Compounds 4h-and-pirido[ 1.2-and-a]pirimidin-and-4-and-it

Compounds 4h - pyrido [1, 2 - and] pyrimidine - 4 - one

The present invention relates to compounds of pyrido [1, 2 - and] pyrimidine - 4 - one, methods of their production and their use as pharmaceutical agents or in compositions for treatment of neurological disorders.

Neurologic disorder, including neurodegenerative disorder, can undergo pathologically connected interaction between proteins and oxidation - oxidation with ions of metals, such as zinc, copper or iron. Such reaction is generated active oxygen form (afk), which are capable destroy cell components are oxidizing proteins, lipid and DNA. This may cause changes in conformation proteins, activity of enzymes and become cause aggregation of proteins.

Afk include free radicals, such as superoxide anion -, hydro ksilnyi radical and other molecular compounds, such as hydrogen peroxide (Bush and Goldstein, 2001). Hydro ksilnye radicals are the most reactive and-breaking afk. They mainly are formed in reaction of Fenton between transition metals (usually iron (of II) or copper (1)) and hydrogen peroxide.

While cells show antioxidant systems for protection from damage afk, including protective enzymes, such as copper - zinc superoxide dismutase, these enzymes contain metals. So, cells should maintain careful balance between free and fixed prooksidantom and antioxidant with ions of metals, which are critical for cellular homeostasis. Usually is considered to be, that aging brain has slow and progressing imbalance between antioxidant protection and intracellular concentrations of afk.

It is necessary to identify compounds, intended for control and modulation ionny biological metals, which, being non-adjustable, have installed communication with the growing number of diseases, including those, which are characterized by the presence of oxidative stress, aggregation of proteins and intracellular or extracellular unbalance metals.

Authors detected compounds, having two condensed 6 - membered ring with nitrogen atoms in positions 1 and 5 and group of or-⁸ in position 9, which are used for treatment of neurological disorders. These compounds can possess one or more of the following properties of: cross hematoencephalic barrier (geb), show reduced adverse side effects and/or are stable in aqueous media.

In the first aspect of the present invention invention proposes compound of formula I

where

R² represents H, (CH-₂ )_n- THE NR⁹R¹⁰ , With - m alkyl, optionally interrupted with oxygen or (CH-₂ )_n-SC=SNR⁹R¹⁰ ;

R³ represents H, with - m alkyl, optionally interrupted with oxygen, C1 - 4 alkoxy, sz_b cycloalkyl, (CH₂ )_T optionally substituted aryl, (CH₂ )_P optionally substituted aryl, optionally condensed with 5ili 6 - chlennymgeterotsiklilom, of c (0) the NR⁹R¹ °C, (CH-₂ )_n- THE NR⁹R¹⁰ or c (0) NN=CR⁹R¹⁰ ;

R⁵ represents H or C1 - 4 alkyl;

R⁶ represents H, halogen, (CH₂ )_P optionally substituted 5 - or 6 - members or with heterocyclyl₂_4 alkynyl;

R⁷ represents H, halogen, (CH₂ )_P of 5 - members optionally substituted heterocyclyl, optionally substituted C1 - 4 alkyl, with₂_4 alkynyl, (CH-₂ )_n- THE NR⁹R¹⁰ , N0₂ , THE NR⁵ S0₂ optionally substituted aryl or NR⁵ S0₂ optionally substituted C1 - 4 alkyl;

R⁸ represents H, s0₂ optionally substituted aryl, C1 - 4 alkyl or (CH₂ )_P aryl; or

R⁷ together with carbon atom, to which it is connected, and R⁸ together with atom of oxygen, to which it is connected, form 5 - membered ring;

R⁹ and R¹⁰ are independently chosen from H, C1 - 8 alkyl, optionally interrupted about, the CN, (CH₂ ) u optionally substituted aryl, optionally condensed with 5ili 6 - chlennymgeterotsiklilom, (CH2)_P optionally substituted C3 - 8 cycloalkyl, (CH₂ )_P optionally substituted 5ili 6 - membered optionally substituted heterocyclyl, s0₂ optionally substituted aryl and with m - alkoxy; or

R⁹ and R¹⁰ together with nitrogen atom, to which they are connected, form 5 - or 6 - members optionally substituted heterocyclyl;

X represents n or CH;

of m is equal to 1, 2 or 3; and

u is equal to 0, 1.2 or 3;

provided, that:

(i) at least one R² , OF R³ , OF R⁵ , OF R⁶ and R⁷ differs from H;

(ii) when R of³ represents a C1 - 4 alkyl and R² , OF R⁵ and R⁸ represent H, then R is⁷ or R⁶ differ from H;

(iii) when R of³ is a with - m alkyl, R of² , OF R⁵ and R⁸ represent H and R⁷ is a 1, then of R⁶ differs from H,

its salts, isomers or prodrugs or compound, selected from:

1655 1659

In the second aspect invention proposes compound of formula II

where

R² , OF R³ , OF R⁵ , OF R⁶ and R⁷ are such, given in the m represents transition metal;

its salts, isomers or prodrugs.

In the third aspect the method of preparation of compounds of formula I, its salts, isomers or prodrugs, certain above, including interaction of compound of formula III

where

R⁵ , OF R⁶ , OF R⁷ of R h of⁸ are such, as defined above in formula I;

with compound of the formula of IV

where

R² and R³ are such, as defined above in formula I;

to produce of a formula V compound

where

R² , OF R³ , OF R⁵ , OF R⁶ , OF R⁷ of R h of⁸ are such, as defined above in formula I; and by cyclization of a formula V compound.

In the fourth aspect a method for preparing compound of formula II, its salts, isomers or prodrugs, certain above, including the interaction of compounds of formula I, its salts, isomers or prodrugs, certain above, with source of m, the m is such, as defined above in formula II of.

In the fifth aspect invention proposes a pharmaceutical agent, including compound of the formula i or ii, its salts, isomers or prodrug, as defined above.

Also application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, as pharmaceutical agent.

Is additionally suggested compound of the formula i or ii, its salts, isomers or prodrug, as defined above, for use as pharmaceutical agent.

Pharmaceutical agent can be neiroterapevticheskim or neuroprotective agent.

In the sixth aspect a neiroterapevticheskii or neiroprotektivnyi agent, including compound of the formula i or ii, its salts, isomers or prodrug, as defined above.

Also application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, as neiroterapevticheskogo or neiroprotektivnogo agent.

Is additionally suggested compound of the formula i or ii, its salts, isomers or prodrug, as defined above, for use as neiroterapevticheskogo or neiroprotektivnogo agent.

Compound of the formula i or ii, its salts, isomers or prodrugs may be introduced in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

In the seventh aspect invention proposes a pharmaceutical composition, containing compound of the formula i or ii, its salts, isomers or prodrugs, and a pharmaceutically acceptable carrier.

In one version pharmaceutical composition additionally contains therapeutically effective amount of one or more additional active agents, such as chemotherapeutic compound, immunotherapeutic compound, cytokine, genetic molecule and/or anesthetic.

In eighth aspect the method of treatment of neurological disorders, including introduction of, requiring in this, effective amount of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, or pharmaceutical agent or pharmaceutical composition, certain above.

Also application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, or pharmaceutical agent or pharmaceutical composition, as defined above, for preparing a drug for treatment of neurological disorders.

Additionally application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, or pharmaceutical composition, as defined above, for treatment of neurological disorders.

Also is additionally suggested compound of the formula i or ii, its salts, isomers or prodrug, as defined above, or pharmaceutical agent or pharmaceutical composition, the described, for application in treatment of neurological disorders.

At least preferable subject man is, the present invention may be used in branches of veterinary science and animal husbandry and, consequently, spreads on animals, not related to humans.

The present invention relates to compounds of formula I, above to.

In one embodiment compound of the formula I is compound of the formula 1a

where R is³ and from R⁵ of R to⁸ are such, as defined above in formula I.

In one version of the formula La is of R³ is a with - m alkyl, optionally interrupted about, C5 - 6 cycloalkyl, (CIS) U optionally substituted aryl, optionally condensed with 5ili 6 - chlennym heterocycle dwg Ohm, of c (0) the NR⁹R¹ °C, where R is⁹ represents H and R¹⁰ represents a C1 - 6 alkyl, optionally substituted phenyl or optionally substituted 5 - members heterocyclyl; R of⁶ represents H, halogen, such as Cl or vg, 5 - members heterocyclyl, optionally substituted benzyl or o

cyclopentyl, Cl-and-4 alkyl or C2 - 4 alkynyl; R of⁷ represents H, halogen, such as 1, 5ili 6 - members optionally substituted heterocyclyl, optionally substituted phenyl, (ch2)_n- THE NR⁹R¹⁰ , C1 - 4 alkyl, C2 - 4 alkynyl or NR⁵ S02 optionally substituted phenyl; and R⁸ represents H or with - m alkyl.

Typical examples of compounds of the formula La include compounds 1235, 1607, 1621, 1622, 1623, 1624, 1643, 1599, 1611, 1650, 1674, 1675, 1685, 1686, 1596, 1597, 1600, 1601, 1602, 1603, 1605, 1629, 1630, 1633, 1639, 1641, 1648, 1651, 1652, 1653, 1654, 1655, 1656, 1659, 1660, 1668, 1671, 1680, 1681, 1683, 1627, 1631, 1632, 1640, 1642, 1645, 1647, 1679, 1691, 1693, 1706, 1606, 1615, 1616, 1617, 1626, 1613, 1619, 1620, 1625, 1628, 1644, 1658, 1664, 1669, 1682, 1704, 1710, 1712, 1722, 1657, 1660, 1661, 1717, 1708 and 1716, as shown on circuits 1 - 4, 7 - 9 and 15 - 17 examples 1 - 4, 7 - 9 and 15 - 17.

In another embodiment compound of the formula I is compound of the formula lb-

where R is³ and R⁸ are such, as defined above in formula I.

In one version of the formula lb-, of R³ represents H, of c (0) the NR⁹R¹ ° or (of c (0) of n-NH-=CR⁹R¹ °C; and R⁸ represents H or benzyl.

Typical examples of compounds of the formula lb-include 1394, 1422, 1423, 1425, 1426, 1427, 1428, 1429, 1431, 1432, 1433, 1436, 1437, 1440, 1441, 1445, 1446, 1447, 1450, 1452, 1453, 1454, 1461, 1462, 1532, 1533, 1649, 1723, 1724 and 1732, as shown on circuits 5 and 13 examples 5 and 13.

In additional version compound of the formula I is compound of the formula the IC

R⁵O

where R is² , OF R⁵ , OF R⁶ and R⁸ are such, as defined above in formula I.

In one version of the formula of R the IC² is a (CH-₂ )_n-R⁹R¹⁰ , C1 - 4 alkyl, optionally interrupted O or (CH-₂ )_n-SC=SNR⁹R¹⁰ ; OF R⁵ represents H or C1 - 4 alkyl, such as methyl; and R⁶ is a halogen, such as Cl.

Typical examples of compounds of the formula the IC include compounds of 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1435, 1438, 1439, 1442, 1443, 1444, 1448, 1449, 1451, 1455, 1456, 1457, 1458, 1459, 1463, 1464, 1466, 1467, 1468, 1469, 1470, 1471, 1476, 1478, 1479, 1485, 1490, 1491, 1500, 1503, 1504, 1506, 1508, 1515, 1516, 1517, 1518, 1519, 1521, 1522, 1523, 1525, 1527, 1531, 1604, 1608, 1609, 1610, 1612, 1614, 1618, 1634, 1635, 1636, 1637, 1638, 1670, 1699, 1707, 1591, 1646, 1701, 1705, 1713, 1714, 1720 and 1721, as shown on circuits 6, 10 and 12 examples 6, 10 and 12.

In one more embodiment, compound of formula I is a compound of the formula of ID

where R is² , OF R³ and from R⁶ of R to⁸ are such, as defined above in the formula of

In one version of the formula of R of ID² is a with - m alkyl, such as methyl; R of³ is a with - m alkyl or benzyl; R of⁶ is a halogen, such as is Cl; R of⁷ is a halogen, such as I or 5ili 6 - members optionally substituted heterocyclyl; and R⁸ represents H or with - m alkyl, such as propyl.

Typical examples of compounds of the formula of ID include compounds of 1662, 1663, 1665, 1666, 1667, 1672, 1673, 1687, 1688, 1689, 1690, 1694 and 1698, as indicated on circuit diagram 14 coded 14.

In one embodiment compound II is a compound of the formula mA.

TTa

where

R³ , OF R⁷ and m are such, as defined above in formula II of.

In one version of the formula mA of R³ is a with - m alkyl, such as propyl, or c (0) the NR⁹R¹ °C; OF R⁷ is a with - m alkyl, such as propyl, and m is a ζη or xi.

Typical examples of compounds of the formula mA include compounds of 1678, 1692, 1700, 1715, 1718, 1719, 1744, 1745 and 1748, as indicated on circuit diagram 18 coded 18.

If not or other as indicated, the following terms should be understand, as having a common value, given below.

Term "of c-of i-6 alkyl" relates to optionally substituted hydrocarbon groups with non-or branched chain, having from 1 to 6 carbon atoms. Examples include methyl (IU), ethyl (is Et), propyl (head), isopropyl (/ - head), butyl (MI), isobutyl (/ - MI), E/tyur - butyl (S-S-Bu), / 7?pE/7?- butyl (F-Bu), pentyl, neopentyl, hexyl and T. U. If context does not require other, term "of c-of i-6 alkyl" also embraces alkyl groups, containing one less than hydrogen atom, so that the group is through two position, T. E. dvukhvalentno. "Of c-of i-4 alkyl" and "of c-of i-3 alkyl", including methyl, ethyl, propyl, uzopropil, n - butyl, ouzo - butyl, E/tyur - butyl and/77re/77 - butyl, are preferable group, the methyl is especially preferable.

Term "C2 - 6 alkenyl" relates to optionally substituted hydrocarbon groups with non-or branched chain, having at least one double bond or stereochemistry E, or Z of, where it applicable, and from 2 to 6 carbon atoms. Examples include vinyl, 1 - propenyl, 1 [i1 2 - butenyl and 2 - methyl - 2 - propenyl. If context does not require other, term "C2 - 6 alkenyl" also embraces alkenyl group, containing on one atom is less than hydrogen, so that the group is through two position, T. E. dvukhvalentno. "C2 - 4 alkenyl" and "C2 - 3 alkenyl", including ethenyl, propenyl and butenyl, are preferred group, the ethenyl is especially preferable.

Term "C2 - 6 alkynyl" relates to optionally substituted hydrocarbon groups with non-or branched chain, having at least one triple bond and from 2 to 6 carbon atoms. Examples include ethynyl, 1 - propynyl, 1 [i1 2 - butinyl, 2 - methyl - 2 - propynyl, 2 - pentyneyl, 3 - pentyneyl, 4 - pentyneyl, 2 - hexenyl, 3 - hexenyl, 4 - hexenyl and 5 - hexenyl and T. U. If context does not require other, term "C2 - 6 alkynyl" also embraces alkynyl group, containing one less than hydrogen atom, so that the group is through two position, T. E. dvukhvalentno. C2 - 4 alkynyl is preferable.

Term "C3 - 8 cycloalkyl" relates to-aromatic cyclic groups, having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Understandable, that cycloalkyl groups can be saturated, such as cyclohexyl, or unsaturated, such as cyclohexenyl. C3 - 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, are preferable.

Terms "hydro xy" and "hydro ksil" field to group - it.

Term "C1 - 6 alkoxy" relates to alkyl group, as defined above, covalently connected through about - communication, containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, izoproksi, butoxy, / lre/tbutoksi and pentoksi. "Of c-of i-4 alkoxy" and "of c-of i-3 alkoxy", including methoxy, ethoxy, propoxy and butoxy, are preferred group, the methoxy is especially preferable.

Term "aryl" relates to carbocyclic (negeterotsiklicheskomu) aromatic ring or mono -, biili tricyclic ring system. Aromatic ring or ring system usually consists of 6 - 10 carbon atoms. Examples of aryl groups include, but are not limited by said, phenyl, biphenyl, naphthyl and tetrahydro naphthyl. of 6 - membered the aryls, such as phenyl, are preferable. Term "alkylaryl" relates to with -|_balkilarilu, such as benzyl.

Term "heterocyclyl" relates to fragment, obtained removal of hydrogen atom from the ring atom heterocyclic compound, the fragment has from 3 to 10 ring atoms (if not as indicated or other), of which 1, 2, 3 or 4 are annular the heteroatoms, each heteroatom independently is selected from O, S and n-.

In this context of prefixes 3 -, 4 -, 5 -, 6 -, 7 -, 8 -, 9i 10 - membered having the number of ring atoms or range of ring atoms, as carbon atoms, and heteroatoms. For example, used in this document term "3 - 10 - members heterocyclyl" relates to heterocyclyl group, having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples heterocyclyl groups include 5 - 6 - membered monocyclic geterotsiklily and 9 - 10 - membered condensed bicyclic geterotsiklily.

Examples monocyclic heterocyclyl groups include, but are not limited by said, containing one nitrogen atom, such as aziridine (3 - membered ring), azetidine (4 - membered ring), pyrrolidine (tetrahydro pyrrole), pyrroline (for example, 3 - pyrroline, 2.5 - dihydro pyrrole), 2h - pyrrole or troublesome zone - pyrrole (izopirrol, izoazol) or pirrolidinon (5 - membered ring), piperidine, dihydro pyridine, tetrahydro pyridine (6 - membered ring) and azepine (7 - membered ring); containing two nitrogen atoms, such as imidazoline, the pyrazolidine (diazolidin), imidazoline, pyrazoline (dihydro pyrazole) (5 - membered ring), piperazine (6 - membered ring); containing one oxygen, such as oxirane (3 - membered ring), oxetane (4 - membered ring), oksolan (tetrahydro furan), oksol (dihydro furan) (5 - membered ring), ocean (tetrahydro pyran), dihydro pyran, pyran (6 - membered ring), oxepin (7 - membered ring); containing two oxygen atom, such as dioxolan (5 - membered ring), dioxane (6 - membered ring) and dioxepan (7 - membered ring); containing three atoms of oxygen, such as trioxane (6 - membered ring); containing one sulfur atom, such as tiiran (3 - membered ring), thietan (4 - membered ring), thiolane (tetrahydro thiophene) (5 - membered ring), Tian (tetrahydro thiopyran) (6 - membered ring), tipan (7 - ring members); containing one nitrogen atom and one oxygen atom, such as tetrahydro oxazol, dihydro oxazole, tetrahydro isoxazole, dihydro isoxazole (5 - membered ring), morpholine, tetrahydro oxazine, dihydro oxazine, oxazine (6 - membered ring); containing one nitrogen atom and one sulfur atom, such as thiazoline, thiazolidine (5 - membered ring), thiomorpholine (6 - membered ring); containing two nitrogen atoms and one oxygen atom, such as oxadiazin (6 - membered ring); containing one oxygen and one sulfur atom, such as oxathiol (5 - membered ring) and oksatian (thioxane) (6 - membered ring); and containing one nitrogen atom, one oxygen and one sulfur atom, such as oxathiazine (6 - membered ring).

Geterotsiklily also enclose aromatic geterotsikpily and nonaromatic geterotsiklily. Such groups can be substituted or unsubstituted.

Term "aromatic heterocyclyl" may be used interchangeably with the term of query of query "heteroaromatic" or "heteroaryl" or "hetaryl". The heteroatoms in aromatic heterocyclyl group may be independently selected from ν, S and about.

"Heteroaryl" is used in this document for designations of heterocyclic group, having aromatic character, and female aromatic monocyclic ring system and polycyclic (for example, bitsikpicheskie) ring system, containing one or several aromatic rings. Term "aromatic heterocyclyl" also embraces psevdoaromaticheskiegeterotsiklily. Term "psevdoaromaticheskii" relates to circular system, which is not strictly aromatic, but stabilized by means of relocation of electrons and performs similarly includes aromatic rings. Term "aromatic heterocyclyl", so, embraces polycyclic ring system, in which all condensed ring are aromatic, and ring system, in which one or more rings are non-aromatic, provided, that at least one ring is aromatic. In polycyclic systems, as containing aromatic, and nonaromatic ring, condensed together, group can be connected to the other fragment aromatic ring or-aromatic ring.

Examples of heteroaryl groups are monocyclic and bitsikpicheskie group, containing from five to ten ring members. Heteroaryl group can be, for example, five-membered or six-membered monocyclic ring or bicyclic structure, formed by from condensed five and hexamerous rings or two condensed hexamerous rings, or two condensed five rings. Each ring may contain up to approximately four heteroatoms, usually selected from nitrogen, sulfur and oxygen. Heteroaryl ring will contain up to 4 heteroatoms, more such clusters to 3 heteroatoms, more such clusters to 2, for example, one heteroatom. In one embodiment heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in the heteroaryl rings can be main, as in case of imidazole or pyridine, or, essentially, non-core, as in case of indole or pyrrole nitrogen. In general case, number of main nitrogen atoms, present in heteroaryl group, including any amino group substituents in ring, will be less than five.

Aromatic heterocyclyl groups can be 5 - membered or 6 - membered monocyclic aromatic ring systems.

Examples 5 - membered monocyclic heteroaryl groups include, but are not limited by said, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1.2, 3 [i3 1.2, 4 - oksadiazolily and furazanyl, T. E. 1.2, 5 - oxadiazolyl), thiazolyl, isoxazolyl, izotiazolil, pyrazolyl, imidazolyl, triazolyl (including 1.2, 3 -, 1.2, 4AND 1.3, 4 - triazolily), oksatriazolil, tetrazolyl, thiadiazolyl (including 1.2, 3 [i3 1.3, 4 - tiadiazolily) and T. U.

Examples 6 - membered monocyclic heteroaryl groups include, but are not limited by said, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazineyl, dioxinyl, thiazinyl, tiadiazinil and T. U. Examples 6 - membered aromatic geterotsiklilov, containing nitrogen, include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogen atoms).

Aromatic heterocyclyl group may also be bitsikpicheskimi or polycyclic heteroaromatic ring systems, such as condensed ring system (including purine, pteridinyl, naphthyridinyl, 1h-thieno [2, 3 - with] pyrazolyl, thieno [2, 3 - mpile] furyl and T. U.) or connected ring system (such as oligotiofen, poly-pyrrole and T. U.). Condensed ring systems can also include aromatic 5 - membered or 6 - membered geterotsiklily, condensed with karbotsiklicheskimi aromatic rings, such as phenyl, naphthyl, indenyl, azulenyl, fluorohenyl, anthracenyl and T. U ., such as 5 - membered aromatic geterotsiklily, containing nitrogen atom, condensed with phenyl rings, 5 - membered aromatic geterotsiklily, containing 1 or 2 nitrogen atoms, condensed with phenyl ring.

Bicyclic heteroaryl group can be, for example, group, chosen from: and) benzene ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 ring heteroatom; b) pyridine ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; in) pyrimidine ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; g) pyrrole ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; d) pyrazole ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; E) imidazole ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; solid) oxazolic ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; 3) isoxazole ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; and) thiazol ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; to) isothiazol ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; l) of phiophenic ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; m) furan ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; H) cyclohexyl ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; and on) cyclopentyl ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom.

Specific examples bicyclic heteroaryl groups, containing five ring, condensed with other five-membered ring, include, but are not limited by said, the imidazothiazole (for example, imidazo [2, 1 - mpile] thiazole) and the imidazoimidazol (for example, imidazo [1, 2 - and] imidazole).

Specific examples bicyclic heteroaryl groups, containing six-member ring, condensed with five-membered ring, include, but are not limited by said, benzofuranovuyu, benzotiofenovuyu, benzimidazolnuyu, benzoksazolnuyu, izobenzoksazolnuyu, benzizoksazolnuyu, benzotiazolnuyu, benzizotiazolnuyu, izobenzofuranovuyu, indole, izoindolnuyu, indolizinovuyu, indolinovuyu, izoindolinovuyu, purinovuyu (for example, adenine, guanine), indazolnuyu, pirazolopirimidinovuyu (for example, pyrazolo [1, 5 - and] pyrimidine), benzodioksolnuyu and pirazolopiridinovuyu (for example, pyrazolo [1, 5 - and] pyridine) group. Additional example of six-membered ring, condensed with five-membered ring, is pirrolopiridinovaya group, such as pyrrolo [2, 3 - mpile] pyridine group.

Specific examples bicyclic heteroaryl groups, containing two condensed hexamerous ring, include, but are not limited by said, quinoline, izokhinolinovuyu, khromanovuyu, tiokhromanovuyu, khromenovuyu, izokhromenovuyu, izokhromanovuyu, benzodioksanovuyu, khinolizinovuyu, benzoksazinovuyu, benzodiazinovuyu, piridopiridinovuyu, khinoksalinovuyu, khinazolinovuyu, tsinnolinovuyu, ftalazinovuyu, naftiridinovuyu and pteridinovuyu group.

Examples of heteroaryl groups, containing aromatic ring and nonaromatic ring, include tetrahydro naftalinovuyu, tetrahydro izokhinolinovuyu, tetrahydro quinoline, dihydro benzotiofenovuyu, dihydro benzofuranovuyu, 2.3 - dihydro benzo [1.4] dioksinovuyu, benzo [1.3] dioksolnuyu, 4.5, 6.7 - tetrahydro benzofuranovuyu, indolinovuyu, izoindolinovuyu and indanovuyu group.

Examples aromatic geterotsiklilov, condensed with karbotsiklicheskimi aromatic rings, can so include, but are not limited by said, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazoleyl, benzoxazolyl, benzisoxazolyl, izobenzoksazoil, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolynyl, cinnolinyl, benzotriazinil, phtalazinyl, carbolinyl and T. U.

Term "nonaromatic geterotsikpil" embraces optionally substituted saturated and unsaturated ring, which contain at least one heteroatom, selected from the group, consisting of ν, S and about.

Nonaromatic heterocycle of Elah can represent 3 - 7 - membered monocyclic ring.

Examples 5 - membered nonaromatic heterocyclyl rings include 2h - pyrrolyl, 1 - pyrrolinyl, 2 - pyrrolinyl, 3 - pyrrolinyl, pyrrolidinyl, 1 - pyrrolidinyl, 2 - pyrrolidinyl, 3 - pyrrolidinyl, tetragidrofuranil, tetrahydro thiophenyl, pyrazolinyl, 2 - pyrazolinyl, 3 - pyrazolinyl, pyrazolidinyl, 2 - pyrazolidinyl, 3 - pyrazolidinyl, imidazolidinyl, 3 - dioksalanil, tiazolidinyl, isoxazolidinyl, 2 - imidazolinyl and T. U.

Examples 6 - membered nonaromatic geterotsiklilov include piperidinyl, piperidinonil, pyranyl, digirdopiranil, tetrahydro-pyranyl, 2H-pyranyl, 4H-pyranyl, tianil, tianiloksid, tianildioksid, piperazinyl, diozanil, 1.4 - dioxinyl, 1.4 - dithianeyl, 1.3, 5 - triozalanil, 1.3, 5 - tritianil, 1.4 - morpholinyl, thiomorpholinyl, 1.4 - oksatianil, triazinyl, 1.4 - thiazinyl IT. U.

Examples 7 - membered nonaromatic geterotsiklilov include azepanyl, oksepanil, tiepanil and T. U.

Nonaromatic heterocyclyl ring may also be a bicyclic heterocyclyl ring, such as connected ring system (for example, uridinil and T. U.) or condensed ring system. Condensed ring systems include nonaromatic 5 - membered, 6 - membered or 7 - membered geterotsiklily, condensed with karbotsiklicheskimi aromatic rings, such as phenyl, naphthyl, indenyl, azulenyl, fluorohenyl, anthracenyl and T. U. Examples nonaromatic 5 - membered, 6 - membered or 7 - membered geterotsiklilov, condensed with karbotsiklicheskimi aromatic rings, include indolineyl, benzodiazepinil, benzazepinil, dihydro benzofuranyl and T. U.

Term "halogen" relates to fluorine, chlorine, bromine or to iodine.

Term "optionally substituted" relates to group, which can be or not be additionally substituted one or more groups, selected from with -|_b alkyl, sz_b cycloalkyl, C2 - 6 alkenyl, C2 - 6 alkinila, aryl, heterocyclyl, halogen, halogen C1 - 6 alkyl, of cf3, halogen C3 - 6 cycloalkyl, halogen C2 - 6 alkenyl, halogen C2 - 6 alkinila, galogenarila, galogengeterotsiklila, hydro xy, C1 - 6 alkoxy, OCF3, C2 - 6 alkeniloksi, C2 - 6 alkiniloksi, aryloxy, geterotsikliloksi, carboxy, halogen with -|_b alkoxy, halogen C2 - 6 alkeniloksi, halogen C2 - 6 alkiniloksi, galogenariloksi, nitro, nitro C1 - 6 alkyl, nitro C2 - 6 alkenyl, nitroarila, nitrogeterotsiklila, azido, amino, C1 - 6 alkylamino, C2 - 6 alkenilamino, C2 - 6 alkynylamino, arylamino, geterotsiklilaminoatsila, C1 - 6 alkilatsila, C2 - 6 the alkenylacyl, C2 - 6 alkinilatsila, arilatsila, geterotsiklilatsila, acylamino, acyloxy, ester-, C1 - 6 alkylsulfonyl, arilsulfonila, C1 - 6 alkylsulphonylamino, arilsulfonilamino, C1 - 6 alkilsulfoniloksi, arilsulfoniloksi, C1 - 6 alkilsulfenila, C2 - 6 alkilsulfenila, arilsulfenila, carboalkoxy, karboariloksi, mercapto, with -|_b alkylthio, arylthio, atsiltio, cyano and T. U. Preferably, optional substituent is a with - m alkyl, of cf3, hydro xy, halogen, such as Cl or F, C1 - 4 alkoxy, such as methoxy or OCF3.

Understandable, that suitable derivatives of aromatic geterotsiklilov, containing nitrogen, include their N--oxides.

Salts of compounds of formula I or ii are preferably pharmaceutically acceptable, but should be understand, that not pharmaceutically acceptable salts also of multislit under volume of the present invention, since they can be used in as intermediate products production of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids, such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, coal, boric, sulfamic and hydrobromic acid; or salts of pharmaceutically acceptable organic acids, such as acetic, propionic, oil, tartaric, maleicor, hydro ksimaleinovaya, fumaric, citric, lactic, mutsinovaya, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trigalogenmetansulfonovaya, toluenesulfonic, benzenesulfonic, salicylic, of pH, aspartic, glutamic, ethylenediaminetetraacetic, stearic, palmitic, oleic, lauric, pantothenic, Tan-, ascorbic and valeric acid. Salt amine groups may also contain quaternary ammonium salts, in which nitrogen atom carries amino group of suitable organic group, such as alkyl, alkenyl, alkynyl or aralkyl group.

Salt can be obtained by common methods, such as interaction of free of initial form compounds with one or more equivalents corresponding acid.

Should be understand, that link on the pharmaceutically acceptable salt includes shape connection solvent or their crystalline forms, in particular solvates or polymorphs. Solvates contain either stoichiometric, or nonstoichiometric amount of solvent and may be formed by in process of crystallization by means of pharmaceutically priemlemymykh solvents, such as water, alcohols, such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethylformamide (dimethylformamide) and T. U ., the solvate forms part of crystal lattice or by noncovalent binding, or by filling holes in the crystal lattice. Hydrates are formed, when solvent is water, alcoholates are formed, when solvent is alcohol. Solvates compounds according to the present invention can be easily obtained or are formed in the course of described in this document methods. As a rule, solvated form are considered to be equivalent not solvated forms for purpose compounds and methods, presented in this document.

Additionally, compounds the present invention can arranged between in non-solvated, as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol and T. U. Solvated form compounds according to the present invention also are considered to be discovered in the present invention.

Understandable, that compounds of the formula i or ii can possess chiral center and can, so, arranged between in the form of isomer, such as racemate or r [ilir S-S enantiomer. Therefore compounds can be used as purified enantiomer or diastereomer, or in the form of mixture of any of their ratio. Isomers may be separated traditional chromatographic methods or by using the separating agent. Alternatively, separate isomers can be obtained asimmetricheskim synthesis with application of chiral intermediate products. When connection has carbon - carbon double bond, it may be in Zilieforme, and all isomeric forms compounds are included in the present invention.

The invention also embraces prodrugs of compounds of the formula i or ii.

Prodrug can be pharmacologically inactive derivatives of active compound, which requires transformation in organism to release active compound, and which has improved properties delivery as compared with active compound. Transformation in vivo of may be, for example, result of some metabolic process, such as chemical or enzymatic hydro lys carboxyl, phosphorus or sulfate ester, or reduction or oxidation of acquisitive functional group. In one version or-group⁸ on compounds of the formula (1) can be blocked with formation of prodrug, of R when⁸ represents H, in particular ester prodrug. Hydro ksilnaya group represents main site metabolism compounds: conjugation with glucuronic acid or sulfate results in the formation of hydro philic molecules, finished isolation.

In volume of the present invention includes compounds of the formula i or ii, to which is connected at least one of detected mark, affinity marker and fotoreaktivnoi group.

Compounds of the formula (1) can be used for treatment of neurological disorders.

As a rule, term "treatment" means action on distinguished, tissue or cell for desired pharmacological and/or physiological effect and includes: (and) inhibition of neurological disorders, T. E. stopping of its development or further development of; (b) simplification of or attenuation of the effects neurological disorders, T. E. regression effects neurological disorders; (in) WiFi client continuously tracks the morbidity or neurological disorders or (g) prevention of disorder in a subject, tissue or cell, predisposed to nevrologicheskomu disruption or having risk of its development, but not diagnostirovannomu, by means of protective pharmacological and/or physiological effect, so, that neurological disorder does not develop or not occurs in a subject, tissue or cell.

Term "distinguished", used in this document, relates to any animal, in particular mammals, such as people, having disorder or state, which requires treatment of compound of the formula i or ii.

Term "introduction" relates to provision compounds or pharmaceutical composition by invention subject, suffering from or having risk of development of diseases or conditions, to be treatment or prevention.

Term "neurologic disorder" is used in this document in its proper wide sense and relates to disturbances, at which various types of cells nervous system degeneriruyut and/or have been damaged as a result of neurodegenerative disorders or traumas, or actions. In particular, compounds of the formula i or ii can be used for treatment of obtained disorders, at which damage cells nervous system takes place from - the surgical interventions, infections, action toxic agents, tumors, deficiency nutrient substances or metabolic disorders.

Term "neurodegenerative disorder", used in this document, relates to anomaly, integrity at which neurons is under threat. Neuron integrity may be rim under threat, when neural cells demonstrate WiFi client continuously tracks the survival rate or, when neurons can not more distribute signal.

In addition, compounds of the formula i or ii may also be used for reinforcing effects from other methods of treatment, for example, for reinforcing neiroprotektivnykh effects produced by brain nerve growth factor.

Term "disease, characterized by unbalance metallv" relates to disease, at which the total amount of metal in a subject or too high, or too low. This term also relates to subject with normal total amount of metal, but metal incorrectly or abnormally is distributed.

Term "disease, characterized by the presence of oxidative stress" relates to disease, at which biological components subject injured active oxygen forms. In particular, supposed, that such components are injured active oxygen forms, such as hydro ksilnyi radical, hydrogen peroxide and superoxide, formed when the reaction Fenton and similar reactions. In particular, understandable, that metals, such as iron, copper, zinc, chromium, vanadium and cobalt, are able to oxidation - to reducing cycle, in which one electron can be received or given to metal, facilitating oxidising reaction. The actual damage occurs, when oxidative factor causes modification of amino acids (for example, formation of metatirozina and ortotirozina from phenylalanine), carbohydrates and fats (causing peroxide oxidation). In some cases such modification may cause toxic enhancement of function or damage biological component substrate.

Indication on "agent" further comprises combination of two or more active agents. "Combination" also further comprises much component, such as two-component composition, where agents are separated by and supplied separately or preliminarily are mixed. For example, much component pharmaceutical package may contain two or more agents, stored separately. Consequently, this aspect of the present invention includes combined therapy. Combined therapy includes combined introduction of agent and other active substance, such as chemotherapeutic compound, immunotherapeutic compound, cytokine, genetic molecule and/or anesthetic.

Terms "effective amount" and "therapeutically effective amount", used in this document, mean sufficient amount of agent to provide for desired therapeutic or physiological effect or result. Such effect or result includes inhibition of growth or cell viability, associated with gliomoi in brain. Undesirable effects, for example, adverse effects, sometimes manifested along with desired therapeutic effect;

consequently, city balances potential benefit with potential marks when determining the, which is the suitable "effective amount". Accurate desired amount will vary from subject to subject, depending on the type, age and general state subject, method of administration and T. U. So, is impossible indicate accurate "effective amount". However suitable "effective amount" in any individual case can be determined common specialist in the given engineering, with application of only standard investigating.

Effective amount of amount of is considered to be, required for inhibition of growth or cell viability, associated with gliomoi. Effective amounts of include introduction of from approximately 1 ng to approximately 1 g/distinguished. Administration can be a single dose or series of doses separated by. Number of includes introduction of from approximately 5 ng to approximately 800 mg/distinguished. Actual amount of include approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 ng or 200, 300, 400, 500, 600, 700, 800, 900, 1000 ng or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, on distinguished.

The composition is contain at least one of compounds of the formula i or ii together with one or more pharmaceutically acceptable carriers and optionally with other therapeutic agents. Each carrier should be pharmaceutically "acceptable" the point of view of compatibility with other ingredients of medicinal form and not to inflict harmful to subject. Carriers can include excipients and other additives, such as diluents, detergents, dyes, wetting or emulsifying agents, pH of buffer-agents, preserving agents and T. U. Compositions include suitable for oral, rectal, nasal, local (including transbukkalnoe and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intracutaneous) composition introduction. Compositions can be convenient are presented in form of standard medicinal form and can be obtained methods, well known in the field of pharmacy. Such methods include the stage of bringing in contact active ingredient with carrier, which consists of one or more additional ingredients. As a rule, medicinal forms is obtained by uniform and thorough bringing into contact the active ingredient with liquid carriers, diluents, adjuvants and/or excipients, or finely ground solid carriers, or with both, and then if necessary molding product.

Compounds of the formula i or ii may be introduced orally, locally or parenterally in medicinal forms of single metering, containing common nontoxic pharmaceutically acceptable carriers, adjuvants and fillers. Term "parenteral", used in this document, includes subcutaneous injection, aerosol into lungs or nasal cavity, intravenous, intramuscular, intrathecal, intrakranialnyi, injection, intraocular or infusion methods.

The present invention also provides suitable local, oral and parenteral pharmaceutical compositions for use in new methods of treatment according to the present invention. Proposed compounds may be introduced orally in the form of tablets, aqueous or oil suspensions, candies, lozenges, powders, granules, emulsions, capsules, syrups or elixirs. Composition for oral use may contain one or more agents, selected from the group sweeteners, flavorings, dyes and preservatives, for production of pharmaceutically original and delicious preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable deglomerative agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthane gum, bentonite, alginic acid or agar. Suitable flavorings include oil of peppermint, oil seeds wintering, cherry, orange or raspberry. Suitable preservatives include sodium benzoate, vitamin E, alfatokoferol, ascorbic acid, methylparaben, propylparaben or sodium bisulfite. Suitable lubricating substance include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable agents holding include glycerol monostearate or glitserildistearat. Tablets contain active ingredient in mixture with intoxic pharmaceutically acceptable excipients, which are suitable for of producing tablets.

Such excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and deglomerative agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or gum arabic; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets can not have coating or may be coated with known methods for delay decay and suction in digestive - tract and, so, provide prolonged effect in for prolonged. For example, can be used substance, providing holding, such as glitserilmonostearat or glitserildistearat. Coating also can be made with use of methods, disclosed in Patent USA № 4256108, 4160452 and 4265874, for forming osmotic therapeutic tablets for controlled release.

Above indicated compounds, and also farmatsevticheskiaktivnyi agent, used in method of the invention, can be introduced for use in vivo of parenterally by injection or gradual perfusion in time independently or together. Administration can be intraocular, intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, intracavity, transdermal or infusion by means of, for example, osmotic pump. For research in vitro of agents may be added or dissolved in corresponding biologically acceptable buffer and added to cell or tissue.

Composition for parenteral administration contain sterile aqueous or non-aqueous solutions, suspension and emulsion. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsion or suspension, including physiological solution and buffer medium. Parenteral carriers include sodium chloride solution, the dextrose Ringer, the dextrose and sodium chloride, laktatnye intravenous Ringer carriers include liquid and nutrient fillers, electrolytic fillers (such as based on dekstroze Ringer) and T. U. Also can be present preserving agents and other additives, such as, for example, antimicrobial, antioxidant, weaken the agents, growth factors and inert gases and T. U.

The present invention includes various pharmaceutical compositions, applicable for facilitating disease. Pharmaceutical compositions according to one version of the present invention is obtained by combination of above said compound, its analogs, derivatives or salts, or combinations of above indicated compounds and one or more farmatsevticheskiaktivnykh agents into shape, suitable for administration to a subject, with use of carriers, fillers and additives or auxiliary substances. Frequently used carriers or auxiliary substances include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugar, talc, milk protein, gelatin, starch, vitamins, cellulose and their derivatives, animal and vegetable oil, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and much atomic alcohols. Carriers for intravenous administration include liquid and nutrient fillers. Preserving agents are antimicrobial, antioxidant, weaken the agents and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, nontoxic excipients, salt including, preserving agents, buffers and T. U ., as described, for example, in Remington's the PharmaceuticalSciences, 20 - E of 2 yr. The Williams and sort Wilkins (2000) and The the British the National Formulary 43-and-of E of 2 yr. (British medical association and the Royal society pharmacists Great Britain, 2002; http://bnf.rhn.net), whose content is connected into the present description as references. Level of pH and accurate concentration of different components pharmaceutical compositions is regulated according to by common methods in this area. Cm. Goodman and sort Gilman's the of The Pharmacological BASIS team for Laptops therapeutics (7 - E of 2 yr ., 1985).

Pharmaceutical compositions is preferably produced and introduced in dose units. Solid unit dose can be tablets, capsule and suppositories. For treatment of a subject, depending on activity of compounds, method of administration, nature and severity of disorder, age and body weight of a subject, can be used various daily dose. However at certain circumstances, more suitable may be higher or more low daily dose. Introduction of daily dose may be accomplished as by single introduction of, in form of a separate unit dose, so and several units at dose, and by much introductions of doses separated by intervals.

Pharmaceutical compositions may be introduced locally or systemic in therapeutically effective dose. Amount, effective for such application, end, will be depend on disease severity, mass and general state subject. Usually, dose, used in vitro of, can be used as useful guidance for determining amounts of, acceptable for introduction of the in situ pharmaceutical composition, and model of animals can be used for of determination of effective doses for treatment of cytotoxic side effects. Different recommendations are described, for example, in Langer, the science, 249:1527, 1990.

Composition for oral use may be in the form of solid gelatin capsules, where active ingredient mixed with inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules, where active ingredient mixed with water or oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain usually active substances in mixture with excipients, suitable for production of aqueous suspension. Such excipients may be (1) suspending agent, such as carboxymethyl cellulose sodium, methyl cellulose, hydro ksipropilmetiltsellyuloza, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; (2) dispersing or wetting agents, which may be (and) natural fosfatidom, such as lecithin; (b) condensation product of alkylene oxide with fatty acid, such as the polyoxyethylenestearate; (in) condensation product of ethylene oxide with-chain aliphatic alcohol, such as geptadekaetilenoksitsetanol; (g) condensation product of ethylene oxide with incomplete ester of, obtained from fatty acid and hexitol, such as polioksietilensorbitmonooleat, or (d) condensation product of ethylene oxide with incomplete ester, obtained from fatty acids and hexitol anhydrides, such as polioksietilensorbitanmonooleat.

Pharmaceutical compositions can be in the form of sterile injection aqueous or oil suspension. Such suspension can be obtained in accordance with the known methods using suitable dispersing or moistening agents and suspending agents, which have been mentioned above. Sterile injection preparation can also be a sterile injection solution or suspension in nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1.3 - butanediol. Acceptable carriers and solvents, which can be used, are water, Ringer solution and isotonic sodium chloride solution. In addition, as a solvent or suspending medium generally used sterile nonvolatile oil. For this purpose can be used any soft non-volatile oil, including synthetic mono diglycerides. In addition, fatty acids, such as oleic acid, are used in injection preparations.

Above indicated compounds can also be introduced in the form of systems of the liposomal delivery, such as small single-layer vesicles, large single-layer vesicles and much sloinye vesicles. Liposomes may be formed by from multiple phospholipids, such as cholesterol, stearylamine or phosphatide ylcholines.

Compounds can also be presented for use in the form of veterinary compositions, which may be obtained, for example, methods, which are common in this area. Examples of such veterinary compositions include those, which adapted for:

(and) oral administration, external application, for example, liquid medicinal forms (for example, water or Non-aqueous solutions, or suspension); tablet or pill; powders, granules or pellets for mixing with fodder products; paste for applying on tongue;

(b) parenteral administration, for example, subcutaneous, intramuscular or intravenous injection, for example, in the form of a sterile solution or suspension;

or (if necessary) by intramammarnoi injection, when suspension or solution is introduced in udder through teat;

(in) local application, for example, in the form of cream, ointment or aerosol, applied on skin; or

(g) introduction of intravaginal, T. E. in the form of a pessary, cream or foam.

The present invention then is disclosed by means of the following limited.

Example 1

Circuit 1

Substituted 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - ones can be obtained by synthetic, illustrated on circuit 1. starting from intermediate ester 1 - 1, interaction with diizopropilamidom lithium (poison) at low temperature causes formation of enolyatnogo anion, which is suppressed etilformiatom, to produce aldehyde 1 - 2. Heating aldehyde to temperature reflux with 3 - hydro ksipiridinolom1 - 3 results in production of ester 1 - 4. Cyclization compounds 1 - 4 in boiling acetic acid provides after crystallization required target compounds of 1 - 5 (circuit 1).

Circuit 1

where R is³ is a with - m alkyl, optionally interrupted about, C5 - 6 cycloalkyl or benzyl, optionally condensed with 5 - containing about chlennymgeterotsiklilom;

R⁶ is a Cl or vg; and

R⁷ is a 1.

Compound 1621

Ethyl - 2 - cyclohexyl - 3 - oksopropanoat (1 - 2)

Ethyl - 2 - cyclohexanol acetate (7.5 g, 44 mmole) dissolved in volatile anhydrous tetrahydrofurane (20 ml) and then added to the solution poison (28.6 ml, 2.0 m solution in heptane/tetrahydrofurane/ethylbenzene) at -78 theoretically. After stirring at that temperature for 1 hour added to ethyl formate (4.8 ml, 59 mmol) and reaction mixture was heated UP to room temperature in 3 hours. Reaction carefully quenched H2O, then tetrahydrofurane they moved away on rotor evaporator. Mixture then extracted with petroleum ether 60 - 80 theoretically (khz). Then aqueous layer acidified up to pH 2 concentrated Histidinum and extracted ch2ci2 (^X 2). Organic extracts dried above Na2S04, filtered and they concentrated to produce desired aldehyde 1 - 2 in the form of orange oil (5.65 g, 65%).¹ H NMR (500 MHz, CDCI₃ ) b 1.14 (of m, 4h), 1.31 (T, 4h), 1.76 (T, 2h), 2.18 (T, 2h), 3.00 (T, 1h), 4.24 (T, 2h), 7.01 (d of, j=12, 5 Hz, 1H), 9.70 (Dd1, j=4, 1 Hz, 1H), 11.66 (d of, j=12, 5 Hz, 1H).

Ε-: Ζ - Ethyl - 2 - cyclohexyl - 3 - (3 - hydro ksipiridin - 2 - ylamino) acrylate (1 - 4) Aldehyde 1 - 2 (4.0 g, 20.2 mmol) dissolved in volatile eyun (100 ml), to which added to the 2 - amino - 3 - hydro ksipiridin1 - 3 (2.0 g, 18.2 mmol) and reaction mixture was heated UP to temperature reflux for 3 hours. Solvent they moved away under vacuum to produce brown solid substance (5.4 g, quantitative yield). Approximate NMR - analysis proved mixture of isomers E.Z1 - 4 and material weathered the next stage without purification.

Of 3 - tsikpogeksil - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (1 - 5) (1621) Ketoenol mixture 1 - 4 (5.4 g, 18.6 mmol) dissolved in volatile ice ason (100 ml) and prepared dark - brown solution was heated UP to temperature reflux for 3 hours. Solvent they moved away under vacuum to produce yellow/brown solid substance. Crude material dissolved in volatile hot eyun (100 ml) and left to stand during night time. Produced yellow solid collected by filtration and dried to produce 3 - cyclohexyl - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - one 1 - 5 in the form of yellow plates (2.8 g, 62%).¹ H NMR (500 MHz, CDCI₃ ) of Δ 1.31 (of m, 1η), 1.47 (of m, 4η), 1.78 (of m, 1η), 1.87 (of m, 2η), 1.97 (of m, 2η), 2.93 (of m, 1η), 7.03 (t of, j=7, 5 Hz, 1η), 7.08 (Dd1, j=7, 5, 1.5 Hz, 1η), 8.13 (of c, 1η), 8.55 (Dd1, j=7, 5, 1.5 Hz, 1η). HPLC: t of_R =9.39 min (98.1%), Msh-m/z 245.09 [m + h]⁺ .

Example 2

Substituted aryl and heteroaryl 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - ones can be, taking 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it 1 - 5, where R is⁷ represents H, synthesized in example 1, shown above on circuit 1, and having iodirovanie in ortho position - phenol with application of iodine and hydrogen peroxide to produce 2 - 1 (Circuit 2). After protection of phenol for production of 2 - 2, may be reaction combination Suzuki with of Pd (PPh3) 4 as catalyst, and commercially available boron acids of R⁷ B of (OH of) 2 or boronatnymi esters of R⁷ B OF (OR-⁵ ) 2 to produce aryl and heteroaryl compounds 2 - 3. Removal of protection with izopropoksigruppy in connection 2 - 3 action of nvg gives target compounds of 2 - 4 (circuit 2).

where R is³ is a with - malkil or s^yns - malkil;

R⁶ is a Cl; and

R⁷ is a 5ili 6 - members optionally substituted heterocyclyl, optionally substituted phenyl or I.

Compound 1629

Of 7 - chloro - 9 - hydro xy - 8 - iodine - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (2 - 1)

Of 7 - chloro - 9 - hydro xy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 1 - 4 (500 mg, 2.1 mmol) dissolved in volatile eyun (20 ml) and then treated with iodine (585 mg, 2.3 mmol) and 30% aqueous H2O2 (0.24 ml, 2.35 mmol) and reaction mixture stirring for 48 hours. The precipitate formed is filtered, washed eyun and then dried to produce iodine compound 2 - 1 in the form of yellow powder (520 mg, 68%).¹ H NMR (500 MHz, CDCI₃ ) b 1.00 (t of, j=7, 5 Hz, troublesome zone), 1.70 (sext, j=7, 5 Hz, 2H), 2.62 (t of, j=7.5 Hz, 2H), 5.31 (s-, 1h), 8.81 (s-, 1h), 8.65 (s-, 1h).

Of 7 - chloro - 9 - hydro xy - 8 - iodine - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it (450 mg, 1.2 mmole) dissolved in volatile anhydrous dimethylformamide (10 ml), to which then added to K2CO3 (511 mg, 3.7 mmol) and 2 - brominepropane (290 mcl, 3.08 mmole), and the obtained mixture is dark color of stirring at 60 theoretically in argon atmosphere during night time. Reaction mixture diluted EtOAc (50 ml) and H2O (70 ml) and they separated layer EtOAc. Aqueous layer additionally extracted EtOAc (χ2) and combined organic extracts washed salt solution, dried above Na2S04, filtered and they concentrated to produce isopropyl ester 2 - 2 in the form of yellow solid substance (230 mg, 46%).¹ H NMR (500 MHz, CDCI3) b 0.99 (t of, j=7, 5 Hz, troublesome zone), 1.44 (d of, j=6, 0 Hz, 6h), 1.69 (sext, j=7, 5 Hz, 2H), 2.61 (t of, j=7, 5 Hz, 2H), 5.51 (sept, j=6, 0 Hz, 1H), 8.15 (s-, 1h), 8.92 (s-, 1h).

Of 7 - chloro - 8 - (pyridine - 3 - yl) - 9 - isopropoxy - 3 - propyl - 4 [ya4 - pyrido [1, 2 - and]

pyrimidine - 4 - it (2 - 3)

Of 7 - chloro - 8 - iodine - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 2 - 2 (100 mg, 0.25 mmol), 3 - piridilboronovuyu acid (37 mg, 0.30 mmole) dissolved in volatile dimethylformamide (5 ml), and then added to 2M to₂ CS (0.5 ml, 1 mmol)). Solution degassed by means of bubbling argon/ultrasound, then added to the of Pd (cooling systems₃ )₄ (15 mg, 0.013 mmol) and reaction mixture was heated UP to 100 theoretically for 18 hours. Reaction mixture diluted EtOAc and filtered through Celite, washing EtOAc. Solvent they moved away under vacuum and residue they cleaned flash - chromatography, elyuiruya 40% eyuas/petroleum ether 40 - 60 theoretically, to produce resinous solid substance. The second elution of column 10 - 20% ether/CH₂ C12 led to production of desired pyridine 2 - 3 in the form of white solid substance (53 mg, 60%).¹ H NMR (500 MHz, CDCI3) of Δ 1.01 (t of, J=7.5 Hz, troublesome zone), 1.05 (d of, j=6, 0 Hz, 6h), 1.72 (sext, J=7.5 Hz, 2H), 2.66 (t of, J= 7.5 Hz, 2H), 4.93 (sept, j=6, 0 Hz, 1H), 7.45 (of DDD, J=8, 5, 0.5 Hz, 1H), 7.77 (of dT, j=8, 0, 2.0 Hz, 1H), 8.23 (s-, 1h), 8.68 (d of, J= 1.5 Hz, 1H), 8.71 (Dd1, J=5.0, 1.5 Hz, 1H), 9.02 (s-, 1h).

Of 7 - chloro - 9 - hydro xy - 3 - propyl - 8 - (pyridine - 3 - yl) - 4 [ya4 - pyrido [1, 2 -

and] pyrimidine - 4 - it (2 - 4) (1629)

of 7 - chloro - 8 - (pyridine - 3 - yl) - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 -

and] pyrimidine - 4 - it 2 - 3 (50 mg, 0.14 mmol) to added to the 48% aqueous nvg (3 ml) and was heated UP to 120 theoretically for 1.5 hours. After cooling, obtained of fistula solution neutralized by means of saturated water yansoz. Aqueous layer extracted ch2ci2 (^X 3) and organic layer dried above of Na₂S04, filtered and they concentrated to produce 7 - chloro - 9 - hydro xy - propyl - 8 - (pyridine - 3 - yl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one (2 - 4) in the form of svetlozelenogo powder (38 mg, 86%).¹ H NMR (500 MHz, CDCI₃ ) of Δ 1.02 (t of, 4=7.5 Hz, troublesome zone), 1.72 (sext, 4=7,5 Hz, 2η), 2.67 (t of, 4=7,5 Hz, 2η), 7.47 (Dd1, 4=7,5, 5.0 Hz, 1η), 7.84 (d of, 4=7,5 Hz, 1η), 8.14 (s-, 1η), 8.71 (d of, 4=5,0 Hz, 1η), 8.74 (s-, 1η), 8.75 (brr s-, 1η), HPLC:

t of_R =7.99 min. (91.7%), MSH-: m/z 316.1 [M + H]⁺ .

Substituted methylamino compounds can be obtained from 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - ones, synthesized according to scheme 1 above, adapting method, described in Chemistry care HeterocyclicCompounds, 1992, 28, 1425 - 1431. Interaction of commercially available amines with 9 - hydro xy - 4npirido [1, 2 - and] pyrimidine - 4 - onami1 - 5 provided desired compounds 3 - 1 (Circuit 3).

Circuit 3

where R is³ is a C5 - 6 cycloalkyl, with - m alkyl, optionally interrupted O or benzyl;

R⁷ is a CH-₂ THE NR¹⁰R¹⁰ , where R is⁹ and R¹⁰ are C1 - 2 alkyl or together with n, to which they are connected, form morpholinyl.

Compound 1627

Of 3 - tsikpopentil - 8 - (dimethylamino) - methyl - 9 - hydro xy - 4h - pyrido [1, 2 -

and] pyrimidine - 4 - it (3 - 1)

Solution cyclopentyl - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one (137 mg, 0.60 mmol) 1 - 5 in anhydrous toluene (4 ml) treated ν, ν, ν, νtetrametilmetilendiaminom (240 mcl, 1.76 mmole) for 4 hours. Reaction mixture was, they concentrated and produced solid crystallized from hot acetonitrile to produce desired amine 3 - 1 in the form of pale - green solid substance (50 mg, 29%).¹ H NMR (500 MHz, dmsod6) B 1.71 (of m, 4h), 1.84 (T, 2h), 1.66 (t, 2H), 2.07 (T, 2h), 2.41 (s-, 6h), 3.23 (T, 1h), 3.72 (s-, 2h), 6.84 (d of, J=7.5 Hz, 1H), 8.26 (s-, 1h), 8.57 (d of, J= 7.5 Hz, 1H), HPLC: t of_R =7.64 min. (92.6%), MS: m/z 288.1 [M + H]⁺ .

Example 4

Substituted triazole compounds can be obtained from compounds 1 - 5 on circuit 1. protection of compounds 1 - 4 to yield compound 4 - 1 followed by reaction of combination sonogashiry results in the formation of compounds trimetilsililatsetilenovykh4 - 2. Removal of silane group in main conditions results in production of acetylenes 4 - 3. Compound 4 - 3vzaimodeistuet with known azide in the presence of catalyst of Cu (lit). Followed by 1.3 - dipolar the cycloaddition (click - chemistry) flows smoothly, to produce substituted triazoles 4 - 4. Finally, removal of protection compounds 4 - 4 leads to obtaining desired compounds 4 - 5 (Circuit 4). Note: azides obtained in accordance with known method, described in Synthesis 1997, 4, 413 - 414 (circuit 4).

where R is³ is a with - m alkyl;

R¹¹ is a vg; and

R¹² is a benzyl or cyclopentyl.

Compound 1616

Of 7 - bromo - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 1) Of 7 - bromo - 9 - hydro xy - 3 - propyl - 4 / - / - pyridone [1, 2 - and] pyrimidine - 4 - it 1 - 5 (2.0 g, 7.1 mmol) dissolved in volatile anhydrous dimethylformamide (30 ml), then treated to₂ C0₃ (2.93 g, 2.1 mmol) followed by addition of 2 - bromopropane (1.65 ml, 17.7 mmol) and reaction mixture stirring at 60 theoretically during night time. Volatile components they moved away under vacuum and residue treated H₂ 0 (50 ml) and eyuas (50 ml). Layer eyuas they separated and aqueous layer additionally extracted eyuas (2x50 ml). Combined organic layers washed salt solution, dried above of Na₂ S0₄ , filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 10% eyuas/petrolinym ether 40 - 60 theoretically to produce isopropyl ester 4 - 1 in the form of brown oil (1.50 g, 65%).¹ H NMR (500 MHz, CDCI₃ ) b 0.98 (t of, J=7.5 Hz, troublesome zone), 1.53 (d of, j=6, 0 Hz, 6h), 1.68 (sext, J=7.5 Hz, 2H), 2.63 (t of, J=7.5 Hz, 2H), 4.73 (sept, j=6, 0 Hz, 1H), 6.96 (d of, j=1, 5 Hz, 1H), 8.24 (s-, 1h), 8.80 (d of, j=1, 5 Hz, 1H).

9 of - isopropoxy - 3 - propyl - 7 - ((trimetilsoliil) ethynyl) - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 2)

Of 7 - bromo - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 4 - 1 (1.45 g, 4.5 mmole) dissolved in volatile anhydrous tetrahydrofurane (60 ml) and diizopropilamine (5 ml, 35.7 mmole). Solution degassed by means of bubbling argon and ultrasound, then in reaction vessel 1.20 the following reagents. PdCl2 (cooling systems₃ )₂ (188 mg, 0.27 mmole), cUL Listing Mark (17 mg, 0.09 mmol) and TMS acetylene (1 ml, 7.08 mmol), then the reaction mixture was heated UP to 70 theoretically for 2 hours. Reaction mixture filtered through small layer of silica gel, washing EtOAc. They concentrated filtrate and residue they cleaned flash - chromatography, elyuiruyapetroleinm ether 40 - 60 theoretically - 40% EtOAc/petroleum ether 40 - 60 theoretically to silane 4 - 2 in the form of yellow solid substance (1.40 g, 92%). ¹N NMR (500 MHz, CDCI₃ ) of Δ 0.29 (s-, 9η), 0.98 (t of, J=7.5 Hz, 3η), 1.52 (d of, j=6, 0 Hz, 6η), 1.68 (sext, J=7.5 Hz, 2η), 2.62 (t of, J=7.5 Hz, 2η), 4.75 (sept, j=6, 0 Hz, 1η), 6.85 (d of, j=1, 5 Hz, 1η), 8.22 (s-, 1 η), 8.79 (d of, j=1, 5 Hz, 1η).

7 of - ethynyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 3) 9 of - isopropoxy - 3 - propyl - 7 - ((trimetilsoliil) ethynyl) - 4 / - / - pyrido [1, 2 -

and] pyrimidine - 4 - it 4 - 2 (1.40 g, 4.1 mmole) dissolved in volatile meon (20 ml), then added to the to₂ CS (622 mg, 4.5 mmol) to reaction. After stirring at room temperature for 15 minutes reaction mixture diluted ether (20 ml) and n₂ 0 (20 ml). Organic layer they separated, and aqueous layer additionally extracted ether (2x20 ml). Combined organic layers washed salt solution, dried above of Na₂S04, filtered and they concentrated to produce acetylene 4 - 3 in the form of orange solid substance (950 mg, 86%).¹ H NMR (500 MHz, CDCI₃ ) b 0.98 (t of, J=7.5 Hz, troublesome zone), 1.53 (d of, j=6, 0 Hz, 6h), 1.68 (sext, J=7.5 Hz, 2H), 2.63 (t of, j7, 5 Hz, 2H), 3.20 (s-, 1h), 4.74 (sept, j=6, 0 Hz, 1H), 6.87 (d of, j=1, 5 Hz, 1H), 8.23 (s-, 1h), 8.83 (s-, j=2, 0 Hz, 1η).

Of 7 - (1 - benzyl-of f ON , 2, 3 - triazole - 4 - yl) - 9 - isopropoxy - 3 - propyl - 4 [ya4 -

pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 4)

7 of - ethynyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 3) (200 mg, 0.74 mmol) dissolved in volatile eyun (5 ml), then added to the benzilazid (125 mg, 0.94 mmole) in eyun (5 ml) followed by addition of H₂ 0 (10 ml). Then to reaction mixture added to the CuS04 ' 5h₂ 0 (123 mcl, 0, magnetic core aqueous solution, 5 mole %) and sodium ascorbate (148 mcl, M aqueous solution, 20 mole %) and reaction mixture stirring in the darkness for 24 hours. Reaction mixture diluted H₂ 0 and extracted CH-₂ CL₂ (khz). Organic layer washed salt solution, dried above of Na₂S04, filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 10 - 40% eyuas/petrolinym ether 40 - 60 theoretically, to produce triazole 4 - 4 in the form of white solid substance (308 mg, quantitative yield).¹ H NMR (500 MHz, CDCI₃ ) b 0.98 (t of, J= 7.5 Hz, troublesome zone), 1.56 (d of, (d of, 4=2,0 Hz, 1η).

Of 7 - (1 - benzyl-of f Η - of λ , 2, 3 - triazole - 4 - yl) - 9 - hydro xy - 3 - propyl - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 5) (1616)

Of 7 - (1 - benzyl - 7 / - / - 1.2, 3 - triazole - 4 - yl) - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 4 - 4 (300 mg, 0.74 mmol) added to the to 48% aqueous nvg (4 ml) and mixture was heated UP to temperature reflux for 1 hour. After cooling reaction mixture neutralized with saturated water yansoz, then extracted ch2ci2 (^X 3). Organic layer washed salt solution, dried above Na2S04, filtered and they concentrated to produce product of 4 - 5 in the form of almost white powder (256 mg, 95%).¹ H NMR (500 MHz, CDCI3) 61.00 (t of, 4=7,5 Hz, troublesome zone), 1.70 (sext, 4=7, 5 [gts5, 2h), 2.64 (t of, 4=7, 5 [gts5, 2h), 5.61 (s-, 2h), 7.39 (of m, 5h), 7.72 (d of, j=1, 5 [gts5, 1H), 7.79 (s-, 1h), 8.11 (s-, 1η), 8.85 (d of, 4=1, 5 [gts5, 1h), vezhkh7_K=11, 13 min (93.5%), ms: m/z 362.1 [M + H]⁺ .

Example 5

Series of 9 - hydro xy - 4 - oxo - 4h - pyrido [1, 2 - and] pirimidinkarboksamidov may be obtained by condensation of 3 - hydro xy - 2 - aminopiridinolov1 - 3 with diethyl (etoksimetilen) low natom to produce intermediate compounds 5 - 1. Followed by closure ring in boiling acetic acid results in production of ethyl ester of 5 - 2. Hydro lys 2ν of NaOH gives acid 5 - 3, further transformation of to chloride 5 - 4 is achieved due to application of thionyl chloride. Then target compounds of 5 - 5 are synthesized by mixing chloride 5 - 4 with corresponding amine (circuit 5).

R⁷ represents H or methyl;

R⁹ represents H;

R¹⁰ is a C3 - 8 alkyl, optionally interrupted about, (CIS) 1 - 2 5 - or 6 - members of n-containing heterocyclyl, (CH2) about - 1 C3 - 6 cycloalkyl or CH2 optionally substituted phenyl, optionally condensed with 5 - containing about chlennymgeterotsiklilom; or

R⁹ and R¹⁰ together with n, to which they are connected, form 5ili 6 - membered ring.

Compound 1460

Diethyl - 2 - ((3 - hydro ksipiridin - 2 - ylamino) methylene) low NAT (5 - 1)

of 2 - amino - 3 - hydro ksipiridin(1 - 3) (20.0 g, 0.18 mole) and diethyl - 2 (etoksimetilen) low NAT (55.0 ml, 0.27 mole) stirring together in flask at 130 theoretically for 40 min. Pyridine clisked in solution at heating, then from solution dropped new yellow solid substance. Reaction mixture was and solid substance recrystallized (eyun) and then dried in air with production of the product 5 - 1 in the form of yellow solid substance (39.0 g, 77%).¹ H NMR (DMSO De, 500 MHz) 61.20 (of m, 6h), 4.17 (of Q, J= 6.5 Hz, 2H), 4.22 (of Q, J= 6.5 Hz, 2H), 7.10 (t of, J= 7.0 Hz, 1H), 7.32 (d of, J= 7.0 Hz, 1H), 7.87 (d of, J= 2.1 Hz, 1H), 9.13 (d of, J= 12.5 Hz, 1H), 10.88 (of BS, 1h), 11.10 (d of, J= 12.5 Hz, 1H).

Ethyl - 9 - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carboxylate (5 - 2) Diethyl - 2 - ((3 - hydro ksipiridin - 2 - yline) methylene) low NAT 5 - 1 (47.7 g, 0.17 mole) was heated UP to temperature reflux in acetic acid (400 ml) for 4.5 hours. Reaction mixture they concentrated at spider nnom pressure to produce yellow solid substance. Recrystallization (ethanol) febrifuges desired product 5 - 2 in the form of pale - yellow solid substance (30.6 g, 76%).¹ H NMR (DMSO De, 500 MHz) 61.30 (t of, J= 7.0 Hz of troublesome zone), 4.26 (of Q, J= 7 Hz, 2H), 7.41 (t of, J= 8.5 Hz, 1H), 7.49 (d of, J= 8.5 Hz, 1H), 7.63 (d of, J= 8.5 Hz, 1H), 7.80 (s-, 1h).

9 of - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carboxylic acid (5 - 3).

Ester (5 - 2) (5.0 g, 0.02 mole) suspended in ethanol (400 ml), to which added to the 2n aqueous solution of hydro ksida sodium (192 ml, 0.38 mole). Reaction mixture was heated UP at 40 theoretically for 3 hours, during this period in reaction mixture it was manifested - bright yellow precipitate. Ethanol they moved away at spider nnom pressure and aqueous solution extracted with ethyl acetate (150 ml).

Aqueous solution acidified up to pH 3, of a 10% aqueous solution of Histidinum, and left on the 17 hours in refrigerator. Reaction mixture filtered and yellow solid washed with water (20 ml) and then dried at spider nnom pressure up to synthesis of end compound 5 - 3 in the form of its Histidinum salt (4.17 g, 86%).¹ H NMR (D OF₂ 0, 400 MHz) 62.74 (of BS, 1h), 7.35 (brr s-, 2h), 8.61 (brr s-, 1h).

9 of - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carbonylchloride (5 - 4) 9 of - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxylic acid (5 - 3) (4.3 g, 19.5 mmol) was heated UP to 80 theoretically in tionilkhloride for 2.5 hours. Volatile substances they moved away under vacuum. Excess thionyl chloride they moved away by means of azeotropic distillation with toluene. Prepared 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carbonylchloride 5 - 4 allocate with quantitative yield solid substance in the form of beige color.

M - tsikpogeksil - 9 - hydro xy - 4 - oxo - 4h - pyrido [1, 2 - and] pyrimidine - 3 -

carboxamide (5 - 5) (1460)

9 of - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxylic acid (5 - 3) (4.3 g, 19.5 mmol) was heated UP to 80 theoretically in tionilkhloride for 2.5 hours. Volatile substances they moved away under vacuum. Excess thionyl chloride they moved away by means of azeotropic distillation with toluene. Obtained chloroanhydride allocate in the form of solid substance beige color. Chloroanhydride (3.9 g, 17.4 mmol) suspended in ch2ci2 (65 ml) and was to 0 theoretically. Added to the diisopropylethylamine (4.0 ml) and tsiklogeksilamin (4.5 ml) and reaction mixture stirring at room temperature for 2 days. Added to 1 μ Histidinum up to pH 3, then added to the eyun (65 ml). Suspension filtered, and filtrate is they concentrated to volume (10 ml). Solution was and green solid collected by filtration, washing meon/H₂ 0 (2:1) (khz) to produce desired 1p - cyclohexyl - 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 5 - 4 (1.21 g, 24%).¹ H NMR (400 MHz, DMSO - slices) 61.30 (T, 1h), 1.39 (T, 2h), 1.87 (T, 1H), 3.86 (t, 1H), 7.48 (t of, J=7.2 Hz, 1H), 7.53 (d of, J=7.2 Hz, 1H), 8.71 (d of, 4=6,8 Hz, 1H), 8.99 (s-, 1h), ms: m/z 288.1 [M + H]⁺ .

Compound structure mm ¹ H NMR MS

1394 ABOUT ABOUT 317.4 ¹ H NMR (400 MHz, m/z 316.2 [M -

VV entries^H DMSO - C16) 50.82 (of m, troublesome zone), 1.95 (of m, 12η), 3.45 h of]⁺

it (of m, 2η), 1.79 (of m, 2η),

Of 2 - methylamino substituted pyrimidones can be obtained according to scheme 6. field aniline 1 - 3 and heating with etilkhloratsetoatsetatom in rra (polyphosphoric acid) in accordance with the method Ferrarini, P.LOf II Farmaco 1995.50 (1), with. 69 - 72, leads, after isolation of the reaction product, to production of desired khlormetilnogo derivative 6 - 1. Substitution of chlorine substitute different amines leads to obtaining target amine compounds 6 - 2 (circuit 6).

R⁶ ,

Circuit 6

where R is⁵ represents H or methyl;

R⁶ represents H or Cl;

R⁹ and R¹⁰ are independently chosen from H, Ci_₈ alkyl, the CN, (CH₂ ) about - 2 with₃ .₆ cycloalkyl, CH₂ optionally substituted phenyl or (CH₂ ) about - 3 optionally substituted N--containing 5ili6chlennogo heterocyclyl;

or

R⁹ of R h of¹⁰ together with n, to which they are connected, form optionally substituted 5ili 6 - membered ring.

Compound 1408

Of 2 - (chloromethyl) - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (6 - 1)

Of 2 - amino - 3 - hydro ksipiridin (5.1 g, 46.3 mmol) was heated UP together with etilkhloratsetoatsetatom (6.0 ml, 44.1 mmol) in polyphosphoric acid (60 g) at 110 theoretically for 2 hours. Reaction mixture was, then added to the ice. Then carefully added to the 2ν of NaOH up to pH 4. the obtained precipitate beige color collected by filtration and dried to obtain 2 - (chloromethyl) - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 6 - 1 (4.73 g, 49%) in the form of light - brown solid substance.¹ H NMR (400 MHz, DMSO - Sue) 64.62 (s-, 2 H), 6.43 (s-, 1h), 7.20 (of m, 2H), 8.40 (d of, 4=6, 8 [gts8, 1h).

9 of - hydro xy - 2 - ((izobutilamino) methyl) - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it hydro chloride (6 - 2)

To 2 - (chloromethyl) - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - TOC (6 - 1) (206 mg, 0.978 mmol) in anhydrous meon (5 ml) at 0 theoretically added to isobutylamine (0.5 ml, 5.03 mmol). Mixture then stirring at room temperature for night. Solvent they moved away under vacuum and added to the eyun (5 ml) and concentrated Histidinum (1 ml). Product dropped sediment, and its collected by filtration, washing cold ethanol. Obtained 9 - hydro xy - 2 - ((izobutilamino) methyl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it hydro chloride 6 - 2 allocate in the form of beige solid substance color (82 mg, 30%).¹ H NMR (400 MHz, DMSO) 60.93 (t of, J=7.0 Hz, troublesome zone), 1.64 (of m, 2H), 2.85 (T, 2h), 4.20 (s-, 2h), 6.39 (s-, 2η), 10.2 (brr s-, 1 η), Msh-: m/z 248.1 [M + H]⁺ .

Example 7

7 [i7 8 - substituted alkinililietilpiridopirimidinony7 - 1 and 7 - 3 can be obtained from etinilnogo intermediate compound 4 - 3, shown on the circuit 7. removal of izopropoksiefira concentrated nvg by trichloride or boron results in production of the end compound 7 - 1. Alternatively, 4 - 3 can be subjected to recovery by action of sodium boron hydride in the presence of palladium on carbon to produce ethyl derivative 7 - 2. Removal of protective group, both for 4 - 3, results in production of the end compound 7 - 3 (Circuit 7).

where R is³ is a propyl.

Compound 1620

7 of - ethynyl - 9 - hydro xy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (7 - 1)

7 of - ethynyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it 4 - 3 (150 mg, 0.55 mmole) dissolved in volatile anhydrous ch2ci2 and was to 0 theoretically. To solution by drops added to the boron trichloride (0.85 ml, 0.85 mmol, 1.0 m solution in ch2ci2). Reaction mixture gave heat up to room temperature in 3 h. Reaction quenched with saturated water yansoz and aqueous layer extracted ch2ci2 (^X 3). Combined organic layers washed salt solution, dried above of Na₂S04, filtered and they concentrated to light - yellow solid substance. Solid substance dissolved in volatile meon (10 ml) and they concentrated on rotor evaporator. Method of repeated three times. Prepared residue is then recrystallized from hot ethanol to produce 7 - ethynyl - 9 - hydro xy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one 7 - 1 in the form of white of loose solid substance (32 mg, 25%).¹ H NMR (500 MHz, dmsoo

1η), 7.45 (s-, 1η), 8.20 (s-, 1η), 8.58 (d of, j=1, 5 Hz, 1η), HPLC: /_to=9, 31min (99%), Msh-:

m/z 229.0 [M + H]⁺

Of 7 - ethyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (7 - 2) 7 of - ethynyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it 4 - 3 (135 mg, 0.5 mmole) dissolved in volatile isopropanol (5 ml), to which then added to ason (57 mcl, 1.0 mmole) and 10% of Pd/of c (14 mg). To mixture added to the NaBH₄ (76 mg, 2.0 mmole) with observed vskipaniem, and reaction mixture stirring for 30 minutes. Additionally added to 38 mg NaBH₄ and reaction mixture stirring for 30 minutes. Reaction then quenched 0.1 m Histidinum until boils. Added to saturated aqueous NaHC0₃ to weakly alkaline value and mixture then filtered through a layer of the celite, washing ch2ci2. Aqueous layer extracted ch2ci2 (^X 3). Combined extracts were dried above of Na₂S04, filtered and they concentrated to of producing ethyl derivative 7 - 2 in the form of light - brown oil (130 mg, 95%).¹ H NMR (500 MHz, DMSO - slices) b 0.98 (t of, J=7.5 Hz, troublesome zone), 1.32 (t of, J=7.5 Hz, troublesome zone), 1.52 (d of, j=6, 0 Hz, 6h), 1.69 (sext, J=7.5 Hz, 2H), 2.63 (t of, J=7.5 Hz, 2H), 2.71 (dq, J=7.5, 1.0 Hz, 2H), 4.76 (sept, j=6, 0 Hz, 1H), 6.83 (d of, J= 1.5 Hz, 1H), 8.25 (s-, 1h), 8.52 (of dT, J= 1.5, 1.0 Hz, 1H).

Of 7 - ethyl - 9 - hydro xy - 3 - propyl - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (7 - 3) (1620)

Of 7 - ethyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (7 - 2) (128 mg, 0.47 mmole) dissolved in volatile 48% nvg (3 ml) and then was heated UP to etmperatury reflux for 1 hour. After cooling, reaction mixture podshchelachivali with saturated water yansoz and aqueous layer extracted ch2ci2 (khz). Combined organic layers washed salt solution, dried above na2s0₄ , filtered and they concentrated to 7 - ethyl - 9 - hydro xy - 3 - propyl - 4h - piridio [1, 2 - and] pyrimidine - 4 - one 7 - 3 (101 mg, 93%) in the form of light - green powder.¹ H NMR (500 MHz, DMSO - slices) 61.00 (t of, J=7, 5 [gts5, troublesome zone), 1.31 (t of, J=7, 5 [gts5, troublesome zone), 1.70 (sext, J=7, 5 [gts5, 2h), 2.64 (t of, J=7, 5 [gts5, 2h), 2.71 (of Q, ^=7, 5 [gts5, 2h), 7.02 (d of, j=1, 5 [gts5, 1h), 8.10 (s-, 1h), 8.40 (d of, j=1, 5 [gts5, 1h), HPLC; t of_R=8, 80 min (98.1%), Msh-: m/z 233.0 [M + H]⁺ .

MM

NUCLEAR MAGNETIC RESONANCE

ms

An example 8

Derivatives of 8 - substituted aminometilkarboksamida8 - 1 can be obtained similarly aminometilnym compounds 3 - 1, synthesized by circuit 3. carboxamide 5 - 1 is heated with commercially available aminalom with production of target compounds 8 - 1 (Circuit 8).

where R is⁹ and R¹⁰ independently are selected from C5 - 6 cycloalkyl, CH2 optionally substituted phenyl, with 1.4 alkyl and phenyl, condensed with 5 - containing about chlennymgeterotsiklilom.

Compound 1628

/ In - tsikpogeksil - 8 - ((dimethylamino) methyl) - 9 - hydro xy - 4 - oxo - 4 [ya4 -

pyrido [1, 2 - and] pyrimidine - 3 - carboxamide (8 - 1) (1628)

L / - cyclohexyl - 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide (181 mg, 0.63 mmole) dissolved in volatile toluene (6 ml), then was heated UP with Ν, Ν, Ν, Νtetrametilmetilendiaminom (500 mcl, 3.67 mmol) at 85 theoretically for 3 hours. Obtained yellow precipitate collected by filtration after cooling. A crude product washed toluene to produce carboxamide 8 - 1 in the form of yellow solid substance (173 mg, 80%).¹ H NMR (500 MHz, DMSO - slices) B 1.37 (of m, 5h), 1.39 (T, 1h), 1.66 (t, 2H), 1.87 (T, 2h), 2.35 (s-, 6h), 3.72 (s-, 2h), 3.86 (t, 1H), 7.45 (d of, 4=7.0 Hz, 1H), 8.61 (d of, 4=7,0 Hz, 1H), 8.97 (s-, 1h), 9.04 (d of, 4=8,0 Hz, 1H), HPLC: of f_R=8, 60 min (97.8%), ms: m/z 345.2 [M + H]⁺ .

Example 9 and

Derivatives of 8 - substituted arili heteroaryl - 3 - carboxamide can be obtained according to scheme 9a. Carboxamide 9 - 1 can be iodirovaniyu in orthoposition to produce intermediate product 9 - 2, which is then protected to yield compound 9 - 3. Reaction conditions combination Suzuki then is used for preparing aryl or heteroaryl compounds 9 - 4. Finally, removal of protection results in production of the desired compounds 9 - 5.

where R is⁷ represents optionally substituted 5 - members of n-containing heterocyclyl or optionally substituted phenyl; R of⁹ is a butyl.

Rv1657/in - butyl - 9 - hydro xy - 8 - iodine - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3karboksamid 9 - 2

To solution of l / - butyl - 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide (80 mg, 0.31 mmol) in eyun (5 ml) added to the iodine (90 mg, 0.34 mmol) followed by addition of 30% aqueous solution of hydrogen peroxide (34 mcl). Reaction mixture left to get mixed at room temperature for 3 days, during which l / - butyl - 9 - hydro xy - 8 - iodine - 4 - oxo - 4 / - / pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 9 - 2 they separated by precipitation from solution and collected by filtration (71 mg, yield 60%).¹ H NMR (400 MHz, DMSO - slices) b 0.91 (t of, J=7.0 Hz, troublesome zone), 1.35 (of m, 2h), 1.49 (T, 2h), 3.2 (T, 2h, coated solvent), 7.81 (d of, j=8, 0 Hz, 1H), 8.40 (d of, j=8, 0 Hz, 1H), 8.96 (brr s-, 1h), 8.98 (s-, 1h).

/ In - butyl - 9 - isopropoxy - 8 - iodine - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 9 - 3

L / - butyl - 9 - hydro xy - 8 - iodine - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 9 - 2 (1.49 g, 38.5 mmol) dissolved in volatile dimethylformamide (50 ml) and treated to₂ C0₃ (2.12 g, 154 mmol), and then 2 - brompropanom (5 ml). Reaction mixture was heated UP to 50 theoretically for 17 hours, was and they concentrated to dryness. Residue dissolved in volatile EtOAc and n₂ 0 and aqueous layer extracted EtOAc (χ2). Combined organic layers washed H₂ 0, salt solution, dried above yagesy, filtered and they concentrated to l / - butyl - 9 - isopropoxy - 8 - iodine - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 9 - 3 (1.41 g, yield 85%).¹ H NMR (400 MHz, CDCI₃ ) of Δ 0, 98 (t of, 4=7,6 Hz, troublesome zone), 1.44 (of m, 9η), 1.62 (of m, 2η), 3.49 (of m, 2η), 5.44 (of m, 1η), 7.63 (d of, 4=7,6 Hz, 1η), 8.63 (d of, 4=7,6 Hz, 1η), 8.95 (brr s-, 1η), 9.28 (s-, 1η).

/ In - butyl - 8 - (3.5 - dimethyl isoxazole - 4 - yl) - 9 - isopropoxy - 4 - oxo - 4 [ya4 -

pyrido [1, 2 - and] pyrimidine - 3 - carboxamide (9 - 4)

Solution l / - butyl - 9 - isopropoxy - 8 - iodine - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 9 - 3 (235 mg, 0.607 mmol), to₂ CS (1.21 ml, 2.42 mmol, 2M aqueous solution), 3.5 - dimethylisoxazol complex pinakolovogo ester (176 mg, 0.789 mmole), of Pd (cooling systems₃ )₄ (59 mg, 0.051 mmol) in anhydrous dimethylformamide (10 ml) degassed in argon atmosphere (χ3), then was heated UP to 100 theoretically for 4 hours. After cooling reaction mixture diluted H₂ 0 (20 ml)/eyuas (30 ml). Aqueous layer extracted eyuas (* 2). Combined organic layers washed H₂ 0, salt solution, dried above of Na₂S04, filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 30 - 40% eyuas/hexane to l / - butyl - 8 - (3.5 - dimethylisoxazol - 4 - yl) - 9 - isopropoxy - 4 - oxo - 4 / - / - pyrido [1, 2 -

and] pyrimidine - 3 - carboxamide 9 - 4 (119 mg, 54%) in the form of almost white solid substance.¹ H NMR (400 MHz, DMSO - slices), 0.97 (t of, 4=7,2 Hz, troublesome zone), 1.21 (d of, 4=6,4 Hz, 6h), 1.44 (sext, 4=7,2 Hz, 2H), 1.66 (quin, 4=7,2 Hz, 2H), (2.30 (s-, 3η), 2.43 (s-, troublesome zone), (3.50 (of Q, 4=7,2 Hz, 6.0 Hz, 2H), 4.94 (sept, 4=6,0 Hz, 1H), 7.15 (d of, 4=7,2 Hz, 1H), 8.97 (brr t of, 4=6,0 Hz, 1H), 9.01 (d of, 4=7,2 Hz, 1H), 9.38 (s-, 1h).

/ In - butyl - 8 - (3.5 - dimethyl isoxazole - 4 - yl) - 9 - hydro xy - 4 - oxo - 4h -

pyrido [1, 2 - and] pyrimidine - 3 - carboxamide (9 - 5) (rv1657)

L / - butyl - 8 - (3.5 - dimethylisoxazol - 4 - yl) - 9 - isopropoxy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide (9 - 4) (110 mg, 0.276 mmol) was heated UP to temperature reflux in 48% aqueous nvg (3 ml) for 2 hours. Reaction mixture was, then quenched with saturated water solution of yansoz. Compound extracted CH₂ C1₂ (* 3) and they concentrated to l / - butyl - 8 - (3.5 - dimethylisoxazol - 4 - yl) - 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 -

carboxamide (9 - 5) (RV1657).¹ H NMR (400 MHz, CDCI₃ ) b 0.93 (t of, 4=7,6 Hz, troublesome zone), 1.37 (sext, 4=7,6 Hz, 2H), 1.51 (quin, 4=7,6 Hz, 2H), 3.37 (of Q, 4=6,8 Hz, 2H), 7.49 (d of, 4=6,8 Hz, 1H), 8.69 (d of, 4=6,8 Hz, 1H), 8.90 (t of, 4=6,8 Hz, 1H), 9.03 (s-, 1h), mass spectrum: m/z 357.1187 [M + H]⁺ .

Example 9 mpile

Compounds, containing alkyl chain of three carbon atoms or more in position 9, can be obtained according to scheme 9 [9 []. The attempt reaction combination hake compounds 2 - 2 with vinyl acid unexpectedly led to formation of dekarboksilirovannogo product 9 - 1. Selective reduction of alkene drug production of compounds 9 - 2. Removal of isopropyl ester with application of nvg drug to production of the end compound 9 - 3

Compound 1605

9 of - isopropoxy - 3 - isopropyl - 8 - (prop - 1 - enyl) - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (9 - 1)

8iod - 9 - isopropoxy - 3 - isopropyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 2 - 2 (195 mg, 0.524 mmol) dissolved in volatile anhydrous dimethylformamide (10 ml) and then degassed in argon atmosphere (khz). Added to the triphenylphosphine (14 mg, 0.053 mmol), of Pd (OAc) 2 (35 mg, 0.0524 mmol) and viniluksusnuyu acid (1.0 ml, 11.5 mmol), and then was carried out one more round degassing. Then the reaction mixture was heated UP to 100 theoretically for 4 h. Reaction mixture was and then were distributed between eyuas/H₂ 0. aqueous layer additionally three times extracted EtOAc. Combined organic extracts then dried above of Na₂S04, filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 10% eyuas/petroleum ether 40 - 60 theoretically to 9 - isopropoxy - 3 - isopropyl - 8 - (prop - 1 - enyl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one 9 - 1 in the form of yellow oil (147 mg, 85%).¹ H NMR (500 MHz, CDCI₃ ) b 1.30 (d of, 4=7,0 Hz, 1H), 1.36 (d of, 4=6,5 Hz, 1H), 2.01 (d of, 4=6,5 Hz, troublesome zone), 3.24 (T, 1h), 5.05 (sept, 4=6,5 Hz, 1H), 6.49 (dq, 4=16,0, 6.5 Hz, 1H), 6.90 (Dd1, 4=16,0, 1.5 Hz, 1H), 7.17 (d of, 4=7,5 Hz, 1H), 8.21 (s-, 1h), 8.73 (d of, 4=7,5 Hz, 1H).

9izopropoksi - 3 - isopropyl - 8 - propyl - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (9 - 2)

9 of - isopropoxy - 3 - isopropyl - 8 - (prop - 1 - enyl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it (9 - 1) (540 mg, 1.87 mmol) dissolved in volatile meon (20 ml), was to 0 theoretically, then treated 5 portions of sodium boron hydride (500 mg, 13.5 mmol) for 5 hours. Reaction mixture left to get mixed for 2 days, then they concentrated. Residue dissolved in volatile Ngo and ch2ci2. Aqueous layer then extracted ch2ci2 (^X 3) and organic layer dried above of Na₂ S0₄ , filtered and they concentrated to the main product, 9 - isopropoxy - 3 - isopropyl - 8 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one (9 - 2) in the form of oil (410 mg, 75%).¹ H NMR of Δ 0.99 (t of, J=7.0 Hz, troublesome zone), 1.32 (d of, J=6.5 Hz, 6h), 1.35 (d of, J=6.5 Hz, 6h), 1.66 (t, 2H), 2.74 (t of, J=7.0 Hz, 2H), 3.25 (sept, J=6.5 Hz, 1H), 5.13 (sept, J=6.5 Hz, 1H), 6.94 (d of, J=7.5 Hz, 1H), 8.22 (s-, 1h), 8.77 (of d, j=7, 5 Hz, 1H).

Compounds, containing 2 - substituted alkiloksimetilnye group, can be obtained in accordance with the 10. Intermediate khlormetilnoe compound 6 - 1 is heated together with appropriate alcohol in the presence of NaOH with formation of desired ether product 10 - 1 (Circuit 10).

about about

6 - 1

Circuit 10

where

R⁶ represents H or Cl; and

R¹⁴ represents a C1 - 3 alkyl

Of 2 - (ethoxymethyl) - 9 - hydro xy - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (10 - 1)

Khlormetilnoe compound 6 - 1 (231 mg, 1.09 mmol) dissolved in volatile eyun (17 ml), then treated with aqueous solution of NaOH (5 ml, 6.25 mmol, 1.25 m). Then the reaction mixture was heated UP to 70 theoretically during night time. Reaction mixture was and filtered, to remove insoluble material. They concentrated filtrate to 7 ml and obtained orange solution extracted ether (15 ml). Then aqueous layer acidified up to pH 2 concentrated Histidinum (1 ml). Aqueous layer then extracted ch2ci2 (^X 3) and organic layers dried above Na2S04, filtered and they concentrated to produce orange oil. Addition of 20% eyuas/petroleum ether 40 - 60 theoretically (10 ml) gave almost white solid substance 10 - 1, which collected by filtration (45 mg, yield 19%).¹ H NMR (500 MHz, CDCI3) of Δ 1.21 (t of, J=9.0 Hz, troublesome zone), 3.59 (of Q, J=9.0 Hz, 2H), 4.47 (s-, 2h), 6.37 (s-, 1η), 7.20 (m, 2H), 8.46 (d of, J=9.0 Hz, 1H), HPLC: of f_R=6, 2lmhh (98.3%), ms: m/z 221.1 [M + H]⁺ .

1705 ABOUT 240.6 ¹ H NMR (400 MHz, DMSO - m/z^S ' Chemoluminescence the JL 2h), 6.61 (s-, 1H), 7.15 (d of, d6) 5 3.51 (s-, troublesome zone), 4.46 (s-, J= 2.0 Hz, 1H), 8.58 (d of, J= 2.0 241.1 [M + H]⁺

- [o x - about/Hz, 1H)

Example 11

Compounds, containing alkoksimetilnuyu group in position 3, can be obtained from ester 5 - 2. Conversion of phenol in gasoline ether 11 - 1 followed by restoration of diisobutylaluminum hydride (DIBAL) gives alcohol 11 - 2. Then alcohol introducing in reaction with thionyl chloride with formation of intermediate alkilkhlorida. Chloride displacement alcohol gives alkoksimetilnoe compound 11 - 3. Splitting of ether provides the target compound alkoksimetilnoe11 - 4. Similarly, compounds, containing and alkilaminometilnuyu group in position 3, can be obtained similar manner. Alcohol 11 - 2 converted into alkilaminometilnoe compound 11 - 5 through khloridnoe intermediate compound. Substitution of amine gives desired alkilaminometilnyi product 11 - 5. Removal of protective group gives target compounds of 11 - 6 (circuit 11).

Compound 1424 ethyl - 9 - (benzyloxy) - 4 - oxo - 4h - pyrido [1, 2 - and] pyrimidine - 3 - carboxylate (11 - 1)

Ethyl - 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxylate (7.5 g, 32.0 mmol) dissolved in volatile dimethylformamide (150 ml), then treated to₂ C0₃ (6.63 g, 48 mmol), then benzyl bromide (8.0 ml, 67.3 mmol). Reaction mixture stirring in nitrogen atmosphere for 3 days. To reaction mixture added to the H₂ 0 (50 ml) and produced tan - brown solid collected by filtration, washed H₂ 0 (khz), then gasoline (* 3) to produce (7.78 g, 75%) ethyl - 9 - (benzyloxy) - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxylate (11 - 1) in the form of tan - brown solid substance.¹ H NMR (400 MHz, DMSO - slices) B 1.28 (t of, 4=7,2 Hz, troublesome zone), 4.26 (of Q, 4=7, 2η, 2η), 5.31 (s-, 2η), 7.43 (of m, 5η), 7.50 (t of, 4=6,8 Hz, 1η), 7.72 (d of, 4=6,8 Hz, 1η), 8.76 (d of, 4=6,8 Hz, 1η), 8.82 (s-, 1η).

9 of - (benzyloxy) - 3 - (methyl hydro) - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (11 - 2) Ethyl - 9 - (benzyloxy) - 4 - oxo - 4h - pyrido [1, 2 - and] pyrimidine - 3 - carboxylate (11 1) (1.54 g, 4.75 mmol) dissolved in volatile anhydrous 1:1 CH₂ C1₂/ anhydrous ether (60 ml) and was to -10 theoretically on bath with ice/salt. Solution DIBAL H (11.0 ml, 11 mmol, 1.0 m in hexane) added to by drops for 15 minutes. Obtained light - yellow solution stirring in an argon atmosphere for 2 hours. Additionally added to 1.0 ml above said solution DIBAL-h-and reaction mixture left heated to room temperature during night time. Reaction mixture was to 0 theoretically and carefully quenched 10% solution of k/of Na⁺ tartrate. Stirring at room temperature for 2 hours, then the suspension extracted CH₂ C1₂ (* 4). Combined organic layers washed salt solution, dried above MgS04, filtered and they concentrated to produce alcohol 11 - 2 in the form of oil (712 mg, 53%).¹ H NMR (400 MHz, dmsod6) of Δ 4.44 (d of, 4=6,0 Hz, 2H), 7.21 (t of, 4=7,2 Hz, 1H), 7.41 (of m, 5h), 7.57 (d of, 4=7,2 Hz, 1H), 8.36 (s-, 1h), 8.58 (d of, 4=7,2 Hz, 1H).

9 of - (benzyloxy) - 3 - (methoxymethyl) - 4 [ya4 - pyrido [1, 2 - and] - 4 - it (11 - 3)

Alcohol 11 - 2 (317 mg, 1.13 mmole) dissolved in volatile anhydrous CH₂ C1₂ (7 ml) and was to 0 theoretically. Added to by drops thionyl chloride (0.5 ml) and reaction mixture stirring for 1.5 hours, then they concentrated to chloride with quantitative yield. Crude chloride suspended in anhydrous CH₂ C1₂ (10 ml), was to 0 theoretically, then treated methanolic solution of dimethylamine (1.5 ml, 3.0 mmol, 2.0 m). Reaction mixture was heated UP to room temperature and stirring for 3 days. Volatile compounds they moved away under vacuum and crude product they cleaned flash - chromatography, elyuiruya mixture 90% eyuas/petroleum ether 40 - 60 theoretically to unreacted initial material. Further elution of 10% MeOH/CH-₂ Cl2 ensuring metoksimetilnoe compound 11 - 3 (115 mg, yield 34%) in the form of yellow oil.¹ H NMR (400 MHz, DMSO - the station of the) of Δ 3.21 (s-, troublesome zone), 4.38 (s-, 2h), 5.25 (s-, 2h), 7.29 (t of, 4=7,2 Hz, 1H), 7.39 (of m, 5h), 7.56 (d of, 4=7,2 Hz, 1H), 8.30 (s-, 1h), 8.49 (d of, 4=7,2 Hz, 1H).

9 of - hydro xy - 3 - (methoxymethyl) - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (11 - 4) (1398)

9 of - (benzyloxy) - 3 - (methoxymethyl) - 4 / - / - pyrido [1, 2 - and] - 4 - it 11 - 3 (112 mg, 0.362 mmole) in anhydrous ch2ci2 (7 ml) was to 0 theoretically, then treated by tribromide boron (180 mcl, 1.86 mmol). Reaction mixture was heated UP to room temperature and then stirring for 18 hours. Reaction mixture was to 5 theoretically, then carefully quenched meon (15 ml). Reaction mixture stirring at room temperature for 30 minutes, then meon they moved away under vacuum. Method of repeated (khz) and compound dried in high vacuum. Residue then treated meon (1 ml) and ether (20 ml) to falling out in precipitate brown powder after of ultrasound treatment. Product collected by filtration, washing three times ether to 9 - hydro xy - 3 (methoxymethyl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one 11 - 4 in the form of brown solid substance (28 mg, 38%).¹ H NMR (400 MHz, DMSO - slices) of Δ 3.29 (s-, troublesome zone), 4.36 (s-, 2h), 7.46 (t of, 4=7,2 Hz, 1H), 7.54 (d of, 4=7,2 Hz, 1H), 8.22 (s-, 1h), 8.59 (d of, 4=7,2 Hz, 1H), HPLC: t of_R =2.31 min (98.1%), ms: m/z 207.0 [M + H]⁺ .

Alcohol 11 - 2 (317 mg, 1.13 mmole) dissolved in volatile anhydrous ch2ci2 (7 ml) and was to 0 theoretically. Added to by drops thionyl chloride (0.5 ml) and reaction mixture stirring for 1.5 hours, then they concentrated, to produce chloride with quantitative yield. Khloridnoe intermediate compound (344 mg, 1.14 mmole) dissolved in volatile anhydrous ch2ci2 (10 ml) and was to 0 theoretically. Added to the hydro chloride dimethylamine (512 mg, 6.28 mmol), then diizopropilmetilamin (DIEA) (1.10 ml, 6.28 mmol) and prepared oranzhevokrasnyi solution was heated UP to room temperature during night time. Volatile substances they moved away under vacuum, then treated ch2ci2 and saturated yansoz. Aqueous layer extracted ch2ci2 (^X 2) and combined organic extracts dried above Na2S04, filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 5% MeOH/CH-₂ Cl2. Then product converted into the salt of hydrogen chloride. Residue stirring in concentrated Histidinum (2 ml) for 30 minutes, then solvent they moved away under vacuum. Allocate white solid substance and washed meon (2 ml)/ether (15 ml). Further washing ether led to formation of salt 9 - benzyloxy - 3 ((dimethylamino) methyl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it Histidinum 11 - 5 in the form of white powder (104 mg, 29%).¹ H NMR (400 MHz, DMSO - slices) of Δ 2.77 (s-, troublesome zone), 2.79 (s-, troublesome zone), 4.25 (d of, j=6, 0 Hz, 2H), 5.36 (s-, 2h), 7.42 (of m, 5h), 7.55 (d of, j=6, 8 Hz, 1H), 7.44 (d of, j=6, 8 Hz, 1H), 7.66 (d of, j=6, 8 Hz, 1H), 8.37 (s-, 1h), 8.68 (d of, j=6, 8 Hz, 1H), 10.29 (brr s-, 1h).

Of 3 - ((dimethylamino) methyl) - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it hydro chloride (11 - 6) (1424)

9 of - benzyloxy - 3 - ((dimethylamino) methyl) - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it

HISTIDINUM 11 - 5 dissolved in volatile meon (8 ml). Then added to 10% Pd on carbon (13 mg) in argon atmosphere. Bulb benefit three times, then reburied under balloon with hydrogen. Reaction mixture stirring at room temperature for 4 hours, then filtered and they concentrated to 3 - ((dimethylamino) methyl) - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - one

hydro chloride 11 - 6, solid substance pale - yellow (30 mg, yield 37%).¹ H NMR (400 MHz, d of₂ 0) 63.01 (s-, 6η), 4.48 (s-, 2η), 7.73 (t of, J= 6.8 Hz, 1η), 7.88 (d of, J=6.8 Hz, 1η), 8.84 (s-, 1η), 8.84 (d of, j=6, 8 Hz, 1η). HPLC: of f_R=1, 74 min (100%), Msh-:

m/z 220.1 [M + H]⁺

Compounds, containing S-S metilenditiokarbamatnuyu group 12 - 2, can be obtained by reacting intermediate compound 6 - 1 with carbon disulfide and corresponding way substituted amine in tetrahydrofurane (circuit 12).

R⁶ is a Cl;

R⁹ and R¹⁰ are independently chosen from H, C1 - 2 alkyl and CH2 pyridine; or

R⁹ and R¹⁰ together with n, to which they are connected, form optionally substituted 6 - membered ring, optionally containing n-.

Compound 1713

Of 7 - chloro - 2 - (chloromethyl) - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (12 - 2)

of 5 - chloro - 2 - aminopiridinol12 - 1 (4.3 g, 29.7 mmol), 4 - khloratsetoatsetat (8.5 ml) was heated UP together in polyphosphoric acid (20 ml) at 110 theoretically for 2.5 hours. Reaction mixture was, added to the cleaving ice (30 g) and pH value mixture space to 5 by adding 2ν of NaOH. Chlorid brown precipitate, which collected by filtration, washed H₂ 0 the, until washing not becoming colourless. Product dried to produce khlormetilnogo derivative in the form of brown powder (7.27 g, 100%).¹ H NMR (500 MHz, DMSO - slices) B 4.67 (s-, 2h), 6.59 (s-, 1H), 7.27 (d of, J=2.0 Hz, 1H), 8.46 (d of, J=2.0 Hz, 1H).

(7 - chloro - 9 - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 2 -

dwg)-methylmorpholine-- 4 - dithio (12 - 3) (1713)

of 7 - chloro - 2 - (chloromethyl) - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it (12 - 1) (235 mg, 0.96 mmol) dissolved in volatile tetrahydrofurane (4 ml), then added to the carbon disulfide (65 mcl) at 0 theoretically followed by addition of morpholine (175 mcl). Reaction mixture stirring at 0 theoretically for 30 minutes, then left heated to room temperature in 18 hours. Reaction quenched addition of H₂ 0 (2 ml). After stirring for 2 hours at room temperature chlorid cungus precipitate, which collected by filtration.¹ H NMR (400 MHz, DMSO - slices) of Δ 3.67 (of m, 4h), 3.97 (T, 2h), 4.23 (T, 2H), 4.59 (s-, 2h), 6.50 (s-, 1η), 7.23 (d of, J=2.0 Hz, 1η), 8.41 (d of, J=2.0 Hz, 1η), Msh-(ier + the VE): m/z 371.9 [M + H]⁺

1713

Example 13

Derivatives of atsilgidrazina and atsilgidrazida can be obtained from ester intermediate compound 11 - 1 (Circuit 11) by heating with aqueous solution of hydrazine hydrate in ethanol to yield compound 13 - 1. Hydrazine 13 - 1 interacts with commercially available aldehydes to produce hydrazide 13 - 2 (circuit 13).

R⁹ represents optionally substituted imidazolyl.

Compound 1723 9 - benzyloxy - lh ' - 2 - (hydro ksibenziliden) - 4 - oxo - 4 - I - pyrido [1, 2a] pyrimidine - 3 - carbohydrazide (13 - 2) (1723)

9 of - (benzyloxy) - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pirimidinin - 3 - carbohydrazide (13 - 1) (80 mg, 0.258 mmol), salitsilaldegid (50 mg, 0.41 mmol) was heated UP to temperature reflux in eyun (12 ml) for 4 hours. Obtained cream precipitate. After the reaction mixture ostyvala, obtained 9 - benzyloxy - l /" - 2 - (hydro ksibenziliden) - 4 - oxo - 4 - / - / - pyrido [1, 2 - and] pyrimidine - 3 - carbohydrazide (13 - 2) (80 mg, 75%) collected by filtration.¹ H - NMR (400 MHz, DMSO - slices) B 5.32 (s-, 2h), 6.89 (of m, 2H), 7.27 (t of, 4=8,0 Hz, 1H), 7.37 (T, 4h), 7.52 (T, troublesome zone), 7.74 (d of, 4=8,0 Hz, 1H), 8.68 (s-, 1h), 8.80 (d of, 4=7,2 Hz, 1H), 9.03 (s-, 1h), 11.25 (brr s-, 1h), 12.1 (brr s-, 1h), ms (ier + the VE): m/z 415.2 [M + H]⁺ .

Example 14

Derivatives of 2 - methyl-substituted pyridopyrimidine be synthesized by reacting 2 - amino - 3 - piridinolov14 - 1 with commercially available ethyl (atsetoatsetatami) 14 - 2 with formation of 2 - substituted piridopirimidinovoi ring system 14 - 3.Regioselektivnoeiodirovanie to provide for 14 - 4 was achieved action of iodine and hydrogen peroxide. Reaction combination Suzuki can be with of Pd (PPh3) 4 as catalyst and commercially available boron acids of R⁷ B of (OH of) 2 or boronatnymi esters of R⁷ B OF (OR-⁵ ) 2 to produce aryl and heteroaryl compounds 14 - 5 (Circuit 14).

where R is³ is a with - m alkyl or benzyl;

R⁶ represents H or Cl; and

R⁷ represents H, 1, pyridinyl optionally substituted pyrazolyl or optionally substituted isoxazolyl.

of 3 - butyl - 7 - chloro - 9 - hydro xy - 2 - methyl - 4 [ya4 [1, 2 - and] pyrimidine - 4 - it (14 - 3) (1667)

of 2 - amino - 5 - khlorpiridinol (2.0 g, 14 mmol), ethyl - 2 - butilatsetoatsetat (3.87 g, 20 mmol) and polyphosphoric acid (25 g) was heated UP together at 110 theoretically for 4 hours. After cooling added to the Ngo and pH value space to 4 by means of 2ν of NaOH. Formed yellow precipitate collected by filtration, washed H₂ 0, then ether and then dried to produce 3 - butyl - 7 - chloro - 9 - hydro xy - 2 [metil2 - 4 / - / [1, 2 - and] pyrimidine - 4 - one RV1667 (2.54 g, 69%) in the form of yellow powder.¹ H NMR (500 MHz, DMSO - Sue) 60.94 (t of, 4=7,5 Hz, 2H), 1.42 (of m, 2h), 1.52 (T, 2h), 2.48 (s-, troublesome zone), 2.67 (t of, 4=7,4 Hz, 2H), 7.01 (s-, 1h), 8.48 (s-, 1h), ms: m/z 267.1 [M + H]⁺ .

of 3 - butyl - 7 - chloro - 9 - hydro xy - 8 - iodine - 2 - methyl - 4 [ya4 [1, 2 - and] pyrimidine - 4 - it (14 - 4) (1688)

To solution of 3 - butyl - 7 - chloro - 9 - hydro xy - 2 - methyl - 4 / - / [1, 2 - and] pyrimidine - 4 - one (14 - 3) (900 mg, 3.4 mmol) in eyun (35 ml) added to the iodine (940 mg, 3.7 mmol) followed by addition of by drops 30% aqueous hydrogen peroxide (380 mcl). Reaction mixture stirring during night time at room temperature and the precipitate formed is filtered, washing eyun (3x5 ml) to produce 3butil - 7 - chloro - 9 - hydro xy - 8 - iodine - 2 - methyl - 4 / - / [1, 2 - and] pyrimidine - 4 - one (14 - 4) RV1688 in the form of yellow powder (955 mg, yield 72%).¹ H NMR (500 MHz, DMSO - slices) of Δ 0.90 (t of, 4=7,0 Hz, troublesome zone), 1.33 (of m, 2H), 1.43 (T, 2h), 2.53 (s-, troublesome zone), 2.55 (s-, 2h), 8.31 (s-, 1h).

of 3 - butyl - 7 - chloro - 9 - isopropoxy - 8 - iodine - 2 - methyl - 4 [ya4 [1, 2 - and] pyrimidine - 4 - it (14 - 5) (1689)

To stirred solution of 3 - butyl - 7 - chloro - 9 - hydro xy - 8 - iodine - 2 - methyl -4H [THE \, 2 - and] pyrimidine - 4 - one 14 - 4 (955 mg, 2.40 mmol) in dimethylformamide (12 ml) added to the to₂ CS (1.35 g, 9.7 mmol), then 2 - brominepropane (700 mcl, 7.5 mmole) and reaction mixture stirring at 50 theoretically for 6 days. Reaction mixture diluted H₂ 0 and EtOAc and aqueous layer additionally extracted EtOAc (χ2). Obtained organic layers washed H₂ 0, salt solution, dried above of Na₂S04, filtered and they concentrated to produce 3 - butyl - 7 - chloro - 9 - isopropoxy - 8 - iodine - 2 - methyl - 4 / - / [1, 2 - and] pyrimidine - 4 - one (14 - 5) 1689 in the form of yellow solid substance (611 mg, yield 59%).¹ H NMR (500 MHz, d of 6 - DMSO) of Δ 0.97 (t of, 4=7,0 Hz, troublesome zone), 2.38 (of m, 8h), 1.42 (T, 2h), 2.41 (s-, troublesome zone), 2.58 (T, 2h), 5.39 (T, 1h), 8.67 (s-, 1h), ms: m/z 435.0 [M + H]⁺ .

of 3 - butyl - 7 - chloro - 9 - isopropoxy - 2 - methyl (pyridine - 4 - yl) - 4h - [1, 2 -

and] pyrimidine - 4 - it (14 - 6)

of 3 - butyl - 7 - chloro - 9 - isopropoxy - 8 - iodine - 2 - methyl - 4h [1, 2 - and] pyrimidine - 4 - it 14 - 5 (300 mg, 0.69 mmole) dissolved in volatile dimethylformamide (15 ml) and 2M to₂ CS (1.4 ml) in flask shlenka. Solution degassed and filled with argon (χ2). Then to reaction added to the 4 - piridinilboronovuyu acid (130 mg, 1.03 mmol) and cryogenic stage (rriz) 4 (55 mg, 7 mole %) and in this moment bulb degassed additionally more 5 times. Reaction flask was heated UP to 95 theoretically during night time. After cooling, volatile compounds they moved away at spider nnom pressure. Residue then diluted H₂ 0 (20 ml) and extracted eyuas (3x10 ml). Combined organic layers washed H₂ 0 (2x10 ml), dried of Na₂S04, filtered and they concentrated to produce crude 3 - butyl - 7 - chloro - 9 - isopropoxy - 2 - methyl (pyridine - 4 - yl) - 4 / - / [1, 2 - and] pyrimidine - 4 - one (14 - 6) in the form of brown oil (284 mg). Compound weathered the next stage without purification.

of 3 - butyl - 7 - chloro - 9 - hydro xy - 2 - methyl (pyridine - 4 - yl) - 4 [ya4 [1, 2 - and] pyrimidine - 4 - it (14 - 7) (1690)

of 3 - butyl - 7 - chloro - 9 - isopropoxy - 2 - methyl (pyridine - 4 - yl) - 4 / - / [1, 2 - and] pyrimidine - 4 - it (14 - 6) (284 mg, 0.74 mmol) dissolved in volatile anhydrous CH₂ C1₂ (5 ml), cooled to -10 theoretically, then added to the 1.0 M solution of boron trichloride in CH₂ C1₂ (5.2 ml, 5.2 mmol). After mixing for 5 minutes reaction mixture was heated UP to room temperature during night time. To reaction mixture carefully added to the methanol, and then they concentrated under vacuum. This procedure is repeated five times, then residue treated ultrasound only with eyun, to produce 3 - butyl - 7 - chloro - 9 - hydro xy - 2 - methyl (pyridine - 4 - yl) - 4 / - / [1, 2 - and] pyrimidine - 4 - it (14 - 7) RV1690 in the form of solid substance color, which collected by filtration (116 mg, yield 46%).¹ H NMR (500 MHz, dmsod6) 60.91 (t of, 4=7,0 Hz, troublesome zone), 1.35 (of m, 2η), 1.47 (of m, 2η), 2.58 (s-, 3η), 2.60 (of m, 2η), 8.17 (s-, 1η), 8.23 (s-, 1η), 9.34 (brr s-, 1η), Msh-: m/z 344.1 [m + h]⁺ .

Example 15

Of 7 - substituted sulfonamide can be obtained from pyridopyrimidines 15 - 1.Regioselektivnoe support grate/TiO2 - directed nitrovanie phenol with followed by reduction to aniline 15 - 3 is achieved by means of sodium dithionite. Interaction of aniline with sulfonilkhloridom results in production of the target sulfonamide 15 - 4.

To being mixed suspension nitrocompound (15 - 2) (0.77 g, 3.50 mmol) in mixture of methanol and water 1:1 (by 12 ml of each) added to the sodium dithionite (3.24 g, 18.6 mmol) and mixture of stirring in nitrogen atmosphere for 17 hours. Larger part of methanol they moved away at spider nnom pressure up to the, as precipitate filtered and washed water (* 3) and then dried in air. Desired product 8 - amino - 9 - hydro xy - 3 - isopropyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it (15 - 3) allocate in the form of yellow solid substance (0.46 g, 60%).¹ H NMR (400 MHz, DMSO De) 61.25 (s-, troublesome zone), 1.27 (s-, troublesome zone), 3.13 (T, 4=6,8 Hz, 1H), 5.82 (of BS, 2h), 6.88 (d of, J= 7.6 Hz, 1H), 7.98 (s-, 1H), 8.45 (d of, J= 7.6 Hz, 1H).

Of 4 - chloro - m - (9 - hydro xy - 3 - isopropyl - 4 - oxo - 4h - pyrido [1, 2 - and] pyrimidine -8- dwg) benzenesulfoneamide 15 - 4 (1717)

Reaction was carried out in accordance with the common method, described above, with use of amine (50 mg, 0.23 mmol) and 4 - khlorbenzolsulfonilkhlorida (60 mg, 0.30 mmole). Concentration gave brown resin, which treated ultrasound in water, filtered, washed with water and then dried in air. Of 4 - chloro - s - (9 - hydro xy - 3 - isopropyl - 4 - oxo - 4h - pyrido [1, 2 - and] pyrimidine - 8 -

dwg) benzenesulfoneamide obtained in the form of tan - brown solid substance (38.4 mg, 51%).¹ H NMR (500 MHz, DMSO De) 6 1.13 (s-, troublesome zone), 1.15 (s-, troublesome zone), 2.98 (T, 1H), 6.84 (d of, J= 8.0 Hz, 1H), 6.97 (of BS, 1H), 7.62 (s-, 1h), 7.67 (d of, J= 9.0 Hz, 2H), 7.99 (d of, J= 9.0 Hz, 2H), 8.58 (d of, J= 8.0 Hz, 1H), ms (ier) t/T. 394.0621 [M + H]⁺ , HPLC (254 nm): t of_R = 10.86 (82%).

Example 16

Circuit 16

Condensed oxazol (16 - 1) (1708)

Circuit 17 9 - hydro xy - 3 - isopropyl - 8 - (4 - methoxybenzylamino) - 4h - pyrido [1, 2 -

and] pyrimidine - 4 - it (17 - 1) (1716)

Potassium carbonate (40 mg, 0.31 mmol) to added to the stirred solution of 4 - metoksibenzilkhlorida (40 mg, 0.25 mmol) and aniline 15 - 3 (50 mg, 0.23 mmol) in dimethylformamide (1 ml) and was heated UP at 90 theoretically for 17 hours. Reaction mixture they concentrated, to produce dark - brown resin, which diluted with ethyl acetate and washed with water (5 ml) and with salt solution (5 ml), and then dried (na2s04). Concentration at spider nnom pressure gave brown resin, which they cleaned flash - chromatography on silica gel (5 g), elyuiruya 4% solution of methanol in dichloromethane (400 ml). Allocate yellow resin and identified it as a 9 - hydro xy - 3 - isopropyl - 8 - (4 - methoxybenzylamino) - 4npirido [1, 2 - and] pyrimidine - 4 - it (17 - 1) 1716 (20 mg, 25%).¹ H NMR (400 MHz, DMSO - B₆ )

Metal complexes copper and zinc different compounds 9 - hydro ksipiridopirimidina can be obtained by mixing solution pyridopyrimidine in solvent together with copper chloride (of II) or zinc (of II). Obtained precipitate is filtered off and dried, to obtain desired complexes.

Zinc complex 9 - hydro xy - 3 - propyl - 4h - pyridine [1, 2 - and] pyrimidine - 4 - one (1678)

To stirred solution of 9 - hydro xy - 3 - propyl - 4 / - / - pyridine [1, 2 - and] pyrimidine - 4 - one (150 mg, 0.75 mmol) in eyun (75 ml) solution is added to the zinc chloride (of II) (100 mg, 0.75 mmol) in Ngo (36 ml). Through 10 min sedimentation, which they moved away by filtration. Mother liquors left to stand during night time, during this period small white crystals ornaments precipitate from solution. After holding for more 7 days, crystals filtered (91 mg) and washed cold ethanol to produce desired of zinc complex of (1678). Has been x-ray crystal structure.

Example 19

Circuit 19

Compound 1761 (28.38, 48, 5p., 68) - 2 - (methoxycarbonyl) - 6 - (4 - oxo - 3 - propyl - 4h - pyrido [1, 2a] pyrimidine - 9 - yloxy) tetrahydro - 2H - pyran - 3.4, 5 - triiltriatsetat (19 - 2)

Cesium carbonate (0.65 g, 2.0 mmole) added to the to stirred solution of 9 - hydro xy - 3 - propyl - 4h - pyridine [1, 2 - and] pyrimidine - 4 - one (19 - 1) (0.13 g, 0.67 mmol) and (shutoff cone, 48.58, 68) - 2 - bromo - 6 - (methoxycarbonyl) tetrahydro - 2H - pyran - 3.4, 5 - triiltriatsetata (0.80 g, 2.0 mmol) in acetonitrile (7.0 ml). Mixture stirring at room temperature in an argon atmosphere for 6 days. To reaction mixture added to the water (5.0 ml), which is then extracted dichloromethane (10 ml X 3). Organic layers dried (sodium sulfate) and they concentrated at spider nnom pressure to produce brown resin. Purification by chromatography on silica gel (10 g), elution with mixture of dichloromethane/methanol in the ratio of 20:1 febrifuges (2s, 3s, 4s, 5r, 6s) - 2 - (methoxycarbonyl) - 6 - (4 - oxo - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 9 - yloxy) tetrahydro - 2H - pyran - 3.4, 5 - triiltriatsetat(19 - 2) in the form of cream-like solid substance (0.30 g, 86%).¹ H NMR (600 MHz, CDCI₃ ) b 0.92 (t of, J=7.2 Hz, troublesome zone), (28.38, 48, 5p., 68) - 3.4, 5 - triatset<zhsi - 6 - (4 - oxo - 3 - propyl - 4h - pyrido [1, 2a] pyrimidine - 9 - yloxy) tetrahydro - 2H - pyran - 2 - carboxylic acid (19 - 3)

2M aqueous solution of potassium carbonate (0.29 ml, 0.58 mmole) added to the solution A (0.05 g, 0.10 mmol), dissolved in tetrahydrofurane/water (4:1, 8 ml) at 0 theoretically. Reaction mixture stirring at this temperature for 5 minutes, then was heated UP to room temperature and stirring for 2 hours. Then the reaction mixture neutralized resin AmberliteIRA (H⁺ ) and filtered. Resin washed with methanol (5 ml X 2) and filtrates they concentrated. Chromatography (silica gel, 20 g), elution with mixture of ethyl acetate, methanol and water (7:2:1, 300 ml) febrifuges (2s, 3s, 4s, 5r, 6s) - 3.4, 5 - triatsetoksi - 6 - (4 - oxo - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 9 - yloxy) tetrahydro - 2H - pyran - 2 - carboxylic acid (19 - 3) in the form of tar cream-like solid substance (78 mg, 74%).¹ H NMR (600 MHz, DMSO - B₆ ) of Δ 0.89 (t of, J=7.8 Hz, troublesome zone), 1.59 (of m, 2h), 1.90 (s-, troublesome zone), 1.98 (s-, troublesome zone), 1.99 (s-, troublesome zone), 2.50 (T, 2h), 3.98 (d of, j=10, 2 Hz, 1H), 5.09 (t of, J=9.6 Hz, 1H), 5.13 (t of, J=7.8 Hz, 1H), 5.26 (t of, J=9.6 Hz, 1H), 5.58 (d of, j=8, 4 Hz, 1H), 7.25 (t of, J=7.2 Hz, 1H), 7.48 (d of, J=7.8 Hz, 1H), 8.23 (s-, 1h), 8.66 (d of, J=7.2 Hz, 1H).

(28.38, 48, 5p., 68) - 3.4, 5 - trigidro xy - 6 - (4 - oxo - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 9 - yloxy) tetrahydro - 2H - pyran - 2 - carboxylic acid (1761)

Triethylamine (0.21 ml, 1.50 mmol) to added to the stirred solution of acid 19 - 3 (0.15 g, 0.30 mmol) in methanol (1.5 ml) and was in argon atmosphere 17 hours. Reaction mixture was on ice bath and formed white precipitate filtered and washed minimum number of cold methanol. (2s, 3s, 4s, 5r, 6s) - 3, 4, 5-and-TpnrnflpoKCH-and-6 - (4-and-OKCO-and-3-propyl-and-4h-and-pirido[ 1.2-and-a]pirimidin-and-9-and-yloxy) tetrahydro - 2H - pyran - 2 - carboxylic acid (1761) allocate in the form of white solid substance (54 mg, 47%).¹ H NMR (600 MHz, DMSO De) of Δ 0.90 (t of, J=7.2 Hz, troublesome zone), 1.59 (of m, 2h), 2.50 (T, 2h), 3.12 (t of, j=9, 0 Hz, 1H), 3.26 - 3.31 (T, 2h), 3.44 (d of, J=9.6 Hz, 1H), 5.02 (of BS, 1h), 5.06 (d of, J=7.8 Hz, 1H), 5.41 (d of, j=5, 4 Hz, 1H), 7.22 (t of, J=7.8 Hz, 1H), 7.42 (d of, J=7.8 Hz, 1H), 8.23 (s-, 1h), 8.61 (d of, J=6.6 Hz, 1η). 13C NMR (150 MHz, flMCO-and-d6) of Δ 14, 11, 21.75, 30.20, 72.41, 73.38, 74.01, 77.34, 101.05, 115.59, 116.61, 117.81, 119.92, 144.80, 150.10, 151.48, 157.85, 171.22, ms (ier) m/z: 381.1302 [m + H]⁺ , HPLC (300 nm): t of_R =4.99 (97%).

Example 20

Compound 1756 (glycoside 9 - hydro xy - 3 - propyl - 4h - pyridine [1, 2 - and] pyrimidine - 4 - one 19 - 1)

(2p, zr, 48, 5p., 68) - 2 - (acetoxymethyl) - 6 - (4 - oxo - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 9 - yloxy) tetrahydro - 2H - pyran - 3.4, 5 - triiltriatsetat (20 - 1)

Cesium carbonate (2.4 g, 7.3 mmole) added to the to stirred solution of 9 - hydro xy - 3 - propyl - 4h - pyridine [1, 2 - and] pyrimidine - 4 - one (19 - 1) (0.50 g, 2.5 mmole) and (2p, 38.48, 5p.) - 2 - (acetoxymethyl) - 4, 6 - dihydro ksitetragidro - 2h - pyran - 3, 5diildiatsetata (3.0 g, 7.3 mmol) in acetonitrile (24.0 ml). Mixture stirring at room temperature in an argon atmosphere for 6 days. To reaction mixture added to the water (30.0 ml), and then extracted dichloromethane (10 ml X 3). Organic layers dried (sodium sulfate) and they concentrated at spider nnom pressure to obtain brown oil. Purification chromatography on silica gel (40 g), elution with mixture of dichloromethane/methanol (500 ml) in the ratio of 20:1 febrifuges (2r, 3r, 4s, 5r, 6s) - 2 - (a4etokchmetnn) - 6 - (4-and-OKCO-and-3-and-nponnn-and-4h-and-pirido[ 1.2-and-a]pirimidin-and-9-and-yloxy) tetrahydro - 2H - pyran - 3.4, 5 - triiltriatsetat(20 - 1) in the form of cream-like solid substance (0.98 g, 75%).¹ H NMR (600 MHz, CDCI₃ ) b 0.91 (t of, J=7.2 Hz, troublesome zone), 0.62 (of m, 2h), 1.97 (s-, 6h), 2.00 (s-, troublesome zone), 2.05 (s-, troublesome zone), 2.56 (t, 2H), 3.75 (T, 1h), 4.11 (Dd1, j=2, 4, 12.0 Hz, 1H), 4.20 (Dd1, j=4, 8, 12.6 Hz, 1H), 5.13 (T, 1h), 5.31 (T, troublesome zone), 6.93 (t of, J=7.8 Hz, 1H), 7.29 (Dd1, j=1, 2, 7.2 Hz, 1H), 8.11 (s-, 1h), 8.76 (Dd1, j=1, 2, 7.2 Hz, 1H).¹³ With nuclear magnetic resonance (150 MHz, CDCI₃ ) of Δ 14.52, 21.23, 21.28, 3-and-riponMn-and-9 - ((2s, 3r, 4s, 5s, 6r) - 3, 4, 5-and-TpMmflpoKCM-and-6 - (hydro ksimetil) tetrahydro - 2H - pyran - 2 - yloxy) - 4h - pyrido [1, 2 - and] pyrimidine - it (1756)

Triethylamine (0.48 ml, 3.50 mmol) added to the to stirred solution of acetate 20 - 1 (0.37 g, 0.69 mmol) in methanol (7.0 ml) and was in argon atmosphere 17 hours. During this period in reaction mixture sightings precipitate. Reaction mixture was on ice bath and white precipitate filtered and washed minimum number of cold methanol. Solid recrystallized from methanol to produce 3 - propyl - 9 - ((28, zr, 48.58, 6p) - 3.4, 5 - trigidro xy - 6 - (hydro ksimetil) tetrahydro - 2H - pyran - 2iloksi) - 4h - pyrido [1, 2 - and] pyrimidine - 4 - one (1756) in the form of white solid substance (151 mg, 60%).¹ H NMR (600 MHz, DMSO - B₆ ) b 0.89 (t of, J=7.2 Hz, troublesome zone), 1.58 (of m, 2h), 2.53 (T, 2h), 3.16 (T, 1h), 3.32 (T, 2h), 3.46 (T, 1h), 3.68 (T, 1h), 4.56 (T, 1h), 5.06 (d of, j=4, 8 Hz, 1H), 5.11 - 5.12 (T, 2h), 5.51 (d of, j=4, 8 Hz, 1H), 7.22 (d of, J=6.6 Hz, 1H), 7.43 (d of, J=7.2 Hz, 1H), 8.22 (s-, 1h), 8.61 (d of, J=6.6 Hz, 1H).¹³ With nuclear magnetic resonance (150 MHz, DMSO De) of Δ 14.11, 21.76, 30.18, 61.05, 69.06, 73.46, 77.16, 77.73, 100.78, 115.52, 116.19, 117.94, 119.96, 142.75, 144.80, 149.84, 151.39, 157.63. Ms (ier) m/z: 367, 1509 [m + H]⁺ . HPLC (300 nm): t of_R =4.

The following analysis used for evaluation of properties of compounds, to determine their fitness for use in methods according to the present invention.

Analysis 1. Analysis of hydrogen peroxide

H2O2 is strong oxidant and high-reaction type of oxygen, which, as known, toxic for surrounding proteins and organelles, by inhibiting their function. Analysis on inhibition of hydrogen peroxide (H2O2) is a fluorescent analysis, which estimates capacity of testing compound inhibit formation of H2O2 in the presence of copper and of reducing substrate, or dopamine, or ascorbic acid. In the analysis of interaction is carried out in the form of copper sis1z with ascorbic acid or dofaminom by incubation for 1 hour at 37 theoretically in the presence of fluorescent compounds dikhlorfluorestsina and horse radish peroxidase. H2O2, generated system, is evaluated by measuring specific profile fluorescence on wave lengths excitation and radiation 485 and 530 nm respectively in the presence of of tested compounds. Tested compounds dissolved in volatile DMSO and jointed at concentrations 0.4 mcm. Tested compounds ranked in accordance to their ability to inhibit H2O2, generated system, where lower values reflect greater ability to inhibit formation of H2O2.

Value cLog P

Theoretical values of the log P determined by means of software the ACD the log p. said values have been are calculated from non-data base and field types of combined.

E D of the log

Are effective values of the log D of measured using chromatographic method on column SUPELCOSIL LC--and-ABZ with application of oktanolnoi saturated mobile phase at pH 7.4. Cm. Means F. Lombardo is Et al., J the MED. Chem. 2000, 43, 2922 - 2928.

In the following table are presented properties and structure of compounds according to the present invention. Properties of salt Histidinum analyzed for the compounds in the table, is presented where molecular mass (mm) salt Histidinum.

Bush of Al, Goldstein Le of. specific recovery of Metal-and-catalysedproteinoxidationreactions of in vitro chronicdegenerativedisorders care ageing: in Focus of an Alzheimer's of the disease and sort of AGE-and-relatedcataracts. Novartis is completed Found Are Symp. 2001; 235:26 - 38; discussion 38 - 43.

Should be understandable, that, if what - or publication of previous level of technology mentioned in the present invention, such reference is not recognition, that publication is part of total level of technology in this area in australia or any other country.

In the formula of invention, the following then, and in preceding invention description, except for cases, when context requires other in connection with linguistic expression or required meaning, word "contain" or its variants, such as "contains" or "containing", is used in a wide sense, that is for indicating availability of given signs, but not for limiting presence or addition of additional signs in various versions of realization by invention.

Compounds 4h - pyrido [1, 2 - and] pyrimidine - 4 - one

The present invention relates to compounds of pyrido [1, 2 - and] pyrimidine - 4 - one, methods of their production and their use as pharmaceutical agents or in compositions for treatment of neurological disorders.

Neurologic disorder, including neurodegenerative disorder, can undergo pathologically connected interaction between proteins and oxidation - oxidation with ions of metals, such as zinc, copper or iron. Such reaction is generated active oxygen form (afk), which are capable destroy cell components are oxidizing proteins, lipid and DNA. This may cause changes in conformation proteins, activity of enzymes and become cause aggregation of proteins.

Afk include free radicals, such as superoxide anion -, hydro ksilnyi radical and other molecular compounds, such as hydrogen peroxide (Bush and Goldstein, 2001). Hydro ksilnye radicals are the most reactive and-breaking afk. They mainly are formed in reaction of Fenton between transition metals (usually iron (of II) or copper (1)) and hydrogen peroxide.

While cells show antioxidant systems for protection from damage afk, including protective enzymes, such as copper - zinc superoxide dismutase, these enzymes contain metals. So, cells should maintain careful balance between free and fixed prooksidantom and antioxidant with ions of metals, which are critical for cellular homeostasis. Usually is considered to be, that aging brain has slow and progressing imbalance between antioxidant protection and intracellular concentrations of afk.

It is necessary to identify compounds, intended for control and modulation ionny biological metals, which, being non-adjustable, have installed communication with the growing number of diseases, including those, which are characterized by the presence of oxidative stress, aggregation of proteins and intracellular or extracellular unbalance metals.

Authors detected compounds, having two condensed 6 - membered ring with nitrogen atoms in positions 1 and 5 and group of or-⁸ in position 9, which are used for treatment of neurological disorders. These compounds can possess one or more of the following properties of: cross hematoencephalic barrier (geb), show reduced adverse side effects and/or are stable in aqueous media.

In the first aspect of the present invention invention proposes compound of formula I

where

R² represents H, (CH-₂ )_n- THE NR⁹R¹⁰ , With - m alkyl, optionally interrupted with oxygen or (CH-₂ )_n-SC=SNR⁹R¹⁰ ;

R³ represents H, with - m alkyl, optionally interrupted with oxygen, C1 - 4 alkoxy, sz_b cycloalkyl, (CH₂ )_T optionally substituted aryl, (CH₂ )_P optionally substituted aryl, optionally condensed with 5ili 6 - chlennymgeterotsiklilom, of c (0) the NR⁹R¹ °C, (CH-₂ )_n- THE NR⁹R¹⁰ or c (0) NH--n-=CR⁹R¹⁰ ;

R⁵ represents H or C1 - 4 alkyl;

R⁶ represents H, halogen, (CH₂ )_P optionally substituted 5 - or 6 - members or with heterocyclyl₂_4 alkynyl;

R⁷ represents H, halogen, (CH₂ )_P of 5 - members optionally substituted heterocyclyl, optionally substituted C1 - 4 alkyl, with₂_4 alkynyl, (CH-₂ )_n- THE NR⁹R¹⁰ , N0₂ , THE NR⁵ S0₂ optionally substituted aryl or NR⁵ S0₂ optionally substituted C1 - 4 alkyl;

R⁸ represents H, s0₂ optionally substituted aryl, C1 - 4 alkyl or (CH₂ )_P aryl; or

R⁷ together with carbon atom, to which it is connected, and R⁸ together with atom of oxygen, to which it is connected, form 5 - membered ring;

R⁹ and R¹⁰ are independently chosen from H, C1 - 8 alkyl, optionally interrupted about, the CN, (CH₂ ) u optionally substituted aryl, optionally condensed with 5ili 6 - chlennymgeterotsiklilom, (CH2)_P optionally substituted C3 - 8 cycloalkyl, (CH₂ )_P optionally substituted 5ili 6 - membered optionally substituted heterocyclyl, s0₂ optionally substituted aryl and with m - alkoxy; or

R⁹ and R¹⁰ together with nitrogen atom, to which they are connected, form 5 - or 6 - members optionally substituted heterocyclyl;

X represents n or CH;

of m is equal to 1, 2 or 3; and

u is equal to 0, 1.2 or 3;

provided, that:

(i) at least one R² , OF R³ , OF R⁵ , OF R⁶ and R⁷ differs from H;

(ii) when R of³ represents a C1 - 4 alkyl and R² , OF R⁵ and R⁸ represent H, then R is⁷ or R⁶ differ from H;

(iii) when R of³ is a with - m alkyl, R of² , OF R⁵ and R⁸ represent H and R⁷ is a 1, then of R⁶ differs from H,

its salts, isomers or prodrugs or compound, selected from:

1655 1659

In the second aspect invention proposes compound of formula II

where

R² , OF R³ , OF R⁵ , OF R⁶ and R⁷ are such, given in the m represents transition metal;

its salts, isomers or prodrugs.

In the third aspect the method of preparation of compounds of formula I, its salts, isomers or prodrugs, certain above, including interaction of compound of formula III

where

R⁵ , OF R⁶ , OF R⁷ of R h of⁸ are such, as defined above in formula I;

with compound of the formula of IV

where

R² and R³ are such, as defined above in formula I;

to produce of a formula V compound

where

R² , OF R³ , OF R⁵ , OF R⁶ , OF R⁷ of R h of⁸ are such, as defined above in formula I; and by cyclization of a formula V compound.

In the fourth aspect a method for preparing compound of formula II, its salts, isomers or prodrugs, certain above, including the interaction of compounds of formula I, its salts, isomers or prodrugs, certain above, with source of m, the m is such, as defined above in formula II of.

In the fifth aspect invention proposes a pharmaceutical agent, including compound of the formula i or ii, its salts, isomers or prodrug, as defined above.

Also application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, as pharmaceutical agent.

Is additionally suggested compound of the formula i or ii, its salts, isomers or prodrug, as defined above, for use as pharmaceutical agent.

Pharmaceutical agent can be neiroterapevticheskim or neuroprotective agent.

In the sixth aspect a neiroterapevticheskii or neiroprotektivnyi agent, including compound of the formula i or ii, its salts, isomers or prodrug, as defined above.

Also application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, as neiroterapevticheskogo or neiroprotektivnogo agent.

Is additionally suggested compound of the formula i or ii, its salts, isomers or prodrug, as defined above, for use as neiroterapevticheskogo or neiroprotektivnogo agent.

Compound of the formula i or ii, its salts, isomers or prodrugs may be introduced in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

In the seventh aspect invention proposes a pharmaceutical composition, containing compound of the formula i or ii, its salts, isomers or prodrugs, and a pharmaceutically acceptable carrier.

In one version pharmaceutical composition additionally contains therapeutically effective amount of one or more additional active agents, such as chemotherapeutic compound, immunotherapeutic compound, cytokine, genetic molecule and/or anesthetic.

In eighth aspect the method of treatment of neurological disorders, including introduction of, requiring in this, effective amount of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, or pharmaceutical agent or pharmaceutical composition, certain above.

Also application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, or pharmaceutical agent or pharmaceutical composition, as defined above, for preparing a drug for treatment of neurological disorders.

Additionally application of compounds of the formula i or ii, its salts, isomers or prodrugs, as defined above, or pharmaceutical composition, as defined above, for treatment of neurological disorders.

Also is additionally suggested compound of the formula i or ii, its salts, isomers or prodrug, as defined above, or pharmaceutical agent or pharmaceutical composition, the described, for application in treatment of neurological disorders.

At least preferable subject man is, the present invention may be used in branches of veterinary science and animal husbandry and, consequently, spreads on animals, not related to humans.

The present invention relates to compounds of formula I, above to.

In one embodiment compound of the formula I is compound of the formula 1a

where R is³ and from R⁵ of R to⁸ are such, as defined above in formula I.

In one version of the formula La is of R³ is a with - m alkyl, optionally interrupted about, C5 - 6 cycloalkyl, (CIS) U optionally substituted aryl, optionally condensed with 5ili 6 - chlennym heterocycle dwg Ohm, of c (0) the NR⁹R¹ °C, where R is⁹ represents H and R¹⁰ is a of c-of i-6 alkyl, optionally substituted phenyl or optionally substituted 5 - members heterocyclyl; R of⁶ represents H, halogen, such as Cl or vg, 5 - members heterocyclyl, optionally substituted benzyl or o

cyclopentyl, Cl-and-4 alkyl or C2 - 4 alkynyl; R of⁷ represents H, halogen, such as 1, 5ili 6 - members optionally substituted heterocyclyl, optionally substituted phenyl, (ch2)_n- THE NR⁹R¹⁰ , C1 - 4 alkyl, C2 - 4 alkynyl or NR⁵ S02 optionally substituted phenyl; and R⁸ represents H or with - m alkyl.

Typical examples of compounds of the formula La include compounds 1235,

1660, 1661, 1717, 1708 and 1716, as shown on circuits 1 - 4, 7 - 9 and 15 - 17 examples 1 - 4, 7 - 9 and 15 - 17.

In another embodiment compound of the formula I is compound of the formula lb-

where R is³ and R⁸ are such, as defined above in formula I.

In one version of the formula lb-, of R³ represents H, of c (0) the NR⁹R¹ ° or (of c (0) of n-NH-=CR⁹R¹ °C; and R⁸ represents H or benzyl.

Typical examples of compounds of the formula lb-include 1394, 1422, 1423,

shown on circuits 5 and 13 examples 5 and 13.

In additional version compound of the formula I is compound of the formula the IC

OR-⁸

The IC

where R is² , OF R⁵ , OF R⁶ and R⁸ are such, as defined above in formula I.

with changes according to article 34 (2) (b of) see

1607, 1621, 1622, 1623, 1624, 1643, 1599, 1611, 1650, 1674, 1675, 1685, 1686, 1596, 1597, 1600, 1601, 1602, 1603, 1605, 1629, 1630, 1633, 1639, 1641, 1648, 1651, 1652, 1653, 1654, 1655, 1656, 1659, 1660, 1668, 1671, 1680, 1681, 1683, 1627, 1631, 1632, 1640, 1642, 1645, 1647, 1679, 1691, 1693, 1706, 1606, 1615, 1616, 1617, 1626, 1613, 1619, 1620, 1625, 1628, 1644, 1658, 1664, 1669, 1682, 1704, 1710, 1712, 1722, 1657,

1425, 1426, 1427, 1428, 1429, 1431, 1432, 1433, 1436, 1437, 1440, 1441, 1445, 1446, 1447, 1450, 1452, 1453, 1454, 1461, 1462, 1532, 1533, 1649, 1723, 1724 and 1732, as

R⁵O

In one version of the formula of R the IC² is a (CH-₂ )_n- THE NR⁹R¹⁰ , C1 - 4 alkyl, optionally interrupted O or (CH-₂ )_n-SC=SNR⁹R¹⁰ ; OF R⁵ represents H or C1 - 4 alkyl, such as methyl; and R⁶ is a halogen, such as Cl.

Typical examples of compounds of the formula the IC include compounds of 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1435, 1438, 1439, 1442, 1443, 1444, 1448, 1449, 1451, 1455, 1456, 1457, 1458, 1459, 1463, 1464, 1466, 1467, 1468, 1469, 1470, 1471, 1476, 1478, 1479, 1485, 1490, 1491, 1500, 1503, 1504, 1506, 1508, 1515, 1516, 1517, 1518, 1519, 1521, 1522, 1523, 1525, 1527, 1531, 1604, 1608, 1609, 1610, 1612, 1614, 1618, 1634, 1635, 1636, 1637, 1638, 1670, 1699, 1707, 1591, 1646, 1701, 1705, 1713, 1714, 1720 and 1721, as shown on circuits 6, 10 and 12 examples 6, 10 and 12.

In one more embodiment, compound of formula I is a compound of the formula of ID

where R is² , OF R³ and from R⁶ of R to⁸ are such, as defined above in the formula of

In one version of the formula of R of ID² is a with - m alkyl, such as methyl; R of³ is a with - m alkyl or benzyl; R of⁶ is a halogen, such as is Cl; R of⁷ is a halogen, such as I or 5ili 6 - members optionally substituted heterocyclyl; and R⁸ represents H or with - m alkyl, such as propyl.

Typical examples of compounds of the formula of ID include compounds of 1662, 1663, 1665, 1666, 1667, 1672, 1673, 1687, 1688, 1689, 1690, 1694 and 1698, as indicated on circuit diagram 14 coded 14.

In one embodiment compound II is a compound of the formula mA.

Pa 2

where

R³ , OF R⁷ and m are such, as defined above in formula II of.

In one version of the formula mA of R³ is a with - m alkyl, such as propyl, or c (0) the NR⁹R¹ °C; OF R⁷ is a with - m alkyl, such as propyl, and m is a ζη or xi.

Typical examples of compounds of the formula mA include compounds of 1678, 1692, 1700, 1715, 1718, 1719, 1744, 1745 and 1748, as indicated on circuit diagram 18 coded 18.

If not or other as indicated, the following terms should be understand, as having a common value, given below.

Term "of c-of i-6 alkyl" relates to optionally substituted hydrocarbon groups with non-or branched chain, having from 1 to 6 carbon atoms. Examples include methyl (IU), ethyl (is Et), propyl (head), isopropyl (/ - head), butyl (MI), isobutyl (/ - MI), E/tyur - butyl (S-S-Bu), / 7?pE/7?- butyl (F-Bu), pentyl, neopentyl, hexyl and T. U. If context does not require other, term "of c-of i-6 alkyl" also embraces alkyl groups, containing one less than hydrogen atom, so that the group is through two position, T. E. dvukhvalentno. "Of c-of i-4 alkyl" and "of c-of i-3 alkyl", including methyl, ethyl, propyl, uzopropil, n - butyl, ouzo - butyl, E/tyur - butyl and/77re/77 - butyl, are preferable group, the methyl is especially preferable.

Term "C2 - 6 alkenyl" relates to optionally substituted hydrocarbon groups with non-or branched chain, having at least one double bond or stereochemistry E, or Z of, where it applicable, and from 2 to 6 carbon atoms. Examples include vinyl, 1 - propenyl, 1 [i1 2 - butenyl and 2 - methyl - 2 - propenyl. If context does not require other, term "C2 - 6 alkenyl" also embraces alkenyl group, containing on one atom is less than hydrogen, so that the group is through two position, T. E. dvukhvalentno. "C2 - 4 alkenyl" and "C2 - 3 alkenyl", including ethenyl, propenyl and butenyl, are preferred group, the ethenyl is especially preferable.

Term "C2 - 6 alkynyl" relates to optionally substituted hydrocarbon groups with non-or branched chain, having at least one triple bond and from 2 to 6 carbon atoms. Examples include ethynyl, 1 - propynyl, 1 [i1 2 - butinyl, 2 - methyl - 2 - propynyl, 2 - pentyneyl, 3 - pentyneyl, 4 - pentyneyl, 2 - hexenyl, 3 - hexenyl, 4 - hexenyl and 5 - hexenyl and T. U. If context does not require other, term "C2 - 6 alkynyl" also embraces alkynyl group, containing one less than hydrogen atom, so that the group is through two position, T. E. dvukhvalentno. C2 - 4 alkynyl is preferable.

Term "C3 - 8 cycloalkyl" relates to-aromatic cyclic groups, having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Understandable, that cycloalkyl groups can be saturated, such as cyclohexyl, or unsaturated, such as cyclohexenyl. C3 - 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, are preferable.

Terms "hydro xy" and "hydro ksil" field to group - it.

Term "C1 - 6 alkoxy" relates to alkyl group, as defined above, covalently connected through about - communication, containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, izoproksi, butoxy, / lre/tbutoksi and pentoksi. "Of c-of i-4 alkoxy" and "of c-of i-3 alkoxy", including methoxy, ethoxy, propoxy and butoxy, are preferred group, the methoxy is especially preferable.

Term "aryl" relates to carbocyclic (negeterotsiklicheskomu) aromatic ring or mono -, biili tricyclic ring system. Aromatic ring or ring system usually consists of 6 - 10 carbon atoms. Examples of aryl groups include, but are not limited by said, phenyl, biphenyl, naphthyl and tetrahydro naphthyl. of 6 - membered the aryls, such as phenyl, are preferable. Term "alkylaryl" relates to with -|_balkilarilu, such as benzyl.

Term "heterocyclyl" relates to fragment, obtained removal of hydrogen atom from the ring atom heterocyclic compound, the fragment has from 3 to 10 ring atoms (if not as indicated or other), of which 1, 2, 3 or 4 are annular the heteroatoms, each heteroatom independently is selected from O, S and n-.

In this context of prefixes 3 -, 4 -, 5 -, 6 -, 7 -, 8 -, 9i 10 - membered having the number of ring atoms or range of ring atoms, as carbon atoms, and heteroatoms. For example, used in this document term "3 - 10 - members heterocyclyl" relates to heterocyclyl group, having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples heterocyclyl groups include 5 - 6 - membered monocyclic geterotsiklily and 9 - 10 - membered condensed bicyclic geterotsiklily.

Examples monocyclic heterocyclyl groups include, but are not limited by said, containing one nitrogen atom, such as aziridine (3 - membered ring), azetidine (4 - membered ring), pyrrolidine (tetrahydro pyrrole), pyrroline (for example, 3 - pyrroline, 2.5 - dihydro pyrrole), 2h - pyrrole or troublesome zone - pyrrole (izopirrol, izoazol) or pirrolidinon (5 - membered ring), piperidine, dihydro pyridine, tetrahydro pyridine (6 - membered ring) and azepine (7 - membered ring); containing two nitrogen atoms, such as imidazoline, the pyrazolidine (diazolidin), imidazoline, pyrazoline (dihydro pyrazole) (5 - membered ring), piperazine (6 - membered ring); containing one oxygen, such as oxirane (3 - membered ring), oxetane (4 - membered ring), oksolan (tetrahydro furan), oksol (dihydro furan) (5 - membered ring), ocean (tetrahydro pyran), dihydro pyran, pyran (6 - membered ring), oxepin (7 - membered ring); containing two oxygen atom, such as dioxolan (5 - membered ring), dioxane (6 - membered ring) and dioxepan (7 - membered ring); containing three atoms of oxygen, such as trioxane (6 - membered ring); containing one sulfur atom, such as tiiran (3 - membered ring), thietan (4 - membered ring), thiolane (tetrahydro thiophene) (5 - membered ring), Tian (tetrahydro thiopyran) (6 - membered ring), tipan (7 - ring members); containing one nitrogen atom and one oxygen atom, such as tetrahydro oxazol, dihydro oxazole, tetrahydro isoxazole, dihydro isoxazole (5 - membered ring), morpholine, tetrahydro oxazine, dihydro oxazine, oxazine (6 - membered ring); containing one nitrogen atom and one sulfur atom, such as thiazoline, thiazolidine (5 - membered ring), thiomorpholine (6 - membered ring); containing two nitrogen atoms and one oxygen atom, such as oxadiazin (6 - membered ring); containing one oxygen and one sulfur atom, such as oxathiol (5 - membered ring) and oksatian (thioxane) (6 - membered ring); and containing one nitrogen atom, one oxygen and one sulfur atom, such as oxathiazine (6 - membered ring).

Geterotsiklily also enclose aromatic geterotsikpily and nonaromatic geterotsiklily. Such groups can be substituted or unsubstituted.

Term "aromatic heterocyclyl" may be used interchangeably with the term of query of query "heteroaromatic" or "heteroaryl" or "hetaryl". The heteroatoms in aromatic heterocyclyl group may be independently selected from ν, S and about.

"Heteroaryl" is used in this document for designations of heterocyclic group, having aromatic character, and female aromatic monocyclic ring system and polycyclic (for example, bitsikpicheskie) ring system, containing one or several aromatic rings. Term "aromatic heterocyclyl" also embraces psevdoaromaticheskiegeterotsiklily. Term "psevdoaromaticheskii" relates to circular system, which is not strictly aromatic, but stabilized by means of relocation of electrons and performs similarly includes aromatic rings. Term "aromatic heterocyclyl", so, embraces polycyclic ring system, in which all condensed ring are aromatic, and ring system, in which one or more rings are non-aromatic, provided, that at least one ring is aromatic. In polycyclic systems, as containing aromatic, and nonaromatic ring, condensed together, group can be connected to the other fragment aromatic ring or-aromatic ring.

Examples of heteroaryl groups are monocyclic and bitsikpicheskie group, containing from five to ten ring members. Heteroaryl group can be, for example, five-membered or six-membered monocyclic ring or bicyclic structure, formed by from condensed five and hexamerous rings or two condensed hexamerous rings, or two condensed five rings. Each ring may contain up to approximately four heteroatoms, usually selected from nitrogen, sulfur and oxygen. Heteroaryl ring will contain up to 4 heteroatoms, more such clusters to 3 heteroatoms, more such clusters to 2, for example, one heteroatom. In one embodiment heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in the heteroaryl rings can be main, as in case of imidazole or pyridine, or, essentially, non-core, as in case of indole or pyrrole nitrogen. In general case, number of main nitrogen atoms, present in heteroaryl group, including any amino group substituents in ring, will be less than five.

Aromatic heterocyclyl groups can be 5 - membered or 6 - membered monocyclic aromatic ring systems.

Examples 5 - membered monocyclic heteroaryl groups include, but are not limited by said, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1.2, 3 [i3 1.2, 4 - oksadiazolily and furazanyl, T. E. 1.2, 5 - oxadiazolyl), thiazolyl, isoxazolyl, izotiazolil, pyrazolyl, imidazolyl, triazolyl (including 1.2, 3 -, 1.2, 4AND 1.3, 4 - triazolily), oksatriazolil, tetrazolyl, thiadiazolyl (including 1.2, 3 [i3 1.3, 4 - tiadiazolily) and T. U.

Examples 6 - membered monocyclic heteroaryl groups include, but are not limited by said, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazineyl, dioxinyl, thiazinyl, tiadiazinil and T. U. Examples 6 - membered aromatic geterotsiklilov, containing nitrogen, include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogen atoms).

Aromatic heterocyclyl group may also be bitsikpicheskimi or polycyclic heteroaromatic ring systems, such as condensed ring system (including purine, pteridinyl, naphthyridinyl, 1h-thieno [2, 3 - with] pyrazolyl, thieno [2, 3 - mpile] furyl and T. U.) or connected ring system (such as oligotiofen, poly-pyrrole and T. U.). Condensed ring systems can also include aromatic 5 - membered or 6 - membered geterotsiklily, condensed with karbotsiklicheskimi aromatic rings, such as phenyl, naphthyl, indenyl, azulenyl, fluorohenyl, anthracenyl and T. U ., such as 5 - membered aromatic geterotsiklily, containing nitrogen atom, condensed with phenyl rings, 5 - membered aromatic geterotsiklily, containing 1 or 2 nitrogen atoms, condensed with phenyl ring.

Bicyclic heteroaryl group can be, for example, group, chosen from: and) benzene ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 ring heteroatom; b) pyridine ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; in) pyrimidine ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; g) pyrrole ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; d) pyrazole ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; E) imidazole ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; solid) oxazolic ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; 3) isoxazole ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; and) thiazol ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; to) isothiazol ring, condensed with 5ili 6 - chlennym ring, containing 1 or 2 heteroatom; l) of phiophenic ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; m) furan ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; H) cyclohexyl ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom; and on) cyclopentyl ring, condensed with 5ili 6 - chlennym ring, containing 1, 2 or 3 heteroatom.

Specific examples bicyclic heteroaryl groups, containing five ring, condensed with other five-membered ring, include, but are not limited by said, the imidazothiazole (for example, imidazo [2, 1 - mpile] thiazole) and the imidazoimidazol (for example, imidazo [1, 2 - and] imidazole).

Specific examples bicyclic heteroaryl groups, containing six-member ring, condensed with five-membered ring, include, but are not limited by said, benzofuranovuyu, benzotiofenovuyu, benzimidazolnuyu, benzoksazolnuyu, izobenzoksazolnuyu, benzizoksazolnuyu, benzotiazolnuyu, benzizotiazolnuyu, izobenzofuranovuyu, indole, izoindolnuyu, indolizinovuyu, indolinovuyu, izoindolinovuyu, purinovuyu (for example, adenine, guanine), indazolnuyu, pirazolopirimidinovuyu (for example, pyrazolo [1, 5 - and] pyrimidine), benzodioksolnuyu and pirazolopiridinovuyu (for example, pyrazolo [1, 5 - and] pyridine) group. Additional example of six-membered ring, condensed with five-membered ring, is pirrolopiridinovaya group, such as pyrrolo [2, 3 - mpile] pyridine group.

Specific examples bicyclic heteroaryl groups, containing two condensed hexamerous ring, include, but are not limited by said, quinoline, izokhinolinovuyu, khromanovuyu, tiokhromanovuyu, khromenovuyu, izokhromenovuyu, izokhromanovuyu, benzodioksanovuyu, khinolizinovuyu, benzoksazinovuyu, benzodiazinovuyu, piridopiridinovuyu, khinoksalinovuyu, khinazolinovuyu, tsinnolinovuyu, ftalazinovuyu, naftiridinovuyu and pteridinovuyu group.

Examples of heteroaryl groups, containing aromatic ring and nonaromatic ring, include tetrahydro naftalinovuyu, tetrahydro izokhinolinovuyu, tetrahydro quinoline, dihydro benzotiofenovuyu, dihydro benzofuranovuyu, 2.3 - dihydro benzo [1.4] dioksinovuyu, benzo [1.3] dioksolnuyu, 4.5, 6.7 - tetrahydro benzofuranovuyu, indolinovuyu, izoindolinovuyu and indanovuyu group.

Examples aromatic geterotsiklilov, condensed with karbotsiklicheskimi aromatic rings, can so include, but are not limited by said, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazoleyl, benzoxazolyl, benzisoxazolyl, izobenzoksazoil, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolynyl, cinnolinyl, benzotriazinil, phtalazinyl, carbolinyl and T. U.

Term "nonaromatic geterotsikpil" embraces optionally substituted saturated and unsaturated ring, which contain at least one heteroatom, selected from the group, consisting of ν, S and about.

Nonaromatic heterocycle of Elah can represent 3 - 7 - membered monocyclic ring.

Examples 5 - membered nonaromatic heterocyclyl rings include 2h - pyrrolyl, 1 - pyrrolinyl, 2 - pyrrolinyl, 3 - pyrrolinyl, pyrrolidinyl, 1 - pyrrolidinyl, 2 - pyrrolidinyl, 3 - pyrrolidinyl, tetragidrofuranil, tetrahydro thiophenyl, pyrazolinyl, 2 - pyrazolinyl, 3 - pyrazolinyl, pyrazolidinyl, 2 - pyrazolidinyl, 3 - pyrazolidinyl, imidazolidinyl, 3 - dioksalanil, tiazolidinyl, isoxazolidinyl, 2 - imidazolinyl and T. U.

Examples 6 - membered nonaromatic geterotsiklilov include piperidinyl, piperidinonil, pyranyl, digirdopiranil, tetrahydro-pyranyl, 2H-pyranyl, 4H-pyranyl, tianil, tianiloksid, tianildioksid, piperazinyl, diozanil, 1.4 - dioxinyl, 1.4 - dithianeyl, 1.3, 5 - triozalanil, 1.3, 5 - tritianil, 1.4 - morpholinyl, thiomorpholinyl, 1.4 - oksatianil, triazinyl, 1.4 - thiazinyl IT. U.

Examples 7 - membered nonaromatic geterotsiklilov include azepanyl, oksepanil, tiepanil and T. U.

Nonaromatic heterocyclyl ring may also be a bicyclic heterocyclyl ring, such as connected ring system (for example, uridinil and T. U.) or condensed ring system. Condensed ring systems include nonaromatic 5 - membered, 6 - membered or 7 - membered geterotsiklily, condensed with karbotsiklicheskimi aromatic rings, such as phenyl, naphthyl, indenyl, azulenyl, fluorohenyl, anthracenyl and T. U. Examples nonaromatic 5 - membered, 6 - membered or 7 - membered geterotsiklilov, condensed with karbotsiklicheskimi aromatic rings, include indolineyl, benzodiazepinil, benzazepinil, dihydro benzofuranyl and T. U.

Term "halogen" relates to fluorine, chlorine, bromine or to iodine.

Term "optionally substituted" relates to group, which can be or not be additionally substituted one or more groups, selected from with -|_b alkyl, sz_b cycloalkyl, C2 - 6 alkenyl, C2 - 6 alkinila, aryl, heterocyclyl, halogen, halogen C1 - 6 alkyl, of cf3, halogen C3 - 6 cycloalkyl, halogen C2 - 6 alkenyl, halogen C2 - 6 alkinila, galogenarila, galogengeterotsiklila, hydro xy, C1 - 6 alkoxy, OCF3, C2 - 6 alkeniloksi, C2 - 6 alkiniloksi, aryloxy, geterotsikliloksi, carboxy, halogen with -|_b alkoxy, halogen C2 - 6 alkeniloksi, halogen C2 - 6 alkiniloksi, galogenariloksi, nitro, nitro C1 - 6 alkyl, nitro C2 - 6 alkenyl, nitroarila, nitrogeterotsiklila, azido, amino, C1 - 6 alkylamino, C2 - 6 alkenilamino, C2 - 6 alkynylamino, arylamino, geterotsiklilaminoatsila, C1 - 6 alkilatsila, C2 - 6 the alkenylacyl, C2 - 6 alkinilatsila, arilatsila, geterotsiklilatsila, acylamino, acyloxy, ester-, C1 - 6 alkylsulfonyl, arilsulfonila, C1 - 6 alkylsulphonylamino, arilsulfonilamino, C1 - 6 alkilsulfoniloksi, arilsulfoniloksi, C1 - 6 alkilsulfenila, C2 - 6 alkilsulfenila, arilsulfenila, carboalkoxy, karboariloksi, mercapto, with -|_b alkylthio, arylthio, atsiltio, cyano and T. U. Preferably, optional substituent is a with - m alkyl, of cf3, hydro xy, halogen, such as Cl or F, C1 - 4 alkoxy, such as methoxy or OCF3.

Understandable, that suitable derivatives of aromatic geterotsiklilov, containing nitrogen, include their N--oxides.

Salts of compounds of formula I or ii are preferably pharmaceutically acceptable, but should be understand, that not pharmaceutically acceptable salts also of multislit under volume of the present invention, since they can be used in as intermediate products production of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids, such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, coal, boric, sulfamic and hydrobromic acid; or salts of pharmaceutically acceptable organic acids, such as acetic, propionic, oil, tartaric, maleicor, hydro ksimaleinovaya, fumaric, citric, lactic, mutsinovaya, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trigalogenmetansulfonovaya, toluenesulfonic, benzenesulfonic, salicylic, of pH, aspartic, glutamic, ethylenediaminetetraacetic, stearic, palmitic, oleic, lauric, pantothenic, Tan-, ascorbic and valeric acid. Salt amine groups may also contain quaternary ammonium salts, in which nitrogen atom carries amino group of suitable organic group, such as alkyl, alkenyl, alkynyl or aralkyl group.

Salt can be obtained by common methods, such as interaction of free of initial form compounds with one or more equivalents corresponding acid.

Should be understand, that link on the pharmaceutically acceptable salt includes shape connection solvent or their crystalline forms, in particular solvates or polymorphs. Solvates contain either stoichiometric, or nonstoichiometric amount of solvent and may be formed by in process of crystallization by means of pharmaceutically priemlemymykh solvents, such as water, alcohols, such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethylformamide (dimethylformamide) and T. U ., the solvate forms part of crystal lattice or by noncovalent binding, or by filling holes in the crystal lattice. Hydrates are formed, when solvent is water, alcoholates are formed, when solvent is alcohol. Solvates compounds according to the present invention can be easily obtained or are formed in the course of described in this document methods. As a rule, solvated form are considered to be equivalent not solvated forms for purpose compounds and methods, presented in this document.

Additionally, compounds the present invention can arranged between in non-solvated, as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol and T. U. Solvated form compounds according to the present invention also are considered to be discovered in the present invention.

Understandable, that compounds of the formula i or ii can possess chiral center and can, so, arranged between in the form of isomer, such as racemate or r [ilir S-S enantiomer. Therefore compounds can be used as purified enantiomer or diastereomer, or in the form of mixture of any of their ratio. Isomers may be separated traditional chromatographic methods or by using the separating agent. Alternatively, separate isomers can be obtained asimmetricheskim synthesis with application of chiral intermediate products. When connection has carbon - carbon double bond, it may be in Zilieforme, and all isomeric forms compounds are included in the present invention.

The invention also embraces prodrugs of compounds of the formula i or ii.

Prodrug can be pharmacologically inactive derivatives of active compound, which requires transformation in organism to release active compound, and which has improved properties delivery as compared with active compound. Transformation in vivo of may be, for example, result of some metabolic process, such as chemical or enzymatic hydro lys carboxyl, phosphorus or sulfate ester, or reduction or oxidation of acquisitive functional group. In one version or-group⁸ on compounds of the formula (1) can be blocked with formation of prodrug, of R when⁸ represents H, in particular ester prodrug. Hydro ksilnaya group represents main site metabolism compounds: conjugation with glucuronic acid or sulfate results in the formation of hydro philic molecules, finished isolation.

In volume of the present invention includes compounds of the formula i or ii, to which is connected at least one of detected mark, affinity marker and fotoreaktivnoi group.

Compounds of the formula (1) can be used for treatment of neurological disorders.

As a rule, term "treatment" means action on distinguished, tissue or cell for desired pharmacological and/or physiological effect and includes: (and) inhibition of neurological disorders, T. E. stopping of its development or further development of; (b) simplification of or attenuation of the effects neurological disorders, T. E. regression effects neurological disorders; (in) WiFi client continuously tracks the morbidity or neurological disorders or (g) prevention of disorder in a subject, tissue or cell, predisposed to nevrologicheskomu disruption or having risk of its development, but not diagnostirovannomu, by means of protective pharmacological and/or physiological effect, so, that neurological disorder does not develop or not occurs in a subject, tissue or cell.

Term "distinguished", used in this document, relates to any animal, in particular mammals, such as people, having disorder or state, which requires treatment of compound of the formula i or ii.

Term "introduction" relates to provision compounds or pharmaceutical composition by invention subject, suffering from or having risk of development of diseases or conditions, to be treatment or prevention.

Term "neurologic disorder" is used in this document in its proper wide sense and relates to disturbances, at which various types of cells nervous system degeneriruyut and/or have been damaged as a result of neurodegenerative disorders or traumas, or actions. In particular, compounds of the formula i or ii can be used for treatment of obtained disorders, at which damage cells nervous system takes place from - the surgical interventions, infections, action toxic agents, tumors, deficiency nutrient substances or metabolic disorders.

Term "neurodegenerative disorder", used in this document, relates to anomaly, integrity at which neurons is under threat. Neuron integrity may be rim under threat, when neural cells demonstrate WiFi client continuously tracks the survival rate or, when neurons can not more distribute signal.

In addition, compounds of the formula i or ii may also be used for reinforcing effects from other methods of treatment, for example, for reinforcing neiroprotektivnykh effects produced by brain nerve growth factor.

Term "disease, characterized by unbalance metallv" relates to disease, at which the total amount of metal in a subject or too high, or too low. This term also relates to subject with normal total amount of metal, but metal incorrectly or abnormally is distributed.

Term "disease, characterized by the presence of oxidative stress" relates to disease, at which biological components subject injured active oxygen forms. In particular, supposed, that such components are injured active oxygen forms, such as hydro ksilnyi radical, hydrogen peroxide and superoxide, formed when the reaction Fenton and similar reactions. In particular, understandable, that metals, such as iron, copper, zinc, chromium, vanadium and cobalt, are able to oxidation - to reducing cycle, in which one electron can be received or given to metal, facilitating oxidising reaction. The actual damage occurs, when oxidative factor causes modification of amino acids (for example, formation of metatirozina and ortotirozina from phenylalanine), carbohydrates and fats (causing peroxide oxidation). In some cases such modification may cause toxic enhancement of function or damage biological component substrate.

Indication on "agent" further comprises combination of two or more active agents. "Combination" also further comprises much component, such as two-component composition, where agents are separated by and supplied separately or preliminarily are mixed. For example, much component pharmaceutical package may contain two or more agents, stored separately. Consequently, this aspect of the present invention includes combined therapy. Combined therapy includes combined introduction of agent and other active substance, such as chemotherapeutic compound, immunotherapeutic compound, cytokine, genetic molecule and/or anesthetic.

Terms "effective amount" and "therapeutically effective amount", used in this document, mean sufficient amount of agent to provide for desired therapeutic or physiological effect or result. Such effect or result includes inhibition of growth or cell viability, associated with gliomoi in brain. Undesirable effects, for example, adverse effects, sometimes manifested along with desired therapeutic effect;

consequently, city balances potential benefit with potential marks when determining the, which is the suitable "effective amount". Accurate desired amount will vary from subject to subject, depending on the type, age and general state subject, method of administration and T. U. So, is impossible indicate accurate "effective amount". However suitable "effective amount" in any individual case can be determined common specialist in the given engineering, with application of only standard investigating.

Effective amount of amount of is considered to be, required for inhibition of growth or cell viability, associated with gliomoi. Effective amounts of include introduction of from approximately 1 ng to approximately 1 g/distinguished. Administration can be a single dose or series of doses separated by. Number of includes introduction of from approximately 5 ng to approximately 800 mg/distinguished. Actual amount of include approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 ng or 200, 300, 400, 500, 600, 700, 800, 900, 1000 ng or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, on distinguished.

The composition is contain at least one of compounds of the formula i or ii together with one or more pharmaceutically acceptable carriers and optionally with other therapeutic agents. Each carrier should be pharmaceutically "acceptable" the point of view of compatibility with other ingredients of medicinal form and not to inflict harmful to subject. Carriers can include excipients and other additives, such as diluents, detergents, dyes, wetting or emulsifying agents, pH of buffer-agents, preserving agents and T. U. Compositions include suitable for oral, rectal, nasal, local (including transbukkalnoe and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intracutaneous) composition introduction. Compositions can be convenient are presented in form of standard medicinal form and can be obtained methods, well known in the field of pharmacy. Such methods include the stage of bringing in contact active ingredient with carrier, which consists of one or more additional ingredients. As a rule, medicinal forms is obtained by uniform and thorough bringing into contact the active ingredient with liquid carriers, diluents, adjuvants and/or excipients, or finely ground solid carriers, or with both, and then if necessary molding product.

Compounds of the formula i or ii may be introduced orally, locally or parenterally in medicinal forms of single metering, containing common nontoxic pharmaceutically acceptable carriers, adjuvants and fillers. Term "parenteral", used in this document, includes subcutaneous injection, aerosol into lungs or nasal cavity, intravenous, intramuscular, intrathecal, intrakranialnyi, injection, intraocular or infusion methods.

The present invention also provides suitable local, oral and parenteral pharmaceutical compositions for use in new methods of treatment according to the present invention. Proposed compounds may be introduced orally in the form of tablets, aqueous or oil suspensions, candies, lozenges, powders, granules, emulsions, capsules, syrups or elixirs. Composition for oral use may contain one or more agents, selected from the group sweeteners, flavorings, dyes and preservatives, for production of pharmaceutically original and delicious preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable deglomerative agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthane gum, bentonite, alginic acid or agar. Suitable flavorings include oil of peppermint, oil seeds wintering, cherry, orange or raspberry. Suitable preservatives include sodium benzoate, vitamin E, alfatokoferol, ascorbic acid, methylparaben, propylparaben or sodium bisulfite. Suitable lubricating substance include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable agents holding include glycerol monostearate or glitserildistearat. Tablets contain active ingredient in mixture with intoxic pharmaceutically acceptable excipients, which are suitable for of producing tablets.

Such excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and deglomerative agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or gum arabic; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets can not have coating or may be coated with known methods for delay decay and suction in digestive - tract and, so, provide prolonged effect in for prolonged. For example, can be used substance, providing holding, such as glitserilmonostearat or glitserildistearat. Coating also can be made with use of methods, disclosed in Patent USA № 4256108, 4160452 and 4265874, for forming osmotic therapeutic tablets for controlled release.

Above indicated compounds, and also farmatsevticheskiaktivnyi agent, used in method of the invention, can be introduced for use in vivo of parenterally by injection or gradual perfusion in time independently or together. Administration can be intraocular, intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, intracavity, transdermal or infusion by means of, for example, osmotic pump. For research in vitro of agents may be added or dissolved in corresponding biologically acceptable buffer and added to cell or tissue.

Composition for parenteral administration contain sterile aqueous or non-aqueous solutions, suspension and emulsion. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsion or suspension, including physiological solution and buffer medium. Parenteral carriers include sodium chloride solution, the dextrose Ringer, the dextrose and sodium chloride, laktatnye intravenous Ringer carriers include liquid and nutrient fillers, electrolytic fillers (such as based on dekstroze Ringer) and T. U. Also can be present preserving agents and other additives, such as, for example, antimicrobial, antioxidant, weaken the agents, growth factors and inert gases and T. U.

The present invention includes various pharmaceutical compositions, applicable for facilitating disease. Pharmaceutical compositions according to one version of the present invention is obtained by combination of above said compound, its analogs, derivatives or salts, or combinations of above indicated compounds and one or more farmatsevticheskiaktivnykh agents into shape, suitable for administration to a subject, with use of carriers, fillers and additives or auxiliary substances. Frequently used carriers or auxiliary substances include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugar, talc, milk protein, gelatin, starch, vitamins, cellulose and their derivatives, animal and vegetable oil, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and much atomic alcohols. Carriers for intravenous administration include liquid and nutrient fillers. Preserving agents are antimicrobial, antioxidant, weaken the agents and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, nontoxic excipients, salt including, preserving agents, buffers and T. U ., as described, for example, in Remington's the PharmaceuticalSciences, 20 - E of 2 yr. The Williams and sort Wilkins (2000) and The the British the National Formulary 43-and-of E of 2 yr. (British medical association and the Royal society pharmacists Great Britain, 2002; http://bnf.rhn.net), whose content is connected into the present description as references. Level of pH and accurate concentration of different components pharmaceutical compositions is regulated according to by common methods in this area. Cm. Goodman and sort Gilman's the of The Pharmacological BASIS team for Laptops therapeutics (7 - E of 2 yr ., 1985).

Pharmaceutical compositions is preferably produced and introduced in dose units. Solid unit dose can be tablets, capsule and suppositories. For treatment of a subject, depending on activity of compounds, method of administration, nature and severity of disorder, age and body weight of a subject, can be used various daily dose. However at certain circumstances, more suitable may be higher or more low daily dose. Introduction of daily dose may be accomplished as by single introduction of, in form of a separate unit dose, so and several units at dose, and by much introductions of doses separated by intervals.

Pharmaceutical compositions may be introduced locally or systemic in therapeutically effective dose. Amount, effective for such application, end, will be depend on disease severity, mass and general state subject. Usually, dose, used in vitro of, can be used as useful guidance for determining amounts of, acceptable for introduction of the in situ pharmaceutical composition, and model of animals can be used for of determination of effective doses for treatment of cytotoxic side effects. Different recommendations are described, for example, in Langer, the science, 249:1527, 1990.

Composition for oral use may be in the form of solid gelatin capsules, where active ingredient mixed with inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules, where active ingredient mixed with water or oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain usually active substances in mixture with excipients, suitable for production of aqueous suspension. Such excipients may be (1) suspending agent, such as carboxymethyl cellulose sodium, methyl cellulose, hydro ksipropilmetiltsellyuloza, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; (2) dispersing or wetting agents, which may be (and) natural fosfatidom, such as lecithin; (b) condensation product of alkylene oxide with fatty acid, such as the polyoxyethylenestearate; (in) condensation product of ethylene oxide with-chain aliphatic alcohol, such as geptadekaetilenoksitsetanol; (g) condensation product of ethylene oxide with incomplete ester of, obtained from fatty acid and hexitol, such as polioksietilensorbitmonooleat, or (d) condensation product of ethylene oxide with incomplete ester, obtained from fatty acids and hexitol anhydrides, such as polioksietilensorbitanmonooleat.

Pharmaceutical compositions can be in the form of sterile injection aqueous or oil suspension. Such suspension can be obtained in accordance with the known methods using suitable dispersing or moistening agents and suspending agents, which have been mentioned above. Sterile injection preparation can also be a sterile injection solution or suspension in nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1.3 - butanediol. Acceptable carriers and solvents, which can be used, are water, Ringer solution and isotonic sodium chloride solution. In addition, as a solvent or suspending medium generally used sterile nonvolatile oil. For this purpose can be used any soft non-volatile oil, including synthetic mono diglycerides. In addition, fatty acids, such as oleic acid, are used in injection preparations.

Above indicated compounds can also be introduced in the form of systems of the liposomal delivery, such as small single-layer vesicles, large single-layer vesicles and much sloinye vesicles. Liposomes may be formed by from multiple phospholipids, such as cholesterol, stearylamine or phosphatide and lkhol and n s.

Compounds can also be presented for use in the form of veterinary compositions, which may be obtained, for example, methods, which are common in this area. Examples of such veterinary compositions include those, which adapted for:

(and) oral administration, external application, for example, liquid medicinal forms (for example, water or Non-aqueous solutions, or suspension); tablet or pill; powders, granules or pellets for mixing with fodder products; paste for applying on tongue;

(b) parenteral administration, for example, subcutaneous, intramuscular or intravenous injection, for example, in the form of a sterile solution or suspension;

or (if necessary) by intramammarnoi injection, when suspension or solution is introduced in udder through teat;

(in) local application, for example, in the form of cream, ointment or aerosol, applied on skin; or

(g) introduction of intravaginal, T. E. in the form of a pessary, cream or foam.

The present invention then is disclosed by means of the following limited.

Example 1

Circuit 1

Substituted 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - ones can be obtained by synthetic, illustrated on circuit 1. starting from intermediate ester 1 - 1, interaction with diizopropilamidom lithium (poison) at low temperature causes formation of enolyatnogo anion, which is suppressed etilformiatom, to produce aldehyde 1 - 2. Heating aldehyde to temperature reflux with 3 - hydro ksipiridinolom1 - 3 results in production of ester 1 - 4. Cyclization compounds 1 - 4 in boiling acetic acid provides after crystallization required target compounds of 1 - 5 (circuit 1).

Circuit 1

where R is³ is a with - m alkyl, optionally interrupted about, C5 - 6 cycloalkyl or benzyl, optionally condensed with 5 - containing about chlennymgeterotsiklilom;

R⁶ is a Cl or vg; and

R⁷ is a 1.

Compound 1621

Ethyl - 2 - cyclohexyl - 3 - oksopropanoat (1 - 2)

Ethyl - 2 - cyclohexanol acetate (7.5 g, 44 mmole) dissolved in volatile anhydrous tetrahydrofurane (20 ml) and then added to the solution poison (28.6 ml, 2.0 m solution in heptane/tetrahydrofurane/ethylbenzene) at -78 theoretically. After stirring at that temperature for 1 hour added to ethyl formate (4.8 ml, 59 mmol) and reaction mixture was heated UP to room temperature in 3 hours. Reaction carefully quenched H2O, then tetrahydrofurane they moved away on rotor evaporator. Mixture then extracted with petroleum ether 60 - 80 theoretically (khz). Then aqueous layer acidified up to pH 2 concentrated Histidinum and extracted ch2ci2 (^X 2). Organic extracts dried above Na2S04, filtered and they concentrated to produce desired aldehyde 1 - 2 in the form of orange oil (5.65 g, 65%).¹ H NMR (500 MHz, CDCI₃ ) b 1.14 (of m, 4h), 1.31 (T, 4h), 1.76 (T, 2h), 2.18 (T, 2h), 3.00 (T, 1h), 4.24 (T, 2h), 7.01 (d of, j=12, 5 Hz, 1H), 9.70 (Dd1, j=4, 1 Hz, 1H), 11.66 (d of, j=12, 5 Hz, 1H).

Ε-: Ζ - Ethyl - 2 - cyclohexyl - 3 - (3 - hydro ksipiridin - 2 - ylamino) acrylate (1 - 4) Aldehyde 1 - 2 (4.0 g, 20.2 mmol) dissolved in volatile eyun (100 ml), to which added to the 2 - amino - 3 - hydro ksipiridin1 - 3 (2.0 g, 18.2 mmol) and reaction mixture was heated UP to temperature reflux for 3 hours. Solvent they moved away under vacuum to produce brown solid substance (5.4 g, quantitative yield). Approximate NMR - analysis proved mixture of isomers E.Z1 - 4 and material weathered the next stage without purification.

Of 3 - tsikpogeksil - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (1 - 5) (1621) Ketoenol mixture 1 - 4 (5.4 g, 18.6 mmol) dissolved in volatile ice ason (100 ml) and prepared dark - brown solution was heated UP to temperature reflux for 3 hours. Solvent they moved away under vacuum to produce yellow/brown solid substance. Crude material dissolved in volatile hot eyun (100 ml) and left to stand during night time. Produced yellow solid collected by filtration and dried to produce 3 - cyclohexyl - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - one 1 - 5 in the form of yellow plates (2.8 g, 62%).¹ H NMR (500 MHz, CDCI₃ ) of Δ 1.31 (of m, 1η), 1.47 (of m, 4η), 1.78 (of m, 1η), 1.87 (of m, 2η), 1.97 (of m, 2η), 2.93 (of m, 1η), 7.03 (t of, j=7, 5 Hz, 1η), 7.08 (Dd1, j=7, 5, 1.5 Hz, 1η), 8.13 (of c, 1η), 8.55 (Dd1, j=7, 5, 1.5 Hz, 1η). HPLC: t of_R =9.39 min (98.1%), Msh-m/z 245.09 [m + h]⁺ .

Example 2

Substituted aryl and heteroaryl 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - ones can be, taking 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it 1 - 5, where R is⁷ represents H, synthesized in example 1, shown above on circuit 1, and having iodirovanie in ortho position - phenol with application of iodine and hydrogen peroxide to produce 2 - 1 (Circuit 2). After protection of phenol for production of 2 - 2, may be reaction combination Suzuki with of Pd (PPh3) 4 as catalyst, and commercially available boron acids of R⁷ B of (OH of) 2 or boronatnymi esters of R⁷ B OF (OR-⁵ ) 2 to produce aryl and heteroaryl compounds 2 - 3. Removal of protection with izopropoksigruppy in connection 2 - 3 action of nvg gives target compounds of 2 - 4 (circuit 2).

where R is³ is a with - malkil or shcho^ns - malkil;

R⁶ is a Cl; and

R⁷ is a 5ili 6 - members optionally substituted heterocyclyl, optionally substituted phenyl or I.

Compound 1629

Of 7 - chloro - 9 - hydro xy - 8 - iodine - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (2 - 1)

Of 7 - chloro - 9 - hydro xy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 1 - 4 (500 mg, 2.1 mmol) dissolved in volatile eyun (20 ml) and then treated with iodine (585 mg, 2.3 mmol) and 30% aqueous H2O2 (0.24 ml, 2.35 mmol) and reaction mixture stirring for 48 hours. The precipitate formed is filtered, washed eyun and then dried to produce iodine compound 2 - 1 in the form of yellow powder (520 mg, 68%).¹ H NMR (500 MHz, CDCI₃ ) b 1.00 (t of, j=7, 5 Hz, troublesome zone), 1.70 (sext, j=7, 5 Hz, 2H), 2.62 (t of, j=7.5 Hz, 2H), 5.31 (s-, 1h), 8.81 (s-, 1h), 8.65 (s-, 1h).

Of 7 - chloro - 8 - iodine - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (2 - 2)

Of 7 - chloro - 9 - hydro xy - 8 - iodine - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it (450 mg, 1.2 mmole) dissolved in volatile anhydrous dimethylformamide (10 ml), to which then added to K2CO3 (511 mg, 3.7 mmol) and 2 - brominepropane (290 mcl, 3.08 mmole), and the obtained mixture is dark color of stirring at 60 theoretically in argon atmosphere during night time. Reaction mixture diluted EtOAc (50 ml) and H2O (70 ml) and they separated layer EtOAc. Aqueous layer additionally extracted EtOAc (χ2) and combined organic extracts washed salt solution, dried above Na2S04, filtered and they concentrated to produce isopropyl ester 2 - 2 in the form of yellow solid substance (230 mg, 46%).¹ H NMR (500 MHz, CDCI3) b 0.99 (t of, j=7, 5 Hz, troublesome zone), 1.44 (d of, j=6, 0 Hz, 6h), 1.69 (sext, j=7, 5 Hz, 2H), 2.61 (t of, j=7, 5 Hz, 2H), 5.51 (sept, j=6, 0 Hz, 1H), 8.15 (s-, 1h), 8.92 (s-, 1h).

Of 7 - chloro - 8 - (pyridine - 3 - yl) - 9 - isopropoxy - 3 - propyl - 4 [ya4 - pyrido [1, 2 - and]

pyrimidine - 4 - it (2 - 3)

Of 7 - chloro - 8 - iodine - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 2 - 2 (100 mg, 0.25 mmol), 3 - piridilboronovuyu acid (37 mg, 0.30 mmole) dissolved in volatile dimethylformamide (5 ml), and then added to 2M to₂ CS (0.5 ml, 1 mmol)). Solution degassed by means of bubbling argon/ultrasound, then added to the of Pd (cooling systems₃ )₄ (15 mg, 0.013 mmol) and reaction mixture was heated UP to 100 theoretically for 18 hours. Reaction mixture diluted EtOAc and filtered through Celite, washing EtOAc. Solvent they moved away under vacuum and residue they cleaned flash - chromatography, elyuiruya 40% eyuas/petroleum ether 40 - 60 theoretically, to produce resinous solid substance. The second elution of column 10 - 20% ether/CH₂ C12 led to production of desired pyridine 2 - 3 in the form of white solid substance (53 mg, 60%).¹ H NMR (500 MHz, CDCI3) of Δ 1.01 (t of, J=7.5 Hz, troublesome zone), 1.05 (d of, j=6, 0 Hz, 6h), 1.72 (sext, J=7.5 Hz, 2H), 2.66 (t of, J= 7.5 Hz, 2H), 4.93 (sept, j=6, 0 Hz, 1H), 7.45 (of DDD, J=8, 5, 0.5 Hz, 1H), 7.77 (of dT, j=8, 0, 2.0 Hz, 1H), 8.23 (s-, 1h), 8.68 (d of, J= 1.5 Hz, 1H), 8.71 (Dd1, J=5.0, 1.5 Hz, 1H), 9.02 (s-, 1h).

Of 7 - chloro - 9 - hydro xy - 3 - propyl - 8 - (pyridine - 3 - yl) - 4 [ya4 - pyrido [1, 2 -

and] pyrimidine - 4 - it (2 - 4) (1629)

of 7 - chloro - 8 - (pyridine - 3 - yl) - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 -

and] pyrimidine - 4 - it 2 - 3 (50 mg, 0.14 mmol) to added to the 48% aqueous nvg (3 ml) and was heated UP to 120 theoretically for 1.5 hours. After cooling, obtained of fistula solution neutralized by means of saturated water yansoz. Aqueous layer extracted ch2ci2 (^X 3) and organic layer dried above of Na₂S04, filtered and they concentrated to produce 7 - chloro - 9 - hydro xy - propyl - 8 - (pyridine - 3 - yl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one (2 - 4) in the form of svetlozelenogo powder (38 mg, 86%).¹ H NMR (500 MHz, CDCI₃ ) of Δ 1.02 (t of, 4=7.5 Hz, troublesome zone), 1.72 (sext, 4=7,5 Hz, 2η), 2.67 (t of, 4=7,5 Hz, 2η), 7.47 (Dd1, 4=7,5, 5.0 Hz, 1η), 7.84 (d of, 4=7,5 Hz, 1η), 8.14 (s-, 1η), 8.71 (d of, 4=5,0 Hz, 1η), 8.74 (s-, 1η), 8.75 (brr s-, 1η), HPLC:

t of_R =7.99 min. (91.7%), MSH-: m/z 316.1 [M + H]⁺ .

Substituted methylamino compounds can be obtained from 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - ones, synthesized according to scheme 1 above, adapting method, described in Chemistry care HeterocyclicCompounds, 1992, 28, 1425 - 1431. Interaction of commercially available amines with 9 - hydro xy - 4npirido [1, 2 - and] pyrimidine - 4 - onami1 - 5 provided desired compounds 3 - 1 (Circuit 3).

Circuit 3

where R is³ is a C5 - 6 cycloalkyl, with - m alkyl, optionally interrupted O or benzyl;

R⁷ is a CH-₂ THE NR¹⁰R¹⁰ , where R is⁹ and R¹⁰ are C1 - 2 alkyl or together with n, to which they are connected, form morpholinyl.

Compound 1627

Of 3 - tsikpopentil - 8 - (dimethylamino) - methyl - 9 - hydro xy - 4h - pyrido [1, 2 -

and] pyrimidine - 4 - it (3 - 1)

Solution cyclopentyl - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - one (137 mg, 0.60 mmol) 1 - 5 in anhydrous toluene (4 ml) treated ν, ν, ν, νtetrametilmetilendiaminom (240 mcl, 1.76 mmole) for 4 hours. Reaction mixture was, they concentrated and produced solid crystallized from hot acetonitrile to produce desired amine 3 - 1 in the form of pale - green solid substance (50 mg, 29%).¹ H NMR (500 MHz, dmsod6) B 1.71 (of m, 4h), 1.84 (T, 2h), 1.66 (t, 2H), 2.07 (T, 2h), 2.41 (s-, 6h), 3.23 (T, 1h), 3.72 (s-, 2h), 6.84 (d of, J=7.5 Hz, 1H), 8.26 (s-, 1h), 8.57 (d of, J= 7.5 Hz, 1H), HPLC: t of_R =7.64 min. (92.6%), MS: m/z 288.1 [M + H]⁺ .

Example 4

Substituted triazole compounds can be obtained from compounds 1 - 5 on circuit 1. protection of compounds 1 - 4 to yield compound 4 - 1 followed by reaction of combination sonogashiry results in the formation of compounds trimetilsililatsetilenovykh4 - 2. Removal of silane group in main conditions results in production of acetylenes 4 - 3. Compound 4 - 3vzaimodeistuet with known azide in the presence of catalyst of Cu (lit). Followed by 1.3 - dipolar the cycloaddition (click - chemistry) flows smoothly, to produce substituted triazoles 4 - 4. Finally, removal of protection compounds 4 - 4 leads to obtaining desired compounds 4 - 5 (Circuit 4). Note: azides obtained in accordance with known method, described in Synthesis 1997, 4, 413 - 414 (circuit 4).

where R is³ is a with - m alkyl;

R¹¹ is a vg; and

R¹² is a benzyl or cyclopentyl.

Compound 1616

Of 7 - bromo - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 1) Of 7 - bromo - 9 - hydro xy - 3 - propyl - 4 / - / - pyridone [1, 2 - and] pyrimidine - 4 - it 1 - 5 (2.0 g, 7.1 mmol) dissolved in volatile anhydrous dimethylformamide (30 ml), then treated to₂ C0₃ (2.93 g, 2.1 mmol) followed by addition of 2 - bromopropane (1.65 ml, 17.7 mmol) and reaction mixture stirring at 60 theoretically during night time. Volatile components they moved away under vacuum and residue treated H₂ 0 (50 ml) and eyuas (50 ml). Layer eyuas they separated and aqueous layer additionally extracted eyuas (2x50 ml). Combined organic layers washed salt solution, dried above of Na₂ S0₄ , filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 10% eyuas/petrolinym ether 40 - 60 theoretically to produce isopropyl ester 4 - 1 in the form of brown oil (1.50 g, 65%).¹ H NMR (500 MHz, CDCI₃ ) b 0.98 (t of, J=7.5 Hz, troublesome zone), 1.53 (d of, j=6, 0 Hz, 6h), 1.68 (sext, J=7.5 Hz, 2H), 2.63 (t of, J=7.5 Hz, 2H), 4.73 (sept, j=6, 0 Hz, 1H), 6.96 (d of, j=1, 5 Hz, 1H), 8.24 (s-, 1h), 8.80 (d of, j=1, 5 Hz, 1H).

9 of - isopropoxy - 3 - propyl - 7 - ((trimetilsoliil) ethynyl) - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 2)

Of 7 - bromo - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 4 - 1 (1.45 g, 4.5 mmole) dissolved in volatile anhydrous tetrahydrofurane (60 ml) and diizopropilamine (5 ml, 35.7 mmole). Solution degassed by means of bubbling argon and ultrasound, then in reaction vessel 1.20 the following reagents. PdCl2 (cooling systems₃ )₂ (188 mg, 0.27 mmole), cUL Listing Mark (17 mg, 0.09 mmol) and TMS acetylene (1 ml, 7.08 mmol), then the reaction mixture was heated UP to 70 theoretically for 2 hours. Reaction mixture filtered through small layer of silica gel, washing EtOAc. They concentrated filtrate and residue they cleaned flash - chromatography, elyuiruyapetroleinm ether 40 - 60 theoretically - 40% EtOAc/petroleum ether 40 - 60 theoretically to silane 4 - 2 in the form of yellow solid substance (1.40 g, 92%). ¹N NMR (500 MHz, CDCI₃ ) of Δ 0.29 (s-, 9η), 0.98 (t of, J=7.5 Hz, 3η), 1.52 (d of, j=6, 0 Hz, 6η), 1.68 (sext, J=7.5 Hz, 2η), 2.62 (t of, J=7.5 Hz, 2η), 4.75 (sept, j=6, 0 Hz, 1η), 6.85 (d of, j=1, 5 Hz, 1η), 8.22 (s-, 1 η), 8.79 (d of, j=1, 5 Hz, 1η).

7 of - ethynyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 3) 9 of - isopropoxy - 3 - propyl - 7 - ((trimetilsoliil) ethynyl) - 4 / - / - pyrido [1, 2 -

and] pyrimidine - 4 - it 4 - 2 (1.40 g, 4.1 mmole) dissolved in volatile meon (20 ml), then added to the to₂ CS (622 mg, 4.5 mmol) to reaction. After stirring at room temperature for 15 minutes reaction mixture diluted ether (20 ml) and n₂ 0 (20 ml). Organic layer they separated, and aqueous layer additionally extracted ether (2x20 ml). Combined organic layers washed salt solution, dried above of Na₂S04, filtered and they concentrated to produce acetylene 4 - 3 in the form of orange solid substance (950 mg, 86%).¹ H NMR (500 MHz, CDCI₃ ) b 0.98 (t of, J=7.5 Hz, troublesome zone), 1.53 (d of, j=6, 0 Hz, 6h), 1.68 (sext, J=7.5 Hz, 2H), 2.63 (t of, j7, 5 Hz, 2H), 3.20 (s-, 1h), 4.74 (sept, j=6, 0 Hz, 1H), 6.87 (d of, j=1, 5 Hz, 1H), 8.23 (s-, 1h), 8.83 (s-, j=2, 0 Hz, 1η).

Of 7 - (1 - benzyl-of f ON , 2, 3 - triazole - 4 - yl) - 9 - isopropoxy - 3 - propyl - 4 [ya4 -

pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 4)

7 of - ethynyl - 9 - isopropoxy - 3 - propyl - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 3) (200 mg, 0.74 mmol) dissolved in volatile eyun (5 ml), then added to the benzilazid (125 mg, 0.94 mmole) in eyun (5 ml) followed by addition of H₂ 0 (10 ml). Then to reaction mixture added to the CuS04 ' 5h₂ 0 (123 mcl, 0, magnetic core aqueous solution, 5 mole %) and sodium ascorbate (148 mcl, M aqueous solution, 20 mole %) and reaction mixture stirring in the darkness for 24 hours. Reaction mixture diluted H₂ 0 and extracted CH-₂ CL₂ (khz). Organic layer washed salt solution, dried above of Na₂S04, filtered, they concentrated and they cleaned flash - chromatography, elyuiruya 10 - 40% eyuas/petrolinym ether 40 - 60 theoretically, to produce triazole 4 - 4 in the form of white solid substance (308 mg, quantitative yield).¹ H NMR (500 MHz, CDCI₃ ) b 0.98 (t of, J= 7.5 Hz, troublesome zone), 1.56 (d of, (d of, 4=2,0 Hz, 1η).

Of 7 - (1 - benzyl-of f Η - of λ , 2, 3 - triazole - 4 - yl) - 9 - hydro xy - 3 - propyl - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it (4 - 5) (1616)

Of 7 - (1 - benzyl - 7 / - / - 1.2, 3 - triazole - 4 - yl) - 9 - isopropoxy - 3 - propyl - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 4 - 4 (300 mg, 0.74 mmol) added to the to 48% aqueous nvg (4 ml) and mixture was heated UP to temperature reflux for 1 hour. After cooling reaction mixture neutralized with saturated water yansoz, then extracted ch2ci2 (^X 3). Organic layer washed salt solution, dried above Na2S04, filtered and they concentrated to produce product of 4 - 5 in the form of almost white powder (256 mg, 95%).¹ H NMR (500 MHz, CDCI3) 61.00 (t of, 4=7,5 Hz, troublesome zone), 1.70 (sext, 4=7, 5 [gts5, 2h), 2.64 (t of, 4=7, 5 [gts5, 2h), 5.61 (s-, 2h), 7.39 (of m, 5h), 7.72 (d of, j=1, 5 [gts5, 1H), 7.79 (s-, 1h), 8.11 (s-, 1η), 8.85 (d of, 4=1, 5 [gts5, 1h), vezhkh7_K=11, 13 min (93.5%), ms: m/z 362.1 [M + H]⁺ .

Example 5

Series of 9 - hydro xy - 4 - oxo - 4h - pyrido [1, 2 - and] pirimidinkarboksamidov may be obtained by condensation of 3 - hydro xy - 2 - aminopiridinolov1 - 3 with diethyl (etoksimetilen) low natom to produce intermediate compounds 5 - 1. Followed by closure ring in boiling acetic acid results in production of ethyl ester of 5 - 2. Hydro lys 2ν of NaOH gives acid 5 - 3, further transformation of to chloride 5 - 4 is achieved due to application of thionyl chloride. Then target compounds of 5 - 5 are synthesized by mixing chloride 5 - 4 with corresponding amine (circuit 5).

R⁷ represents H or methyl;

R⁹ represents H;

R¹⁰ is a C3 - 8 alkyl, optionally interrupted about, (sngshchg 5 - or 6 - members of n-containing heterocyclyl, (CH2) about - 1 C3 - 6 cycloalkyl or CH2 optionally substituted phenyl, optionally condensed with 5 - containing about chlennymgeterotsiklilom; or

R⁹ and R¹⁰ together with n, to which they are connected, form 5ili 6 - membered ring.

Compound 1460

Diethyl - 2 - ((3 - hydro ksipiridin - 2 - ylamino) methylene) low NAT (5 - 1)

of 2 - amino - 3 - hydro ksipiridin(1 - 3) (20.0 g, 0.18 mole) and diethyl - 2 (etoksimetilen) low NAT (55.0 ml, 0.27 mole) stirring together in flask at 130 theoretically for 40 min. Pyridine clisked in solution at heating, then from solution dropped new yellow solid substance. Reaction mixture was and solid substance recrystallized (eyun) and then dried in air with production of the product 5 - 1 in the form of yellow solid substance (39.0 g, 77%).¹ H NMR (DMSO De, 500 MHz) 61.20 (of m, 6h), 4.17 (of Q, J= 6.5 Hz, 2H), 4.22 (of Q, J= 6.5 Hz, 2H), 7.10 (t of, J= 7.0 Hz, 1H), 7.32 (d of, J= 7.0 Hz, 1H), 7.87 (d of, J= 2.1 Hz, 1H), 9.13 (d of, J= 12.5 Hz, 1H), 10.88 (of BS, 1h), 11.10 (d of, J= 12.5 Hz, 1H).

Ethyl - 9 - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carboxylate (5 - 2) Diethyl - 2 - ((3 - hydro ksipiridin - 2 - yline) methylene) low NAT 5 - 1 (47.7 g, 0.17 mole) was heated UP to temperature reflux in acetic acid (400 ml) for 4.5 hours. Reaction mixture they concentrated at spider nnom pressure to produce yellow solid substance. Recrystallization (ethanol) febrifuges desired product 5 - 2 in the form of pale - yellow solid substance (30.6 g, 76%).¹ H NMR (DMSO De, 500 MHz) 61.30 (t of, J= 7.0 Hz of troublesome zone), 4.26 (of Q, J= 7 Hz, 2H), 7.41 (t of, J= 8.5 Hz, 1H), 7.49 (d of, J= 8.5 Hz, 1H), 7.63 (d of, J= 8.5 Hz, 1H), 7.80 (s-, 1h).

9 of - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carboxylic acid (5 - 3).

Ester (5 - 2) (5.0 g, 0.02 mole) suspended in ethanol (400 ml), to which added to the 2n aqueous solution of hydro ksida sodium (192 ml, 0.38 mole). Reaction mixture was heated UP at 40 theoretically for 3 hours, during this period in reaction mixture it was manifested - bright yellow precipitate. Ethanol they moved away at spider nnom pressure and aqueous solution extracted with ethyl acetate (150 ml).

Aqueous solution acidified up to pH 3, of a 10% aqueous solution of Histidinum, and left on the 17 hours in refrigerator. Reaction mixture filtered and yellow solid washed with water (20 ml) and then dried at spider nnom pressure up to synthesis of end compound 5 - 3 in the form of its Histidinum salt (4.17 g, 86%).¹ H NMR (D OF₂ 0, 400 MHz) 62.74 (of BS, 1h), 7.35 (brr s-, 2h), 8.61 (brr s-, 1h).

9 of - hydro xy - 4 - oxo - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 3 - carbonylchloride (5 - 4) 9 of - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxylic acid (5 - 3) (4.3 g, 19.5 mmol) was heated UP to 80 theoretically in tionilkhloride for 2.5 hours. Volatile substances they moved away under vacuum. Excess thionyl chloride they moved away by means of azeotropic distillation with toluene. Prepared 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carbonylchloride 5 - 4 allocate with quantitative yield solid substance in the form of beige color.

M - tsikpogeksil - 9 - hydro xy - 4 - oxo - 4h - pyrido [1, 2 - and] pyrimidine - 3 -

carboxamide (5 - 5) (1460)

9 of - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxylic acid (5 - 3) (4.3 g, 19.5 mmol) was heated UP to 80 theoretically in tionilkhloride for 2.5 hours. Volatile substances they moved away under vacuum. Excess thionyl chloride they moved away by means of azeotropic distillation with toluene. Obtained chloroanhydride allocate in the form of solid substance beige color. Chloroanhydride (3.9 g, 17.4 mmol) suspended in ch2ci2 (65 ml) and was to 0 theoretically. Added to the diisopropylethylamine (4.0 ml) and tsiklogeksilamin (4.5 ml) and reaction mixture stirring at room temperature for 2 days. Added to 1 μ Histidinum up to pH 3, then added to the eyun (65 ml). Suspension filtered, and filtrate is they concentrated to volume (10 ml). Solution was and green solid collected by filtration, washing meon/H₂ 0 (2:1) (khz) to produce desired 1p - cyclohexyl - 9 - hydro xy - 4 - oxo - 4 / - / - pyrido [1, 2 - and] pyrimidine - 3 - carboxamide 5 - 4 (1.21 g, 24%).¹ H NMR (400 MHz, DMSO - slices) 61.30 (T, 1h), 1.39 (T, 2h), 1.87 (T, 1H), 3.86 (t, 1H), 7.48 (t of, J=7.2 Hz, 1H), 7.53 (d of, J=7.2 Hz, 1H), 8.71 (d of, 4=6,8 Hz, 1H), 8.99 (s-, 1h), ms: m/z 288.1 [M + H]⁺ .

Compound structure mm ¹ H NMR MS

1394 ABOUT ABOUT 317.4 ¹ H NMR (400 MHz, m/z 316.2 [M -

VV entries^H DMSO - C16) 50.82 (of m, troublesome zone), 1.95 (of m, 12η), 3.45 h of]⁺

it (of m, 2η), 1.79 (of m, 2η),

Of 2 - methylamino substituted pyrimidones can be obtained according to scheme 6. field aniline 1 - 3 and heating with etilkhloratsetoatsetatom in rra (polyphosphoric acid) in accordance with the method Ferrarini, P.LOf II Farmaco1995.50 (1), with. 69 - 72, leads, after isolation of the reaction product, to production of desired khlormetilnogo derivative 6 - 1. Substitution of chlorine substitute different amines leads to obtaining target amine compounds 6 - 2 (circuit 6).

R⁶ ,

Circuit 6

where R is⁵ represents H or methyl;

R⁶ represents H or Cl;

R⁹ and R¹⁰ are independently chosen from H, Ci_₈ alkyl, the CN, (CH₂ ) about - 2 with₃ .₆ cycloalkyl, CH₂ optionally substituted phenyl or (CH₂ ) about - 3 optionally substituted N--containing 5ili6chlennogo heterocyclyl;

or

R⁹ of R h of¹⁰ together with n, to which they are connected, form optionally substituted 5ili 6 - membered ring.

Compound 1408

Of 2 - (chloromethyl) - 9 - hydro xy - 4h - pyrido [1, 2 - and] pyrimidine - 4 - it (6 - 1)

Of 2 - amino - 3 - hydro ksipiridin (5.1 g, 46.3 mmol) was heated UP together with etilkhloratsetoatsetatom (6.0 ml, 44.1 mmol) in polyphosphoric acid (60 g) at 110 theoretically for 2 hours. Reaction mixture was, then added to the ice. Then carefully added to the 2ν of NaOH up to pH 4. the obtained precipitate beige color collected by filtration and dried to obtain 2 - (chloromethyl) - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it 6 - 1 (4.73 g, 49%) in the form of light - brown solid substance.¹ H NMR (400 MHz, DMSO - Sue) 64.62 (s-, 2 H), 6.43 (s-, 1h), 7.20 (of m, 2H), 8.40 (d of, 4=6, 8 [gts8, 1h).

9 of - hydro xy - 2 - ((izobutilamino) methyl) - 4 [ya4 - pyrido [1, 2 - and] pyrimidine - 4 - it hydro chloride (6 - 2)

To 2 - (chloromethyl) - 9 - hydro xy - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - TOC (6 - 1) (206 mg, 0.978 mmol) in anhydrous meon (5 ml) at 0 theoretically added to isobutylamine (0.5 ml, 5.03 mmol). Mixture then stirring at room temperature for night. Solvent they moved away under vacuum and added to the eyun (5 ml) and concentrated Histidinum (1 ml). Product dropped sediment, and its collected by filtration, washing cold ethanol. Obtained 9 - hydro xy - 2 - ((izobutilamino) methyl) - 4 / - / - pyrido [1, 2 - and] pyrimidine - 4 - it hydro chloride 6 - 2 allocate in the form of beige solid substance color (82 mg, 30%).¹ H NMR (400 MHz, DMSO) 60.93 (t of, J=7.0 Hz, troublesome zone), 1.64 (of m, 2H), 2.85 (T, 2h), 4.20 (s-, 2h), 6.39 (s-, 2η), 10.2 (brr s-, 1 η), Msh-: m/z 248.1 [M + H]⁺ .