of 2.86 (m, 1H), 2,96 was 3.05 (m, 1H), 3,42-to 3.49 (m, 1H), 3,49 (user., 3H), by 5.87 (s, 1H), 6.89 in (user., 2H), 7,31 (d, 2H, J=8.6 Hz), to 7.64 (d, 2H, J=8.6 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-511,43-to 1.59 (m, 2H), 1,60 (s, 6H), 1,87 is 2.01 (m, 3H), of 2.18 (s, 6H), 2,28-of 2.34 (m, 4H), 2,79-is 2.88 (m, 1H), 3,18 (q, 2H, J=6.4 Hz), 4,05-4,10 (m, 1H), 5,67 (s, 1H), 6.89 in (user., 2H), 7,31 (d, 2H, J=81 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,69 (t, 1H, J=6.4 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-52212-215of 1.41 (s, 9H), 1,47-to 1.63 (m, 2H), 1,60 (s, 6H), 1,88-2,03 (m, 3H), 2,28-of 2.34 (m, 2H), 2,82-2,89 (m, 1H), 3,74 (d, 2H, J=6,1 Hz), 3,98-4,06 (m, 1H), 5,72 (s, 1H), 6.90 to (user., 2H), 7,31 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,94 (s, 1H), 8,11 (t, 1H, J=6,1 Hz)DMSO-d6, 400 MHz
2-53>270of 1.65 (s, 6H), to 3.64 (s, 2H),? 7.04 baby mortality (users, 2H), 7,39 (d, 2H, J=9.0 Hz), 7,69 (d, 2H, J=9.0 Hz), of 7.75 (d, 2H, J=9.0 Hz), to 7.84 (d, 2H, J=9.0 Hz), 12,32 (users, 1H)DMSO-d6, 300 MHz
2-54267 (decomp.)of 1.12 (s, 3H), 1.28 (in s, 3H), 3,62 (s, 2H), 4,22 (users, 1H), 5,35 (users, 1H), 6,27 (users, 2H), was 7.36 (d, 2H, J=9.0 Hz), 7,54 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), to 7.64 (s, 1H), of 7.70 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
2-55>250for 1.49 (s, 6H), to 1.60 (s, 6H), 6,98 (users, 2H), 7,40 (d, 2H, J=8,4 Hz), to 7.68 (d, 2H, J=8,4 Hz), 7,95 (s, 1H), 12,4 (users, 1H)DMSO-d6, 300 MHz
2-56
2-57
2-58251-2521,01-of 1.13 (m, 2H), 1,39-of 1.53 (m, 3H), 1,60 (s, 6H), 1,82 is 1.91 (m, 4H), 2,53-to 2.57 (m, 1H), and 2.83 (t, 2H, J=6.0 Hz), 2,89 (s, 3H), 6,94 (users, 2H), 7,01 (t, 1H, J=6.0 Hz), 7,32 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9,0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-59>2501,04 by 1.12 (m, 2H), 1,43 is 1.60 (m, 3H), 1,60 (s, 6H), 1.77 in of-1.83 (m, 4H), of 2.38 (d, 2H, J=6.9 Hz), 2.49 USD (m, 1H), 5,24 (s, 1H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz), 7,94 (s, 1H), 9,20 (users, 1H), 11,20 (users, 1H)DMSO-d6, 400 MHz
2-60173-175A mixture of keto - and enol-forms; 1,04 by 1.12 (m, 2H), 1,43 is 1.60 (m, 2H), 1,60 (s, 6H), to 1.70 (m, 1H), 1,81-of 1.85 (m, 4H), 2,33 (d, 1H, J=6,9 Hz) and 2.37 (d, 1H, J=6.9 Hz), 2,50 (m, 1H), 3,85 (s, 1H) and 5,00 (s, 0,5H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.64 (d, 2H, J=8,3 Hz), 7,95 (s, 1H), 12,40 (users, 0,5H)DMSO-d6, 400 MHz

2-61159-1620,97 is 1.13 (m, 2H), 1,35-of 1.52 (m, 3H), 1,60 (s, 6H), 1,76-to 1.87 (m, 4H), 2,46 at 2.59 (m, 1H), 2.91 in (t, 2H, J=6.0 Hz), 5,02 (s, 2H), 6,94 (user., 2H), 7.23 percent-7,40 (m, 8H), to 7.64 (d, 2H, J=7,7 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-62 >2301,25-1,40 (m, 2H), 1,45-1,55 (m, 2H), 1,60 (s, 6H), 1,83 (userd, 2H, J=12,6 Hz), 2,11 (userd, 2H, J=9.6 Hz), to 2.55 (m, 1H), 3,35 (m, 1H), of 4.05 (s, 2H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H,J=8,3 Hz), 7,94 (s, 1H),

12,30 (users, 1H)
DMSO-d6, 400 MHz
2-630,99-1,08 (m, 2H), 1,24 is 1.34 (m, 1H), 1,39-is 1.51 (m, 2H), 1,60 (s, 6H), 1,76-of 1.92 (m, 4H), 2,44 (d, 2H, J=6.6 Hz), 2,47-of 2.56 (m, 1H),

6,89 (user., 2H), 7,30 (d, 2H, J=8,2 Hz), 7,63 (d, 2H, J=8,2 Hz), 7,95 (s, 1H)
DMSO-d6, 400 MHz
2-64>2301,04 is 1.20 (m, 2H), 1,43 of 1.50 (m, 3H), 1,60 (s, 6H), 1,75-of 1.88 (m, 5H), 2,02 (m, 1H), of 2.51 (m, 1H), 4,60 (m, 1H), 6,88 (users, 2H), 7,30 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H), 12,02 (users, 1H)DMSO-d6, 400 MHz
2-65243-244of 1.05 to 1.14 (m, 2H), 1,33 (s, 6H), 1,38-is 1.51 (m, 2H), 1,60 (s, 6H), 1,76-of 1.85 (m, 5H), from 2.00 (d, 2H, J=6.0 Hz), 2,54 is 2.55 (m, 1H), 6,94 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H), 7,98 (s, 1H)DMSO-d6, 300 MHz
2-66176-177of 1.59 (s, 6H), 1,72-to 1.77 (m, 4H), 2,72-2,82 (m, 4H), 6,92 (user., 2H), 7,11 (d, 1H, J=7,7 Hz), 7,40 (d, 1H, J=7,7 Hz), 7,39 (s, 1H), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-67>2500,80-to 0.96 (m, 2H), 1,11 (s, 3H), 1.41 to of 1.65 (m, 4H), of 1.62 (s, 6H), 1,65-to 1.79 (m, 1H), 1,96 (d, 2H, J=7.0 Hz), 2,31-to 2.41 (m, 2H), 6,95 (user., 2H), 7,44 (d, 2H, J=8,4 Hz), of 7.70 (d, 2H, J=8,4 Hz), 7,95 (s, 1H), up 11,86 (users, 1H)DMSO-d6, 300 MHz
2-68>2501,53-1,90 (m, 5H), to 1.59 (s, 6H), 2.40 a-2,52 (m, 2H), 2,66-2,82 (m, 3H), 6,93 (user., 2H), 7,13 (d, 1H, J=7,7 Hz), 7,44 (d, 1H, J=7,7 Hz)to 7.50 (s, 1H), 7,95 (s, 1H), 12,15 (users, 1H)DMSO-d6, 300 MHz
2-69>250of 1.06 (d, 3H, J=7,1 Hz), 1,11-of 1.28 (m, 2H), 1,43-of 1.52 (m, 2H), 1,55-1,65 (m, 1H), 1,61 (s, 6H), 1,71 is 1.91 (m, 4H), 2,15-of 2.23 (m, 1H), 2,49-of 2.56 (m, 1H), 6,92 (user., 2H), 7,31 (d,2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,95 (s, 1H), of $ 11.97 (users, 1H)DMSO-d6, 400 MHz
2-70212-2141,04 is 1.20 (m, 2H), 1,43 of 1.50 (m, 2H), 1,60 (s, 6H), to 1.61 (m, 1H), 1,75-of 1.88 (m, 4H), of 2.51 (m, 1H), 3,11 (d, 2H, J=7,2 Hz), of 3.95 (s, 2H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.64 (d, 2H, J=8,3 Hz), 7,94 (s, 1H), is 10.68 (users, 1H)DMSO-d6, 400 MHz
2-71>250of 1.59 (s, 6H), 3,10-is 3.21 (m, 4H), 3,26-to 3.34 (m, 1H), 6,94 (user., 2H), 7,28 (d, 1H, J=7,7 Hz), of 7.48 (d, 1H, J=7,7 Hz), 7,55 (s, 1H), 12,29 (users, 1H)DMSO-d6,300 MHz
2-72>250of 1.59 (s, 6H), 2,42 (d, 2H, J=7,3 Hz), 2.57 m) is 2.80 (m, 3H), 3.04 from is 3.15 (m, 2H), 6,92 (user., 2H), 7,26 (d, 1H, J=8.1 Hz), 7,46 (d, 1H, J=8.1 Hz), 7,53 (s, 1H), 7,95 (s, 1H), 12,06 (users, 1H)DMSO-d6, 300 MHz
2-73>2501,03 is 1.13 (m, 2H), only 1.08 (s, 3H), 1,22 (s, 3H), 1,32 (s, 6H), 1,36 is 1.48 (m, 2H), 1,67 is 1.86 (m, 5H), 1,99 (d, 2H, J=6.6 Hz), 2,42-of 2.50 (m, 1H), 4,11 (s, 1H), 5.25 in (s, 1H), 6,20 (UserN), from 7.24 (d, 2H, J=8.1 Hz), to 7.35 (d, 2H, J=8.1 Hz), to 7.61 (s, 1H), 7,94 (s, 1H), 11,93 (users, 1H)DMSO-d6, 400 MHz
2-74>2501,11-of 1.27 (m, 2H), 1,36-and 1.54 (m, 2H), 1,60 (s, 6H), 1,68-to 1.87 (m, 5H), 2,50-2,61 (m, 1H), and 2.83 (d, 2H, J=7.0 Hz), 6,93 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-75244-245of 1.03 (s, 3H), 1.26 in (s, 3H), 1,33 was 1.43 (m, 4H), of 1.46 (s, 3H), 1,68 and 1.80 (m, 6H), 2,52 is 2.55 (m, 1H), 5,16 (s, 1H), 6,23 (users, 2H), 7.23 percent (d, 2H, J=9.0 Hz), 7,53 (d, 2H, J=9.0 Hz), to 7.61 (s, 1H)DMSO-d6, 300 MHz

1,03-to 1.21 (m, 2H), 1,39-of 1.55 (m, 2H), of 1.62 (s, 6H), 1,71-of 1.95 (m, 8H), 2,13-of 2.36 (m, 2H), 2,43 at 2.59 (m, 1H), 3,22-to 3.52 (m, 4H), 3,85-was 4.02 (m, 1H), 4,67 to 4.92 (m, 1H), 6,91 (UserN), 7,31 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)
2-76>2501,11-of 1.27 (m, 2H), 1,36-is 1.51 (m, 2H), 1,68-to 1.87 (m, 5H), 2,41-2,52 (m, 1H), and 2.83 (d, 2H, J=6.6 Hz), 4,11 (s, 1H), 5.25 in (C, 1), 6,20 (user., 2H), 7.23 percent (d, 2H, J=8.1 Hz), 7,35 (d, 2H, J=8.1 Hz), to 7.61 (s, 1H), 15,98 (users, 1H)DMSO-d6, 400 MHz
2-77137-139the 1.04 to 1.34 (m, 4H), 1,43 of 1.50 (m, 2H), 1,60 (s, 6H), 1,63-of 1.88 (m, 7H), of 2.23 (d, 2H, J=7,2 Hz), of 2.51 (m, 1H), 3,00 (m, 1H), 3.15 in (m, 1H), 3,68 of 3.75 (m, 2H), 3,94 (m, 1H)and 4.65 (users, 1H), 6,88 (users, 2H), 7,30 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-78185-1871,04 is 1.20 (m, 2H), 1,12 (s,6H), 1,31 (d, 2H, J=5.4 Hz), 1,43 of 1.50 (m, 3H), 1,60 (s, 6H), 1,75-of 1.95 (m, 4H), of 2.51 (m, 1H), 4,01 (s, 1H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-79207-2081,00-to 1.14 (m, 2H), 1,34-is 1.51 (m, 5H), 1,80 is 1.91 (m, 4H), 2,53-to 2.57 (m, 1H), 3.43 points-to 3.49 (m, 2H), 4,27 (users, 1H), 6,92 (users,2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-80271-2720,98-1,24 (m, 2H), 1,33-of 1.64 (m, 10H), 1,76-to 1.98 (m, 5H), 2,52-of 2.58 (m, 1H), 3,98-a 4.03 (m, 1H), 6,04 (users, 1H), 6,91 (users, 2H), 7,31 (d, 2H, J=8.0 Hz), to 7.64 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-811,00-1,11 (m, 5H), 1,22 (s, 3H), 1,3-1,49 (m, 5H), a 1.75-of 1.85 (m, 4H), 2,41-2,49 (m, 1H), 3.43 points-to 3.49 (m, 2H), 4,11 (users, 1H), 4,28-to 4.33 (m, 1H), 5,26 (users, 1H), 6.22 per (users, 2H), 7,24 (d, 2H, J=9.0 Hz), was 7.36 (d, 2H, J=9.0 Hz), a 7.62 (s, 1H)DMSO-d6, 300 MHz
2-82209-2101,06-1,17 (m, 2H), 1.32 to of 1.52 (m, 6H), 1,58-1,90 (m, 11H), to 1.61 (s, 6H), of 2.54 2.63 in (m, 1H), 2.77-to 2,89 (m, 2H), 2,99-3,10 (m, 2H), 7,03 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), 7,98 (s, 1H)DMSO-d6, 300 MHz
2-83142-1431,04 is 1.16 (m, 2H), 1,37-and 1.54 (m, 6H), 1,60 (users, 6H), 1,79-2,02 (m, 9H), 2,54-2,60 (m, 1H), 2.91 in-3,03 (m, 2H), 3,07-up 3.22 (m, 2H), 7,03 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), 7,66 (d, 2H, J=9.0 Hz), 7,98 (users, 1H)DMSO-d6, 300 MHz
2-84217-218of 1.02-1.14 in (m, 2H), 1,33-1,49 (m, 10H), to 1.60 (s, 6H), 1,69 is 1.86 (m, 9H), 2,54-of 2.58 (m, 1H), 2.71 to of 2.81 (m, 2H), 3,42-to 3.52 (m, 1H), 4,56 (users, 1H), 6,92 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7.95 is (s, 1H)DMSO-d6, 300 MHz
2-85115-1161,04-of 1.18 (m, 2H), 1,34-is 1.51 (m, 6H), 1,58-of 1.66 (m, 2H), 1,60 (s, 6H), 1,80 is 1.96 (m, 7H), of 2.38-2.49 USD (m, 2H), of 2.51-2,60 (m, 1H), 2,68 is 2.80 (m, 2H), 4,80 (users, 1H), 6,92 (users, 2H), 7.18 in-7,34 (m, 5H), 7,49 (d, 2H, J=9,0 Hz), the 7.65 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-86 190-1911,01-of 1.23 (m, 4H), 1.30 and 1.57 in (m, 7H), to 1.60 (s, 6H), 1,74 is 1.86 (m, 7H), 2,25-2,31 (m, 2H), 2,53-to 2.57 (m, 1H), 2,80-of 2.86 (m, 2H), 3,30 (s, 2H), 6,91 (users, 2H), 7,14-7,30 (m, 7H), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-87221-222of 1.02-1.14 in (m, 4H), 1,31-of 1.64 (m, 9H), to 1.60 (s, 6H), 1,78-to 1.87 (m, 7H), 2,27-is 2.37 (m, 2H), 2,54-to 2.57 (m, 1H), 2,80-2,90 (m, 2H), 3,40-of 3.46 (m, 2H), 4,29 (t, 1H, J=4.5 Hz), 6,92 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-88175-176of 1.05 to 1.13 (m, 2H), 1,34 of 1.50 (m, 6H), to 1.60 (s, 6H), 1,79-of 1.85 (m, 5H), 2,31 at 2.45 (m, 8H), 2,53-to 2.57 (m, 1H), 3.46 in (s,2H), 6,92 (users, 2H), 7.24 to 7,35 (m, 7H), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-891,47-to 1.67 (m, 6H), to 1.70 (s, 6H), 1,74 is 1.86 (m, 3H), 1,88-2,07 (m, 4H), 2,17-of 2.27 (m, 1H), 2,44-2,61 (m, 3H), 2,64-to 2.74 (m, 1H), 5.40 to (user., 2H), 7,34 (user., 2H), 7,55 (user., 2H), 8,14 (s, 1H)DMSO-d6, 400 MHz
2-901,34-of 1.65 (m, 10H), to 1.61 (s, 6H), 1,81 of 1.99 (m, 5H), 2,14-of 2.27 (m, 1H), 2,31 at 2.45 (m, 3H), 2,68-and 2.83 (m, 1H), 6.90 to (UserN), 7,31 (user., 2H), 7,65 (user., 2H), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-91 1,04 is 1.13 (m, 2H), 1,38 is 1.58 (m, 3H), 1,60 (s, 6H), 1,75-of 1.95 (m, 3H), of 2.51 (m, 1H), 3,01 (ushort, 2H, J=6.4 Hz), 3,80 (d, 2H, J=5.6 Hz), 5,41 (ushort, 1H, J=5.6 Hz), 6.90 to (users, 2H), 7,28 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz), 7,69 (ushort, 1H, J=6.4 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-92113-1151,04-1,17 (m, 2H), 1,43 of 1.50 (m, 2H), 1,60 (s, 6H), 1,80-of 1.84 (m, 5H), are 2.19 (s, 3H), 2.23 to-2,31 (m, 6H), of 2.51 (m, 1H), 3.43 points-of 3.48 (m, 4H), 6,91 (users, 2H), 7,30 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,95 (, 1H)DMSO-d6, 300 MHz
2-93146-1471,03-1,20 (m, 2H), 1,37-of 1.88 (m, 19H), 2,22 (d, 2H, J=6.0 Hz), 2,53-of 2.58 (m, 1H), 3,39-of 3.46 (m, 4H), 6,92 (users, 2H), 7,31 (d,2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-94232-2331,06-1,19 (m, 2H), 1.41 to to 1.63 (m, 8H), 1,71 is 1.91 (m, 9H), of 2.16 (d, 2H, J=6.0 Hz), of 2.51 at 2.59 (m, 1H), 3,28-of 3.31 (m, 2H), 3,41 (t, 2H, J=6.0 Hz), 6,92 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), of 7.95 (s, 1H)DMSO-d6, 300 MHz
2-95199-2001,08-to 1.21 (m, 2H), 1.41 to and 1.56 (m, 2H), 1,60 (s, 6H), 1,74-to 1.87 (m, 4H), of 2.25 (d, 2H, J=9.0 Hz), 3,41-3,59 (m, 10H), 6,93 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MG is
2-96112-1130,89-of 1.18 (m, 4H), 1.32 to 1.55V (m, 4H), to 1.60 (s, 6H), 1,67 of-1.83 (m, 7H), 2,22 (d, 2H, J=6.0 Hz), 2,52-to 2.57 (m, 1H), 2,92-to 3.02 (m, 2H), 3,41-3,47 (m, 2H), 3,84-to 3.92 (m, 2H), 4,33 was 4.42 (m, 2H), 6,93 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-97225-2261,06-of 1.18 (m, 2H), 1.41 to 1,53 (m, 2H), 1,60 (s, 6H), 1,74 of-1.83 (m, 5H), of 2.23 (d, 2H, J=6.0 Hz), 2,33-to 2.42 (m, 6H), 2,53-of 2.58 (m, 1H), 3.43 points-of 3.54 (m, 6H), to 4.41 (t, 1H, J=6.0 Hz), 6,93 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-98131-1331,04 is 1.13 (m, 2H), 1,16 (s, 6H), 1,38 is 1.58 (m, 2H), equal to 1.59 (s, 6H), 1,65-of 1.85 (m, 5H), of 1.97 (d, 2H, J=6.8 Hz), of 2.51 (m, 1H), 3,36 (d, 2H, J=5,9 Hz), 4,89 (t, 1H, J=5,9 Hz), 6,92 (users, 2H), 7,24 (s, 1H), 7,27 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), 7,92 (s, 1H)DMSO-d6, 400 MHz
2-99113-115A mixture of 2 conformers; 1,04 is 1.13 (m, 2H), 1,38 is 1.58 (m, 2H), 1,60 (s, 6H), 1,65-of 1.85 (m, 5H), 2,20-of 2.28 (m, 2H), of 2.51 (m, 1H), 2,82 and a 3.01 (s, 3H), 3,30-3,51 (m, 4H), 4,60 and 4,77 (ushort, 1H, J=5.6 Hz), 6,92 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-100184-185DMSO-d6, 300 MHz
2-101237-2391,02-1,20 (m, 2H), 1,37-of 1.57 (m, 2H), 1,60 (s, 6H), 1,69-of 1.95 (m, 7H), 2,09-of 2.20 (m, 2H), 2,44 at 2.59 (m, 1H), 3.33 and-of 3.54 (m, 2H), 4,20-to 4.38 (m, 2H), 4.80 to 5,00 (m, 1H), 6,92 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-102214-215from 0.84 (t, 3H, J=7,3 Hz), 1,02-1,19 (m, 2H), 1,34-of 1.53 (m, 4H), to 1.60 (s, 6H), 1,69 is 1.86 (m, 5H), 1,99 (d, 2H, J=6.6 Hz), 2,48-to 2.57 (m, 1H), 3.00 and (q, 2H, J=6.6 Hz), 6,93 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,74 (t, 1H, J=6.6 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-103231-2321,02-1,22 (m, 2H), 1,39-of 1.57 (m, 2H), 1,60 (s, 6H), 1,69-of 1.97 (m, 5H), 2,08-of 2.21 (m, 2H), 2,47 at 2.59 (m, 1H), 3,29 of 3.56 (m, 4H), 4,15-to 4.41 (m, 2H), 4,81-5,00 (m, 1H), 6.89 in (user., 2H), 7,31 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-104186-1881,00-of 1.55 (m, 7H), to 1.60 (s, 6H), 1,78-of 1.94 (m, 4H), 2,46-2,61 (m, 1H), 2,85 (s, 3H), of 4.05 (s, 1,4H), 4,08 (s, 0,6H), 6,92 (user., 2H), 7,30 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz

2-105>2501,52-of 1.92 (m, 8H), to 1.61 (s, 6H), 2,49-to 2.65 (m, 1H), was 2.76 (s, 1,8H), and 2.79 (s, 1,2H), 4,06 (s, 0,6H), 4,16 (s, 0,4H), 4,25-4,47 (m, 1H), 6,93 (user., 2H), 7,33 (userd, 2H, J=8,2 Hz), the 7.65 (d, 2H, J=8,2 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-106250-2521,03-1,22 (m, 2H), 1,39 is 1.58 (m, 2H), 1,60 (s, 6H), 1,69-of 1.92 (m, 5H), 2,12 (d, 2H, J=6.6 Hz), 2,45-of 2.58 (m, 1H), 3,16-to 3.41 (m, 3H), 3,55-of 3.60 (m, 1H), 3,94-4.09 to (m, 2H), 4,84 (user., 1H), 4.92 in (user., 1H), 6,93 (user.,2H), 7,31 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-107>2501,07-of 1.18 (m, 2H), 1.41 to 1,53 (m, 2H), equal to 1.59 (s, 6H), 1,71 is 1.86 (m, 5H), of 2.15 (d, 2H, J=4.0 Hz), 2,24 (s, 3H), of 2.51-2.57 m (m, 1H), 6,84 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), 12,04 (users, 1H)DMSO-d6, 400 MHz
2-108202-2031,06-of 1.16 (m, 2H), 1,36 is 1.48 (m, 2H), 1,59-of 1.84 (m, 5H), to 1.59 (s, 6H), of 2.51-of 2.56 (m, 1H), 3,86 (d, 2H, J=8.0 Hz), 6.89 in-to 7.15 (m, 1H),

6,91 (users,2H), 7,27 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)
DMSO-d6, 400 MHz
2-109>2301,15-1,35 (m, 2H), 1,37 is 1.58 (m, 3H), 1,60 (s, 6H), 180-1,95 (m, 5H), of 2.51 (m, 1H), 2,75 (d, 2H, J=9,3 Hz)6,91 (users, 2H), 7.03 is-7,22 (m, 2H), 7,30 (d, 2H, J=8,3 Hz), 7,39-EUR 7.57 (m, 2H), 7,63 (d, 2H,J=8,3 Hz), 7,95 (s, 1H), 12,19 (users, 1H)DMSO-d6, 400 MHz
2-110155-1561,01-of 1.18 (m, 2H), 1,38-to 1.59 (m, 2H), 1,60 (s, 6H), 1,72 is 1.86 (m, 5H), 2,34 (d, 2H, J=6.0 Hz), 2,54-of 2.58 (m, 1H), 4,05 (d, 2H, J=6.0 Hz), 5,04 (t, 1H, J=6.0 Hz), 6,91 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-111>2501,04-to 1.21 (m, 2H), 1,38 is 1.58 (m, 2H), of 1.66 (s, 6H), 1.70 to 1,89 (m, 5H), to 2.29 (d, 2H, J=6.4 Hz), 2,45-of 2.58 (m, 1H), 2,96-3,13 (m, 4H), 3,60-of 3.77 (m, 4H), 7,32 (d, 2H, J=8,3 Hz), 7,65 (user., 2H), 7,68 (d, 2H, J=8,3 Hz), 8,16 (s, 1H), to 9.32 (user., 2H)DMSO-d6, 300 MHz
2-112>2501,31 is 1.58 (m, 4H), to 1.60 (s, 6H), 1,82 is 1.91 (m, 2H), 2.06 to of 2.16 (m, 2H), 2,53-to 2.65 (m, 1H), 2.77-to is 2.88 (m, 1H), 3,30 (s, 2H), 6,93 (users, 2H), 7,31 (d, 2H, J=6.0 Hz), to 7.64 (d, 2H, J=6.0 Hz), 7,94 (s, 1H), 12,40 (users, 1H)DMSO-d6, 300 MHz
2-113172-1731,04 is 1.13 (m, 2H), 1,34 of 1.46 (m, 2H), equal to 1.59 (s, 6H), 1,78-of 1.84 (m, 5H), of 2.23 (s, 3H), of 2.36 (d, 2H, J=8.0 Hz), of 2.51-of 2.58 (m, 1H), return of 6.58 (s, 1H), 6,92 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-114 2501,04-1,22 (m, 2H), of 1.16 (d, 6H, J=6,1 Hz), 1,38 by 1.68 (m, 4H), to 1.60 (s, 6H), 1,80-of 1.97 (m, 5H), 2,49-2,62 (m, 1H), 2,63-2,70 (m, 1H), 6,93 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-115127-1350,99-of 1.23 (m, 6H), of 1.17 (t, 3H, J=7,1 Hz), 1,36-of 1.52 (m, 2H), 1,60 (s, 6H), 1,72-of 1.94 (m, 8H), 2,45 at 2.59 (m, 1H), 2,79-to 2.94 (m, 2H), 3,81-to 3.89 (m, 2H), was 4.02 (q, 2H, J=7,1 Hz), 6,93 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-116>2500,93-1,22 (m, 6H), 1.32 to of 1.52 (m, 4H), to 1.60 (s, 6H), 1,74-of 1.95 (m, 7H), 2,20-of 2.34 (m, 1H), 2,41 (d, 2H, J=6.4 Hz), 2,47-of 2.58 (m, 1H),

3.27 to 3,39 (m, 1H), of 4.44 (d, 1H, J=4.5 Hz), 6,95 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,95 (s, 1H)
DMSO-d6, 300 MHz
2-117>2501,07-of 1.18 (m, 2H), 1,43-of 1.53 (m, 2H), 1.55V (s, 6H), 1.70 to of 1.85 (m, 5H), of 2.15 (d, 2H, J=8.0 Hz), of 2.51 is 2.55 (m, 1H), 6,21 (users, 2H), of 6.31 (d, 1H, J=8.0 Hz), 7,29 (d, 2H, J=8.0 Hz), 7,49 (d, 1H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz), 11,94 (users, 1H)DMSO-d6, 400 MHz
2-118215-2161,08 is 1.23 (m, 2H), 1,38 of 1.50 (m, 2H), equal to 1.59 (s, 6H), 1,68 of-1.83 (m, 5H), 2,52 is 2.55 (m, 1H), 2,58 (d, 2H, J=4.0 Hz), 2,62 (s, 3H), 6,95 (users, 2H), 7,06 (s, 1H), 7,28 d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-119>2501,08-of 1.18 (m, 2H), 1.26 in (s, 9H), 1,35-1,49 (m, 2H), 1,60 (s, 6H), 1,75-of 1.85 (m, 5H), of 2.38 (d, 2H, J=4.0 Hz), 2,52-of 2.58 (m, 1H), 6,55 (users, 1H), 6,94 (users, 2H), 7,29 (d, 2H, J=12.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-120226-227 of0,68-1,19 (m, 7H), 1,36-and 1.54 (m, 2H), equal to 1.59 (s, 6H), 1,74-of 1.88 (m, 5H), 2,33 (d, 2H, J=4.0 Hz), 2,53-of 2.56 (m, 1H), 6,50 (s, 1H), 6,94 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-121to 1.14 to 1.34 (m, 2H), 1,37 is 1.58 (m, 3H), 1,60 (s, 6H), 1,80-of 1.95 (m, 5H), of 2.51 (m, 1H), 2,71 (d, 2H, J=9,3 Hz), of 3.77 (s, 3H), 6,74 (DD, 1H, J=2,2, 8,4 Hz)6,91 (users, 2H), 6,99 (d, 1H, J=2.2 Hz), 7,30 (d, 2H, J=8,3 Hz), 7,35 (d, 1H, J=8,4 Hz), to 7.64 (d, 2H, J=8,3 Hz), 7,95 (s, 1H), 12,05 (users, 1H),DMSO-d6, 300 MHz
2-122>2301,15-of 1.33 (m, 2H), 1,37 is 1.58 (m, 3H), 1,60 (s, 6H), 1,80-of 1.95 (m, 5H), of 2.51 (m, 1H), 2,75 (d, 2H, J=9,3 Hz), 6,92 (users, 2H), 7,14 (d, 1H, J=8,4 Hz), 7,30 (d, 2H, J=8,3 Hz), 7,39-of 7.55 (m, 2H), 7,63 (d, 2H, J=8,3 Hz), 7,95 (s, 1H), 12,37 (users, 1H)DMSO-d6, 300 MHz
2-123 230-2311,09-1,19 (m, 2H), 1,41 2H), equal to 1.59 (s, 6H), 1,76-of 1.88 (m, 5H), 2,53-of 2.58 (m, 1H), 3,18 (d, 2H, J=12.0 Hz), of 6.71 (users, 1H), 6,93 (users, 2H), 7,27-7,42 (m, 5H), a 7.62 (d, 2H, J=8.0 Hz), 7,88 (d, 2H, J=8.0 Hz), 7,93 (, 1H)DMSO-d6, 400 MHz
2-124>230to 1.14 and 1.33 (m, 2H), 1,37 is 1.58 (m, 3H), 1,60 (s, 6H), 1.70 to 2,03 (m, 5H), of 2.51 (m, 1H), 2,73 (d, 2H, J=7.0 Hz), 6,72-7,13 (m, 3H), 7,17-7,35 (m, 3H), 7,44 (users, 1H), 7.62mm (d, 2H, J=8,3 Hz), to 7.93 (s, 1H), 12,30 (users, 1H)DMSO-d6, 400 MHz
2-1250,97-1,11 (m, 2H), 1,34-and 1.54 (m, 12H), to 1.60 (s, 6H), 1,78-of 1.95 (m, 4H), 2,53-of 2.58 (m, 1H), was 2.76-and 2.83 (m, 2H), 6,94 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), EUR 7.57 (users, 1H), 7,65 (d, 2H, J=9.0 Hz), 7,95 (s, 1H), 10,76 (users, 1H)DMSO-d6, 300 MHz
2-126234-2350,93 of 1.50 (m, 4H), to 1.60 (s, 6H), 1,72 is 1.91 (m, 5H), of 2.16 (d, 2H, J=6.0 Hz), 2.57 m) of 2.68 (m, 1H), 6,95 (users, 2H), 7,29 (d, 2H, J=6.0 Hz), to 7.64 (d, 2H, J=6.0 Hz), 7,95 (s, 1H), 11,94 (users, 1H)DMSO-d6, 300 MHz
2-127228-2301,03-1,17 (m, 2H), 1,39-is 1.51 (m, 2H), 1,58-to 1.67 (m,7H), 1,82-of 1.95 (m, 4H), of 2.09 (s, 3H), of 2.51 at 2.59 (m, 1H), 3,06-3,10 (m, 2H), 6,11 (users, 1H), 6,94 (users, 2H), 7,31 (d, 2H,J=9.0 Hz), 7,45-7,49 (m, 1H), 7,65 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2- 128253-2540,98 is 1.13 (m, 2H), 1,35-is 1.51 (m, 3H), 1,60 (s, 6H), 1.77 in-a 1.88 (m, 7H), 2,52-of 2.58 (m, 1H), 2.91 in-2,95 (m, 2H), 6,93 (users, 2H), 7,30 (d, 2H, J=6.0 Hz), 7,63 (d, 2H, J=6.0 Hz), 7,82 (t, 1H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-129206-2070,93-1,08 (m, 2H), 1.32 to about 1.47 (m, 3H), 1,60 (s, 6H), 1,76-of 1.85 (m, 4H), 2,39 (s, 3H), of 2.51-of 2.54 (m, 1H), 2.57 m-2,62 (m, 2H), 6,93 (users, 2H), 7,29 (d, 2H, J=9.0 Hz), 7,41 (d, 2H, J=9.0 Hz), 7,54 (t, 1H, J=6.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,69 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-130226-227 of0,96-1,11 (m, 2H), 1,37-of 1.55 (m, 3H), 1,60 (s, 6H), 1,79 is 1.96 (m, 4H), 2,53-to 2.57 (m, 1H), 2,74-and 2.79 (m, 2H), to 6.43 (s, 2H), 6,50 (t, 1H, J=6.0 Hz), 6,93 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9,0 Hz), to 7.95 (s, 1H)DMSO-d6, 300 MHz
2-131230-2310,99-of 1.13 (m, 2H), 1,35 for 2.01 (m, 18H), of 2.51-of 2.58 (m, 1H), 2.77-to of 2.86 (m, 2H), 2,96-a 3.01 (m, 2H), 3,49-of 3.53 (m, 1H), 6,93 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), to $ 7.91-of 7.97 (m, 2H)DMSO-d6, 300 MHz
2-132217-2180,98-to 1.14 (m, 2H), 1,37-to 1.98 (m, 16H), 2,53-of 2.58 (m, 1H), 2,72-to 2.85 (m, 2H), 2,96-3,00 (m, 2H), 3,71 (t, 1H, J=7.5 Hz), 4,16 (users, 1H)and 4.65 (users, 1H), 6,93 (users, 2H), 7,30 (d, 2H, J=9.0 G is), to 7.64 (d, 2H, J=9.0 Hz), 7,94-7,98 (m, 2H)DMSO-d6, 300 MHz
2-133>230to 1.61 (s, 6H), 1,60-1,75 m, 8H), to 2.18 (m, 1H), 2,37 (d, 2H, J=7,2 Hz), 2,60 (m, 1H), 6,94 (users, 2H), 7,34 (d, 2H, J=8,3 Hz), to 7.64 (d, 2H, J=8,3 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-134225-2261,07-of 1.18 (m, 2H), 1,42-of 1.53 (m, 2H), 1,58 (s, 6H), 1.77 in-of 1.85 (m, 5H), 1.91 a (s, 3H), 2,20 (d, 2H, J=4.0 Hz), 2,24 (s, 3H), 2,54-to 2.57 (m, 1H), up 3.22 (s, 3H), for 6.81 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=12.0 Hz), 11,66 and 11,93 (users, 1H)DMSO-d6, 400 MHz
2-135229-2301,01-of 1.13 (m, 2H), 1,17 (s, 6H), 1.41 to a rate of 1.51 (m, 2H), 1,58 (s, 6H), 1,68-of 1.84 (m, 5H), to 1.98 (d, 2H, J=8.0 Hz), 2,24 (s, 3H), 2,52-of 2.56 (m, 1H), 3,38 (d, 2H, J=4.0 Hz), the 4.90 (t, 1H, J=4.0 Hz), 6,80 (users, 2H), 7,26 (users, 1H), 7,28 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz)DMSO-d6, 400 MHz
2-136210-2111,07-1,19 (m, 2H), 1,42-of 1.52 (m, 2H), 1,58 (s, 6H), 1,76 is 1.86 (m, 5H), 2,12 (d, 2H,J=8.0 Hz), 2,24 (s, 3H), of 2.51 is 2.55 (m, 1H), 3,15-3,26 (m, 2H), 3,35-3,39 (m, 1H), 3,54-to 3.58 (m, 1H), 3.95 to 4,06 (m, 2H), 4,87 (d, 1H, J=4.0 Hz), of 4.95 (d, 1H, J=4.0 Hz), 6,80 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz)DMSO-d6, 400 MHz
2-137 >2501,13-1,24 (m, 2H), 1,38 of 1.50 (m, 2H), 1.57 in (s, 6H), 1,73 of-1.83 (m, 5H), 2,24 (s, 3H), 2,82 (d, 2H, J=8.0 Hz), 3,35-3,39 (m, 1H), for 6.81 (users, 2H), 7,27 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz)DMSO-d6, 400 MHz
2-138235-2380,96 is 1.13 (m, 2H), 1,35-of 1.55 (m, 3H), 1,58 (s, 6H), 1,75-1,89 (m, 4H), 2,24 (s, 3H), 2,47-2,61 (m, 1H), 3,01 (t, 2H, J=6.0 Hz), 3,80 (d, 2H, J=6.0 Hz), 5,42 (t, 1H, J=6.0 Hz), 6,82 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), 7,69 (t, 1H, J=6.0 Hz)DMSO-d6, 300 MHz
2-139249-250of 1.03 (s, 6H), 1.06 a-a 1.08 (m, 2H), 1,36 is 1.48 (m, 3H), 1,58 (s, 6H), is 1.81 (m, 4H), of 2.25 (s, 3H), of 2.66 (m, 2H), 3,37 (d, 2H, J=5.3 Hz), a 4.86 (t, 1H, J=5.3 Hz), 6,80 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), 7,44 (t, 1H, J=5.6 Hz), a 7.62 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-140P.223-2240,98-1,10 (m, 2H), 1,37 is 1.48 (m, 3H), 1,58 (s, 6H), is 1.82 (m, 4H), of 2.25 (s, 3H), of 2.25 (t, 2H, J=6.5 Hz), 2.95 and (m, 2H), 3,61 (dt, 1H, J=6,5 Hz, 5.3 Hz), a 4.53 (t, 1H, J=5.3 Hz), 6,80 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), 7,78 (t, 1H, J=5.3 Hz)DMSO-d6, 300 MHz
2-141221-2230,97-of 1.15 (m, 2H), 1,24 (s, 6H), 1,25-of 1.53 (m, 5H), was 1.58 (s, 6H), 1,76-of 1.93 (m, 4H), of 2.25 (s, 3H), 2,45-2,62 (m, 1H), 3,12 (kV, J=6,4 Hz, 2H), 5,28 (s, 1H), 6,83 (users, 2H), 7,28 (d, J=8,3 Hz, 2H), 7,53-to 7.61 (m, 1H), to 7.61 (d, J=8,3 Hz, H) DMSO-d6, 300 MHz
2-142142-1440,99-1,19 (m, 2H), 1,34 is 1.58 (m, 3H), 1,60 (s, 6H), 1,67-1,89 (m, 5H), 2,08 (d, 2H, J=6.9 Hz), 2,24 (s, 3H), of 2.51 (m, 1H), 3,63 (d, 2H, J=5.5 Hz), for 6.81 (users, 2H),

of 6.96 (users, 1H), 7,24 (users, 1H), 7,30 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz), 7,95 (t, 1H, J=5,5 Hz)
DMSO-d6, 300 MHz
2-143196-198A mixture of 2 conformers; 1,02-1,22 (m, 2H), 1,34 is 1.58 (m, 3H), 1,58 (s, 6H), 1,72-of 1.92 (m, 5H), 2,13 and of 2.27 (d, 2H, j=6.9 Hz), 2,24 (s, 3H), of 2.51 (m, 1H), 2,81 and 3,03 (s, 3H), 3,98 and 4.09 to (s, 2H), 6,82 (users, 2H), 7,28 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz), 11,70 (users, 1H)DMSO-d6, 300 MHz
2-144>230A mixture of 2 conformers; 0,99-1,20 (m, 2H), 1,34 is 1.58 (m, 3H), 1,58 (s, 6H), 1,73-of 1.92 (m, 5H), 2,12 and 2.26 (d, 2H, J=6.9 Hz), 2,24 (s, 3H), of 2.51 (m, 1H), 2,79, and 3,98 (s, 3H), 3,85, and to 3.92 (s, 2H), 6,82 (users, 2H), of 6.96 and 7,14 (users, 1H), 7,29 (d, 2H, J=8,3 Hz), 7.27 and 7,43 (users, 1H), to 7.61 (d, 2H, J=8,3 Hz)DMSO-d6, 400 MHz
2-145>250of 0.55 (s, 3H), 1,21 (s, 3H), of 1.55 (s, 6H), 1,95-2,02 (m, 1H), 2,14-of 2.36 (m, 4H), 2,24 (s, 3H), 3,14-3,20 (m, 1H), 6,83 (users, 2H), 7,16 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz)DMSO-d6, 400 MHz
2-146 >250was 1.58 (s, 6H), 1,74-to 1.82 (m, 2H), 2,24 (s, 3H), 2,37 (d, 2H, J=8.0 Hz), 2,44-2,60 (m, 4H), 3,36-of 3.43 (m, 1H), 6,80 (users, 2H), 7,27 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), 11,98 (users, 1H)DMSO-d6, 400 MHz
2-147>2301,05-1,20 (m, 2H), 1,38-of 1.52 (m, 2H), 1,58 (s, 6H), 1,73-to 1.87 (m, 5H), 2,24 (s, 3H), to 2.29 (d, 2H, J=6.9 Hz), of 2.51 (m, 1H), for 6.81 (users, 2H), 7,28 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H,J=8,3 Hz), 11,07 (s, 1H), 11,10 (users, 1H)DMSO-d6, 400 MHz
2-148>2501,13-1,24 (m, 2H), 1,43-of 1.55 (m, 2H), 1,58 (s, 6H), 1,82-of 1.85 (m, 4H), 2,24 (s, 3H), 2,38-to 2.41 (m, 2H), 2,50-of 2.58 (m, 1H), 6,82 (user., 7,30 (d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz), 11,96 (users, 1H), 15,85 (user., 1H)DMSO-d6, 300 MHz
2-149237-238was 1.58 (s, 6H), 1.60-to 1,71 (m, 4H), 2,04-of 2.23 (m, 3H), of 2.23 (s, 3H), 2,24 (s, 3H), 2.40 a is 2.46 (m, 2H), 3,35-to 3.41 (m, 1H), for 6.81 (users, 2H), 7,25 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), 11,99 (users, 1H)DMSO-d6, 400 MHz
2-150228-2290,99-1,10 (m, 2H), 1,25 (s, 6H), of 1.37 to 1.48 (m, 2H), 1,58 (s, 6H), 1,76-of 1.85 (m, 5H), 2,24 (s, 3H), 2,53-to 2.57 (m, 1H), 2,96-to 2.99 (m, 2H), 5,32 (s, 1H), for 6.81 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), 7,58 (users, 1H), 7,60 (d, 2H,J=8.0 Hz)DMSO-d6, 400 MHz
2- 151>2501,11-of 1.23 (m, 2H), 1,42-of 1.52 (m, 2H), 1.57 in (s, 6H), 1.77 in is 1.86 (m, 5H), of 2.25 (s, 3H), 2,44 (d, 2H, J=8.0 Hz), 2,53-2,62 (m, 1H), for 6.81 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), 12,70 (users, 1H)DMSO-d6, 400 MHz
2-152225-2261,11-of 1.23 (m, 2H), 1.41 to 1,49 (m, 2H), 1.57 in (s, 6H), 1,76-of 1.84 (m, 5H), 2,24 (s, 3H), 2,44 (d, 2H, J=8.0 Hz), 2,53-2,61 (m, 1H), 6,82 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), 12,69 (users, 1H)DMSO-d6, 400 MHz
2-1531,11-1,24 (m, 2H), 1,40-is 1.51 (m, 2H), 1,58 (s, 6H), 1.77 in-to 1.87 (m, 5H), 2,24 (s, 3H), 2,46 (d, 2H, J=8.0 Hz), 2,52-of 2.58 (m, 1H), for 6.81 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), 11,41 (users, 1H)DMSO-d6, 400 MHz
2-154229-2331,00-1,11 (m, 2H), 1,37 is 1.58 (m, 3H), of 1.65 (s, 6H), 1,76-to 1.87 (m, 4H), 2,49-to 2.57 (m, 1H), 2,99 totaling 3.04 (m, 2H), 3,81 (d, 2H, J=6.0 Hz), 5,42 (t, 1H, J=6.0 Hz), 7,32 (d, 2H, J=6.0 Hz), 7,69 (d, 2H, J=6.0 Hz)DMSO-d6, 300 MHz
2-1551,01-1,22 (m, 2H), 1,34-of 1.52 (m, 2H), 1.57 in (s, 6H), 1,68-1,89 (m, 4H), 2,24 (s, 3H), 2,37 (d, 2H, J=6.9 Hz), 2,50 (m, 1H), 5,23 (s, 1H), for 6.81 (users, 2H), 7,27 (d, 2H, J=8,3 Hz), 7,60 (d, 2H, J=8,3 Hz), 9,25 (users, 1H), 11,20 (users, 1H) DMSO-d6, 400 MHz
2-156>2501,09 is 1.23 (m, 2H)and 1.15 (t, 3H, J=8.0 Hz), 1,43-of 1.52 (m, 2H), 1.57 in (s, 6H), 1,71-1,90 (m, 5H), 2,24 (s, 3H), 2,44 (d, 2H, J=8.0 Hz), 2,53-of 2.58 (m, 1H), to 3.58 (q, 2H, J=8.0 Hz), 6,80 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz), 11,34 (s, 1H)DMSO-d6, 400 MHz
2-1571,11-1,24 (m, 2H), 1,44-and 1.54 (m, 2H), 1,58 (s, 6H), 1,68-to 1.87 (m, 5H), 2,24 (s, 3H), 2,53-to 2.57 (m, 1H), 3,51 (d, 2H, J=8.0 Hz), 6,80 (users, 2H), 7,29 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=8.0 Hz), to 12.28 (users, 1H)DMSO-d6, 400 MHz
2-158240-241of 1.03-1.14 in (m, 2H), 1.41 to 1,53 (m, 2H), 1,58-1,71 (m, 1H), 1,58 (s, 6H), 1.77 in is 1.86 (m, 4H), of 2.25 (s, 3H), 2,50-of 2.58 (m, 1H), 3.04 from (d, 2H, J=9.0 Hz), of 3.56 (t, 2H, J=7.5 Hz), 4,27 (t, 2H, J=7.5 Hz), 6,80 (user., 1H), 7,29 (d, 2H, J=6.0 Hz), 7,63 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
2-159148 (decomp.)1,01-of 1.13 (m, 2H), 1,39-is 1.51 (m, 2H), 1,58 was 1.69 (m, 1H), 1,58 (s, 6H), 1,76 is 1.86 (m, 4H), of 2.25 (s, 3H), 2,50-to 2.57 (m, 1H), 3,11 (d, 2H, J=6.0 Hz), of 3.95 (s, 2H), for 6.81 (user., 1H), 7,29 (d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=6.0 Hz)DMSO-d6, 300 MHz
2-160185-1861,00-of 1.13 (m, 2H), 1.30 and is 1.51 (m, 6H), was 1.58 (s, 6H), 1,79-to 1.87 (m, 4H),2,24 (s, 3H), 2,50-of 2.58 (m, 1H), 0,00-0,00 (m, 2H), 3,17 (q, 2H, J=7.0 Hz), of 3.78 (d, 2H, J=6.0 Hz), of 5.40 (t, 1H, J=6.0 Hz), 6,80 (user., 2H), 7,29 (d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz), 7,66 (t, 1H, J=6.0 Hz)DMSO-d6, 300 MHz

/tr>
2-161219-2210,95-1,12 (m, 2H), 1,35-of 1.52 (m, 3H), 1,58 (s, 6H), 1,73 is 1.91 (m, 4H), 2,24 (s, 3H), 2,47-to 2.57 (m, 1H), 2,86 (t, 2H,J=6.2 Hz), 5,33 (user., 2H), 5,98 (t, 1H, J=5.7 Hz), 6,80 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-162216-2500,95-1,11 (m, 2H), 1,36-of 1.53 (m, 3H), 1,58 (s, 6H), 1,76-1,90 (m, 4H), 2,24 (s, 3H), 2,45-of 2.56 (m, 1H), 2.91 in (d, 2H, J=6.8 Hz), of 3.56 (t, 2H, J=8.5 Hz), of 4.13 (t, 2H, J=8.5 Hz), 6,79 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-163219-221of 0.82 (s, 3H), or 0.83 (s, 3H), and 0.98-1.14 in (m, 2H), 1,35-and 1.54 (m, 3H), 1,58 (s, 6H), 1,76-of 1.88 (m, 4H), 2,24 (s, 3H), 2,44-of 2.56 (m, 1H), 2,94-3,1O (m, 2H), 3,16-to 3.34 (m, 2H), of 3.73 (d, 1H, J=5.7 Hz), 4,48 (t, 1H, J=5.7 Hz), 5,31 (d, 1H, J=5.7 Hz), 6,79 (user., 2H), 7,29 (d, 2H,J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), to 7.68 (t, 1H, J=5.8 Hz)DMSO-d6, 300 MHz
2-164222-225of 0.96-1.14 in (m, 2H), 1,35-to 1.61 (m, 4H), was 1.58 (s, 6H), 1,75-1,89 (m, 5H), 2,24 (s, 3H), 2,46 at 2.59 (m, 1H), 2,99 (t, 2H, J=6.6 Hz), 3.45 points-of 3.54 (m, 2H), 3,5 (dt, 1H, J=5,7, and 3.8 Hz), 4,42 (t, 1H, J=5.7 Hz), of 5.39 (d, 1H, J=5.7 Hz), for 6.81 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), to 7.68 (t, 1H, J=6.2 Hz)DMSO-d6, 300 MHz
2-165>250A mixture of 2 conformers;1,02-of 1.15 (m, 2H), 1,37 is 1.48 (m, 2H), 1.57 in (s, 6H), 1,78-of 1.85 (m, 5H), 2,24 (s, 3H), and 2.27 (d, 2H, J=4.0 Hz), 2,52 is 2.55 (m, 1H), 3.30, and of 3.56 (s, 3H), 5,12 (users, 1H), for 6.81 (users, 2H), 7,27 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz), at 10.64 (users, 1H)DMSO-d6, 400 MHz
2-166225-2330,98 is 1.13 (m, 2H), 1,35-is 1.51 (m, 2H), 1,58 (s, 6H), 1,63-to 1.87 (m, 6H), 2,21 of-2.32 (m, 1H), 2,24 (s, 3H), 2,45-2,60 (m, 1H), 3,06 (d, 2H, J=7,1 Hz), 3,17-to 3.35 (m, 2H),

Android 4.04-4,16 (m, 1H), 5,45 (user., 1H), 6,82 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz)
DMSO-d6, 300 MHz
2-167of 0.90 (s, 3H), 0,99-to 1.14 (m, 2H), only 1.08 (s, 3H), 1.30 and is 1.51 (m, 2H), 1,58 (s, 6H), 1,62-1,90 (m, 5H), 2,24 (s, 3H), 2,45 at 2.59 (m, 1H), 2.95 and-of 3.12 (m, 4H), 3,74 (d, 1H, J=5.7 Hz), 5,41 (d, 1H, J=5.7 Hz), 6,79 (user., 2H), 7,28 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-168of 1.13 to 1.31 (m, 2H), 1,38 is 1.58 (m, 2H), 1,58 (s, 6H), 1,74-of 1.92 (m, 5H), of 2.25 (s, 3H), of 2.50 (m, 1H), 2,58 (d, 2H, j=6.9 Hz), and 3.72 (s, 3H), 6,80 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-169>2301,10-1,25 (m, 2H), 1,38-of 1.53 (m, 2H), 1.57 in (s, 6H), 1,69-to 1.87 (m, 5H), 2,24 (s, 3H), of 2.50 (m, 1H), 2,54 (d, 2H, j=6.9 Hz), to 3.58 (s, 3H), 6,80 (users, 2H), 7,27 (d, 2H, J=8,3 Hz), 7,60 (d, 2H, J=8,3 Hz), 10,66 (users, 1H)DMSO-d6, 400 MHz
2-170228-2291,05-1,15 (m, 2H), 1,38 is 1.48 (m, 2H), 1,58 (s, 6H), 1,66 for 2.01 (m, 7H), 2,24 (s, 3H), of 2.51 is 2.55 (m, 1H), is 3.08-3,30 (m, 6H), 3,85-3,90 (m, 2H), equal to 4.97 (d, 1H, J=4.0 Hz), 6,80 (users, 2H), 7,27 (d, 2H, J=8.0 Hz), to 7.61 (d, 2H, J=12.0 Hz)DMSO-d6, 400 MHz
2-1711,09 of 1.28 (m, 2H), 1,38 and 1.80 (m, 3H), 1.69 in (s, 6H), 1,84-2,04 (m, 4H), of 2.44 (s, 3H), 2,48-2,60 (m, 1H), 3,09 (d, 2H, J=6.0 Hz), 3,38-of 3.53 (m, 4H), 4,59 (s, 1H), 5,50 (user., 2H), 7,24 (d, 2H, J=8,3 Hz), 7,54 (d, 2H, J=8,3 Hz)CDCl3, 300 MHz
2-172>2501,04-of 1.09 (m, 2H), USD 1.43 (m, 1H), 1,43 of 1.50 (m, 4H), to 1.60 (s, 6H), 1,80-1,90 (m, 4H), of 5.24 (s, 1H), 6,88 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz), 7,94 (s,1H), 9,20 (users, 1H), 11,20 (users, 1H)DMSO-d6, 400 MHz
2-173218-2191,02-of 1.13 (m, 2H), 1,40-1,49 (m, 5H), to 1.60 (s, 6H), 1,81-of 1.85 (m, 4H), 2,53-to 2.57 (m, 1H), 2,89 (s, 3H), 2,96-to 3.02 (m, 2H), 6,88-6,97 (m, 3H), 7,31 (d, 2H, J=9.0 in the TS) the 7.65 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-174238-2390,99-to 1.14 (m, 2H), 1,31-of 1.52 (m, 5H), to 1.60 (s, 6H), to 1.79 (s, 3H), 1,80 is 1.86 (m, 4H), 2,53 at 2.59 (m, 1H), 3,05-of 3.12 (m, 2H), 6,93 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), to 7.77 (t, 1H, J=4.5 Hz), to 7.95 (s, 1H)DMSO-d6, 300 MHz
2-175230-2310,91 was 1.06 (m, 2H), 1,27-of 1.45 (m, 5H), to 1.60 (s, 6H), 1,67-to 1.82 (m, 4H), 2,39 (s, 3H), of 2.44-2.49 USD (m, 1H), 2,74 is 2.80 (m, 2H), 6,93 (users, 2H), 7,28 (d, 2H, J=9.0 Hz), 7,41 (d, 2H, J=9.0 Hz), was 7.45 (t, 1H, J=7.5 Hz,), to 7.64 (d, 2H, J=9.0 Hz), 7,69 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-176196-1980,98-to 1.14 (m, 2H), 1,29-of 1.65 (m, 11H), 1,76-of 1.93 (m, 4H), of 2.51-of 2.58 (m, 1H), 3,14-is 3.21 (m, 2H), 3,79 (d, 2H, J=6.0 Hz), of 5.39 (t, 1H, J=6.0 Hz), 6,92 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), 7,62-to 7.67 (m, 3H), 7,95 (, 1H)DMSO-d6, 300 MHz
2-177198-200from 0.84 (t, 3H, J=7.4 Hz), 0,97 by 1.12 (m, 2H), 1,18-of 1.53 (m, 7H), to 1.60 (s, 6H), 1,76-of 1.88 (m, 4H), 2,10 (t, 2H, J=7,7 Hz), 2,45-to 2.57 (m, 1H), 2,99 (q, 2H, J=6.5 Hz), 6,94 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.64 (d, 2H, J=8,3 Hz), of 7.75 (t, 1H, J=6.5 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-178143-160 1,03-1,17 (m, 2H), 1,25-of 1.56 (m, 5H), of 1.64 (s, 6H), 2,30 (t, 1,2H, J=7,7 Hz), 2,39 (t, 0,8H, J=7,7 Hz), of 2.51-2,62 (m, 1H), 3,17-of 3.54 (m, 5H), 3,89-4,00 (m, 1H), 4,77 (user., 0,6H), 4,95 (user., 0,4H), 6,99 (user., 2H), 7,33 (d, 2H, J=8,3 Hz), to 7.67 (d, 2H, J=8,3 Hz), 7,98 (s, 1H)DMSO-d6, 300 MHz
2-179168-1700,98 is 1.16 (m, 2H), 1,25-of 1.55 (m, 5H), to 1.60 (s, 6H), 1,75-of 1.94 (m, 4H), 2,24 is 2.44 (m, 2H), 2,48-2,60 (m, 1H), 2,81 (s, 1,5H), 3.00 and (C, 1,5H), 3.25 to to 3.41 (m, 2H), 3,43-3,55 (m, 2H), 4,60 (user., 0,5H), 4,78 (user., 0,5H), 6,92 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-180200-2020,98-of 1.55 (m, 9H), to 1.60 (s,6H), 1,61-of 1.94 (m, 6H), of 2.33 (t, 2H, J=7.8 Hz), 2,48 at 2.59 (m, 1H), 2,90 totaling 3.04 (m, 1H), 3,07-3,20 (m, 1H), 3,60 of 3.75 (m, 2H), 3,85-a 4.03 (m, 1H), 4,71 (user., 1H), 6,92 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-18183-207of 1.02-1.14 in (m, 2H), 1,24-is 1.51 (m, 5H), to 1.60 (s, 6H), 1.77 in is 1.91 (m, 4H), 2,16-is 2.37 (m, 8H), 2,46-of 2.54 (m, 1H), 3,38-to 3.50 (m, 4H), 6,93 (user., 2H), 7,29 (d, 2H, J=8,3 Hz), to 7.64 (d, 2H, J=8,3 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-182167-1690,99-of 1.13 (m, 2H), 1,27 of 1.50 (m, 6H), 1,55 was 1.69 (m, 9H), 1,76 is 2.00 (m, 5H), of 2.51-2.57 m (m, 1H), 2,80-2,87 (m, 2H), 3,09-and 3.16 (m, 2H), 3,49-of 3.53 (m, 1H), 6,94 (users, 2H), 7,29 (d, 2H, J=6.0 Hz), 7,63 (who, 2H, J=6.0 Hz), 7,88-a 7.92 (m, 1H), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-183201-2030,98 is 1.13 (m,2H), 1,24 is 1.70 (m, 13H), 1,77-to 1.98 (m, 5H), of 2.51-of 2.58 (m, 1H), 2.71 to 2,87 (m, 2H), 3,07-and 3.16 (m, 2H), 3,70 (t, 1H, J=7.5 Hz), 4,17 (users, 1H), 4,67 (d, 1H, J=3.0 Hz), 6,92 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,92 (t, 1H, J=4.5 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-184>2501,03-1,17 (m, 2H), 1,37-and 1.54 (m, 5H), to 1.60 (s, 6H), of 1.78-1.90 (m, 4H), of 2.08 (s, 3H), 2,53 at 2.59 (m, 1H), 3,19-of 3.25 (m, 2H), 6,12 (users, 1H), 6,94 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), 7,34-7,39 (m, 1H), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-185193-194of 1.02-1.14 in (m, 2H), 1,27-is 1.51 (m, 6H), to 1.60 (s, 6H), 1,80-1,89 (m, 4H), of 2.20 (s, 3H), 2,44 is 2.46 (m, 2H), 2,52-of 2.56 (m, 1H), 6,53 (s, 1H), of 6.96 (users, 2H), 7,29 (d, 2H, J=12.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), 7,93 (, 1H)DMSO-d6, 400 MHz
2-186200-2010,98 is 1.13 (m, 2H), 1,25-is 1.51 (m, 5H), to 1.60 (s, 6H), 1.77 in-1,90 (m, 4H), 2,31 (t, 2H, J=7,7 Hz), 2,50-to 2.57 (m, 1H), 2,81 (s, 3H), of 2.97 (s, 3H), 6,93 (user., 2H), 7,30 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-187206-208096-1,11 (m,2H), the 1.04 (d, 6H, J=6.6 Hz), 1,20-is 1.51 (m, 5H), to 1.60 (s, 6H), 1,76-of 1.92 (m, 4H), 2,07 (t, 2H, J=7,3 Hz), 2,45-of 2.58 (m, 1H), 3,83 (dt, 1H, J=20,9, and 6.6 Hz), 6,93 (user., 2H), 7,30 (d, 2H, J=8.0 Hz), 7,63 (t, 1H, J=7,3 Hz), to 7.64 (d, 2H, J=8.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-188173-1750,99 (t, 1,5H, J=7,1 Hz), 1,01-of 1.15 (m, 2H), 1,10 (t, 1,5H, J=7,1 Hz), 1,22-and 1.54 (m, 5H), to 1.60 (s, 6H), 1,76-to 1.87 (m, 4H), to 2.29 (t, 1H, J=7,7 Hz), 2,32 (t, 1H, J=7,7 Hz), 2,46-of 2.58 (m, 1H), 2,78 (s, 1,5H), to 2.94 (s, 1,5H), 3,26-3,37 (m, 2H), 6,92 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-189192-1940,96 is 1.13 (m,2H), and 1.00 (t, 3H, J=7.0 Hz), is 1.11 (t, 3H, J=7.0 Hz), 1,25-of 1.52 (m,5H), to 1.60 (s, 6H), 1,75-of 1.92 (m,4H), 2,30 (t, 2H, J=7,7 Hz), 2.49 USD at 2.59 (m, 1H), 3,22-to 3.34 (m, 4H), 6,94 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-190210-2120,80 (t, 1,5H, J=7,3 Hz), 0,84 (t, 1,5H, J=7,3 Hz), 0,98-of 1.15 (m, 2H), 1,22-of 1.57 (m, 8H), to 1.60 (s, 6H), 1,74 is 1.91 (m, 4H), 2,28-is 2.37 (m, 2H), 2,47 at 2.59 (m, 1H), and 2.79 (s, 1,5H), 2.95 and (C, 1,5H), 3,24 (kV, 2H, J=7,3 Hz), 6,93 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz

160-162
2-191>2501,00-1,11 (m, 2H), 1,25-1,35 (m, 1H, 1,43 of 1.50 (m, 4H), was 1.58 (s, 6H), 1,78 is 1.86 (m, 4H), 2,22-of 2.28 (m, 2H), 2,24 (s, 3H), 6,82 (users, 2H), 7,29 (d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz), 11,99 (users, 1H)DMSO-d6, 300 MHz
2-192>2500,99 by 1.12 (m, 2H), 1,22-of 1.33 (m, 1H), 1,42-of 1.52 (m, 4H), was 1.58 (s, 6H), 1,80-of 1.84 (m, 4H), 2,24 (s, 3H), 2,32 (t, 2H, J=7.5 Hz), 3,23 (s, 3H), for 6.81 (users, 2H), 7,29 (d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz), 11,66 (users, 1H)DMSO-d6, 300 MHz
2-193>2400,95-1,12 (m, 2H), 1,17 (s, 6H), 1,21-of 1.30 (m, 1H), 1,36-1,49 (m, 4H), was 1.58 (s, 6H), 1.77 in-to 1.87 (m, 4H), of 2.09 (t, 2H, J=7.5 Hz), 2,24 (s, 3H), 2,47-of 2.58 (m, 1H), 3,37 (d, 2H, J=6.0 Hz), 4,88 (t, 1H, J=6.0 Hz), 6,80 (user., 2H), 7,24 (users, 1H), 7,29 (d,2H,J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
2-194230-2310,99 by 1.12 (m, 2H), 1,25-of 1.36 (m, 1H), 1,37-of 1.52 (m, 4H), was 1.58 (s, 6H), 1,79-to 1.87 (m, 4H), 2,22 (t, 2H, J=7.5 Hz), 2,24 (s, 3H), 2,49-to 2.57 (m, 1H), 3,17 (DD, 1H, J=12,0, 6,0 Hz)at 3.25 (DD, 1H, J=12,0, 6,0 Hz), 3,36 (DD, 1H, J=12,0, 6,0 Hz), 3,57 (DD, 1H, J=12,0,6,0 Hz), 3,94-4,01 (m, 1H), 4,01-4,08 (m, 1H), a 4.86 (d, 1H, J=6.0 Hz), is 4.93 (d, 1H, J=6.0 Hz), for 6.81 (user., 1H), 7,29 (l,

2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz)
DMSO-d6, 300 MHz
2-195250 (decomp.)1,06-of 1.13 (m, H), 1,43-154 (m, 5H), was 1.58 (s, 6H), of 1.84 (m, 4H), 2,24 (s, 3H), by 2.55 (d, 2H, J=7.5 Hz), 6,83 (ush the D.C, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz)DMSO-d6, 400 MHz
2-196211 (decomp.)1,06-of 1.13 (m, 2H), 1,44-154 (m, 5H), was 1.58 (s, 6H), of 1.84 (m, 4H), 2,24 (s, 3H), by 2.55 (d, 2H, J=7.5 Hz), 6,82 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-197250 (decomp.)1,04-of 1.15 (m, 2H), 1,36-1,49 (m, 5H), was 1.58 (s, 6H), to 1.86 (m, 4H), 2,24 (m, 2H), 2,54 (m, 1H), 2,66 (m, 2H), 3,69 (s, 3H), 6,82 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-198>2501,04-1,11 (m, 2H), 1,39-of 1.52 (m, 5H), was 1.58 (s, 6H), to 1.86 (m, 4H), 2,24 (s, 3H), of 2.64 (m, 2H), only 3.57 (s, 3H), a 4.86 (t, 1H, J=5.3 Hz), 6,83 (users, 2H), 7,29 (d, 2H, J=8,3 Hz), 7,44 (t, 1H, J=5.6 Hz), a 7.62 (d, 2H, J=8,3 Hz)DMSO-d6, 300 MHz
2-199198-2001,10-1,15 (m, 2H), 1,43 of 1.50 (m, 3H), 1.69 in (s, 6H), of 1.78 (m, 2H), was 1.94 (m, 4H), 2,47 (s, 3H), to 2.67 (m, 1H), 2,90 (m, 2H), 5,74 (users, 2H), 7,25 (d, 2H, J=8,3 Hz), 7,54 (d, 2H, J=8,3 Hz)CDCl3, 300 MHz
2-200>2501,04-1,19 (m, 3H), 1,37-of 1.52 (m, 2H), 1,58 (s, 6H), 1,62 was 1.69 (m, 2H), 1,79 is 1.91 (m, 4H), 2,24 (s, 3H), 2,47-of 2.58 (m, 1H), 2,93 (t, 2H,J=7.5 Hz), for 6.81 (users, 2H), 7,29(d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
2-201>2501,03-of 1.15 (m, 2H), 1,27-of 1.41 (m, 1H), 1,39-of 1.53 (m,4H), was 1.58 (s, 6H), 1,81-to 1.87 (m,4H), 2,24 (s, 3H), 2,46 of $ 2.53 (m, 2H), 2.57 m (OSiR., 1H), for 6.81 (user., 1H), 7,29 (d, 2H, J=9.0 Hz), a 7.62 (d, 2H, J=9.0 Hz), 11,96 (users, 1H), 15,78 (user., 1H)DMSO-d6, 300 MHz
2-202>2251,02-of 1.18 (m, 2H), 1,11 (s,6H), 1,34-of 1.53 (m, 5H), was 1.58 (s, 6H), 1,69-of 1.85 (m, 4H), 2,24 (s, 3H), 2,43 of $ 2.53 (m, 1H), for 6.81 (user., 2H), 7,28 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), a 12.03 (users, 1H)DMSO-d6, 300 MHz
2-203235-2371,35-of 1.55 (m, 4H), to 1.60 (s, 6H), 1.77 in-between 1.79 (m, 4H), 2,15 was 2.25 (m, 1H), 2,48-2,61 (m, 1H), 3,11 (q, 2H, J=6.0 Hz), 3,39 (q, 2H, J=6.0 Hz), with 4.64 (t, 1H, J=6.0 Hz), 6,97 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,74 (t, 1H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-204>2501,43-and 1.54 (m, 4H), to 1.60 (s, 6H), 1,81-of 1.95 (m, 4H), 2,10-of 2.24 (m, 1H), 2.49 USD 2.63 in (m, 1H), 6,70 (users, 1H), 6,95 (user., 2H), 7.23 percent (users, 1H), 7,31 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-205>2501,41-to 1.59 (m, 4H), to 1.61 (s, 6H), 1,81 is 1.91(m, 4H), 2.21 are 2,31 (m, 1H), 2,54-2,60 (m, 1H), 3,74 (d, 2H, J=5.6 Hz), 6,97 (user., 2H), 7,31 (d, 2H, J=8.1 Hz), the 7.65 (d, 2H, J=8.1 Hz), of 7.96 (s, 1H), 8,04 (t, 1H, J=5.6 Hz)DMSO-d6, 400 MHz
2-206>250a 1.08 (s, 3H), 1,22 (s, 3H), 1.41 to and 1.54 (m, 4H), 1,80-of 1.88 (m, 2H), 1,96-2,04 (m, 2H), 2,22-of 2.30 (m, 1H), 2,47 is 2.55 (m, 1H), 4,11 (s, 1H), 5,27 (s, 1H), 6,23 (s, 2H), 7,25 (d, 2H, J=8.1 Hz), was 7.36 (d, 2H, J=8.1 Hz), a 7.62 (s, 1H)DMSO-d6, 400 MHz
2-207>2501,45-of 1.65 (m, 7H), to 1.60 (s, 6H), 1,80-of 1.95 (m, 6H), 2,50-2,78 (m, 3H), 3,05-3,26 (m, 1H), 3,86-4,30 (m, 2H), 6.90 to (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H), 12,05 (users, 1H)DMSO-d6, 300 MHz
2-208193-1941,45-of 1.65 (m,4H), to 1.60 (s, 6H), 1,80-of 1.95 (m, 7H), 2,08-2,19 (m, 2H), 2,53-2,63 (m, 1H), 3,55-3,63 (m, 2H), 4,21-of 4.25 (m, 1H), 6,95 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), 7,66 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-209>2501,23-of 1.36 (m, 2H), 1,48-of 1.57 (m, 2H), 1,60 (s, 6H), to 1.79 (s, 3H), 1,83-of 1.92 (m, 4H), 2,53-of 2.58 (m, 1H), 3,55-3,66 (m, 1H), 6,94 (users, 2H), 7,33 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), 7,76 (d, 1H, J=6.0 Hz), to 7.95 (s, 1H)DMSO-d6, 300 MHz
2-210>250 to 1.24 to 1.48 (m, 4H), was 1.58 (s, 6H), 1,69 to 1.76 (m, 4H), 2,39 (s, 3H), 2,41 is 2.46 (m, 1H), 2,98-is 3.08 (m, 1H), 6,93 (users, 2H), 7,27 (d, 2H, J=9.0 Hz), 7,40 (d, 2H, J=9.0 Hz), to 7.61 (d, 2H, J=9.0 Hz), the 7.65 (d, 1H, J=6,0 Hz), 7,73 (d, 2H, J=9.0 Hz), 7,94 (s, 1H)DMSO-d6, 300 MHz
2-211>250A mixture of 2 conformers; and 1,25 1,27 (s, 3H), 1,42-of 1.57 (m, 4H), to 1.61 (s, 6H), 1,79 is 1.91 (m, 4H), 2.21 are of 2.30 (m, 1H), 2,52-2,63 (m, 1H), 4,14-of 4.25 (m, 1H), of 6.96 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=6.0 Hz), of 7.96 (s, 1H), 8,04 (d, 1H, J=6.0 Hz)DMSO-d6, 300 MHz
2-212>250of 1.33 (s, 6H), 1,42-and 1.54 (m, 4H), to 1.60 (s, 6H), 1,81-of 1.88 (m, 4H), 2,17 was 2.25 (m, 1H), 2,53 at 2.59 (m, 1H), 6,97 (users, 2H), 7,31 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), of 7.90 (users,1H), of 7.96 (s, 1H)DMSO-d6, 300 MHz
2-213>2501,45-of 1.57 (m, 4H), to 1.61 (s, 6H), 1,84 is 1.91 (m, 4H), 2,30-is 2.37 (m, 1H), 2,53-2,60 (m, 1H), 3,60-3,70 (m, 2H), 4,25-or 4.31 (m, 1H), 4,91 (users, 1H), 6,97 (users, 2H), 7,32 (d, 2H, J=9.0 Hz), 7,66 (d, 2H, J=9.0 Hz), the 7.85 (d, 1H, J=9.0 Hz), of 7.96 (s, 1H)DMSO-d6, 300 MHz
2-214>250A mixture of 2 conformers; 1,49-to 1.63 (m, 4H), to 1.61 (s, 6H), 1,80-1,89 (m, 4H), 2,81 and to 3.09 (s, 3H), 3,98 and 4,20 (s, 2H), 6,93 (users, 2H), 7,31 and 7,33 (d, 2H, J=9.0 Hz), 7,65 and 7,66 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)The MCO-d6, 300 MHz
2-215>2501,34-of 1.44 (m, 2H), 1,51 is 1.58 (m, 2H), 1,60 (s, 6H), 1,78-to 1.87 (m, 2H), 1,97-to 2.06 (m, 2H), of 2.51-of 2.56 (m, 1H), 2,93 (s, 3H), 3,19 is 3.23 (m, 1H), 6.90 to (users, 2H), 7,03 (d, 1H, J=6.0 Hz), 7,31 (d, 2H, J=6.0 Hz), of 7.64 (d, 2H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-2161,01-1,10 (m, 2H), 1,40-1,49 (m, 3H), 1,60 (s, 6H), 1,83-to 1.87 (m, 4H), 2,52 is 2.55 (m, 1H), 3,22 of 3.28 (m, 2H), 6.90 to (users, 2H), 7,30 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=8.0 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-217225-2271,09 is 1.20 (m, 2H), 1,36 of 1.46 (m, 2H), 1,58 (s, 6H), 1,76-of 1.81 (m, 5H), 2,52-of 2.56 (m, 1H), 3,48 (d, 2H, J=8.0 Hz), 6.89 in (users, 2H), 7,27 (d, 2H, J=12.0 Hz), to 7.61 (d, 2H, J=12.0 Hz), 7,82-7,88 (m, 4H), 7,92 (s, 1H)DMSO-d6, 400 MHz
2-2182121,32-and 1.54 (m, 4H), to 1.60 (s, 6H), 1,81-of 1.85 (m, 2H), 2.05 is is 2.10 (m, 2H), 2,53-of 2.56 (m, 1H), 3,09-3,18 (m, 1H), 6,46 (s, 2H), is 6.54 (d, 1H, J=9.0 Hz), 6,94 (users, 2H), 7,31 (d, 2H, J=6.0 Hz), to 7.64 (d, 2H, J=6.0 Hz), to 7.95 (s, 1H)DMSO-d6, 300 MHz
2-219243-248a 1.08 (s, 3H), 1,22 (s, 3H), 1,44-of 1.62 (m, 4H), 1,69-1,90 (m, 4H), 2,45-of 2.58 (m, 1H), 2,63-2,77 (m, 1H), 2,81 (s, 1,2H), is 3.08 (s, 1,8H), 4,11 (s, 0,6H), 4,18 (s, 0,4H), of 5.26 (s, 1H), 6,2 (user., 2H), 7,26 (d, 2H,J=8.1 Hz), 7,37 (d, 2H, J=8.1 Hz), to 7.61 (s, 1H), 12,48 (users, 1H)DMSO-d6, 400 MHz
2-220>2501,16-of 1.29 (m, 2H), 1,43-of 1.56 (m, 2H), 1.61 of (s, 6H), 1,80-2,11 (m, 5H), 2,53 at 2.59 (m, 1H), 2,94 (d, 2H, J=6.0 Hz), 6,79 (s, 2H), 6,93 (users,2H), 7,31 (d, 2H, J=9.0 Hz), 7,66 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-221>250a 1.08 (s, 3H), 1,16-of 1.27 (m, 5H), 1,43-of 1.52 (m, 2H), 1,80-of 2.08 (m, 5H), 2,46-2,49 (m, 1H), 2,93 (d, 2H, J=8.0 Hz), 4,11 (users, 1H), 5.25-inch (users, 1H), 6,20 (users, 2H), 6,76 (s, 2H), 7,24 (d, 2H, J=8.0 Hz), was 7.36 (d, 2H, J=8.0 Hz), to 7.61 (s, 1H)DMSO-d6, 400 MHz
2-222>250of 1.07 (s, 3H), 1,22 (s, 3H), 1,24-of 1.53 (m, 4H), 1,75-2,11 (m, 4H), 2,41-2,48 (m, 1H), 3,05-3,17 (m, 1H), 4,11 (users, 1H), 5,26 (users, 1H), 6,21 (users, 2H), 6,45 (users, 2H), of 6.52 (d, 1H, J=12.0 Hz), 7,24 (d, 2H, J=8.0 Hz,), to 7.35 (d, 2H, J=8.0 Hz), 7,60 (s, 1H)DMSO-d6, 300 MHz
2-2231,00-1,11 (m, 5H), 1,22 (s, 3H), of 1.37 to 1.48 (m, 3H), 1.77 in-of 1.85 (m, 4H), 2,43-2,48 (m, 1H), 3,24-of 3.27 (m, 2H), 4,11 (users, 1H), 4,30-4,32 (m, 1H), 5,26 (users, 1H), 6,20 (users, 2H), 7,24 (d, 2H, J=8.0 Hz), was 7.36 (d, 2H, J=8.0 Hz), to 7.61 (s, 1H)DMSO-d6, 400 MHz
2-224 169-1710,94 was 1.06 (m, 2H), 1,36 is 1.60 (m, 16H), 1,76-of 1.93 (m, 4H), 2,03 and 2.13 (m, 2H), of 2.25 to 2.35 (m, 3H), 2,52-of 2.56 (m, 1H), 6,91 (users, 2H), 7,30 (d, 2H, J=12.0 Hz), to 7.64 (d, 2H, J=12.0 Hz), 7,94 (s, 1H)DMSO-d6, 400 MHz
2-2250,92-1,08 (m, 2H), 1,29-of 2.15 (m, 21H), 2,53-of 2.58 (m, 1H), 2,64-by 2.73 (m, 2H), 3,38-of 3.48 (m, 1H), 4,47-4,51 (m, 1H), 6,91 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-2260,97-1,11 (m, 2H), 1,40 by 1.68 (m, 11H), 1,79 is 2.01 (m, 7H), 2,18-2,31 (m, 2H), 2,39-2,47 (m, 2H), 2,62-to 2.74 (m, 2H), 4.75 in (users, 1H), 6,92 (users, 2H), 7,18 and 7.36 (m, 5H), 7,49 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), of 7.95 (s, 1H)DMSO-d6, 300 MHz
2-227198-2000,91 was 1.69 (m, 21H), 1,77-of 1.94 (m, 4H), 2.05 is-of 2.16 (m, 1H), 2,53-2,61 (m, 1H), 2,74-2,89 (m, 2H), 3,40-of 3.46 (m, 2H), 4,30 (users, 1H), 6,91 (users,2H), 7,30 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-228119-1200,91-of 1.65 (m, 19H), a 1.75-1,90 (m, 6H), 2,11 (users, 1H), 2,55-of 2.58 (m, 1H), 2,72-only 2.91 (m, 2H), 6,91 (users, 2H), 7,15-7,33 (m, 7H), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-2290,97-1,11 (m, 2H), 1,39-of 1.97 (m, 19H), and 2.27 2.63 in (m, 3H), 3,24 (users, 2H), 6,91 (users, 2H), 7,30 (d, 2H, J=6.0 Hz), to 7.64 (d, 2H, J=6.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-2300,91-1,10 (m, 2H), 1,37-to 1.63 (m, 11H), 1,78-of 1.92 (m, 5H), 2.06 to to 2.42 (m, 10H), 2,52 at 2.59 (m, 1H), 6,91 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz

2-2310,95-of 1.07 (m, 2H), 1,37-of 1.65 (m, 11H), 1,78 is 1.91 (m, 4H), 2,15-of 2.23 (m, 2H), 2,32-2,47 (m, 6H), 3,45-3,51 (m, 2H), 6,91 (users, 2H), 7,25-7,35 (m, 7H), to 7.64 (d, 2H, J=9.0 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-232171-1720,98-1,08 (m, 2H), 1.39 in (s, 9H), 1.41 to a rate of 1.51 (m,2H), 1,60 (s, 6H), 1,80 is 1.91 (m, 5H), 2.13 and (users, 2H), 2.26 and of-2.32 (m, 4H), 2,48 of $ 2.53 (m, 4H), 2,52-to 2.57 (m, 1H), 6.90 to (users, 2H), 7,28 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-233224-229of 1.06 (d, 3H, J=6.0 Hz), of 1.09 to 1.31 (m, 3H), 1,36-of 1.52 (m, 2H), 1.61 of (s, 6H), 1,71-to 1.82 (m, 1H), 1,90-of 1.93 (m, 2H), 2,01-2,47 (m, 1H), 3,37-of 3.46 (m, 1H), 6,93 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 400 MHz
2-234 226-2301,37-to 1.67 (m, 4H), to 1.61 (s, 6H), 1,78-of 1.92 (m, 4H), 2,46-2,60 (m, 1H), 3,62-of 3.78 (m, 1H), 3,79 (s, 2H), 6,93 (user., 2H), 7,33 (d, 2H, J=8,4 Hz), of 7.48 (d, 1H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-235201-2021,46-of 1.66 (m,4H), to 1.61 (s, 6H), 1,71-of 1.93 (m, 8H), 2,43-2,63 (m, 2H), 3,26-to 3.35 (m, 2H), 3.43 points-of 3.54 (m, 2H), 6,93 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-236220-2241,33-1,89 (m, 14H), to 1.61 (s, 6H), of 2.51 (s, 2H), 3,36 (s, 4H), 6,92 (user., 2H), 7,31 (d, 2H, J=8.1 Hz), the 7.65 (d, 2H, J=8.1 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-237250-2521,16-of 1.39 (m, 2H), 1,46-of 1.92 (m, 8H), to 1.61 (s, 6H), of 2.51-of 2.81 (m, 2H), 2,87 was 3.05 (m, 1H), 3,12-of 3.25 (m, 1H), 3,62-3,99 (m, 4H), with 4.64-4,78 (m, 1H), 6,93 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-238190-1911,48-of 1.65 (m, 4H), to 1.61 (s, 6H), 1,72-of 1.92 (m, 4H), of 2.20 (s, 3H), 2,22-of 2.38 (m, 4H), of 2.51 is 2.75 (m, 2H), 3,41-3,55 (m, 4H), 6,93 (user., 2H), 7,31 (d,2H,J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-239233-2351,47-to 1.67 (m, 4H), of 1.57 (s, 6H), 1.70 to of 1.92 (m, 4H), 2,47-2,77 (m, 2H), 3,37-the 3.65 (m, 8H), 6,92 (user., 2H), 7,31 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-240233-2350,95-of 1.09 (m, 2H), 1,37-of 1.65 (m, 3H), 1,60 (s, 6H), 1.77 in is 1.96 (m, 4H), 2,19 (userd, 2H, J=7.0 Hz), 2,39 2,49 (m, 4H), 2,50-2,61 (m, 1H), 3,07-3,14 (m, 4H), 6,91 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-241120-1260,96-1,10 (m, 2H), 0,99 (d, 6H, J=6.6 Hz), 1.41 to of 1.65 (m,3H), 1,60 (s,6H), 1,81-of 1.93 (m,4H), 2,15 (userd, 2H, J=7.0 Hz), 2,27-of 2.38 (m, 4H), 2.49 USD at 2.59 (m, 1H), 2,80-2,89 (m, 1H), 3,40-3,51 (m, 4H), 6,92 (user., 2H), 7,30 (d, 2H, J=8,4 Hz), to 7.64 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-242171-1720,98-1,08 (m, 2H), 1.39 in (s, 9H), 1.41 to a rate of 1.51 (m, 2H), 1,60 (s, 6H), 1,80 is 1.91 (m, 5H), 2.13 and (users, 2H), 2.26 and of-2.32 (m, 4H), 2,48 of $ 2.53 (m, 4H), 2,52-to 2.57 (m, 1H), 6.90 to (users, 2H), 7,28 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-243208-210A mixture of 2 conformers; 1,02-of 1.13 (m, 2H), 1,38 is 1.58 (m, 2H), equal to 1.59 (s, 6H), 1,61 is 1.91 (m, 5H), of 2.51 (m, 1H), 2,85 are 2.87 (s, 3H), 3,06 and 3,20 (d, 2H, J=6.8 Hz), 4.06 and 4,07 (users, 2H), 4,30 and 4.35 (users, 1H), 6,91 (users, 2H), 7,27 (d, 2H,J=8,3 Hz), to 7.61 (d, 2H, J=8,3 Hz), 7,92 (s, 1H)DM is About-d6, 400 MHz
2-244208-2090,94-of 1.05 (m, 2H), 1.41 to 1.50 in (m, 2H), 1,60 (s, 6H), 1,79-1,90 (m, 5H), 2,08 (d, 2H, J=8.0 Hz), 2,23-to 2.29 (m, 4H), 2,69-a 2.71 (m, 4H), 6,92 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), a 7.62 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-245180-182of 0.82 (t, 3H, J=7.4 Hz), 1.04 million-of 1.13 (m, 2H), 1,37 is 1.58 (m, 5H), to 1.60 (s, 6H), 1,80-of 1.95 (m,4H), 2,01-to 2.18 (m, 2H), 2,19-2,39 (m, 4H), of 2.51 (m, 1H), 2.95 and (q, 2H, J=7.4 Hz), 3,20 of 3.28 (m, 4H), 6,40 (users, 1H), 6,91 (users, 2H), 7,28 (d, 2H, J=8,3 Hz), a 7.62 (d, 2H,J=8,3 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-246158-1601,04 is 1.13 (m, 2H), 1,37 is 1.58 (m, 3H), of 1.59 (s, 6H), 1,80-of 1.95 (m, 4H), 2,01-to 2.18 (m, 2H), 2,19-2,39 (m, 4H), of 2.51 (m, 1H), 3,20 of 3.28 (m, 4H), of 5.89 (users, 2H), 6,91 (users, 2H), 7,27 (d, 2H, J=8,3 Hz), to 7.61 (d, 2H,J=8,3 Hz), 7,92 (s, 1H)DMSO-d6, 400 MHz
2-247205-2060,98-of 1.07 (m, 2H), 1,43-is 1.51 (m, 2H), 1,60 (s, 6H), 1,80-of 1.92 (m, 5H), and 2.14 (d, 2H, J=8.0 Hz), 2,28-of 2.36 (m, 4H), 2,52-of 2.58 (m, 1H), 3.43 points-of 3.48 (m, 4H), 4,07 (d, 2H, J=6.0 Hz), 4,33 (t, 1H, J=6.0 Hz), 6,93 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-248207-2081,00 of-1.04 (m, 2H), 1,30 (who, 6H), 1,40-of 1.52 (m, 2H), 1,60 (s, 6H), 1,79-of 1.93 (m, 5H), 2.13 in (d, 2H, J=8.0 Hz), is 2.30 to 2.35 (m, 4H), 2,53-of 2.58 (m, 1H), 3,79-of 3.97 (m, 4H), 6,92 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=12.0 Hz), 7,93 (s, 1H)DMSO-d6, 400 MHz
2-249202-2030,97 was 1.06 (m, 2H), 1,43-of 1.52 (m, 2H), 1,60 (s, 6H), 1,81-of 1.92 (m, 5H), to 1.98 (s, 3H), and 2.14 (d, 2H, J=8.0 Hz), 2.26 and-a 2.36 (m, 4H), 2,52-of 2.56 (m, 1H), 3,38 is-3.45 (m, 4H), 6,93 (users, 2H), 7,28 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=12.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-250220-2401,43 was 1.69 (m, 4H), to 1.61 (s, 6H), 1,73-of 1.92 (m, 4H), 2,36-of 2.64 (m, 2H), 3,13-to 3.41 (m, 3H), of 3.65 (DD, 1H, J=5,9, 9.9 Hz), 3.96 points-of 4.11 (m, 2H), 4,85 (user., 1H), 4.92 in (user., 1H), 6,93 (user., 2H), 7,32 (d, 2H, J=8,4 Hz), the 7.65 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-251159-164,09 (m, 2H), 1,39-1,72 (m, 8H), to 1.60 (s, 6H), 1.77 in-of 1.93 (m, 6H), 1,97-of 2.16 (m, 2H), 2,45-2,61 (m, 1H), was 2.76-2,89 (m, 1H), 6,67 (user., 1H), 6,91 (user.,2H), 7,17 (user., 1H), 7,30 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8.1 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
2-252209-211the 1.04 (t, 3H, J=7.4 Hz), 1,20-of 1.29 (m, 2H), 1,46 is 1.58 (m, 2H), 1,60 (s, 6H), 1,80-of 1.95 (m,4H), 2,01-2,07 (m, 2H), of 2.51 (m, 1H), 2,92-a 3.01 (m, 4H), 6.90 to (users, 1H), of 7.96 (ushort, 1H, J=5.6 Hz), 7,29 (d, 2H, J=8,3 Hz), 7,63 (d, 2H, J=8,3 Hz), 7,94 (s, 1H)LCA is-d6, 400 MHz
2-253248 (decomp.)1,03-1,17 (m, 2H), 1,38-of 1.64 (m, 8H), 1,78 is 1.96 (m, 4H), to 2.55 (d, 2H, J=9.0 Hz), up 3.22 (s, 2H), 3,30 (s, 2H), 6,92 (users, 2H), 7,30 (d, 2H, J=6.0 Hz), to 7.64 (d, 2H, J=6.0 Hz), 7,95 (s, 1H), 12,40 (users, 1H)DMSO-d6, 300 MHz
2-254213-2141,39-of 1.52 (m,4H), to 1.60 (s, 6H), 1.85 to of 1.93 (m, 4H), 2,52 of 2.68 (m, 2H), 4,18 (users, 2H), equal to 4.97 (users, 1H), 6,93 (users, 2H), 7,29 (d, 2H, J=8.0 Hz), 7,63 (d, 2H, J=8.0 Hz), to 7.93 (s, 1H)DMSO-d6, 400 MHz
2-255>250the 1.44-of 1.53 (m, 4H), was 1.58 (s, 6H), 1,82-1,89 (m, 2H), 1,98-2,03 (m, 2H), 2,24 (s, 3H), 2.26 and (users, 1H), 6,84 (users, 2H), 7,30 (d, 2H, J=9.0 Hz), 7,63 (d, 2H, J=9.0 Hz), 12,05 (users, 1H)DMSO-d6, 300 MHz
2-256172-1751,42-of 1.55 (m, 4H), was 1.58 (s, 6H), 1,84-of 1.97 (m, 4H), 2,24 (s, 3H), 2.26 and-of 2.28 (m, 1H), 2,73 (users, 1H), 3,23 (users, 3H), 7,30 (d, 2H, J=6.0 Hz), 7,63 (d, 2H, J=9.0 Hz), 11,67 (users, 1H)DMSO-d6, 300 MHz
2-257220-225of 1.18 (s, 6H), 1,36-of 1.56 (m, 4H), was 1.58 (s, 6H), 1,79-to 1.87 (m, 4H), 2,15-2,22 (m, 1H), 2,24 (s, 3H), 2,55 at 2.59 (m, 1H), 3,37 (d, 2H, J=6.0 Hz), the 4.90 (t, 1H, J=6.0 Hz), 6,82 (user., 2H), 7,18 (users, 1H), 7,29 (d, 2H, J=9.0 Hz), 7,63 (d, 2H,J=9.0 Hz) DMSO-d6, 300 MHz
2-258>250the 1.44-of 1.61 (m, 4H), was 1.58 (s, 6H), 1,75-of 1.88 (m,4H), of 2.25 (s,3H), 2,41 is 2.51 (m, 2H), 2,54-2,62 (m, 1H), 3,18 (DD, 1H, J=12,0, 6,0 Hz), 3,37 (DD, 1H, J=12,0, 6,0 Hz), the 3.65 (DD, 1H, J=9,0, 6,0 Hz), 3.96 points-was 4.02 (m, 1H)that was 4.02-4,10 (m, 1H), 4,87 (d, 1H, J=6.0 Hz), of 4.95 (d, 1H, J=6.0 Hz), 6,83 (user., 1H), 7,31 (d, 2H, J=9.0 Hz), 7,63 (d, 2H, J=9.0 Hz)DMSO-d6, 300 MHz
2-259271-2771,05-1,20 (m, 2H), 1,36-of 1.62 (m, 3H), 1,58 (s, 6H), 1.77 in-to 1.98 (m, 4H), 2,24 (s, 3H), 2,47 at 2.59 (m, 1H), 2,54 (d, J=6.0 Hz, 2H), and 3.31 (s, 2H), for 6.81 (user s, 2H), 7,29 (d, J=9.0 Hz, 2H), 7.62mm (d, J=9.0 Hz, 2H), 12,48 (s, 1H)DMSO-d6, 300 MHz
2-260235-2391,01-to 1.21 (m, 2H), 1.32 to and 1.54 (m, 3H), of 1.41 (s, 6H), was 1.58 (s, 6H), 1.77 in-of 1.97 (m, 4H), 2,24 (s, 3H), 2,43-2,61 (m, 3H), 6,83 (users, 2H), 7,28 (d, J=8,2 Hz, 2H), to 7.61 (d, J=8,2 Hz, 2H), 12,49 (users, 1H)DMSO-d6, 300 MHz
2-261225-2271,17-to 1.38 (m, 2H), 1,44-of 1.66 (m, 2H), 1,58 (s, 6H), 1.77 in-a 1.88 (m, 2H), 1,96-of 2.16 (m, 3H), of 2.25 (s, 3H), 2,45-2,62 (m, 1H), 3.27 to (d, J=6.0 Hz, 2H), 4.26 deaths (s, 2H), for 6.81 (users, 2H), 7,30 (d,J=8,2 Hz, 2H), 7.62mm (d, J=8,2 Hz, 2H), made 13.36 (users, 1H)DMSO-d6, 300 MHz
2-262>166 of 1.18 to 1.37 (m, 2H), 1,46-of 1.64 (m, 2H), 1,58 (s, 6H), 1,79-of 1.94 (m, 4H), 1,98-of 2.09 (m, 1H), 2,24 (s, 3H), 2,44-2,61 (m, 1H), 2,64-to 2.74 (m, 1H), 2,81-2,89 (m, 1H), 3,66 (d, J=14.1 Hz, 1H), 3,92 (d, J=14.1 Hz, 1H), 6,80 (user s, 2H), 7,29 (d, J=8,4 Hz, 2H), to 7.61 (d, J=8,4 Hz, 2H), 13,06 (s, 1H)DMSO-d6, 400 MHz
2-263>250of 1.59 (s, 6H), 1,61 is 1.75 (m, 4H), 1,89 of 1.99 (m, 2H), 2,10-of 2.21 (m, 2H, in), 2.25 (s, 3H), 2,67 (user., 1H), 3,09 (user., 1H), 6,83 (user., 2H), 7,35 (d, 2H, J=6.0 Hz), the 7.65 (d, 2H, J=6.0 Hz), 16,07 (users, 1H)DMSO-d6, 300 MHz
2-264>250the 1.44-1.69 in (m, 4H), to 1.59 (s, 6H), 1,89-of 1.94 (m, 2H), 2.00 in 2,04 (m, 2H, in), 2.25 (s, 3H), 2,55-of 2.66 (m, 2H), 3,16-3,18 (m, 2H), 6,83 (user., 1H), 7,33 (d, 2H, J=9.0 Hz), to 7.64 (d, 2H, J=9.0 Hz), 11,99 (user., 1H)DMSO-d6, 300 MHz
2-265
2-266
2-267
2-268

Table 3
New example No.MastrocolaTPLNMR (δ)Solvent
3188-1901,46-of 1.65 (m, 2H), 1,60 (s, 6H), 1,81-of 1.94 (m, 2H), 2,73-2,96 (m, 2H), 3,22-to 3.34 (m, 1H), 3,63-3,70 (m, 1H), 4,33-of 4.44 (m, 1H), 7,00 (user., 2H), 7,33 (d, 2H, J=8,4 Hz), to 7.67 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
3-2of 1.63 (s, 6H), 1,76-2,02 (m, 4H), 2,83-3,11 (m, 3H), 3,32-3,47 (m, 2H), 7,24 (user., 2H), 7,32 (d, 2H, J=8.1 Hz), 7,73 (d, 2H, J=8.1 Hz), of 8.04 (s, 1H), 8,69 (user., 1H)DMSO-d6, 300 MHz
3-3232-2371,39-and 1.54 (m, 2H), 1,60 (s, 6H), 1,73-of 1.84 (m, 2H), 2,04 (s, 3H), 2,54-of 2.64 (m, 1H), 2.77-to 2,90 (m, 1H), 3,07-3,20 (m, 1H), a 3.87-3,98 (m, 1H), 4,49-4,60 (m, 1H), 6,95 (user., 2H), 7,33 (d, 2H, J=8,4 Hz), 7,66 (d, 2H, J=8,4 Hz), of 7.96 (s, 1H)DMSO-d6, 300 MHz

Table 4
New example No.MastrocolaTPLNMR (δ)Solvent
4191-13 1,58-of 1.62 (m, 6H), of 1.62 (s, 6H), 3,26 (users, 4H), 6,79 (users, 2H), 7,29 (d, 2H, J=9.0 Hz), 7,63 (d, 2H, J=9.0 Hz),to $ 7.91 (s, 1H)DMSO-d6, 400 MHz
4-21,21-of 1.30 (m,2H), of 1.62 (s, 6H), 1.61 of and 1.80 (m, 3H), of 2.54 (d, 2H, J=7.0 Hz), 2,73 (ushort, 2H, J=12,8 Hz), 3,83 (userd, 2H, J=12,8 Hz), 6,79 (users, 2H), 6,91 (d, 2H, J=9.0 Hz), 7,17-7,31 (m, 5H), a 7.62 (d, 2H,J=9.0 Hz), to $ 7.91 (s, 1H)DMSO-d6, 400 MHz
4-3176-177to 1.19 (t, 3H,J=6.0 Hz), 1,57 was 1.69 (m, 8H), 1.85 to of 1.92 (m, 2H), 2,54-2,61 (m, 1H),2,86-2,95 (m, 2H), 3,76-a 3.83 (m, 2H), 4.09 to (q, 2H, J=7.0 Hz), 6.87 in (users, 2H), of 6.96 (d, 2H, J=9.0 Hz), the 7.65 (d, 2H, J=6.0 Hz), a 7.92 (s, 1H)DMSO-d6, 300 MHz
4-4>2401,57-of 1.66 (m, 8H), 1,87-of 1.92 (m, 2H), 2,45-2,47 (m, 1H), 2,87-of 2.93 (m, 2H), 3,76-of 3.80 (m, 2H), 6,82 (users, 2H), 6,94 (d, 2H, J=8.0 Hz), to 7.64 (d, 2H, J=8.0 Hz), to $ 7.91 (s, 1H)DMSO-d6, 400 MHz
4-5174-175to 1.21 (t, 3H, J=6.0 Hz), of 1.62 (s, 6H), 3.25 to 3.27 to (m, 2H), 3,50-of 3.53 (m, 2H), 4,08 (q, 2H, J=6,7 Hz), 6,83 (users, 2H), 6,97 (d, 2H, J=12.0 Hz), 7,66 (d, 2H, J=8.0 Hz), 7,92 (s, 1H)DMSO-d6, 400 MHz
4-6191-196of 1.63 (s, 6H), 1,96 of 1.99 (m, 4H), 3.25 to 3,31 (who, 4H),6,55 (d, 2H, J=8.6 Hz), 6,77 (user., 2H), the 7.65 (d, 2H, J=8.6 Hz), of 7.90 (s, 1H)DMSO-d6, 400 MHz
4-7214-219of 1.62 (s, 6H), up 3.22 (t, 4H, J=4,8 Hz in), 3.75 (t, 4H, J=4,8 Hz), 6,83 (user., 2H), of 6.96 (d, 2H, J=8,4 Hz), to 7.67 (d, 2H, J=8,4 Hz), 7,92 (s, 1H)DMSO-d6, 400 MHz

Table 5
New example No.MastrocolaTPLNMR (δ)Solvent
5117-133to 1.60 (s, 6H), 7,01 (user., 2N), of 7.48 (t, 1H,J=8.1 Hz), 7,55 (DDD, 1H, J=1,0, 2,0, 1.0 Hz), to 7.67 (dt, 1H, J=8,1, 1.0 Hz), 7,76 (t, 1H, J=2.0 Hz), of 7.97 (s, 1H)DMSO-d6, 400 MHz
5-2130-131was 1.58 (s, 6H), 5,20 (s, 2H), 6,93 (user., 2H), 7,15 (d, 1H, J=8,3 Hz), 7,25-7,49 (m, 8H), of 7.97 (s, 1H)DMSO-d6, 400 MHz
5-3151-1521,02-of 1.33 (m, 5H), to 1.60 (s, 6H), 1,65-of 1.88 (m, 6H),3,85 (d, 2H, J=6.2 Hz), 6,94 (user., 2H), 7,05 (DD, 1H, J=2.5 and 8.0 Hz), 7,17 (d, 1H, J=2.5 Hz), of 7.23 (d, 1H, J=8.0 Hz), 7,35 (t, 1H, J=8.0 Hz), of 7.97 (s, 1H)DMSO-d6, 400 MHz

Table 6
New example No.MastrocolaTPLNMR (δ)Solvent
6>2301,09-1,22 (m, 2H), 1.41 to and 1.56 (m, 2H), 1,58 (s, 6H), 1.70 to at 1.91 (m, 5H), of 2.16 (d, 2H, j=6,7 Hz), 2,24 (s, 3H), of 2.92 (m, 1H), 6,91 (users, 2H), 7,42 (d, 1H, J=8.1 Hz), 7,63 (DD, 1H, J=8,1, 1.8 Hz), 7,72 (d, 1H, J=1,8 Hz), 12,10 (users, 1H)DMSO-d6, 400 MHz
6-2229-2320,98 is 1.16 (m, 2H), 1,34-of 1.64 (m, 3H), 1,58 (s, 6H), 1,76-1,89 (m, 4H), 2,24 (s, 3H), 2,83 are 2.98 (m, 1H), to 3.02 (t, J=6.0 Hz, 1H), 3,81 (s, 2H), 5,42 (users, 1H), 6,91 (users, 2H), 7,41 (d, J=8,3 Hz, 1H), 7,63 (d, J=8,3 Hz, 1H), 7,65-7,72 (m, 1H), 7,73 (s, 1H)DMSO-d6, 300 MHz
6-3280 (decomp.)1,15-of 1.42 (m, 5H), and 1.56 (s, 6H), of 1.80 (m, 4H), of 2.23 (s, 3H), 2.13 in (d, 2H, J=6.8 Hz), equal to 4.97 (users, 2H), 6.75 in (users, 2H), PC 6.82 (DD, 1H, J=8,3 Hz, 1.9 Hz), 6,93 (d, 1H, J=1.9 Hz), 7,01 (d, 1H, J=8,3 Hz)DMSO-d6, 300 MHz
6-4177 (decomp.)1,01-of 1.09 (m, 2H), 1,45-1 56 (m, 3H), of 1.59 (s, 6H), 1.70 to to 1.83 (m, 6H),2,13-2,19 (m, 4H),of 2.25 (s, 3H), 2,41 is 2.46 (m, 2H), 3,63 at 3.69 (m, 2H), 6.87 in (users, 2H), 7,42 (d, 1H, J=8,3 Hz), 7,51 (d, 1H, J=1.9 Hz), a 7.62 (DD, 1H, J=8,3, 1.9 Hz)DMSO-d6, 300 MHz
6-5>3001,15-1,25 (m, 2H), 1,37-of 1.57 (m, 2H), 1,58 (s, 6H), 1,65-of 1.94 (m, 5H), 2,24 (s, 3H), 2,31 (d, J=6,8 Hz, 2H), 2,85-a 3.01 (m, 1H), 6.90 to (s, 2H), 7,41 (d, J=8,3 Hz, 1H), 7,63 (DD, J=1,9, 8,3 Hz, 1H), 7,73 (d, J=1.9 Hz, 1H), 11,07 (s, 1H), 11,17 (s, 1H)DMSO-d6, 300 MHz
6-6>2821,13-of 1.32 (m, 2H), 1,39-of 1.57 (m, 2H), 1,58 (s, 6H), 1.70 to a 1.96 (m, 5H), of 2.25 (s, 3H), of 2.45 (d, J=6,8 Hz, 2H), 2,87-a 3.01 (m, 1H), 6,91 (s, 2H), 7,42 (d, J=8,3 Hz, 1H), to 7.64 (DD, J=1,9, 8,3 Hz, 1H), 7,74 (d, J=1.9 Hz, 1H), 12,17 (s, 1H)DMSO-d6, 300 MHz
6-7>2801,02-1,20 (m, 2H), 1,33-of 1.53 (m, 2H), and 1.56 (s, 6H), 1,65-1,89 (m, 5H), and 2.14 (d, J=6,8 Hz, 2H), 2,24 (s, 3H), 2,75 - 2,89 (m, 1H), 6,77 (user. s, 1H), 7,07 (d, J=7.9 Hz, 1H), was 7.08 (s, 1H), 7,15 (d, J=7.9 Hz, 1H), to 9.45 (s, 1H), 11,99 (s, 1H)DMSO-d6, 300 MHz
6-8224-2251,02-to 1.21 (m, 2H), 1,31-to 1.60 (m, 2H), 1,35 (t, J=6.9 Hz, 3H), 1,58 (s, 6H), 1,66-1,89 (m, 5H), of 2.15 (d, J=6.6 Hz, 2H, in), 2.25 (s, 3H), 2,78-of 2.93 (m, 1H), 4,10 (kV, J=6,9 Hz, 2H), 6,83 (users, 2H), 7,17-7,29 (m, 3H), 11,98 (s, 1H)DMSO-d6, 300 MHz
6-9>2691,07 is 1.23 (m, 2H), 1,44-to 1.63 (m, 2H), equal to 1.59 (s, 6H), 1,71-1,90 (m, 5H), of 2.16 (d, J=6,8 Hz, 2H), 2,24 (s, 3H), 2,70-is 2.88 (m, 1H), 6,88 (users, 2H), 7,34-7,42(m, 1H), 7,46 - of 7.55 (m, 2H), 12,02 (s, 1H)DMSO-d6, 300 MHz
6-10212-214a 1.01-1.14 in (m, 2H), 1,42-of 1.57 (m, 3H), of 1.59 (s, 6H), is 1.81 (m, 4H), 2,24 (s, 3H), 2,80 (m, 1H), to 3.02 (m, 2H), 3,81 (d, 2H, J=6.0 Hz), 5,1 (t, 1H, J=6.0 Hz), 6,88 (users, 2H), 7,34-7,40 (m, 1H), of 7.48-rate of 7.54 (m, 2H,), to 7.67-7,71 (m, 1H)DMSO-d6, 300 MHz
6-11>282of 1.10 to 1.31 (m, 2H), 1,42-of 1.64 (m, 2H), equal to 1.59 (s, 6H), 1,67-1,89 (m, 5H), 2,24 (s, 3H), 2,44 (d, J=6,8 Hz, 2H), 2,75-is 2.88 (m, 1H), 6.89 in (user s, 1H), 7,33-7,42 (m, 1H), 7,47-7,56 (m, 2H), 12,16 (s, 1H)DMSO-d6, 300 MHz
6-12171-1731,03-1,19 (m, 2H), 1,34-is 1.51 (m, 2H), 1,58 (s, 6H), 1,72-of 1.85 (m, 4H), 2,24 (s, 3H), 2,39 (d, 2H, j=6,7 Hz), of 2.92 (m, 1H), 5,23 (s, 1H), 6.90 to (users, 2H), 7,40 (d, 1H, J=8.1 Hz), a 7.62 (d, 1H, J=8.1 Hz), 7,72 (s, 1H),9,20 (users, 1H), 11,20 (users, 1H)DMSO-d6, 400 MHz
6-13>250of 1.09 (t, 3H, J=7.4 Hz), 1,03 is 1.16 (m, 2H), 1,34-and 1.54 (m, 2H), 1,58 (s, 6H), 1,76-1,89 (m, 4H), of 2.25 (s, 3H), 2,83-is 3.08 (m, 5H), 5,70 (t, 1H, J=5.6 Hz), to 5.85 (t, 1H, J=5,9 Hz), 6.90 to (users, 2H), 7,43 (d, 1H, J=8.1 Hz), to 7.64 (d, 1H, J=8.1 Hz), 7,73 (s, 1H)DMSO-d6, 300 MHz
6-14205-209to 0.88 (d, 6H, J=6.0 Hz), 1,01 is 1.13 (m, 2H), 1,37-of 1.52 (m, 3H), 1,58 (s, 6H), 1.77 in-to 1.87 (m, 5H), of 2.25 (s, 3H), 2,89 (t, 2H, J=6.0 Hz), 2,89-2,95 (m, 1H), of 3.73 (d, 2H, J=6.0 Hz), 6.90 to (user., 2H), 7,13 (user., 1H), 7,42 (d, 1H, J=9.0 Hz), 7,63 (DD, 1H, J=9,0, 3.0 Hz), 7,73 (d, 1H, J=3.0 Hz)DMSO-d6, 300 MHz
6-15225-2281,00-1,11 (m, 2H), 1,36-is 1.51 (m, 3H), 1,58 (s, 6H), 1,78 is 1.86 (m, 4H), 2,24 (s, 3H), 2,92-2,96 (m, 2H), 3,24-of 3.27 (m, 4H), 3,52-3,55 (m, 4H), 6,53 (t, 1H, J=6.0 Hz), 6.90 to (user., 1H), 7,42 (d, 1H, J=9.0 Hz), 7,63 (DD, 1H, J=9,0, 3.0 Hz), 7,73 (d, 1H, J=3.0 Hz)DMSO-d6, 300 MHz
6-16>2500,98-1,10 (m, 2H), 1,36-of 1.52 (m, 3H), 1,58 (s, 6H), 1,81-of 1.85 (m, 4H), of 2.25 (s, 3H), 2,78 (s, 6H), 2,89-to 2.94 (m, 3H), and 6.25 (t, 1H, J=6.0 Hz), 6.89 in (user., 2H), 7,42 (d, 1H, J=9.0 Hz), 7,63 (DD, 1H, J=9,0, 3.0 Hz), 7,73 (d, 1H, J=3.0 Hz)DMSO-d6, 300 MHz
6-17>2501,07-1,19 (m, 2H), 1,45-and 1.54 (m, 2H), equal to 1.59 (s, 6H), 1,64-of 1.74 (m, 1H), 1,80-to 1.87 (m, 4H), of 2.25 (s, 3H), 2.91 in-3,00 (m, 1H), 3,05 (d, 2H, J=6.0 Hz), of 3.56 (t, 2H, J=9.0 Hz), 4,27 (t, 2H, J=9.0 Hz), 6.90 to (user., 2H), 7,42 (d, 1H, J=9.0 Hz), to 7.64 (DD, 1H, J=9,0, 3.0 Hz), 7,74 (d, 1H,J=3.0 Hz)DMSO-d6, 300 MHz
6-18>2500,99-of 1.16 (m, 2H), 1,25 (s, 6H), 1,35-of 1.53 (m, 3H), 1,58 (s, 6H), 1.77 in is 1.86 (m, 4H), 2,24 (s, 3H), 2,86-2,96 (m, 1H), 2,99 (t, 2H, J=6.0 Hz), 5,32 (s, 1H), 6.89 in (user., 2H), 7,42 (d, 1H, J=8,3 Hz), EUR 7.57-the 7.65 (m, 2H, 7,73 (d, 1H, J=1.9 Hz)DMSO-d6, 300 MHz
6-19225-226of 1.05 to 1.19 (m, 2H), 1,37-is 1.51 (m, 2H), 1,58 (s, 6H), 1.60-to of 1.66 (m, 1H), 1,71-to 1.87 (m, 5H), 1,95-2,02 (m, 1H), 2,24 (s, 3H), 2,89-2,96 (m, 1H), 3,09 is 3.15 (m, 1H), 3,20-of 3.31 (m, 4H), 3,85-3,91 (m, 2H), equal to 4.97 (d, 1H, J=4.0 Hz), 6.90 to (users, 2H), 7,40 (d, 1H, J=8.0 Hz), a 7.62 (d, 1H, J=8.0 Hz), 7,72 (s, 1H)DMSO-d6, 400 MHz
6-20247-2481,07-to 1.21 (m, 2H), 1,44-of 1.55 (m, 2H), of 1.65 (s, 6H), 1,70-1,90 (m, 5H), of 2.16 (d, 2H, J=8.0 Hz), 2,89 are 2.98 (m, 1H), 7,45 (d, 1H, J=8.0 Hz), 7,49 and 7,83 (users, 2H), 7,69 (DD, 1H, J=8,0, 4.0 Hz), 7,80 (d, 1H, J=4.0 Hz), 12,04 (users, 1H)DMSO-d6, 400 MHz
6-21>2501,06-1,19 (m, 2H), 1.41 to 1.55V (m, 2H), of 1.66 (s, 6H), 1,68 is 1.75 (m, 1H), 1.77 in-1,89 (m, 4H), 2.91 in-a 3.01 (m, 1H), 3,05 (d, 2H, J=6.0 Hz), of 3.56 (DD, 2H, J=9,0, 9.0 Hz), 4,27 (DD, 2H, J=9,0, 6,0 Hz), 7,44 (d, 1H, J=6,0 Hz), 7,71 (DD, 1H, J=6,0, 3.0 HZ), 7,82 (d, 1H, J=3.0 Hz)DMSO-d6, 300 MHz
6-22147 (decomp.)a 1.01-1.14 in (m, 2H), 1,38-of 1.53 (m, 3H), of 1.65 (s, 6H), 1,78-1 88 (m, 4H), 2,88 (t, 1H, J=6.0 Hz), 2,88 are 2.98 (m, 2H), 5,34 (users, 2H), 6,00 (t, 1H, J=4.5 Hz), was 7.45 (d, 1H, J=6.0 Hz), of 7.70 (DD, 1H, J=9,0, 3,0 Hz), 7,81 (d, 1H, J=3.0 Hz)DMSO-d6, 300 MHz
6-23 160-1660,99-of 1.13 (m, 2H), 1,36-is 1.51 (m, 3H), 1,58 (s, 6H), 1,76-1,90 (m, 4H), of 2.25 (s, 3H), 2,86-a 3.01 (m, 1H), 2,88 (t, 2H, J=5.8 Hz), of 5.34 (s, 2H), of 5.99 (t, 1H, J=5.8 Hz), 6.89 in (user., 2H), 7,42 (d, 1H, J=8,3 Hz), 7,63 (DD, 1H, J=1,9, 8,3 Hz), 7,73 (d, 1H, J=1.9 Hz)DMSO-d6, 300 MHz
6-24213-2160,99-of 1.18 (m, 2H), 1,33-of 1.62 (m, 3H), of 1.65 (s, 6H), 1.77 in-1,89 (m, 4H), 2,87 are 2.98 (m, 1H), 3,03 (t, 2H, J=6.0 Hz), 3,81 (d, 2H, J=6.0 Hz), 5,42 (t, 1H, J=6.0 Hz), 7,44 (d, 1H, J=8,3 Hz), 7,52 (user., 1H), 7,66-7,73 (m, 1H), 7,69 (d, 1H, J=8,3 Hz), 7,78 (user., 1H), 7,81 (s, 1H)DMSO-d6, 300 MHz
6-25236-2371,16-of 1.26 (m, 2H), 1,43-of 1.53 (m, 2H), of 1.65 (s, 6H), 1,73-to 1.87 (m, 5H), 2,44 (d, 2H, J=8.0 Hz), 2,92-2,99 (m, 1H), 7,43 (d, 1H, J=8.0 Hz), 7,69 (DD, 1H, J=8,0, 4.0 Hz), 7,81 (d, 1H, J=4.0 Hz)DMSO-d6, 400 MHz

Table 7
New example No.MastrocolaTPLNMR (δ)Solvent
7>2251,04-1,19 (m, 2H), 1,39-of 1.55 (m, 2H), 1,49 (s, 6H), 1,65-1,89 (m, 5H), and 2.14 (d, 2H, J=7,2 Hz), of 2.21 (s, 3H), 2,42-2,52 (m, 1H), 6,55 (s, 1H), 6,78 (user., 2H), 7.23 percent (d, 2H, J=8,3 Hz), 7,27 (d, 2H, J=8,3 Hz), 12,01 (s, 1H)DMSO-d6, 300 MHz
7-2of 1.05 to 1.22 (m, 2H), 1,13 (s, 3H), 1,21 (s, 3H), 1,36-of 1.52 (m, 2H), 1,65 is 1.86 (m, 5H), and 2.14 (d, 2H, J=6.8 Hz), measuring 2.20 (s, 3H), 2,38-2,70 (m, 3H), 2,98 totaling 3.04 (m, 1H), 6,45 (user., 2H), 7,18 (d, 2H, J=8,3 Hz), 7,22 (d, 2H, J=8,3 Hz), 11,99 (users, 1H)DMSO-d6, 300 MHz
7-3>250of 1.50 (s, 6H), 2,32 (s, 3H), 6,56 (s, 1H), 6,88 (user., 2H), 7,20 (d, 2H, J=8,4 Hz), 7,26 (d, 2H, J=8,4 Hz), 7,95 (s, 1H)DMSO-d6, 300 MHz
7-4of 8.09 (s, 1H), 7,33 (users, 2H), 7,30 (d, J=8.1 Hz, 2H), 7,26 (d, J=8.1 Hz, 2H), is 6.61 (s, 1H), 2,47 (m, 1H), 2,15 (d, J=6,9 Hz, 2H), equal to 1.82 (m, 4H), of 1.74 (m, 1H), 1.55V (s, 6H)and 1.51 (m, 2H), 1,13 (m, 2H)DMSO-d6, 400 MHz
7-5to 8.14 (s, 1H), 7,50 (users, 2H), 7,20 (m, 3H),of 6.61 (s, 1H), 2,86 (t, J=7.2 Hz, 2H), 2,17 (d, J=6,8 Hz, 2H), 1,96 (t, J=7,3 Hz, 2H), 1,71 (m, 1H), 1,67 (m, 2H), and 1.63 (m, 3H), and 1.56 (s, 6H), 1,50 (m, 2H), 1,22 (m, 2H)DMSO-d6, 400 MHz

Table 9
New example No.MastrocolaTPLNMR (δ)Solvent
9 1,24 (d, J=6.8 Hz, 3H), between 1.25-1.30 (m, 2H), 1,48-to 1.59 (m, 3H), 1,71 (s, 6H), 1.91 a is 2.00 (m,4H), a 2.36-2.40 a (m, 1H), 2,46 (s, 3H), of 2.51-2.57 m (m, 1H), 7,27 (d, J=8,4 Hz, 2H), 7,55 (d, J=8,4 Hz, 2H)CDCl3
9-2
9-3of 1.10-1.20 (m, 2H), 1,42-1,90 (m, 13H), 2,17 (d, J=6,8 Hz, 2H), 2,45-2,60 (m, 1H), 7,34 (d, J=8 Hz, 2H), was 7.36 (users, 1H), 7,71 (d, J=8 Hz, 2H), 7,74 (users, 1H), 12,04 (users, 1H)DMSO-d6

DMSO-d6, 400 MHz
Table 10
New example No.MastrocolaTPLNMR (δ)Solvent
10of 0.85 (t, J=7,1 Hz, 3H), 1,05-2,02 (m, 19H), 6,97 (users, 2H), 7,30 (d, J=7.8 Hz, 2H), 7,66 (d, J= 7.8 Hz, 2H), 7,95 (s, 1H), 12,05 (s, 1H)DMSO-d6, 400 MHz
10-21,78-of 1.85 (m, 9H), 1,96-2,07 (m, 1H), 2,35-2,48 (m, 4H), 2,86-of 2.93 (m, 2H), 3,03-was 4.02 (m, 1H), 3,82 (userd, J=12 Hz, 1H), of 5.81 (s, 1H), 7,19 (d, J=8.0 Hz, 1H), was 7.36-7,40 (m, 2H), 8,17 (s, 1H)DMSO-d6, 400 MHz
10- 3of 1.06 (s, 6H), 1,14-1,22 (m, 2H), 1,40-of 1.46 (m, 2H), 1,61 is 1.75 (m, 10H), 1,82-of 1.85 (m, 2H), 7,3 (users, 2H), 7,31 (d, J=7.7 Hz, 2H), to 7.64 (d, J=7.7 Hz, 2H), to 7.99 (s, 1H)DMSO-d6, 400 MHz
10-40,87-0,93 (m, 1H), 0,97 (t, J=4.9 Hz, 1H), 1,02-1,10 (m, 1H), 1,20 to 1.31 (m, 1H), 1,48 (DD, J=5.4 Hz, J=2.1 Hz, 1H), 1,57-of 1.85 (m, 10H), 1,91-to 1.98 (m, 1H), 2,63-of 2.72 (m, 1H), 7,29 (d, J=8,3 Hz, 2H), 7,69 (d, J=8,3 Hz, 2H), with 8.05 (s, 1H)DMSO-d6, 400 MHz
10-5of 0.75 (m, 2H), 0,99 (m, 2H), 1,38-of 1.62 (m, 12H), 1,68-to 1.87 (m, 4H), 6,97 (users, 2H), 7,29 (d, J=8,2 Hz, 2H), 7,63 (d, J=8,2 Hz, 2H), 7,94 (s, 1H), 12,00 (s, 1H)DMSO-d6, 400 MHz
10-61,25-of 1.55 (m, 4H), to 1.59 (s, 6H), 1,62-1,72 (m, 3H), 1,80-to 1.87 (m, 2H), 2,43 is 2.55 (m, 1H), 3,82 (users, 1H), of 5.05 (users, 1H), 6,98 (users, 2H), 7,31 (d, J=8,2 Hz, 2H), to 7.64 (d, J=8,2 Hz, 2H), 7,94 (s, 1H), a 12.03 (users, 1H)DMSO-d6, 400 MHz
10-71,5-of 1.85 (m, 6H), of 1.80 (s, 6H), to 2.06 (m, 2H), 2,22 (m, 2H), 2,72-2,90 (m, 2H), 5,67 (s, 1H), 7,20-7.5 (m, 2H), 7,51 (d, J=6.2 Hz, 2H), to 7.84 (d, J=6.2 Hz, 2H), 8,18 (s, 1H)DMSO-d6, 400 MHz
10-8 1,5-of 1.85 (m, 6H), of 1.78 (s, 6H), 2,0-2,1 (m, 2H), about 2.2-2.3 (m, 2H), of 2,75 2,95 (m, 2H), 5,94 (s, 1H), 7,10 to 7.2 (m, 1H), 7,50 (d, J=5.5 Hz, 2H), 7,83 (d, J=5.5 Hz, 2H), 8,12 (s, 1H)DMSO-d6, 400 MHz
10-91,50-of 1.85 (m, 6H), 1.77 in (s, 6H), 2,0-2,1 (m, 2H), about 2.2-2.3 (m, 2H), 2,65-to 2.85 (m, 2H), and 5.30 (s, 1H), 7,10-7,20 (m, 1H), 7,49 (d, J=6,1 Hz, 2H), 7,81 (d, J=6,1 Hz, 2H), 8,11 (s, 1H)DMSO-d6, 400 MHz
10-101,05-1,20 (m, 2H), 1,35-2,07 (m, 15H), of 2.15 (d, J=6,9 Hz, 2H, only the main isomer), 2,28 (d, J=7,4 Hz, 2H, only a small isomer), 2,77 is 2.80 (m, 2H), 5,97 (users, 2H), 7,03 (d, J=7.9 Hz, 1H), 7,25-7,30 (m, 2H), of 7.97 (s, 1H)CDCl3, 400 MHz
10-111,05-1,17 (m, 8H), 1,35-1,71 (m, 17H), 2,02 (d, J=6,9 Hz, 2H), 6,37 (users, 2H), 7,13-7,21 (m, 2H), 7,31 (s, 1H), 7,88 (s, 1H)CDCl3, 400 MHz
10-120,72-0,76 (m, 2H), 0,99-of 1.03 (m, 2H), 1,40-to 1.82 (m, 19H), a 2.75 (t, J=6.0 Hz), 7,15 (users, 2H), was 7.36 (s, 1H), 7,46 (s, 2H), to 7.99 (s, 1H)DMSO-d6, 400 MHz
10-13of 1.23 (s, 6H), 1,21-of 1.45 (m, 4H), 1,55-of 1.85 (m, 7H), is 1.81 (s, 6H), 2.06 to (who, 2H), 2,96 (m, 2H), 7,25 (m, 1H), 7,51-rate of 7.54 (m, 3H), 12,0 (users, 1H)DMSO-d6, 400 MHz
10-14of 1.06 (s, 6H), 1,15-of 1.26 (m, 2H), 1,42-is 1.51 (m, 2H), 1.60-to of 1.66 (m, 7H), 1,68-of 1.73 (m, 2H), 1,82-1,89 (m, 2H), 2,34 (s, 3H), 2,50 of $ 2.53 (m, 1H), 7,31 (d, J=6.0 Hz, 2H), 7,55 (users, 2H), 7,66 (d, J=6.0 Hz, 2H)DMSO-d6, 400 MHz
10-15of 1.06 (d, J=5.6 Hz, 3H), 1,13-1,24 (m, 2H), 1,42-of 1.53 (m, 2H), 1,54-to 1.60 (m, 7H), 1,71-of 1.92 (m, 4H), 2,19 (Queen, J=5.6 Hz, 1H), of 2.51-of 2.58 (m, 1H), 7,32 (d, J=6.6 Hz, 2H), 7,69 (d, J=6.6 Hz, 2H), 12,06 (users, 1H)DMSO-d6, 400 MHz
10-16of 1.23 (s, 6H), 1,20-1,50 (m, 3H), 1,55-of 1.85 (m, 7H), of 1.80 (s, 6H), to 2.06 (m, 2H), 2,65 (s, 3H), 2,96 (m, 2H), 6,50 (users, 1H), 7,25 (m, 1H), 7,51-rate of 7.54 (m, 2H), 10,75 (users, 1H)CDCl3, 400 MHz
10-171,24 (d, J=7,0 Hz, 3H), 1,20-1,50 (m, 3H), 1,55-of 1.85 (m, 7H), of 1.75 (s, 6H), was 2.05 (m, 2H), 2,48 (m, 1H), 2,96 (m, 2H), 5,76 (users, 1H), 7,15-7,25 (m, 3H), 7,45 is 7.50 (m, 1H)CDCl3, 400 MHz
10-181,12-1,22 (m, 5H), 1,46-and 1.54 (m, 2H), 1,60 (s, 6H), 1,75-of 1.88 (m, 5H), of 2.16 (d, J=7.2 Hz, 2H), 2,45 of $ 2.53 (m, 1H), 3,42-of 3.48 (m, 2H) 7,40 (users, 2H), 7,31(d, J=8,4 Hz, 2H), 7,63 (d, J=8,4 Hz, 2H), 12,05 (users, 1H)DMSO-d6, 400 MHz
10-190,84-0,89 (m, 2H), of 1.27 and 1.33 (m, 2H), 1,44-of 1.53 (m, 5H), to 1.76 (s, 6H), 1,84-1,90 (m, 2H), 1,94 is 2.01 (m, 2H), 2,55-2,62 (m, 1H), 5,75 (users, 2H), 7,29 (d, J=8,4 Hz, 2H), 7,58 (d, J=8,4 Hz, 2H)CDCl3, 400 MHz
10-20of 1.23 (s, 6H), 1,25-of 1.55 (m, 5H), to 1.76 (s, 6H), 1,83-1,89 (m, 2H), 1,98-2,04 (m, 2H), 2,52-2,60 (m, 1H), 5,70 (users, 2H), 7,29 (d, J=8.0 Hz, 2H), 7,58 (d, J=8.0 Hz, 2H)CDCl3, 400 MHz
10-210,83-0,88 (m, 2H), of 1.27 to 1.31 (m, 2H), 1,47 is 1.60 (m, 5H), 1,72 (s, 6H), 1.85 to 1.91 a (m, 2H), 1.93 and is 2.00 (m, 2H), 2,44 (s, 3H), 2,55-2,62 (m, 1H), 6,13 (users, 2H), 7,29 (d, J=8.0 Hz, 2H), 7,56 (d, J=8.0 Hz, 2H)CDCl3, 400 MHz
10-221,11-1,22 (m, 2H), 1,43-is 1.51 (m, 13H), of 2.16 (d, J=5.3 Hz, 2H), 2,34 (s, 3H), of 2.35 (s, 3H), 2,62-to 2.74 (m, 1H), 7,29 (d, J=6,5 Hz, 1H), 7,46-7,52 (m, 4H)DMSO-d6, 400 MHz
10-231,08-to 1.21 (m, 11H), 1,42-of 1.53 (m, 2H), 1,69-87 (m, 5H), of 2.15 (d, J=7.2 Hz, 2H), 2,42-2,52 (m, 3H), 4,07 (s, 1H), 5,10 (s, 1H), 6,14 (s, 2H), 7,26 (d, J=8,2 Hz, 2H), 7,37 (d, J=8,2 Hz, 2H), 12,05 (users, 1H)
10-24to 0.88 (m, 2H), 1,3 (m, 2H), 1.50 is of 1.99 (m, 10H)to 1.79 (s, 6H), 2,1 (m, 2H), 2,65 (s, 3H), 2,96 (m, 2H), 6,5 (users, 1H), 7,15-7,25 (m, 1H), 7,45 is 7.50 (m, 2H), 10,5 (users, 1H)CDCl3, 400 MHz
10-250,76 (m, 2H), 1,02 (m, 2H), 1,45 of-1.83 (m, 10H), and 1.7 (s, 6H), 2.0 (m, 2H), 2.95 and (m, 2H), 3.33 and (m, 1H), 7,15-7,25 (m, 1H), 7,45 is 7.50 (m, 2H), 12,0 (users, 1H)CDCl3, 400 MHz
10-261,0 (m, 2H), 1,23 (s, 6H), 1,20-1,50 (m, 3H), 1,55-of 1.85 (m, 6H), to 1.76 (s, 6H), to 2.06 (m, 2H), 2.95 and (m, 2H), 5,91 (users, 1H), 7,15-7,25 (m, 2H), 7,45 is 7.50 (m, 1H)CDCl3, 400 MHz
10-270,86 (t, J=7.2 Hz, 3H), of 1.05 to 1.12 (m, 2H), 1,33-to 1.60 (m, 10H), 1.70 to 2,04 (m, 6H), of 2.25 (s, 3H), 2,45-2,52 (m, 1H), 6,80 (users, 2H), 7,29 (d, J=8,4 Hz, 2H), 7.62mm (d, J=8,4 Hz, 2H)DMSO-d6, 400 MHz
10-280,99 (t, J=7.2 Hz, 3H), 1.25 and a 1.25 (m, 18H), 2,50-2,60 (m, 1H), 5,76 (users, 2H), 7,29 (d, J=8,4 Hz, 2H), 7,58 (d, J=8,4 Hz, 2H)CDCl3, 400 MHz
10-29#x0200A; 0,90-of 1.05 (m, 1H), 1,10-of 1.28 (m, 2H), of 1.40-1.50 (m, 2H), 1.57 in (s, 6H), 1,60-1,70 (m, 2H), 1,80-1,90 (m, 2H), 1,90 (s, 2H), 2,24 (s, 3H), 2,35-of 2.50 (m, 1H), for 6.81 (users, 2H), 7,21 (d, J=8,2 Hz, 2H), 7,60 (d, J=8,2 Hz, 2H), 11,9 (users, 1H)DMSO-d6, 400 MHz
10-30of 1.05 (d, J=6.9 Hz, 3H), 1,10-of 1.26 (m, 2H), 1.41 to a rate of 1.51 (m, 2H), 1,52 is 2.01 (m, 7H), 1,71-to 1.87 (m, 4H), 2,15-2,22 (m, 1H), 2,39 (s, 3H), of 2.44-2.50 (m, 1H), 6,65 (s, 1H), 7,30 (Abq, J=8.0 Hz, 2H), 8.0 a (users, 2H)DMSO-d6, 400 MHz
10-31of 1.05 (d, J=6.9 Hz, 3H), 1,10-1,25 (m, 2H), 1.41 to of 1.62 (m, 9H), 1,71-of 1.88 (m, 4H), 2,14-of 2.21 (m, 1H), 2,42-of 2.50 (m, 1H), return of 6.58 (s, 1H), 7,03 (users, 2H), 7,27 (Abq, J=7.9 Hz, 2H), 12,0 (users, 1H)DMSO-d6, 400 MHz

Example 10

This example describes the tests that can be used to identify compounds that have the activity of DGAT.

Numerous systems in vitro assays can be used to determine the modulation of DGAT activity. Examples of such analysis systems use systems overexpression-based insect cells, tissue microsome preparations and cell culture. In systems analysis overexpression on the basis of insect cells and tissue microsome preparation system itself provides a source of enzyme for activity measurements. Such izmereniya conduct, using radiolabelled substrate, where radiolabelled product, which is obtained, then separated by thin-layer chromatography (TLC) (see, for example, Cases, et al., Proc. Natl. Acad. Sci. (1998) 95:13018 and Cases, et al., J. Biol. Chem. (2001) 276:38870).

For comparison, the analysis system on the basis of the cell culture is measured intracellular triglyceride synthesis by incubation of living cells with radiolabelled fatty acid. Radiolabelled fatty acid used in the biosynthesis of triglycerides. Triglycerides can then be extracted from the cells with an organic solvent and separated by thin-layer chromatography to determine the degree of incorporation of radioactive label as a measure of enzyme activity (see, for example, Cases, et al., J. Biol. Chem. (2001) 276:38870).

Analyses based on cells

In the preferred cellular analysis of tumor cells CaCO2human colon, human hepatoma HepG2 or murine adipocytes 3T3-L1 (undifferentiated or differentiated as described below) were cultured to confluence in 24-hole plates. The environment is replaced by medium without serum and the cells incubated for an additional 24-48 hours and Then the medium is replaced by medium without serum but containing 400 μm oleic acid (komplikovanoj with BSA, 2:1 mol:mol) and compound at various doses in konecne the m volume of 200 µl per well. Cells incubated for 30 min before addition of 0.1 µci14C oleic acid directly to the cells and incubation continued for 10-30 min depending on the cell type. Cells are washed twice with 1 ml PBS and air-dried at 37oC for 10 minutes Cellular lipids extracted with 0.5 ml of a mixture of hexane:isopropanol (3:2 vol./about.) within 5 min twice. Lipid extracts evaporated to dryness and used for TLC using the solvent mixture of hexane:simple ethyl ether:acetic acid (80:20:1 vol./vol.). Radioactive bands visualize and quantify by opening access to x-ray film or screen forming the fluorescent image.

Cell differentiation 3T3-L1 in adipocytes induce by incubation fused cells in a medium containing 10% serum, insulin (10 μg/ml), dexamethasone (1 μm), isobutylether-xanthine (IBMX, 0.5 mm) and three-motionin (T3, 10 nm). After 2 days of support cells in medium containing serum, insulin, T3 and BRL49653 (1 μm), within 4-10 days.

Biochemical analysis

The preferred analysis that can be used to identify inhibitors of DGAT, contains highly effective screening scintillation similarity analysis (SPA). In this analysis of DGAT1 human clone from a cDNA library of a human liver. PCR used in isout to attach a restriction site, and a flag epitope at the most 5' end and a restriction site at the 3' end of the sequence. Subsequently can be created baculovirus with flagterm (FT) DGAT1 person using the baculovirus expression system Bac-to-Bac Baculovirus Expression System®(Invitrogen). Of insect cells (such as sf9, sf21, or High Five) infect within 24-72 h and harvested by centrifugation. Precipitated cells re-suspended in the buffer for homogenization and subjected to lysis using a homogenizer, such as a Microfluidizer. All cell membranes are collected by ultracentrifugation at 45,000 rpm min for 1 h

A small aliquot of the sample (0.2 ág/well) membranes incubated with 10 μm of the compounds or mercury chloride (as a positive control of inhibition) in the presence of the substrate of the enzyme, dioleoyl-glycerol (200 μm) in 384-well tablets, the final volume of 50 μl per well. The reaction starts by adding a radioactive substrate,14C acyl-coenzyme A (25 μm, such as decanoyl-CoA, Palmitoyl-CoA, oleoyl-CoA) and incubated at room temperature for 2 hours the Reaction is stopped by adding granules SPA with agglutinin wheat germ (WGA) (0.2 mg) mercury chloride. Cell membranes allow contact with the balls during the night. The signal can be measured using, for example, chemiluminescent reader tablets Chemiluminescence Image Plate Reader (CLIPR) or device TopCount.

Found that the compounds according to izopet the tion, evaluated the above analysis, have DGAT-inhibitory activity. Cm. table 11 below.

Table 11

ExamplehDGAT1 IC50*
1+
1-2+
1-3+
1-4+
1-5+
1-6+
1-7+
1-8+
1-9+
1-10+
1-11+
1-12+
1-13+
1-14+
1-15+
1-16+
1-17+
1-18+
1-19+
1-20+
1-21+
1-22+
1-23+
1-24+
1-25+
1-26+
1-27+
1-28+
1-29+
1-30+
1-31+
1-32+
1-33+
1-34+
1-35+
1-36+
1-37+

2+++
2-2++
2-3++
2-4+++
2-5++
2-6++
2-7++
2-8+
2-9+
2-10+
2-11+
2-12+
2-13+
2-14+
2-15+
2-16+
2-17+
2-18++
2-19+
2-20+
2-21+
2-22+
2-23+
2-24+
2-25+
2-26++
2-27+
2-28+
2-29+
2-30+
2-31+
2-32+
2-33++
2-34++
2-35+
2-36++
2-37+
2-38+
2-39+
2-40+++
2-41+
2-42++
2-43++
2-44++
2-45++
2-46++
2-47++
2-48++
2-49++
2-50++
2-51++
2-52++
2-53++
2-54++
2-55++
2-58++
2-59++
2-60++
2-61++
2-62++
2-63++
2-64++
2-65+++
2-66+
2-67++
2-68+
2-69+++
2-70++
2-71+
2-72++
2-73++
2-74+++
2-75+
2-76++
2-77++
2-78++
2-79++
2-80++
2-81+
2-82+
2-83+
2-84+
2-85+
2-86+
2-87+
2-88+
2-89+
2-90+
2-91++
2-92++
2-93++
2-94++
2-95++
2-96++
2-97++
2-98++
2-99++
2-100++
2-101++
2-102++
2-103++
2-104++
2-105++
2-106++
2-107+++
2-108++
2-109++
2-110++
2-111++
2-112++
2-113++
2-114++
2-115+
2-116++
2-117++
2-118++
2-119++
2-120++

tr>
2-121++
2-122++
2-123++
2-124++
2-125+++
2-126++
2-127++
2-128++
2-129++
2-130++
2-131++
2-132++
2-133++
2-134+++
2-135++
2-136++
2-137+++
2-138++
2-139++
2-140++
2-141++
2-142++
2-143+++
2-144++
2-145++
2-146++
2-147++
2-148+++
2-149++
2-150++
2-151+++
2-152++
2-153+++
2-154++
2-155++
2-156++
2-157+++
2-158++
2-159++
2-160++
2-161++
2-162++
2-163++
2-164++
2-165++
2-166++
2-167++
2-168++
2-169++
2-170++
2-171+
2-172++
2-173++
2-174++
2-175++
2-176++
2-177++
2-178++
2-179++
2-180++
2-181++
2-182++
2-183++
2-184++
2-185++
2-186++
2-187+++
2-188++
2-189++
2-190++
2-191+++
2-192+++
2-193++
2-194++
2-195++
2-196++
2-197++
2-198++
2-200+++
2-201+++
2-202 ++
2-203++
2-204++
2-205++
2-206++
2-207++
2-208++
2-209++
2-210++
2-211++
2-212+++
2-213++
2-214+++
2-215++
2-216++
2-217++
2-218++
2-219++

2-220++
2-221+
2-222+
2-223+
2-224+
2-225+
2-226+
2-227+
2-228+
2-229+
2-230++
2-232++
2-233+
2-234++
2-235++
2-236++
2-237++
2-238+
2-239+
2-240++
2-241++
2-242+
2-243++
2-244++
2-245++
2-246++
2-247++
2-248++
2-249++
2-250++
2-251++
2-252++
2-253+++
2-254++
2-255++
2-256++
2-257++
2-258++
2-259++
2-260++
2-261++
2-262++
2-263+++
2-264++

3++
3-2+
3-3+
4+
4-2+
4-3+
4-4++
4-5+
4-6+
4-7+
5+
5-2+
5-3+
6+++
6-2++
6-3++
6-4+
6-8++
6-9+++
6-10++
6-11++
6-12+++
6-13+++
6-14++
6-15++
6-16+
6-17+
6-18++
6-19++
6-20+++
6-21++
6-22++
6-23++
6-24++
6-25++
7++
7-2++
7-3+
7-4++
7-5++
8 +++
8-2++
8-3++
8-4++
8-5++
8-6++
8-7+++

9++
9-2++
9-3+++
10+++
10-2++
10-3+++
10-4++
10-5++
10-6++
10-7++
10-8++
10-9++
10-10+++
10-11++
10-12++
10-13+++
10-14++
10-15+++
10-16++
10-17+++
10-18++
10-19++
10-20++
10-21++
10-22++
10-23++
10-24++
10-25++
10-26++
10-27++
10-28+++
10-29++
10-30++
10-31++

*The sign: "+" means: the value of the IC50> 0,1μM;

"++" means: 0,1μM ≥ the value of the IC50≥ 0,01μM;

"+++" means: the value of the IC50< 0,01μm

All publications and patent applications cited in this specification, attached to this reference, as if it was specifically and individually indicated that each individual publication or patent application was filed by reference. Although the above invention is described in some detail by way of illustration and example for purposes of clarity of understanding, the usual specialists should be obvious in the light of the indications of this invention that certain changes and modifications can be made without going beyond the essence or scope of the attached claims.

APPLICATION

Example pharmaceutical compositions (pill)

(a) the Compound of the present invention (example 5)10 g
(b) Lactose50 g
(c) Corn starch15 g
(d) Sodium carboxymethyl the vine 44 g
(e) magnesium Stearate1 g

The given amounts of ingredients(a), (b), (C) and 30 g (d) are mixed until a homogeneous mass with water, then dried in vacuum and granularit. The obtained granules are mixed with 14 g (d) and 1 g (e) and pressed into tablets in a tablet press machine, obtaining 1000 tablets each containing 10 mg of active ingredient (a).

1. The compound of formula (I)

or its pharmaceutically acceptable salt, or stereoisomer,

where X is selected from the group consisting of C(R1and N;

Y is selected from the group consisting of C(R1), C(R2(R2), N and N(R2);

Z is selected from the group consisting of O;

W1selected from cyclo(C3-C8)alkyl, aryl and 5 - or 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of nitrogen and sulphur,

moreover, the aryl and heteroaryl optionally substituted by substituents selected from halogen, -OR', -NR'r R", R, -NO2, -CO2R', PERFLUORO (C1-C4)alkoxy, and PERFLUORO(C1-C4)alkyl, and these substituents can be attached to the aryl or heteroaryl through a spacer, representing1-C4alkylen;

where R' and R" are independently selected from hydrogen and (C1-C8)al the sludge, R is selected from hydrogen, (C1-C3)alkyl and unsubstituted aryl, and when the aryl group is 1,2,3,4-tetrahydronaphthalen or indan, it does not necessarily substituted (C3-C7)spirocyclohexane group, and (C3-C7)spiratically group optionally substituted-CO2R' group and the Deputy can be attached to (C3-C7)spirocyclohexane group via a spacer selected from C1-C4alkylene, where R' is selected from hydrogen, (C1-C3)alkyl;

W2selected from cyclo(C3-C8)alkyl, (C5-C6)geterotsiklicheskie containing 1 or 2 heteroatoms selected from the group consisting of nitrogen or oxygen, benzene and 5 - or 6-membered heteroaryl containing 1 or 2 nitrogen atom as a heteroatom, and cyclo(C3-C8)alkyl group and C5-C6heterocytolysine group optionally substituted by substituents selected from-OR',=O, -NR'r R", halogen, -C(O)R', -CO2R', -CONR'R", -NR"C(O)R', -NR'-(CO)NR"R"', -NR"CO2R', -NR'-SO2NR"R"', -SO2NR'r R" and-NR"SO2R', and these substituents can join cyclo(C3-C8)alkyl or C5-C6heteroseksualci via a spacer selected from C1-C4alkylene and =CH-,

where R', R" and R"'are, each independently, vibrant hydrogen, unsubstituted (C1-C8)alkyl and 5 - or 6-membered heteroalkyl, including nitrogen atoms, and aryl(C1-C4)alkyl group, or where R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom with the formation of 5-, 6 - or 7-membered ring, and the benzene and heteroaryl can be replaced by substituents selected from-CO2R' and-NR'r R", these substituents can be attached to an aryl or heteroaryl group via a spacer selected from (C1-C4)alkylene, and R' and R" independently can be selected from hydrogen and (C1-C8) alkyl;

L1is communication;

L2selected from the group consisting of ties, Oh, (C1-C4)alkylene and (C1-C4)oxyalkylene;

m denotes 0 or 1;

optionally, when m is 1 and L2means of communication, Deputy for W2can be combined with the Deputy on W1with the formation of 5 - or 6-membered ring condensed with W1and forming spinosissima or condensed with W2where the specified ring is saturated or unsaturated and has 0 or 1 atom O as ring members;

R1is N;

R2is N;

R3and R4independently selected from the group consisting of H and (C1 -C8)alkyl;

optional, R3and R4may together form a 3-, 4-, 5 - or 6-membered spirocerca;

R5and R6independently are H;

optional, when Y includes a group of R1or R2, R5or R6can be combined with R1or R2with the formation of 5 - or 6-membered condensed ring containing the nitrogen atom to which R5or R6attached, and optionally containing oxoprop;

R7selected from the group consisting of H, (C1-C8)alkyl, halogen (C1-C4)alkyl, ORaand NRaRb;

Raselected from the group consisting of (C1-C8) alkyl; and

Rbselected from the group consisting of H and (C1-C8)alkyl;

the dotted line indicates a possible link.

2. The compound according to claim 1, where X is N.

3. The compound according to claim 2, where W1selected from the group consisting of benzene, pyridine, thiophene, thiazole, benzthiazole, benzothiophene, 1,2,3,4-tetrahydronaphthalene and indane, each optionally have substituents as defined for W1in item 1.

4. The compound according to claim 3, where W1selected from the group consisting of benzene, pyridine, thiophene, 1,2,3,4-tetrahydronaphthalene and indane, each optionally have substituents as defined for W1 in item 1.

5. The compound according to claim 4, where m means 1.

6. The compound according to claim 4, where m is 1 and L2means the connection.

7. The connection according to claim 6, where W2selected from the group consisting of benzene, pyridine, (C4-C7)cycloalkane, pyrrolidine, piperidine, piperazine and the research, each optionally have substituents as defined for W2in item 1.

8. Compound having a formula selected from the group consisting of Ia, Ib, Ic, Id, Ie, If and Ig

,,,,,and

or its pharmaceutically acceptable salt, or stereoisomer, where R3and R4independently selected from the group consisting of H and (C1-C8) alkyl;

optional R3and R4may together form a 3-, 4-, 5 - or 6-membered spirocerca;

R5and R6independently are H;

R7selected from the group consisting of H, (C1-C8)alkyl, halogen(C1-C4)alkyl;

n is an integer 0-4; and

RcDeputy selected from Rc1, ORc1N(Rc1)2, NO2, halogen, (C1-C8)halogenoalkane and (C1-C8g is loganholme, where each Rc1regardless, mean N, (C1-C8)alkyl, and when Rcis N(Rc1)2group, the two groups Rc1can be combined with the formation of five - or six-membered ring, and optionally, If and Ig, the two groups Rc1can be combined to form a 3-, 4-, 5-, 6 - or 7-membered ring, optionally substituted spirocycles ring.

9. Compound having a formula selected from the group consisting of In, Ii, Ij and Ik

,,and

or its pharmaceutically acceptable salt, or stereoisomer,

where R3and R4independently selected from the group consisting of H and (C1-C8)alkyl;

R5and R6independently are H;

R7represents N;

n=0;

and p is an integer of 0-1, and

RdDeputy, is independently selected from Rd1N(Rd1)2, -(CH2)t-CO2Rewhere R6represents hydrogen;

where t is in each case means an integer from 0 to 8,

u represents an integer from 0 to 2,

each Rd1selected from H, (C1-C8)alkyl.

10. The connection according to claim 9, where Rdselected from Rd1N(Rd1 )2, -CH2-CO2Re, Rd1and Rehave the meanings specified in claim 9 in respect of formulas In, Ii, Ij and Ik.

11. Compound having a formula selected from the group consisting of Il, Im, In, Io, Ip, and Iq

,,,,and

or its pharmaceutically acceptable salt, or stereoisomer,

where R2is hydrogen;

R3and R4independently are h, (C1-C8)alkyl;

R5and R6independently are H;

R7selected from the group consisting of H, (C1-C8)alkyl and halogen(C1-C4)alkyl;

n is an integer 0-1;

q is an integer 0-1;

s is an integer 0-2;

and each RcDeputy, independently selected from halogen, Rc1, ORc1N(Rc1)2,

where each Rc1independently mean H, (C1-C8)alkyl, and when Rcrepresents N(Rc1)2two groups of Rc1can be combined with the formation of five - or six-membered ring,

each Rhmeans the Deputy, independently selected from oxo, halogen, Rh1 , ORh1N(Rh1)2, -(CH2)tS(O)uRe, (C1-C8)halogenoalkane, (C1-C8)halogenoalkane, aryl(C1-C4)alkyl, -CH(Rf)-CO2Re-C(Rf)2-CO2Re, -C(O)CO2Re, =CH-CONReRf, =CH-CO2Re, -(CH2)t-CO2Re, -(CH2)t-C(O)Re, -(CH2)t-C(O)NReRf, -(CH2)t-NHSO2Re, -(CH2)t-SO2NReRf, -(CH2)t-NReRf, -(CH2)t-ORe, -(CH2)t-NHSO2NHCO2Re, -(CH2)tNHSO2NReRf, -(CH2)t-CONHSO2Re, -(CH2)t-W3, -(CH2)t-NHCO2Re, -(CH2)t-NRfCORe, -(CH2)tNHCONReRfand -(CH2)t-NHCO-(CH2)t-OCORe,

where t is in each case means an integer from 0 to 8,

u represents an integer from 0 to 2,

each Rh1selected from H, (C1-C8)alkyl, (C3-C8)cycloalkyl, where the aliphatic portion of the optionally substituted HE CO2N, NH2, CONH2, phenyl, halogen, halogen (C1-C4)- alkyl and CO2Rgand optional two groups of Rh1attached to a common nitrogen atom, combine the modern with the formation of five - or six-membered ring, or group, Rhand Rh1can be combined to form a 3-, 4-, 5 - or 6-membered Spiro - or condensed ring; and

where each Reand Rfindependently denotes H, or (C1-C8)alkyl or being attached to a common nitrogen atom, they merged to form a 5 - or 6-membered ring, or selected from the

,and

and where any alkyl part in Reand Rfoptionally substituted by a Deputy selected from HE, COOH, NH2, CONH2, phenyl, dialkylamino and COORgwhere Rgmeans (C1-C4)alkyl; and

W3selected from the

and

where each Riand each Rjindependently selected from H, HE, COOH, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C4)alkyl and COO(C1-C4)alkyl, where the aliphatic part are unsubstituted or optionally substituted with halogen.

12. Connection to item 11, where Rhselected from oxo, halogen, Rh1, ORh1N(Rh1)2, (C1-C8)halogenoalkane, (C1-C8)halogenoalkane, aryl(C1-C4)alkyl, (C1-C8)alkylene-CO2ReC(O)Re, CO2Re, =CH-CON eRf, =CH-CO2Re, -CH2-CO2Re, -CH(Rf)-CO2Re-C(Rf)2-CO2Re, -CH2CH2CO2Re-C(O)NReRf, -CH2C(O)NReRf, -CH2CH2CONReRf, -NHSO2Re, -CH2NHSO2Re, -CH2CH2NHSO2Re, -CH2SO2NReRf, -CH2CH2SO2NReRf, -CH2OH, -CH2NReRfCH2CH2OH, -CH2-W3, -CH2CH2-W3and-C(O)CO2Rewhere any alkyl part of Reand Rfoptionally substituted by a Deputy selected from HE, COOH, NH2, CONH2, phenyl, dialkylamino and COOR6where Rgmeans (C1-C4)alkyl;

where Rh1, Re, Rfand W3have the meanings specified in claim 11 in relation to formula Il, Im, In, Io, Ip, and Iq.

13. Compound having a formula selected from the group consisting of Ir, Is, It, Iu, Iv, Iw, Ix and Iy

or its pharmaceutically acceptable salt, or stereoisomer,

where R3 and R 4independently selected from the group consisting of H and (C1-C8)alkyl;

R5and R6independently are H;

R7selected from the group consisting of H, (C1-C8)alkyl, halogen (C1-C4)alkyl;

n is the integer 0; and

q is an integer 0-1;

s is calm number of 0-2;

each Rhmeans the Deputy, independently selected from oxo, halogen, Rh1, -CH(Rf)-CO2Re-C(Rf)2-CO2Reand -(CH2)t-CO2R6,

where t is in each case means an integer from 0 to 8,

each Rh1selected from H, (C1-C8)alkyl and (C3-C6)cycloalkyl, where the aliphatic portion of the optionally substituted HE or CO2N, and

where each Reand Rfindependently denotes H or (C1-C8)alkyl.

14. The connection indicated in paragraph 13, where Rhmeans the Deputy, having the formula C(O)2Re, -CH2-CO2Re, -CH(Rf)-CO2Re, -C(Rf)2-CO2Re, -CH2CH2CO2Rewhere each Reand Rfhave the values specified in clause 13 in respect of formula Ir, Is, It, lu, Iv, Iw, Ix and ly.

15. A compound selected from the group consisting of

and

or its pharmaceutically acceptable salt, or stereoisomer.

16. The compound according to claim 1, selected from the group consisting of

and

or its pharmaceutically acceptable salt, or stereoisomer.

17. A compound selected from the group consisting of

and

or its pharmaceutically acceptable salt, or stereoisomer.

18. A compound selected from the group consisting of

or its pharmaceutically acceptable salt, or stereoisomer.

19. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

20. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

21. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

22. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

23. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

24. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

25. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

26. The compound represented by the formula

or its pharmaceutically acceptable salt, or stereoisomer.

27. The compound represented by the formula

28. Pharmaceutical composition having DGAT inhibitory activity containing a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 27.

29. The use of compounds according to any one of claims 1 to 27 for obtaining a medicinal product for the treatment or prevention of diseases or conditions mediated by DGAT activity.

30. The application of clause 29, where the disease or condition selected from the group consisting of obesity, diabetes, syndrome X, insulin resistance, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease nonalcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, bole is no coronary artery and myocardial infarction.

31. The application of clause 29, where the specified connection can be used to produce a medicinal product intended for oral administration.

32. The application of clause 29, where the specified disease or condition selected from the group consisting of diabetes, obesity and syndrome X.

33. The application of clause 29, where the specified disease or condition is obesity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention was targeted at obtaining crystals of acetonitrile solvate of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (compound B), which is an intermediate compound in obtaining crystals of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of III type (compound A). Compound B crystals are mostly precipitated by regulation of super-saturation during crystallisation involving acetonitrile as a solvent. Then compound A crystals of III type are obtained crystal desolvation.

EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to cyclic sulphonamide derivatives of general formula I where bonds indicated with wavy lines represent mutually cis- in relation to cyclohexane ring; R3 represents H or hydrocarbon group having up to 10 carbon atoms; Ar1 and Ar2 independently represent phenyl which carries 0-3 substitutes independently selected from halogen, CF3, CHF2; or its pharmaceutically acceptable salt. Besides, invention refers to technology of compounds of general formula I and to pharmaceutical composition based on compounds of general formula I and applied as gamma-secretase inhibitor.

EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted of dihydropyranoindole-3,4-dione of formula I and formula II: where X stands for H, R1 stands for H, phenyl, benzyl, cycles of said phenyl and benzyl can be substituted with 1-3 substituents, selected independently on each other from group, which includes halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup; where R2 stands for H, -OH; R3 stands for H, phenyl, benzyl, benzyloxygroup, cycles of these groups can be optionally substituted with 1-3 substituents, selected independently on each other from group including phenyl, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup, pharmaceutically acceptable salts of said compounds. Compounds demonstrate activity of inhibiting plasminogene activator inhibitor (PAI-1), which allows using them for production of medication for treatment of pathological states resulting from fibrinolytic disorders.

EFFECT: obtaining compounds, demonstrating activity in inhibiting plasminogene activator inhibitor which allows using them in pharmacology.

23 cl, 1 dwg, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the agent strongly inhibiting thrombocyte aggregation, it doesn't inhibit COX-1 or COX-2. The invention offers the compounds of formula (I) or their pharmaceutically acceptable salts, where residuals and groups in the specified structure of the compounds have the values denoted in the formula of the invention. The pharmaceuticals containing any of the compounds of formula (I) or their pharmaceutically acceptable salts, and phylactic and/or therapeutic agents for coronary heart disease, which contain any of the compounds of formula (I) or their pharmaceutically acceptable salts are suggested. Moreover, application of the compounds and their pharmaceutically acceptable salts for preparation of the medicine having anti-thrombotic potency, and method of the treatment of coronary heart disease are suggested.

EFFECT: production of the medicines having anti-thrombotic potency on basis of pyrazole.

12 cl, 1 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

FIELD: organic chemistry, pharmacy, biochemistry.

SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new compounds with general formula (1), which includes compounds (VI), which relate to conformational stable compounds that imitate the secondary structures of parts of molecules of biologically active peptides and proteins with reverse configurations. The compounds can be used as antitumoral compounds for the treatment and prophylaxis of cancer such as, colorectal cancer, for treating rheumatoid arthritis and ulcerative colitis. The compound facilitates the increase of apoptosis and increases the proliferation of neurites, and inhibits survirin expression in the cell. In compounds, corresponding to the general formula (I) and (VI) , in formula (I) W denotes -Y(C=O)-, -(C=O)NH-, -(SO2)- or is absent, Y denotes an oxygen atom, Z denotes a nitrogen atom or CH, X denotes a nitrogen atom or CH, n=0 or 1, on the condition that when Z denotes CH, X denotes a nitrogen atom and n=1; and when Z denotes a nitrogen atom, then n=0; in formula (VI) X1 denotes a hydroxyl, and at least one of X2 is X3 is a hydroxyl, or X1 denotes hydrogen, and X2 and X3 can be similar of different and independently selected from hydrogen, hydroxyl and halogen. Other radicals have the value specified in the formula of the invention.

EFFECT: obtaining compounds which can be used as antitumoral compounds for the treatment and prophylaxis of cancer such as, colorectal cancer, for treating rheumatoid arthritis and ulcerative colitis.

26 cl, 33 dwg, 9 tbl, 14 ex

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