EA004403B1 - Pirazolotriazine derivatives, pharmaceutical compositions containing them, methods of treating - Google Patents

Abstract

1. A compound of Formula (1) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrugs thereof, wherein: A is N; Z is CR<2>; Ar is selected from the group: phenyl, pyridyl, where each Ar is optionally substituted with 1 to 5 R<4> groups; R<1> is independently selected at each occurrence from H, C1-C4 alkyl; R<2> is selected from H, C1-C4 alkyl; R<3> is selected from: -H, OR<7>, NR<6A>R<7A> or phenyl, substituted with 1-3 halogen atoms or morpholino, or -C1-C10 alkyl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halogen; R<4> is independently selected at each occurrence from: C1-C10 alkyl, halo, CN, C1-C4 haloalkyl, NR<6>R<7>, OR<7>, R<6>, R<7>, R<6A> are independently selected at each occurrence from: H, C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; R<15> and R<16> are independently selected at each occurrence from H, C1-C6 alkyl, C3-C6 alkyl; with proviso that: when A is N, Z is CR<2>, R<2> is H, R<3> is -OR<7> and R<7> is H, R<1> is not H; when A is N, Z is CR<2>, R<1> is CH3, or C2H5, R<2> is H, and R<3> is OH, H, CH3, C2H5, C6H5, n-C3H7, iso- C3H7, NHC4H9, or N(C2H5)2, then Ar is not phenyl or m-CH3-phenyl; when A is N, Z is CR<2>, R2 is H, and Ar is pyridyl, and R<3> is NR<6A>R<7A>, then R<6A> and R<7A> are not H or alkyl; when A is N, Z is CR<2>, R<1> is methyl or ethyl, R<2> is H, and R<3> is H, OH, CH3, C2H5, C6H5, n-C3 H7, iso-C3H7, NH(n-C4H9), or N(C2H5)2, then Ar is not unsubstituted phenyl or m-methylphenyl; 2. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein Ar is phenyl, pyridyl, each being optionally substituted with 1-4 substituents R<4>. 3. A compound of claim 2 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein A is N, Z is CR<2>, Ar is 2,4-dihydrophenyl, 2,4-dimethylphenyl or 2,4,6,-trimethylphenyl, R<1> or R<2> are CH3 and R<3> is NR<6A>R<7A>. 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3. 6. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein R<3> is NR<6A>R<7A> or OR<7>. 7. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein Ar is phenyl, pyridyl, each being optionally substituted with 1-4 substituents R<4>, R<3> is NR<6A>R<7A> or OR<7>. 8. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein Ar is phenyl, pyridyl, each being optionally substituted with 1-4 substituents R<4>, - R<3> is NR<6A>R<7A> or OR<7> - R<1> and R<2> are independently selected from H, C1-C4-alkyl. 9. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein R<6A> is independently selected from the group: -H, -C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; R<7A> is selected independently in each occurrence from the group: - H, -C5-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; 10. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein R<6A> and R<7A> is independently selected from the group: -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo. 11. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein R<6A> is independently selected from the group: -H, -C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; R<7A> is selected independently in each occurrence from the group: -C1-C4 alkyl and each of -C1-C4 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo. 12. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein R<6A> and R<7A> are independently H or C1-C10 alkyl, each of that C1-C10 alkyl is optionally substituted with 1-3 substituents, independently selected in each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo. 13. A compound of claim 1 of Formula (50) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, selected from the group, comprising: compound of formula (50), wherein where R<3> is -NHCH(n-Pr)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Et)(n-Bu), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -(n-Pr)(CH2 and-Pr), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(CH2CH2OMe)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(n-Bu), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(CH2OMe) R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(CH2OMe)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Et)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(CH2OEt)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Me)(Ph), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Pr)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(n-Pr), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is Me; compound of formula (50), where R<3> is -NHCH(CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(CH2CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -OEt, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Et)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(CH2CN)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Me)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -OCH(Et)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Pr)(CH2 and-Pr), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Me)(CH2N(Me)2), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(and-Pr)(CH2CH2CN), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Pr)(CH2CH2CN), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Bu)(CH2CN), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is Me; compound of formula (50), where R<3> is -NHCH(Et)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is Me; compound of formula (50), where R<3> is -N(CH2CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C

Description

This invention relates to the treatment of disorders caused or exacerbated by SKE, psychiatric disorders and neurological diseases, including deep depression, anxiety disorders, disorders associated with post-traumatic stress, supranuclear palsy and nutritional disorders, as well as the treatment of immunological, cardiovascular vascular or heart-related diseases and hypersensitivity (allergies) of the colon associated with psychopathological disturbance and stress, by introducing some [1,5-a] -pyr Zolo-1,3,5triazinov.

BACKGROUND OF THE INVENTION

Corticotropin-releasing factor (hereinafter referred to as SKE), a peptide consisting of 41 amino acids, is the primary physiological regulator of secretion of a peptide derived from proopiomelanocortin (POMC) from the anterior pituitary gland [1. KMet e! A1., Prgos. Ya11. Asab. 8c1. I8L, 80: 4851 (1983); Wa1e e! A1., 8c1eise 213: 1394 (1981)]. In addition to its endocrine role in the pituitary gland, the immunohistological localization of SKE has shown that this hormone is widely distributed outside the hypothalamus in the central nervous system and produces a wide range of autonomous, electrophysiological and behavioral effects consistent with the role of the neurotransmitter or neuromodulator in the brain | \ U. Wa1e e! A1., Kes. Reg. Nogsh. Kek. 39: 245 (1983); S.E. Koob, Reg.Weyau.Meb. 2:39 (1985); E.V. Ee 8onha e! A1., 1. No. igoksg 5: 3189 (1985)]. It has also been proven that SKE plays a significant role in integrating the response of the immune system to physiological, psychological and immunological stress factors [TE. B1a1osk, Ruku1oduya1 Keu1eik 69: 1 (1989); THOSE. Mogléu, LHe 8sk 41: 527 (1987)].

Clinical results prove that SKE plays a role in psychiatric disorders and neurological diseases, including depression, anxiety disorders, and eating disorders. The role of SKE has been established in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, since they are associated with dysfunction of SKEurons in the central nervous system [see Review of E.V.Ie 8onha. No. Rtaseis 23:59 (1988)].

In affective disorders or major depression, the concentration of SKE is significantly increased in cerebrospinal fluid (C8E) in individuals not taking drugs [S.V. No Teto £ E e! A1., 8c1eise 226: 1342 (1984); CM. Wai e! A1., At.TrkusYayu 144: 873 (1987); K.I. Egapse e !. A1., Vu1. RkusYayu 28:86 (1988); M. Yeah! Oh e! A1., VyukRkusYayu 25: 355 (1989)]. In addition, the density of SKE receptors is significantly reduced in the anterior part of the cerebral cortex of suicide victims, which is consistent with SKE hypersecretion [S.V. No Teto £ E e! A1., Atsy. 6ep. Rkusy! gu 45: 577 (1988)]. In addition, there is a sharp response of adrenocorticotropin (ACTH) to SKE (iv), observed in depressed patients [P. ^. So1b e! A1., At.TrkusYayu 141: 619 (1984); E. But1 is e! A1., Rkusyopeitis bosgtoodu 9: 147 (1984); R. ^. 6o1b e! A1., Hei E.p.TMeb. 314: 1129 (1986)]. Preclinical studies in rats and primates (non-human) additionally confirm the hypothesis that hypersecretion of SKE can take part in the symptoms observed in human depression [K.M. 8arokku, Atsy. Bep. RkusYayu 46: 1047 (1989)]. There is preliminary evidence showing that tricyclic antidepressants can alter SKE levels and, therefore, modulate the amount of SKE receptors in the brain. A1., Heitorkusyoryagtasodu 2:53 (1989)].

The role of SKE in the etiology of anxiety-related disorders has also been reported. SKE causes anxiogenic effects in animals, and interactions between benzodiazepine / nonbenozodiazepine anxiolytic agents and SKE have been demonstrated in many behavioral models of anxiety

R.K. Villop e! a1., bje δοΐ. 31: 363 (1982); C.№. Wegde ap ap. Jippus Kedi1. Reyye 8 16:83 (1986)]. Preliminary studies using a possible SKE receptor antagonist, α-helical sheep SKE (9-41), in many behavioral models have shown that this antagonist induces anxiolytic-like effects that are qualitatively similar to those caused by benzodiazepines [C. ^. Vetbde ap ad. Enpp Nail. Weiau. 21: 393 (1987), Vgash Kekeatsi Keu1ei8 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have shown interactions between SKE and benzodiazepine anxiolytic agents, which is additional evidence of SKE's involvement in these disorders. Chlordiazepoxide attenuates the anxiogenic effects of SKE, as in a conflict test [K.T. Whatever! A1., P8syoryoryattasodod 86: 170 (1985); K.T. What a fuck! A1., P8syoryoryattasodod 94: 306 (1988), and in the test of acoustic (sound) fright [I.K. 8ieb1oe e! A1., Rkusjoryattaslodu 88: 147 (1986)] in rats. An antagonist of the benzodiazepine receptor (Ko15-1788), which separately had no behavioral activity in the operant conflict test, removed the action of SKE in a dose-dependent manner, while the inverse agonist of benzodiazepine (E67142) enhanced the effect of SKE [K.T. Vyop e! A1., P8syoryoryattasodod 94: 306 (1988)].

The mechanisms and sites of action through which standard anxiolytic agents and antidepressants produce therapeutic effects remain to be seen. However, it has been hypothesized that they are involved in suppressing the hypersecretion of OKB observed in these disorders. It is particularly interesting that preliminary studies of the effects SYAE receptor antagonist (α-helical SYAE _{9. 41)} in many behavioral models showed that EDO antagonist produces anxiolytic effects qualitatively similar to the benzodiazepines effects [see. review of OB. Kooib aib K.T. Βπΐΐοη, Ιη: Sogyso1gort-Ya1ea8td Bass! Og: Βηδίο aib SNshsa1 81ib1sk οί Meigorerbbe, E.V. Όε Zoiga aib S.V. Νεπιετοίί ssk. BMS Rg5555 r221 (1990)].

Some publications describe corticotropin releasing factor antagonist compounds and their use in the treatment of psychiatric disorders and neurological diseases. Examples of such publications include OiRoi! Metek PCT arrNsaboy IZ 94/11050, Ρίϊζετ \ UO 95/33750, Ρίϊζετ \ UO 95/34563, Ρίϊζετ \ UO 95/33727 and Ρίϊζετ EP 0778277 A1.

As far as known, [1,5-a] -pyrazolo1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5triazines, [1,5-a] -pyrazolopyrimidines and [1,5a] -1,2,3-triazolopyrimidines have not been previously indicated as corticotropin-releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications describing other uses of these compounds.

For example, in EP 0269859 (OkSchka, 1988) pyrazolotriazine derivatives of the formula are described

where I ¹ denotes OH or alkanoyl,

I ² represents H, OH or ZN and

I ³ denotes an unsaturated heterocyclic group, naphthyl or substituted phenyl, and it is indicated that these compounds have xanthine oxidase inhibitory activity and are useful for the treatment of gout.

EP 0594149 (Oyika, 1994) describes pyrazolotriazine derivatives and pyrazolopyrimi

where a denotes CH or Ν,

I ⁰ and I ³ denote H or alkyl and

Z ¹ and Z ² are H, alkyl, alkoxy, alkylthio, nitro, etc., and it is indicated that these compounds inhibit androgen and are useful for treating benign prostatic hypertrophy and prostate cancer.

In υδ 3910907 (1C1, 1975) pyrazolotriazines of the formula are described

X where I ¹ is CH ₃ , C ₂ H _5, or St ₅ ;

X is H, CbH ₅ , m-CH ₃ C ₆ H ₄ , ΟΝ, COOE1, C1.1 or W,

Υ is H, CbH ₅ , O-CH ₃ CbH ₄ or pCH ₃ C ₆ H ₄ , and

Ζ means OH, H, CH ₃ , C ₂ H ₅ , C ₆ H ₅ , nC ₃ H ₇ , ISO-C ₃ H ₇ , ZH, CHF ₃ , ΝΗΟ ₄ Η ₉ or Ν (Ο ₂ Η ₅ ) ₂ , and it is indicated that these compounds are cAMP-phosphodiesterase inhibitors and are useful as bronchodilators.

In υδ 3995039 pyrazolotriazines of the formula are described

where I ¹ denotes H or alkyl,

I ² is H or alkyl,

I ³ is H, alkyl, alkanoyl, carbamoyl or lower alkylcarbamoyl and

I stand for pyridyl, pyrimidinyl or pyrazinyl, and it is indicated that these compounds are useful as bronchodilators.

In υδ 5137887 pyrazolotriazines of the formula are described

where I stands for lower alkoxy, and it is claimed that these compounds are xanthine oxidase inhibitors and are useful for the treatment of gout.

In υδ 4892576 pyrazolotriazines of the formula are described

where X is O or 8,

Ag is phenyl, naphthyl, pyridyl or thienyl,

Kb-K ₈ is H, alkyl, etc. and

K ₉ is H, alkyl, phenyl, etc.

This patent states that these compounds are useful as herbicides and plant growth regulators.

U 8 5484760 and W) 92/10098 describe herbicidal compositions comprising, among other substances, a herbicidal compound of the formula

where A may be Ν,

B may be SC ₃ , K ₃ may be phenyl or substituted phenyl, etc.,

K stands for -Ν (Κ4) 8Ο ₂ Κ ₅ or -8Ο ₂ Ν (Κ ₆ ) Κ ₇ , and

Nd and K ₂ taken together can form where X, Υ and Ζ are H, alkyl, acyl, etc. and

Ό stands for O or 8.

In υδ 3910907 and Zeid e! A1., PMeFset., 1982, 25, 243-249 triazolotriazines, which are inhibitors of cAMP phosphodiesterase, of the formula

where Ζ is H, OH, CH ₃ , C ₂ H ₅ , C ₆ H ₅ , nC ₃ H ₇ , ISO-C ₃ H ₇ , 8H, 8CH ₃ , ΝΗ (1ι-Ο ₄ Η ₉ ) or Ν (Ο ₂ Η ₅ ) ₂ ,

K denotes H or CH ₃ and

Nd is CH ₃ or C ₂ H ₅ .

This link lists eight therapeutic areas where cAMP phosphodiesterase inhibitors could be used: asthma, diabetes mellitus, birth control, male infertility, psoriasis, thrombosis, anxiety and hypertension.

G) 95/35298 (O15ika, 1995) describes pyrazolopyrimidines and states that they are useful as analgesics. These compounds are represented by the formula

where ζ) is carbonyl or sulfonyl, η is 0 or 1,

A is a single bond, alkylene or alkenylene,

K ¹ is H, alkyl, etc.,

K ² is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy,

K ³ is H, alkyl or phenyl,

K ⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio substituted phenyl or halogen,

K ⁵ and K ⁶ are H or alkyl.

EP 0591528 (O15ika, 1991) describes the anti-inflammatory use of pyrazolopyrimidines represented by the formula

where Kd, K ₂ , K ₃ and Kd are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl or phenyl,

K ₅ stands for 8Kb or ΝΚ ₇ Κ ₈ ,

KB is pyridyl or optionally substituted phenyl, and

K ₇ and K ₈ are H or optionally substituted phenyl.

In Zrppdeg e! ak., RMeskSiet., 1976, νοΐ.19, No. 2, 291-296 and Zrppdeg i. 8. pa1ep15 4021556 and 3920652 pyrazolopyrimidines of the formula he are described

to where K may be phenyl substituted with phenyl or pyridyl, and their use for treating gout based on their ability to inhibit xanthine oxidase.

In eosy e! ak, GRgakSzegshe, 321, 2, 1979, 341-344, compounds of the formula are described

where K ¹ denotes CE ₃ , C ₂ E ₅ or C ₆ H ₄ E and

K ² is CH ₃ , C ₂ H ₅ , CE ₃ or C ₆ H ₄ E.

In Madiyezai e! A1., Vi11.8os. Be1§., νοΐ.101, No. 2, 1992, sections 131-136 described pyrazolo [1,5a] -pyrimidine of the formula

In lbut e! A1., AgskRyagt., (λνεΐηΐιεΐιη) 320, 487-491 (1987) pyrazolo [1,5-a] pyrimidines of the formula are described

4-phenyl-3-cyano-2-aminopyrid-2-yl.

Other references describing azolopyrimidines include EP 0511528 (Sisika, 1992), FROM 4997940 (λολν, 1991), EP 0374448 (Mzzap, 1990), FR 4621556 (ΙΟΝ, 1997), EP 0531901 (Erzalua, 1993), FROM 4567263 ( VAZE, 1986), EP 0662477 (1sagigo, 1995), ϋΕ 4243279 (Vaueg, 1994), IZ 5397774 (ODOEi, 1995), EP 0521622 (υρΐοΐιη, 1993), XV O 94/109017 (ODOEi, 1994), 1.Meb.Syet., 24, 610-613 (1981) and 1.Ne1.Syet., 22, 601 (1985).

SUMMARY OF THE INVENTION

In accordance with one aspect, this invention relates to new compounds, pharmaceutical compositions and methods that can be used to treat affective disorder, anxiety, depression, irritable bowel syndrome (mucous colitis), post-traumatic stress disorder, supranuclear palsy, immune suppression, disease Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other appetite disorder, withdrawal symptoms of a drug (drug) or alcohol, drug addiction, inflammatory disorder, childbearing problems, disorders whose treatment can be accelerated or alleviated by antagonistic effects on SKE, including, but not limited to, disorders induced or exacerbated by SKE, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; a disorder manifested in general anxiety; panic attacks, phobias, obsessive obsessive disorder; post-traumatic stress disorder; sleep disturbances caused by stress; mood disorders such as depression, including major depression, episodic depression, childhood, abuse-induced depression, and postpartum depression; dysthymia (dull mood); bipolar disorders; cyclothymia, fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; diseases of the gastrointestinal tract, such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea and postoperative hypersensitivity (allergy) of the ileum or colon caused by psychopathological disorders or stress; appetite disorders, such as anorexia nervosa and bulimia (abnormally increased appetite); hemorrhagic stress; stress-induced psychotic episodes; euthyroid weakness syndrome; inappropriate antidiuretic hormone syndrome (ΑϋΗ); obesity infertility head injuries; spinal injuries; ischemic damage to neurons (e.g., cerebral ischemia, such as cerebral ischemia of the hippocampus); excitatory toxic damage to neurons; epilepsy; cardiovascular and hearing impairment disorders, including hypertension, tachycardia, and congestive heart failure; stroke (stroke); immune dysfunctions, including stress-induced immune dysfunctions (for example, stress-induced febrile illness, pig stress syndrome, cattle transport fever, horse febrile convulsions and chick-free dysfunctions, shearing stress or stress in dogs or dog stress caused by human-animal interaction); muscle cramps; urinary incontinence; senile dementia of the Alzheimer's type; multiple heart attack dementia; amyotrophic lateral sclerosis; chemical addictions and addictions (for example, alcohol addiction, addiction to cocaine, heroin, benzodiazepines or other medicines); withdrawal symptoms of the drug and alcohol; osteoporosis; psychosocial dwarfism and hyperglycemia in mammals.

This invention relates to new compounds that bind to receptors of a corticotropin-releasing factor, thereby modifying the anxiogenic effects of SKE secretion. The compounds of this invention are useful for the treatment of psychiatric disorders and neurological diseases associated with anxiety disorders, post-traumatic stress disorder, supranuclear palsy and appetite disorders, as well as for the treatment of immunological, cardiovascular or heart related diseases and hypersensitivity (allergies) of the colon, associated with psychopathological disorders and stress in mammals.

In accordance with another aspect, the present invention relates to new compounds of formula (1) (described below) that are useful as antagonists of a corticotropin-releasing factor. The compounds of this invention exhibit corticotropin-releasing factor antagonist activity and appear to suppress the hypersecretion of CJE. The invention also includes pharmaceutical compositions containing compounds of formula (1), and methods of using such compounds to suppress hypersecretion of SLE and / or for the treatment of anxiogenic (anxiety) disorders.

In accordance with another aspect of the invention, the compounds of the invention (and, in particular, the labeled compounds of the invention) are also useful as standards and reagents for determining the ability of potential pharmaceuticals to bind to SLE receptor.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of the formula (1)

(I) and its isomers, its stereoisomeric forms or a mixture of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where A is Ν;

Ζ stands for CB ² ;

Ag is selected from the group phenyl, pyridyl, each Ar is optionally substituted with 1-5 groups of ⁴ and each Ar is attached to an unsaturated carbon atom;

I ^{1 is} independently selected at each occurrence from the group: H, _C1-C4 alkyl;

I ^{2 is} independently selected from group H, CpC ₄ alkyl;

I ^{3 is} selected from the group -H, OH ⁷ , ΝΚ / 'Ά' ¹ . phenyl optionally substituted with 1-3 halogen atoms; or morpholino; or —C 1 -Ci-alkyl optionally substituted with 1-3 substituents independently selected in each case from the group consisting of CO ₂ Z ¹⁵ , ^{15 16} Κ ¹⁵ , phenyl optionally substituted with halogen;

I ^{4 is} independently selected in each case from the group C1-Ci-alkyl, halogen, CI, C1-C4 haloalkyl, ΝΚ / Я. OH ⁷ ;

I ⁶ and I ⁷ , I ^6a and I ^{7a are} independently selected in each case from the group -H, -C1-Ci-alkyl, C2C8-alkoxyalkyl, C4-C12-cycloalkylalkyl, each of which is optionally substituted by 1-3 substituents independently selected in each case, from substituents such as C] -Balkyl, C3-C6 cycloalkyl, cyano, OK ¹⁵ , SOY ¹⁵ , СО2Я ¹⁵ , ΝΒ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen;

I ¹⁵ and I ¹⁶ are independently selected at each occurrence from the group H, _C1-C6 alkyl;

under the conditions that when A denotes Ν, СК denotes CK ² , I ² denotes H, I ³ denotes OH ⁷ and I ⁷ denotes H, I ^{1 is} not H, when A denotes Ν, Ζ denotes CK ² , I ¹ denotes CH3 or C2H5, I ² denotes H, I ³ denotes OH, H, CH3, C ₂ H ₅ , C ₆ H ₅ , nC ₃ H ₇ , iso C ₃ H ₇ , ΝΗΟ | Η ₉ or Ν (€. ' ₂ Η ₇ ) ₂ . Ag is not phenyl or m-CH ₃ -phenyl;

when A is Ν, Ζ is CE ² , I ² is H and Ar is pyridyl, and ³ is XA ^{6a, 7a} , ^6a and ^7a are not H or unsubstituted alkyl;

when A denotes Ν, Ζ denotes CJ ² , I ¹ denotes methyl or ethyl, I ² denotes H and I ³ denotes OH, H, CH ₃ , C ₂ H ₅ , CbH ₅ , nC ₃ H ₇ , iso-C ₃ H ₇ , ΝΗ (η-Ο, Η,) or Ν (€. ' ₂ Η ₇ ) ₂ . Ar is not unsubstituted phenyl or methylphenyl.

Preferred compounds of this invention also include compounds of formula (1), their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts and prodrugs, where Ag is phenyl, pyridyl, each of which is optionally substituted with 1-4 substituents I ⁴ .

Preferred compounds of this invention also include compounds of formula (1) and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts and prodrugs, where A is Ν, Ζ is CJ ² , Ar is 2,4-dichlorophenyl, 2 , 4-dimethylphenyl or 2,4,6-trimethylphenyl, I ¹ and I ² are CH ₃ , and I ³ is AH ^{6a and 7a} .

More preferred compounds of this invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs.

More preferred compounds of this invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs, where K ³ is 1MK ^6a K ^7a or OK ⁷ .

More preferred compounds of this invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs, where Ag is phenyl, pyridyl and each Ag is optionally substituted with 1-4 K ⁴ substituents, and K ³ means ΝΡ ⁶ 'Κ ² ' or OK ⁷ .

More preferred compounds of this invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrugs, where K ^{6a is} independently selected from the group —H, —C] Ci-alkyl, C2-C8- alkoxyalkyl, C4-C12 cycloalkylalkyl, each of which is optionally substituted by 1-3 substituents independently selected in each case from substituents such as C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen atoms;

K ^{7a is} independently selected in each case from the group -H, -C5-Ci-alkyl, C2-C8-alkoxyalkyl, C4-C12-cycloalkylalkyl, each of which is optionally substituted with 1-3 substituents independently selected in each case from such substituents, as C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , Κ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen.

More preferred compounds of this invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs, where K ^6a and K ^7a are identical and are selected from the group —C1-C4-alkyl optionally substituted with 1 -3 substituents independently selected in each case from substituents such as C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen atoms.

More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs, where K ^{6a is} selected from the group —H, —C-Ci-alkyl, C2C8-alkoxyalkyl, C4- C12-cycloalkylalkyl, each of which is optionally substituted by 1-3 substituents independently selected in each case from such substituents as C] -Balkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ phenyl optionally substituted with phenyl;

K ^{7a is} selected from the group —C] -C4-alkyl, and each such C1-C4-alkyl is substituted by 1-3 substituents independently selected in each case from such substituents as C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , CO2K ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen atoms.

More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs, where K ^6a and K ^{7a are} independently H or C, Cl-alkyl, and each such Cl-Cu -alkyl is optionally substituted with 1-3 substituents independently selected in each case from such substituents as C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ , phenyl, optionally substituted by halogen atoms.

More preferred compounds of this invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrugs, where

Ag is phenyl, pyridyl, and each Ag is optionally substituted with 1-4 K ⁴ substituents,

K ³ denotes 1MK ^6a K ^7a or OK ⁷ and

K ¹ and K ^{2 are} independently selected from H, C1-C4 alkyl.

Particularly preferred compounds of this invention are compounds of formula (50)

(50) and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and pharmaceutically acceptable salts and prodrugs selected from the group consisting of a compound of formula (50), wherein K ³ is —ΝΗΟΗ (π-Ργ) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (E1) (p-Vi),

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes - (i-Rg) (CH ₂ 1-Rg),

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ is —H (CH _; CH _; OMC) _; .

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -XNCH (E1) (p-Vi)

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -HnSn (E1) (CH ₂ OME), K ^4A denotes C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; a compound of formula (50), wherein K ³ is —ΝΗί′Ή (CH ₂ OMe) ₂ , K ^4a is C1, K ^4b is H, K ^4c is C1, K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ means ^ HCH / CHE!) ^

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ means -Νη / η / ΕΙ) ^

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; a compound of formula (50), wherein K ³ is —Y (Me) (Pk),

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (η-Ρτ) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -HCHS (E1) (p-Pr),

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ is —YanCH (CH ₂ OMe) ₂ , K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H, and K ^4e is Me;

the compound of formula (50), where K ³ is —YanCH (CH ₂ OMe) ₂ , K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes -InSn (CH ₂ CH ₂ OMe) ₂ , K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ is —XCHCH (E1) (CH ₂ OMe), K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes -InSn (E1) ₂ , K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes -OE1,

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1, K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -Y (E1) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Y (Sn ₂ CM) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁰ is H and

K ^4e is H;

a compound of formula (50), wherein K ³ is —INSH (Me) (CH ₂ OMe), K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁰ is H and K ^4e is H;

a compound of formula 50, where K ³ is —OCH (E!) (CH ₂ OMe), K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁰ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes -Y (p-Pr) (CH ₂ 1-Pr),

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁰ is H and

K ^4e is H;

a compound of formula (50), wherein K ³ is —CHNS (Me) (CH ₂ X (Me) ₂ ), K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁰ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes -Y (1-Pr) (CH ₂ CH ₂ CX),

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁰ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes -Y (p-Pr) (CH ₂ CH ₂ CU),

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁰ is H and

K ^4e is H; the compound of formula 50, where K ³ means -Y (p-Vi) (CH ₂ CX),

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁰ is H and

K ^4e is H; the compound of formula (50), where K ³ is —InSn (E!) (CH ₂ OMe), K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁰ is H and K ^4e is Me;

the compound of formula (50), where K ³ is -InSn (E!) ₂ , K ^4a is Me, K ^4b is H,

K ^4c is Me, K ⁴⁰ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ ,

K ^4a is Me, K ^4b is H, K ^4c is Me, ⁴⁰ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes -InSn (CH ₂ OME) ₂ ,

K ^4a means Br,

K ^4b denotes H,

K ^4c is OMe, K ⁴⁰ is H and K ^4e is H; a compound of formula (50), where K ³ is —InSn (E!) (CH ₂ OMe), K ^4a is Br, K ^4b is H, K ^4c is OMe, K ⁴⁰ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes -Y (E!) ₂ ,

K ^4a is Me, K ^4b is H, K ^4c is Me, ⁴⁰ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes -InSn (CH ₂ OE!) ₂ ,

K ^4a is Me, K ^4b is H, K ^4c is Me, ⁴⁰ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes -INSN (CH ₂ CH ₂ OME) (CH2OMe) 2,

K ^4a is Me, K ^4b is H, K ^4c is Me, ⁴⁰ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes morpholino,

K ^4a is Me, K ^4b is H, K ^4c is Me, ⁴⁰ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ ,

K ^4a means Br,

K ^4b denotes H,

K ^4c is OMe, K ⁴⁰ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -InSn (E!) ₂ ,

K ^4a means Br,

K ^4b denotes H,

K ^4c is OMe, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a means Br,

K ^4b denotes H,

K ^4c is OMe, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -ΝΗ (ι-Ργ),

K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes-NCHS (CH ₂ ΟMe) ₂ ,

K ^4a means ΟΝ,

K ^4b denotes H,

K ^4c is OMe, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes-S (1-Rg) (CH ₂ CH ₂ C№),

K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes-ISN (CH ₂ OME) ₂ ,

K ^4a is Me, K ^4b is H, K ^4c is Br, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -MHCH (CH ₂ OME) (W)

K ^4a is Me, K ^4b is H, K ^4c is Br, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -sch (CH ₂ OMe) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is Me and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is OMe, K ⁴⁴ is Me and K ^4e is H;

a compound of formula (50), wherein K ³ is —ΝΗί.ΝΗί (Εΐ) _; .

K ^4a means Me,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is Me; and K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is Me; and K ^4e is H; the compound of formula (50), where K ³ is -sCH (CH ₂ OMe) ₂ , K ^4a is C1, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ is -sCH (E1) (CH ₂ OMe), K ^4a is C1, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ is —Y (CH ₂ CH ₂ OMe) ₂ , K ^4a is C1, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ OME) (CH ₂ CH ₂ OME),

K ^4a is C1, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ is —Y (1-Pr) (CH ₂ CH ₂ C ₂ ), K ^4a is Me, K ^4b is H, K ^4c is OMe, K ⁴⁴ is Me and K ^4e is H ;

the compound of formula (50), where K ³ is —Y (1-Pr) (CH ₂ CH ₂ C№), K ^4a is C1, K ^4b is H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H ;

the compound of formula (50), where K ³ denotes (8) -HCHS (CH _; OMe) (CH ₂ CH ₂ OMe),

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1, K ⁴⁴ is H and K ^4e is H; a compound of formula (50), wherein K ³ is —ΝΗί′Ή (CH ₂ OMe) (CH ₂ CH ₂ OMe),

K ^4a is C1, K ^4b is H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ is -Νη№ (Ε1) ₂ , K ^4a is Me, K ^4b is H, K ^4c is Br, K ⁴⁴ is H and K ^4e is H;

the compound of formula (50), where K ³ denotes-MSN ₂ CH ₂ OME) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is Br, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes ^ N (CH ₂ OMe) (CH ₂ 1-Rg),

K ^4a means Me,

K ^4b denotes H,

K ^4c is Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ means - ^ CH ₂ CH ₂ OMe) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is H, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ means - ^ CH ₂ CH ₂ OMe) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is NMe2, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes ^ HCH (CH2OMe) (p-Pr),

K ^4a is Me, K ^4b is H, K ^4c is Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ means -ΝΗ№ ^ Η ₂ ΟΕΐ) (Εΐ),

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -YANSN (CH ₂ OME) (CH ₂ CH ₂ OME),

K ^4a means Me,

K ^4b denotes H,

K ^4c is NME ₂ ,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ means -ΝΗί'Ή (Εΐ) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ means - ^ CH ₂ CH ₂ OMe) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -YanSn (CH ₂ OME) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is Br

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a is C1,

K ^4b denotes Η,

K ^4c means Me,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ means -ΝΗί'Ή (Εΐ) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -ΝΗίΉ (Εΐ) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c is NME ₂ ,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes (§) -CHF (CH ₂ OMe) (CH ₂ CH ₂ OMe),

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -№CH (CH ₂ OMe) (W)

K ^4a means Me,

K ^4b denotes H,

K ^4c means Me,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes (8) -№НСН (СН ₂ ОМе) (W)

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -№iCH (CH ₂ OMe) (CH ₂ CH ₂ OMe),

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ means -Ν (ί-ΡΓ) (ίΉ ₂ ίΉ ₂ ί'Ν).

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -ΝΉ (Εΐ) (ίΉ ₂ ί'Ν),

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a means Me,

K ^4b means Me,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes-MSN ₂ CH ₂ OME) (W)

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes-MSN ₂ CH ₂ OME) ₂ ,

K ^4a means Me,

K ^4b means Me,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes ANSN (E1) ₂ ,

K ^4a means Me,

K ^4b means Me,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes - ^ CH ₂ s-Pr) (i-Pr),

K ^4a means Me,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes - ^ 1-Pr) (CH ₂ CH ₂ SS,

K ^4a means Me,

K ^4b means Me,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes ANSN (E1) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H; the compound of formula (50), where K ³ denotes-MSN ₂ CH ₂ OME) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -MCHS (E1) (CH ₂ OME),

K ^4a is C1,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c means ΟΝ,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -Y (1-Pr) (Sn ₂ Sn ₂ CM),

K ^4a is C1,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -YanSn (Sn ₂ He) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c is C1

K ⁴⁴ is H and

K ^4e is H; and a compound of formula (50), wherein K ³ is —Y (Sn ₂ Sn ₂ OMe) ₂ ,

K ^4a means Me,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is H and

K ^4e is H;

the compound of formula (50), where K ³ denotes -XnSn (E1) ₂ ,

K ^4a is C1,

K ^4b denotes H,

K ^4c stands for OMe,

K ⁴⁴ is P and

K ^4e denotes N.

More specifically, 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl8- (2-methyl-4-methoxyphenyl) - [1,5-a] pyrazolo 1,3,5-triazine is preferred and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs.

More specifically, 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl8- (2,5-dimethyl-4-methoxyphenyl) - [1,5-a] pyrazolo-1,3 is preferred , 5-triazine and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salt or prodrug forms.

This invention also relates to pharmaceutical compositions comprising compounds of formula (1) and a pharmaceutically acceptable carrier.

The present invention also includes a method of treating disorders caused or exacerbated by CKD, affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, diseases of the gastrointestinal tract, neuropsychic anorexia or other impaired appetite, drug addiction, withdrawal symptoms of the drug or alcohol, inflammatory diseases, cardiovascular or ser Examples of diseases, problems of childbearing, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, traumatic brain and spinal cord injuries, epilepsy, stroke (stroke), ulcers, amyotrophic lateral sclerosis, hypoglycemia, or a disorder that can be treated or alleviated antagonistic effect on SCR, including, but not limited to, disorders caused or exacerbated by SCR in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the forms uly (1).

Many compounds of this invention have one or more asymmetric centers or one or more asymmetric planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in this invention. Many geometric isomers of olefins, ί. '= Ν double bonds, etc. may also be present in these compounds, and all such stable isomers are contemplated by this invention. These compounds may be isolated in optically active or racemic forms. Methods for preparing optically active forms are well known in the art, for example, by resolution of racemic forms or synthesis from optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of the structure are meant, unless a specific stereochemistry or isomeric form is indicated.

The term alkyl includes both branched and straight chain alkyl having the indicated number of carbon atoms. Commonly used abbreviations have the following meanings: Me stands for methyl, E stands for ethyl, Pr stands for propyl, and Vi stands for butyl. The prefix n stands for straight chain alkyl. The prefix s stands for cycloalkyl. The letter (8) in front stands for 8 enantiomer and (K) stands for K-enantiomer Alkenyl includes straight or branched chain hydrocarbon chains and one or more unsaturated carbon-carbon bonds that can occur at any stable point along this chain, such as ethenyl, propenyl, etc. Alkynyl in It includes hydrocarbon chains of a straight or branched configuration and one or more carbon-carbon triple bonds that can occur at any stable point along this chain, such as ethynyl, propynyl, etc. Haloalkyl includes both branched and straight chain alkyl having the indicated number of carbon atoms substituted with one or more halogens; alkoxy means an alkyl group with the specified number of carbon atoms attached via an oxygen bridge; cycloalkyl includes saturated ring groups, including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Halo or halogen includes fluoro, chloro, bromo and iodo.

The term substituted, as used herein, means that one or more hydrogens on said atom is replaced by a group selected from said groups, provided that the normal valency of said atom is not exceeded and that substitution leads to a stable compound. If the substituent is keto (i.e., = 0), then 2 hydrogen atoms on the given atom are replaced.

Combinations of substituents and / or variations thereof are acceptable only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound which is sufficiently stable to transfer the isolation to the desired degree of purity from the reaction mixture and the preparation of an effective therapeutic agent from it.

The term “suitable amino acid protecting group” means any group known in the field of organic synthesis for protecting amino groups or carboxyl groups. Such amino protecting groups include those listed in Sgr. RgoYusbgs Sgoirk ίη Ogdashs Ξνηΐΐιοδίδ ίοΐιη XV Isu apb §op8, Νε \ ν Wogk (1991) and Thys Rurbbek: Apa1u515. 8up111s515. Vyuoguu, Vu1.3, Asabeiys Rgekk, Νε \ ν Wogk (1981), is incorporated herein by reference. Any amino protecting group may be used. Examples of amino protecting groups include, but are not limited to: 1) acyl type groups such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl; 2) aromatic carbamate groups such as benzyloxycarbonyl (Cb) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Egios); 3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkyl carbamate groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups such as triphenylmethyl and benzyl;

6) trialkylsilane, such as trimethylsilane; and

7) thiol-containing groups such as phenylthiocarbonyl and dithiasuccinoyl.

The term pharmaceutically acceptable salts includes acidic or basic salts of the compounds of formulas (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines; salts with alkalis or organic bases of acid residues such as carboxylic acids; etc.

Pharmaceutically acceptable salts of the compounds of this invention can be obtained by reacting the free acid or base of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or in a mixture of water and an organic solvent; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. A list of suitable salts can be found in Kegshid Boi'k P11agtassi Isa1 8s1spss5. 17111 eb., Musk Riyuyid Soshrapu, Yeoyoi, RA, 1985, p. 1418, is incorporated here by reference.

Prodrugs include any covalently linked carriers that release the active parent drug of formula (I) or (II) ίη νίνο when such a prodrug is administered to a mammal. Pro drugs of the compounds of formula (I) or (II) are obtained by modifying the functional groups present in these compounds, such that these modifications are cleaved in the usual way or ίη νίνο to the starting compounds. Prodrugs include compounds in which hydroxy, amino, or sulfhydryl groups are linked to any group that, when administered to a mammal, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol group and an amino group in the compounds of formula (I) and (II), and the like.

The term “therapeutically effective amount” of a compound of this invention refers to an amount effective to antagonize an abnormal level of CKD or to treat symptoms of an affective disorder, anxiety or depression in a subject.

Synthesis

Some compounds of formula (1) can be prepared from intermediates of formula (7) using the procedures shown in Scheme 1.

(1) a = N

Compounds of formula (7) (where Υ is O) can be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base, in the presence or absence of an inert solvent at reaction temperatures from -80 to 250 ° C to obtain products of formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, 80CB. ROSE. PC1 ₃ , PC1 ₅ , ROVGZ, RVGZ or RVg ₅ . Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or trisulfonyl sulfonyl sulfonyl chloride or anhydride), or halides. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably Ν.Ν-ΛΗΗ3θπρθΓΠΓΓ-Ν-3τιτΓ3ΜΗΗ or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν dialkylformamides (preferably dimethylformamide ), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν-methylpyrrolidin2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or luol) or haloalkanes of 1-10 carbon atoms and 1-10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 to 100 ° C.

Compounds of formula (8) can interact with compounds of formula I ³ H (where K ³ has the above meanings, except that I ^{3 is} not 8H, SOY ⁷ , CO ₂ I ⁷ , aryl or heteroaryl) in the presence or absence of base, in the presence or absence of an inert solvent at reaction temperatures from -80 to 250 ° C. with the formation of compounds of formula (1). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably Ν, из diisopropyl-X-ethylamine) or aroma ttic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably No. methylpyrrolidin-2one), dialkyl sulfoxides (preferably dimethyl tilsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing 1-10 carbon atoms and 1-10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures range from 0 to 140 ° C.

Scheme 2 shows the methods for converting intermediates of formula (7) (where Υ is 8) into some compounds of formula (1).

Scheme 2

The compounds of formula (7) (where Υ is 8) can be treated with an alkylating agent I ¹³ X (where I ¹³ has the above meanings, except that I ^{13 is} not aryl or heteroaryl) in the presence or absence of a base, in the presence of or in the absence of an inert solvent at reaction temperatures from -80 to 250 ° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably diisopropylamide lithium), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably Ν, Ν-diisopropylΝ-ethylamine or triethyl lamin) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν-methylpyrrolidin2-one), dialkyl sulfoxides (preferably dimethyl ilsulfoksid), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing 1-10 carbons and 1-10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -80 to 100 ° C.

Compounds of formula (12) (formula (1), where H ³ is 8H ¹³ ) can then be reacted with compounds of formula H ³ H to form compounds of formula (1) using the same conditions and reagents used to convert the compounds of formula (8) to the compounds of formula (1) as described for scheme 1 above. Alternatively, compounds of formula (12) (formula (1), where H ³ is 8H ¹³ ) can be oxidized to compounds of formula (13) (formula (1), where ³ is 8 (O) _II ¹³ , and is 1 , 2) treatment with an oxidizing agent in the presence of an inert solvent at temperatures from -80 to 250 ° C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane or aryl acid (preferably peracetic acid or chloroperbenzoic acid), dioxirane, oxone or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3-10 carbon atoms, preferably acetone), water, alkyl alcohols (1-6 carbon atoms), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing 1-10 atoms carbon and 1-10 halogen atoms (preferably dichloromethane) or a combination thereof.

The choice of oxidizing agent and solvent is known to those skilled in the art (see Yeshig 8., ΟχίώιΙίοη о £ 8и1 £ иг, 8е1ешиш аиб TeIipit, ίη Sotrgs11sp51 \ with Ogdashs 8uSh11S515. Tgo81, V.M. eb., (Е1ш8 £ ogb, ΝΥ: Regdatop Rgeck, 1991), 7, 762769). Preferred reaction temperatures range from -20 to 100 ° C. The compounds of formula (13) (formula (1), where I ³ denotes 8 (O) _P ¹³ , and 1, 2) can then interact with compounds of the formula I ³ H to form compounds of the formula (1) using the same conditions and reagents that were used to convert the compounds of formula (8) to compounds of formula (1) as described for scheme (1) above.

The compounds of formula (1), where I ³ can be ⁸ soybean ⁷ , soya, νρΥονρ'κ / II ⁸ СО2Я ¹³ , II ⁶ I ⁷ , IJ ⁸ 8О2Я ⁷ , can be obtained from compounds of formula (7), where Υ stands for ΝΗ, using the techniques presented in Scheme 3.

A Ν; “ΜίΛΡ, NIXON ⁷ , S (JUICE ⁷ ) ₂ , ΝΒβΟΟΝΑ ^β Α ⁷ , -ΝΚθΟθ2 * ¹³ ,

The reaction of compounds of formula (7), where Υ is ΝΗ, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with their combinations in the presence or absence of a base in an inert solvent at reaction temperatures from -80 to 250 ° C can give compounds of the formula (1) where I ³ can be -II ⁸ SOYA ⁷ , -G0I) 2. -IA ⁸ SOPA ⁶ I ⁷ , -IIA ⁸ СО2Я ¹³ , -IIA ⁶ I ⁷ , -Chryaska. Alkylating agents may include, but are not limited to, C 1 -Ci alkyl halides, tosylates, mesylates, or triflates; C1-Cyu-haloalkyl (1-10 halogens) halides, tosylates, mesylates or triflates; C ₂ -C ₈ alkoxyalkyl halides, tosylates, mesylates or triflates; C ₃ -C ₆ cycloalkyl halides, tosylates, mesylates or triflates; C ₄ -C ₂ cycloalkylalkyl halides, tosylates, mesylates or triflates; aryl _(C1-C4 alkyl) halides, -tozalaty, -mezilaty or -triflaty; heteroaryl (C 1 -C ₄ alkyl) halides, -tozilaty, -mezilaty or -triflaty; or heterocyclyl (C1C ₄ alkyl) halides, -tozilaty, -mezilaty or -triflaty. Acylating agents may include, but are not limited to, C 1 -Syalkanoyl halides or anhydrides, C 1 -Syhaloalkanoyl halides or anhydrides with ΙΙΟ halogen atoms, C ₂ -C ₈ -alkoxyalkanoyl halides or anhydrides, C ₃ -C ₆ -cycloalkylalkano or _{4 2} tsikloalkilalkanoilgalogenidy or anhydrides, aroyl halide or anhydrides, aryl (C1C ₄₎ alkanoyl halides or anhydrides, geteroaroilgalogenidy or anhydrides, heteroaryl (C1C ₄₎ alkanoyl halides or anhydrides, halides or anhydrides geterotsiklilkarbonovoy ki slots or heterocyclyl (C1C ₄ ) alkanoyl halides or anhydrides. Sul foniliruyuschie agents include, but are not limited to, C1-Hsiu-alkylsulfonyl halide or anhydrides, C1-Hsiu-galogenalkilsulfonilgalogenidy or anhydrides with 1-10 halogens, C ₂ -C ₈ -alkoksialkilsulfonilgalogenidy or anhydrides, C ₃ -C ₆ tsikloalkilsulfonilgalogenidy or anhydrides , C ₄ -C 1 ₂ -tsikloalkilalkilsulfonilgalogenidy or anhydrides, arylsulfonyl halide or anhydrides, aryl _(C1-C4 alkyl) -, geteroarilsulfonilgalogenidy or anhydrides, heteroaryl _(C1-C4 alkyl) sulfonyl halides or anhydrides, geterotsiklilsulfonilgalog Nida or anhydrides or heterocyclyl _(C1-C4 alkyl) sulfonyl halides or anhydrides. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide; trialkylamines (preferably 1 \ G,] \ 1-diisopropyl-M-ethylamine) or aromatic amines (preferred but pyridine) Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably No. methylpyrrolidin-2one), dialkyl sulfoxides (preferably especially dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 to 100 ° C.

Scheme 4 shows the methods that can be used to obtain intermediate compounds of formula (7), where Υ is O, 8 and Ζ is SK ² .

Scheme 4

A SON ^{2 b,} the base

YS solvent · ”* AgSNgSM ---—-- ►

ΝΗ ₂ ΝΗ? - Η, Ο, solvent

+ / -acid, solvent

Compounds of the formula ΑιΌΉ ₂ 0'Ν interact with compounds of the formula K ² SOK ^b , where K ² is as defined above and K ^b is halogen, cyano, lower alkoxy (1-6 carbon atoms) or lower alkanoyloxy (1-6 carbon atoms) , in the presence of a base in an inert solvent at reaction temperatures from -78 to 200 ° C to form compounds of formula (3). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably HH-diisopropyl-H-ethylamine) or aroma specific amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or

1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C.

The compounds of formula (3) can be treated with hydrazine hydrate in the presence of an inert solvent at temperatures from 0 to 200 ° C, preferably 70-150 ° C, to obtain compounds of formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or

1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of formula (4) can interact with compounds of formula (5) (where K ^c is alkyl (1-6 carbon atoms)) in the presence or absence of an acid, in the presence of an inert solvent at temperatures from 0 to 200 ° C to form compounds of the formula (6). Acids include, but are not limited to, alkanoic acids containing 2-10 carbon atoms (preferably acetic acid), haloalkanoic acids (2-10 carbon atoms, 1-10 halogen atoms such as trifluoroacetic acid), arylsulfonic acids (preferably ptoluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids containing 1-10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkanenitriles (1-6 carbon atoms, preferably acetonitrile), carbon halides of 1-6 carbon atoms and 1-6 halogen atoms (preferably dichloromethane or chloroform), alkyl alcohols containing 1- 10 carbon atoms (preferably ethanol), dialkyl ethers (4-12 carbon atoms, preferably diethyl ether or diisopropyl ether) or cyclic ethers such as dioxane or tetrahydrofuran. Preferred temperatures range from ambient temperature to 100 ° C.

Compounds of formula (6) can be converted into intermediates of formula (7) by treatment with compounds C = Y (K ⁴ ) ₂ (where Υ is O or § and K ⁴ is halogen (preferably chlorine), alkoxy (1-4 carbon atoms) or alkylthio (1-4 carbon atoms)) in the presence or absence of a base in an inert solvent at reaction temperatures from -50 to 200 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkylamines (preferably Ν, Ν-Λππ3οπροωϋΐ-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or

1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons ( or toluene). Preferred reaction temperatures range from 0 to 150 ° C.

Intermediates of formula (7), where Ζ is Ν, can be synthesized by the methods shown in scheme 5.

AgSN ₂ SI

reducing agent, solvent

+ / - acid, solvent

Ag (11)

(7) Υ = 0, 3; Ζ = Ы

Compounds ΑιίΉ ₂ 0'Ν reacted with compounds of formula K ^H CH ₂ AND ₃ (where R ⁴ represents a phenyl group optionally substituted by H, alkyl (1-6 carbons), or alkoxy (1-6 carbons)) in the presence or the absence of a base in an inert solvent at temperatures from 0 to 200 ° C with the formation of compounds of formula (9). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide, sodium ethoxide or potassium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides ( preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide, trialkylamines (preferably Ν, Ν-diisopropylΝ- tilamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, алки dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (pre preferably Ν-methylpyrrolidin2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from ambient temperature to 100 ° C.

Compounds of formula (9) can be treated with a reducing agent in an inert solvent at (-100) -100 ° C to give products of formula (10). Reducing agents include, but are not limited to, (a) hydrogen gas in combination with noble metal catalysts such as Ρά on carbon, P1O ₂ , P1 on coal, Y1 on aluminum or Raney nickel, (b) alkali metals (preferably sodium) in combined with liquid ammonia, or (c) cerium ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydro furan or

1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -50 to 60 ° C. Compounds of formula (9) are then converted to compounds of formula (7) (where Ζ is Ν) via intermediates of formula (11) using the reagents and reaction conditions described in Scheme 4 to convert compounds of formula (4) to compounds of formula (7) (where Ζ stands for SC ² ).

Compounds of formula (1) can also be prepared from compounds of formula (7) (where Υ is O, 8 and Ζ has the meaning given above), as described in Scheme 6.

Scheme 6

Υ

Ag

K ^E B, + / - acid, ♦ / - dehydrating agent + / - solvent

(7) Y = O, 3; Ζ = Ν, CH ² (1) A = N

Compounds of formula (7) can interact with compounds of formula K ³ H in the presence of a dehydrating agent in an inert solvent at reaction temperatures from up to 250 ° C. Dehydrating agents include, but are not limited to, P ₂ C> 5, molecular sieves, or inorganic or organic acids. Acids include, but are not limited to, alkanoic acids containing 2-10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids containing 1-10 carbon atoms (preferably methanesulfonic acid) , hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkyl acetamides (preferably dimethyl acetamide), cyclic amides (preferably I-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl lphoxide) or aromatic hydrocarbons (preferably benzene or toluene) and halocarbons (1-10 carbon atoms and 1-10 halogen atoms), preferably chloroform. Preferred reaction temperatures range from ambient temperature to 150 ° C.

Some compounds of formula (1) (where A is Ν) can also be prepared by the methods shown in Scheme 7:

Intermediates of formula (14), where Ζ has the meaning given above, can react with compounds of the formula K ³ C (OK ^e ) ₃ , where K ^e can be alkyl (1-6 carbon atoms), in the presence or absence of acid, in inert solvent at temperatures from 0 to 250 ° C. Acids may include, but are not limited to, alkanoic acids of 2-10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1-10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably No. methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or oluol) or haloalkanes of 1-10 carbon atoms and 1-10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50 to 150 ° C.

Intermediates of formula (7) can also be synthesized using the reactions shown in Scheme 8.

Ζ = Ν, CB ² , (7) A = N

X = Bx, C1, I, B (OB) 2

The compounds of formula (15) (where Υ is OH, 8H. ΝΚ ⁶ Κ ⁷ ; Ζ has the above meanings, X is Br, C1, I, O ₃ 8CE ₃ or B (OK) ₂ and B is H or alkyl (1 -6 carbon atoms) can interact with a compound of the formula AgM (where M is halogen, alkali metal, ΖηΟΙ, ΖπΒγ, ΖηΙ, MDBr, MDC1, MD1, CeC1 ₂ , CeBg ₂ or copper halides) in the presence or absence of an organometallic catalyst, in the presence or absence of a base in an inert solvent at temperatures from -100 to 200 ° C. Those skilled in the art will understand that Gent AGM can be formed ίη Shi Organometallic catalysts include, but are not limited to, palladiyfosfinovye complexes (such as Ρά (ΡΡ1ι ₃₎ 4), palladium halides or alkanoates (such as _Rs1S'1;. (PP11 _3); or Pc1 (0As ) _; ) or nickel complexes (such as ΝίΟΊ ₂ (ΡΡ1ι ₃ ) ₂ ). The bases may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably HX-diisopropyl-X-ethylamine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably No. methylpyrrolidin-2 he), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -80 to 100 ° C.

The choice of M and X is known to specialists in this field (see 1, T.I., Ogdaposspsp Veadepj ίη SotrgsyspShs Ogdashs 8up111sSh. Τ1Ό51 V.M. Kposye1 R., Ogdogogts, Ogdosabtsht apb Ogdopotegsigu Veadepiy ίη SotrgsNspShs Ogdashs 8up111sSh. Tgo§1 V.M. ss1 .. (ΕΙπίδίοτά, ΝΥ: Regdatop Rgs55. 1991), 1, 211230; KshdY ϋ.V., SoirNpd VsasOosch s1 \\ SSP gp ² Sagop Ssp1sg5. ίη SotrgsNspShs Ogdashs 8up111s515. Τ1Ό51 V.M. ss1. (Е1т5Гогс1. ΝΥ:

Regdatop Rgeck, 1991), 3, 481-520).

Compounds of formula (1) can also be prepared using the methods shown in Scheme 9.

Scheme 9

(16) X = Bx, C1, I, in “g”) ₂ , OZZsGz

The compounds of formula (16), where Α, Ζ, B ¹ and B ³ have the above meanings and X is Br, C1, I, O ₃ 8CE ₃ or B (OB) ₂ and B is H or alkyl (1-6 atoms carbon) can be reacted with a compound of formula AGM (where M is halogen, alkali metal, ΖηΟ. ΖπΒγ, ΖηΙ, MdS1, MD1, SeS1 ₂ Sevgim ₂ or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base , in an inert solvent at temperatures from -100 to 200 ° C. It will be understood by those skilled in the art that AgM reagents can be formed ίη δίΐιι (see the references above in Sotrgssyshs Ogdashs 8up111sSh). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Ρά (ΡΡ1ι ₃ ) 4), palladium halides or alkanoates (such as Pc1C1 ₂ (PP11 ₃ ) ₂ or Pc1 (0Ac) ₂ ) or nickel complexes (such as ΝίΟΙ ₂ (ΡΡ1ι ₃ ) ₂ ). The bases may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably X, X-diisopropyl-X-ethylamine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, ди-dialkylformamides (preferably dimethylformamide), Ν, Ν dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably No. methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -80 to 100 ° C.

Intermediates of formula (7) (where Υ is O, 8, ΝΗ, Ζ is SK ² and K ¹ , K ² and Ar have the above meanings) can be prepared as shown in Scheme 10.

(7) Υ = 0, 3, ΝΗ; Ζ = SC ² ,

Compounds of formula (3) can interact with compounds of formula Η ₂ ΝΝΗ (€ = Υ) ΝΗ ₂ . where Υ is O, 8 or ΝΗ, in the presence or absence of a base or acid, in an inert solvent at temperatures from 0 to 250 ° C. to form compounds of formula (17). Acids may include, but are not limited to, alkanoic acids containing 2-10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids containing 110 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide, sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), bis (trialkylsilyl) amides of alkali metals (preferably bis (trimethylsilyl) sodium amide, trialkylamines (preferably Ν, Ν-diisopropyl-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert Solvents may include, but are not limited to, alkyl alcohols (1-6 carbon atoms, lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4- dioxane), Ν, Ν dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν-methylpyrrolidin2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing 1-10 carbon atoms and 1-10 halogen atoms (preferably dichloromethane).

Preferred reaction temperatures range from 0 to 150 ° C. The compounds of formula (17) can then interact with compounds of the formula K ³ C (OK ^e ) ₃ , where K ^e can be alkyl (1-6 carbon atoms), in the presence or absence of acid, in an inert solvent at temperatures from 0 to 250 ° C. Acids may include, but are not limited to, alkanoic acids containing 2-10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids containing 1-10 carbon atoms (preferably methanesulfonic acid ), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides ( preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably P-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or t oluene) or haloalkanes containing 1-10 carbon atoms and 1-10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures range from 50 to 150 ° C.

Scheme 11 shows the methods that can be used to convert compounds of formula (1), where K ³ is SOK ⁷ , CO2K ⁷ , ΝΚ ⁸ ΟΟΚ ⁷ and ΟΟΝΚ ⁶ Κ ⁷ , into other compounds of formula (1), where K ³ is CH (OH) K ⁷ , CH 2 OH, ΝΚ ⁸ ΟΗ 2Κ ⁷ and ΟΗ 2ΝΚ ⁶ Κ ⁷ , treatment with a reducing agent in an inert solvent at temperatures from -80 to 250 ° C.

Scheme 11

Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as diisoamylborane), alkali metal hydrides (preferably lithium aluminum hydride), (trialkoxy) aluminum alkali metal hydrides or dialkyl hydrides such as diisobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1-6 carbon atoms) dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80 to 100 ° C.

Scheme 12 shows the procedures that can be used to convert compounds of formula (1), where K ³ is SOK ⁷ or CO2 ² , to other compounds of formula (1), where K ³ is C (OH) (K ⁷ ) 2, treatment with a reagent of formula K ⁷ M in an inert solvent at temperatures from -80 to 250 ° C.

Pattern 12

(1) K ³ = СОН ⁷ , СО ₂ К ⁷ , (1) Н ³ = С (ОН) (В ⁷ '

M stands for halogen, alkali metal, ΖηΟ. ΖπΒγ, ΖηΙ, MdBr, MgC1, Mg1, CeC1 ₂ , CeBg ₂ or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80 to 100 ° C.

The compounds of formula (1), where K ³ may be -Ν (Ο3Κ ⁷ ) 2, ΝΚ ⁸ ΟΟΚ ⁷ . -W ^x S0W ^b L. -ΝΚ ⁸ 002Κ ¹³ , -ΝΚ ⁶ Κ ⁷ , -ΝΚ ⁸ §Ο ₂ Κ ⁷ can be synthesized, as shown in scheme 13.

Pattern 13

(4) Ζ = SK ₂ (10) Ζ = N

A - CB

B ₃ = LK ⁶ K ⁷ , YN® SON ⁷ , s (ow ') 2, LKVSONV ⁵ V ⁷ , LKVSO2Y13

The reaction of compounds of formula (18), where K and K ¹ have the above meanings, with compounds of formula (4) or (10) in the presence or absence of a base in an inert solvent can give compounds of formula (19) at reaction temperatures from -50 to 250 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyr dyne). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydro furan or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν dialkyl acetamides (preferably dimethylacetamide), cyclic amides (preferably M-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dim sulfoxide), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 to 100 ° C.

The compounds of formula (19) can then interact with alkylating agents, sulfonylating agents or acylating agents, or sequential reactions with their combinations in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80 to 250 ° C can give compounds of the formula (1), where K ³ may be -II ⁸ SOYA ⁷ , -Ν (ΟΟΚ ⁷ ) 2, -νΑοόνΑρΓ. -IA ⁸ CO2YA ¹³ , -Sh'YA / -ΝΚ ⁸ §Ο2Κ ⁷ . Alkylating agents may include, but are not limited to, C1-Ci-alkyl halides, tosylates, mesylates or triflates; C1-halogenated (1-10 halogens) halides, tosylates, mesylates or triflates; _C2-C8 -alkoksialkilgalogenidy, -tozilaty, -mezilaty or -triflaty; Cs-C ₆ -tsikloalkilgalogenidy, -tozilaty, -mezilaty or -triflaty; C ₄ -C _{2 2} -cycloalkylalkyl halides, tosylates, mesylates or triflates; aryl _(C1-C4 alkyl) halides, -tozilaty, -mezilaty or -triflaty; heteroaryl _(C1-C4 alkyl) halides, -tozilaty, -mezilaty or -triflaty; or heterocyclyl _(C1-C4 alkyl) halides, -tozilaty, -mezilaty or -triflaty. Acylating agents may include, but are not limited to, C 1 -Syalkanoyl halides or anhydrides, C 1 -Syhaloalkanoyl halides or anhydrides with ΙΙΟ halogen atoms, C ₂ -C ₈ -alkoxyalkanoyl halides or anhydrides, C ₃ -C ₆ -cycloalkylalkano or _{4 2} tsikloalkilalkanoilgalogenidy or anhydrides, aroyl halide or anhydrides, aryl (C1C ₄₎ alkanoyl halides or anhydrides, geteroaroilgalogenidy or anhydrides, heteroaryl (C1C ₄₎ alkanoyl halides or anhydrides, halides or anhydrides geterotsiklilkarbonovoy ki lots or heterocyclyl (C1C ₄₎ alkanoyl halides or anhydrides. Sulfonylating agents include but are not limited to, C1-Hsiu-alkylsulfonyl halide or anhydrides, C1-Hsiu-galogenalkilsulfonilgalogenidy or anhydrides with 1-10 halogens, C ₂ -C ₈ -alkoksialkilsulfonilgalogenidy or anhydrides, C ₃ -Sbtsikloalkilsulfonilgalogenidy or anhydrides, C ₄ -C1 ₂ -tsikloalkilalkilsu lfonilgalogenidy or anhydrides, arylsulfonyl halide or anhydrides, aryl _(C1-C4 alkyl) -, geteroarilsulfonilgalogenidy or anhydrides, heteroaryl _(C1-C4 alkyl) sulfonyl halides or anhydrides, geterotsiklilsulfonilgaloge Nida or anhydrides or heterocyclyl _(C1-C4 alkyl) sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms, (preferably sodium methoxide or sodium ethoxide)), alkaline earth metal hydrides, alkali metal dialkylamides (preferably diisopropylamide lithium), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pi Idin). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably M-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dim sulfoxide), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 to 100 ° C.

The compounds of formula (1), where A denotes CE and I have the above meanings, can be synthesized by the methods shown in scheme 14.

Scheme 14

about

n (21) * / - base solvent,

K ³ V, + / - base, + / - solvent he x

Ag Ag (22) (23)

Compounds of formula (4) or (10) can be treated with compounds of formula (20), wherein Z ¹ and Z ^{3 are} defined above, in the presence or absence of a base, in an inert solvent at temperatures from 0 to 250 ° C to obtain compounds of formula (1 ), where A denotes CJ and I has the above meanings. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyr idin). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably X-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dim sulfoxide), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C. Alternatively, compounds of formula (1), where A is SK and K is as defined above, can be synthesized via intermediates (22) and (23).

Compounds of formulas (4) or (10) can be treated with compounds of formula (21), where K ¹ has the above meanings and K ^e is alkyl (1-6 carbon atoms), in the presence or absence of a base in an inert solvent at temperatures in the range from 0 to 250 ° C to obtain the compounds of formula (1), where A denotes SC and K has the above meanings. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyri din). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν dialkyl acetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dime ilsulfoksid) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from

0 ° C to 100 ° C. Compounds of formula (22) can be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures from -80 to 250 ° C to obtain products of formula (23) (where X is halogen, alkanesulfonyloxy , arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, §OC1 ₂ , POC1 ₃ , PC1 ₃ , PC1 ₅ , ROVg ₃ , Rvg ₃ or Rvg ₅ . Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or halides, for example, halides or trifluorides. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), bis (trialkylsilyl) amides of alkali metals (preferably bis (trimethylsilyl) sodium amide) (or triethylamine), or aromatic amines (preferably propyl-I-ethylamine), or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4 dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide ), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or luol) or haloalkanes of 1-10 carbon atoms and 1-10 halogen atoms (preferably dichloromethane). Preferred reaction temperatures range from -20 to 100 ^s .

Compounds of formula (23) can interact with compounds of formula K ³ H (where K ³ is as defined above, except K ^{3 is} not 8H, SOK ⁷ , CO ₂ K ⁷ , aryl or heteroaryl) in the presence or absence of base, in the presence or absence of an inert solvent at reaction temperatures from -80 to 250 ° C to form compounds of formula (1). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably Ν, Ν-diisopropyl-Y-ethylamine) or aroma cal amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydro furan or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν dialkyl acetamides (preferably dimethylacetamide), cyclic amides (preferably M-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dim sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1-10 carbons and 1-10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0 to 140 ° C.

Some compounds of formula (1) can also be obtained by the methods shown in scheme 15.

Scheme 15

The compound of formula (24) (where K _c is lower alkyl and Ar has the above meanings) can react with hydrazine in the presence or absence of an inert solvent to form an intermediate of formula (25), where Ar has the above meanings. The conditions used are similar to those used to prepare the intermediate of formula (4) from the compound of formula (3) in Scheme 4. The compounds of formula (25), where A is Ν, can react with reagents of the formula ΚΉ (= ΝΗ) ΟΚ ₆ , where K ¹ has the above meanings and K _e is lower alkyl, in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of the formula Υ is C (K ^a ) (where Υ is O or 8 and is halogen, preferably chlorine), alkoxy (1-4 carbon atoms) or alkylthio (1-4 carbon atoms) in the presence or absence of a base in an inert solvent to form compounds of formula (27) (where A is N and Υ is O, 8). The conditions for these transformations are the same as those used to convert the compound of formula (4) to the compound of formula (7) in Scheme 4.

Alternatively, compounds of formula (25), where A is CK, can interact with compounds of formula K ¹ (C = O) SNK (C = Y) OK _C (where K ¹ and K are as defined above and Kc is a lower alkyl group) with the formation of a compound of formula (27) (where A is SK) using conditions similar to those used to convert compounds of formula (21) to compounds of formula (22) in Scheme 14. Intermediates of formula (27) (where Υ is O) can be treated with halogenating or sulfonylating agents in the presence or in absence of a base in an inert solvent followed by reaction with R ³ H or K ² H in the presence or absence of a base in an inert solvent to give compounds of formula (1) (wherein Ζ represents SC ^2).

Specialists in this field should be clear that various combinations of halogenating agents, sulfonylating agents can be used, K ³ H or K ² N can be used in different order of reaction sequences in scheme 15 to obtain compounds of formula (1). For example, in some cases, it may be desirable for the compounds to interact with stoichiometric amounts of halogenating agents or sulfonylating agents, to interact with K ² H (or K ³ H), then react again with halogenating agents or sulfonylating agents and react with K ³ N (or K ² H) to form compounds of formula (1). The reaction conditions and reagents used for these transformations are similar to those used for the transformations of intermediate compounds of formulas (22) in (23) to (1) in Scheme 14 (for A, which is an SC) or for the transformations of intermediate compounds of formulas (7) in (8 ) in (1) in scheme 1 (where A denotes Ν).

Alternatively, compounds of formula (27) (where Υ is §) can be converted to compounds of formula (1) in Scheme 15. Intermediates of formula (27) can be alkylated with compound H ^D X (where K 'is lower alkyl and X is halogen , alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent (then optionally oxidized with an oxidizing agent in an inert solvent) and then can react with H ³ N in the presence or absence of a base in an inert solvent to form a compound of formula (1). The conditions and reagents used are similar to those used in the conversion of intermediate compounds of formulas (7) to (12) (or in (13)) and to compounds of formula (1) in scheme 2.

Compounds of formula (1) can be prepared from compounds of formula (24) using a different route, as shown in Scheme 15. Compounds of formula (24) can be converted to compounds of formula (27) by reaction with compounds of formula TCH ₂ TCH (C = ΝΗ ) ΝΗ ₂ in the presence or absence of acid in an inert solvent, followed by reaction with compounds I ² C (OA _c ) ₃ (where K _c denotes lower alkyl and K ¹ has the above values) using the conditions used to convert the compounds of formulas ( 3) in (17) in (7) in scheme 10.

Some compounds of formula (2) can be obtained by the methods presented in scheme 16.

Pattern 16

k ¹ 'x, + / - main <

solvent

see text

The compounds of formula (27b) can be treated with various alkylating agents I ¹⁴ X (where I ¹⁴ has the above meanings and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base, in an inert solvent to give structures of formula (28). Compounds of formula (28) (Υ is O) can then be converted into compounds of formula (2) by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base, in an inert solvent, followed by reaction with Z ³ H in the presence or absence of a base in an inert solvent to obtain compounds of formula (2). The reaction conditions used for these transformations are similar to those used for the conversion of intermediate compounds (22) in (23) to (1) in Scheme 14 (for A, which is an SC) or for the conversion of intermediate compounds of formulas (7) in (8) to (1) in scheme 1 (where A represents Ν). Alternatively, the compounds of formula (28) (Υ is §) can be alkylated with the compound H ^G X (where ^{G g} is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent (then optionally oxidized with an oxidizing agent in an inert solvent) and then can interact with R ³ H in the presence or absence of a base in an inert solvent to form a compound of formula (1). The conditions and reagents used are similar to those used in the conversion of the intermediates of formulas (7) to (12) (or (13)) and to the compounds of formula (1) in Scheme 2.

Compounds of formula (1), where Ζ is СОН, can be converted to compounds of formula (2), as shown in Scheme 16. Treatment with various alkylating agents I ¹⁴ X (where I ¹⁴ has the above meanings and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy ) in the presence or absence of a base, in an inert solvent gives structure (2). For specialists in this field it is obvious that the methods used in scheme 16, can also be used to obtain compounds of formula (1), where Ζ represents SOY ⁷ .

For Scheme 16, the terms base and inert solvent can have the meanings given below. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) ), bis (trialkylsilyl) amides of alkali metals (preferably bis (trimethylsilyl) sodium amide), trialkylamines (preferably Ν, из diisopropyl-X-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4 dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Ν methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or t oluene) or haloalkanes containing 1-10 carbon atoms and 1-10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 to 100 ° C.

Examples

Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on a 1BMBgikeg ETAMC instrument. (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethylsilane standard in deuterochloroform or deuterodimethyl sulfoxide, as described below. Mass spectra (M8) or high resolution mass spectra (NKM8) were recorded on an Iiiedai MAT 8230 spectrometer (using chemoionization (C1) with ΝΉ ₃ as a carrier gas or gas chromatography (OS), as indicated below) or a He \\ spectrometer 1e11 Raskag4 to4e1 5988a. The melting points were recorded in a device for determining the melting point of Visa Mo4e1 510 and they are uncorrected. Boiling points are uncorrected. All pH determinations during processing were carried out using indicator paper.

Reagents were purchased from commercial sources and, if necessary, purified before use in accordance with the general methods described by Ό. Reti ai4 ^ .b.R. Agageddo, RigShsayoi ίί а Ь Ь ога ога 1 1 1 С етка етка етка Е Е, 3g4 e4., (No. \ ν Wogk: Regdatop Rge88, 1988). Chromatography was performed on silica gel using the solvent systems indicated below. Volumetric ratios are given for mixed solvent systems. In other cases, parts and percentages are given by weight.

The following examples are provided to further illustrate the present invention. These examples, which represent the preferred methods currently under consideration for carrying out the present invention, are intended to illustrate, but not to limit, the present invention.

Example 1. Obtaining 2,7-dimethyl-8- (2,4dimethylphenyl) - [1,5-a] pyrazolo - [1,3,5] triazin-4 (3H) -one.

(Formula 7, where Υ is O, K ¹ is CH ₃ , Ζ is C-CH ₃ , Ar is 2,4-dimethylphenyl).

A. 1-Cyano-1 - (2,4-dimethylphenyl) propan2-one.

Sodium granules (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 ml) at ambient temperature. The reaction mixture was refluxed and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then dried in air. The solid was dissolved in water and a 1N HCl solution was added until pH 5-6. The mixture was extracted with ethyl acetate (3 x 200 ml); the combined organic layers were dried over Md8O ₄ and filtered. The solvent was removed in vauum to obtain a white solid (45.7 g, yield 74%):

NMR (SES1 ₃ , 300 MHz);

C1-M8: 188 (M + H).

B. 5 - amino-4- (2,4-dimethylphenyl) -3 methylpyrazole.

A mixture of 1-cyano-1 - (2,4-dimethylphenyl) propan-2-one (43.8 g, 0.23 mol), hydrazine hydrate (22 ml, 0.46 mol), glacial acetic acid (45 ml, 0 78 mol) and toluene (500 ml) were stirred at the boil under reflux for 18 h in an apparatus equipped with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in 6N HCl and the resulting solution was extracted with ether three times. Concentrated ammonium hydroxide was added to the aqueous layer to pH 11. The resulting half-solution was extracted three times with ethyl acetate. The combined organic layers were dried over Md8O ₄ and filtered. The solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield):

NMR (SES1Z, 300 MHz): 7.10 (8, 1H), 7.05 (4, 2H, 1 = 1), 2.37 (8, 3H), 2.10 (8, 3H);

C1-M8: 202 (M + H).

C. 5 - Acetamidino-4- (2,4-dimethylphenyl) 3-methylpyrazole, acetic acid salt.

Ethylacetamidate hydrochloride (60 g, 0.48 mol) was added quickly to an intensively stirred mixture of potassium carbonate (69.5 g, 0.50 mol), dichloromethane (120 ml) and water (350 ml). The layers were separated and the aqueous layer was extracted with dichloromethane ( 2 x 120 ml). The combined organic layers were dried over Md8O ₄ and filtered. The solvents were removed by simple distillation and the residue in the vessel, a clear pale yellow liquid (35.0 g), was used without further purification.

Glacial acetic acid (9.7 ml, 0.17 mol) was added to a stirred mixture of 5 amino-4- (2,4-dimethylphenyl) -3-methylpyrazole (34 g, 0.17 mol), ethyl acetate (22 g, 0, 25 mol) and acetonitrile (500 ml). The resulting reaction mixture was stirred at room temperature for 3 days; at the end of this time, it was concentrated in vacuo to approximately one third of its original volume. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. The white solid was dried in vacuo (31.4 g, 61% yield):

NMR (IM8O-b ₆ , 300 MHz): 7.00 (8, 1H),

6.90 (bb, 2H, 1 = 7.1), 2.28 (8, 3H), 2.08 (8, 3H), 2.00 (8, 3H), 1.90 (8, 3H), 1.81 (8, 3H);

C1-M8: 243 (M + H).

I. 2,7-Dimethyl-8- (2,4-dimethylphenyl) [1,5a] pyrazolo- [1,3,5] triazin-4 (3H) -one.

Sodium granules (23 g, 1 mol) were added portionwise to ethanol (500 ml) with vigorous stirring. After all of the sodium reacted, 5-acetamidino-4- (2,4-dimethylphenyl) -3methylpyrazole acetic acid salt (31.2 g, 0.1 mol) and diethyl carbonate (97 ml, 0.8 mol) were added. The resulting reaction mixture was refluxed and stirred for 18 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water and 1N was slowly added. HC1 solution to pH 5-6. The aqueous layer was extracted with ethyl acetate three times; the combined organic layers were dried over Md8O ₄ and filtered. The solvent was removed in vacuo to give a pale reddish-brown solid (26 g, yield 98%):

NMR (SIS1 ₃ , 300 MHz): 7.15 (8, 1H), 7.09 (8, 2H), 2.45 (8, 3H), 2.39 (8, 3H), 2.30 (3, 3H);

C1-M8: 269 (M + H).

Example 2. Obtaining 5-methyl-3- (2,4,6trimethylphenyl) - [[1,5-a] - [1,2,3] -triazolo- [1,3,5] triazin-7 (6H) -she.

(Formula 7, where Υ is O, I ¹ is CH ₃ , Ζ is Ν, Ar is 2,4,6-trimethylphenyl).

A. 1-Phenylmethyl-4- (2,4,6-trimethylphenyl) 5-aminotriazole.

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzylazide (0.92 g, 6.9 mmol) and potassium tert-butoxide (0.78 g 6.9 mmol) in tetrahydrofuran ( 10 ml) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over Md8O ₄ and filtered. The solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration gave a yellow solid (1.12 g, 61% yield):

NMR (SIS1 ₃ , 300 MHz): 7.60-7.30 (t, 5H), 7.30-7.20 (t, 2H), 5.50 (8, 2H), 3.18 (L8, 2H),

2.30 (8, 3H); 2.10 (8, 6H);

C1-M8: 293 (M + H).

B. 4- (2,4,6-Trimethylphenyl) -5-aminotriazole.

Sodium (500 mg, 22 mmol) was added with stirring to a mixture of liquid ammonia (30 ml) and 1-phenylmethyl-4- (2,4,6-trimethylphenyl) -5-aminotriazole (1.1 g, 3.8 mmol). The reaction mixture was stirred until a stable dark green color. A solution of ammonium chloride was added and the mixture was stirred while heating to ambient temperature for 16 hours. The residue was treated with a 1 M HC1 solution and filtered. The aqueous layer was made basic with a concentrated solution of ammonium hydroxide (pH 9) and then extracted with ethyl acetate three times. The combined organic layers were dried over Md8O ₄ and filtered. The solvent was removed in vacuo to give a yellow solid (520 mg), which was homogeneous according to thin layer chromatography (ethyl acetate).

NMR (SIS1 ₃ , 300 MHz): 6.97 (8, 2H), 3.683.50 (L8.8, 2H), 2.32 (8, 3H), 2.10 (8, 6H);

C1-M8: 203 (M + H).

C. 4- (2,4,6-Trimethylphenyl) -5-acetamidinotriazole, acetic acid salt.

A mixture of 4- (2,4,6-trimethylphenyl) -5-aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate (261 mg, 3 mmol) and glacial acetic acid (0.1 ml, 1.98 mmol) in acetonitrile (6 ml) was stirred at ambient temperature for 4 hours. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. Drying in vacuo afforded a white solid (490 mg, 82% yield):

NMR (IM8O- ₆ , 300 MHz): 7.90-7.70 (L8, 0.5H), 7.50-7.20 (L8.8, 0.5H), 6.90 (8, 2H), 6.90 (8, 2H), 3.50 -3.10 (L8, 3H), 2.30-2.20 (L8, 3H), 2.05 (b, 1H, 1 = 7), 1.96 (8, 6H), 1.87 (8, 6H);

C1-M8: 244 (M + H).

I. 5-Methyl-3 - (2,4,6-trimethylphenyl) [1,5a] - [1,2,3] -triazolo- [1,3,5] -triazin-7 (4H) -one.

Sodium (368 mg, 16.2 mmol) was added with stirring to ethanol (10 ml) at room temperature. After the sodium reacted, 4- (2,4,6-trimethylphenyl) -5-acetamidinotriazole acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 ml, 13 mmol) were added. The reaction mixture was stirred at reflux for 5 hours, then cooled to room temperature. The reaction mixture was diluted with water; 1n was added. HCl solution to pH 5-6 and extracted three times with ethyl acetate. The combined organic layers were dried over Md8O ₄ and filtered. Trituration with ether and filtration gave a yellow solid (300 mg, 69% yield):

NMR (SIS1 ₃ , 300 MHz): 6.98 (8, 2H), 2.55 (8, 3H), 2.35 (8, 3H), 2.10 (8, 6H);

C1-M8: 270 (M + H).

Example 3. Obtaining 4- (di (carbomethoxy) methyl) -2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5a] pyrazolo -1,3,5-triazine.

(Formula 1, where I ³ is CH (CHcO2CH3) 2, I ¹ is CH3, Ζ is CH- ₃ , Ar is 2,4-dimethylphenyl).

A. 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolotriazine.

A mixture of 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo-1,3,5-triazin-4-one (example 1,

1.38 g, 4.5 mmol), Ν, Ν-dimethylaniline (1 ml, 8 mmol) and phosphorus oxychloride (10 ml) were stirred at reflux for 48 hours. Excess phosphorus oxychloride was removed in vacuo. The residue was poured into a mixture of ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over Md80 ₄ and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexanes, 1: 4) gave one fraction (KB = 0.5). The solvent was removed in vacuo to give a yellow oil (1.0 g, 68% yield):

NMR ^ C1 ₃ , 300 MHz): 7.55 (ά, 1H, 1 = 1),

7.38 (άά, 1H, 1 = 7.1), 7.30 (ά, 1H, 1 = 7), 2.68 (5, 3H), 2.45 (5, 3H);

C1-M8: 327 (M + H).

B. 4- (Di (carbomethoxy) methyl) -2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo -1,3,5 triazine.

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed twice with hexanes, decanted after each washing and placed in anhydrous tetrahydrofuran (THF, 1 ml). A solution of diethyl malonate (0.32 g, 2 mmol) in THF (2 ml) was added dropwise over 5 minutes, with intense gas evolution during this time. A solution of 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolotriazine (0.5 g, 1.75 mmol) in THF (2 ml) was added and then the reaction mixture stirred under nitrogen for 48 hours. The resulting suspension was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed once with brine, dried over Md80 ₄ and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexanes, 1: 9) gave, after removal of the solvent in vacuo, a pale yellow solid (KB = 0.2, 250 mg, 35% yield): mp. 50-52 ° C.

NMR ^ Cl ₃ , 300 MHz): 12.53 (Lr.5, 1H), 7.15-7.00 (t, 3H), 4.40 (ς, 2H, 1 = 7), 4.30 (f 2H, 1 = 7), 2.4, 2.35, 2.3, 2.2, 2.1 (55, 12H), 1.4 (1, 3H, 1 = 7), 1.35-1.25 (t, 3H);

C1-NKM8: Calculated: 411.2032; Found: 411.2023.

Example 6. Preparation of 4- (1,3-dimethoxy-2propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolo-1,3,5-triazine.

(Formula 1, where K ³ is N1C11 (C11.ΌΓΙ К. K ¹ is CH ₃ , Ζ is C-CH ₃ , Ar is 2,4-dichlorophenyl).

A. 4-Chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolotriazine.

A mixture of 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo-1,3,5-triazin-4-one (example 1,

1.38 g, 4.5 mmol), Ν, Ν-dimethylaniline (1 ml, 8 mmol) and phosphorus oxychloride (10 ml) were stirred at reflux for 48 hours. Excess phosphorus oxychloride was removed in vacuo. The residue was poured into a mixture of ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over Md80 ₄ and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexanes, 1: 4) gave one fraction (KB = 0.5). The solvent was removed in vacuo to give a yellow oil (1.0 g, 68% yield):

NMR ^ C1 ₃ , 300 MHz): 7.55 (ά, 1H, 1 = 1),

7.38 (άά, 1H, 1 = 7.1), 7.30 (ά, 1H, 1 = 7), 2.68 (5, 3H), 2.45 (5, 3H);

C1-M8: 327 (M + H).

B. 4- (1,3 - Dimethoxy-2-propylamino) -2,7dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolo1,3,5-triazine.

A mixture of 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolotriazine (part A, 570 mg, 1.74 mmol), 1,3-dimethoxypropyl-2-aminopropane ( 25 mg, 2.08 mmol) and ethanol (10 ml) were stirred at ambient temperature for 18 hours. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate three times. The combined organic layers were dried over MD80 ₄ and filtered. The solvent was removed in vacuo. Column chromatography (CH ₂ Cl ₂ : CH ₃ OH, 50: 1) gave one fraction. Removal of the solvent in vacuo afforded a solid (250 mg, 35% yield): mp. 118-120 ° C.

NMR (<ЖС1 ₃ , 300 MHz): 7.50 (5, 1Н), 7.28 (άά, 2Н, 1 = 8.1), 6.75 (ά, 1Н, 1 = 8), 4.70-4.58 (t, 1Н), 3.70-3.55 (t, 4H), 3.43 (5, 6H), 2.50 (5, 3H),

2.35 (3, 3H);

C1-NKM8: Calculated: 409.1072; Found: 409.1085;

Analysis for C ₁₈ H ₂₁ C12 ^ 02:

Calculated With 52.69; H 5.17; N, 17.07; C1 17.28;

Found: C, 52.82; H 5.06; N, 16.77; C1 17.50.

Using the above methods and modifications known to specialists in this field, the following additional examples of the table can be obtained. 1-4.

The examples presented in table. 1 can be obtained by the methods described in examples 1, 2, 3 or 6. Commonly used abbreviations: Ρ1ι stands for phenyl, Pr stands for propyl, Me stands for methyl, E1 stands for ethyl, Vi stands for butyl, Ex stands for example.

Table 1

2 Sme IN 2 Innsn (Sngome! 2 M T.sh..tsao. 2,4-C12-RP 118-120 Sme INSNRG2 2,4-C12 “₽ 114-116 Sme YESVI 2,4-C12-RN oil S-me LRG (CH2-C-C3H5) 2,4-C12-RN oil Sme N <CH2CH2OMe) 2 2,4-C12-P & oil S-me ΝΗ-3-.g.heptyl 2,4-C12-RN 90-92 S-me ONSN (EsDsNgOMe · 2,4-C12-RN 179-181 S-me ΝΕΕ2 2,4-C12-P1 " 133-134 Sme ONSN (CH2O6e + 2 2,4-C12-RN oil S-me ΝΗ-3-pentyl 2,4-C12-P & 139-140 S-me YMERD 2,4-C12-RL 60-62 S-me ΝΡΓ2 2,4-C12-P & oil S-me ΝΗ-3- hexyl 2,4-C12-₽ 130-132 S-me morpholino 2,4-C12-RB S-me ν (СН2РК) sngsngome 2,4-C12-RN S-me hoarfrost (СН2₽М снгоме 2,4-C12-Pb S-me ON-4- tetrahydropyranyl 2.4-C12-RN S-me ΝΗ-cycle lopentyl 2,4-C12-₽ S-me 1,2,3,4-tetrahydroiso- quinolinyl 2,4-C12-RD Sme CH2 ^- (1,2,3,4-herrahydroisoquinolinyl) 2,4-C12-P & S-me oes 2,4-C12-RY 141-143 Sme OCH (Ec) SNOME 2,4-C12 “Pb S-me OS2 2,4-C12-RI C-not 0-3 pentyl 2,4-C12-? B S-me 5 £ s 2,4-C12-RN S-me 5 (O) EU 2,4-C12-Pb S-me 6O2ES 2,4-C12-RY Sme CH (CO2Eg> 2 2,4-C12-RP S-me C (EU) (CO2EO2 2,4-C12-Pb S-me sn (ec) cngon 2,4-C12-Pb Sme CH (EU) CHgOMe 2,4-C12-RN Sme SOYMeg 2,4-C12-RP S-me SOSN3 2,4-С12РЬ S-me CH (OH) CH3 2,4-C12-Pb S-me C (OH) RD-3-Diridyl 2,4-C12-RN S-me RD 2,4-C12-RP S-me 2-SG3-RD 2,4-C12-RP Sme 2-RD-RD 2,4-C12 “Pb S-me 3-pentyl 2,4-C12-RP S-me cyclobutyl 2,4-С12РЬ Sme 3-pyridyl 2,4-C12-RI C-not CH (Ec) CH2CO2 <2 2,4-C12-RB S-me CH (Ec) SNGCHNgMeg 2,4-C12-RN S-me Inns (CIS) 2 2,4, b-Mez-RP 125-127 Sme ivenvgg 2,4,6-mez-b Sme YESVi 2.4, b-mez-pb S-me ΝΡΓ {CH2-C-C3H5} 2, 4,6-Mez-Rb S-me S (CH2CH2OMe> 2 2,4,6-Mez-RD 123-124 S-me eun-3-: heptyl 2,4,6-Mez-RD S-me ONSN (EU) SNOME 2,4, b-Mez-RO 145-146 S-me HEC2 2,4,6-Mez-RD 88-90 sme ONSN (CH2OES) 2 2,4, b-Mez-RD 132-134 sme ΝΗ-Z-'Pentyl 2,4, b-Mez-RD 134-135 Sme YMERD 2.4, b-Mez-RL S-me ΝΡΓ2 2,4,6-Mez-RD Sme EYN-Z 2,4,6-Mez-RD S-me morpholino 2,4,6-Mez-RD S-me N (СН2РП) СНгСНгОМе 2,4,6-Mez-RD

64 S-me ONSN (SNGRD) CH? OMe 2.4, b-mez-pb 65 Sme ΝΗ-4-tetrahydropyranyl 2,4,6-mes-RD 66 Sme ΝΗ- 'cyclopentyl 2.4, b-mez ~ pb 67 S-me 1,2,3,4-tetrahydroiso- quinolinyl 2.4, b-mez-pb 68 Sme CH? - (1,2,3,4-tetrahydroI9 oquinolinyl) 2.4, b-mez-pb 69 Sme Oes 2,4,6-Mez-RD 70 S-me OCH (Ec) SNOME 2,4, b-Mez-RD 71 S-me OSNgRD 2,4,6-Mez-RD 72 sme o-pentyl 2,4,6-Mez-RD 73 Sme 5ES 2,4, b-mez-RD 74 Sme 5 (O) EU 2,4,6-Mez-RD 75 Sme ZOGES 2,4, b-Mez-RD 76 Sme CH (CO2EC> 2 2,4,6-Mez-RD 77 sme C (EU) (CO2EO2 2,4,6-Mez-RD 78 S-me CH (EOSN20N 2,4,6-Mez-RD 79 S-me CH (EU) CHgOMe 2,4,6-Mez-RD 80 S-me SOYMeg 2,4,6-Mez-RD 81 S-me SOSNz 2,4, b-mez-RD 82 S-me CH (OH) CHZ 2,4,6-Mez-RD 83 S-me C (OH) RD-3-pyridyl 2,4,6-Mez-RD 84 S ~ me RD 2,4,6-Mez-RD 85 S-me 2-sez-rd 2,4,6-Mez-RD 86 Sme 2-RD-RD 2,4,6-Mez-RD 87 S-me 3-? 1entyl 2,4,6-Mez-RD 88 S-me cyclobutyl 2,4, b-mez-RD 89 S-me 3 - pyridyl 2,4,6-Mez-RD 90 S-me CH (EOSNGSOYMeg 2,4,6-Mez-RD 91 Sme sn (Yeosingsngmmeg 2,4,6-Mez-RD 92₽ S-me ONSN (SNGOMe) 2 2,4-Me2’ 44-45 934 S-me S (CH2CH2OMe> 2 2,4-Meg-RD oil 94 ^g S-me InSn (Sun »sn2OMe 2,4-meg-pb 102-104 95 ⁸ sme ΝΗ-3-pentyl 2,4-Meg-RD 102-104 96 ^e Sme NEC 2 2,4-Me2 “₽ oil 97 ^th Sme S (CH2CY) 2 2,4-Meg-RD 148-150 98 ^ν Sme Inns (Me) Sngome 2,4-Meg-RD 102-104 99 * S-me OCH (EOSN20Me 2,4-Meg-RD oil 100 ^x S-me Ы₽г-с-СзН5 2,4-Meg-RD oil 101U Sme INSN (Me) СН2ЫМег 2,4-Meg-RD 47-48 102 ² s-me S (s-CzH5) 2,4-Meg-RD 117-118 103 ^aa Sme S (Pr) CH2CH2SY 2,4-Meg-RD oil 104 ^ab Sme S (Vi) SNGSN2SY 2,4-Meg-RD oil 105 S-me INSNRG2 2,4-Meg-RD 106 Sme YESVi 2,4-Meg-RD 107 Sme LRG (CH2-C-C3H5) 2,4-Meg-RD 108 s-me eun-3- heptyl 2,4-Meg-RD 109 Sme ES2 2,4-Meg-RD 110 Sme INSN (SNCOES> 2 2,4-Meg-RD 111 S-me ΝΗ-3-.pentyl 2,4-Meg-RD 112 S-me YMERD 2,4-meg-pb 113 Sme YRG2 2,4-Meg-RD 114 S-me EUN-3- hexyl 2.4 megapixel taxiway 115 sme morpholino. 2,4-Meg-RD 116 Sme N (SNgRD) CH2CH2OMe 2,4-meg-pb 117 Sme ONSN (SNGRD) SNgOMe 2,4-meg-pb 118 S-me eun-4 tetrahydropyranyl 2,4-Meg-RD 119 S-me un-cyclopentyl 2,4-Meg-RD 120 Sme 1,2, 3,4-tetrahydro- I9OCHINOLINYL 2,4-meg-pb 121 Sme CH2- (1,2,3,4 — tetrahydro— isoquinolinyl 2,4-Meg-RD 122 S-me BOTH 2.4 megapixel taxiway 123 S-me OCH (EU) SNOME 2.4 megapixel taxiway 124 S-me OSNgRD 2,4-Meg-RD 125 S-me OZ pentyl 2.4 megapixel taxiway 126 S-me 5Ec 2.4 megapixel taxiway 127 S-me 5 (O) EU 2,4-Meg-RD 128 Sme 5O2ES 2,4-Meg-RD 3 S-me CH (CO2EC) 2 2,4-Meg-RD 50-52 129 S-me C (EU) (C02EO2 2.4 megapixel taxiway

sme SYA (HER) SIGON 2,4-Me2 ~ ₽ Sme UZBE) SNGOMe 2,4-meg-pb S-me LATER) SNGOES 2,4-meg-pb sme SOYMeg 2,4-meg-pb sme SOSNz 2,4-meg-pb S-me CH (OH) CH3 2,4-Meg-pH S-me C (OH) P-E-pyridyl 2,4-Meg-pH S-me ₽p 2.4 megapixel S-me 2-Crz-pb 2,4-meg-pb S-me 2-₽-R 2,4-Meg-R sme 3- pentyl 2.4 megapixel S-me cyclobutyl 2.4-Meg-pH S-me 3-pyridyl 2, 4-Meg-Pb S-me CH (EE) SNgSOYMeg 2.4 megapixel Sme szEosngsingimeg 2,4-meg-pb S-me ONSN (SNGOMe) g 2-Me-4-MeO-R 45-46 S-me ZhSN2SN2OMe) g 2-Me-4-MeO-₽ oil S-me ONSN (EE) SNGOMe 2-Me-4-MeO-RP 86-88 S-me W $ g) CH2CH2SY 2-Me-4-meO-Pb oil S-me DOS (Eskgome 2-Me-4-MeO ~ Pb Sme ONSN (SNGOMe) 2 2-B £ -4-MeO-? B 88-90 S-me ν (sngsngome) g 2-Br-4-MeO-Pb oil S-me ONSN (EU) SNOME 2-Vg-4-MeO-RP 95-97 S-me N (Pr) CH2CH2CYA 2-Bx-4-MeO-Pb S-me OSN (BY) SNOM g-vh-4-meo-rn S-me ONSN (SNGOMe) 2 2-Me-4-YMeg “PH S-me S (CH2CH2OMe> 2 2-Me-4-YMeg-R oil S-me ONSN (ITS (SNGOMe 2-Me-4-YMeg-R S-me S (rg> sngsn2sy 2-Me-4-YMeg-R S-me OSJ EU) 2-Me-4-YMeg-R S-me Inns (CIS) 2 g-vg-4-imeg-rn sme s (sngsngome) g 2-Vg-4-YMeg-R Sme Inns (her> hengome 2-Vg-4-YMeg-R S-me jrosingsngs 2-Vg-4-YMeg-R S-me OSN (EE) SNGOMe 2-Vg-4-YMeg-R S-me ONSN (SNGOMe) 2 2-Vg-4-1-₽g-R Sme S (CH2CH2OMe) 2 Mr. Wg-4-ί-Ρχ-ΡΙϊ S-me INJEOSNGOME 2-Be-4-1-Pr-Rb S-me S <₽x) CH2CH2SY 2-Vg-4-1-Rs-₽N S-me OSN (EE) SNGOMe 2-Vg-4-x-₽ £ -РЬ Sme ONSN (SNGOMe) 2 2-ag-4-me-pb sme s (sngsngome) g 2-Br-4-Me-Pb S-me Inns {Eosn20Me 2-sun-4-me-pb S-me S (Pr) CH2CHNGSY 2-Br-4-Me-Pb S-me OSJEISNGOME 2-Br-4-Me-Pb S-me INGSSN2OMe) 2 2-Me-4-Sun-RP 108-109 Sme S (CH2CH2OMe) 2 2-Me-4-Vg-RN Sme ONSN (EU) SNOME 2-Me-4-Br-Rb S-me jrosingsngs 2-Me-4-Bg-Pb S-me CCH (Ec) CH20me 2-Me-4-Br-Rb S-me ONSN (SNGOMe) 2 2-C1-4,6-Meg-R Sme N (CH2CH20M6) 2 2-C1-4, b-Meg-Pb S-me ONSN (SNGOMe) g 4-VG-2,6- (Me) 2 ~ RL Sme S (SNGSN20Me) 2 4-Br-2,6- (Me) g-RO Sme ONSN (SNGOMe) 2 4-1-Pr-2-5Me-Rb S-me ZhSNgSN2OMe) 2 4-1-Rg-2-5Me-R S-me InSN (CH20me> 2 2-Br-4-Ces-Pb S-me S (SNGCH2OMe) 2 2-VG-4-SG3-RP S-me Inns (CIS) 2 2-Br-4,6- (MeO) 2 ~ Pb S-me S (CH2CHNgome> 2 2-Br-4,6- (MeO) 2 “₽ S-me ONSN (SNGOMe) 2 2-C1-4.6- (MeO) 2-Pb Sme s (sngsngome) g 2-C1-4.6- (MeO) g Pb S-me Young Engome) g 2.6- <me) 2 “4-5Me-Pb S-me S (SNGCH2OMe) 2 2.6- (Me) 2 ”4-5Me-Ry S-me ONSN (SNGOMe) 2 4- (COMe) -2-Br-Pb S-me W <CH2CH2O3) 2 4- (COME) -2-Eg-Pb S-me Innsn (Engome) g 2,4,6-mes-pyrid-3-yl S-me S (SNGCH2OMe) 2 2, 4, b-Mez-pyrid'-Zil S-me ONSN (SNGOMe) 2 2. 4- (Br "g pb S-me S (CH2CHNgome) 2 2,4- (Вг> г-₽ ¹ » S-me Innsssngome) g 4-1-P £ -2-5Me-Pb S-me S (sngsngome) g 4-1-Pr-2-5Me-Rb

202 S-me ONSN (SNGOMe) 2 4-1-Pr-2-50gMe-Pb 203 S-me S (SNGCH2OMe) 2 4-x-rg-2-50gme-pb 204 S-me Inns (England) 2 2.6- (Me) 2-4-5Me-RN 205 S-me s (sngsngome) 2 2.6- (Me) 2-4-5Me-Pb 206 S-me Inns (England) 2 2.6- (Me) 2-4-50 gMe-Pb 207 S-me s (sngsngome) 2 2.6- (Me) 2-4-ZOGMe-RP 208 S-me ONSN (SNGOMe) 2 2-1-4-x-Pr-Rb 209 S-me ν (sngsngome) g 2-1-4-x-Pr-Rb 21C S-me Inns (England> 2 2-bg-4-s (Me) gb-MeO-Pb 211 sme s (sngsngome) 2 2-Br-4-S (me> r-6-Me0-₽ 212 Sme ssngome) 2 2,4- (3Me) 2-Pb 213 S-me s (sngsngome) 2 2,4- (5Me) 2-Pb 214 Sme Inns (England) 2 2,4- (HogMe) 2-Pb 215 Sme s (sngsngome) 2 2,4- [SOGMe] 2-Pb 216 Sme ONSN (SNGOMe) 2 4-x-rg-2-5me-pb 217 S-me s (sngsngome) 2 4-x-rg-2-zme-pb 218 S-me Inns (England) 2 4-x-rg-2-30gme-pb 219 S-me s (sngsngome) g 4-1-Rg-2-30gMe-RN 220 S-me Inns (England) 2 2-S (Me) 2-4-Me-RN 221 S-me s (sngsngome) g 2-S (Me) g-4-Me-R 222 S-me ONSN (SNGOMe) 2 2-MeZ-4,6- (Me) 2-Pb 223 S-me to (sngsngome) 2 2-MeZ-4.6- (Me) 2 “₽ 224 S-me Innsssngome) 2 2- (CH3CO) -4.6- (Me) 2-Pb 225 S-me s (sngsngome) 2 2- (СНзСО) -4,6- (Ме) г-₽Ь 226 I AM ONSN (SNGOMe) 2 2.4 megapixel 227 I am ONSN (SNGOMe) 2 2,4-Meg-pH 228 Cez s (sngsngome) 2 2.4 megapixel 229 SGZ S (CH2CH20Me) 2 2,4-meg-pb 230 N Innsn (Engome) g . 2.4, b-mez-pb 231 N INSNRG2 2.4, b-mez-pb 232 S YESVi 2,4,6-Mez-pb 233 N yybd (cng-s-szn5) 2,4,6-Mez-pb 234 N S (CH2CH2 ^OMe '2 2,4,6-Mez-pb 235 N EUN-3-Heptyl 2,4,6-Mez-pb 236 N ONSN (EU) SNOME 2,4,6-Mez-pb 237 N ΝΕΕ2 2,4,6-mes-RH 238 N ONSN (SNGOES) g 2,4, b-mez-pH 239 N ΝΗ-3-dentil 2,4,6-Mez-pb 240 N IMeR 2,4,6-Mez-pb 241 N Ы₽Г2 2.4, b-mez-b 242 S Eun-z-hexyl 2,4,6-Mez-R 243 N morpholino 2,4,6-Mez-pb 244 N s (cng ₽msngsngome 2,4,6-Mez-R 245 N ЫНСН (СН ₂ ₽Ь) СНгОМе 2,4,6-Mez-pb 242 N YN-4-tetrahydropyranyl 2, 4, 6-Mez-Pb 247 N Cyclopentyl 2,4,6-Mez-pb 248 N 1,2,3,4-tetrahydro I9OCHINOLINYL 2,4,6-Mez-pb 249 N CHg- (1,2,3,4-tetrahydro-4, b-Mez-Pb isoquinolinyl) 250 N ABOUT HER 2.4, b-mez-pb 251 N OSN (S) SNOM 2,4,6-Mez-pb 252 N osngr 2.4, b-mez-pb 253 N 0-3-pentyl 2.4, b-mez-pb 254 N 5EE 2,4,6-Mez-pb 255 N 5 (O) Her 2.4, b-mez-pb 256 N HEALTH 2.4, b-mez-pb 257 N sogsogog 2.4, b-mez-pb 258 N C (EE) (SOHE) g 2.4, b-mez-pb 259 N CH (EE) CHgON 2,4,6-Mez-pb 260 N CH (EE) CHgOMe 2.4, b-mez-pb 261 N soimeg 2.4, b-mez-pb 262 N SOSNz 2.4, b-mez-pb 263 N CH (OH) CH3 2.4, b-mez-pb 264 N C (OH) Pb-3-; pyridyl 2,4,6-Mez-pb 265 N ri 2,4,6-Mez-pb 266 N 2-Crz-? B 2,4,6-Mez-pb 267 N 2-pb-pb 2,4,6-Mez-pb 268 N 3-lentil 2.4, b-mez-pb 269 N cyclobutyl 2.4, b-mez-pb 270 N 3-pyridyl 2.4, b-mez-pb 271 N CH (EE) CH2CO2MEG 2,4,6-Mez-pb

272 N CH (Ec) CH ₂ CH ₂ UMe ₂ 2,4,6-Mez-pb 343 344 Sme S-me ONSN (CH ₂ -1Rg) CHgOMe 2,4-me ₂ -RP oil ONSN (₽g) CH ₂ OMe 2,4-meg-RG 94-95 273 N YKSN (CH ₂ OMe) ₂ 2, 4-me ₂ -? B 345 Sme ONSN (EE) CH ₂ OES 2,4-Meg-RN 76-77 274 N INSNRG2 2, 4-Me ₂ -RP 346 Sme INSN (SNGOMe) SNGSNgOME 2-Me-4-Me ₂ SIRP oil 275 N YEEE 2,4-Me ₂ -RY 347 C-not 2Ee 2-me-4-C1PH oil 276 N LRG (CH2-C-C3H5) 2,4-Me ₂ -Pb 348 S-me _ΝΗ -3- pentyl 2-Me-4-S1RP 122-124 349 S-me S (CH ₂ CHgOMe) 2 2-Me-4-C1P6 oil 277 N S (CH ₂ CH ₂ OMe) ₂ 2,4-Me ₂ -Pb 350 S-me ONSN (CH ₂ OMe) ₂ 2-Me-4-C1P 122-123 278 N eun-z-wh-gil 2,4-Me ₂ -Pb 35 Sme WES ₂ 2-Me-4-S1RP _{mas o} 279 N Inns (Eosn ₂ OME 2,4-Me ₂ -Pb 352 S-me HUB ₂ 2-C1-4-Me 28. N ΝΕΕ ₂ 2,4-Me ₂ -P 353 Sme EN-3-pentyl 2-C1-4-MeRN 120-121 354 S-me ONSN (CH ₂ OMe) ₂ 2-C1-4-MeORN 281 TO ONSN (CH ₂ OEO2 2,4-Me ₂ -RP 355 * 1 S-me S (CH ₂ CH ₂ OMe> ₂ 2-C1-4-MeORP oil 282 N ΝΗ-3-pentyl 2,4-Me ₂ -Pb 356 ^bt Sme ONSN (EU) CH ₂ OMe 2-C1-4-MeORN 108-110 283 N IMeR 2,4-Me ₂ -P E57 * ^L Sme S (s-Rg) CH ₂ CH ₂ CU 2-C1-4-MeORP 127-129 358 * ® Sme EXTERNAL ₂ 2-C1-4-MeORN _oil 284 N Yrg ₂ 2,4-me ₂ -Pb 359 * P Sme eun-3-; pentyl 2-C1-4-MeORP 77-79 285 N ΝΗ-3-.hexyl 2,4-Me ₂ -P 360 sme ONSN (EOS) ( ₂ CH ₂ OMe 2-C1-4-MeORP 286 N morpholino 2,4-Me ₂ -? N 361 S-me ONSN (Me) CH ₂ CH ₂ OMe - 2-C1-4-MeORP 287 N S (CH ₂ RP) CH ₂ CH ₂ OMe 2,4-Me ₂ -RN 362 S-me ONSN (EOSN ₂ CH ₂ OMe 2-Br-4-MeOR6 363 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-Br-4-MeOR 288 N ONSN (CH ₂ RY) CH ₂ OMe 2, 4-Me ₂ -Ry 364 S-me ONSN (EOSN ₂ CH ₂ OMe 2-Me-4-MeORP 289 N ΝΗ-4-tetrahydropyranyl 2,4-Me ₂ -P 365 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-Me-4-MeORN 290 N ΝΗ- · cyclopentyl 2,4-Me ₂ -₽ Zbb S-me ONSN (CH ₂ OMe) ₂ 2-C1-4, 5- (MeO) ₂ Pb 367 S-me S (CH ₂ CH ₂ OMe) ₂ 2-C1-4.5- (MeO) ₂ Pb 291 N 1, s, 4 - tetrahydro- 2,4-Me ₂ -RP from ochinoline 368 Sme ONSN (EU) CH ₂ OMe 2-C1-4.5- (MeO) ₂ ₽N 369 S-me N (e-Pr) CH ₂ CH ₂ CO 2 -C1-4.5- (Meo) ₂ pH 292 N CH ₂ - (1,2,3,4-tetrahydro- 2,4-Me ₂ -RN 370 Sme WES ₂ 2-C1-4.5- (MeO) 2₽ * from okhinoliniya) 371 Sme EUN-3- pentyl 2-C1-4.5- (MeO) g 372 S-me ONSN (EU) CH ₂ CH ₂ OMe 2-C1-4.5- (MeO) ₂ RP 293 N Oes 2,4-Me ₂ -P 373 S-me InSn (Me) SNgCH ₂ ohm 2-C1-4.5- <meO) ₂ Ry 294 N DOS (EE) CH ₂ 0Me 2,4-Me ₂ -RL 374 * 4 Sme ONSN (CH ₂ OMe) ₂ 2-VG-4,5- (MeO) ₂ PH 137-138 295 N DOS ₂ ₽N 2,4-Me ₂ -? B 375 S-me S (SNGCH ₂ OMe) ₂ g-Br-4,5- (MeO) 2₽ * 296 N 0-3.-pentyl 2,4-Me ₂ -Pb 376 * ^g Sme ONSN (EU) CH ₂ OMe 2-Br-4.5- (MeO) 2 ^₽ * 147-148 377 S-me N (s-Pr) SNGSN ₂ NN 2-VG-4,5- (MeO) 2₽ * 297 N 5ΕΕ 2,4-Me ₂ -RI 3? 8 * ^a S-me ЫЕС ₂ 2-ВС-4,5- (МеО) ₂ ₽ * 52-58 298 N 3 (Οΐ EU 2,4-Me ₂ -RP 379 S-me NN-3-pentyl 2-Vs-4,5- (MeO) ₂ ? L 299 N zo ₂ ec 2,4-Me ₂ -RK 380 Sme ONSN (EU) CH ₂ CH ₂ OMe 2-Br-4,5- (MeO) ₂ ₽ 300 N CH (CO ₂ EU> 2 2,4-Me ₂ -Pb 381 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-Br-4,5- (MeO) ₂ ₽ 301 N C (EU) (CO ₂ EU) ₂ 2,4-Me ₂ -RN 382 sme ONSN (CH ₂ OMe) ₂ 2-C1-4,6- (MeO) ₂ Pb 302 N CH (EE) CH ₂ OH 2,4-Me ₂ -Pb 383 sme S (CH ₂ CH ₂ OMe> 2 2-C1-4,6- (MeO) ₂ ₽ 303 N CH (EU) CH ₂ OMe 2,4-Me ₂ -P1t 384 sme ONSN (EE) CH ₂ OMe 2-C1-4.6- (MeO) ₂ ₽ 385 Sme S (s-₽g) СН ₂ СН ₂ СЫ 2-С1-4,6- (МеО) ₂ ₽ 304 N Soyme ₂ 2,4-Me ₂ -Pb 386 S-me EXIT ₂ 2 -C1-4,6- (MeO) ₂ Pb 305 N SOC 2,4-Me ₂ -RN 387 S-me EN-3-pentyl 2-C1-4, 6- (MeO) ₂ Pb 306 N CH (OH) CH3 2,4-Me ₂ * ₽ * 388 S-me ONSN (Ec) СН ₂ СН ₂ ОМе 2-С1-4,6- (МеО) ₂ ₽ 307 N C (OH) RL-Z-pyridyl 2,4-Me2 * ₽ 308 N 2,4-Me ₂ -RN 389 Sme INSN (Me) CH ₂ CH ₂ OMe 2-C1-4.6- (MeO) ₂ Pb 309 N g-szg-ry 2,4-Me ₂ -RN 390 S-me ONSN (CH ₂ OMe) ₂ 2-Me-4,6- (MeO) ₂ ₽ 3X0 N 2-RK-RP 2.4 megapixel 391 Sme N (CH ₂ CH ₂ OMe) g 2-Me-4,6- (MeO) 2? * 311 N 3-pentyl 2,4-Me ₂ -RN 392 Sme ONSN (EU> СН ₂ ОМе 2-Ме-4,6- (МеО) ₂ ₽ 312 N cyclobutyl 2,4-meg-pb 393 S-me S (s-₽g) СЯ ₂ СН ₂ СЫ 2-Ме-4,6- (МеО) ₂ ₽ * 313 ^Ν 3_PRIDIDIL 2,4-Me ₂ -RN 395 S-me YES ₂ 2-Me-4,6- (MeO) ₂ ₽N 31; N CH (EE) CH ₂ C0HMe2 2,4-Me ₂ -₽ 396 S-me EIN-Z-Peitil 2-Me-4.6- (MeO) ₂ ₽ * 315 N sn (Yeosn ₂ sn ₂ ym ₂ 2,4-Me ₂ -RN 397 S-me ONSN (EU) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO) ₂ ₽ 31b ^up S-me ₂ 2-Vg-4-MeO-RN oil 398 S-me INSN (Me) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO) ₂ ₽ E17 ^at S-me eun-3-, pentyl 2-Br-4-meO-RN 310 ^a 3 sme ONSN (CH2CH ₂ OMe) CH ₂ OMe 2.4, b-Mez-RN 101-103 399 S-me S (s-tG) CH2CH ₂ CU 2-Br-4.6- (MeO) ₂ ? 319 ^a ® S-me ΝΗ (C-C3H5) 2,4-Me ₂ “₽N oil 400 Sme EX ₂ 2-Br-4,6- (MeO) 2₽ 320 ^a * Sme morpholino 2,4, b-Mez-RG 139-141 401 S-me YNN-3-pentyl 2-Vg-4,6- (MeO) ₂ ₽ * 321 ^a ₽ Sme ONSN (SNGOMe) 2 2-SY-4-non-P1 152-153 402 Sme INSN (Ec> CH ₂ CH ₂ OMe 2-VG-4,6- (MeO) ₂ Pb 322 ^a h Sme n (s-szYa5) sngsn2 2.4, b-Mez-R) 149-151 403 S-me ONSN (Me) NW ₂ CH ₂ OMe 2-Br-4,6- (MeO) ₂ Pb 324 “ Sme ONSN (СН ₂ СН2СМе) СН ₂ Оме 2-Me-4-Vg-R) 115-117 404 S-me ONSN (EE) CH ₂ CH ₂ OMe 2-Me-4-MeORN 325 " Sme ONSN (SNGOMe) 2 2 5-MS2-4-MeO- PH 55-57 405 S-me InSn (Me) CH ₂ CH ₂ OMe 2-Me-4-MeO 326 ^ai S-me ν (sngsngome, ₂ 2 5-Me ₂ -4-MeO- PH 72 406 S-me Inns (Sn ₂ ohm) g 2-me0-4-mer 327 " S-me ΝΗ-3-rentil 2 5-Me ₂ -4-MeO- PH 45-47 320 " Sme WES ₂ 2 5-Me ₂ -4-MeO- oil 407 S-me S (CH ₂ CH ₂ OMe) 2 2-MeO-4-Me 329 ^ah Sme Inns (England) 2 2-C1-4-MeRP 80-81 408 C ^ me ONSN (EE) CH ₂ OMe 2-Me0-4-Me 330 ^a Sme her (EU) sn ₂ ohm 2-C1-4-Me 77-79 409 S-me S ("- ₽g) CH ₂ CH ₂ CH 2-MeO-4-Me 331 " S-me N (CH ₂ CH ₂ OMe) 2 2-C1-4-MeRP oil 410 S-me EXT ₂ 2-MeO-4-MERN 332 * ^a S-me (3) -insn (sngsngome) ₂ ohm 2-C1-4-MeRN 139-140 411 Sme UN-3-.p ^entio 2-MeO-4-MeRN 333 ** S-me M (s-SzN5) СягСН2С «2 5-Me ₂ -4-MeORN 120-122 412 S-me ONSN (ЕЕ) СН ₂ СЯ ₂ ОМе 2-Ме0-4-Ме₽Н 334 * 9 Sme IE2 2-Me-4-MeORS oil MYAG.LO 413 S-me extra <me) sn ₂ sn ₂ ohm 2-meO-4-meRN 335 ** Stme Oes 2-Me-4-MeORN ZZb * ¹ S-me (5) -INSN (CH ₂ CH ₂ OMe) SC ₂ CMe 2-me-4-meO? G oil 414 S-me ONSN (SY ₂ OMe) ₂ 2-MeO-4-MeRP 337 * 3 S-me ν (С-С3Н5) 2-Me-4-MeOR1- 129 415 S-me S (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MER 338 * ^k Sme ONSN (CH ₂ CH ₂ OEE) ₂ 2-Me-4-MeORG amorphous. 416 Sme ONSN (EE) CH ₂ OMe 2-MeO-4-MER 339 Sme N (s-CzH5) CH2SY2SN 2,4-C12-₽ 109-110 417 S-me S (s-₽g) CH ₂ CH ₂ SY 2-MeO-4-MeRk 340 Sme (5) -INSN (CH ₂ CH ₂ OMe) CH ₂ OMe 2,4-C12-RN 93-94 418 S-me EXT ₂ 2-MeO-4-MER 341 Sme yn-z-p® ”™ 2-Me-4-VgRb 118-119 419 S-me UN-3-pentyl 2-MeO-4-MeRN 342 C-not S (CH ₂ CH ₂ OMe) 2 2-Me-4-EgR 420 S-me ONSN (EE) CH ₂ SK2OMe 2-MeO-4-MER 421 Sme ONSN (Me) CH ₂ CH ₂ OMe 2-Me0-4-Mer ₄₂₃ bc S-me ONSN (SNOMe) 2 2-MeO-4-C1PB 424 S-me S (CH ₂ CH ₂ OMe) ₂ 2-Me0-4-C1Pb 42e S-me ONSN (EE) CH ₂ OMe 2-MeO-4-C1 426 Sme N (s-₽g) СН ₂ СН ₂ СЫ 2-МеО-4-С1РЬ 427 S-me NSE7 2-MeO-4-S1RP 428 S-me ΝΗ-3-pentyl 2-MeO-4-C1Pk 429 Sme ONSN (EE) CH ₂ CH ₂ OMe 2-MeO-4-C1 433 Sme ONSN (Me) CH ₂ CH ₂ OMe 2-MeO-4-C1PH

Notes for the table. one:

a) Anal. Calculated: C 52.69, H 5.17, N 17.07, C1 17.28; Found: C 52.82, H 5.06, N 16.77, C1 17.50.

b) C1-NKM8: Calculated: 406.1565; Found: 405.1573 (M + H);

Anal Calculated: C 59.11, H 6.20, N 17.23, C1 17.45; Found: C 59.93, H 6.34, N 16.50, C1 16.95.

NMR (SBS1 ₃ , 300 MHz): 0.95 (ΐ, 1 = 8, 4H), 1.30-1.40 (t, 4H), 1.50-1.75 (t, 4H), 2.35 (8, 3H), 2.48 (8, 3H) ), 4.30-4.45 (t, 1H), 6.15 (4, 1 = 8, 1H),

7.30 (8, 2H); 7.50 (8, 1H).

c) C1-NKM8: Calculated: 392.1409; Found: 392.1388 (M + H);

NMR (SPS1 ₃ , 300 MHz): 1.00 (ΐ, 1 = 8, 3H),

1.35 (ΐ, 1 = 8, 3H), 1.41 (f 1 = 8, 2H), 1.65-1.85 (t, 2H), 2.30 (8, 3H), 2.40 (8, 3H), 3.85-4.20 (t, 4H),

7.30 (8, 2H); 7.50 (8, 1H).

4) C1-NKM8: Calculated: 404.1409; Found: 404.1408 (M + H);

NMR (SBS1 ₃ , 300 MHz): 0.35-0.45 (t, 2H), 0.52-0.62 (t, 2H), 0.98 (ΐ, 1 = 8, 3H), 1.70-1.90 (t, 2H), 2.30 (8 , 3H), 2.40 (8, 3H), 3.85-4.02 (t, 2H), 4.02-4.20 (t, 2H), 7.30 (8, 2H), 7.50 (8, 1H).

e) C1-NKM8: Calculated: 424.1307; Found: 424.1307 (M + H);

NMR (SPS1 ₃ , 300 MHz): 2.28 (8, 3Н), 2.40 (8, 3Н), 3.40 (8, 6Н), 3.75 (ΐ, 1 = 8, 4Н), 4.20-4.45 (t, 4Н), 7.30 (8, 2H); 7.50 (8, 1H).

1) C1-NKM8: Calculated: 406.1565; Found: 405.1578 (M + H);

NMR (SBS1 ₃ , 300 MHz): 0.90 (ΐ, 1 = 8, 3H), 1.00 (ΐ, 1 = 8, 3H), 1.28-1.45 (t, 4H), 1.50-1.80 (t, 4H), 2.35 (8, 3H), 2.50 (8, 3H), 4.20-4.35 (t, 1H), 6.10-6.23 (t, 1H), 7.30 (8, 2H), 7.50 (8, 1H).

d) C1-NKM8: Calculated: 394.1201; Found: 394.1209 (M + H);

NMR (SPS1 ₃ , 300 MHz): 1.02 (ΐ, 1 = 8, 3H), 1.65-1.90 (t, 2H), 2.35 (8, 3H), 2.48 (8, 3H), 3.40 (8, 3H), 3.50-3.60 (t, 2H), 4.35-4.45 (L8, 1H), 6.50-6.60 (t, 1H), 7.30 (8, 2H), 7.50 (8, 1H).

g) C1-NKM8: Calculated: 364.1096; Found: 364.1093 (M + H);

Anal Calculated: C 56.05, H 5.27, N 19.23, C1 19.46; Found: C 55.96, H 5.24, N 18.93, C1 19.25.

NMR (SPS1 ₃ , 300 MHz): 1.35 (ΐ, 1 = 8, 6H),

2.30 (3, 3H), 2.40 (8, 3H), 3.95-4.15 (t, 4H), 7.30 (8, 2H), 7.50 (4, 1 = 1, 1H).

ί) C1-NKM8: Calculated: 438.1464; Found: 438.1454 (M + H);

NMR (SBS1 ₃ , 300 MHz): 1.22 (ΐ, 1 = 8, 6H),

2.35 (8, 3H), 2.47 (8, 3H), 3.39 (f 1 = 8, 4H), 3.65 (44, 1 = 8, 1, 2H), 3.73 (44, 1 = 8, 1, 2H), 4.55-4.65 (t, 1H), 6.75 (4, 1 = 8, 1H), 7.30 (4, 1 = 1, 2H), 7.50 (8, 1H).

_)) C1-NKM8: Calculated: 378.1252; Found: 378.1249 (M + H);

Anal Calculated: C 57.15, H 5.61, N 18.51, C1 18.74; Found: C 57.56, H 5.65, N 18.35, C1 18.45.

NMR (СОС1 ₃ , 300 MHz): 1.00 (ΐ, 1 = 8, 6Н),

1.55-1.70 (t, 2H), 1.70-1.85 (t, 2H), 2.35 (8, 3H), 2.50 (8, 3H), 4.15-4.25 (t, 1H), 6.18 (4, 1 = 8, 1H) ),

7.30 (8, 2H); 7.50 (8, 1H).

k) C1-NKM8: Calculated: 398.0939; Found: 398.0922 (M + H);

Anal Calculated: C 60.31, H 4.30, N 17.58, C1 17.80; Found: C 60.29, H 4.59, N 17.09, C1 17.57.

NMR (SBS1 ₃ , 300 MHz): 2.05 (8, 3Н), 2.50 (8, 3Н), 3.78 (8, 3Н), 7.20-7.45 (t, 7Н), 7.50 (4, 1 = 1, 1Н).

l) C1-NKM8: Calculated: 392.1409; Found: 392.1391 (M + H);

NMR (СОС1 ₃ , 300 MHz): 0.98 (ΐ, 1 = 8, 6Н), 1.70-1.85 (t, 4Н), 2.30 (8, 3Н), 2.40 (8, 3Н), 3.80-

4.10 (t, 4H), 7.30 (8, 2H), 7.50 (4, 1 = 1, 1H).

r) C1-NKM8: Calculated: 392.1409; Found: 392.1415 (M + H);

Anal Calculated: C 58.17, H 5.92, N 17.85, C1 18.07; Found: C 58.41, H 5.85, N 18.10, C1

17.75.

NMR (ϋϋα ₃ , 300 MHz): 0.90-1.05 (t, 6H),

1.35-1.55 (t, 2H), 1.55-1.85 (t, 4H), 2.35 (8, 3H), 2.48 (8, 3H), 4.20-4.35 (t, 1H), 6.15 (4, 1 = 8, 1H) ),

7.30 (8, 2H); 7.50 (4, 1 = 1, 1H).

o) C1-NKM8: Calculated: 337.0623; Found: 337.0689 (M + H);

Anal Calculated: C 53.43, H 4.18, N 16.62, C1 21.03; Found: C 53.56, H 4.33, N 16.56, C1

20.75.

NMR (СОС1 ₃ , 300 MHz): 1.60 (ΐ, 1 = 8, 3Н),

2.40 (8, 3H), 2.55 (8, 3H), 4.80 (f 1 = 8, 2H), 7.30 (4, 1 = 8, 1H), 7.35 (44, 1 = 8, 1, 1H), 7.55 ( 4, 1 = 1, 1H).

O) C1-NKM8: Calculated: 383.2321; Found: 383.2309 (M + H);

NMR (SHS1 ₃ , 300 MHz): 2.00 (8, 6Н), 2.20 (8, 3Н), 2.30 (8, 3Н), 2.45 (8, 3Н), 3.45 (8, 6Н), 3.61 (44, 1 = 8, 8, 2H), 3.70 (44, 1 = 8, 8, 2H), 4.60-4.70 (t, 1H), 6.70 (4, 1 = 8, 1H), 6.94 (8, 2H),

p) C1-NKM8: Calculated: 370.2243; Found: 370.2246 (M + H);

Anal Calculated: C 65.02, H 7.38, N 18.96; Found: C 65.22, H 7.39, N 18.71.

NMR (SHS1 ₃ , 300 MHz): 2.18 (8, 3Н), 2.30 (8, 3Н), 2.45 (8, 3Н), 3.45 (8, 6Н), 3.60 (44, 1 = 8, 8, 2Н), 3.69 (44, 1 = 8, 8, 2H), 4.60-4.70 (t, 1H), 6.70 (4, 1 = 8, 1H), 7.05 (4, 1 = 8, 1H), 7.07 (4, 1 = 8, 1H),

7.10 (3, 1H).

p. |) C1-NKM8: Calculated: 384.2400; Found: 384.2393 (M + H);

NMR (SHS1 ₃ , 300 MHz): 2.16 (8, 3Н), 2.25 (8, 3Н), 2.35 (8, 3Н), 2.39 (8, 3Н), 3.40 (8, 6Н), 3.77 (ΐ, 1 = 8, 4H), 4.20-4.45 (t, 4H), 7.02 (4, 1 = 8, 1H), 7.05 (8, 1H), 7.10 (4, 1 = 7, 1H).

d) C1-NKM8: Calculated: 354.2294; Found: 354.2271 (M + H);

Anal Calculated: C 67.96, H 7.71, N 19.81;

Found: C 67.56, H 7.37, N 19.60.

NMR (СОС1 ₃ , 300 MHz): 1.03 (ΐ, 1 = 8, 3Н),

1.65-1.88 (t, 2H), 2.17 (8, 3H), 2.30 (8, 3H), 2.35 (5, 3H), 2.45 (5, 3H), 3.40 (β, 3H), 3.50-3.62 (t, 2H), 4.30-4.45 (t, 1H), 6.51 (ά, 1 = 8, 1H), 7.04 (ά, 1 = 8, 1H), 7.10 (ά, 1 = 8, 1H), 7.12 (5, 1H )

5) C1-NKM8: Calculated: 338.2345; Found: 338.2332 (M + H);

Analit. Calculated: C 71.18, H 8.06, N 20.75; Found: C 71.43, H 7.80, N 20.70.

NMR (SES1 ₃ , 300 MHz): 1.00 (1, 1 = 8, 6H),

1.55-1.70 (t, 2H), 1.70-1.85 (t, 2H), 2.19 (5, 3H),

2.30 (5, 3H), 2.35 (5, 3H), 2.46 (5, 3H), 4.15-4.26 (t, 1H), 6.17 (ά, 1 = 8, 1H), 7.06 (ά, 1 = 8, 1H ), 7.10 (ά, 1 = 1, 1Н), 7.13 (5, 1Н).

1) C1-NKM8: Calculated: 324.2188; Found: 324.2188 (M + H);

NMR (SES1 ₃ , 300 MHz): 1.25 (1, 1 = 8, 6H),

2.16 (5, 3H), 2.28 (5, 3H), 2.35 (5, 3H), 2.40 (5, 3H),

3.95-4.20 (t, 4H), 7.05 (άά, 1 = 8, 1H), 7.07 (5, 1H), 7.12 (ά, 1 = 1, 1H).

i) C1-NKM8: Calculated: 346.1780; Found: 346.1785 (M + H);

Anal Calculated: C 66.07, H 5.54, N 28.39; Found: C 66.07, H 5.60, N 27.81.

NMR (SES1 ₃ , 300 MHz): 2.15 (5, 3Н), 2.32 (5, 3Н), 2.17 (5, 3Н), 2.52 (5, 3Н), 5.25-5.35 (t, 4Н), 7.08 (5, 2H), 7.15 (5, 1H).

ν) C1-NKM8: Calculated: 340.2137; Found: 340.2137 (M + H);

Anal Calculated: C 67.23, H 7.42, N 20.63; Found: C 67.11, H 7.39, N 20.26.

NMR (SES1 ₃ , 300 MHz): 1.40 (ά, 1 = 8, 3H),

2.16 (5, 3H), 2.32 (5, 3H), 2.35 (5, 3H), 2.47 (5, 3H), 3.42 (5, 3H), 3.50-3.60 (t, 2H), 4.50-4.15 (t, 1H), 6.56 (ά, 1 = 8, 1H), 7.00-7.15 (t, 3H).

ν) C1-NKM8: Calculated: 355.2134; Found: 355.2134 (M + H);

NMR (SES1 ₃ , 300 MHz): 1.05 (1, 1 = 8, 3H), 1.85-2.00 (t, 2H), 2.17 (5, 3H), 2.36 (5, 6H), 2.50 (5, 3H), 3.41 (5, 3Н), 3.45 (άά, 1 = 8, 3, 1Н), 3.82 (άά, 1 = 8, 1, 1Н), 5.70-5.80 (t, 1Н), 7.00-7.20 (t, 3Н) .

x) C1-NKM8: Calculated: 364.2501; Found: 364.2501 (M + H);

NMR (SES1 ₃ , 300 MHz): 0.35-0.43 (t, 2H), 0.50-0.60 (t, 2H), 0.98 (1, 1 = 8, 3H), 1.20-1.30 (t, 1H), 1.72-1.90 (t, 2H), 2.18 (5, 3H), 2.28 (5, 3H),

2.35 (5, 3H), 2.40 (5, 3H), 3.88-4.03 (t, 2H), 4.03-

4.20 (t, 2H), 7.00-7.15 (t, 3H).

y) C1-NKM8: Calculated: 353.2454; Found: 353.2454 (M + H);

Anal .. Calculated: C 68.15, H 8.02, N 23.84; Found: C 67.43, H 7.81, N 23.45.

NMR (SES1 ₃ , 300 MHz): 1.38 (ά, 1 = 8, 3H),

2.18 (5, 3H), 2.30-2.40 (t, 12H), 2.47 (5, 3H), 2.60-2.75 (t, 2H), 4.30-4.45 (t, 1H), 6.60-6.70 (t, 1H), 7.00-7.15 (t, 3H).

ζ) C1-NKM8: Calculated: 361.2140; Found: 361.2128 (M + H);

NMR (SES1 ₃ , 300 MHz): 0.75-0.83 (t, 2H), 1.00-1.10 (t, 2H), 2.17 (5, 3H), 2.30 (5, 3H), 2.36 (5, 3H), 2.47 ( 5, 3H), 2.85 (1, 1 = 8, 2H), 3.30-3.40 (t, 1H), 4.40-4.55 (t, 2H), 7.00-7.18 (t, 3H).

aa) C1-NKM8: Calculated: 363.2297; Found: 363.2311 (M + H);

NMR (SES1 ₃ , 300 MHz): 1.01 (1, 3Н, 1 = 8), 1.75-1.90 (t, 2Н), 2.15 (5, 3Н), 2.19 (5, 3Н), 2.35 (5, 3Н), 2.40 (5, 3H), 2.40 (5, 3H), 2.98 (1, 2H, 1 = 8), 3.97-4.15 (t, 2H), 4.15-4.30 (t, 2H), 7.03 (ά, 1H, 1H ), 7.08 (ά, 1H, 1 = 8), 7.10 (5, 1H).

ab) C1-NKM8: Calculated: 363.2297; Found: 363.2295 (M + H);

NMR (SES1 ₃ , 300 MHz): 1.01 (1, 3H, 1 = 8),

1.35-1.55 (t, 2H), 1.75-1.90 (t, 2H), 2.15 (5, 3H),

2.30 (5, 3H), 2.36 (5, 3H), 2.46 (5, 3H), 4.10-4.30 (t, 2H), 4.95-5.10 (L.5, 2H), 7.05 (ά, 1H, 1 = 8 ),

7.10 (ά, 1H, 1 = 8), 7.15 (5, 1H).

ac) C1-NKM8: Calculated: 368.2450; Found: 368.2436 (M + H);

Anal Calculated: C 68.62, H 7.95, N 19.06;

Found: C 68.73, H 7.97, N 19.09.

NMR (SES1 ₃ , 300 MHz): 1.05 (1, 1 = 8, 3H), 1.70-1.90 (t, 2H), 2.01 (ά, 1 = 3, 6H), 2.20 (5, 3H),

2.30 (5, 3H), 2.46, 2.465 (5, 5, 3H), 3.42, 3.48 (5, 5, 3H), 3.53-3.63 (t, 2H), 4.35-4.45 (t, 1H), 6.73 (ά , 1 = 8, 1H); 6.97 (5, 2H).

aά) C1-NKM8: Calculated: 352.2501; Found: 352.2500 (M + H);

Anal Calculated: C 71.76, H 8.33, N 19.92; Found: C 71.55, H 8.15, N 19.28.

NMR (SES1 ₃ , 300 MHz): 1.01 (1, 1 = 8, 6H), 1.58-1.70 (t, 2H), 1.70-1.85 (t, 2H), 2.02 (5, 6H),

2.19 (5, 3H), 2.45 (5, 3H), 4.12-4.28 (t, 1H), 6.18 (ά, 1 = 8, 1H), 6.95 (5, 2H).

ae) C1-NKM8: Calculated: 398.2556; Found: 398.2551 (M + H);

Anal Calculated: C 66.47, H 7.86, N 17.62; Found: C 66.74, H 7.79, N 17.70.

NMR (SES1 ₃ , 300 MHz): 2.00 (5, 6Н), 2.12 (5, 3Н), 2.30 (5, 3Н), 2.37 (5, 3Н), 3.40 (5, 6Н), 3.78 (1, 1 = 8, 4H), 4.25-4.40 (t, 4H), 6.93 (5, 2H).

a!) C1-NKM8: Calculated: 450.1141; Found: 450.1133 (M + H);

Anal Calculated: C 50.67, H 5.37, N 15.55, Vg 17.74; Found: C 52.36, H 5.84, N 14.90, Vg 17.44.

NMR (SES1 ₃ , 300 MHz): 2.32 (5, 3Н), 2.57 (5, 3Н), 3.42 (5, 6Н), 3.60 (ф 1 = 8, 2Н), 3.69 (φ 1 = 8, 2Н), 3.82 (5, 3H), 4.60-4.70 (t, 1H), 6.73 (ά, 1 = 8, 1H), 6.93 (άά, 1 = 8, 1H), 7.22 (ά, 1 = 8, 1H).

hell) C1-NKM8: Calculated: 434.1192; Found: 434.1169 (M + H);

Anal Calculated: C 52.54, H 5.58, N 16.12, Vg 18.40; Found: C 52.57, H 5.60, N 15.98, Vg 18.22.

NMR (SES1 ₃ , 300 MHz): 1.00-1.07 (t, 3H), 1.65-1.85 (t, 2H), 2.35 (5, 3H), 2.46, 2.47 (5, 5, 3H), 3.40, 3.45 (5 5, 3H), 3.83 (5, 3H), 4.35-4.45 (t, 1H), 6.55 (ά, 1 = 8, 1H), 6.92 (άά, 1 = 8, 1, 1H),

7.20-7.30 (t, 2H).

a) C1-NKM8: Calculated: 337.2266; Found: 337.2251 (M + H);

Anal Calculated: C 70.18, H 8.06, N 20.75;

Found: C 70.69, H 7.66, N 20.34.

NMR (SES1 ₃ , 300 MHz): 1.35 (1, 1 = 8, 6H),

2.01 (5, 6H), 2.15 (5, 3H), 2.30 (5, 3H), 2.38 (5, 3H),

4.07 (φ 1 = 8, 4Η), 6.93 (8, 2H).

a1) C1-NKM8: Calculated: 412.2713; Found: 412.2687 (M + H);

Anal Calculated: C 67.13, H 8.08, N 17.02; Found: C 67.22, H 7.85, N 17.13.

NMR (ATP1 ₃ , 300 MHz): 1.24 (1, 1 = 8, 6Η), 2.00 (8, 6Η), 2.20 (8, 3Η), 2.30 (8, 3Η), 2.43 (8, 3Η),

3.60 (f 1 = 8, 4Η), 3.66 (44, 1 = 8, 3, 2Н), 3.75 (44, 1 = 8, 3, 2Η), 4.55-4.65 (t, 1Η), 6.75 (4, 1 = 8, 1Η),

6.95 (8, 2H).

a.)) C1-NKM8: Calculated: 398.2556; Found: 398.2545 (M + H);

Anal Calculated: C 66.47, H 7.86, N 17.62; Found: C 66.87, H 7.62, N 17.75.

NMR (SPS1 ₃ , 300 MHz): 1.95-2.10 (t, 8H),

2.20 (8, 3H), 2.32 (8, 3H), 2.44 (8, 3H), 3.38 (8, 3H), 3.42 (8, 3H), 3.50-3.70 (t, 4H), 4.58-4.70 (t, 1H)

6.87 (4, 1 = 8, 1H); 6.95 (8, 2H).

ak) C1-NKM8: Calculated: 338.1981; Found: 338.1971 (M + H);

Anal Calculated: C 67.63, H 6.87, N 20.06; Found: C 67.67, H 6.82, N 20.31.

NMR (SBSl, 300 MHz): 2.15 (8, 3H), 2.29 (8, 3H), 2.35 (8, 3H), 2.43 (8, 3H), 3.90 (1, 1 = 8, 4H),

4.35-4.45 (t, 4H), 7.00-7.15 (t, 3H).

al) C1-NKM8: Calculated: 464.1297; Found: 464.1297 (M + H);

NMR (SPS1 ₃ , 300 MHz): 2.28 (8, 3Н), 2.40 (8, 3Н), 3.40 (8, 6Н), 3.75 (1, 1 = 8, 4Н), 3.83 (8, 3Н),

4.20- 4.50 (t, 4H), 6.93 (44, 1 = 8, 1, 1H), 7.20 (8, 1H), 7.24 (4, 1 = 1, 1H).

at) C1-NKM8: Calculated: 418.1242; Found: 418.1223 (M + H);

NMR (SBSl, 300 MHz): 1.00 (1, 4, 1 = 8, 1, 6H), 1.55-1.75 (t, 4H), 2.34 (8, 3H), 2.49 (3, 3H),

2.84 (8, 3H), 4.15-4.27 (t, 1H), 6.19 (4, 1 = 8, 1H),

6.93 (44, 1 = 8, 1, 1H), 7.21-7.30 (t, 2H).

ap) C1-NKM8: Calculated: 404.1086; Found: 404.1079 (M + H);

NMR (SPS1 ₃ , 300 MHz): 1.35 (1, 1 = 8, 6Н), 2.28 (8, 3Н), 2.40 (8, 3Н), 3.83 (8, 3Н), 3.90-4.08 (t, 2Н), 4.08-4.20 (t, 2H), 6.92 (44, 1 = 8, 1, 1H),

7.20-7.25 (t, 2H).

ao) C1-NKM8: Calculated: 308.1875; Found: 308.1872 (M + H);

NMR (SBSl, 300 MHz): 0.75-0.80 (t, 2H), 0.93-1.00 (t, 2H), 2.16 (8, 3H), 2.28 (8, 3H), 2.35 (8, 3H), 2.53 (8 , 3H), 3.00-3.10 (t, 1H), 6.50-6.55 (t, 1H), 7.00-7.15 (t, 3H).

ar) C1-NKM8: Calculated: 397.1988; Found: 397.1984 (M + H);

NMR (SBSl, 300 MHz): 2.43 (8, 3H), 2.50 (8, 3H), 3.43 (8, 3H), 3.61 (44, 1 = 8, 8, 2H), 3.69 (44, 1 = 8, 8, 2H), 3.88 (8, 3H), 4.58-4.70 (t, 1H), 6.75 (4, 1 = 8, 1H), 7.20 (44, 1 = 8, 1, 1H), 7.25 (4, 1 = 1, 1H), 7.40 (8, 1H).

hell) C1-NKM8: Calculated: 375.2297; Found: 375.2286 (M + H);

Anal Calculated: C 70.56, H 7.01, N 22.44;

Found: C 70.49, H 6.99, N 22.45.

NMR (SPS1 ₃ , 300 MHz): 0.79-0.85 (t, 2H),

1.00-1.05 (t, 1H), 2.00 (8, 6H), 2.19 (8, 3H), 2.32 (8, 3H), 2.44 (8, 3H), 2.84 (1, 1 = 8, 2H), 3.30- 3.40 (t, 1H), 4.50 (1, 1 = 8, 2H), 6.95 (8, 2H).

ag) C1-NKM8: Calculated: 434.1192; Found: 434.1189 (M + H);

Anal Calculated: C 52.54, H 5.58, N 16.12, Vg 18.40; Found: C 52.75, H 5.59, N 16.09, Br 18.67.

NMR (SBSl, 300 MHz): 2.19 (8, 3H), 2.30 (8, 3H), 2.47 (8, 3H), 3.43 (8, 6H), 3.60 (44, 1 = 8, 8, 2H), 3.70 (44, 1 = 8, 8, 2H), 4.58-4.70 (t, 1H), 6.71 (4, 1 = 8, 1H), 7.08 (4, 1 = 8, 1H), 7.37 (44, 1 = 8 , 1, 1H); 7.45 (4, 1 = 1, 1H).

a8) C1-NKM8: Calculated: 448.1348; Found: 448.1332 (M + H);

Anal Calculated: C 53.58, H 5.85, N 16.62, Vg 17.82; Found: C 53.68, H 5.74, N 15.52, Vg 13.03.

NMR (SBSl, 300 MHz): 1.95-2.10 (t, 2H),

2.20 (8, 3H), 2.30 (8, 3H), 2.47 (8, 3H), 3.38 (8, 3H),

3.41 (8, 3H), 3.50-3.67 (t, 4H), 4.55-4.70 (t, 1H),

6.89 (4, 1 = 8, 1H), 7.05 (4, 1 = 8, 1H), 7.35 (44, 1 = 8, 1, 1H), 7.47 (4, 1 = 1, 1H).

a1) C1-NKM8: Calculated: 400.2349; Found: 400.2348 (M + H);

Anal Calculated: C 63.14, H 7.32, N 17.53; Found: C 63.40, H 7.08, N 17.14.

NMR (SPS1 ₃ , 300 MHz): 2.16 (8, 3Н), 2.20 (8, 3Н), 2.30 (8, 3Н), 2.46 (8, 3Н), 3.42 (8, 6Н), 3.60 (i, 1 = 8, 2H), 3.70 (Ф 1 = 8, 2Н), 3.85 (8, 2Н), 4.594.70 (t, 1Н), 6.70 (4, 1 = 8, 1Н), 6.76 (8, 1Н), 6.96 (8, 1H).

ai) C1-NKM8: Calculated: 414.2505; Found: 414.2493 (M + H);

NMR (SBSl, 300 MHz): 2.15 (8, 3H), 2.19 (8, 3H), 2.25 (8, 3H), 2.40 (8, 3H), 3.40 (8, 6H), 3.76 (1, 1 = 8 , 4H), 3.84 (8, 3H), 4.20-4.45 (t, 4H), 6.77 (8, 1H), 6.93 (8, 1H).

ay) C1-NKM8: Calculated: 368.2450; Found: 368.2447 (M + H);

NMR (СОС1 ₃ , 300 MHz): 1.00 (1, 1 = 8, 6Н),

1.55-1.85 (t, 4H), 2.19 (8, 3H), 2.20 (8, 3H), 2.30 (8, 3H), 2.47 (8, 3H), 3.88 (8, 3H), 4.10-4.30 (t, 1H), 6.15 (4, 1 = 8, 1H), 6.78 (8, 1H), 6.98 (8, 1H).

а \ у) С1-НКМ8: Calculated: 353.2216; Found: 353.2197 (M + H);

NMR (СОС1 ₃ , 300 MHz): 1.35 (1, 1 = 8, 6Н),

2.17 (8, 3H), 2.19 (8, 3H), 2.28 (8, 3H), 2.40 (8, 3H),

3.85 (8, 3H), 3.90-4.20 (t, 4H), 6.78 (8, 1H), 6.95 (8, 1H).

ax) C1-NKM8: Calculated: 390.1697; Found: 390.1688 (M + H);

Anal Calculated: C 58.53, H 6.20, N 17.96, C1 9.09; Found: C 58.95, H 6.28, N 17.73, C1 9.15.

NMR (SBSl, 300 MHz): 2.35 (8, 3H), 2.37 (8, 3H), 2.48 (8, 3H), 3.42 (8, 6H), 3.60 (44, 1 = 8, 8, 2H), 3.68 (44, 1 = 8, 8, 2Н), 4.59-4.72 (t, 1Н), 6.72 (4, 1 = 8, 1Н), 7.12 (4, 1 = 8, 1Н), 7.23 (4, 1 = 8 , 1H),

7.32 (8, 1H).

ay) C1-NKM8: Calculated: 374.1748; Found: 374.1735 (M + H);

Anal Calculated: C 61.04, H 6.47, N 18.73,

C1 9.48; Found: C 61.47, H 6.54, Ν 18.23, C1 9.61.

NMR (SPS1 ₃ , 300 MHz): 1.01 (ΐ, 1 = 8, 3Н), 1.62-1.88 (t, 4Н), 2.35 (8, 3Н), 2.37 (8, 3Н), 2.48 (4, 1 = 1 , 3H), 3.40, 3.45 (8, 8, 3H), 3.50-3.64 (t, 2H), 4.38-4.47 (t, 1H), 6.53 (4, 1 = 8, 1H), 7.12 (4, 1 = 8, 1H), 7.07 (4, 1 = 8, 1H), 7.12 (8, 1H).

αζ) C1-NKM8: Calculated: 404.1853; Found: 404.1839 (M + H);

NMR (SPS1 ₃ , 300 MHz): 2.29 (8, 3Н), 2.38 (8, 3Н), 2.40 (8, 3Н), 3.40 (8, 6Н), 3.76 (ΐ, 1 = 8, 4Н),

4.20-4.45 (t, 4H), 7.11 (4, 1 = 8, 1H), 7.22 (4, 1 = 8, 1H), 7.31 (8, 1H).

ba) C1-NKM8: Calculated: 404.1853; Found: 404.1859 (M + H);

Anal Calculated: C 59.47, H 6.50, Ν 17.34, C1 8.79; Found: C 59.73, H 6.46, Ν 17.10, C1 8.73.

NMR (SPS1 ₃ , 300 MHz): 1.95-2.08 (t, 2H),

2.35 (8, 3H), 2.38 (8, 3H), 2.46 (8, 3H), 3.38 (8, 3H),

3.41 (8, 3H), 3.50-3.65 (t, 4H), 4.56-4.70 (t, 1H),

6.85 (4, 1 = 8, 1H), 7.12 (4, 1 = 8, 1H), 7.45 (4, 1 = 8, 1H), 7.32 (8, 1H).

bb) C1-NKM8: Calculated: 391.2246; Found: 391.2258 (M + H);

Anal Calculated: C 67.67, H 6.71, Ν 21.52; Found: C 67.93, H 6.70, Ν 21.48.

NMR (SPS1 ₃ , 300 MHz): 0.76-0.84 (t, 2H), 0.84-0.91 (t, 2H), 1.00-1.08 (t, 2H), 2.15 (8, 3H),

2.20 (8, 3H), 2.29 (8, 3H), 2.45 (8, 6H), 2.85 (ΐ, 1 = 8, 2H), 3.28-3.30 (t, 1H), 3.85 (8, 3H), 6.78 ( 8, 1H),

6.95 (8, 1H).

bc) C1-NKM8: Calculated: 386.2192; Found: 386.2181 (M + H);

Anal Calculated: C 62.32, H 7.06, Ν 18.17; Found: C 62.48, H 6.83, Ν 18.15.

NMR (CBC1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 8), 6.9 (4, 1H, 1 = 1), 6.8 (44, 1H, 1 = 8, 1), 6.7 (Lg.4, 1H, 1 = 8), 4.7-4.6 (t, 1H), 3.85 (8, 3H), 3.70-3.55 (t, 4H), 3.45 (8, 6H), 2.5 (8, 3H), 2.3 (8, 3H), 2.15 (8, 3H).

B4) C1-NKM8: Calculated: 400.2349; Found: 400.2336 (M + H);

NMR (CBC1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 7),

6.85 (4, 1H, 1 = 1), 6.75 (44, 1H, 1 = 7, 1), 4.45-4.25 (L8, 4H), 3.75 (ΐ, 4H, 1 = 7), 3.4 (8, 6H), 2.4 (8, 3H), 2.25 (8, 3H), 2.15 (8, 3H).

B) C1-NKM8: Calculated: 370.2243; Found: 370.2247 (M + H);

Anal Calculated: C 65.02, H 7.38, Ν 18.96; Found: C 65.28, H 7.27, Ν 18.71.

NMR (CBC1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 8),

6.85 (4, 1H, 1 = 1), 6.8 (44, 1H, 1 = 8, 1H), 6.5 (L.4, 1H, 1 = 1), 4.5-4.3 (t, 1H), 3.85 (8, 3H), 3.65-3.5 (t, 2H), 3.4 (8, 2H), 2.5 (8, 3H), 2.3 (8, 3H), 2.2 (8, 3H), 1.9-1.7 (t, 2H), 1.05 (ΐ, 3H, 1 = 7).

Bts C1-NKM8: Calculated: 379.2246; Found: 379.2248 (M + H);

NMR (CBC1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 8),

6.85 (4, 1H, 1 = 1), 6.8 (44, 1H, 1 = 8, 1), 4.3-4.0 (t, 4H), 3.85 (8, 3H), 3.0 (ΐ, 2H, 1 = 7) , 2.45 (8, 3H), 2.3 (8, 3H), 2.2 (8, 3H), 1.9-1.8 (t, 2H), 1.0 (7, 3H,

1 = 7).

Bd) C1-NKM8: Calculated: 340.2137; Found: 340.2122 (M + H);

NMR (SPS1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 8),

6.85 (4, 1H, 1 = 1), 6.75 (44, 1H, 1 = 8, 1), 4.2-4.0 (LH, 4H), 3.85 (8, 3H), 2.4 (8, 3H), 2.3 (3, 3H),

2.2 (3, 3H), 1.35 (ΐ, 6H, 1 = 7).

B) C1-NKM8: Calculated: 313.1665; Found: 313.6664 (M + H).

B1) C1-NKM8: Calculated: 400.2349; Found: 400.2346 (M + H);

NMR (SPS1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 7), 6.9-6.75 (t, 3H), 4.7-4.55 (t, 1H), 3.8 (8, 3H), 3.7-

3.5 (t, 4H), 3.45 (8, 3H), 3.35 (8, 3H), 2.5 (8, 3H),

2.3 (8, 3H), 2.2 (8, 3H), 2.1-1.95 (t, 2H).

B)) C1-NKM8: Calculated: 377.2090; Found: 377.2092 (M + H);

Anal Calculated: C 67.00, H 6.44, Ν 22.32; Found: C 67.35, H 6.44, Ν 22.23.

NMR (SPS1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 8), 6.9 (4, 1H, 1 = 1), 6.8 (44, 1H, 1 = 8, 1), 4.55-4.4 ( t, 2H),

3.85 (8, 3H), 3.4-3.3 (t, 1H), 2.85 (ΐ, 2H, 1 = 7), 2.5 (8, 3H), 2.3 (8, 3H), 2.2 (8, 3H), 1.1- 1.0 (t, 2H), 0.85-0.75 (t, 2H).

bk) C1-NKM8: Calculated: 413.2427; Found: 413.2416 (M + H);

NMR (SPS1 ₃ , 300 MHz): 7.1 (4, 1H, 1 = 8),

6.85 (4, 1H, 1 = 1), 6.75 (44, 1H, 1 = 8, 1), 4.6 (t, 1H), 3.85 (8, 3H), 3.75-3.6 (t, 4H), 3.6 (q , 4H, 1 = 7), 2.5 (8, 3H), 2.3 (8, 3H), 2.2 (8, 3H), 1.25 (ΐ, 6H, 1 = 7).

bl) C1-NKM8: Calculated: 420.1802; Found: 420.1825 (M + H).

Bm) C1-NKM8: Calculated: 390.1697; Found: 390.1707 (M + H).

B) C1-NKM8: Calculated: 397.1465; Found: 397.1462 (M + H).

bo) C1-NKM8: Calculated: 360.1513; Found: 360.1514 (M + H).

bp) C1-NKM8: Calculated: 374.1748; Found: 374.1737 (M + H).

Bd) C1-NKM8: Calculated: 479.1155; Found: 479.1154 (M + H).

Bd) C1-NKM8: Calculated: 463.1219; Found: 463.1211 (M + H);

Anal Calculated: C 51.96, H 5.23, Ν 15.15, Vg 17.28; Found: C 52.29, H 5.62, Ν 14.79, Vg 17.47.

B8) C1-NKM8: Calculated: 433.1113; Found: 433.1114 (M, ⁷⁹ Vg).

B) ΝΉ ₃ -Ο M8: Calculated: 406; Found: 406 (M + H) ⁺ ;

NMR (SHS1 ₃ , 300 MHz): δ 7.28 (4, 1 = 10Hz, 1H), 7.03 (4, 1 = 8Hz, 1H), 6.96 (8, 1H), 6.7 (4, 1 = 9, 1H), 4.63 (t, 1H), 3.79 (8, 3H), 3.6 (t, 4H), 3.42 (8, 6H), 2.47 (8, 3H), 2.32 (8, 3H).

Example 431. Preparation of 2,4,7-dimethyl-8 (4-methoxy-2-methylphenyl) [1,5-a] pyrazolo1,3,5-triazine.

(Formula 1, where K ³ is CH3, K ¹ is CH3, Ζ is C-CH ₃ , Ar is 4-methoxy-2-methylphenyl).

Acetic acid salt of 5-acetamidino-4 (4-methoxy-2-methylphenyl) -3-methylpyrazole (602 mg, 2 mmol) was mixed with saturated solution of No. HH Oz (10 ml). The aqueous mixture was extracted with EAAc three times. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was taken up in toluene (10 ml) and trimethylorthoacetate (0.36 g, 3 mmol) was added to the suspension. The reaction mixture was refluxed under nitrogen and stirred for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo to give an oily solid. Column chromatography (CHCl ₃ : MeOH, 9: 1) gave, after removal of the solvent in vacuo, a yellow viscous oil (KB = 0.6, 210 mg, 37% yield):

NMR (СОС1 ₃ , 300 MHz): 7.15 (ά, 1Н, 1 = 8), 6.9 (ά, 1Н, 1 = 1), 6.85 (άά, 1Н, 1 = 8, 1), 3.85 (5, ЗН) , 2.95 (5, ZN), 2.65 (5, ZN), 2.4 (5, ZN), 2.15 (5, ZN);

C1-NKM8: Calculated: 283.1559; Found: 283.1554 (M + H).

Example 432. 7-Hydroxy-5-methyl-3- (2chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine.

(Formula 1, where A is CH, K ¹ is Me, K ³ is OH, Ζ is CMe, Ar is 2-chloro-4-methylphenyl).

- Amino-4 - (2-chloro-4-methylphenyl) -3 methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 ml) with stirring. Then, ethyl acetate-acetate (1.18 ml, 9.2 mmol) was added dropwise to the resulting mixture. Then, the reaction mixture was refluxed and stirred for 16 hours, then cooled to room temperature. Ether (100 ml) was added and the resulting precipitate was collected by filtration. Drying in vacuo afforded a white solid (1.0 g, 42% yield):

NMR (COC1 ₃ , 300 MHz): 8.70 (Lr.5, 1H), 7.29 (5, 1H), 7.21-7.09 (br, 2H), 5.62 (δ, 1H), 2.35 (5, 6H), 2.29 ( 5, ZN);

C1-M8: 288 (M + H).

Example 433. 7-Chloro-5-methyl-3- (2-chloro-4-methyl-phenyl-l) pyrazolo [1,5-a] pyrimidine.

(Formula 1, where A is CH, K ¹ is Me, K ³ is C1, Ζ is CMe, Ar is 2-chloro-4-methylphenyl).

A mixture of 7-hydroxy-5-methyl-3 - (2-chloro-4methylphenyl) pyrazolo [1,5-a] pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 ml, 17.4 mmol), Ν, Ν-diethylaniline (0.63 g, 0.7 ml, 4.2 mmol) and toluene (20 ml) were stirred at reflux for 3 hours, then cooled to a temperature the environment. Flash chromatography (EULAc: hexane, 1: 2) of the residue gave 7-chloro-5-methyl-3- (2chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (900 mg, 84% yield) in as a yellow oil:

NMR (СОС1 ₃ , 300 MHz): 7.35 (δ, 1Н), 7.287.26 (ш, 1Н), 7.16 (ά, 1Н, 1 = 7), 6.80 (3, 1Н), 2.55 (5, ЗН), 2.45 (5, ZN); 2.40 (5, ZN); C1-M8: 306 (M + H).

Example 434. 7- (Pentyl-3-amino) -5-methyl3 - (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine.

(Formula 1, where A is CH, K ¹ is Me, K ³ is pentyl-3-amino, Ζ is C-Me, Ar is 2-chloro-4-methylphenyl).

A solution of 3-pentylamine (394 mg, 6.5 mmol) and 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (200 mg, 0.65 mmol ) in dimethyl sulfoxide (DMSO) was stirred at 150 ° C for 2 hours; then it was cooled to ambient temperature. Then the reaction mixture was poured onto water (100 ml) and stirred. Three extractions with dichloromethane, washing the combined organic layers with brine, drying over MgSO ₄ , filtering and removing the solvent in vacuo gave a yellow solid. Flash chromatography (EULAc: 1: 4 hexanes) gave a white solid (140 mg, 60% yield): mp. 139-141 ° C.

NMR (СОС1 ₃ , 300 MHz): 7.32 (δ, 1Н), 7.27 (ά, 1Н, 1 = 8), 7.12 (ά, 1Н, 1 = 7), 6.02 (ά, 1Н, 1 = 9), 5.78 (5, 1H), 3.50-3.39 (w, 1H), 2.45 (5, ZN), 2.36 (5, ZN), 1.82-1.60 (w, 4H), 1.01 (1, 6H, 1 = 8);

Analysis for C ₂₀ N ₂₅ RLS ₄ :

Calculated: C 67.31, H 7.06, N 15.70, C1 9.93; Found: C 67.32, H 6.95, N 15.50, C1 9.93.

Compounds of the examples presented in table. 2 can be obtained by the methods described in examples ΙΑ, 1B, 432, 433, 434. Commonly used abbreviations: PH stands for phenyl, Pr stands for propyl, Me stands for methyl, El stands for ethyl, Bu stands for butyl, Ex stands for example, -

table 2

F 2 to OH T.pl ^ 435 ^b No I1SI2SN2OMe) 2 2,4 C1 ₂ -₽ 71-73 436 ^e Sme S (Vi) EU 2, 4 C1 ₂ -₽ 86-87 437 * Sme knsn (EOSN20me 2,4 S12-RN 110-111 438 " S-me S (9g) СН2СМгСЫ 2,4 C1 ₂ -₽ 83-85 439 ^£ Sme ΝΗ-3-pentyl 2,4 S12-RY 175-176 4409 Sme MNSN (CH ₂ OMe) 2 2,4 S12-RN 107 441G1 Sme Inns (Ye ₂ 2, 4 Me ₂ -RN oil 442 ¹ S-me MNSN (CH ₂ OMe) 2 2,4 Meg ry 103-105 4433 Sme N (CH2CH2OM ·) 2 2, 4 me ₂ ~ pb 87-89 444 * Sme S (s-ROSN2SN2SY 2, 4 Mb2-₽ 132 445 ¹ S-me ν (sngsngome) g 2-C1 , 4-meRy 77-78 446 ^t S-me knsn (cngome) 2-C1 , 4-MeR 131-133 447 ^p Sme YaSN (She 2 2-C1 , 4-Merl 139-141 448 ° Sme ΝΕΕ2 2, 4 Me2 ^_ pH 92-94 449? Sme ν (₽ ₽) sngsngsi 2, 4 Me ₂ -RP 143-144 4504 Sme N (Vi> СЫ2СЫ2СМ 2, 4 Me ₂ 115-117 451 ^g S-me nsn (EU (SM20me 2, 4 Μ "2 ~ ₽ & oil 452 ^a S-me ONSN (EU> 2 2nd 4-MeORN 104-106 453 * S-me ONSN (CH2OMe> 2 2-me 4 MeOR 115-116 454 ^th S-me ν (sngsngome) 2 2-me 4-MeORN oil 455 ^ν S-me <δ) -nksn (sngsngome> - 2-me 4-meORP oil (CH ₂ OMe) 456 " S-me sz> -yansn (sngsngome »- 2,4 Μβ2 “? Λ oils

(CH2OMv)

457 ^x S-me Schsngsngome) g 2-Me, 4-C1PH oil 458 * S-me Eunes 2,4-me ₂ -Pb oil 459 * No ONSN (EU) ₂ 2-Me, 4-S1RP 94-96 460 ^aa S-me ONSN (CH ₂ OMe) ₂ 2-Me, 4-C1PH 113-114 461 ^ab S-me s (ac) ec 2,4-Me ₂ -Pb oil 462 ^ac S-me (5) -insn (sn ₂ sn ₂ ohm) - (sn ₂ ohm) 2-Me, 4-C1PB ί oil 463 ^{a <1} S-me N (Pc) CH ₂ CH ₂ SY 2-Me, 4-MeORN 118-119 464 ^av S-me EU ₂ 2-Me, 4-MeORN 97-99 465 ^{a £} S-me (5) -INSN (CH ₂ CH ₂ OMe) - <CH ₂ OMe) 2-C1,4-MER 101-103 466 ^a 9 S-me EU ₂ 2-C1,4-MER 129-130 467 ^ab S-me N (C-Rg) CH ₂ CH ₂ SY 2-Me, 4-MeOR 177-178 468 ^a1 S-me N (s-Pr) CH ₂ CH ₂ SY 2-C1,4-MER 162-163 469 ^a 3 S-me ONSN (EU) CH ₂ OMe 2-Me, 4-MeORN oil 470 ^ak S-me ONSN (EU) CH ₂ OMe 2-C1,4-MeRN 111-113 471 S-me ynsk (sn ₂ ohm) ₂ 2-C1-4-MeORL 472 S-me s (sn ₂ sn ₂ ohm) 2 2-C1-4-MeOR 473 Sme ONSN (EU) CH ₂ OMe 2-C1-4-M6ORN 474 S-me N (s-₽g) CH ₂ CH ₂ SY 2-C1-4-MeORk 475 S-me EU ₂ 2-C1-4-MeO 476 S-me ΝΗ-3- pentyl 2-C1-4-MaORP 477 S-me ONSN (EU) CH ₂ CH ₂ OMe 2-C1-4-MeO RUB 478 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-C1-4-MvORN 479 S-me ONSN (EU) CH ₂ CH ₂ OMe 2-Vg-4-MeOR 480 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-Vg-4-MeO₽N 481 sme ONSN (EU) CH ₂ CH ₂ OMe 2-Me-4-MeORP 482 Sme Inns (me) sn ₂ sn ₂ ohm 2-Me-4-MeOR 483 S.-me Inns (CIS) 2 2-C1-4.5- (MeO) ₂ Pb 484 Sme S (CH ₂ CH ₂ OMe) 2 2-C1-4.5- (MeO) ₂ RK 485 Sme ONSN (EU) CH ₂ OMe 2-C1-4.5- (MeO) ₂ pH 486 S-me S (s-Re) CH ₂ CH ₂ SY 2-C1-4.5- (MeO) ₂ RP 487 Sme ES2 2-C1-4.5- (MeO) ₂ pH 99-101 488 S-me EUN-Z-pentyl 2-C1-4.5- (MeO) 2₽ 169-170 489 S-me ONSN (EU) CH ₂ SC ₂ OMe 2-01-4.5- (MeO) 2RN 490 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-C1-4.5- (MeO) 491 S-me ONSN (CH ₂ OMe) ₂ 2-Br-4,5- (MeO) 2? N 90-93 492 S-me S (CH ₂ CH ₂ OMe) 2 2-Br-4,5- (MeO) ₂ pH 110 493 Sme ONSN (BC) CH ₂ OMe 2-VG-4,5- (MeO) ₂ RP 494 Sme S (s-Rg) CH ₂ CH ₂ SY 2-VG-4,5- (MeO) ₂ pH 495 Sme EU ₂ 2-Vg-4,5- (MeO) 2₽Н 496 Sme eun-3-five 2-VG-4,5- (MeO) 497 Sme ONSN (Her) CH ₂ CH ₂ OMe 2-VG-4,5- (MeO) ₂ pH 49 £ G Sme Inns <me) sngsn2ome 2-Br-4,5- (MeO) ₂ pH 499 Sme ONSN (CH ₂ OMe) ₂ 2-C1-4.6- (MeO) ₂ pH 500 Sme s (sn ₂ sn ₂ ohm) ₂ 2-C1-4.6- (MeO) 2? B 501 Sme ONSN (EU) CH ₂ OMe 2-C1-4.6- (MeO) 2? B 502 S-me N (C-ROSN ₂ CH ₂ SY 2-C1-4.6- (MeO) 2PH 503 S-me EU ₂ 2-C1-4.6- (MeO) 2PB 504 S-me EUN-3 — pentyl 2-C1-4.6- (MeO) ₂ Pb 505 S-me InSn (Her) sn ₂ sn ₂ ohm 2-C1-4.6- (MeO) 2? & 506 Sme InSn (me> sn ₂ sn ₂ ohm 2-C1-4.6- (MeO) ₂ pH 507 Sme ONSN (CH ₂ OMe) ₂ 2-Me-4,6- (MeO) ₂ pH 508 Sme N (CH ₂ CH ₂ OMe) ₂ 2-Me-4,6- (MeO) ₂ ₽ 509 Sme ONSN (EU) CH ₂ OMe 2-Me-4,6- (MeO) ₂ pH 510 Sme S (s-Rg) CH ₂ CH ₂ SY 2-Me-4,6- (MeO) ₂ Pb 511 S-me EU ₂ 2-me-4,6- (MeO) ₂ Pb 512 S-me EUN-3- pentyl 2-me-4.6- (MeO) 513 Sme ONSN (ЕОСН2СН20Ме 2-Me-4,6- (MeO) ₂ pH 514 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO> 2₽ 515 S-me S (e-Px) CH ₂ CH ₂ SY 2-BE-4,6- (MeO) ₂ Pb 516 S-me ES2 2-Vs-4,6- (MeO) ₂ P) t 517 S-me EUN-W-Gpentyl 2-VG-4,6- (MeO) ₂ pH 518 Stme ONSN (EU) CH ₂ CH ₂ OMe 2-BC-4.6- (MeO) 519 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-VG-4,6- (MeO) 520 S-me ONSN (EU) CH ₂ CH ₂ OMe 2-Me-4-MeORN 521 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-me-4-MeORN 522 S-me Inns (CIS) 2 2-MeO-4-MeR 523 sme s (sngsngome) 2 2-MeO-4-MER 524 S-me Innsngösngome 2-MeO-4-MeRP 525 S-me s (s-₽g) sn ₂ sn ₂ sy 2-MeO-4-MER

526 S-me EU ₂ 2-MeO-4-MER 527 sme ΝΗ-3-pentyl 2-MeO-4-MER 528 Sme ONSN (EU) CH ₂ CH ₂ OMe 2-me0-4-meR 529 Sme ONSN (Me) CH ₂ CH ₂ OMe 2-MeO-4-meRK 530 Sme Inns (CIS) 2 2-MeO-4-MeRN 531 Sme s (sngsngome) 2 2-MeO-4-MeRN 532 Sme ONSN (EU) CH ₂ OMe 2-Me0-4-MER 533 Sme S (C-Rg) CH ₂ CH ₂ SY 2-meo-4-mer 53-g S-me EU ₂ 2-MeO-4-MER 535 Sme Eun-3-centil 2-MeO-4-MeRN 536 S-me ONSN (EU) CH ₂ CH ₂ OMe 2-MeO-4-meRP 537 S-me ONSN (Me) CH ₂ CH ₂ OMe 2-MeO-4-MeRN 538 S-me ONSN (SY ₂ OMe) 2 2-MeO-4-S1RP 539 sme N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-C1 540 sme ONSN (EU) CH ₂ OMe 2-Ме0-4-С1₽П 541 S-me S (s-Rg) CH ₂ CH ₂ SY 2-Me0-4-C1P 542 S-me EU ₂ 2-MeO-4-S1RP 543 sme EUN-3- pentyl 2-MeO-4-S1RN 544 sme ONSN (EU) CH ₂ CH ₂ OMe 2-Me0-4-C1RI 545 sme ONSN (Me) CH ₂ CH ₂ OMe 2-Me0-4-C1PB

Notes for the table. 2:

b) C1-NKM8: Calculated: 423.1355; Found: 423.1337 (M + H);

c) Anal. calculated: C 61.38, H 6.18, N 14.32; Found: C 61.54, H 6.12, N 14.37.

b) Anal. calculated: C 58.02, H 5.65, N 14.24; Found: C 58.11, H 5.52, N 14.26.

e) Anal. calculated: C 59.71, H 5.26, N 14.85; Found: C 59.94, H 5.09, N 17.23.

ί) Anal. calculated: C 60.48, H 5.89, N 14.85; Found: C 60.62, H 5.88, N 14.82.

j) C1-NKM8: Calculated: 337.2388; Found: 337.2392 (M + H).

ί) Anal. calculated: C 68.45, H 7.669, N 15.21; Found: C 68.35, H 7.49, N 14.91.

_)) Anal. calculated: C 69.08, H 7.915, N 14.65; Found: C 68.85, H 7.83, N 14.54.

k) Anal. calculated: C 73.51, H 7.01, N 19.48; Found: C 71.57, H 7.15, N 19.12.

l) C1-NKM8: Calculated: 403.1899; Found: 403.1901 (M + H).

Fri) Anal. calculated: C 61.77, H 6.49, N 14.41, C1 9.13; Found: C 61.90, H 6.66, N 13.62, C1 9.25.

n) Anal. calculated: C 67.31, H 7.06, N 15.70, C1 9.93; Found: C 67.32, H 6.95, N 15.50, C19.93.

o) Anal. calculated: C 74.50, H 8.14, N 17.38; Found: C 74.43, H 7.59, N 17.16.

p) Anal. calculated: C 73.10, H 7.54, N 19.37; Found: C 73.18, H 7.59, N 18.81.

d) Anal. calculated: C 73.57, H 7.78, N 18.65; Found: C 73.55, H 7.79, N 18.64.

d) СI-НЯМ 8: Calculated: 353.2333; Found: 353.2341 (M + H).

8) Anal. calculated: C 71.56, H 8.02, N 15.90; Found: C 71.45, H 7.99, N 15.88.

1) Anal. calculated: C 65.60, H 7.34, N 14.57; Found: C 65.42, H 7.24, N 14.37.

i) C1-NKM8: Calculated: 399.2398; Found: 399.2396 (M + H).

ν) C1-NKM8: Calculated: 399.2398; Found: 399.2396 (M + H).

\ ν) C1-NKM8: Calculated: 383.2450; Found: 383.2447 (M + H).

x) C1-NKM8: Calculated: 403.1887; Found: 403.1901 (M + H).

y) C1-NKM8: Calculated: 295.1919; Found: 295.1923 (M + H).

ζ) Ayal, calculated: C 67.31, H 7.06, N 15.70; Found: C 67.12, H 6.86, N 15.53.

aa) Ayal, calculated: C 61.77, H 6.49, N 14.41, C1 9.13; Found: C 62.06, H 6.37, N 14.25, C19.12.

ab) C1-NKM8: Calculated: 337.2017; Found: 337.2028 (M + H).

ac) C1-NKM8: Calculated: 403.1893; Found: 403.1901 (M + H).

ay) Ayal, calculated: C 70.00, H 7.22, N 18.55; Found: C 70.05, H 7.22, N 18.36.

ae) Ayal, calculated: C 70.98, H 7.74, N 16.55; Found: C 71.15, H 7.46, N 16.56.

a§) Ayal, calculated: C 66.59, H 6.76, N 16.34; Found: C 66.69, H 6.82, N 16.20.

ay) Ayal, calculated: C 70.38, H 6.71, N 18.65; Found: C 70.35, H 6.82, N 18.83.

A1) Ayal, calculated: C 66.39, H 5.85, N 18.44, C1 9.33; Found: C 66.29, H 5.51, N 18.36, C19.31.

a)) C1-NKM8: Calculated: 369.2278; Found: 369.2291 (M + H).

ak) Ayal, calculated: C 64.42, H 6.77, N 15.02; Found: C 64.59, H 6.51, N 14.81.

Compounds of the examples presented in table. 3 can be obtained by the methods described in examples 1, 2, 3 or 6. Commonly used abbreviations: PH is phenyl, Pr is propyl, Me is methyl, E1 is ethyl, Vi is butyl, Ex is an example.

Table 3

Pr-- ί

546 * S-Me

547 ^b St. Me

548 "S-Me

549 ^th C-Me

ONSN (EU> 2

ΔΧ T.PL .__ £ a £$

2-Me-4-Megy-R

154-166

2-INSN (SNGSNgOMe>

2,4-Me2-₽P oil

-sngome z-ynsn (sngsngome)

2-Me-4-C1-Pb oil

jagone

N (s-₽g) СН2СН2СМ

2-Me-4-C1-Pb 115-116

550 * S-me ONSN (ECH> CH2CX 2-Me-4-C1-Pb 131-132 551 " S-me N {EU) 2 2,3-Me2-4-OMe-P oil 552 " S-me S (CH2CH2OMe) CH2CH2ON 2,4-C12-RY oil 553 ^b S-me S (CH2CH20Me) 2 2,3-Me2-4-OM-? B oil 554 * Sme ONSN (EU) 2 2, Z-MEG-4-OMER 123-124 5553 S-me Y (CH2-s-₽g> Rg 2-Me-4-C1-Pb oil 556 * S-me ν (s-₽gίngsngsya 2,3-МВ2-4-ОМе₽Ь 156-160 557 no K (C-WG) EU 2-C1-4-OMER 558 Sme Y (e-₽g) Me 2-C1-4-OMER 559 Sme M (C-? G> RG 2-C1-4-OMER 560 Sme Y (s-₽g) Vee 2-C1-4-OMeRN 5611 S-me N (EU) 2 2-C1-4-SY-RN 115-117 562 sme S (s-Rg) 2 2-C1-4-OMe 127-129 563 ^t S-me INSN (CH2OH) 2 2,4-C12-₽Y 128-129 564 S-me S (s-WG) EU 2-0G-4. 5- (MeO) 2PB 565 Sme S (s-Rg) Me 2-Br-4,5- (MeO) 2Pb 566 Sme EIN-s-Rg 2-Me-4-meOR 126-128 567 S-me UNSN (EU) CH2OH 2-me-4-meOR 60-62 568 sme nmeg 2-Br-4,5- (MeO) 2RP 569 S-me ONSN (ЕО2 2-me-4-meOR 103-105 5th S-me S (C-WG) EU 2-Me-4-MeOR 173-174 571 S-me Eun-2-reps1 2,4-C12-RY 118-120 572 Sme ONSN (EU) CH2SY 2,4-C12-RN 141-142 573 S-me ONSN (Pr) CH2OMe 2.4-C12-RY 8? -9v 574 S-me ONSN (CH2-1Rg) CH2OMe 2,4-C12-RY amorphous 575 S-me ΝΗ-2 butyl 2,4-Mv2 “Ry oil 576 S-me EUN-2-pentyl 2,4-meg-pb oil 577 S-me ΝΗ-2-hexyl 2,4-Me2 ~ Pb oil 578 S _r me ONSN (1-Rg) Me 2,4-yeg-ry oil 579 S-me ONSN (Me) СН2-1₽г 2,4-meg-pb oil 580 S-me ONSN (Me) -s-SbII 2,4-Me2-Pb oil 581 S-me ΝΗ-2-indanyl 2.4 megapixel oil 582 S-me ΝΗ-1-indanyl 2.4 megapixel oil 583 Sme ONSN (Me) Rb 2,4-mb2-pb oil 584 S-me ONSN (Me) CH2- (4-C1PY) 2,4-Me2 “₽ oil 585 S-me INSN (Me) СН2СОСНз 2, 4-mb2 ~ pb oil 586 S-me ONSN (Pb) SNgR 2,4-M62-RN oil 587 S-me INSN (Me) (SI2) ЗЫ £ И2 2,4-Me2-RN oil 568 S-me YN- (2-RN-S-S3N4) 2,4-mb2-pb oil 589 S-me ONSN (EU) SY2SY 2,4-meg-pb 119-120 590 S-me UN-3-hexyl 2.4 meg pH butter 591 ^p S-me ES2 2-MeO-4-s oil 592 ° S-me ONSN (EU> 2 2-MeO-4-C1PB oil 59? ₽ S-me INSN (£ C) CH2OMe 2-MeO-4-C1PB oil 594 S-me YMe2 2-MeO-4-C1PB oil 5954 S-me ONSN (EU> 2 2-OMe-4-MeRP oil 596 ^g S-me ES2 2-OM-4-ME oil 5973 S-S-Rg ONSN (CH2OMe) 2 2,4-C1 ₂ -Pb oil 598 S-me S (S-Rg) YOS 2, 4-Me ₂ -PB 599 S-me S (s-WG) EU 2,4-C12-RN 600 S-me S (C-WG) EU 2,4,6-Mez-pb 601 sme S (C-WG) EU 2-Me-4-C1-Pb 602 S-me S (S-8g) EU 2-C1-4-Me-₽ 603 S-me ONSN (S-₽g) 2 2,4-C12 ^₽ b 604 S-me ONSN (s-Rg> 2 2,4-meg-pb 605 Sme ONSN (S-RS) 2 2-Me-4-C1-Pb 606 Sme ONSN (e-WG) 2 2-C1-4-Me-Pb 607 S-me ONSN (s-₽) 2 2-Me-4-OMe-₽ 608 S-me ONSN (s-Rg »2 2-C1-4.-OMe-Pb 609 S-me ONSN (CH2OMe) 2 2-C1-5-E-OMER 610 S-me ES2 2-C1-5-G-OMER 611 sme S (s-Pr) CH2CH2SY 2-C1-5-G-OMER 612 S-me ONSN (EU> 2 2-C1-5-G-OMER 613 Sme zhngsngome) 2 2-C1-5-G-OMER 614 S-me ES2 r ^ -meg-pyridg-z-yl 615 S-me S (s-₽g) СН2СнгСЫ 2,6-Me ₂ -pyrid-3- silt 616 S-me ONSN (EU> 2 2,6 -me g-pyrid-- 3 - silt 617 Sme S (CH2CH2OMe) 2 2, 6-Me2 pi.rid * -3-yl 616 sleep InSN (CH2OMe> 2 2,4-meg-pb 619 Sleep ES2 2,4-meg-pb 620 sleep S (s-? G) СН2СН2СЫ 2,4-meg-pb

621 SLEEP ONSN (E) 2 2,4-meg-pb 623 SLEEP ν (sngsngome) g 2,4-Meg-pH 624 C-EUC2 ONSN (SNGOMe) 2 2,4-meg-pb 625 C-S Yeeh 2,4-Meg-pH 626 ST-2 ν (s-₽g) sngsngsi 2,4-meg-pb 627 C-S ONSN (Her> 2 2,4-meg-pb 62Θ C-S ν (sngsngome) 2 2,4-meg-pb 629 S-me Inns (Her) g 2-Me-4-SY-R 633 S-me to (sngsngome) g 2-Me-4-SK’-RN

Notes to the table. 3.

a) C1-NKM8: Calculated: 367.2610; Found: 367.2607 (M + H).

τι

b) C1-NKM8: Calculated: 384.2400; Found: 384.2393 (M + H).

c) C1-NYM8: Calculated: 404.1853; Found: 404.1844 (M + H).

b) C1-NKM8: Calculated: 381.1594; Found: 381.1596 (M + H).

Ayal, calculated: C 63.07, H 5.57, N 22.07, C1 9.32; Found: C 63.40, H 5.55, N 21.96, C1 9.15.

e) C1-NYM8: Calculated: 369.1594; Found: 369.1576 (M + H).

ί) C1-NKM8: Calculated: 354.2216; Found: 354.2211 (M + H).

§) C1-NKM8: Calculated: 410.1072; Found: 410.1075 (M + H).

I) C1-NKM8: Calculated: 414.2427; Found: 414.2427 (M + H).

ί) С1-НЯМ8: Calculated: 368.2372; Found: 368.2372 (M + H).

_)) C1-NYaM8: Calculated: 384.1955; Found: 384.1947 (M + H).

k) C1-NKM8: Calculated: 391.2168; Found: 391.2160 (M + H).

l) C1-NYM8: Calculated: 335.1984; Found: 335.1961 (M + H).

Fri) C1-NYaM8: Calculated: 382.0759; Found: 382.0765 (M + H).

η) ΝΗ ₃ -ΟΊ M§: Calculated: 360; Found: 360 (M + H) ⁺ .

o) ΝΗ ₃ -ΟΊ Mg: Calculated: 374; Found: 374 (M + H) ⁺ .

NMR (SIS1 ₃ , 300 MHz): δ 7.29 (b, 1 = 8.4 Hz, 1H), 7.04 (bb, 6 = 1.8, 8 Hz, 1H), 6.96 (b, 1 = 1.8 Hz, 1H), 6.15 ( b, 1 = 10, 1H), 4.19 (w, 1H), 3.81 (8, ZN), 2.47 (8, ZN), 2.32 (8, ZN), 1.65 (w, 4H), 0.99 (1, 1 = 7.32 Hz, 6H);

p) ΝΗ ₃ -ΓΊ Mg: Calculated: 390; Found: 390 (M + H) ⁺ ;

NMR (SIS1 ₃ , 300 MHz): δ 7.28 (b, 1 = 8 Hz, 1H), 7.03 (b, 1 = 8 Hz, 1H), 6.96 (δ, 1H), 6.52 (b, 1 = 9 Hz, 1H), 4.36 (w, 1H), 3.8 (8, H), 3.55 (w, 2H), 3.39 (8, H), 2.47 (3, H), 2.32 (δ, H), 1.76 (w, 2H) ), 1.01 (1.1 = 7.32 Hz, ЗН).

c |) C1-NKM8: Calculated: 354.2294; Found: 354.2279 (M + H).

d) C1-NKM8: Calculated: 340.2137; Found: 340.2138 (M + H).

δ) C1-NMN8: Calculated: 436.1307; Found: 436.1296 (M + H).

Compounds of the examples presented in table. 4 can be obtained by the methods described in examples ΙΑ, 1B, 432, 433, 434. Commonly used abbreviations: Ρΐι stands for phenyl, Pr stands for propyl, Me stands for methyl, E1 stands for ethyl, B stands for butyl, Ex stands for example, EU Ac denotes ethyl acetate.

Table 4

Cabbage soup. Ζ Vd DG 631 no ONSN (EU) 2 2-Br-4,5- (Me0) 2Pb 160-161 632 S-me ONSN (EU) 2 2-Vg-4-MeOR) 1 110-111 633 Sme yusgsngome) 2 2-Vg-4-MeORN 74-76 634 sme Inns (CIS> 2 2-vg-4-MeO₽P 128-130 635 S-me S (EU) 2 2-me-4-s1РЬ 113-114 636 Sme S (s-WG) EU 2,4-S12RG1 637 S-me S (s-WG) EU 2,4-Me2? 638 S-me S (s-WG) EU 2,4,6-MezR 639 S-me S (s-WG) EU 2-Me-4-MeOR 640 S-me S (s-WG) EU 2-C1-4-MeOR 641 Sme S (C-WG) EU 2-C1-4-MER 642 S-me S (C-WG) EU 2-Me-4-C1? 643 S-me ONSN (S-Rg) 2 2,4-C12-₽ 644 S-me ONSN (s-Rg> 2 2, 4-Μβ2-? Ϊ> 645 Sme INSN (S-Rg> 2 2-Me - 4-C1-RL 646 Sme ONSN (S-₽g> 2 2-C1-4-me-p 647 S-me ONSN (s-₽) 2 2-Me-4-OMe-R 64 8 Sme ONSN (s-Rg) 2 2-C1-4-OMe-Pb 649 S-me Innsn (S.chgome) 2 2-C1-5-G-OMERN 650 Sme ES2 2-C1-5-E-OMER 651 sme S (s-₽G) СН2СН2СЫ 2-C1-5-G-OMER 652 S-me ONSN {-ES) 2 2-C1-5-P-OMER 653 S-me N (SNGCHNgOMe) 2 2-C1-5-G-OMER 654 Sme HEC2 2,6-Me ₂ ' ^pi R ^and D-3-yl 655 S-me N (s-₽) SNgSNgSK 2, b-Meg-pyrid-3-yl 656 Sme ONSN (EU) 2 2, b-Meg ~ pyrid-3-yl 657 S-me S (CH2CH2OMe) 2 2, 6-Me2 * pyrid-3-yl 658 SLEEP ONSN (SNGOMe) 2 2,4-mb2-? B 659 sleep ES2 2,4-Meg-RP 660 sleep N (C-Rg) CH2CH2CH 2, 4-Meg-Ry 661 sleep ONSN (EU) 2 2.4-Me2 ~? Th 662 sleep S (CH2CH20Me) 2 2,4-Me2 ^_ ₽ 663 s-yvsg insn (cngome) 2 2,4-meg-pb 664 C-EUC2 ES2 2,4-meg ry 665 C-EUC2 M (s-Pr> CH2CH2CY 2, 4-me2-₽ <1 666 C-EUC2 ONSN (EU) 2 2,4-Meg-PE 667 C-EUC2 N (SNGCHNgOMe) g 2,4-Meg-pH 668 Sme ONSN (EU) 2 2-Me-4-SY-Ry 669 S-me s (sngsngome) g 2-Me ~ 4-SY-RN

Compounds of the examples presented in table. 5 or 6, can be obtained by the methods illustrated in examples ΙΑ, 1B, 2, 3, 6,

431, 432, 433, 434 or combinations thereof. Commonly used abbreviations: Ρΐι stands for phenyl, Pr stands for propyl, Me stands for methyl, E1 stands for ethyl, Vi stands for butyl, Ex stands for example.

Table 5

Etc.* V1D IN 1 & £. 720 Me EUN · cyclopentyl 2,4,6-Mez-pb 670 me Inns (sn ₂ ohm) ₂ 2,4-C1 ₂ -? B 721 Me Oes 2.4, b-mvz-pb 671 me INSNRg ₂ 2,4-C1 ₂ -Pb 722 Me OCH (EU) CH ₂ OMe 2.4, b-mez-pb 672 Me YESVi 2,4-C1 ₂ -Pb 723 me OCH ₂ Pb 2.4, b-mez-pb 673 Me LHr (CH2-s-CzH5) 2,4-C1 ₂ -Pb 724 Me OZ - pentyl 2.4, b-mez-pb 674 me S (CH ₂ CH ₂ OMe) ₂ 2,4-C12-Pb 725 Me 5ES 2.4, b-mez-pb 675 Me ON-3 heptyl 2,4-C1 ₂ -Pb 726 Me 5 (0) EU 2,4,6-Mez-pb 676 Me ONSN (EU) CH ₂ 0M € 2,4-C12 ~ Pb 727 Me 50 ₂ EU 2.4, b-mez-pb 677 Me EU ₂ 2,4-C1 ₂ -Pb 728 Me CH (CO ₂ EU) ₂ 2,4,6-Mez-RN 678 me ONSN (CH ₂ OES) 2 2,4-C1 ₂ -Pb 729 me C (EU) (CO2EO2 2.4, b-mez-pb 679 me ΝΗ-Z- pentyl! 2,4-C1 ₂ -Pb 730 Me CH (EU) CH2OH 2,4, b-Mez-₽ 680 Me IMeR 2,4-C1 ₂ -Pb 731 me sn (ec) cngome 2,4,6-Mez-pb 681 me Yrg ₂ 2,4-C1 ₂ -Pb 732 me Soyme ₂ 2,4,6-Mez-pb 682 Me ΝΗ-3-hexyl 2,4-C1 ₂ -Pb 733 Me SOC 2.4, b-mez-pb 683 me morpholino 2,4-C1 ₂ -RP 734 Me SNYUSNz 2,4,6-Mez ~ Pb 684 me ν (sn ₂ pb) sn ₂ sn ₂ ohm 2,4-C12 ’? B 735 Me C (OH) ₽-3-pyridyl 2.4, b-mez-pb 685 Me ONSN (CH ₂ Pb) CH ₂ OMe 2,4-C1 ₂ 'Pb 736 me Pb 2.4, b-mez-pb 686 Me ΝΗ-4-tetrahydropyraiyl 2,4-C1 ₂ -Pb 737 me 2-Pb * -Pb 2.4, b-mez-pb 687 Me ΝΗ-.cyclopentyl 2,4-C1 ₂ -Pb 738 Me 3 - pentyl 2,4,6-Mez-pb 688 Me ABOUT 2,4-C1 ₂ -Pb 739 me cyclobutyl 2.4, b-mez-pb 689 Me OSN (EOSN ₂ OMe 2,4-C1 ₂ -₽ 740 me 3-pyridyl 2.4, b-mez-pb 690 not OCH ₂ Pb 2,4-C1 ₂ -Pb 741 Me CH (EU) CH ₂ SOYME ₂ 2,4,6-mes-pb 691 Me OZ pentyl 2,4-C1 ₂ -Pb 742 me sn (Yeosn ₂ sn ₂ ym ₂ 2,4,6-mes-pb 692 me WEU 2,4-C1 ₂ -Pb 743 me ONSN (CH ₂ OMe) 2 2,4-Me2 “Pb 693 Me 5 (O) EU 2,4-C1 ₂ -Pb 744 Me N (CH ₂ CH ₂ OMe) 2 2,4-Me ₂ -Pb 694 Me 5O ₂ EU 2,4-C1 ₂ -₽ 745 me ONSN (EU) CH ₂ OMe 2,4-Me ₂ “Pb 695 Me Pb 2,4-C1 ₂ -Pb 746 me EUN-3- pentyl 2,4-Me ₂ -Pb 696 Me 2-Crz-pb 2,4-C1 ₂ -? B 747 Me EU ₂ 2,4-Me ₂ -Pb 697 Me 2-pb-pb 2,4-C1 ₂ -Pb 748 me S (CH ₂ CH) ₂ 2,4-Me ₂ -Pb 698 me 3-pentyl 2,4-C1 ₂ -Pb 749 me Inns (Me) sn ₂ ohm 2,4-meg-pb 699 Me cyclobutyl 2,4-C1 ₂ -Pb 750 Me OCH (EU) CH2OMe 2,4-me ₂ -Pb 700 Me 3-pyridyl 2,4-C1 ₂ -Pb 751 me YaRg-S-SzNz 2,4-Me ₂ -Pb 701 Me sn (Ec) sn ₂ soime ₂ ' 2,4-C12 “Bb” 752 Me INSN (Me) CH ₂ UMe ₂ 2,4-Me ₂ -Pb 702 me cN (at ₂ CH ₂ CH ₂ yme 2,4-C12-RP 753 Me ν (С-С3Н5) sn ₂ sn ₂ sy 2,4-Me ₂ -Pb 703 me Inns (CIS) 2 2,4,6-Mez’RP 754 me N (Pc) CH ₂ CH ₂ SY 2,4-Me ₂ -Pb 704 me INSNRg ₂ 2,4,6-Mez-RP 755 Me N (Vi) CH ₂ CH ₂ SY 2,4-Me ₂ -Pb 705 me yosai 2,4,6-Mez-pb 756 me INSNRgg 2,4-Me ₂ - Pb 706 Me YRG (СН2-С-С3Н5) 2,4, b-mez-pH 757 me YESVi 2,4-Me ₂ -Pb 707 me ν (sn ₂ sn ₂ ohm) 2 2.4, b-mez-pb 758 me LRG (CH2-C-C3H5) 2,4-meg-pb 708 me ΝΗ-З — heptyl 2.4, b-mez-pb 759 Me YN-3 “Heptyl 2,4-Me ₂ -Pb 709 me Inns (Yeo sn ₂ ohm 2,4,6-Mez-pb 760 Me WES ₂ 2,4-Me ₂ -Pb 710 me EU ₂ 2,4,6-Mez-pb 761 Me ONSN (CH ₂ OES) 2 2,4-Me ₂ -Pb 711 Me ONSN (CH ₂ OEO ₂ 2,4,6-mes-pb 762 Me ΝΗ-3-pentyl 2,4-Me ₂ -Pb 712 Me EUN-Ztgentil 2.4, b-mez-pb 763 Me IMeR 2,4-Me ₂ -Pb 713 Me IMeR 2.4, b-mez-pb 764 Me Yrg ₂ 2,4-Me ₂ -Pb 714 Me Yrg ₂ 2.4, b-mez-pb 765 me UN-3-hexyl 2,4-Me ₂ -₽Н 715 Me З-Z- hexyl 2,4,6-mes-pb 766 me morpholino 2,4-Me ₂ -₽ 716 Me morpholino 2.4, b-mez-pb 767 me N (CH ₂ Pb) CH ₂ CH ₂ OMe 2,4-Me ₂ -₽ 717 Me S (CH ₂ Pb) CH ₂ CH ₂ OMe 2.4, b-mez-pb 768 me ONSN (CH ₂ Pb) CH ₂ OMe 2,4-Me ₂ -Pb 718 me ЫНСН (СН ₂ ₽Ь) СН ₂ ОМе 2,4,6-Mez-pb 769 Me UN-4-tetrahydropyraiyl 2,4-Me ₂ -RN 719 me ON-4- tetrahydropyraiyl 2.4, b-mez-pb 770 me EUN-Cichlopentyl 2,4-Me ₂ -₽ 771 Me ONSN (CH ₂ OMe) 2 2-Me-4-MeO-R 772 me n (sngsngome) ₂ 2-Me-4-MeO-R 773 me ONSN (Her) CH ₂ ONE 2-Me-4-MeO-₽ 774 me N (Pc) CH ₂ CH ₂ SY 2-me-4-meo-pb 775 Me OCH (EU) CH ₂ OMe 2-Me-4-MeO-R 776 me InSN (CH ₂ OMe) 2 2-sun-4-meo-pb 777 Me s (sn ₂ sn ₂ ohm) ₂ 2-Br-4-MeO-Pb 778 Me ONSN (EU) CH ₂ OMe 2-Br-4-MeO-₽ 779 me S (Rg) CH ₂ CH ₂ SY 2-Br-4-MeO-Pb 780 me main (EU) sn ₂ ohm 2-sun-4-meo-pb 781 me ONSN (CH ₂ OMe) 2 2-Me-4-YMe ₂ -R 782 me N (CH ₂ CH ₂ OMe) 2 2-Me-4-YMe ₂ -R 783 me ONSN (EU) CH ₂ OMe 2-me-4-yme ₂ 784 me N (Rg) CH ₂ CH ₂ SY 2-Me-4-YMe ₂ -R 785 me DOS (Yeosngome 2-Me-4-YMe ₂ -R 706 Me ONSN (SN20M6) 2 2-Br-4-Ime ₂ -R 787 me s (sn ₂ sn ₂ ohm) 2 2-Br-4-Ime ₂ -R 788 me InSN (EU) CH2Ome 2-Sun-4-Ime ₂ -R 709 Me s (rg) sn ₂ sn ₂ sy 2-Vg-4-yme ₂ 790 Me OCH (EU) CH2OMe 2-Br-4-Ime ₂ -R 791 me ONSN (CH ₂ OMe) ₂ 2-Br-4-1-Pr-Pb

792 Not Schsngsngome) g 2-VG-4-1-RG-RN 864 Me Eun-3-repyu1 2-C1-4-M6RN 793 Me ONSN (Her) SNGOMe 2-0G-4-X-RG-RN 865 Me ONSN (SNGOMe) 2 2-C1-4-meO Ruby 794 Me S (Pr) CH2CHNGSY 2-VG-4-X-RG-RM 866 Me ν (sngsngome) 2 2-C1-4-MeORN 795 me OCH (Her) SNGOMe 2-Vg-4 -! - ₽g-p 867 Me Inns (Sin) 2-C1-4-MeOR 796 Me ONSN (SNGOMe) 2 2-Vg-4-Me-R 868 Me S (s-₽g) СН2СН2СЫ 2-C1-4-MeOR 797 Me AND (CH2CIA2OMe) 2 2-Br-4-Me-Pb 869 me SHY2 2-C1-4-MeOR 798 Me ONSN (Her) SNGOMe 2-Vg-4-Me-₽K 870 Me ΝΗ-3-.pentyl 2-C1-4-MeORN ν (₽g) singsngs 871 Me Innsn (Her Sngsngome 2-C1-4-meOR 799 me 2-Br-4-Me-Pb 872 me InSn (Me) CH2CH2OMe 2-C1-4-MeOR 80? me OCH (Her) SNGOMe 2-Vg-4-Me-RN 873 me 2-Vg-4-MeOR ssngsome 801 me ONSN (CH2OMe> 2 2-Me-4-Vg-₽N 874 Me 2-Vg-4-MeOR inns (me) sngsngome 802 me S (CH2CH2OMe) 2 2-Me-4-Vg-RN 875 me ssngsome 2-Me-4-MeOR 803 me ONSN (Her) SNGOMe 2-Me-4-Vg-RN 876 Me inns (me) sngsngome 2-Me-4-MeO 804 me N (Pr) SI2CH2CY 2-me-4-vy-rp 877 Me ONSN (SNGOMe) 2 2-C1-4.5- (MeO) 805 me OCH (Her) SNGOMe 2-Me-4-Vg-RK 878 Me s (sngsngome) 2 2-C1-4.5- (MeO) 806 me Innsnskgome) 2 2-C1-4,6-Μβ2-? Π 879 Me ONSN (Her) CH2OMe 2-C1-4.5- (MeO) gr 807 me L (CH2CH2OMe) 2 2-C1-4, b-Meg-RP 880 Me N (s-₽g) СН2СН2СЫ 2-C1-4.5- (MeO) 808 me mnzhsngome) 2 4-VG-2,6- (Me) 2-₽ 881 me YUY2 2-C1-4.5- (MeO) 2₽Н 809 Me S (SNGCH2OMe) 2 4-Br-2.6- (Me) 2-? B 882 me EUN-3-pentyl 2-C1-4.5- (MeO) 810 Me ONSN (SNGOMe) 2 4-1-rg-2-3Me-pb 883 Me ONSN (Her) CH2CH2OMe 2-C1-4.5- (MeO) 2₽ 811 me M (CH2CH2OMe) 2 4-1-Rg-2-5Me-RP 884 Me inns (me) sngsngome 2-C1-4.5- (MeO) 2RP 812 Me ONSN (SNGOMe) 2 2-Br-4-Ces-Pb 885 Me Inns (CIS) 2 2-VG-4,5- (MeO) 813 me s (sngsngome) g 2-Sun-4-SEZ-₽P 886 Me s (sngsngome) 2 2-VG-4,5- (MeO) gr 814 me ONSN (CH2OMe) 2 2-Br-4,6- (MeO) 2-Pb 887 me ONSN (Her) CH2OMe 2-Br-4.5- (MeO) 815 me M (SNGCH2OMe) 2 2-VG-4,6- (MeO) 2-Pb 888 Me S (s-Pr) CH2CHNGSY 2-Br-4,5- (MeO) 2? 816 me ONSN (CH2OMe) 2 2-C1-4.6- (MeO) 2 “ ^p b 889 Me SHY2 2-VG-4,5- (MeO) 2₽П 817 me S (CH2CHNgome) 2 2-C1-4.6- (MeO) 2 “Pb 890 Me EUN-Z-pentyl 2-Br-4,5- (MeO) 2RP 818 me ONSN (SNGOMe) 2 2.6- (Me) 2-4-3Me-Pb 891 me Inns (CIS) 2 2-C1-4.6- (MeO) 819 Me M (CH2CHNgOMe) 2 2.6- (Me) 2-4-ZMe-RK 892 me s (sngsngome) 2 2-C1-4.6- (MeO) 2PH 820 me INGSSNGOME) 2 4- (СОМе) -2-Вг-Р1х 893 Me SHY2 2-C1-4.6- (MeO) 821 Me mssngsngome) 2 4- (СОМе) -2-Вг-₽Н 894 Me ΝΗ-3-dentyl 2-C1-4.6- (MeO) gr 2,4,6-Mes-pirvd — 3-yl 895 me Inns (CIS) 2 2-Me-4.6- (MeO) 822 Me ONSN (SNGOMe) 2 2,4, b-Meziirid * 3-yl 896 me S (CH2SC2OMe) 2 2-Me-4,6- (MeO) 2₽Н 823 Me ssssngome) g 897 me 2-Me-4,6- (MeO> 2 ^₽ b 2.4- (Vg) Inns (Sin) 824 Me ONSN (SNGOMe) 2 898 Me 2-Me-4.6- (MeO) 2,4- (Vg> 2-₽P SHY2 825 me S (SNGCH2OMe) 2 899 Me 2-Me-4,6- (MeO) 2₽ ^s 4-x-RS-2-ZMe-₽P ΝΗ-3-pentyl 826 Me Youthsome) 2 900 Me 2-Me-4-MeORN 4-1-Pr-2-3Me-Pb ssngsome 827 Me N (CH2CH2 ^OMV) 2 828 me ONSN (CH2OMe> 2 4-1-Rg-2-5O2Me-₽ 901 Me inns (me) sngsngome 2-Me-4-MeORP 829 ν (sngsngome) 2 4-1-Rg-2-5O2Me-₽ 902 Me Inns (CIS) 2 2-Me0-4-MeRP Me 830 Me ONSN (SNGOMe) 2 2,6- (Me) 2 ~ 4-ЗМе-₽й 903 Me s (sngsngome) 2 2-MeO-4-MER 831 M (CH2CH2OMe) 2 904 me Inns (Sin) 2-Me0-4-MER Me 2,6- (Ме) 2 ”4-5Ме-₽й 905 Me 832 S (s-Re) CH2CH2SY 2-MeO-4-MeRN Me ONSN (SNGOMe) 2 2.6- (Me) 2-4-5O2Me-₽ 833 Me S (SNGCH2OMe) 2 2.6- (Me) 2-4-50 gMe? 906 Me SHY2 2-Me0-4-MER 834 Me ONSN (SNGOMe) 2 2-1-4-x-Pr-Rb 907 Me EUN-3 "-dentyl 2-Me0-4-Me? N 835 me S (CH2CH2OMe) 2 2-1-4-ί-ΡΓ-ΡΗ 908 me ssngsome 2-MeO-4-MeRy 835 me Inns (CIS) 2 2-Vg-4-S (Me) 2 “b-MeO-₽ 909 me INSN (Me) CH2CH20Me 2-MeO ~ 4-MER 837 me s (cngCH2OMe) 2 2-0G-4-S (Me) 2 ”6 ~ MeO-Pb 910 me Inns (CIS) 2 2-MeO-4-MeRK 838 me SHY2 2-Vg-4-MeO-₽P 911 me s (sngsngome) 2 2-MeO-4-MER 839 me ΝΗ-3- pentyl 2-Vg-4-MeO-RP 912 me ONSN (Her) SNGOMe 2-MeO-4-MeR 840 me Inns (CIS) 2 2-SY-4-Me? 913 me S (s-Pr) CH2CH2SY 2-Me0-4-MeRK 841 Me s (С-С3Н5) singsngs 2,4,6-Mez-₽ 914 me SHY2 2-MeO-4-MER 842 Me ynsk (sngsngome »sngome 2-Me-4-Vg-RP 915 Me ΝΗ-3-.pentyl 2-meO-4-meRG> 843 Me ONSN (CH2OMe) 2 2,5-Mb2 ~ 4-MeO-Pb 916 me Inns (CIS) 2 2-MeO-4-S1RN 844 me s (sngsngome) 2 2,5-Me2-4-MeO-₽ 917 Me s (sngsngome) 2 2-MeO-4-C1PB 845 Me eunzentil 2,5-Me2-4-MeO-RN 918 Me Inns (Sin) 2-MeO-4-S1RN 846 Me SHY2 2, 5-Me2-4-MeO-Pb 919 Me SHY2 2-MeO-4-S1RP 847 Me Inns (CIS) 2 2-s1-4-MeRN 920 Me ΝΗ-3-pentyl 2-MeO-4-C1PB 848 me YSN (Her) SNGOMe 2-C1-4-MeR 849 me s (sngsngome) 2 2-C1-4-MeRP Table 6 850 Me <5) -insn (sngsngome) sngome 2-C1-4-Me AT, 851 me S (s-CsN5) CH2CHNGSY 2,5-Ме2 “4-МеО₽Ь ’.’3 I> G ⁴ 852 Me SHY2 2-Me-4-MeOR 853 me Ooh 2-Me-4-MeOR 854 me {h) -insn (sngsngome) sngome 2-Me-4-MeORy one \ = o 855 me s (С-С3Н5) singsngs 2-Me-4-MeORN ^ == ¾¾ / 856 Me ONSN (CH2CHNgOey) 2 2-Me-4-MeO < 857 Me S (s-CsN5) CH2CHNGSY 2,4-C12-RP \ Ar 858 Me yeyg 2-Me-4-C1 859 me EUN-pentst 2-Me-4-C1PB 860 me s (sngsngome) 2 2-Me-4-S1RP 861 Me Inns (CIS) 2 2-Me-4-C1PB 862 Me SHY2 2-Me-4-S1₽Н 863 Me SHY2 2-C1-4-MeR £

Hell 980 me C (EU) (CO2EO2 2.4, b-mez-pb Me ONSN (SNGOMe) 2 2,4-C1 ₂ -Pb 981 Me CH (EOSN ₂ OH 2.4, b-mez-pb me INSNRg ₂ 2,4-C1 ₂ -Pb 982 Me sn (ec) cngome 2.4, b-mez-pb me YESVI 2,4-C1 ₂ -Pb 983 me СОЫМе ₂ 2.4, b-mez-pb Me LRG (CH2-C-C3H5) 2,4-C12-RN 984 me SOSNz 2.4, b-mez-pb Me S (CH ₂ SNOMe) 2 2,4-C12-₽ 985 me CH (OK) CHz 2,4,6-Mez-pb me UN-Z-heptyl 2,4-C1 ₂ -Pb 986 Me C (OH) P b-3-pyridyl 2.4, b-mez-pb Me Innsn (Yeosngome 2, 4-C12-RI 987 Me Pb 2.4, b-mez-pb Me EU ₂ 2,4-C12-P & 96-8 Me 2-pb-pb 2.4, b-mez-pb 989 me 3-pentyl 2.4, b-mez-pb me ONSN (CH2OES) 2 2,4-C12-RN 990 Me cyclobutyl 2,4,6-Mez-pb me ΝΗ-3-, pentyl 2, 4-C12-RK 991 Me 3 -. Pyridyl 2.4, b-mez-pb Me YMER 2,4-C1 ₂ “Pb 992 Me sn (Eo sn ₂ soem ₂ 2,4,6-mes-pb Me ΝΡΓ2 2,4-C1 ₂ -Pb 993 Me CH (EU) CH ₂ CH ₂ UMe ₂ 2,4,6-mes-pb Me ΝΗ-3-hexyl 2,4-C12-RN 994 Me ONSN (CH ₂ OMe) 2 2,4-Me ₂ -Pb Me morpholino 2,4-C12 “Pb 995 me S (CH2CH ₂ OMe) 2 2,4-Me ₂ -Pb Me S (SNgr) CH2CH2OMe 2,4-C12-RN 996 me ONSN (EOSN ₂ OMe 2,4-Me ₂ -Pb me ONSN (CH2RN) CH2OMe 2,4-C1 ₂ -Pb 997 Me EUN-3-pentyl 2,4-Me ₂ -Pb Me ON-4- tetrahydropyranyl 2,4-C1 ₂ -Pb 998 Me EU ₂ 2,4-Me ₂ -Pb Me Eun-hdeclopentyl 2,4-C1 ₂ -Pb 999 Me N (CH ₂ CN) 2 2,4-Me ₂ -Pb me Oes 2,4-C1 ₂ -Pb 1000 Me ONSN (Me} CH ₂ OMe 2,4-Me ₂ -Pb me OCH <E) CH2OMe 2,4-C12-RP 1001 Not OCH (EU) CH ₂ OMe 2,4-meg-pb me OSN2RP 2,4-C12-P & 1002 Me YRG-S-S3N5 2,4-me ₂ -Pb me OZ pentyl 2,4-C12-RN 1003 Me Inns (me) sn ₂ ym ₂ 2.4 megapixel 1004 Me S (s-CzH5) CH ₂ CH ₂ SY 2,4-Me ₂ -Pb Me WEU 2,4-C12 ”PH 1005 Me N (Rg) CH ₂ CH ₂ SY 2,4-Me ₂ -Pb me 8 (0) EU 2, 4-C1 ₂ -Pb 1006 Me N (Vi) SK ₂ CH ₂ SY 2,4-Me ₂ -Pb Me 5O ₂ EU 2, 4-C1 ₂ -Pb 1007 Me YNSCRg ₂ 2,4-Me ₂ -Pb Me Pb 2,4-C1 ₂ -Pb 1008 me YESVi 2.4 megapixel Me 2-sez-pb 2,4-C1 ₂ -Pb 1009 me LHr (CH ₂ -s-CzH5) 2,4-Me ₂ -Pb Me 2-pb-pb 2,4-C1 ₂ -Pb 1010 Me ON-3-heptyl 2,4-Me ₂ -Pb Me 3 Chpentil 2,4-C1 ₂ -Pb 1011 Not EU ₂ 2,4-me ₂ -Pb Me cyclobutyl 2,4-C1 ₂ -Pb 1012 Me ONSN (CH ₂ OES) ₂ 2,4-me ₂ -Pb Me 3- C ^ Ridyl 2,4-C1 ₂ -Pb 1013 Me EUN-3- pentyl 2,4-Me ₂ -Pb Me sn (ec) sngsoomeg 2, 4-C1 ₂ -Pb 1014 Me IMeR 2,4-Me ₂ -Pb Me CH (EU) CH2CH2YM62 2,4-C1 ₂ -Pb 1015 Me yrs ₂ 2,4-Me ₂ -Pb me ONSN (CH2OMe) 2 2, 4,6-mes-pb 1016 me EUN-3 * hexyl 2.4 megapixel Me INSNRG2 2,4,6-Mez-pb 1017 Me morpholino 2.4 megapixel Me YESVI 2, 4, b-Mez-Rb 1018 Me S (CH ₂ ₽) CH2CH ₂ OMe 2,4-Me ₂ -Pb Me LRG (CH2-C-C3H5) 2.4, b-mez-pb 1019 Me ONSN (CH ₂ Pb) CH ₂ OMe 2.4 megapixel me s (sn ₂ sn ₂ ohm) 2 2,4,6-Mez-pb 1020 Me ON-4- tetrahydropyranyl 2.4 megapixel me ΝΗ-3-heptyl 2,4,6-Mez? N 1021 me ΝΗ- cyclopentyl 2.4 megapixel Me ONSN (EU) SNOME 2,4,6-Mez-pb 1022 me ONSN (CH ₂ ohm) ₂ 2-me-4-meo-pb Me YIVS ₂ 2,4,6-Mez-pb 1023 Me S (CH ₂ CH ₂ OMe) 2 2-Me-4-MeO-R me ONSN (CH ₂ OES) 2 2,4,6-Mez-pb 1024 me ONSN (EU) CH ₂ OMe 2-Me-4-MeO-R me EUN-3 — pentyl 2.4, b-mez-pb 1025 me S (Rg) CH ₂ CH ₂ SY 2-Me-4-Meo-R me IMeR 2.4, b-mez-pb 1026 Me OCH (EU) CH ₂ OMe 2-Me-4-MeO-R Me Yrg ₂ 2,4,6-mes-pb 1027 Me ONSN (CH ₂ OMe> 2 2-Br-4-MeO-Pb me ΝΗ-3-hexyl 2,4,6-mes-pb 1028 Me N (CH ₂ CH ₂ OMe) 2 2-Br-4-MeO-Pb Me morpholino 2.4, b-mez-pb 1029 Me ONSN (EU) CH ₂ OMe g-vg-4-meo-ry Me N (CH ₂ Pb) CH ₂ CH ₂ OMe 2.4, b-mez-pb 1030 Me S (Rg) CH ₂ CH ₂ SY 2-Br-4-MeO-₽ me ONSN (CH ₂ Pb) CH ₂ OMe 2.4, b-mez-pb 1031 Me OSN (EOSN ₂ OMe 2-Br-4-MeO-Pb Me ON-4- tetrahydropyranyl 2.4, b-mez-pb 1032 Me ONSN (CH ₂ OMe) ₂ 2-Me-4-YMe ₂ -R Me un-cyclopentyl 2.4, b-mez-pb 1033 Me S (CH ₂ CM ₂ OMe) 2 2-Me-4-YMe ₂ -R me Oes 2.4, b-mez-pb 1034 Me ONSN (EU) SNOME 2-Me-4-YMeg-R Me DOS (Ec> Sn ₂ Ohm 2.4, b-mez-pb 1035 Me S (Rg) CH ₂ CH ₂ SY 2-Me-4-YMe ₂ -R me OCH ₂ Pb 2.4, b-mez-pb 1036 Me OCH (EU) CH ₂ OMe Mr. Me-4-YMeg-R Me 0-3-, pentyl 2.4, b-mez-pb 1037 Me ONSN (CH2OMe) ₂ 2-Vg-4-YMeg-R Me WEU 2.4, b-mez-pb 1038 Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-Ime ₂ -R Me 5 (O) EU 2.4, b-mez-pb 1039 me ONSN (EU) CH2OMe 2-sun-4-yme ₂ -rew Me 5O2ES 2,4,6-Mez-pb 1040 me N (Pc) CH ₂ CH ₂ SY 2-Br-4-Ime ₂ -R Me CH (CO2EC) 2 2.4, b-mez-pb 1041 Me OCH (Ec) SNOME 2-sun-4-yme ₂ -rew 1042 me ONSN (CH ₂ OMe) ₂ 2-Br-4-1-Pr-Pb 1043 me s (sngsngome) 2 2-Br-4-1-Pr-Pb 1044 Not ONSN (EU) sn ₂ ohm 2-Be-4-1-? R-pb 1045 me s (Rg) sn ₂ sngs 2-Vg-4-1-₽g-R 1046 Me OCH (EU) sn ₂ ohm 2-Br-4-x-Re-Pb 1047 me ONSN (CH ₂ OMe) 2 2-Br-4-Me-Pb 1048 me S (CH ₂ CH ₂ OMe) 2 2-Br-4-Me-Pb 1049 me ONSN (EU) CH ₂ OMe 2-Br-4-Me-Pb 1050 me N (₽g) СН2СН2СЫ 2-Br-4-Me-Pb 1051 Me OCH (EU) SNOME 2-Br-4-Me-Pb

1052 me Inns (England) 2 2-Me-4-Br-Rb 1053 Me Ν (ΟΗ2θΗ2θΜβ) 2 2 — Me — 4 — Sun — RN 1054 Me ONSN (EOSNgOMe 2-Me-4-Br-Rb 1055 Me ν (? g) singsngs 2-Me-4-Br-Rb 1056 Me OCH (E (ESN2OMe 2-Me-4-Br-Rb 1057 Me ONSN (CH2OMe) 2 2-C1-4, b-Me ₂ -Pb 1058 me S (CH2CH2OMe) 2 2-C1-4,6-Me2-RP 1059 Me ONSN (CH2OMe> 2 4-Br-2,6- (Me) 2-RI 1060 Me N (CH2CH20MO 2 4-Br-2, b- (Me> 2 “ ^₽ b 1061 Me ONSN (SNGOMe) 2 4-1-Pr-2-3Me-Pb 1062 me S (CH2CHNgome) 2 4-x-Rg-2-ZMe-RD 1063 me ONSN (CH2OMe> 2 2-Sun-4-CE3-RN 1064 me S (CH2CH2OMe »2 2-Br-4-Crz-Rb 1065 Me CNSN (CH2OMe> 2 2-Br-4,6- (MeO) 2-? B 1066 me N (CH2CH2OM6) 2 2-VG-4,6- (MeO) 2-₽ 1067 Me ONSN (CH2OMe> 2 2-C1-4.6- (MeO) 2-₽ 1068 me ν (sngsngome) 2 2-C1-4.6- (MeO) 2-₽ 1069 Me ONSN (CH ^ OMe) 2 2.6- (Me) 2 “4-5Me-Pb 1070 Me S (CH2CH2OMe) 2 2.6- (Me) 2 ~ 4-3Me-RN 1071 Me ONSN (CH2OMe> 2 4- (COMe) -2-Sun-RP 1072 me S (SNGCH2OMe) 2 4- (COMe) -2-Br-Pb 1073 Me ONSN (SN20M6) 2 2, 4,6-Mez ~ pyrid'Z-yl 1074 me N (CH2CH20MO) 2 2,4,6-Mes-pyrid 3- 1075 Me ONSN (CH2 <3Me) 2 2,4- (Vg) 2-₽ 1076 Me S (SNGCH2OMe) 2 2,4- (Vg> 2-₽N 1077 me ONSN (SNGOMe) 2 4-x-rg-2-zme-pb 1078 Me S (CH2CH2OMe) 2 4-1-Pr-2-3Me-Pb 1079 me ONSN (SNGOMe) 2 4-1-₽g-2-5O2Me-R 1080 me S (CH2CH2OMe> 2 4-x-Pr-2-5O ₂ Me-Pb 1081 Me ONSN (CH2OMe> 2 2,6- (Me) 2-4-5Me? D 1082 me M (CH2CH2OMe> 2 2,6- (Me) 2 “4-5Me? 1083 me ONSN (CH2OMe) 2 2.6- (Me) 2-4-ZO2Me-RN 1084 Me S (CH2CH2OMe »2 2,6- (Ме) 2-4-ЗО ₂ Ме-₽Ь 1085 Me ONSN (CH2OMe) 2 2-g-4-1-Pr-Rb 1086 Me S (CH2CH2OMO 2 2-1-4-x-Pr-Rb 1087 me ONSN (CH2OMe> 2 2-VG-4-S (Me) 2 “6“ MeO-RP 1088 Me S (CH2CH2OMe) 2 2-Br-4-S (Me> 2-6-MeO-RN 1089 me ES2 2-Br-4-MeO-Pb 1090 Me eun-3-reps1 2-Br-4-MeO-RN 1091 Me ONSN (CH2OMe> 2 2-SY-4-Me-RD 1092 Me S (s-CzH5) CH2CH2SY 2,4,6-Mez-pb 1093 me ONSN (CH2CH2OMe) CHgOMe 2-Me-4-Sun-Pb 1094 Me ONSN (CH2OMe) 2 2,5-Me ₂ -4-MeO-Pb 1095 me s (sngsagome) 2 2,5-Me ₂ -4-MeO-RD 1096 Me EUN-3 — pentyl 2,5-Me2 ~ 4-MeO-₽ 1097 Me ES2 2,5-Me ₂ -4-MeO-Pb 1098 Me ONSN (SNGOMe) 2 2-C1-4-MER 1099 me YSN (EU) CH2OMe 2-C1-4-MeR 1100 Me N (CH2CH2OMe> 2 2-C1-4-MER 1101 Me (5) -insn (sngsngome) sn ₂ sm 2-C1-4-MER 1102 Me N (C-S3N5) CR ₂ CH ₂ CN 2, 5-Me ₂ -4-MeOR 1103 me WES ₂ 2-Me-4-MeO₽N 1104 me Oes 2-Me-4-MeOR 1105 me (5) -INSN (CH2CH2OMe) CHgOMe 2-Me-4-MeO 1106 me S (C-C3H5) CH2CH2SY 2-Me-4-MeOR 1107 me MNSN (SNGSN ₂ OES) 2 2-Me-4-MeOR 1108 me N (C-C3H5) CH2CH2CY 2,4-C12-RN 1109 me EU ₂ 2-Me-4-C1PB 1110 me EUN-D-Dentyl 2-Me-4-C1PB 1111 me ν (engengome) 2 2-Me-4-C1PB 1112 me ONSN (CH ₂ OMe) ₂ 2-Me-4-C1PB 1113 me EU ₂ 2-Me-4-C1PB 1114 Me EU ₂ 2-C1-4-MER 1115 Me ΝΗ-Z- pentyl 2-C1-4-Me 1116 me ONSN (CH ₂ OMe) 2 2-C1-4-MeOR 1117 me S (CH2CH ₂ OMe> 2 2-C1-4-MeORP 1118 me Inns (Eosn ₂ OME 2-C1-4-MeO RUB 1119 me s (s-Pr) CH2CH2CY 2-C1-4-MeOR 1120 me MONTH 2 2-C1-4-MeORN 1121 Me EUN-3 - pentyl 2-C1-4-MeORK 1123 me UNSN (EU) CH2SY2OMe 2-C1-4-MeO 1124 Me INSN (Me) CH2CHNgOM 2-C1-4-MeOR

1125 me InnsEsngsngome 2-Br-4-MeO 1126 me Inns (me) Engengome 2-Vg-4-MeOR 1127 not ONSN (EU) CH ₂ CH ₂ OMe 2-me-4-meO 1128 me ONSN (Me) CH ₂ CH ₂ OMe 2-Me-4-meOR 1129 Me ONSN (CH ₂ OMe) 2 2-C1-4.5- (MeO) 2? B Fine art Me S (CH2CH2OMe) 2 2-C1-4.5- (MeO) 2₽ & 1131 Me ONSN (EU) CH ₂ OMe 2-C1-4.5- (MeO) 1132 me S (s-Pr) CH2CH2SY 2-C1-4.5- (MeO) 1133 me EU ₂ 2-C1-4.5- (MeO) 1134 me ΝΗ-Z- pentyl 2-C1-4.5- (MeO) ₂ Ry 1135 me ONSN (EU) CH ₂ CH ₂ OMe 2-C1-4, 5- (MeO) 1136 me Inns (Me) sn ₂ sn ₂ ohm 2-C1-4.5- (MeO) 1137 me Inns (England) 2 2-Br-4,5- (MeO) 2? B 1138 Me S (CH ₂ CH ₂ OMe) ₂ 2-Br-4.5- (MeO) 1139 Me ONSN (EOSN20Me g-Br-4,5- (MeO) 2? b 1140 Me S (s-Rg) CH ₂ CH ₂ SY 2-VG-4,5- (MeO) 1141 me ES2 2-Br-4.5- (MeO) 1142 me EUN-Z-pentyl 2-Br-4, 5- (MeO) 1143 Me Inns (sn ₂ ohm) 2 2-C1-4.6- (MeO) 1144 me S (CH2CH2OMe) 2 2-C1-4.6- (Moscow Military District) 1145 Me YIVS2 2-C1-4, 6- (MeO) 1146 me EUN-Z-pentyl 2-C1-4.6- (MeO) 2? 1147 me ONSN (CH2OMe> 2 2-me-4, b- (MeO) 1148 me S (SNGCH2OMe) 2 2-me-4.6- (MeO) 1149 Me ONSN (EU) SNOME 2-Me-4,6- (MeO) 2? N 1150 Me ES2 2-Me-4.6- (MeO) 1151 me EUN-Z-pentyl 2-Me-4.6- (MeO) 1152 Me ONSN (EU) CH2CH2OMV 2-Me-4-MeOR 1153 Me INSN (me) CH ₂ CH ₂ ohm 2-Me-4-MeOR 1154 Me Inns (England) 2 2-MeO-4-MER 1155 me s (engengome) ₂ 2-Me0-4-MER 1156 Me ONSN (EU) SC ₂ OMe 2-Me0-4-Me? B 1157 Me yss rostsngsy 2-meO-4-meR 1158 Me ES2 2-meo-4-mer 1159 me EUN-Z-pen’IL 2-MeO-4-MER 1160 Me New Yorksngome 2-Me0-4-MER 1161 Me ONSN (Me) CH2CH2OMe 2-MeO-4-MeRP 1162 Not ONSN (CH ₂ OMe) 2 2-MeO-4-MER 1163 Me S (CH2CH2OMe) 2 2-MeO-4-MER 1164 Me ONSN (EU) SNOMOM 2-MeO-4-MeRP 1165 Me S (s-Pr) CH2CH2SY 2-MeO-4-MER 1166 Me ES2 2-MeO-4-MER 1167 Me EUN-3-; Pentyl 2-meO-4-MER 1168 Me ONSN (SNGOMe) 2 2-MeO-4-C1PB 1169 me s (engengome »2 2-MeO-4-S1RP 1170 me ONSN (EU) SNOME 2-MeO-4-С1₽Н 1171 Me ES2 2-MeO-4-C1PB 1172 me EUN-3- pentyl 2-MeO-4-C1PB

Applicability

SKP-K.1 receptor binding test to evaluate biological activity.

The following is a description of the isolation of cell membranes containing cloned human SKP-K.1 receptors for use in a standard binding assay, as well as a description of the assay itself.

Messenger RNA was isolated from the human hippocampus. This mRNA was back transcribed using oligo (c11) 12-18 and the coding region was amplified by PCR from the start codon to the stop codon. The resulting PCR fragment was cloned into the EcoCU rSEMU website. from where the insert was again extracted using X1y1 + XbA1 and cloned into the X1y1 + XBa1 sites of the rhzag vector (which contains the SMU promoter, ϊ'-splicing signals and early poly A §Y40 signals, Epstein-Barr virus replication source and selectable hygromycin marker). The resulting expression vector, called rysySCCRK, was transfected into 293ΕΒNΑ cells, and cells retaining this episome were selected in the presence of 400 μM hygromycin. Cells surviving after 4 weeks of selection in hygromycin were pooled, adapted for growth in suspension culture and used to prepare membranes for the binding assay described below. Then, individual aliquots of ~ 1 x 10 ⁸ suspended cells were centrifuged to obtain a pellet and frozen.

For the binding test, the frozen pellet described above containing 293ΕΒNΑ cells transfected with YSCP1 receptors is homogenized in 10 ml of ice-cold tissue buffer (50 mM HEPE8 buffer, pH 7.0, containing 10 mM MPS1 ₂ , 2 mM EGTA, 1 μg / l aprotinin, 1 μg / ml leupeptin and 1 μg / ml pepstatin). The homogenate is centrifuged at 40,000 x d for 12 minutes and the resulting pellet is re-homogenized in 10 ml of tissue buffer. After another centrifugation at 40,000 x d for 12 minutes, the pellet was resuspended to a protein concentration of 360 μg / ml for use in the test.

Binding tests are carried out in 96-well plates; each well has a capacity of 300 μl. To each well add 50 μl of dilutions of the test drug (final drug concentration is in the range of 10 ^-10 to 10 ^-5 M), 100 μl of ¹²⁵ 1-CKP sheep ( ¹²⁵ 1-o-CKP) (final concentration 150 pM) and 150 μl of the cell homogenate described above. The plates are then allowed to stand at room temperature for 2 hours before filtering the incubate through CP / P filters (pre-soaked with 0.3% polyethyleneimine) using a suitable cell collection. The filters are washed 2 times with ice-cold test buffer before removing individual filtrates and evaluating their radioactivity on a gamma counter.

Inhibition curves of ¹²⁵ 1-o-SCR binding to cell membranes at various dilutions of the tested drugs are analyzed using an iterative program for constructing LISC curves [R. PMcn8op ap4 O. Ko4bag4, Apa1. Vusyet. 107: 220 (1980)], which gives the values Κι inhibition, which are then used to evaluate biological activity.

A compound is considered active if it has a Κι value of less than ~ 10,000 nM to inhibit SCR.

Inhibition of ASC activity stimulated by adenylate cyclase.

Inhibition of the activity of adenylate cyclase, CKP-stimulated, can be performed as described by S. Vayadna ea al., 8upar8e, 1: 572 (1987). Briefly, tests are carried out at 37 ° C for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37 ° C), 10 mM MDCl ₂ ,

0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (1 BMX), 250 units / ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine-5'-triphosphate, 100 nM oSCR, antagonist peptides (in a concentration range of 10 ^{- 9} 10 ^-6 M / and 0.8 mg of the initial weight of wet tissue (~ 40-60 mg of protein). Reactions are initiated by the addition of 1 mM ATP / ³² R-ATP (~ 2-4 μCi / tube) and stopped by the addition of 100 ml 50 mM Tris-HC1, 45 mM ATP and 2% sodium dodecyl sulfate To monitor cAMP extraction, 1 μl of [ ³² N] -cAMP (~ 40,000 dec / min) is added to each tube before separation. Separation of [ ³² N] cAMP from [ ³² N] cATP performed after ovatelnoy elution column Eo ^ e, and alumina.

Biological test

The activity of ln yl yo compounds of this invention can be evaluated using any of the biological tests available and generally accepted in the art. Illustrative examples of such tests include the Acoustic Winches Test, the Climb Test, and the Chronic Introduction Test. These and other models applicable for testing the compounds of this invention have been described in C.XV. Vet4de ap4 A.R Oppa Vgash Ke8eagsy Keu1e ^ 8, 15:71 (1990).

The compounds of this invention are useful for treating imbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders and / or anxiety.

The compounds of this invention can be administered to treat these pathological conditions in such a way as to provide contact of the active agent with the site of action of this agent in the body of a mammal. These compounds may be administered by any conventional means available for use, together with pharmaceutical agents, either as an individual therapeutic agent or in a combination of therapeutic agents. They can be administered separately, but usually should be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and normal pharmaceutical practice.

The dose administered will depend on the purpose of application and known factors, such as the pharmacodynamic nature of the particular agent, and its mode of action and route of administration; on the age, weight and health of the recipient; the nature and severity of the symptoms; type of parallel (joint) treatment; frequency of administration; and desired effect. For use in the treatment of these diseases or conditions, the compounds of this invention can be administered orally daily at a dose of the active ingredient of 0.002-200 mg / kg body weight. Typically, a dose of 0.01-10 mg / kg in divided doses 1-4 times a day or a sustained sustained release preparation will be effective to obtain the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from ~ 1 to —100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of -0.5-95% by weight, based on the total weight of the composition.

The active ingredient may be orally administered in solid dosage forms, such as capsules, tablets, and powders; or in liquid forms, such as elixirs, syrups and / or suspensions. The compounds of this invention may also be administered parenterally in the form of sterile liquid dosage formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier, such as (but not limited to) lactose, starch, magnesium stearate, stearic acid or cellulose derivatives. Similar diluents can also be used for compressed tablets. Both tablets and capsules can be formulated as sustained release products to provide continuous release of the drug over a period of time. Compressed tablets may be coated with sugar or film to mask an unpleasant taste or to protect the active ingredients from the atmosphere or to provide selective destruction of the tablet in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring or flavoring and odor improving agents to facilitate patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar and glycol solutions, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering agents. Antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its salts and EDTA are also applicable. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in KepypHop'k P11agtasei11sa1 8s1spss5. Α. Οδοί, a standard reference in this field.

Applicable pharmaceutical dosage forms for the administration of the compounds of this invention can be illustrated as follows.

Capsules

A large number of dosage capsules are prepared by filling each of the standard two-piece hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules.

A mixture of the active ingredient in an edible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by positive displacement into gelatin to form soft gelatin capsules containing 100 mg of active ingredient. The capsules are washed and dried.

Pills.

A large number of tablets are prepared using conventional methods so that a single dosage form contains 100 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Suitable coatings may be applied to improve palatability or slow adsorption.

The compounds of this invention can also be used as reagents or standards in biochemical studies of neurological function, dysfunction and disease.

Although the invention has been described and illustrated in the form of some preferred options, other options will be apparent to those skilled in the art. Thus, the present invention is not limited to the specific options described and given as examples, but can be modified or changed without departing from the essence of the present invention, the full scope of which is defined by the attached claims.

Claims (23)

CLAIM 1. The compound of formula (1) (1) and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where A is N Ζ is SK ² ; Ag is selected from the group phenyl, pyridyl, wherein each Ag is optionally substituted with 1-5 K ⁴ groups; K ^{1 is} independently selected at each occurrence from the group H, _C1-C4 alkyl; K ^{2 is} independently selected from the group H, C 1 -C ₄ alkyl; K ^{3 is} selected from the group —H, OK ⁷ , NK ^6a K ^7a , or phenyl optionally substituted with 1-3 halogen atoms or morpholino; or —C1-C1 ₀ -alkyl optionally substituted with 1-3 substituents independently selected in each case from CO ₂ K ¹⁵ , NK ¹⁶ K ¹⁵ , phenyl optionally substituted with halogen; K ^{4 is} independently selected in each case from the group C1-C1 ₀ -alkyl, halogen, CH ₁ -C ₄ haloalkyl, iKK ⁷ , OK ⁷ ; K ⁶ , K ⁷ , K ^6a and K ^{7a are} independently selected in each case from the group H, C1-C1 ₀ -alkyl, C ₂ -C ₈ alkoxyalkyl, C ₄ -C1 ₂ -cycloalkylalkyl, each of which is optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, cyano, OK ^15, SOC ^15, SO2K ^15, NK ¹⁶ tO ^15, phenyl optionally substituted by halogen; K ¹⁵ and K ¹⁶ are independently selected at each occurrence from the group H, _C1-C6 alkyl; provided that when A is N Ζ is SK ² , K ² is H, K ³ is —OK ^7, and K ⁷ is H, K ^{1 is} not H; when A is N Ζ is SK ² , K ¹ is CH3 or C2H5, K ² is H and K ³ is OH, H, CH3, C ₂ H ₅ , C ₆ H ₅ , nC ₃ H ₇ , iso-C ₃ H ₇ , NCH ₄ H9 or N (€ ^ 5) 2, Ar is not phenyl or m-CH ₃ phenyl; when A is N Ζ is SK ² , K ² is H and Ar is pyridyl, and K ³ is NK ^6a K ^7a , K ^6a and K ^7a are not H or unsubstituted alkyl; when A is N Ζ is CK ² , K ¹ is methyl or ethyl, K ² is H and K ³ is H, OH, CH ₃ , C ₂ H ₅ , C ₆ H ₅ , nC ₃ H ₇ , C ₃ H ₇ , NH (nC ₄ H9) or MCXH-SH, Ar is not unsubstituted phenyl or methylphenyl; 2. The compound according to claim 1 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts and prodrugs, where Ag is phenyl, pyridyl, each of which is optionally substituted with 1-4 K ⁴ substituents. 3. The compound according to claim 2 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts and prodrugs, where A is N Ζ is SK ² , Ar is 2,4-dihydrophenyl, 2,4-dimethylphenyl or 2, 4,6trimethylphenyl, K ¹ and K ² are CH ₃ and K ³ is NK ^6a K ^7a . 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3. 6. The compound according to claim 1 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where K ³ is NK ^6a K ^7a or OK ⁷ . 7. The compound according to claim 1 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where Ag is phenyl, pyridyl and each Ag is optionally substituted with 1-4 K ⁴ substituents, and K ³ is NK ^6a to ^7a or OK ⁷ . 8. The compound according to claim 1 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where Ag is phenyl, pyridyl and each Ag is optionally substituted with 1-4 K ⁴ substituents, K ³ denotes NK ^6a K ^7a or OK ⁷ and K ¹ and K ^{2 are} independently selected from H, C ₁ -C ₄ alkyl. 9. The compound according to claim 6 or 8 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where K ^{6a is} independently selected from the group H, C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C! 2cycloalkylalkyl, each of which is optionally substituted with 1-3 substituents independently selected in each case from C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , CO2K ¹⁵ , NK ¹⁶ K ¹⁵ and phenyl optionally substituted with halogen; K ^{7a is} independently selected in each case from the group H, C5-C10-alkyl, C2-C8-alkoxyalkyl, C4-C12-cycloalkylalkyl, each of which is optionally substituted by 1-3 substituents independently selected in each case from C1C6-alkyl, C3 -C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , NК ¹⁶ К ¹⁵ , phenyl substituted by halogen. 10. The compound according to claim 6 or 8 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where K ^6a and K ^7a are the same and are selected from the group C1-C4 alkyl optionally substituted with 1 -3 substituents independently selected in each case from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , CO2K ¹⁵ , NK ¹⁶ K ^15, or phenyl optionally substituted with halogen. 11. The compound according to claim 6 or 8 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where K ^{6a is} selected from the group H, C1-Ci-alkyl, C2-C8-alkoxyalkyl, C4 -C12-cycloalkylalkyl, each of which is optionally substituted by 1-3 substituents independently selected in each case from C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , СО2К ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ and phenyl optionally substituted with halogen; K ^{7a is} selected from the group C1-C4-alkyl and each such C1-C4-alkyl is substituted by 1-3 substituents independently selected in each case from such substituents as C1-C6-alkyl, C3-C6-cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , CO2K ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen. 12. The compound according to claim 6 or 8 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, where K ^6a and K ^{7a are} independently H or C1-Ci-alkyl, each such is C1-Ci -alkyl is optionally substituted with 1-3 substituents independently selected in each case from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OK ¹⁵ , SOK ¹⁵ , CO2K ¹⁵ , ΝΚ ¹⁶ Κ ¹⁵ , phenyl optionally substituted with halogen. 13. The compound according to claim 1 of formula (50) Formula (50) and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts and prodrugs selected from the group consisting of a compound of formula (50), wherein K ³ is —KHCH (n-Pr) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (Ε1) (η-Βπ), K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes - (n-Rg) (CH _{2 and} -Rg), K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -MCHS (E1) (n-Vi), K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -MCHS (E1) (CH ₂ OME) K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -MCHS (CH ₂ OME) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes-NCHS (CH ₂ OE1) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes-INSN (E1) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ means -Ν (Με) (Ρ1Ί), K ^4a is C1, K ^4b denotes H, K ^4c is C1, Κ ^4ά is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (η-Ργ) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is C1, K ⁴⁰ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -№CHN (E1) (n-Rg), K ^4a is C1, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -MCHS (CH ₂ OME) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is Me; the compound of formula (50), where K ³ denotes-INSN (CH ₂ OME) ₂ , K ¹ ' ¹ denotes Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes-INSN (E1) (CH ₂ OME), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes-INSN (E1) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; a compound of formula (50), wherein K ³ is —OE1. K ^4a is C1, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; a compound of formula (50), wherein K ³ is —Ν (Εΐ) ₂ , K ^4a is Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ CH ₂ SC) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -NCHS (Me) (CH ₂ ΟMe), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes-OCH (E1) (CH ₂ OME), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes-Mn-Rg) (CH ₂ and-Rg). K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -NCHS (Me) (CH ^ (Me) ₂ ), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ i-Pr) (CH ₂ CH ₂ SC), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ n-Pr) (CH ₂ CH ₂ SC), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ n-Vi) (CH ₂ SC), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -NCHS (Εΐ) (CH ₂ ΟMe), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is Me; the compound of formula (50), where K ³ means -ΝΉίΉ ^ Ι ^, K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is Me; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ 0Me) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is Me; the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ 0Me) ₂ , K ^4a means Br, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (E1) (CH ₂ 0Me), K ^4a means Br, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Ν (Εΐ) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is Me; the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ 0E1) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is Me; the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ CH ₂ 0Me) (CH20Me), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is Me; the compound of formula (50), where K ³ denotes morpholino, K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ , K ^4a means Br, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (E1) ₂ , K ^4a means Br, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (E1) ₂ , K ^4a means Br, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; a compound of formula (50), wherein K ³ is —HH (i-Pr). K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ 0Me) ₂ , K ^4a means ΟΝ, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (i-Pr) (CH ₂ CH ₂ SC), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ^{4 <1} is H and K ^4e is Me; the compound of formula (50), where K ³ means -SCH (CH ₂ 0Me) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c is Br K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ 0Me) (CH2CH2OMe), K ^4a means Me, K ^4b denotes H, K ^4c is Br K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (CH ₂ 0Me) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c is 0 Me, K ^{4 <1} denotes Me and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ 0Me) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c stands for OMe, 100 I ⁴⁶ stands for Me and I ^4e is H; the compound of formula (50), where I ³ denotes -№CHN (E1) ₂ , I ^4a stands for Me, I ^4b stands for H, I ^4c stands for OMe, I ⁴⁶ stands for Me and I ^4e is H; the compound of formula (50), where I ³ denotes -Ν (Εΐ) ₂ , I ^4a stands for Me, I ^4b stands for H, I ^4c stands for OMe, I ⁴⁶ stands for Me and I ^4e is H; the compound of formula (50), where I ³ is —NCH (CH ₂ OMe) ₂ , I ^4a is C1, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ denotes -NCHS (Εΐ) (CH ₂ OMe), I ^4a is C1, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means - ^ CH ₂ CH ₂ OMe) ₂ , I ^4a is C1, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ is —NCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), I ^4a is C1, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ denotes - ^ i-Pr) (CH ₂ CH ₂ C№), I ^4a stands for Me, I ^4b stands for H, I ^4c stands for OMe, I ⁴⁶ stands for Me and I ^4e is H; the compound of formula (50), where I ³ denotes - ^ i-Pr) (CH ₂ CH ₂ C№), I ^4a is C1, I ^4b stands for H, I ^4c stands for C1, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means (§) -NCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), I ^4a is C1, I ^4b stands for H, I ^4c stands for C1, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ is —NCHH (CH ₂ OMe) (CH — CHOMe). I ^4a is C1, I ^4b stands for H, I ^4c stands for C1, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means -ΝΉΟ ^ Εΐ) ^ I ^4a stands for Me, I ^4b stands for H, I ^4c is Br I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means - ^ CH ₂ CH ₂ OMe) ₂ , I ^4a stands for Me, I ^4b stands for H, I ^4c is Br I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ denotes-NH (CH ₂ OMe) (CH ₂ -RG), I ^4a stands for Me, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means - ^ CH ₂ CH ₂ OMe) ₂ , I ^4a stands for Me, I ^4b stands for H, I ^4c is H, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means - ^ CH ₂ CH ₂ OMe) ₂ , I ^4a stands for Me, I ^4b stands for H, I ^4c stands for NMe ₂ , I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ denotes -NCH (CH ₂ OMe) (n-P ^), I ^4a stands for Me, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and I ^4e is H; the compound of formula (50), where I ³ means -NCH (CH ₂ OΕΐ) (Εΐ), I ^4a stands for Me, I ^4b stands for H, I ^4c stands for Me, I ⁴⁶ stands for H and 101 102 K ^4e is H; the compound of formula (50), where K ³ means - ^ C ^ C ^ OMe) (CH ₂ CH ₂ OMe), K ^4a means Me, K ^4b denotes H, K ^4c is NMe K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (M, K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ SOCHER ^, K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; a compound of formula (50), wherein K ³ is —NCHH (CH ₂ OMe) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (M, K ^4a means Me, K ^4b denotes H, K ^4c is Br K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (M, K ^4a is C1, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ SOCHER ^, K ^4a is C1, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes - ^ SOCHER ^, K ^4a means Me, K ^4b denotes H, K ^4c is NMe ₂ , K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes (b) -CHNSN (CH ₂ OMe) (CH ₂ CH ₂ OMe), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -WELL) (CH ₂ CH ₂ OMe), K ^4a means Me, K ^4b denotes H, K ^4c means Me, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes (b) -CHFN (CH ₂ OMe) (W) K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -WELL) (WHICH), K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; a compound of formula (50), wherein K ³ is —X (i-Pr) (CH ₂ CH ₂ CX), K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -YNDA) (CH ₂ SK), K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (M, K ^4a means Me, K ^4b means Me, K ^4c stands for OMe, K ⁴⁴ is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OMe) (CH ₂ CH ₂ OH), K ^4a is C1, K ^4b denotes H, K ^4c is C1, 103 104 K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ 0Me) ₂ , K ^4a means Me, K ^4b means Me, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (E1) ₂ , K ^4a means Me, K ^4b means Me, K ^4c is 0 Me, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -H (CH ₂ and-Rg) (n-Rg), K ^4a means Me, K ^4b denotes H, K ^4c is C1, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (i-Pr) (CH ₂ CH ₂ SC), K ^4a means Me, K ^4b means Me, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (E1) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (E1) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (CH ₂ CH ₂ OME) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes-ZhSN (E1) (CH ₂ 0Me), K ^4a is C1, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (E1) ₂ , K ^4a is C1, K ^4b denotes H, K ^4c is CH K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ denotes -Y (i-Rg) (CH ₂ CH ₂ CH), K ^4a is C1, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ means - ^ 04 (^^^, K ^4a is C1, K ^4b denotes H, K ^4c is C1, K ^{4 <1} is H and K ^4e is H and a compound of formula (50), where K ³ is —Y (CH ₂ CH ₂ 0Me) ₂ , K ^4a means Me, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} is H and K ^4e is H; the compound of formula (50), where K ³ means - ^ 64 ^ 1) ^ K ^4a is C1, K ^4b denotes H, K ^4c stands for OMe, K ^{4 <1} denotes P, K ^4e denotes N. 14. The compound according to claim 1 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts and prodrugs, wherein said compound is 4- (bis- (2methoxyethyl) amino) -2,7-dimethyl-8 - (2-methyl-4methoxyphenyl) - [1,5-a] pyrazolo-1,3,5-triazine. 15. The compound according to claim 1 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts and prodrugs, wherein said compound is 4- (bis- (2methoxyethyl) amino) -2,7-dimethyl-8 - (2,5-dimethyl-4-methoxyphenyl) - [1,5-a] pyrazolo-1,3,5triazine. 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1. 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 13. 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 14. 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 15. 105 106 20. A method for treating disorders caused or exacerbated by CBP in mammals, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1. 21. A method for treating disorders caused or exacerbated by CBP in mammals, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 13. 22. A method for treating disorders caused or exacerbated by CBP in mammals, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 14. 23. A method of treating disorders caused or exacerbated by CBP in mammals, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 15.