UA75124C2 - Pyrazole derivatives for the treatment of hiv - Google Patents

Abstract

This invention relates to pyrazole derivatives of the formula, or pharmaceutically acceptable salts, solvates or derivative thereof, wherein R1 to R4 are defined in the description, and to processes for the preparation thereof, intermediates used in their preparation of, compositions containing them and the uses of such derivatives. The compounds of the present invention bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. As such the compounds of the present invention are useful in the treatment of a variety of disorders including those in which the inhibition of reverse transcriptase is implicated. Disorders of interest include those caused by Human Immune deficiency Virus (HTV) and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS). , (I)

Description

in MAZA", -(C1-Cv alkylene)-MA?A?, Ci-Cv alkyl, fluoro(Ci-Cv)alkyl or C3-C7 cycloalkyl; oh Mm-Z! (I) And? is a four-seven-membered saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen atoms, or (ii) 1 nitrogen atom and 1 or its pharmaceutically acceptable salt or solvate, an oxygen atom or 1 sulfur atom, or (iii) 1 oxygen atom in which: or a sulfur atom, said heterocyclic group is or B" is H, C1-C6 alkyl, C3-C7 cycloalkyl, optionally substituted oxo, C1-C6 alkyl, C3 - phenyl, benzyl, halogen, -CM, -ОВ"7, - C cycloalkyl, -50285, -"СОМА?В", -СООН", -СО-

СО»2ВЕ, -СОМА5В!О, BZ or P», the mentioned Ci-Ce al- (C1-Cv alkylene)-OB5 or -СОВ5 and optionally ring, C3-C7 cycloalkyl, phenyl and benzyl are non- substituted by a carbon atom that is not adjacent to a necessarily substituted halogen, -СМ, -ОВ'У, heteroatom, halogen, -ОВ?, -МА?В", (- 5(О)хХВ'?, -СбО28 "E, -SOMAZV!, -OSOMARVYA, S- MA?SOV?, -MASOOV?, -MAZSOMAUV?, -MA?5O" Vo

MAZSO»VYA, -MVYAV", -MASOV'YA, -502MAVO, - or -SM;

MAZSOMA5V!E, -MA55O»V': or Vo: and V? is H, E8, VU, BZ, C1-Cv alkyl, C3-C7u cycloal-

IN? is H, C-Cv alkyl, C3-Cv alkenyl, C3-Cv alkyl or -(C1-Cv alkyl)-(C3-C7 cycloalkyl), zganyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, given Ci-Cv alkyl and C3-C7 cycloalkyl are non-phenyl, benzyl, R3 or P, the mentioned Ci-Cv al- necessarily substituted -OH", -OB"Z, VU, VU, VZ or ring, C3-C7 cycloalkyl, phenyl and benzyl are non- -SO!Z; necessarily substituted halogen, -OB?, -OB", - B" is H, Ci-Ce alkyl or C3-C7 cycloalkyl,

СМ, -СО2В", -OSOMAZV?, -СОМАВ5, -- the mentioned C-Cv alkyl and C3-C7 cycloalkyl are not

С(-MAUMAOV?, -"SOMA?MAV?, -MAeVe, -MAZV", - necessarily replaced by -OV?, -MAUV?, -MA?SOVU, -

MAZSOV?, -MASOVZ, -MASOV!:, -MAZSO»V, - SOM, VZ or g;

MASOMAZV, -5O2MAZVH, -MA?5O»2VU, - B!2 is a C-Sve alkyl substituted by B, VU, -ОВ5, -

MAZBO2MAZN", VAZ or in; SOM, -MA?SOVZ or -MAZV?; or B! and Pg, when taken together, represent un- VAZ is phenyl optionally substituted by halogen, branched C3-C4 alkylene optionally substituted, -СМ, -СОВ5, -СОМАЗАВ», -502МА5В5, - substituted oxo, where necessarily one methylene MA?BO2B?, -OB, -MAZVU, -(C1-Cv alkylene)-MAZVU, the group of the mentioned C3-C4 alkylene can be replaced by C-Cv alkyl, halo(Ci-Cv)alkyl or C3- C7 on an oxygen atom or a nitrogen atom, the mentioned atom is a cycloalkyl; and nitrogen is optionally substituted Vo; heh, 1 or 2;

AZ is H, C-Cv alkyl, C3-C7 cycloalkyl, phenyl, provided that (a) when B! and C are both phenyl, lam, benzyl, halogen, -CM, -OB", -CO285, - B? is not methyl; and (b) when E! is ethoxy and BZ is ethoxy-

SOMBAZA?, VZ or RU, the mentioned Ci-Cv alkyl, C3-C7 sycarbonyl, P: is not phenyl. cycloalkyl, phenyl and benzyl are optionally substituted 2. The compound according to item 1, in which B', when combined with a halogen, -СМ, -ОВ?, -СО285, -СОМВАЗВУ, - separately, is H , C-Cv alkyl, C3-C7 cycloalkyl

OSOMAZ?, -MAZSO»B?, -MAUVYA, -MASOV", - lom or -OB", the mentioned C-Ce alkyl and C3-C7 cycloa-

OMA, -MAZSOMAUV», -MA?5О»В», VZ or ve; alkyl is an optionally substituted halogen, -CM, -

B" is phenyl, naphthyl or pyridyl, each is ОВ, 5(0)ХВ!9, -"С02819, -"SOMA?VO, -"OSOMAZVO, - optionally substituted RU, MAZSO»V'YA, -MATOV ", -MASOV!Ya, -502MAZVO, - halogen, -CM, C1-Cv alkyl, C1-Ce haloalky- MAZSOMAZV!E, -MA55O2B!O or 29, scrap, C3z-C7 cycloalkyl, C-Cv alkoxy, - 3. A compound according to item 1 or 2, in which E!, when

SOMAZA", OB, 50.88, O-(C1-Cv alkylene)- taken separately, is H, C1-Cv alkyl, C3-C7 cycloal-

SOMEZV?, O-(C1-Cv alkylene)-MA?A? or O-(C1-Cv alkyl or -OB'", said C1-Cv alkyl is non-alkylene)-OB; necessarily substituted halogen, -OB'E, -MA'EV!, each RE? is independently or H, C1-Cv alkyl or C3- -MA?СОВ' or 29,

WITH; cycloalkyl or, when two C groups are attached 4. A compound according to any of the preceding clauses, to one nitrogen atom, these two groups taken together with wherein P, when taken alone, is H, C1-C6 alkyl, a nitrogen atom, to which they are attached, represented by Ca-Cv alkenyl or P, said Ci-Cv alkyl is azetidinyl, pyrrolidinyl, piperidinyl, optionally substituted halogen, -OB?, -OB", - mopiperidinyl, piperazinyl, homopiperazinyl or CM, -СО287, -OSOMAV5, -SOMAZV", - morpholinyl, mentioned azetidinyl, pyrrolidinyl, pi- С(-MAZ)MAZOV?, -"SOMAZMAA", -MAeVe, -MAZV/?, - peridinyl, homopiperidinyl, piperazinyl, homopi- MASOVU, -MAZSOVU, -MASOV':, -MASO»B», - perazinil and morpholinyl are optionally substituted MAZSOMAUVU, -BO2/MA?А?, -MA?5O»2VU, VU or Z.

C1-Sevier alkyl or C3-C7 cycloalkyl; 5. A compound according to any of the preceding clauses, each R is independently either H, C1-C6 alkyl, or in which B, when taken alone, is H, C1-C6 alkyl,

C3-C7 cycloalkyl; C3-Cv alkenyl or P, the mentioned Ci-Ce alkyl is

B" is C-Cv alkyl or C3-C7 cycloalkyl; optionally substituted -ОВ5, -ОВ82, -СМ, -

VAZ is a five- or six-membered aromatic hete-СО2В', -СОМАЗВ5, -С(-МА)МАРОВ, -rocyclic group containing (i) from 1 to 4 atoms-SOМАМАЗ», -МАЯВЯ, -МАЗВ!2, - MAZSOV8, /- a nitrogen atom, or (ii) 1 or 2 nitrogen atoms and 1 oxygen atom - MASS", -MA?СО2ВУ, VZ or RU. niu or 1 sulfur atom, or (iii) 1 or 2 oxygen atoms 6 The compound according to clause 1, in which B1 and B2, when either sulfur, said heterocyclic group are not taken together, represent an unbranched C3-Ca necessarily substituted by halogen, oxo, -CM, - alkylene optionally substituted by oxo , where one

Sov, -СОМА5В»5, -502М8585, -МА»5О»В?, -ОВ5, - the methylene group of the mentioned C3-Ca alkylene substituted

not by an oxygen atom or a nitrogen atom, mentioned by piperidinyl, azepinyl, oxetanyl, tetrahyd - the nitrogen atom is optionally substituted by Vo. rofuranil, tetrahydropyranil, oxepinil, 7. The compound according to item 1 or 6, in which B! and Pg, morpholinyl, piperazinyl, or diazepinyl, when taken together, represent an unbranched each is an optionally substituted oxo, C1-C8 alkyl-propylene in which one methylene group is replaced by a lam, C3-C7 cycloalkyl, -5028?, -SOMVA? B?, - an oxygen atom or unbranched butylene, in СООВ, -СО-(C1-Ce alkylene)-ОБ? or -SOV? and some one methylene group is replaced by an atom necessarily substituted by a carbon atom that is not nitrogen, the mentioned propylene and butylene are not necessarily adjacent to a heteroatom, halogen, -ОВ", - substituted by oxo and the mentioned nitrogen atom is not MAZA?, -MAZSOV, -MASOOV, -MAZSOMAZV, - must be replaced by EO. MA?BO»2B or -SM. 8. Compound according to any of the previous clauses, 18. Compound according to any from the previous clause, in which BZ is H or C1-C3 alkyl, the mentioned C1-C4 alkyl, in which ER is azetidinyl, piperidinyl, tetraalkyl is an optionally substituted halogen, -CM, - hydrofuranyl, piperazinyl or morpholinyl,

OVU, -SO»В?, -SOMAZV, -"OSOMAZV?, -MA?SO»VU, - each is an optionally substituted oxo, C1-Cv alkyl-

UIA? -MAxSOV?, -502MA?B?, -MASOMAZV?, - scrap, C3-C7 cycloalkyl, -5028?, -SOMVA?B?, -

MAZ5O2VU, VU or RU. СООВ, -СО-(С1-Св alkylene)-ОБЗ or -СОВЗ and not- 9. A compound according to any of the previous clauses, necessarily substituted on a carbon atom, which is not in which C is H or Si-Св alkyl It is adjacent to a heteroatom, a halogen, -ОВ»5, - 10. A compound according to any of the previous points - MA? -MAZSOOV5, -MAZSOOV, MAZSOMAV, - tiv, in which 27 is phenyl, optionally substituted by MA?5О»В: or -SM.

VU, halogen, -CM, C1-Ce alkyl, C1-Ce halogen- 19. A compound according to any of the previous points- alkyl, C3-C7 cycloalkyl, C1-C8 alkoxy, - tives, in which RE? is azetidinyl, piperidinyl, tetra-

SOMA»UA?, ОВ, 50ХАЭ, 0-(C1-Ce alkylene)- hydrofuranyl, piperazinyl or morpholinyl,

SOMEZV?, O-(C1-Cv alkylene)-MA?A? or O-(C1-Cv) each is an optionally substituted C-C alkyl, - alkylene)-ORE, or naphthyl. OA, -СОМА?А?, -СООВ?, -СО-(С1-Св alkylene)- 11. A compound according to any of the previous clauses- ОВ: or -СОВЗ and optionally substituted by atoms, in in which 7 is phenyl substituted by RU, halogen, mu of carbon that is not adjacent to the heteroatom, -CM, C1i-Cv alkyl, Ci-Cv haloalkyl, C3-C7 OB? or - MAZSONVH. cycloalkyl, C-C-Alkoxy, -SOMAZV?, ОВ, 20. The compound according to any of the previous clauses - which BO is H, 28, VU, VZ, C1-Se alkyl or - alkylene)-MA?А? or O-(C1-Cv alkylene)-OR. (C1-C8 alkyl)-(C3-C7 cycloalkyl), mentioned Ci-C8 12. The compound according to any of the previous clauses- alkyl is optionally substituted -ОВ?, -ОВ"С, B8, tiv, in in which 7 is phenyl, substituted by RU, halogen, VU, BZ or -SOV'Z. -CM, C1-C8 alkyl, C1-C8 haloalkyl, C3-C7 21. A compound according to any of the previous clauses - cycloalkyl or C - C 1 -C 6 -alkyl, in which BO is H, 28, VU, BZ, C 1 -C 6 alkyl or - 13. The compound according to any of the previous clauses - (C 1 -C 6 alkyl)-(C 3 -C 7 cycloalkyl), said C1-Cv tiv, in which 27 is phenyl substituted with halogen, -CM alkyl is optionally substituted -OB? or 3. or C1-Cv alkyl. 22. A compound according to any of the preceding clauses- 14. A compound according to any of the previous clauses, in which B! is H or C-Ce alkyl, said C-tiv, in which BZ is pyrrolyl, imidazolyl, pyrazolyl, C-Ce alkyl is optionally substituted -OB?, - MAZV?, scrap, 1,2,3-triazolyl, 1,2,4-triazolyl, tetra- -MA?SOV", -"SOMAZVU, VZ or RU. zolyl, oxazolyl, isoxazolyl, thiazolyl, 23 A compound according to any of the previous clauses - isothiazolyl, 1,2,4-oxadiazolyl, 1,8,4-thiols, in which B!! is H or Ci-Cv alkyl, mentioned Schio- oxadiazolyl, furanyl, thienyl, pyridinyl, Cv alkyl is optionally substituted -ОВ5 or - pyridazinyl, pyrimidinyl or pyrazinyl, MASSOVU, each is optionally substituted halogen, -СМ, 24 A compound according to any of the preceding clauses, -СОВ5, -СОМА?В?, -5О02МAZВ, -МА?5О»В?, -ОВУ, - tives, in which В" is Si1-Ca alkyl substituted by RU , VU, -

MAV", -(C1-Ce alkylene)-MA?A?, Ci-Cv alkyl, OB, -SOMAUV", -MAZSOV? or - MAZ AH. fluoro(C1i-C8)alkyl or C3-C7 cycloalkyl. 25. A compound according to any of the previous clauses 15. A compound according to any of the previous clauses, in which B" is C1-C6 alkyl substituted by P, -OB5, in which KZ is imidazolyl , pyrazolyl, 1,2,4- -MAZSOVZ? or -MAZV5. triazolyl, 1,2,4-oxadiazolyl, 1,3,4- 26. The compound according to any of the previous clauses - oxadiazolyl, pyridinyl, pyrazinyl or pits, in which E!Z is phenyl, substituted by halogen, - rimidinyl, each is optionally substituted by СМ, -СОВ5, -СОМАУА?, -5О2МАВ?, -МА?5О»ВУ, - halogen, -СМ, -SOV?, -SOMA?B?, -5O2MVAV, - OB, -MA?A?, -(C1-Cv alkylene)-MA?B?, Ci-Cv alkyl-

MA?BO2B-, -OB5, -MARVA?, -(C1-Cv alkylene)-MAV?, scrap, halogen (C1i-Cv)alkyl or C3-C7 cycloalkyl-

C-Cv alkyl, fluoro(C1-Cv)-alkyl or C3-C7 cycle. lower alkyl 27. A compound according to any of the preceding clauses, 16. A compound according to any of the preceding clauses, in which E!Z is phenyl, substituted by halogen, in which P8 is imidazolyl, pyrazolyl, 1, 2,4- CM, -SOMA5V», -BO»2MA?VZ or -OVH. triazolyl, 1,2,4-oxadiazolyl, 1,3,4- 28. A compound according to any of the preceding clauses- oxadiazolyl, pyridinyl, pyrazinyl or pita, which is 2-|4-(3,5 -dichlorophenoxy)-3,5-rimidinyl, each is optionally substituted - dimethyl-1H-pyrazol-1-yl|ethanol;

OVU, -MA?V? or C-Cv alkyl. 2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1- 17. The compound according to any of the previous points-yl|ethanol; tives, in which EZ is azetidinyl, tetrahydropyrrolyl, 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole;

14-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl|ethanol; yl|Iacetonitrile; 2-(I4-(2,5-difluorophenoxy)-3,5-diethyl-1H-pyrazole-1- 5-(C4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1 - yl|ethanol; yl|methyl)-1H-pyrazol-3-ol; 2-I(I4-(3,5-difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-6-14-( 3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl|ethanol; yl|methyl)-2-methyl-4(ZH)-pyrimidinone; 4-(3,5-dichlorophenoxy)- 3,5-diethyl-1-(2-2-amino-6-(4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-methoxyethyl)-1H-pyrazole; pyrazol-1-yl| Imethyl)-4(ZH)-pyrimidinone; 4-(3,5-dichlorophenoxy)-3,5-diethyl-1-2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole -1-(methoxymethyl)-1H-pyrazole; yl-|-M-hydroxyethaneimidamide; 4-(3,5-dichlorophenoxy)-3,5-diethyl-1-methyl-1H-methyl I4-(3,5- dichlorophenoxy)-3,5-diethyl-1H-pyrazole; pyrazol-1-ylIIacetate; 4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazole; 2-I4-(3,5-dichlorophenoxy) -3,5-diethyl-1H-pyrazol-1-4-(2-14-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-yl|acetamide; 1-yl|phiethylmorpholine; 2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-M-(2-4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole - il|Iats ethohydrazide; 1-ylethyl)-N-(2-methoxyethyl)amine; 5-(C4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-1-11-(2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H) - yl|methyl)-1,3,4-oxadiazol-2-pyrazol-1-yl|ethyl)-4-(ZH)-one; piperidinyl)ethanone; 2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-M-(2-4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole - yl|stylamine; 1-yl|ethyl)-M,M-dimethylamine; 3-14-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1- -(2-(2-(4-(3,5-dichlorophenoxy)-3,5-diethyl-1H - yl|methyl)-1,2,4-oxadiazol-5-ol, pyrazol-1-yl|styl)amino)ethylacetamide; 5-(C4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-M-(2-4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole - yl|methyl)-1,3,4-oxadiazol-2-amine; 1-yl|ethyl)-M-methylamine;

M-(2-I(I4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazole- M-(2-4-(3,5-dichlorophenoxy)-3,5-diethyl-1 N-pyrazol-1-ylethyl)-2-methoxyacetamide; 1-ylethyl)-N-(tetrahydro-2-furanylmethyl)amine;

M-(2-I(I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-3-C4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole- 1- 1-yl|ethyl)-2-pyridinecarboxamide; yl|methylimorpholine;

M-(2-I(I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-(3-azetidinyl)-4-(3,5-dichlorophenoxy)-3,5- diethyl-1-yl|ethyl)-2-pyrazinecarboxamide; 1H-pyrazole; 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-7-(3,5-dichlorophenoxy)- b-ethyl-2,3-yl|Hyxybenzonitrile; dihydropyrazoloi|5,1-5111,3|oxazole; 4-(3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl- 4-(3,5-dichlorophenoxy)-3,5-dimethyl-1H-pyrazole; oxy)-3,5-dimethylbenzonitrile; 1-(4-(3,5-dichlorophenoxy)-3,5-diethyl-1H -pyrazole-1-

C-chloro-4-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-yl|-2-propanol; 4-yl|oxy)benzonitrile; 2-(2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-5-(I3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-1 -yl)ethoxy)ethanamine; yl|oxy)-2-fluorobenzonitrile; 4-C4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-2-I4-(4-chlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl|Imethylumorpholine; il|ethanol; 4-(3,5-dichlorophenoxy)-3-methyl-5-|(2-methyl-1 H- 2-I4-(3-chlorophenoxy)-3,5-diethyl-1 H-pyrazole-1-imidazole- 1-yl)methyl|-1H-pyrazole; il|ethanol; 2-I(I4-(3,5-dichlorophenoxy)-3-ethyl-5-methoxy-1 H- 2-I4-(2-chlorophenoxy)-3,5-diethyl-1 H-pyrazole-1-pyrazole- 1-yl|ethanol; yl|ethanol; 1-C4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-2-14-(2,6-dichlorophenoxy)-3,5-diethyl -1 H-pyrazol-1-yl|methyl)-1 H-1,-2,4-triazole; il|ethanol; 3-(3,5-diethyl-1H-pyrazol-4-yl)oxy|benzonitrile; 2-I4-(2,3-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-3-(11-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl| ethanol; yl|Xysifbenzonitrile; 2-I4-(2,4-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1- 2-I(I4-(3-cyanophenoxy)-3,5-diethyl-1H -pyrazol-1-yl|ethanol; yl|acetamide; 2-13,5-diethyl-4-(2-fluorophenoxy)-1H-pyrazol-1-ethyl 114-(3-cyanophenoxy)-3,5-diethyl -1H-pyrazol-1-yl|ethanol; yl|Iacetate; 2-3,5-diethyl-4-(3-fluorophenoxy)-1H-pyrazol-1-1-allyl-4-(3,5-dichlorophenoxy) )-3,5-diethyl-1H-yl|ethanol; pyrazole; 2-I4-(3,5-dimethylphenoxy)-3,5-diethyl-1H-pyrazole-M-DC4-(3,5-dichlorophenoxy )-3-methyl-1H-pyrazol-5-1-yl|ethanol; yl|Imethyl)-Im-(4-2-13,5-diethyl-4-(4-fluoro-3-methylphenoxy)-1 N-methoxybenzyl)amine; pyrazol-1-yl|ethanol; M-(cyclopropylmethyl)|4-(3,5-dichlorophenoxy)-3- 2-I4-(2,5-dichlorophenoxy)-3,5-diethyl- 1H-pyrazol-1-methyl-1H-pyrazol-5-yl|methanamine; yl|ethanol; I4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl|- 2-I4- (2,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-M,M-dimethylmethanamine; yl|ethanol; I4-(3,5-dichlorophenoxy)-3 -methyl-1H-pyrazol-5-yl|-2-I4-(3,4-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-M-methylmethanamine; il|ethanol; 1-C4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-2-I4-(2,6-difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl| methyl)-4-methylpiperazine;

1-14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazole-5-4-((3-(3,5-dichlorophenoxy)-2-ethyl-6, 7-yl|methyl)- 4-dihydropyrazolo|1,5-a|pyrazine-5(4H)-piperidinocarboxamide; yl)umethyl-benzonitrile;

M-14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-3-(3,5-dichlorophenoxy)-2-ethyl-5-(4-methoxybenzyl)-yl|methyl)- 2-methoxyethanamine; 4,5,6,7-tetrahydropyrazolo|1,5-a|pyrazine; 1-acetyl-4-(14-(3,5-dichlorophenoxy)-3-methyl-1 H- (1-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H- pyrazol-5-yl|methyl/)piperazine; pyrazol-5-yl|Imethanol; -(2-(14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-2-I(I4-( 3,5-dichlorophenoxy)-5-"ethoxymethyl)-3-ethyl-5-yl|methyl)amino)ethyl|acetamide; 1H-pyrazol-1-yl|ethylamine;

M-(1-14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazole-2-I(I4-(3,5-dichlorophenoxy)-3-ethyl-5-(1H-pyrazole-1 -

B-yl|methyl)-4-ylmethyl)-1H-pyrazol-1-yl|ethylamine; piperidinyl)acetamide; M-(11-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1-14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazole-5-1H- pyrazol-5-yl|methyl)-Nm-(4-methoxybenzyl)amine; yl|methyl)-4-methoxypiperidine; 4-(I411-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-

C-chloro-5-((3,5-dimethyl-1H-pyrazol-4-1H-pyrazol-5-ylmethyl)amino)methyl|benzonitrile; yl)oxy|benzonitrile; 2-I5-K(4-acetyl-1-piperazinyl)methyl|-4-(3-,5-3-5-(Aminomethyl)-3-methyl-1H-pyrazol-4-yl|oxy)-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl|ethylamine;

B-chlorobenzonitrile; M-(2-411-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-

C-chloro-5-|C-methyl-5-(1-piperazinylmethyl)-1H-ethyl-1H-pyrazol-5-yl|methyl)amino)ethyl|acetamide; pyrazol-4-yl|oxyphenzonitrile; I4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazole-5-

C-chloro-5-((5-((4-cyanobenzyl)amino|methyl)-3-yl|Imethanamine hydrobromide; methyl-1H-pyrazol-4-yl)oxy|benzonitrile; M-DC4-(3,5 -dichlorophenoxy)-3-methyl-1H-pyrazole-5-

C-chloro-5-(C-methyl-5-|4-(methylsulfonyl)-1-yl|methyl)-N-(4-fluorobenzyl)amine; piperazinyl|methyl)-1H-pyrazol-4-4-((414-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl)oxy|benzonitrile; yl|methyl)amino)methylbenzonitrile ;

3-chloro-5-(5-(|4-(methoxyacetyl)-1- 3-chloro-5-(1,3,5-trimethyl-1H-pyrazole-4-piperazinyl|methyl)-3-methyl-1H -pyrazol-4-yl)oxy|benzonitrile; yl)oxy|benzonitrile; 3-chloro-5-I(5-(((4-cyanobenzyl)amino|methyl)-1,3- methyl 4-1C4-(33-chloro-5-cyanophenoxy)-3-methyl-1H-dimethyl- 1H-pyrazol-4-yl)oxy|benzonitrile;pyrazol-5-yl|methyl)-1-piperazinecarboxylate; 3-chloro-5-11-(2-hydroxyethyl)-3,5-dimethyl-1H-4-14-(3-chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-4-yl! ioxyphenzonitrile; pyrazole-5-3-chloro-5-15-((4-cyanobenzyl)amino|methyl)-1-(-2-yl|methyl)iamino)methyl|benzenesulfonamide; hydroxyethyl)-3-methyl-1H-pyrazol-4-4-(3,5-dichlorophenoxy)-5-(methoxymethyl)-3-methyl- yl|Xyphbenzonitrile; 1H-pyrazole; 4-((4-(3-chloro-5-cyanophenoxy)-3-methyl-1 H-

3-tert-butyl-4-(3,5-dichlorophenoxy)-5-methyl-1H-pyrazol-b5-yl|methylamino)methyl|benzamide; pyrazole; 3-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-4-(3,5-dichlorophenoxy)-3-ethyl-5-methyl-1H-pyrazole; yl|oxy)-5-fluorobenzonitrile; 4-cyano-M-14-(3,5-dichlorophenoxy)-3-methyl-1H-3-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-pyrazol-5-yl Imethylbenzamide; yl|oxy)-5-methylbenzonitrile;

3-cyano-M-14-(3,5-dichlorophenoxy)-3-methyl-1H-5-13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-pyrazol-5-yl Imethylbenzamide; yl|oxyisophthalonitrile;

M-14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-3-chloro-5-1|3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-yl |methyl)-M-(3-pyridinylmethyl)amine; 4-yl|oxyrfbenzonitrile; 3-(5-(4-acetyl-1-piperazinyl)methyl|-3-methyl-1H- 3-(3,5-diethyl-1H-pyrazol-4-yl)oxy|-5-pyrazol-4- iloxy)-5-chlorobenzonitrile; fluorobenzonitrile;

C-chloro-5-((5-((4-cyanobenzyl)(methyl)amino|methyl)y-5-(3,5-diethyl-1H-pyrazol-4-yl)oxy|isophthalonitrile;

3-methyl-1H-pyrazol-4-yl)oxy|benzonitrile; 3-(3,5-diethyl-1H-pyrazol-4-yl)oxy|-5-

Z-chloro-5-I(5-((4-cyanobenzyl)(2-methylbenzonitrile; hydroxyethyl)amino|methyl)-3-methyl-1H-pyrazole-4-Z-chloro-5-((3,5- diethyl-1H-pyrazol-4-yl)oxy|benzonitrile; yl)oxy|benzonitrile;

C-chloro-5-((3-methyl-5-|(2-methyl-1H-imidazol-1-3-11-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl )umethyl|-1H-pyrazol-4-yloxy)benzonitrile; yl|oxy)-5-methylbenzonitrile; 2-(4-(3,5-dichlorophenoxy)-3-methyl-5-/|(3-3-11-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4-pyridinylmethyl)amino |methyl)-1H-pyrazol-1-yl|oxy)-5-chlorobenzonitrile; il)/ethanol; 5-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-5-((3-isopropyl-5-methyl-1H-pyrazol-4-yl|oxyisophthalonitrile; yl)oxy| isophthalonitrile; 3-(11-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4-5-(1-(2-hydroxyethyl)-3-isopropyl-5-methyl-1H-yl|oxy )-5-fluorobenzonitrile; pyrazol-4-yl|oxyphthalonitrile; 5-(3-cyclopropyl-5-ethyl-1H-pyrazol-4-3-(3,5-dichlorophenoxy)-2-ethyl-6,7- yl)oxy|isophthalonitrile; dihydropyrazolo(|1,5-a|Ipyrazin-4(5H)-one; 5-((3-tert-butyl-5-methyl-1H-pyrazol-4-3-(3,5 -dichlorophenoxy)-2-ethyl-4,5,6,7-yl)oxy|isophthalonitrile; tetrahydropyrazolo|1,5-a|pyrazine; 5-(5-ethyl-3-isopropyl-1H-pyrazole-4- 3-(3,5-dichlorophenoxy)-2-ethyl-5-methyl-4,5,6,7-yl)oxy|isophthalonitrile; tetrahydropyrazolo|1,5-a|pyrazine; 4-(3,5-dichlorophenoxy )-3,5-diethyl-1-(1-methyl-3-

azetidinyl)-1H-pyrazole; 3-1І3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-2-І4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl|oxy)- 5-(1H-1,2,3-triazol-1-yl)benzonitrile; il|stylamine; 3-1І3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-2-І4-(3,5-dichlorophenoxy)-5-ethyl-1H-pyrazol-1-yl|oxy)- 5-(2H-1,2,3-triazol-2-yl)benzonitrile; il|stylamine; 3-1Y3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-tert-butyl 2-(4-(3,5-dichlorophenoxy)-3-ethyl-5-yl|oxy)-5 - fluorobenzamide; (hydroxymethyl)-1H-pyrazol-1-3-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl|stylcarbamate; yl|oxy)-5-(1H-pyrazol-1-yl)benzamide; tert-butyl 2-I4-(3,5-dichlorophenoxy)-5-3-1I3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-(ethoxymethyl)-3-ethyl-1H-pyrazole -1-yl|oxy)-5-(2-oxo-1-(2H)-pyridinyl)benzamide; yl|stilcarbamate; 3-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-tert-butyl 2-IB-(bromomethyl)-4-(3,5-yl|oxy)-5-(6- oxo-1-dichlorophenoxy)-3-ethyl-1H-pyrazole-1-(bH)pyridazinyl)benzamide; yl|stilcarbamate; 3-1Y3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-tert-Butyl 2-15-(aminomethyl)-4-(3,5-yl|oxy)-5-(2, 3-dimethyl-5-oxo-2,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-dihydro-1H-pyrazol-1-yl)benzamide; yl|stilcarbamate; 5-(13-cyclopropyl-5-ethyl-1-(2-hydroxyethyl)-1H-tert-butyl. 2-15-(4-acetyl-1-piperazinyl)methyl|-4-pyrazol-4-yl| oxyisophthalonitrile; (3,5-dichlorophenoxy)-3-ethyl-1H-pyrazole-1-5-Cb-cyclopropyl-3-ethyl-1-(2-hydroxyethyl)-1H-yl|ethylcarbamate; pyrazole-4- yl|oxyisophthalonitrile; tert-butyl 2-I4-(3,5-dichlorophenoxy)-3-ethyl-5-(1H-5-Cb-ethyl-1-(2-hydroxyethyl)-3-isopropyl-1H- pyrazol-1-ylmethyl)-1H-pyrazol-1-yl|ethylcarbamate; pyrazol-4-yl|oxyisophthalonitrile; tert-butyl 2-15-ShC2-5-C3-ethyl-1-(2-hydroxyethyl)-5- isopropyl-1H- (acetylamino)ethyl|amino)methyl)-4-(3,5-pyrazol-4-yl|oxyphthalonitrile; dichlorophenoxy)-3-ethyl-1H-pyrazol-1-2-I(I4- (3,5-dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl|ethylcarbamate; yl|ethylcarbamate; tert-butyl 2-(4-(3,5-dichlorophenoxy)-3-ethyl-5- /|(4-M-(2-(4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-methoxybenzyl)amino|methyl)-1H-pyrazol-1-pyrazol-1-ylphenylethylsulfamide; yl)ethylcarbamate; M-(2-4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-tert-butyl o 2-I5-((4-cyanobenzyl)amino|methyl)- 4- pyrazol-1-ylethyl 2-methoxyacetamide; (3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-5-(1-(3-azetidinyl)-3,5-diethyl-1H-pyrazol-4-yl|ethylcarbamate; yl|oxyisophthalonitrile; 3-C5-(bromomethyl)-1,3-dimethyl-1H-pyrazol-4-5-1H3,5-diethyl-1-(3-hydroxypropyl)-1H-pyrazol-4-yl|oxy)-5 -chlorobenzonitrile; yl|oxyisophthalonitrile; 3-(3,5-diethyl-1-methyl-1H-pyrazol-4-5-(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)oxy|benzonitrile; yl)oxy|isophthalonitrile ; 3-13,5-diethyl-1-(2-methoxyethyl)-1H-pyrazol-4-5-13,5-diethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl|-yl|Hyxybenzonitrile ; oxy)phthalonitrile; 3-(5-(2-(benzyloxy)ethyl|-3-ethyl-1H-pyrazol-4- 5-(1-(3-aminopropyl)-3,5-diethyl-1H-pyrazol-4-yloxy)- 5-Fluorobenzonitrile; yl|oxyisophthalonitrile; 3-(3-ethyl-5-(2-hydroxyethyl)-1H-pyrazol-4-yl|oxy)-methyl and 4-(3,5-dicyanophenoxy)-3,5-diethyl -1 H-5-fluorobenzonitrile; pyrazol-1-yl acetate; 3-(15-(2-(4-cyanophenoxy)ethyl|-3-ethyl-1 H-pyrazol-4-2-I(I4-(3, 5-dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yloxy)-5-fluoro-benzonitrile; yl|acetamide; 3-(3-ethyl-5-(2-((2-methyl-3- pyridinyl)oxy|ethyl)y-5-(3,5-diethyl-1-(hydroxymethyl)-1H-pyrazol-4-1H-pyrazol-4-yl)oxy|-5-fluorobenzonitrile; yl|oxyisophthalonitrile; 3 -((3-ethyl-5-I(2-(3-pyridinyloxy)ethyl|-1 H-pyrazole-4- 3-((4-(3-cyano-5-fluorophenoxy)-3-methyl-1 H - iloxy)-5-fluorobenzonitrile; pyrazol-b5-yl|methylamino)methyl|benzamide; 3-(5-2-(2-amino-3-pyridinyl)oxCetyl)-3-ethyl-1 H- 4-( 4-(3-cyano-5-fluorophenoxy)-3-methyl-1H-pyrazol-4-yl)oxy|-5-fluorobenzonitrile; pyrazol-b5-yl|methyliamino)methyl|benzamide; 5-(15-( 2-(benzyloxy)ethyl|-3-ethyl-1H-pyrazol-4-4-I(4-(3,5-dicyan ophenoxy)-3-methyl-1H-pyrazole-5-yloxy) isophthalonitrile; yl|methyl)amino)methylbenzamide; 5-C3-ethyl-5-(2-hydroxyethyl)-1H-pyrazole-4-3-((4-(3-chloro-5-cyanophenoxy)-3-methyl-1H-yl|oxyisophthalonitrile; pyrazole-b5 -yl|methylamino)methyli|benzamide; 3-C5-(aminomethyl)-1-(2-hydroxyethyl)-3-methyl-1H- 4-((4-(3-cyano-5-methylphenoxy)-3- methyl-1H-pyrazol-4-yl|oxy)-5-chlorobenzonitrile; pyrazol-b5-yl|methylamino)methyl|benzamide; 5-(1-allyl-3-tert-butyl-5-methyl-1H-pyrazole -4- 4-((4-(3-cyanophenoxy)-3-methyl-1H-pyrazol-5-yl)oxy|isophthalonitrile; yl|methyl)amino)methylbenzamide; 5-(3-tert-butyl-1- (2-Hydroxyethyl)-5-methyl-1H-5-(3,5-dicyclopropyl-1H-pyrazol-4-pyrazol-4-yl|oxyisophthalonitrile; yl)oxy|isophthalonitrile; 5-C1-(2- aminoethyl)-3-tert-butyl-5-methyl-1H-5-(13,5-dicyclopropyl-1-(2-hydroxyethyl)-1nH-pyrazol-4-yl|oxyisophthalonitrile; pyrazol-4-yl|oxyisophthalonitrile 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-5-(1-(2-aminoethyl)-3,5-dicyclopropyl-1H-pyrazol-yl|oxy) -5-(1H-1,2,4-triazol-1-yl)benzonitrile; 4-yl|oxyphthalonitrile; 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4- 3-IZ- cyclopropyl-1-(2-hydroxyethyl)-5-methyl-1H-yl|oxy)-5-(4-oxo-1-(4H)-pyridinyl)benzonitrile; pyrazol-4-yl|oxy)-5-methylbenzonitrile;

3-C5-cyclopropyl-1-(2-hydroxyethyl)-3-methyl-1H-methyl-1H-pyrazol-4-yl)oxy|benzonitrile; pyrazol-4-yl|oxy)-5-methylbenzonitrile; 4-(2-(14-(3-chloro-5-cyanophenoxy)-3-methyl-1H- 3-III-cyclopropyl-1-(2-aminoethyl)-5-methyl-1H-pyrazole-5- pyrazol-4-yloxy|-5-methylbenzonitrile; yl|methyl)iamino)dethyl|benzenesulfonamide; 3-(Z-cyclopropyl-5-methyl-1H-pyrazol-4-yl)oxy/|-5-Z-chloro-5-|Z-methyl-5-(((15)-1-methylbenzonitrile; phenylethyl| amino)methyl)-1H-pyrazol-4-3-(11-(3-aminopropyl)-3,5-diethyl-1H-pyrazol-4-yl|Ixybenzonitrile; yl|oxy)-5-methylbenzonitrile; 3-chloro-5-I(5-|(4-chlorobenzyl)amino|methyl)-3-methyl-3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-1H- pyrazol-4-yl)/oxy|benzonitrile; yl|oxy)-4-methoxybenzonitrile; 3-chloro-5-((3-methyl-5-Imethyl(2-2-3,5-diethyl-4-(1-naphthyloxy)-1H-pyrazol-1-phenylethyl)amino|methyl)-1H- pyrazol-4-yl|ethanol; yl)oxy|benzonitrile; 2-3,5-diethyl-4-(2-naphthyloxy)-1H-pyrazol-1-3-chloro-5-((3-methyl-5-K1H-pyrazol-3-yl|ethanol; ylamino) methyl|-1H-pyrazole-4-yloxy)benzonitrile; 2-14-I3,5-di(1H-pyrazol-1-ylphenoxy|-3,5-diethyl- -(2-(14-(3-chloro-5-cyanophenoxy)-3-methyl-1H-1H -pyrazol-1-yl)ethanol, pyrazol-5-yl|methyl)amino)ethyl|acetamide; 2-I3,5-diethyl-4-IZ-fluoro-5-(1H-pyrazol-1-3-chloro-5-I(5-|(3-chlorobenzyl)amino|methyl)-3-methyl-ilophenoxy| -1H-pyrazol-1-yl)ethanol; 1H-pyrazol-4-yl)/oxy|benzonitrile; 3-13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-3-chloro-5-15-(13-fluoro-5-yl|oxy)-5-methoxybenzonitrile; (trifluoromethyl)benzyl|amino)methyl)-3-methyl-1H-2-14-(3,5-difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-pyrazol-4-yl oxyphenzonitrile; il|stylamine; 3-Chloro-5-| )-1H-pyrazol-4-yl|oxy)-5-fluorobenzamide; yl)oxy|benzonitrile; 3-((3-isopropyl-5-methyl-1H-pyrazol-4-yl)oxy|-5-3-chloro-5-I(5-(4-hydroxy-6-methyl-2-methylbenzonitrile; pyrimidinyl) amino|methyl)-3-methyl-1H-pyrazol-4-3-(11-(2-aminoethyl)-3-isopropyl-5-methyl-1H-yl)oxy|benzonitrile; pyrazol-4-yl| oxy)-5-methylbenzonitrile; 3-chloro-5-I(5-1(4-fluorobenzyl)amino|methyl)-3-2-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole-1-methyl- 1H-pyrazol-4-yl)oxy|benzonitrile; yl|-N-(2-pyridinylmethyl)acetamide; Z-chloro-5-115-CC1 8)-2-hydroxy-1-

14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-phenylethyl|Iamino)methyl)-3-methyl-1H-pyrazol-4-yl|Iacetonitrile; yl|Ixifbenzonitrile; 1-14-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-3-(5-Kbenzylamino)methyl|-3-methyl-1H-pyrazol-4-yl|Iacetyl)piperidine; iloxy)-5-chlorobenzonitrile; (38)-1-14-(3,5-dichlorophenoxy)-3-methyl-1H-3-chloro-5-(5-((3-methoxybenzyl)amino|methyl)-3-pyrazol-5-ylacetyl )-Z-piperidinol; methyl-1H-pyrazol-4-yl)oxy|benzonitrile;

M-(2,4-dichlorobenzyl)-2-14-(3,5-dichlorophenoxy)-3-3-chloro-5-(13-methyl-5-(C4-methyl-1H-pyrazol-5-yl) acetamide; (trifluoromethyl)benzyl|amino)methyl)-1H-pyrazol-4-2-I4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl|-yl|oxy)benzonitrile ;

M-(6-methyl-2-pyridinyl)acetamide; C-chloro-5-15-C18)-1-(hydroxymethyl)-2-2-I4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl|-methylpropyl|iamino)methyl )-3-methyl-1H-pyrazole-4-

M-(4-trifluoromethyl)benzyl|acetamide; yl|Ixifbenzonitrile;

M-(3-chlorobenzyl)-2-(4-(3,5-dichlorophenoxy)-3-3-chloro-5-|(5-((2-methoxybenzyl)amino|methyl)-3-methyl-1H- pyrazol-5-yl|acetamide; methyl-1H-pyrazol-4-yl)oxy|benzonitrile; 2-I(I4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl|- C -chloro-5-(3-methyl-5-((C2-(2-

M-(2-«(trifluoromethyl)benzyl|acetamide; thienyl)ethylIamino)methyl)-1H-pyrazole-4- 2-I4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazole-5- yl|- yl|oxy)benzonitrile;

M-(4-fluorobenzyl)acetamide; Z-chloro-5-|(Z-methyl-5-/|(-3-

M-benzyl-2-(4-(3,5-dichlorophenoxy)-3-methyl-1H-pyridinylmethyl)amino|methyl)-1H-pyrazol-4-pyrazol-5-yl|-M-methylacetamide; yl)oxy|benzonitrile;

3-chloro-5-1(5-((2-chlorobenzyl)amino|methyl)-3-methyl-3-chloro-5-(13-methyl-5-(Ce-1H-pyrazol-4-yl)oxy) |benzonitrile; (trifluoromethyl)benzylamino)methyl)-1H-pyrazol-4-3-(5-(benzylamino)methyl|-3-methyl-1H-pyrazol-4-yl|Ixybenzonitrile; yloxy)-5-chlorobenzonitrile; 3-chloro-5-I(5-C((2,4-dichlorobenzyl)amino|methyl)-3- 3-(5-CChbenzyl(methyl)amino|methyl)-3-methyl-1H-methyl-1H -pyrazol-4-yl)oxy|benzonitrile; pyrazol-4-yl)oxy|-5-chlorobenzonitrile; Z-chloro-5-((Z-methyl-5-|-(2-

3-chloro-5-C5-(|(5-chloro-2-pyridinylmethyl)amino|methyl)-1H-pyrazol-4-pyridinyl)umethylamino)methyl)-3-methyl-1H-pyrazol-yl)oxy| benzonitrile; 4-yl|oxy)benzonitrile; C-chloro-5-I(5-1(3,4-dichlorobenzyl)amino|methyl)-3-

Z-chloro-5-|(Z-methyl-5-((4-methyl-1H-pyrazol-4-yl)oxy|benzonitrile; pyridinylmethyl)amino|methyl)-1H-pyrazol-4-Z-chloro-5 -(Z-methyl-5-(|(3-yl)oxy|benzonitrile; phenylpropyl)amino|methyl)-1 H-pyrazol-4-

3-chloro-5-|(3-methyl-5-((4-yl)uoxy|benzonitrile; methylbenzyl)amino|methyl)-1 H-pyrazole-4-3-chloro-5-| 4-methoxybenzyl)amino|methyl)-3-yl)oxy|benzonitrile; methyl-1H-pyrazol-4-yl)oxy|benzonitrile;

3-Chloro-5-((5-((3-methoxypropyl)amino|methyl)-3-3-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-

yl|oxy)-5-(methylsulfanyl)benzonitrile; 3-(11-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl|oxy) -5-methylbenzonitrile (I)-citrate salt; yl|oxy)-5-(methylsulfinyl)benzonitrile; or a pharmaceutically acceptable salt or solvate thereof. 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4- 29. A compound according to any of the preceding points-yl|oxy)-5-(methylsulfonyl)benzonitrile; tives, which is: 3-(І3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4- 3-1І3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4 - yl|oxy)-5-I(2-(dimethylamino)ethoxy|benzonitrile; yl|oxy)-5-fluorobenzonitrile; 3-(І3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-3-1І3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl|oxy)- 5-|(2-(methylamino)ethoxy|benzonitrile; yl|oxy)-5-methylbenzonitrile; 2-(3-cyano-5-1H3,5-diethyl-1-(2-hydroxyethyl)-1H-5-C3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-pyrazole- 4-yl|oxy)phenoxy)acetamide; yl|oxy)isophthalonitrile; 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-3-chloro-5-1|3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-yl |oxy)-5-(2-methoxyethoxy)benzonitrile; 4-yl|oxyrfbenzonitrile; 3-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-5-(3,5-diethyl-1H-pyrazol-4-yl)oxy|zophthalonitrile; yl|oxy)-5 - methoxybenzonitrile; 3-(3,5-diethyl-1H-pyrazol-4-yl)oxy|-5-

ZAG -(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4-methylbenzonitrile; yl|oxy)-5-(1H-pyrazol-1-yl)benzonitrile; C-chloro-5-((3,5-diethyl-1H-pyrazole-4-

3,5-Dichlorophenyl-3-methyl-5-|(3-methyl-1,2,4-yl)oxy|benzonitrile; oxadiazol-5-yl)methyl|-1H-pyrazol-4-yl ether; 3-(11-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4-

C-fluoro-5-11-(2-hydroxyethyl)-5-methyl-3-yl|oxy)-5-methylbenzonitrile; (trifluoromethyl)-1H-pyrazol-4-yl|oxyphenzonitrile; 3-(11-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-5-I(3,5-diethyl-1-y2-((2-methoxyethoxy)methoxy|ethyl)yl) |Ioxy)-5-chlorobenzonitrile and 1H-pyrazol-4-yl)oxy|isophthalonitrile; 5-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4-

C-cyano-5-1|3,5-diethyl-1-(2-hydroxyethyl)-1H-yl|oxyisophthalonitrile; pyrazol-4-yl|ioxybenzamide; or a pharmaceutically acceptable salt or solvate thereof. 5-C5-ethyl-3-(1-hydroxyethyl)-1H-pyrazol-4-30. 5-C5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl|oxyisophthalonitrile; yl|Ioxy)ophthalonitrile or its pharmaceutically 5-(5-ethyl-3-(1-hydroxyethyl)-1-(2-hydroxyethyl)-1H- acceptable salt or solvate. pyrazole-4- 31. Compound of formula (1) : yl|oxyphthalonitrile; 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-yl|oxy)-5-(5-trifluoromethyl-1,2,4-oxadiazole -3- X M (I)yl)benzonitrile;-KM 3-(13,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl|oxy)-5-(5-methyl- 1,2,4-oxadiazole-3- or its pharmaceutically acceptable salt or solvate, yl)benzonitrile, in which: 3-4(3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-B ' is H, C1-C6 alkyl, -O(C1-C6 alkyl), -O(C3-C7 yl|oxy)-5-(5-ethyl-1,2,4-oxadiazole-3-cycloalkyl), mentioned C1-C3 alkyl is optionally yl/)benzonitrile; substituted B'5; 3-(3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4-B is H,C1-C3 alkyl, propenyl or C-linked yl|oxy)-5-(5-isopropyl-1,2,4-oxadiazole-3-B"5, said C-C3 alkyl is optionally substituted yl)benzonitrile; it - ОН, -ОСН3, -"ОСН»СНаМН", -СМ, -СО»СН3, - 5-ЙЦС4-(3-chloro-5-cyanophenoxy)-3-methyl-1 Н-СсОМ mHn»g, -С(-МН)МН», -"СОМНМН», -МНе, -МНОН», - pyrazol-5-yl|methyl)amino)methyl|nicotinamide; M(CH3)", --НСНасНМнНСОСнН», -"INSНоСНоСНоСН 5, - 2-ИЦСХ4-(3-chloro-5-cyanophenoxy)-3-methyl-1 Н- МНН», -МНСОВ5, -НСОСНГОСН» or в5; pyrazol-5-yl|methylamino)methylisonicotinamide; BZ is Ci-Cv alkyl; and di(tert-butyl) 2-I4-(3,5-dicyanophenoxy)-3,5-Be is phenyl optionally substituted by halogen, diethyl-1H-pyrazol-1-yl|butyl phosphate; -CM, Ci-Cv alkyl, Ci-Cv-haloalkyl, C3-C7 2-|4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-pyrazole-1-cycloalkyl or C1-Cv alkoxy; yl|ethyl dihydrogen phosphate; B": is azetidinyl, tetrahydrofuranil, morpho-5-4I3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-linyl, piperazinyl, pyrazolyl, oxadiazolyl|oxyphthalonitrile sulfate salt; scrap, pyridinyl or pyrimidinyl, each is non-5-4N3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4- necessarily substituted -OH, -MH", oxo or Si-Cv yl|oxyisophthalonitrile benzenesulfonate salt; alkyl or -CO(Ci-Cv alkyl). 5-(3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4- 32. Pharmaceutical composition containing spol-yl|oxyisophthalonitrile tosylate salt; ku of formula (I) or its pharmaceutically acceptable 5-(3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazole-4- salt or solvate, according to any of items 1-31, yl|oxyisophthalonitrile mesylate salt; together with one or more 3-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4- pharmaceutically acceptable excipients, diluents or yl|oxy)-5-methylbenzonitrile bis-mesylate salt; carriers. 3-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4- 33. Pharmaceutical composition according to but with item 32, yl|oxy)-5-methylbenzonitrile phosphate salt; containing one or more additional 3-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4- therapeutic agents. yl|oxy)-5-methylbenzonitrile (I.)-tartrate salt; 34. Pharmaceutical composition according to item 33, 3-(1-(2-aminoethyl)-3,5-diethyl-1H-pyrazole-4- wherein said one or more additional yl|oxy)-5-methylbenzonitrile succinate salt and therapeutic agents are selected from the group that mis-

reverse transcriptase inhibitors; non-nucleo-pharmaceutically acceptable salt or solvate gizzard reverse transcriptase inhibitors; bottom inhibitors with point 1, which includes:

HIV proteases; SSK5 antagonists; antagonists of (a) condensation of compounds of formula (II), (MI) or sxe; integrase inhibitors and inhibitors of fusion of (MI): rus. t V! Item 35. "Compound of formula (1) or its pharmaceutically acceptable salt or solvate according to any of clauses 1-31 for use as a medicine. Item 36. Compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of (1) (M) (M) clauses 1-31 for use as an inhibitor or where B", VZ and KE" are as defined in clause 1, for a reverse transcriptase modulator, provided that B! or 23 is other than halogen, -OB" 37. A compound of formula (I) or its pharmaceutical form (where B" is as defined in clause 1) or -CM , and an acceptable salt or solvate according to any one of II112 are the leaving groups of items 1-31 for use in the treatment of HIV, with a compound of formula (M): a retroviral infection genetically dependent on HIV NegMichNA? (M) or the consequences of the syndrome of acquired immunodeficiency or its salt or hydrate, where ER? are such as defined- (AIDS). defined in point 1; and 38. The use of a compound of formula (I) or its drug- (b) is optional, the conversion of onions, received a pharmaceutically acceptable salt or solvate according to noy in stage (a), in it pharmaceutically acceptable by any of items 1-31 for the production of medi-salts or solvates. a compound that inhibits or modulates the activity of reverse transcriptase. 41. Compound of formula (I): t c" 39. Use of the compound of formula (I) or its pharmaceutically acceptable salt or solvate according to g" (I) by any of items 1-31 for the manufacture of a medicinal product for the treatment of HIV, retroviral infection and o genetically dependent on HIV or the consequences of the syndrome where RK", VZ and P" are as defined in point 1. of acquired immunodeficiency (AIDS). 40. The method of obtaining the compound of formula (I) or its

This invention relates to pyrazole derivatives and according to the presented approach, the provision of their preparation, intermediate compounds, the studied compound of the formula are used in this case, compositions that their . Tu contain, and the use of such derivatives. and

The compounds of the present invention bind the reverse transcriptase enzyme and are modulators, especially their inhibitors. Reverse transcriptase included in the infectious cycle of development or its pharmaceutically acceptable salt, salt

HIV, and compounds that interfere with the functions of this vat or a derivative in which: the enzyme have the ability to treat conditions, including or B! is H, C-Ce alkyl, C3-C7 cycloalkyl, giving AIDS. there is a constant need to obtain scrap, phenyl, benzyl, halogen, -SM, -OB" - new and better modulators, especially inhibitors, CO»v'E -SOMA?V!O, Ve? or RU, the mentioned Si-Ce of HIV reverse transcriptase, since the virus is alkyl, C3-C7 cycloalkyl, phenyl, and benzyl, it is impossible to mutate, becoming resistant to the action of known, necessarily, halogen-substituted, -CM, -OB', dulators. 5( ОхХА", -6028', -SOMAZA, -OSOMAVO, -

The compounds of the present invention are useful MAZSO»B!!, -МВ'OV", -MAZSOV!E, -502МА85ВЭ, - in the treatment of various disorders, including those in which MAZSOMAZV'O, -MAZ5O»2B!? or VO; and involved inhibition of reverse transcriptase B2 is H, C3-C6 alkyl, C3-C6 alkenyl, C3-C6

Interesting disorders caused by it are Virus alkynyl, C3-C7 cycloalkyl, C3-C cycloalke-

Human immunodeficiency virus (HIV) and genetically dependent nil, phenyl, benzyl, C or B?, mentioned retroviruses, such as acquired immunodeficiency syndrome, C-Cv alkyl, C3-C7 cycloalkyl, phenyl and benzyl is, physitis (AIDS). optionally, substituted halogen, -ОВ5, -

European patent application EP 0 786 455 Ov', -SM, -СО287, -ОСОМВА5В5, -СОМА5В5, -

A1Й| describes imidazoles that inhibit the growth of HIV. M- S(-MAUMAOV", -SOMAMA5A?, -MAeVe, -MA5B?,

Phenylpyrazoles, which act as inhibitors of reverse -MA5СОВ5, -МА5СОВ5, -МАЗСОВ!2, -МА5СО»ВУ, - transcriptase, described (in U. Med. Spec., 2000, 43, MAZSOMAZVU, -502МAZVU, -МА55О»ВU, - 10341). Antiviral activity is attributed to МА55О2МАЗ VU, VZ or B; by M-(hydroxyethyl)pyrazole described | in pa- or, B! and 22, when taken together, represent awnings 5 3,303,2001|. unbranched N-S. alkylene, optionally,

substituted oxo, where, optionally, one methyl-MAO», -ОВ5, -МАЗА», -(C1-Свё alkylene)-МАЗВ5, the new group of the mentioned C3-С4 alkylene can be C1-Cv alkyl, halogen (С1и- C1)alkyl or C3-C7 replaced by oxygen atoms or a nitrogen atom, mention - cycloalkyl; and the nitrogen atom is, not necessarily, substituted by Co; Heh, 1 or 2;

BZ is H, Ci-Cv alkyl, C3-C7 cycloalkyl, provided that (a) when KE! and BZ are both phenyl, phenyl, benzyl, halogen, -CM, -OB"7, - lams, P: is not methyl; and (b) when B' is ethoxy and 23

СО2В85, -SOMAZV», VZ? or RU, the mentioned C1-Ce al- is ethoxycarbonyl, P? is not phenyl. rings, C3-C7 cycloalkyl, phenyl and benzyl are, optionally, in the above definitions, halogen substituted by halogen, -СМ, -ОБ5, -СО2Б5, - means fluorine, chlorine, bromine or iodine. If not specified

SOMAZA?, -OSOMAZA5, -MASO»B, -MA5VE, - but other, alkyl, alkenyl, alkynyl, alkylene and alkoc-

MASSIVE, -5С2МА8ЗВА, -"МАЗСОМАЗВ?, -МА55О»В5, sy, containing the required number of carbon atoms

VZ or in; this, can be unbranched or

IN? is phenyl, naphthyl or pyridyl, co-branched. Examples of alkyl are methyl, ethyl, benzene, optionally substituted RU, halogen, - n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-

CM, C1-Cv alkyl, C1-Cv haloalkyl, C3-C7 butyl. Examples of alkenyl are ethenyl, propen-1-cycloalkyl, Ci-Cv alkoxy, -SOMVAZV?, ОВ", yl, propen-2-yl, propen-3-yl, 1-buten-1-yl, 1-buten-5OHAY . -kylene)-MAZUA? or O-(C1-Ce alkylene)-OBE; buten-2-yl, 2-methylpropen-1-yl or 2- each PE? is, independently, either H, C1-C6 alkyl methylpropen- 3-yl Examples of alkynyl are ethynyl, or C33-C7 cycloalkyl, or when two B groups are propn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, attached to one nitrogen atom, these two groups are 1-butyn-4-yl, 2-butyn-1-yl Examples of alkylene are those together with the nitrogen atom to which they are attached, methylene, 1,1-ethylene, 1 . , ethoxy, n-propoxy, isinyl or morpholinyl, said azetidinyl, pyropropoxy, n-butoxy, i-butoxy, sec-butoxy and t-lidinyl, piperidinyl, homopiperidinyl, butoxy. Examples of cycloalkyl are cyclopropyl, piperazinyl, homopiperazinyl, and morpholinyl, noncyclobutyl, cyclopentyl, cyclohexyl, and cyclohexyl, optionally substituted C1i-C6 alkyl or C3-C7 ptyl. Where V! and B? taken together form together with cycloalkyl; the nitrogen atom and the carbon atom of the pyrazole ring, each Re is, independently, either H, C-Cv alkyl to which they are attached, a 5- or b-membered ring. or C3-C7 cycloalkyl; When is the heterocyclic group Z or P? attached

B" is Ci-Ce alkyl or C3-C7 cycloalkyl; to oxygen, sulfur or nitrogen, a heterocyclic group

VAZ is a five- or six-membered aromatic VAZ or C must be attached through an atom by a heterocyclic group containing (i) from 1 to 4 ring carbons. In addition, when a heterocyclic nitrogen atom, or (ii) 1 or 2 nitrogen atoms and 1 atom group K" is attached to an oxygen atom, sulfur or oxygen or 1 sulfur atom, or (ii) 1 or 2 nitrogen atoms, the heterocyclic group EE? must be oxygen or sulfur, the mentioned heterocyclic group is dnaed through a carbon atom of the ring, which is not a neighbor - optionally, substituted by halogen, oxo, -CM, - nim to the heteroatom of the ring.

CO, -SOMAUV?, -BO2 MAV, -MA?5O»2B?, -OVU, - Pharmaceutically acceptable salts of compounds

MAV", -(C1-Cv alkylene)-MAVUV?, Ci-Cv alkyl, of the invention (I) are acid additive and basic additives - fluoro(C1i-Cv)alkyl or C3-C7 cycloalkyl; without salt

VZ is a four- to seven-membered, saturated or Suitable acid addition salts form a partially unsaturated heterocyclic group, from acids that form non-toxic salts and containing (ii) 1 or 2 nitrogen atoms, or (ii) 1 atom systems are hydrochloride, hydrobromide, hydroiodo-nitrogen and 1 oxygen atom or 1 sulfur atom, or (ii) 1 didine, sulfate, bisulfate, nitrate, phosphate, an oxygen atom or a sulfur atom, the mentioned heterocyclic hydrophosphates, acetate, maleate, fumarate, per group is, optionally, substituted oxo, C1-Cv lactate, tartrate, citrate, gluconate, succyl-alkyl, C3-C7 cycloalkyl, -5028?, -"SOMVAZVU, - natane, saccharate, benzoate, methanesulfonate,

SOOV?, -CO-(C1-Cv alkylene)-OB? or -SOV? and, ethanesulfonate, benzenesulfonate, para- optionally substituted by a carbon atom, toluenesulfonate and pamoate salts. which is not adjacent to a heteroatom, a halogen, - Suitable basic salts are formed from bases,

ОВ, -MAZV, 0 -MASOVU, -MASOOV, -- which form non-toxic salts and examples are

MAZSOMAZV?, -МА?5О2В: or -СМ; triium, potassium, aluminum calcium magnesium zinc

IN? are H, 8, VU, BZ, C1-C8 alkyl, C3-C7 cyclic and diethanolamine salts. loalkyl or -(C1-C7 alkyl)-(C3-C7 cycloalkyl- For familiarization with suitable salts (|dil), the mentioned C1-C7 alkyl and C3-C7 cycloalkyl are, see Vegde ei ai, 9. Rpagt. ., 66, 1-19, 1977). optionally, substituted -ОВ?, -ОВ"У, ВВ, ВУ, В'Z Pharmaceutically acceptable solvates or -SOV'Z; compounds of formula (I) are their hydrates. Also to compounds

A" is H, C3-C7 alkyl or C3-C7 cycloalkyl; formulas (I) refer to their polymorphs, the mentioned C3-C7 alkyl and C3-C7 cycloalkyl are. Compounds of formula (Y) can be modified optionally, substituted - ОВ5, -МАЗВ», obtaining their pharmaceutically acceptable derivatives

MASOVU, -SOMA?RVU, VZ or RU; by any functional groups of compounds.

B": is C1-Ce alkyl substituted by RU, VU, -OVU, - Examples of such derivatives (described in: Ogide5oi

CATFISH, -MA? OWL? or - MAZV?; Todau, Moshte 19, Mytbreg 9, 1983, pp. 499-538;

VZ is phenyl, optionally substituted with ha- Torisv in Spetizig, Sparieg 31, pp. 306-316; and in logon, -SM, -SOV5, -SOMAZA», -50О2МАЗВ», - "Оезидп ой Ргодгтидве" ru, Vypddaaga, Eivbemivg,

1985, Spargieg 1) (descriptions of these documents include lin-4-ylmethylsm, 2-methylimidazol-1-ylmethyl, herein as a sprinkler) and include: esters, carbo-pyrazol-1-ylmethyl or 1,2,4-triazole -1- esters, hemiesters, phosphoesters, nitroesylmethyl. teres, sulfate esters, sulfoxides, amides, su- Mainly, VE! when taken separately, there are H, -CHZ3, lfonamides, carbamates, azo-compounds, -SnosH», cyclopropyl, -CHNa.MnNeNi(4- phosphoramides, glycosides, ethers, acetals and ketals. cyanophenyl), -bSnaneNa(4-fluorophenyl ), -

The compound of formula (I) can contain one or SnHgMnNONN»(4-methoxyphenyl), -bngchneHzi(4- a larger number of asymmetric carbon atoms and aminosulfonylphenyl) or -SnNa.MneNa(a4- therefore exist in two or more stereoi-aminocarbonylphenyl). isometric forms. The presented invention of the stos- Preferably, B2, when taken separately, is H, C1- of individual stereoisomers of the compounds of the invention (I) Ce alkyl, C3-C6 alkenyl or RU, mentioned Ci- together with, when possible, their individual tau- Ce alkyl is, optionally, a substituted halogen, - tomers, and their mixtures. ОВ, -ОвВ!г, -СМ, -СО287, -"OSOMAZV?, -"SOMAZVU,

Separation of diastereomers can be carried out -С(-MA)MAROV?, -"SOMAMAV?, -MAVeVe, -MA?В'2, using well-known methods, for example - -MAZSOV?, -MAZSOV?, -MAZSOV?, -MAZSO" VU, - clade, with the help of fractional crystallization, MAZSOMAV", -6O2MAUV?, -MA»5O»2VU, VZ or VU. chromatography or high-performance liquid Preferably, B2, when taken separately, is H, C1-chromatography (HPLC) of a stereoisomeric mixture of C6 alkyl, C3-C6 alkenyl or RU, said C6- compound of formula (I) or its suitable salt or C6 alkyl is, optionally, substituted -ORV» - derivative, the individual enantiomer of the compound OvBg, -SM, -BO287, -SOMA»B», -C(-MAP)MARONVU, - formula (I) can also be obtained from the corresponding SOMAZMA?A ?, -MAYAVAYA, -MAZV!?, -MASOVU, - an optically pure intermediate or by separating MAZSOV'"2, -MA?SO»VU, VZ or vu. lation, such as MERH of the corresponding racemate Preferably, P2, when taken separately , is H, Si- using a suitable chiral support or C3 alkyl, propenyl or RU, mentioned C1-C3 by fractional crystallization diastereomer- alkyl is, optionally, substituted -OH, -ОСН»5, - these salts obtained by the reaction from- OSNa.SNaMAN»?, -SM, -СО»СН3, -СО2СНеСН»3, - the appropriate racemate with a suitable optically- SOMNg, -F(-MH)IMNON, -"SOMNMN", -MN", -MNON3, active acids oy or basis, as appropriate. -M(СнНз)», -МНенНгСнНгМноСОснН з, -

Mostly, E! when taken separately, is H, C1-Ce MNOCH»CH»OCn:I, -MNoCH2gVU, -MNHSO8, /- alkyl, C3-C7 cycloalkyl or -OB", the mentioned MNOCOSsNgOosnHZ, -MNSO»C(Cnzi)z, VZ or RU.

C1-C8 alkyl and C3-C7 cycloalkyl are, optionally, Preferably, B, when taken alone, is H, meso-substituted halogen, -CM, -OB'. 5(0)ХВО, - тыл, -СНаСнНАСН:;, -СНоаСМ, -СН»ОСсСН», -

СО»2в'Е. -SOMAZA?, -OSOMAZVO, -MAZSO»VO, - СН»СОМН», -СНаСОМНМН», -СНаСО»сСН», (-

MAV, -MAZSOVO, -502MAZAO, -MASOMAVE, SnНСоОсНноснН», -ОНгОо(-МНУМНОН, -СНгСНоОН, -МА?5О2В!? or vo, -SnasngosnН 5», -Sna.SnNoМН»5, -

Mostly, E! when taken individually, e H, C1-Cv CsngongyanCOsCHngoOsn", -CHNaCnNaMNoCO» CCZ)", alkyl, C3-C7 cycloalkyl or -OB", mentioned 2-(pyrid-2-ylcarbonylamino)eth-1-yl, 2-( pyrazine-

C 1-6 alkyl is, optionally, substituted halo-2-ylcarbonylamino)ethyl-1-yl, - nom, "ОВ, -MA'OV', -МАЗСОВ'": or Vo, Sn. ngosSNnosNoМН 5", - bneSsnagMNe Nz, -

Mostly, E! when taken separately, is H, C1-C4 Sn. nNHHM(SnHz)g, -"SNaSnNaMnNonNasnN"MnNoSOs nn", - alkyl, cyclopropyl or -OSH"z, the mentioned Si- SnNa.CH.MNonH".cSNn".OSN:I, -SNaCH(OH)CH", ( 3-

C 1 -alkyl is, optionally, substituted bromine, - hydroxypyrazol-5-ylmethyl, 2-hydroxy-1,3,4-

OH, -O(C1-C2 alkyl), -MA'9B!",-MHCOV'3 or oxadiazol-5-ylmethyl, 2-amino-1,3,4-oxadiazol-via, B-yl, 5 -hydroxy-1,2,4-oxadiazol-3-ylmethyl,

Mostly, E! when taken separately, is H, -CH3, b-hydroxy-2-methylpyrimidin-4-ylmethyl, 6- -CnaCH3, -CH(CH3)», C(CH3)3, cyclopropyl, - hydroxy-2-aminopyrimidine-4 -ylmethyl, 2-

Osn", -CHzOH, -CHhosnH", -CHg8OSHsSnHz, -CH2Vg, (morpholin-4-yl)eth-1-yl, 2-(4- -SneMnH", -CH».MneHz, -Snghem(SnHZz)» , - methylcarbonylpiperazin-1-yl)eth-1-yl, morpho-

СНоМНеНг(cyclopropyl),, -"СНаМННСН»СНгоОснН", - lin-3-ylmethyl, (2-(tetrahydrofuran-2-

CHnaMnNeSnNgsNaMNSOs with, -CHnMneo(A-ylmethylamino)eth-1-yl, 1-methylazetidin-3-yl cyanophenyl), -SnaMchneo(3-cyanophenyl), - or azetidin-3-yl.

CH.MnNeNaI(4-cyanophenyl), OongMnNONnaI (4- Preferably, E2, when taken separately, is H, - fluorophenyl), -OnNa.MnNONg(4-methoxyphenyl), - CH.SNoOH or -CH.CH»MH» .

SnNgMneNai(4-aminosulfonylphenyl), - Mostly, B! and P2, when taken together, pre-

SnNoMnNeNaI (4-aminocarbonylphenyl), - put an unbranched C3-Ca alkylene, neobo-

СН»МНеОНае(pyrid-3-yl), -Снгем(СН3) (4- is necessarily substituted by oxo, where one methylene cyanophenylmethyl), -бнгеж(СснгсСнгон) (4- the group of the mentioned C3-C4 alkylene is replaced by a cyanophenylmethyl atom) , 4-methoxypiperidine-1- oxygen or a nitrogen atom, said nitrogen atom being, ylmethyl, 4-aminocarbonylpiperidine-1- optionally substituted by BO. ylmethyl, 4-methylcarbonylaminopiperidine-! - Mostly, K! and 2, when taken together, predylmethyl, piperazin-1-ylmethyl, 4- gives unbranched propylene, where one methylpiperazin-1-ylmethyl, 4- methylene group is replaced by an oxygen atom or methylcarbonylpiperazin-1-ylmethyl, 4- unbranched butylene, where one methylene is methoxymethylcarbonylpiperazin-1-ylmethyl, the 4- group is replaced by a nitrogen atom, the mentioned propylene and methoxycarbonylpiperazin-1-ylmethyl, 4- butylene is, optionally, substituted by oxo and zga- methylsulfonylpiperazin-1-ylmethyl, morpho- this nitrogen atom is, not necessarily, substituted

Vo, scrap, each is, not necessarily, a substituted halogen-

Mostly, V! and P, when u: yati together, pre-nom, -SM, -SOVZ, -SOMAZV?, -502МВZV5, - put OSNasSN»g-y, -SOMnNoNasSNn»-U, MA?BO»2B, -ОВ5, - MAZA", -(C1-Cv alkylene)-MAZV",

СНаМНОСНнгсН»-у SnНаМм(СН3)СНгС Neg-у, ona (4-C1-Cv alkyl, fluoro(C1i-Cv)alkyl or C3-C7 cyclo-cyanophenylmethyl)C Nas Ho-U or HongM(4-loalkyl. methoxyphenylmethyl )СНаСНг-У where "x indicates the point Mostly, BEZ is imidazolyl, pyrazolyl, attachment to the carbon atom of the pyrazole ring and" 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4- indicates the point of attachment to the nitrogen atom of the ring by oxadiazolyl, pyridinyl, pyrazinyl or pyrazole.pyrimidinyl, each is optionally substituted-

Preferably, EZ is H or Ci-Cv alkyl, referred to as halogen, -SM, -SOV», -SOMVA5B5, - this Ci-Cv alkyl is, optionally, substituted with gas-ZOM», -MA»5O» B", "OB, -MAUVKH, -(C1-Cv alkylene, -SM, -ОВ85, -СО28?, -SOMVAV5, - len)-MAZA", C1-Cv alkyl, fluoro(C1-Cv)alkyl

OSOMAZ?, -MAZSO»B, -MAYAVYA, -MASOV», - or C3-C7 cycloalkyl.

OMA, -"MAZSOMAUV", -MA?5O»V", VZ or vu. Preferably, RU is imidazolyl, pyrazolyl,

Preferably, E3 is H or C1-C6 alkyl. 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-

Preferably, EZ is H or C1-C6 alkyl. oxadiazolyl, pyridinyl, pyrazinyl or

Preferably, BZ is H, -CH3, -CHNaCH3, -CH(CH33)2 pyrimidinyl, each is, optionally, substituted- or -C(CH33) with it -OB5, -MAZA? or C-Cv alkyl.

Preferably, BZ is -CH3, -CHNaCH3, -CH(CH33)2 Preferably, R3 is imidazolyl, pyrazolyl, or cyclopropyl. 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-

Preferably, B" is phenyl, optionally substituted oxadiazolyl, pyridinyl, pyrazinyl or substituted RU, halogen, -CM, C1-Cv alkyl, C1-Cv pyrimidinyl, each optionally substituted with haloalkyl, C3- C7 cycloalkyl or Ci-Cene -OH, -MNeg or methyl.Alkoxy. Preferably, BZ is opyrazol-1-yl, -2-

Preferably, KE" is phenyl substituted with P, ha-methylimidazol-1-yl, 1,2,4-triazol-yl-1-yl, 3- halogen, -CM, C1-Cv alkyl, C1-Ce haloalkyl-hydroxypyrazol-5- yl, 2-hydroxy-1,3,4-yl, C3-C7 cycloalkyl or C1-C8 alkoxy, oxadiazol-5-yl, 2-amino-1,3,4-oxadiazol-5-

Preferably, B" is phenyl substituted with halogel, 5-hydroxy-1,2,4-oxadiazol-3-yl, 2-methyl, -CM or C1-C8 alkyl. 4-hydroxypyrimidine-b-yl, 2 -amino-4-

Mostly, B? is phenyl substituted with fluoro-hydroxypyrimidin-b-yl, pyridin-3-yl, pyri, chlorine, -CM or methyl. dyn-2-yl or pyrazin-2-yl.

Preferably, B" is 3-cyanophenyl, Ш4- Preferably, P? is azetidinyl, tetrahydropichlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-rolyl, piperidinyl, azepinyl, oxetanyl, fluorophenyl, 2-fluorophenyl, 3,5- tetrahydrofuranyl, tetrahydropyranyl, oxy-dichlorophenyl, 2,6-dichlorophenyl, 2,3-phenyl, morpholinyl, piperazinyl or diazedichlorophenyl, 2,4-dichlorophenyl, 3,4-phenyl, each optionally substituted oxo, dichlorophenyl, 2,5-dichlorophenyl, 2,6-Ci-Cv alkyl, C3z-C7 cycloalkyl, -50285, - difluorophenyl, 2,3-difluorophenyl, 3,5- COM, -SOOVU, -CO-(C1-Cv alkylene)-OB: or - difluorophenyl, 2,5-difluorophenyl, 3,5-SOVZ and, optionally, substituted on the carbon atom dicyanophenyl, 3,5-dimethylphenyl, 4-fluoro-3-lec, which is not adjacent to a heteroatom, halomethylphenyl, 3-cyano-4-fluorophenyl, 3-cyano, -ОВ85, -МАЗА5, -МАСОВ, -МАСООВ», - 5B-fluorophenyl, 2-chloro-4-cyanophenyl, З- chloro- MAZSOMAZ A", -MA?5O»VZ or -SM. 5-cyanophenyl, 3-cyano-5--methylphenyl or 4- Trans. everything, B? is azetidinyl, piperidicyano-2,6-dimethylphenyl. nil, tetrahydrofuranil, piperazinil or

Preferably, B" is 3,5-dicyanophenyl, 3-morpholinyl, each optionally substituted with cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl or oxo, C1-C6 alkyl, C3-C7 cycloalkyl, -

Z-cyano-z-methylphenyl. In alternative per- 5028, -SOMARA?, -СООВ?, -СО-(С1-Св alkylene)- predominant forms: ORZ or -SOVZ? and, optionally, replaced by

Preferably, B" is phenyl, optionally, on the carbon atom that is not adjacent to the heteroatom-substituted P, halogen, -CM, C1-Cv alkyl, C1-Cv mom, halogen, -ОВ5, -МАЗАВ5, - MASOV5, - haloalkyl, C3-C7 cycloalkyl, C1-C7 alkoc- MAZSOOV", -MASOMAZV, -MA?5O2B: or -SM. sy, -SOMA?A?, OB", 50X8Я, O-(C1-Cv alkylene )- Mostly, B? is azetidinil, piperidin-

SOMVAUA?, O-(C1-Ce alkylene)-MA»A? or O-(C1-Cv nyl, tetrahydrofuranyl, piperazinyl or alkylene)-ORE; or naphthyl. morpholinyl, each is, optionally, substituted-

Preferably, B" is a phenyl substituted by P, a C-Cv alkyl, -50285, -"SOMAZV?, -SOOVU, - halogen, -CM, C1-Ce alkyl, C1i-Cv haloalkyl- CO-(C1-Ce alkylene)-OR? or -SOVZ and, optionally, C3z-C7 cycloalkyl, C1-C6 alkoxy, -vo, substituted on a carbon atom that is not a neighbor-

SOMAZA", ОВ, 5ОХА, О-(С1-Св alkylene)- nime with a heteroatom, -ОВ? or -MA?SOVU.

COM", O-(C1-Cv allylene)-MA?A", or O-(C1-Cv Preferably, B? is azetidinyl, piperidyl-alkylene)-OB. nil, tetrahydrofuranil, piperazinil or

Preferably, BZ is pyrrolyl, imidazolyl, pimorpholinyl, each is, optionally, substituted razolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, nim -CH3, -502CH3, -СОМН». -СООСН»z, - tetrazolyl, oxazolyl, isoxazolyl, thiazo-СОоСнНгОосСН» or -СОСН;» and, optionally, zamilyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4- substituted on a carbon atom that is not adjacent to oxadiazolyl, furanyl, thienyl, pyridi-heteroatom, -OSH3 or - MNSOSN". nil, pyridazinil, pyrimidinil or pyrazini- Mainly, PE? is 4-methoxypiperidin-1-yl,

4-aminocarbonylpiperidin-1-yl, 4- in methylcarbonylaminopiperidin-1-yl, piperazin- | in 1-yl, 4-methylpiperazin-1-yl, A- -y and () methylcarbonylpiperazin-1-yl, 4- -k methoxymethylcarbonylpiperazin-1-yl, 4- in methoxycarbonylpiperazin-1-yl, 4- or its pharmaceutical an acceptable salt, methylsulfonylpiperazin-1-yl, morpholin-4-yl, or a derivative in which: yl, tetrahydrofuran-2-yl, morpholin-3-yl, B! is H, C1-C8 alkyl, -OC1-C8 alkyl, -OC3-azetidin-3-yl or 1-methylazetidin-3-yl. WITH; cycloalkyl, the mentioned C1-C8 alkyl is necessarily

Preferably, B" is H, 28, VU, VIZ, C1-Cv alkyl substituted by B"; or -(C1-C6 alkyl)-(C3-C7 cycloalkyl), mentioned in B? is H, C-C3 alkyl, propenyl or C-

Ci-Cv alkyl is, optionally, substituted -OBNH, - attached P", said Ci-C3 alkyl is, optionally-

ОВ", VU, VU, VZ or -SOV'U. mandatory, replaced by -OH, -OSНz, -"ОСНгСНеМН", -

Preferably, B" is H, 28, VU, BZ, C1-Cv alkyl CM, -bO2cCH3, -"СОМН", -С(-МН)МН»г, -СОМНМН", - or -(C1-Cv alkyl) -(C3-C7 cycloalkyl), mentioned by Mne, -МНСН», -Щ(СН3)», -«МНСНаСнНаМнНСОснН», -

C-Cv alkyl is, optionally, substituted -OB? or МНОН»СН»ОСН:, -МНСНаВ!», -МНСОВ'5, 0/-

VZ MNSOSNhOsSnN", or in;

Mostly, B!? is H, 8, B, BZ, -СНu», - BZ is C1-Cv alkyl;

СНосСН3 or -СнНа(cyclopropyl), mentioned -СН3 and - ВИ is phenyl, optionally substituted by ha-

СНесСнН:» is, optionally, substituted -OSH3 or halogen, -CM, C1-Cv alkyl, C1-Cv haloalkyl. scrap, C3-C7 cycloalkyl or Ci-Cv alkoxy; and

Mostly, B!? is H, 8, VU, VZ, -СНu», - B!5 is azetidinil, tetrahydrofuranil,

СнеСН3, -СНгСНгОоСснН», -СНе(cyclopropyl), 4-morpholinyl, piperazinyl, pyrazolyl, oxacyanophenylmethyl, 4-fluorophenylmethyl, 4-diazolyl, pyridinyl or pyrimidinyl each methoxyphenylmethyl, 4- is, optionally, substituted -OH, -MH», oxo or aminosulfonylphenylmethyl or 4-Ci-Cv alkyl or -CO(C1-Ce alkyl). aminocarbonylphenylmethyl. Preferred individual compounds according to

Mostly, V!!! is H or C 1 -C 6 alkyl, mention - the invention is the compounds of the Examples below, especially the C 1 -C 6 alkyl is, optionally, substituted - Examples 117, 118, 119, 120, 122, 123, 124, 125,

OVU, -MA?VU, -MAZSO V, -SOMAZVU, V? or RU. 126, 127 and 128, and their pharmaceutically acceptable salts

Mostly, V! is H or C-Ce alkyl, mention- and solvates. C1-C8 alkyl is optionally substituted - All compounds of the invention (I) can be obtained by

OV? or -MAZSOVZ. well-known ways such as techniques

Preferably, B" is H, -CH3 or -СНеCH", mentioned in the general methods presented here- this -CH3 -СНоСН3 is, optionally, substituted more or with the help of specific methods of description- -ОН or -МНСОСН»: ". sleds in the Examples section, or, in addition, according to the

Preferably, B"! is H, -CH3, -"СНСНаМнНСОСснН» with the help of similar techniques. Presented or -СНСНОН. the invention also covers any one or more-

Preferably, K12 is C1-C4 alkyl substituted with a number of these methods for obtaining compounds

VV, VU -OV5, -"SOMAZV?, -MASOVZ or -MAZ VU. formula (I), in addition to new intermediate con-

Preferably, K12 is C1-C4 alkyl substituted with bow. What are used here.

VU, -ОВ5, -MASOVZ or -МА5АХ. In the following general techniques, V! B2, VZ and

Mostly, V! is C1-C2 alkyl substituted with VI are as described previously for the compound for-tetrahydrofuranil, -OSH3, -MNHSOCH3 or -mules (I), unless otherwise indicated.

MN". Except when either B! or B: is halogen,

Preferably, in which 0 -СНеСНоМН», - -ОВ' or -СМ, the compounds of formula (I) can be obtained

СН.СнН»ОснН», with tetrahydrofuran-2-ylmethyl, - reap using the path shown in Scheme 1,

СНа.СНаМноСОс нн» or -СНгОСН». which is shown below.

Preferably, VIZ is phenyl substituted with halo. In Scheme 1, compounds of formula (I) can be oxidized by odegen, -СМ, -СОВ5, -СОМАЗ», -502МВ5В5, - with the help of condensation of the compound pho-

MA?BO»2B, -OB5, -MAZA», -(C1-Cv alkylene)-MAZV», rmules (II) with the compound of the formula

C-Cv alkyl, halo(Ci-C) alkyl or C3-C7 NgmMnya (M) cycloalkyl. or its salt or hydrate, optionally, c

Predominantly, VIZ is a phenyl substituted halo- the presence of an acid or a base, the base is a perogen, -СМ, -СОМАЗВ?, -БО2МАУВ? or -OVZ. important is a tertiary amine such as triethylamine and

Mostly, B! is phenyl substituted with phto-acid is mainly acetic acid. In a typical rum, -SM, -"СОМН", -5О02МН" or -ОСН". method, a solution of the compound of formula (I) in the

Preferably, B!Z is 4-cyanophenyl, a /3- solvent such as ethanol, is treated with cyanophenyl, 4-fluorophenyl, a 4- compound of formula (M), or a salt or hydrate thereof, methoxyphenyl, 4-aminocarbonylphenyl or 4- and , if used, with a suitable acid or aminosulfonylphenyl. basis, at room temperature

Predominant groups of compounds according to vinification to the boiling point of the solvent. In the transition there are all combinations of preferred definitions for an important technique, the reaction mixture is heated from the individual substances given above. Refrigerant.

Also preferred according to the invention are compounds of the formula (Her)

Scheme 1 is stepwise, or it can be obtained using the reaction of compounds of the formula: ш--ve; n VZSOSsNeHg (x) (in with the compound of the formula no o d'oN (M)

Fo | In a typical procedure, a solution of a compound of formula (XI) in a suitable solvent, such as acetone, is treated with a suitable base, such as cesium carbonate, with a compound of formula (0). in

For (a) the preferred technique, the reaction mixture is heated, for example, with a reflux condenser. No - no - and - necessarily, you can add a nucleophilic cata-

A lyser such as sodium iodide or iodide functional equivalents of the compound of formula (I) may also be used in this reaction. tetrabutylammonium 1; 142 g

These are compounds of the formula (MI) or (MII), in which and x. Compounds of the formula (IX) are either commercially available

Accordingly, each is a suitable group that can be selected from or can be obtained from a compound of the form, preferably -M(C1-C6 alkyl)". The most important were IM(SNz)". В'СОСН»гВг (ХІ)) ц " and the compound of the formula (ХІ) can be obtained from se (M) of the compound of the formula (Х) in the same way as from the compound of the formula (MIP). in io). Compounds of the formula ( Ch) can be obtained by reacting a compound of formula (II) with a compound (MI) of formula (X1). o In a typical method, a solution of a compound of formula (I) in a suitable solvent, such as acetone

Thus, a compound of formula (I) can be treated with a compound of formula (XI) and suitable to obtain by condensation 5 a compound with a base, such as potassium or cesium carbonate, and formula (MI) or (MI) with a compound of formula (M), heated, preferably with the reverse refrigerant or its salt or hydrate, optionally in powder form. Optionally, you can add nucleophilic acid or base, the base is preferably a catalyst, such as sodium iodide or tertiary amine iodide, such as triethylamine and tetrabutylammonium acid. mainly acetic acid. In a typical method, compounds of formula (II) are either commercially dissolved compounds of formula (MI) or (MII) in suitable, or can be obtained using a real solvent, such as ethanol, treatment of compounds of formula (IM) with a chlorinating agent. In a typical procedure, a cooled solution of the compound of formula (M), or a salt or hydrate thereof, and, if used, an acceptable acid of formula (IM) in a suitable solvent, such as or a base, at room temperature- acetonitrile, is first treated with bromide temperature to the boiling point of the solvent. In rabutylammonium and chlorotrimethylsilane and then the preferred method, the reaction mixture is heated with dry dimethylsulfoxide. In another typical one with a reflux refrigerator. Compounds of the formula method, the compound of the formula (IM) is treated with su- (MI) or (MII) are particularly suitable for synthesis lfuryl chloride, optionally, in the presence of compounds of the formula (I), in which P! or RZ, respectively, is a suitable solvent such as dichloromethane. nN. Compounds of formula (I), in which E! or B: there is -ОВ7,

Compounds of the formula (MI), eternal VIENIA! is di- can be obtained using the path shown- methylamino, can be obtained using the rea- in Scheme 2, given below, in which KZ is Section of the compound of the formula (MI) with dimethylformamide-Cv alkyl and 13 is a suitable group that waste - dimethyl acetal at elevated temperature, see, preferably trifluoromethanesulfonate. preferably at about 1002С. Compounds of formula (1) in Scheme 2, in which B! are - mules (MI), in which B' contains H and I! is dimethylamino. (MI) or (MII), in which /! or 12 in the presence of a suitable palladium catalyst is dimethylamino, can be obtained analogously. jam and carbon monoxide. In a typical technique,

A mixture of the compound of formula (XIII) is heated, a suitable palladium catalyst, such as chloride 1,1"-

(MT) bisidiphenylphosphino)-ferrocenepalladium (II), an alcohol of formula (XXI) and, optionally, a suitable solvent, such as M,M-dimethylformamide, is important at about 50"C, in an atmosphere of mono- and (x) carbon dioxide, preferably at a pressure of 345 kPa. at

Compounds of the formula (MI!) are either commercially available

Scheme 2 Chloroketoesters of formula (XIX) and (XX) are or

B" are commercially available, or can be prepared by chlorination of the corresponding ketoester, for example using sulfonyl chloride. Alternatively, compounds of formula (I) in which B' or C is -OB" can be prepared from the compound of the formula (XM) or (XMI), respectively, with the help of

I B and "reactions with the compound of the formula (XXI) under the conditions of dehydra- ) or (XMI) in a suitable solvent, such as tetrahydrofuran, is treated with diethyl azodicarboxylate, triphenylphosphine (Ii in Is a compound of formula (XXI). o on b B: Compounds of formula (I) in which B' or BZ is halo - in Я Ba om gene, it is possible to obtain by means of the reaction, ve ZIM de no ЗM de, respectively, a compound of the formula (ХМ) and a compound of the formula (ХМИ) with a suitable halogenating agent. In a typical method, a compound of the formula (ХМ) or ( KhMI) are treated with ROSI", optionally in the presence of a suitable solvent, such as dimethoylformamide, obtaining a compound of the formula (His), in

With himself) With hmm which V! or RU, respectively, is chlorine.

KM. And if iy and -

Mn Me A specialist in this field should be able to see. - it is interesting that in many cases, compounds of formula (I) can be transformed into other compounds of formula (I) o) by means of transformation of functional

Compounds of formula (Xi) can be obtained by groups. For example: by modifying the compound of the formula (XU). In (a) compounds of formula (I), in which B? is H, it is possible, when IZ is trifluoromethanesulfonate, to convert into compounds of formula (I), in which B? is, a suitable modifying agent is phenyltri- optionally substituted C1-C6 alkyl, by flamide. In a typical technique, when the IR is trifluoro-reaction with an acceptable alkylating agent. In thimethanesulfonate, a solution of the compound of the formula according to the method, a solution of the compound of the formula (I), in (XU) and a suitable base, preferably trialkylamine, which B? is H, in a suitable solvent such as triethylamine, in a suitable solvent, ethanol or M,M-dimethylformamide is treated such as dichloromethane treated with phenyltrialkyl bromide and a base such as ethoxide na- flammide. tritium or sodium hydride and heated at a temperature of

The compound of the formula (XM) can be obtained in a round from room temperature to temperature using the reaction of the compound of the formula (XMII) from refluxing the solvent. compound of formula (M), or a salt or hydrate, A preferred combination is M,M- optionally in the presence of an acid or a base, dimethylformamide as a solvent, sodium hydride, the base preferably being a tertiary amine such as a base, and room temperature , as temperature - triethylamine and the acid is mainly acetic acid. Examples of special alkylating agents are lots. In a typical procedure, a solution of the compound formobromoacetonitrile, ethyl 4-chloroacetoacetate, methyl li (CHMI) in a suitable solvent, such as bromoacetate and chloroethylamine hydrochloride. Use ethanol, treat the compound of formula (M), or its formation with other special alkylating agents with a salt or hydrate, and, if used, shown in the Examples below; with a distinct acid or base, at temperature (b) of the compound of formula (I), in which B', B? or 3 from room temperature to boiling temperature- contain an ester group, a suitable solvent can be recovered. In a preferred method, the reaction mixture is heated under reflux with a reducing agent such as aluminum hydride. lithium chloride, obtaining the corresponding compounds of the formula

Compounds of the formula (CHMII) can be obtained by (), in which E!, B2 or EZ contain a hydroxy group. Using the reaction of the compound of the formula (XIX) with a typical method, a solution of the compound of the formula (1) in the mixture of the formula (XI). In a typical method, which solution is B, B? or EZ contain an ester group, in addition, compounds of the formula (CHMII) in a suitable soluble solvent, such as diethyl ether, such as acetone, are treated with a compound for- treated with lithium aluminum hydride, preferably with muly (Xi) and a suitable base, such as carbo-cooling to a temperature from -782C to 02C; potassium or cesium salt, and heated, preferably from (c) a compound of formula (I), in which B", B2 or EZ is a reflux. Optionally, it is possible to substitute a substituted heterocycle of formula B, a nucleophilic catalyst can be added, such as with the help of standard reactions of sodium iodate or tetrabutylammonium iodide.

In Scheme 2, compounds of formula (I) in which KZ is present - see, for example, Admapsei Ogdapis Spitivig,

ОВ" can be obtained from the compound of formula (XX) Zha Edyop, Bu Segpu Magsp apa Sotrgepepvime in the same way as the compound of formula (1), Neiegosusiis Spetivigu, A.V. Kaigiku, S M. Veev, in which VE! is -OB", which is obtained from the compound for- E. E. M. bsymep, Moshtev 1-11). For example, spomula (XIX), as described above, tshyaii5 tshapaiv5. bows of formula (I), in which B? is (2-amino-6-

hydroxypyrimidin-4-yl)umethyl, it is possible to obtain such solid pharmaceutical compositions, for example, by the following reaction of the compound of formula (I), in a case, tablets, may contain such excipients as in which B2 is H, with chloroacetoacetate and then hydromicrocrystalline cellulose, lactose, citrate na- guanidine chloride. This and other similar reactions of triium, calcium carbonate, calcium dihydrogen phosphate, the formation of a heterocycle are shown in Examples niglycine and starch (mainly corn, starch; and potato or tapioca starch), desynteg- (y) compounds of formula (I), in which B ! or P generators, such as sodium starch glycolate, croscar-

СО»2В?, where B? is other than H, it is possible to obtain sodium molasses and some complex silicates, as well as by conversion into compounds of the formula (II), into binding agents, such as polyvinylpyrrolidone, hydro- which ВЕ! or РZ, respectively, is -СО2Н by hydroxypropylmethylcellulose (HPMC), hydroxypropylolysis. A typical reaction will be carried out in cellulose (HPC), sucrose, gelatin and gum arabic. solvent such as aqueous ethanol or Lubricants such as aqueous 1,4-dioxane and in the presence of a base such as magnesium stearate, stearic acid, sodium glyceryl hydroxide may additionally be included. Thus, the acid can be converted into behenate and talc. into the primary amide by reaction with ammonia A general example and a suitable condensing agent such as ca- Usually, the tablet formulation can typically rbodiimide, such as dicyclohexylcarbodiimide. contain from approximately 0.img to 500mg of active

Such primary amide can then be converted into compounds, while the total weight of the tablet can nitrile by dehydrogenation with a suitable dehydra- range from 5O0mg to 1000Omg. Next, a quenching agent, such as phosphoryl chloride; and an example of a tablet formulation is given: (e) a compound of formula (I), in which B! or VZ is Si-

Sv alkyl, can be converted into compounds for-ingredients up to weight/weight of mule (I), in which B' or RU, respectively, is a Ci-Cv alkyl- Compound of the formula 10.0007 by a substituted halogen (such as bromine ), by Lactose 64.125 halogenation, using a suitable Starch 21.375 halogenating agent. The reaction is usually carried out in the presence of a solvent such as a haloalkane magnesium stearate 1.500 (for example, dichloromethane) and at room temperature. Suitable halogenating agents are the amount determined according to the activity of the halogen (eg bromine) or M-halosuccinimide of the medicinal product (eg M-bromosuccinimide).

Compounds of the formula (I) containing -OH, -MH- or -MH»o group can be obtained by removing Tablets are made with the help of state protection from the corresponding compound bearing -OR'! -MR!- dart techniques, for example, directly pre- or -MNR' group, respectively, where the group P! is the application of either wet or dry granulation. tne protection group. Examples of suitable substances will be apparent to the person skilled in the art. industry (see, for example, "Rgoiesiipd dhotsMirz ip Solid compositions of this type can be

Ogdapis bupipevzie (besopa Eayop)" of Tneodoga are also used as fillers in jela-

M. sgeep apa Reyeg S. M. Mu/tsiv, 1991, dhoppe UUupe tinovyh or GOMTS capsules. Predominantly eksi- apa Bopvi). Such compounds bearing "OR! -MR'!- or pients in this case are lactose, starch, -MNR! group, can be obtained using cellulose, milk sugar or polyethylene glycol ways described above, tshaii5 tshapaiiv. with high molecular weight. For water su-

Compounds of formula (IM), (M) and (XXI) are either commercially available suspensions and/or elixirs of compounds of formula (I) or are readily prepared by combining with various sweeteners by methods known to those skilled in the art. . or flavors, dyes, emulsifiers

Compounds of formula (I) may be administered as carriers and/or suspending agents, as well as alone, but are usually administered in co-diluents such as water, ethanol, admixtures with pharmaceutically acceptable excipients ethylene glycol and glycerol, and combinations thereof. We, diluents or carriers, selected according to the compounds of formula (I) can also be administered by the desired route of administration and the usual parenteral, for example, intravenous pharmaceutical practice. but, intraarterially, intraperitoneally

For example, the compounds of formula (I) can be administered orally, intrathecally, intraventricularly, orally, buccally, or sublingually in fore-intraurethral, intrasternal, intracranial tablets, capsules, multiparticles, gels, pleurally, intramuscularly, or subcutaneously. , or tongues, ovules, elixirs, solutions or suspensions, which are intended to be injected or may contain flavorings or dyes, for injection. For parenteral administration, it is better to use them in the form of sterile water, delayed, combined, controlled solutions that may contain other substances, or pulsating release. Compounds of the formula, for example, a sufficient amount of salts or glucose, (I) can also be administered in the form of doses that make the solution isotonic with blood. Aqueous forms of rapidly dispersing or dissolving solutions should be suitably buffered (drinking or in the form of a high-energy dispersion, preferably up to the level of riHZ3-9), if necessary. or coated particles. Suitable Formulations The preparation of suitable parenteral recep- compounds of formula (I) may be coated or uncoated under sterile conditions is easily carried out as desired. of standard pharmaceutical methods, reports

to our specialists in this field. For local use on the skin, compounds

For oral and parenteral administration, the formulas (I) can be made in the form of human patients, the daily dose of an ointment containing the active compound, a suspension of the compounds of the formula (I) will usually be found or dissolved in, for example, a mixture one or more in the range from 0.01 to 30 mg/kg, preferably from more of the following substances: mineral oil, 0.01 to 5 mg/kg (in a single or divided dose). liquid vaseline, medical vaseline, propylene

So, for example, tablets or capsules of spolicol, compounds of polyoxyethylene, polyoxypropyl alcohol of the formula (I) can contain from 1 mg to 500 mg, emulsifying wax and water. Alternatively, the active compound for single administration, they can be made in a form suitable- or twice, or more times, as suitable. The doctor in the lotion or cream, suspended or dissolved, in any case will determine the dose that will be neni in, for example, a mixture of one or more of the most appropriate for each individual incoming substances: mineral oil, cient and which will vary depending on sorbitol monostearate, polyethylene glycol, liquid age, weight and individual patient response. Vischena-paraffin, polysorbate 60, cetyl esters, administered doses are examples of the average case. wax, cetearyl alcohol, 2-octyldodecanol,

There may be individual cases when benzyl alcohol and water. a higher or lower level of doses is more accept- Compounds of formula (I) may also be the reason- Its such doses are within this range- used in combination with cyclodextrin. Cycling. It should be clear to the expert that when dextrins are known for the formation of inclusion complexes in the treatment of some states of the compound of formula (I), wetting and non-inclusion compounds with molecules should be used in a single dose, i.e., a medicinal product. The formation of a medicinal complex - as needed or desired. Diclodextrin can modify the

Compounds of formula (I) can be determined by their potency, dissolution rate, bioavailability transnasally or by inhalation, and ease of administration and/or stability of the drug molecule. They come from an inhaler containing a dry powder, plexi drug-cyclodextrin, general or aerosol spray with a sealed container, suitable for almost all dosage forms of ner, pump, nebulizer or nebulizer with and routes of administration. As an alternative, formed by the use or not of a suitable propellant, a complex with a drug, cyclodextrin, for example, dichlorodifluoromethane, trichlorofluorostrin can be used as an auxiliary methane, dichlorotetrafluoroethane, hydrofluoroalkane admixture, for example, as a carrier, well, such as 1,1,1,2-terafluoroethane (NEA 134А of a diluent or solvent. In most cases, alpha-, beta- and gamma- heptafluoropropane is used (NEA 227EA Trademarks), cyclodextrins, acceptable examples are described in carbon dioxide or other suitable gases. In the case of MO-A-91/11172, MO-A-94/02518 and M/O-A- aerosol which under pressure, dosed 98/551481). unit may be determined by provid- It should be understood that all references to its valve releasing specified treatment include curative, palliative, and quantity. Hermetic container, pump, powder - preventive treatment. rizer or nebulizer may contain a solution Oral administration is preferred. or a suspension of an active compound, for example, included within the boundaries of the present application of a mixture of ethanol and propellant as the invention are embodiments that include a common in- solvent, which may additionally contain lubrication of the compound of the present invention with one cant, for example, sorbitol trioleate. Capsules and car- or more additional therapeutic triage (made, for example, from gelatin) for agents and compositions containing compounds intended for use in the inhaler or insulfator of the present invention, together with one or more, may contain a powdery mixture of compounds according to the number of additional therapeutic agents. Such but with the present invention and a suitable powdered combination therapy are particularly useful for a base such as lactose or starch. prevention and/or treatment of HIV infection and

Alternatively, the compounds of formula (I) can be administered in the form of a suppository or pessary in strains resistant to any monotherapies. or they may be administered topically in the form Alternatively, additional therapeutic agents of a gel, hydrogel, lotion, solution, cream, ointment, or powder may be desired for the treatment of disease. Compounds of formula (I) can be caused by, or are accompanied by, dermal or transdermal absorption, an abscess treated with the compound shown, for example, in the form of a patch on the skin. They are my invention. For example, in the treatment of HIV or rabies, it can also be prescribed ocularly, depending on retroviral infection, it may be desirable - pulmonary or rectal routes. but additional treatment with opportunistic infections

For ophthalmic use, compounds, neoplasms and other conditions that have ky can be made in the form of finely ground as a result of the state of immunodeficiency in patients suspensions in isotonic, given pH level, nts being treated. sterile saline solution, or, preferably, Preferred combinations of the presented wine- isotonic sterile saline solutions preferably include simultaneous or sequential treatment with a pH level, optionally, in combination with a decoction with a compound of formula (I), as defined above , excipients such as benzalkonium chloride, and Al- or a pharmaceutically acceptable salt thereof, and: alternatively, they can be made in (a) one or more inhibitors in the form of an ointment, based on petroleum jelly. reverse transcriptase, such as zidovudine,

didanosine, zalcitabine, stavudine, lamivudine, rusiv (TSIO5O 10'"/ml) was added to 106 cells and abacavir and adefovir; incubated for 1 hour at 37"C. Cells (b) with one or more non-nucleose- then washed twice with ETS and resuspended in days of reverse transcriptase inhibitors, such as culture medium to the density of nevirapine, delavirdine and efavirenz; 2.2x105 cells/ml. 180 μl of these infected cells (c) with one or more inhibitors were transferred into the wells of a 96-well plate, which

HIV proteases such as indanivir, ritonavir, sac- containing compounds. vinavir and nelfinavir; 4) Were the tablets incubated in CO? incubator with (y) one or more antagonists of 37"C for 4 days. The degree of death was determined

SSR, such as TAK-779; cells using the following recommendations (d) by one or more antagonists (SePTyeg 965 OSueoi Mop-VNadioasiime Avzau-

Skhetya, such as AMO-3100; Rgoteda (cat Me:55430)). The concentration at which (e) by one or more inhibitors, the compound inhibits the cytotoxic effect of the virus on 5095 Tegras; expressed as ESvo. (is) one or more inhibitors of Russian fusion, such as T-20; () a compound of formula (I) or its pharmaceutically acceptable salt, solvate or derivative; (her) method of medicinal products, such as trizivir, KMI-272, obtaining a compound of formula (I) or its pharmaceutical amprenavir, SMU-33908, RTS, PMRA, 5-1153, a technically acceptable salt, solvate or derivative;

MkKo-442, M5O-204, M5N-372, OMRAB5O, RMIO- (its) pharmaceutical composition containing 140690, AVvT-378, KMI-764, YuRO-083, TMO-120 compound of formula (I) or its pharmaceutical composition - or TMO-125; or a distinct salt, solvate, or derivative, together with (3) one or more pharmaceutically acceptable excipients, diluents, or antibacterial agents, such as a diluent or carrier; conazole. (m) a compound of formula (I) or its pharmaceutical

The activity of the compounds of the invention as inhibitors of an acceptable salt, solvate or composition, for oral transcriptase and as agents for the treatment of use as a medicine;

HIV infections can be measured using (m) a compound of formula (I) or its pharmaceutical subsequent studies. acceptable salt, solvate or composition, for

A. inhibition of HIV-1 reverse transcriptase using as an inhibitor or modulator of reverse transcriptase

Activity of the compound of the invention in relation to the transcriptase; of reverse transcriptase can be determined by (m) a compound of formula (I) or its pharmaceutical step. The used purified, acceptable salt, solvate or composition for HIV-1 binding reverse transcriptase (VT, EC, in the treatment of HIV, or genetically dependent ret- 2.1.1.A49) was obtained by expressing a rovirus, an infection or a conditioned syndrome

Ezspegispia Soyii, for the study of severe multiple acquired immunodeficiency (AIDS); hundreds of samples usually use a 96-well (mi) use of a compound of formula (It) or its tablet containing the test system- a pharmaceutically acceptable salt, solvate or

Poly(hA)-oligo(dT) reverse transcriptase

ZRA (Ategzpat MK9UO20) or the studied system inhibits or modulates reverse transcriptase; topic IZNI-flashplate (MEM-ZMR 103) and the following (my) use of the compound of formula (I) or its recommendations for its manufacture. Compounds are dissolved in a pharmaceutically acceptable salt, solvate or lye in 10095 DMSO and diluted with an acceptable bufe- composition, for the manufacture of a medicine for rum to a final concentration of DMSO 5595. |inhibitor- treatment of HIV, or E genetically determined nu activity was expressed as a percentage of retrovirus inhibition, infection or conditioned syndrome relative to control DMSO. Concentration in acquired immunodeficiency (AIDS); which compounds inhibit reverse transcriptase on (their) method of treating a mammal, including lu- 5096 were expressed as ICs of the compounds. Prikladin compounds, using an inhibitor or modulator of divs 7, 20 and 51, when researched using reverse transcriptase, consisting in the introduction of the technique described above, had values of ISvo, the mentioned mammal of the effective amount of the compound, respectively, 39000, 3200 and 2498 nanomoles. of formula (I) or its pharmaceutically acceptable

B. Study of cell culture Anti-Virus salt, solvate or composition; human immunodeficiency virus (HIV-1) (x) a method of treating a mammal, including human

The anti-HIV activity of selected Examples of HIV-affected species or genetic findings was investigated using the following conditioned retrovirus, infection, or condition-methodology. of acquired immunodeficiency syndrome (AIDS), 1) Z,irT1 cells were cultured in an environment that consists in introducing the said mammal

ARMI-640 supplemented with 1095 embryonic teletive amounts of the compound of formula (I) or its whey powder and separated so that they were in a pharmaceutically acceptable salt, solvate, or growth phase on the day of use. positions; and 2) The compounds were dissolved in 10095 DMSO and developed (xi) some new intermediates are described here. in the above-mentioned culture medium. The following Examples reveal the preparation to the given concentrations and distributed as compounds of the formula (I). Synthesis of some intermediate 20μl aliquots in 9b-well microtiter compounds used here is described in tablets (final DMSO concentration 0.190). section Preparation, which is given after the

C) Received infected cells, 10 μm of KE section Examples.

IN spectra of nuclear magnetic resonance (461mg, 3.07mmol) was added sequentially to the solution (NMR) in all cases corresponded to the proposed mixed solution of chloroketone to the prepared structures. Characteristic chemical shifts (5) of 2 (500mg, 3.07mmol) in acetone (15ml) were carried out in parts per million relative to tetra- room temperature and in an atmosphere of nitrogen, or methylsilane using the well-known chewing orange/red suspension. A mixture of heat-abbreviations for the designation of the main peaks: heaps with reflux during 2290 example s, singlet; d, doublet; t, triplet; k, quar- hours, obtaining a yellow suspension. After cooling; m, multiplet; w, wide The following abbreviations were used: the mixture was diluted with water (10 ml) and acetone: VRMS, high resolution was removed under reduced pressure in vapor trap- mass spectroscopy; HPLC, highly efficient extractant (attention: possible presence of remnants of lacrimal chromatography; ISe, nuclear effect of the extractive substance). The remainder was diluted with 2M chlorvohauser; Tpl., melting point; COSys, diacetic acid and deuterochloroform was extracted with dichloromethane; О6-DMSO, deuterodimethyl- (1 (20 ml, 2 (10 ml). The combined organic layers are prosulfoxide; СозОХ0, deuteromethanol. When washed with a saturated aqueous solution of chloride, thin-layer chromatography of sodium (20 ml) was used, dried over magnesium sulfate, (TLC), this means that it was carried out on TLC, filtered and concentrated under reduced silica gel using pressure silica gel plates to obtain crude 4-(3,5- 60 Rgvi, Vi is the distance traveled by the compound dichlorophenoxy)-3,5-heptanedione as orange mass separating from the front of the solvent on TLC (777 mg). A portion of crude /-4-(3,5- plates. dichlorophenoxy)-3,5-heptanedione (250 mg, pr.

Example 1 0.865 mmol) was dissolved in ethanol (8.bml) and treated with 2-14-(3,5-Dichlorophenoxy)-3,5-dimethyl-1-yl-2-hydroxyethylhydrazine (b5ml, pyrazol-1-yl). ethanol 0.951 mmol). The obtained solution was heated with a liquid refrigerator for 16 hours, obtaining a red solution. After cooling, dry, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The stripped solution was washed with 2M hydrogen chloride quinone slot (1Oml), 1M sodium hydroxide solution 2-Hydroxyethylhydrazine (21.5μl, (TOml) and a saturated aqueous solution of chloride 0.316mmol) was added to the stirring solution of sodium (1Oml ), dried over magnesium sulfate, or b-diketone Preparation 100 (75 mg, filtered and concentrated at reduced 0.287 mmol) in ethanol (2.9 ml) at room temperature to give an orange oil (102 mg). The temperature in a nitrogen atmosphere and the obtained orange-purified product was purified using a flash solution was heated under reflux chromatography on silica gel using B for 18 hours. After cooling, the eluent quality mixture of methanol:dichloromethane (5:95, volume-concentrated under reduced pressure. The residue of many) to obtain the title compound was dissolved in dichloromethane (20 ml) and washed with 2M similar solid substance at soy in visco-hydrochloric acid (TOml) and saturated water "H-NMR (400 MHz, SOS"): 5-1.08 (t, ЗН), 1.12 sodium chloride solution (1Oml) and then dried over magnesium sulfate, filtered and concentrated (t, ZNU, 2.38 (k, 2H), 2.48 (K, 2H), 3.69 (she, 1H), centered under reduced pressure to obtain 4.02 (m, 4H), 6.76 ( c, 2H), 6.97 (c, 1n). and a viscous orange oil. Crude product NRMEES (thermospray): t/x МН") 329. purified by means of flash chromatography on Example C and using silica gel as eluent pent-4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol tane: ethyl acetate (10:1, by volume) then dichloromethane to obtain the title compound (32 mg) as a white powder , Tpl. 114-11576. sn, "H-NMR (400MHz, SOSI"): 6-2.08 (s, ЗН), 2.10 о (s, ЗН), 3.30 (t, 1Н), 4.06 (m, 4Н ), 6.79 (c, 2H), 7.01 not - (c, 1H).

NRMS (thermal spraying); t/g MH) 301. Mixture of chloroketone Preparation 2 (g,

Microanalysis: Found: C, 51.76; N, 4.64; M, 30.8 mmol), 3,5-dichlorophenol (5 g, 30.8 mmol), 9.20. SizNi"O2M2O" must be C, 51.85; N, 4.69; M, cesium carbonate (10g, 30.8mmol) and acetone (40ml) 9.309. was heated under reflux

Example 2 18 hours. After cooling, the solid 2-I4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H- was removed by filtration and washed with dichloromepyrazol-1-yl|ethanol (100 ml). The combined filtrates were concentrated under reduced pressure. The crude product was dissolved in ethanol (20 ml), hydrazine hydrochloride (1.5 ml, 30.8 mmol) was added, and the mixture was heated at 60 °C for 30 minutes in a nitrogen atmosphere. After cooling, the mixture was concentrated at - under reduced pressure and the residue was purified using 3,5-Dichlorophenol (501 mg, 3.07 mmol), carbonate flash chromatography on silica gel using potassium (467 mg, 3.38 mmol) and sodium iodide or ether as an eluent :pentane (1:1, by volume)

affording the title compound (5.5g) as (bOmg) as a white solid, m.p. 142-14476. yellow oil, which solidified on standing, giving 1N-NMR (400 MHz, DMSO-iv): 6-0.89 (ZH, t). yellow solid, m.p. 114-11576. 0.99 (ZH, t), 2.26 (2H, yu), 2.45 (2H, yu), 5.01 (2H, s),

IN-NMR (300 MHz, SOCI3): 6-1.15 (6H, t), 2.48 5.19 (1H, s), 6.88 (2H, s), 7.21 (1H, s). (AN, ky), 6.78 (2H, s), 6.95 (1H, s). NRMS (electrospraying): t/2 (M-N"U) 379.

NRMS (thermal spray): t/z2 (MH" | 285. Microanalysis: Found: C, 55.39; H, 4.72; M,

Microanalysis: Found: C, 54.93; H, 5.05; M, 14.69. C17NivSi2MaO" must be C, 53.56; N, 4.76; 9.94. SiZNi«Si2M2O must be C, 54.75; H, 4.95; M, M, 14.6996. 9,829. Example 6

Example 4 6-14-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-

14-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-ylmethyl)-2-methyl-4(ZH)-pyrimidinone pyrazol-1-yl|acetonitrile a c sn, sn, o , y - no g ke s. IN

Sodium hydride (6095 dispersion in oil, 47Omg, p 11.6mmol) was added to the solution, which was stirred. -1 H- of 3, acetamidine hydrochloride (95 mg, pyrazole (Zg, 10.5 mmol, Example 3) in dry 1.0 mmol), sodium ethoxide (68 mg, 1.0 mmol) and

M,M-dimethylformamide (20 ml) at 0"С in atmospheric ethanol (5 ml) was stirred and heated at 707С under a nitrogen atmosphere. The mixture was stirred for 5 minutes - for 1 hour in a nitrogen atmosphere. After cooling, during which hydrogen was released and then addition, the mixture was concentrated under reduced bromoacetonitrile (0.81 ml, 11.6 mmol). Dry M,M- was added with magnesium sulfate and concentrated under reduced dimethylformamide (5 ml) to merge with dissolution under pressure, obtaining the compound indicated in the title, and after 45 minutes the reaction mixture was quenched by adding onion as a white foam (100 mg) or water. (Iml). The mixture was separated between water "H-NMR (300 MHz, SOSIv): b-1.10 (ZH, t), 1.19 (15Oml) and diethyl ether (2 (150ml). Combine- (ZH . , 7.03 (1Н,о) with an aqueous solution of chloride sodium (100 ml), HPMS (thermal spray): t/x (MH) 407. dried over magnesium sulfate and concentrated Example 7 under reduced pressure. The crude product 2-Amino-6-1|4-(3,5-dichlorophenoxy)-3,5-diethyl- was purified by flash chromatography on 1H-pyrazol-1-yl|methyl)-4(ZH)-pyrimidinone silica gel using dichloromethane as an eluent, obtaining the title compound (3.2 g) as a yellow powder, mp. 70-7276. lu sn, "H-NMR (400MHz, SOSIv): 6-1.14 (6Н, m), 2.38 4 (2Н, у, 2.56 (2Н, ку), 4.92 (2Н, с) , 6.75 (2H,s), 7.00 -y- (1H,o). but with -

Microanalysis: Found: C, 55.43; N, 4.69; M, at 12.71. Si5Ni5Si2MzO must be C, 55.57; N, 4.60; student

M, 12.9695. not

Example 5 A mixture of the ester (150 mg, 0.365 mmol) of Prepared 5-(4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-) and guanidine hydrochloride (104 mg, pyrazol-1-yl|methyl )-1H-pyrazol-3-ol 1.08 mmol) and sodium ethoxide (7 mg, 1.08 mmol) in ethanol (ml) were stirred and heated at 707 for 3 hours under a nitrogen atmosphere. After cooling, cooling, the mixture was concentrated under reduced pressure and the resulting oil was dissolved in dichloromethane. no (HOml), washed with water (20ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using

Ester mixture (120mg, 0.29mmol) Preparing as eluent dichloromethane 3, hydrazine hydrate (16mg, 0.29mmol) and ethane:methanol:ammonia (90:10:11, by volume) obtaining zero ( zml) was stirred and heated at 607 to give the title compound as a white solid for 2 hours in a nitrogen atmosphere. After protection (ZOmg), Tpl. 238-24020. cooling, the mixture was concentrated at reduced IN-NMR (400 MHz, DMSO-dv): 6-0.91 (ЗН, t), pressure and the obtained white solid was mixed- 0.99 (ЗН, t), 2.29 (2Н . 87 (2H, c), 7.22 (1H, not obtaining the title compound c).

NRMS (thermal spraying): t/2 МН") 408. p. si

Example 8, 2-I4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-4pyrazol-1-ylI|I-H-hydroxyethaneimidamide and 1,1-Carbonyldiimidazole ( 71mg, 0.44mmol) 7 was added to the stirred solution of the acid (125mg, 0.3bmmol) Preparation 4 in dry M,M-

NM on dimethylformamide at room temperature and

Hydroxylamine hydrochloride (1.1 g, 15.8 mmol) and the reaction mixture were stirred for 30 min and potassium carbonate (2.1 g, 15.2 mmol) was added to the mixture. Concentrated aqueous ammonia was added to the nitrile suspension (1g, 3.1 mmol) of Example 4 in a mixture of methanol (25 ml) and water ( 1 Oml), which was then mixed with the contents for 10 minutes. Dissolved under reflux for 30 days. After cooling, the mixture was extracted and separated between water (1Oml) and ethyl acetate dichloromethane (2 (250ml) and combined organics (1Oml). The organic layer was concentrated under ), dried over sulfate, chromatography on silica gel using magnesium, filtered and concentrated under ethyl acetate as the eluent, obtaining the indicated product as a white solid, title compound as a white solid (bOmg), substance (1.1g), Tpl. 128-13076. Tpl. 164-166. "H-NMR (З3О0МГЦц, СОзО0): 6b-1.10 (6Н, m), "Н-NMR (З00МГу, СОСИ з): 621.15 (ВН, m), 2.50 2.40 (2H, yu), 2.60 (2H, yu), 4.65 (2H, s), 6.90 (AN, m), 4.70 (2H, s) , 5.50 (IN, w s), 6.21 (IN, w s), (2H, s), 719 (1H s), 6.78 (2H, s), 7.04 (1H, s) .

NRMS (electrospraying): t/2 (МН 357. НРМЕС (thermal spraying): t/2 (МН") 342.

Example 9 Example 11

Methyl 1(|4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-2-(4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl |Iacetate pyrazol-1-yl|Iacetohydrazide and iodine; sn, sn, a. o. - va m ra u ne i o

Methyl bromoacetate (984 μl, 1 mmol) and then hydrazine hydrate (520 μl, 10.9 mmol) were added. in ethanol (25 ml) and the resulting mixture was heated with pyrazole (2.6 g, 9.12 mmol) of Example C under reflux for 18 hours. dry M,M'-dimethylformamide (25ml) at 02С in After cooling, the precipitate was collected by filtration under a nitrogen atmosphere. After stirring throughout and washing with ether (50ml) to obtain the indicated ice-water (100ml) and the title compound (550g) were added as a white solid in 1 hour at 0"C, the mixture was extracted with ether (3 (5Oml). The combined Tpl. х25076. ether layers were dried over magnesium sulfate, fi- "H-NMR (ЗО00МГцу, СОзО0): 6-1.10 (ВН, m), filtered and concentrated under reduced pressure - 2.39 (2Н, ю, 2.55 (2Н, ю, 4.72 (2Н, s), 6.93 cu. The residue was purified using flash chromatography on silica gel using NRMES (electrospray) as : t/2 (МН"У) 357. eluent ethyl acetate pentane (20:80, by volume) Example 12 obtaining the compound specified in the title (780 mg) 5-4C4-(3,5-Dichlorophenoxy)-3,5-diethyl- 1H- as a yellow oil, which partially crystallized into pyrazol-1-yl|methyl)-1,3,4-oxadiazol-2(ZN)-one on standing.

1H-NMR (400 MHz, SOSIv): 6-1.10 (6H, m), 2.44 (AN, m), 3.78 (ZH, s), 4.80 (2H, s), 6 .69 (2H, s), sne 6.99 (1H, s).

NRMS (thermal spraying): t/2 (МН) 357. new

Example 10 Kc 2-I4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-"C o pyrazol-1-ylacetamide A stirred solution of the hydrazide (275 mg, 0.77 mmol) of Example 11 and 1, 1"-carbonyldiimidazole 187mg, 1.16bmmol) in dioxane (5Oml) was heated under reflux for 18 hours.

After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane.

rmetani (5Oml) and washed with water (25ml). Orga- days. The obtained solution was diluted with 2M water, the overnight layer was dried over magnesium sulfate, hydrochloric acid (20 ml), extracted, dried and concentrated under reduced pressure. ethyl acetate (2 x 50 ml). Combined organic layers

The residue was purified by flash chromatography, washed with a saturated aqueous solution of raffia chloride on silica gel using sodium (5 Oml) as the eluent, dried over magnesium sulfate, then dichloromethane:methanol (95:5, volume) was filtered and evaporated under reduced pressure by roasting the title compound (112 mg) as a yellow oil. The oil was purified for a white solid. 138-142. with the help of column flash chromatography on the strength

IN-NMR (400 MHz, SOSIz): 6-1.10 (6Н, m), 2.40 kageli using pen- (2Н, ю) as an eluent, 2.55 (2Н, ку), 5.07 (2Н , c), 6.76 (2H, c), 6.98 tan:ethyl acetate (50:50, by volume) obtaining white (TN, c), 10.45 (IN, w c). solid substance The solid substance was dissolved in

NRMS (electrospray): t/z: (МН"| 383. a mixture of tetrahydrofuran (Iml) and 1M aqueous solution

Example 13 sodium hydroxide (1 Oml) and then heated with 2-(4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-reflux for 24 hours. pyrazol-1-yl|ethylamine The resulting solution was diluted 2M hydrochloric acid (20ml) and extracted with dichloromethane (2x5Oml). The combined organic layers were washed with sodium chloride, saturated aqueous solution of sodium chloride (5Oml), dried over magnesium sulfate, filtered, washed and evaporated under reduced pressure "and Mn, chewing the title compound (113mg) as

Mixture of pyrazole (390 mg, 1.37 mmol) Example white solid M.p. 94-9626.

Chloroethylamine hydrochloride (238 mg, H-NMR (400 MHz, SOCI3): b-1.14 (m, 6H), 2.56 2.05 mmol) was stirred and heated at 15070 (m, 4H), 5.06 ( s, 2H), 6.75 (s, 2H), 7.03 (s, 1H). for 24 hours. After cooling, the mixture of HPMS (electrospray): t/2 (M-(H"| 381. was separated between saturated aqueous solution of sodium bicarbonate (100 ml) and dichloromethane 5-C4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H- (gx50ml). The combined organic layers were washed with pyrazol-1-yl| methyl)-1,3,4-oxadiazol-2-amine with a saturated aqueous solution of sodium chloride (SOml), dried over magnesium sulfate, filtered and concentrated under reduced pressure.

The resulting brown oil was purified by flash chromatography on silica gel using dichloromethane:methanol (90:10, by volume) as an eluent to obtain the brown compound indicated in the title (Co, Stwemi) compound 5-09 ( VN, m). 24! Cyanobromide (49 mg, 0.462 mmol) was added to (2H, yu, 2.52 (2H, kyu), 3.18 (2H, t), 4.02 (2H.t), 6.78 Bo that is stirred, pdrazid Gryclad (2N.s), 6.99 (1N,s). (150mg, 0.420mmol) in ethanol (30ml), at room temperature, in a nitrogen atmosphere and obtained

NRMS (electrospray): t/2 (MH) 330. - : I and : NA in and ; , the solution was heated with a reflux condenser for 14 hours. them for 2.5 hours. After cooling, the mixture of vm 12149, ghasyN?O neokohidno C, 52.05; PN, concentrated under reduced pressure, obtaining ! p shi 14 brown butter. The crude product was purified by flash column chromatography on "0 3-Sh43,5-Dichlorophenoxy)-3,5-diethyl-1H-silica gel using dipyrazol-1-yl|methyl1,2-,4 -oxadiazol-5-ol lormethane:methanol:ammonia (98:1.75:0.25, by volume) 9 g to give the title compound (71 mg) as a white powder, mp. 226-22876. sn IN-NMR (400 MHz, SOSIz): 6-1.00 (m, 6H), 2.29 ve (m, 2H), 2.55 (m, 2H), 5.34 (s, 2H), 6 .90 (c, 2H), 7.07 -y! (s2H), 7.24 (s/1H). y y on NRMS (electrospray): t/2 (MN) 382.

I va Microanalysis: Found: C, 49.82; H, 4.52; M, he 17.81. SiovNi7Si2M5O" (0.25 NgO is necessary C,

Ethyl chloroformate (0.3O0ml, 3.08mmol) to - 49.69; N, 4.56; M, 18,1195. added to the stirred solution amidoxy- Example 16 and Example 8 (500 mg, 1.39 mmol) in pyridine M-(2-I4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H- (Vml) at 02С in a nitrogen atmosphere and the obtained pyrazol-1-yl|ethyl)y-2-methoxyacetamide solution were stirred for 10 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of water (4 ml), tetrahydrofuran! be (4ml) and 1M aqueous solution of sodium hydroxide with (2ml). The mixture was heated with a reflux condenser for 1 hour, cooled to room temperature and stirred for another 2. The pyrazole solution of Example 13 (53 MG,

0.161 mmol), 1-(3-substance) hydrochloride was removed by filtration and the filtrate of (dimethylamino)propyl)-3-ethylcarbodiimide (34 mg, concentrated under reduced pressure to obtain 0.178 mmol) and 4-(dimethylamino)pyridine (22 mg, brown oil). was dissolved in ethanol 0.178 mmol) in dichloromethane (Iml) was added to (1Oml), hydroxyethylhydrazine (114mg, a stirred solution, methoxyacetic acid - 1.50mmol) was added and the mixture was heated at 60"C for a lot (14.2μl, 0.178mmol) ) in dichloromethane (1 ml) for 18 hours. After cooling, the mixture was concentrated at room temperature. The reaction was stirred under reduced pressure, the solution of the residue for 12 hours and then concentrated in a stream of dichloromethane (10 ml), washed with 2M aqueous nitrogen chloride, obtaining a yellow solid substance. Hydroxy acid (5 ml) and water (5 ml), dried, the purified product was purified using magnesium sulfate columns, filtered and concentrated flash chromatography on silica gel was used under reduced pressure, obtaining a yellow or dichloromethane:methanol oil as an eluent. The crude product was purified by silica gel flash column chromatography (98:22, v/v) to give the title compound (54 mg) as a brown solid, using ethyl acetate as eluent.

Tpl. 75-7676. yielding the title compound (8Omg) as

IN-NMR (400MGu, SOSI"): 6-1.08 (t, ZN), 1.18 colorless oil. (t, ZN), 2.42 (Kk, 2H), 2.52 (k, 2H), 3.39 (s, ZN), 3.75 IN-NMR (400MHz, SOSIz): 6-1.10 (m, 6H), 2.40 (m, 2H), 3.90 (s, 2H), 4.13 (t, 2H), 6.79 (s, 2H), 6.99 (Kk, 2H) , 2.50 (k, 2H), 3.68 (w s, 1H), 4.07 (m, 4H), (s, 1H), 7.21 (she, 1H). 7.12 (c, 1H), 7.14 (d, 1H), 7.28 (d, 2H).

NRMS (electrospray): t/2 (MN" | 400; NRMS (electrospray): t/2 (MN" | 286;

IM-(NU)) 398. IMMa" | 308.

Microanalysis: Found: C, 54.09; N, 5.79; M, EXAMPLES 20-38 10,39. SivNgzSi2MzOz must be C, 54.01; N, 5.79; Compounds of the following grouped Adjectives

M, 10.50965. divas of the general formula:

EXAMPLES 17 and 18 GU sn,

Compounds of the following grouped Examples 4 of the general formula: U si no. t Mone was obtained by a method similar to that of Example 19 using acceptable phenols and chloroketone. Preparation 2. same dach u. 25 t/h (MH295.. 7 GN-NMR (400 MHz, SOS: 6 and 1.08 (t, o ZNU, 1.15 (t, ZN), 2.44 (k, 2H), 2.54 ( k, .si 2H), 4.02 (m, 2H), 4.09 (m, 2H), 6.89 were obtained by a method similar to the method of OO BShnezhya

of Example 16 using an acceptable acid and (dn) pyrazole of Example 13. 26 ace IMNU 328. "H-NMR (400 MHz, SOS): 8 - 1.01 (t,

ZNU, 1.10 (t, ZN), 2.38 (k, 2H), 2.49 (k,

Example Me NRMS Analytical data IA 2H), Z,B4 (sh s, 1H), 3.99 (m, 4H), 7.01 17 pe MH 43 "H: NMR (400MHz, bOSvX 5-16 | Found: Application МН 4 ZNU 118 (t, ZN), 2.44 (k, 2), 2.52 (k, 2H), m necessary 329.0818 3.92 (m, 2H), 4.24 (t, 2H ), 6.79 (s, 2H), and ! 6yv (s, 1H). 7.40 (m, 1H). 7.82 (m, 1H), 27 v pug (Man Z28. | H-NMR (400 MGu, SOSI"); 5 " 1.09 (t, neoenst kaniya 100 same

Microanalysis: Found: C, 57.01; H, 5.08; 2H), 4.03 (m, 2H), 4.07 (m. 2H). 6.60

M, 11.94. СЛНеСМ.О» is necessary C, | (dk tnu tallow (t tn), background (in Nu 58.21; H, 512; M, 12.0355, 28 Y t/g (MH 329, "H-NMR (400 MHz, SOS): 0 - 1, 08 (t, 18 g tpug (MH 434 "NA-NMR (400 MHz, SOSIv): b o - 1.08 (t, | and ZN), 1.14 (t, ZN), 2.21 (k, 2Н ), 2.51 (k,

SHE PEITISTS

3.96 (m, 28), 4.24 (t, 2), 6.79 (s, 2H), si (d, 18), 7.09 (d, 1H). Microanalysis: 7.01 (s, 7H), 8.22 (w s, 1H), 8.54 (d, 1H), Found: C, 54.68; H, 5.54; M, 812. 8.78 (d, 1H), 9.40 (c, 1H). SuivNcheSi MO" must be C, 54.72; N, 5.51; M, 8.5195, tu IMN 279. H-NMR (400 MHz, SOSC): 5 "1.10 (t,

Example 19 ZNU 114 (t, ЗН), 2.44 (k, 2H), 2.55 (k, 3-1Y3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-pyr 4-yl| Oxybenzonitrile (m, 1H), 698 (m, 2H), 7.12 (m, 1H). dam I KE puh YMNA 279. "H-NMR (400MHz, SOSI"): 5 - 1.09 (t,

T Y ZN), 1.12 (t, ZN), 2.43 (k, 2H), 2.52 (k, 2), 3.78 (sh s, 1H), 4.04 (m. 4H) .

A mixture of chloroketone Preparation 2 (243mg, | (m, 4H), 6.49 (s, 2H), 6.62 (s, 1H). 1.50mmol), 3-cyanophenol (155mg, 1.50mmol), cesium carbonate (488mg , 1.50 mmol) and acetone (1 Oml) were heated under reflux for 2 hours. After cooling, the solid pu/g (МН'Т295., "H-NMR (400 MHz, SOSIv): 5 « 1.08 (t, Example 39) is 4-(3,5-Dichlorophenoxy) )-3,5-diethyl-1-(2-si 2NU, 402 (m, 2H), 4.09 (m, 2H), 6.69 (Z,5-D lord )-8,5-d ( (d. ZNU, ba (t, 10). 70 t, ZN), 740 methoxyethyl)-1H-pyrazole dnu a si 26 pukh (MH 328. TN-NMR (200 MHz, SOSIvu: 5 - 1.01 (t,

ЗН), 1.10 (t, ЗН), 2.38 (k, 2Н), 2.49 (k, сн, 2Н), 3.84 (w s, 14), 3.99 (m, 4Н) , 7.01 b s si (t, 1H), 7.30 (d, 2H). Exact mass: hundred

Found: 3290822 (MN; -

SeNiSMyO" is necessary 329.0818 to M M o-on,

MH, Sodium hydride (6095 dispersion in oil, 34 Amg, 27 pg (MANOIS2av. | H-NMR (400 MHz, SOS); 5 - 1.09 (t, 0.850 mmol)) was added to the solution, which was stirred from scratch (VN , zt Kan vB is found, 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-2H), 4.03 (m, 2H), 4.07 (m, 2H), 8.60 . . BO Tovt of toxyethyl bromide (117mg, 0.850mmol) in dry

ZNU, TM (t, ZN), ZM (Kk. ZM), 21 (K, M,M-dimethylformamide (2 ml) at 0"С in an atmosphere - 2NU, 403 (m, 2Н), 4.08 (m, 2H), 6.62 ri of nitrogen. The mixture was stirred at 0"C for s (d, 1), 7.09 (d, 1H). Microanalysis: 45 minutes during which hydrogen and yellow

Found: C, 54.66; H, 5.54; M, 8, T2. the solution turned dark brown. The reaction mixture

SivNivSCMoO" must be C, 54.72; N, . . . in: MW, the mixture was quenched by adding water (5 ml) and a mixture of conc.

ZNU 114 (t, ZN), 2.44 (k, 2H), 2.55 (k, ly in ethyl acetate (20 ml) and washed with water

E 2H), 379 (w s, 18), 4.06 (m, 4M), 671 (110 ml) and a saturated aqueous solution of chloride k-Y thamnia (zh tn vva (m, VN), lev TU of sodium (10 ml) and then dried over magnesium sulfate. 0 Ex 279. H-NMR (400 MHz, SOSI); 5 - 1.09 (t, H : GP - zn) and t, NI, 24 (con) air, filtered and concentrated under pressure below 2H), 3.78 (sh s, 1H), 4.04 (m, 4H), 6.59 pressure to obtain a brown oil. The crude product was purified using

From t/hIMNoVe. 1 H-NMR (400MG, SOS) 5 - 110, column flash chromatography on silica gel not and ZNO, 447 (t, ZNU, 2.25 (s, VN), 242 (k, using pen-2 as an eluent), 2.2 (un zvo (sh s, TU 505 tan: diethyl ether (80:20, by volume)) obtaining (m, 4H), 6.49 (s, 2H), 6.62 (s, 1H). 7 SHY! the compound indicated in the title (140mg) as colorless 32 powder MH") 293. H-NMR (400MHz, SOS): 6 - 1.09 (t, oil. sc, ЗН), 114 (t, ЗН), 2222 (s, ZNU, 2.42 (Kk, IN-NMR (Z300MHz, SOSIz): 6-1.09-1.15 (m, 6H), Mr. Vom in, won t, 2.41-2.49 (k, 2H), 2.51-2.57 (k, 2H), 3.34 (s, ЗН), plan ' 3.74-3.79 (t, 2H), 4.15-4.17 (t, 2H), 6.81 (s, 2H) vvv(m in). 5 - 11 (t, 7.01 (s, 1n). si ZNU, 117 (t, ZNU, 2.42 (k, 2H), 2.54 (Kk, NRMS (thermal spraying): t/z2 (MN" | 343. 2H), 406 (m, 4), 6.69 (s, 1H), 6.94 Microanalysis: Found: C, 56.25; H, 5.94; M, with (in, NU 78 ( d, 1H). Microanalyves; 7.95. SivNgoSi2M2O" necessary C, 55.99; H, 5.87; M

Found: C, 5A4, BA; H, 5.67; M, 8.48. to ' pa aa

SivNivSk»O» must be C, 54.72; N, 8, 1 (5) o. .

BMI; M, VIeE. EXAMPLES 40 and 41 3 E pukhMN 297. | 'nyMR (abomgi, SOOvu 8 1.09 8, Compounds of the following grouped Examples

ЗН), 1.12 (t, ЗН), 2.42 (k, 2Н), 2.50 (k, general formula: 1 Е 2Н), 3.68 (w s, 18), 4.01 (m , 4H), 6.47 s (m, NU bit (m, NU, 686 (m, NU. o

Microanalysis: Found: C, 60.57; N, ! 623: OM. 09.52. 00 SivNivb»MeO» sleep, necessary C, 60.80; H, 6.12; M, Fr. 9.4505, t ve t/x|mN") 329. "H-NMR (400 MGu, SOS): 5 "1.08 (t, pe zu s ZNU, 112 (t, ZN), 2.41 (k . c, 1H) 7.81 (d, 1). sobu of Example 39 using acceptable ha-

Microanalysis; Found: C, 54.70; H, z and vv M, 850. SeNiSiKio» loids and pyrazole of Example 3. ibhi; C, 5at2: NN, 551; M that Bai PO Ps ponivio Y sb t/x(MH' 297. | H-NMR (400 MHz, SOS): 5 -1.08 (t, Me (thermospray)

ZNU 12 (t, ZN), 2.49 (k, 2H), 2.60 (k, to "on, t/g (MN") 329, "NA-NMR (Z300MHZ, SOS): 6 - 1, 13-

E 2H), ZV! (w s, 1H), 3.99 (m, 4H), 6.91 G 1.18 (m, 6H), 2.45 (k, 2H), 2.50 (k, 2H), 3.37 (c, ЗН), 5.34 (c, 2H), 6.80 (c, 2H), (m. 2H), 6.99 (m, 1H). 37 pUIMNIA 297. | NMR (400Mhz, SOSCH 5 -1.09 (t, t.02 (v, 1H). Microanalysis: Found: k ЗН), 145 (t, ЗН), 2.45 (k, 2Н), 2.55 ( k, s, Bal; NN, bab; M, viyu.

NU, 3.70 (ish s, 1H), 4.06 (m, 48), 6.46 stennbvno" necessary C, 54.72; H, is (m, 1), 6.62 (m, 1H), 7.08 (m, 1H). 51; M, VT, ' 41 I pug IMN'T 299. "H-NMR (Z00MGu, SOS): 8-15 81 pugIMNYA ov? HN-NMR (400MHz, SOS 8-18 (t, ' (m, VNU, 248 (m, YAN), 8.79 (s, ZN),

Also known), 114 (t, ZN), 2.4 (k, ZNU, 2.58 (Kk, vve (b en lo (NU 2H), 3.72 (sh s, 1H), 4.05 (m , 4Н), 6.43 Microanalysis: Found: С, 56.08; Н, (m, ЗН). 5.37; М, 9.29. SanНсСкО is necessary С, 56.20; Н, 5.39; М , 9,365.

using flash chromatography on silica gel

Example 42 using dichloromethane-4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazol tane:methanol:ammonia (95:4:1, by volume) as an eluent resulting in the title compound (125 mg ) as a colorless oil. io/ IN-YAME (400 MHz, SOSIz): 6-1.06 (m, 6H), 2.12 (m, 8H), 2.75 (t, 2H), 3.64 (m, 4H), 4.04 (t, 2H), 6.73 fe; (c, 2H), 6.95 (c, 1H). and NRMS (thermal spraying): t/2 МН") 398.

A solution of enamine Preparation 6 (2.88 g, 10 units of CCO required C, 57 28 N vaz 10.bmol) and hydrazine hydrate (049ml, M To Be 25Mma 3 pi pln 10.Ommol) in ethanol (1Oml) was heated from reverse- EXAMPLES 44-49 in a cold refrigerator for 12 hours. After D and cooling, hydrazine hydrate was added. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel using cyclohexane-ethyl acetate (80:20, by volume) as an eluent, and then cyclohexane:ethyl acetate and (60:40, by volume) obtaining the compound (620 mg) indicated in the title was obtained by a similar method as a yellow oil. using Example Az is acceptable

IN-NMR (400 MHz, SOSIv): 6-1.23 (t, 3H), 2.66 starting amine and pyrazole of Example 64. (Kk, 2H), 6.87 (s, 2H), 7.02 (s , 1H), 7.40 (c, 1H). Sweet dance

NRMS (electrospraying): t/g7 МН") 257; M ВІ

IM-(NU) 255. 84 t/h|MN)386. | H-NMR (Z00MGN, SOB. 5 - 1.09-

Example 43 pen ohm, 117 (m, 6H), 2.40-2.47 (k, 2H), 2.50- 4-(2-I14-(3,5-Dichlorophenoxy)-3,5-diethyl- 1 H- and called pyrazol-1-yl|ethyl morpholine o), 404 (t, З) wt s, pH), si 7.01 (s, 1H), io, ph (MNU) 439. "H - NMR (400 MHz, SOSIV): 5 - 1.04 i m, VN), 2.00 (s, ЗН), 2.38 (m, VN), -- 3.55 (m, 2Н), 4, 05 (m, 2H), 6.71 (s, ?2H), 6.92 (s, 1H). not with pi 7 here (MN ЗB. tn sv SOS 8 - 1.05 slo 700 skis

Osmium tetraoxide (1.00 ml 2.595 wt./vol. solution - 2.45 (Kk 2H), 2.69 (m, 2H), 403 (m, : 2NU, 6.75 (s, 2), 5.95 (s, 1H ). rank in tert-butanol) was added dropwise to its PNY SNYAMEYUbMTI sob BE of a stirring solution of pyrazole of Example AL (m, VNU. 159 (w s, 1), 1.91 (s, ЗН), 64 (3 ,00g, 9.23mmol) and sodium periodate (4.93g, in: in 2.38 (k, 2H), 2.48 (k, 2H), 2.71 (m, 2H). 23.1mmol) in acetone (9Oml) and water (ZOml) at 2.99 (m, 2NU, 328 (m, 2H), 4.02 (m, room temperature. After 5 minutes, it forms), vv (sh s, TN), vt ( o, an), 655 all the white precipitate and the suspension were stirred continuously for 3 hours. The solid substance was removed by filtration and the filtrate was concentrated at 6.34; M, 13.5595 . Tpl. 69-70 20. under reduced pressure. The residue was partitioned between ethyl- - pug(MNtzyag. HGNMR (400MGu, SOC): 5 51.08 (m, acetate (300ml) and water (100ml) and organic n 7 2 ( m, Nu 7l" (b, Z), ma . (Kk, 2H), 5.00 (m, 2H), 4.05 (m, 2H), the phase was separated, dried over sulfate vv (c, 2). 6 96 (p. 1H). magnesium, filtered and concentrated under reduced pressure Mn" | neme (orMha, SOS 5-05 under reduced pressure, obtaining an intermediate aldehyde. | -57o (m. 6НУ 1.49 (m, 1Н), 1.81 (m, 48 ),

An apiquot of aldehyde (100 mg, 0.305 mmol) was dissolved and 2, (k, an), 2B2 (k. 2H), 2.64 (m, 2H), . . . 3.08 (t, 2H), 3.76 (m, 1H), 3.79 (m, dissolved in dichloromethane (5Xml) and added morpholine I nu 400 (m, 1), used (s, 2H) . , 5813: H, 81: M, sodium triacetoxyborohydride (95 mg, 0.451 mmol) was added portionwise and the reaction was stirred for 1 hour. After that, the mixture obtained in Example 50 was diluted with dichloromethane (20 ml) and divided into 3-C4-(3, 5-Dichlorophenoxy)-3,5-diethyl-1H- was washed between water (30ml) and dichloromethane (20ml).pyrazol-1-ylmethylumorpholine

The organic phase was washed with 2M aqueous sodium hydroxide solution (10 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified with sodium chloride (1 Oml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a brown oil.

The oil was purified by column flash chromatography on silica gel using dichloromethane as an eluent, obtaining an intermediate

What; Well, the compound (bOmg) is like yellow oil. The oil was dissolved in dichloromethane (5 ml) and at room temperature

Sodium hydride (6095 dispersion in oil, 37mg, 1-0.925mmol was added to the mixture under nitrogen atmosphere) was added to the mixed solution of porethyl chloroformate (20μl, 0.182mmol). The mesylate of Preparation 11 (27 mg, the mixture was refluxed for 0.925 mmol) and the pyrazole of Example C (220 mg, 4 hours, cooled to room temperature, 0.772 mmol) were mixed in dry M,M-dimethylformamide and concentrated at under reduced pressure (dml) at 0"C in a nitrogen atmosphere. The mixture is heated to obtain a yellow oil. The oil was dissolved in chalk at 502C for 3 hours, during which yellow tanol (5ml) and the resulting solution were heated with water, the solution became dark brown. The reaction was cooled in a refrigerator for 1 hour, quenched by adding water (5 ml), and the mixture was concentrated to room temperature (controlled under reduced pressure. The solution of the residue was concentrated under reduced pressure. Washed with crude ethyl acetate (20 ml) with water (10 ml) and the product was purified by column flash chromatography on silica gel saturated with an aqueous solution of sodium chloride (10 ml), dried over magnesium sulfate, filtered, and dichloromethane:methanol:ammonia was added as an eluent and concentrated under reduced pressure to give (95:41, by volume) the rusting brown oil indicated in the title. The oil was dissolved into the compound (17mg) as a colorless oil. dichloromethane (3 ml), added trifluoroacetic "H-NMR (400 MHz, SOCI3): 6-1.08 (t, ЗН), 1.16 acid (ml) and the reaction was stirred at room- (t, ЗН), 2.48 (m, 4H), 3.87 (t, 2H), 4.40 (t, 2H), 5.07 at temperature for 12 hours. . . a (20 ml). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column flash chromatography and silica gel chromatography using dichloromethane:methanol:ammonia (95:41) as an eluent , total capacity) obtaining the title compound Triflate Preparation 15 (282mg, (Zmg) as colorless oil O, 500 mmol), tributyltin (175 μl,

IN-NMR (400 MHz, SOSIz): 6-1.15 (m, 6H), 2.41 O,bO0Ommol), palladium dibenzylideneacetone (Kk, 2H), 2.51 (k, 2H), 2.89 (m , 2H), 3.30 (m, 2H), 3.58 (23 mg, 0.025 mmol), triphenylarsine /(12 mg, (m, 1H), 3.78 (m, 2H), 3.87 (d, 2H ), 6.88 (s, 2H), 7.00 0.040 mmol) and lithium chloride (b4mg, 1.50 mmol) (1H, s). heated in M,M-dimethylformamide (Zml) at

NRMS (thermal spraying): t/2 МН") 384. 80"С in a nitrogen atmosphere for 12 hours. Reac-

Example 51 tion was cooled to room temperature and 1-(3-Azetidinyl)-4-(3,5-dichlorophenoxy)-3,5- was partitioned between water (20ml) and diethyl-1H-pyrazole ethyl acetate (20ml). The organic layer was washed with a saturated aqueous solution of sodium chloride (1 Oml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column flash chromatography on silica gel using pentanoethyl acetate (90:10, by volume) as the main eluent.

Sodium hydride (6095 dispersion in oil, ZOmg, colorless oil. in the title compound (Zamg) as 0.750 mmol) was added to the stirring solution- IN-NMR (400MHz, SOSI"): 6-1.16 (t, ZN) . 02 1-benzhydryl-3-azetidinylmethanesulfonate (c; 1H) (222 mg, 0.702 mmol) | see 4. Ogd. SPpet,, ! ; ! and 1972, 37, 3953) in M,M-dimethylformamide. (5 ml) at 1 at RT in a nitrogen atmosphere. The mixture was heated at 4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-507C for 4 hours and then cooled to pyrazole at room temperature. The reaction mixture was quenched by adding water (30 ml) and the aqueous mixture was extracted with ether (2 x 50 ml). The combined organic phases were washed with water (100 ml) and saturated aqueous

with aqueous acetic acid at room temperature. The mixture was diluted with dichloromethane (20 ml),

It was washed with water (5 ml) and saturated aqueous solution of sodium chloride (5 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column flash chromatography on

A mixture of 3-chloro-2,4-pentanedione (5.00 g, silica gel using pen as an eluent

ZT, ommol), 3,5-diporphenol (6.03g, tan:ethyl acetate (70:30, by volume) yielding 37.0mmol), cesium carbonate (12.0g, 37.0mmol) and zan in the title compound (300 mg) as colorless acetone (40 ml) was heated under reflux - oil. no one for 18 hours. After cooling, "H-NMR (400 MHz, SOSIv): 6-1.05 (t, ZNU, 1.10 the solid substance was removed by filtration and fil- (t, ZN), 1.21 (d, 28) 2 40 (k , 28) 247 (k, 2n), 379 trat was concentrated under reduced pressure. dissolved in ethanol (30 ml) and added - 6.98 (s, 1N). . for 30 minutes. After Example 55 cooling, the mixture was concentrated under reduced 2-22-I4-(3,5-Dichlorofenoski)-3,5-diethyl-1H- pressure and the residue was purified using copyrazol-1-yl )ethoxy)ethanamine by flash chromatography on silica gel using ethyl acetate/pentane (30:70, v/v) as an eluent, obtaining the title compound (3.00 g) as a yellow oil, which solidified on standing to give a yellow solid , Tpl. 85- and 8776. -

IN-YAME (z00MHz, SOSI»z): b-2.14 (s, 6H), 5.24 her and di (she, 1H), 6.81 (s, 2H), 7.02 (s, 1H ). nn

NRMS (thermospraying): t/2 (MNU) 257. Ги и о и и

Microanalysis: Found: C, 49.58; N, 4.06; M, sodium hydride (6076 dispersion in oil, 24 mg, 11.05. SynNiOSiM2O.0.4NoO is necessary C, 49.98; H, 0.600 mmol) was added to the solution, which was mixed - 4.12. M. 106095, it is, pyrazole of Example 2 (100 mg, 0.30 mmol) in ' Example BA dry M,M-dimethylformamide (A4ml) at 0"C in 1-14-(3,5-Dichlorophenoxy)-3,5- diethyl-1H- under a nitrogen atmosphere. The mixture was stirred at 07C. pyrazol-1-yl|-2-propanol for 30 minutes and 2-chloroethylamine hydrochloride (533 mg, 0.455 mmol) was added. The reaction mixture was stirred at 0"C for 30 minutes and then stirred at room temperature for 30 minutes. The reaction was cooled to about sodium hydride (6095 µl dispersion in oil, 24mg, 0bb00mmol) and 2M chlorethylamine hydrochloride (5µg, 0.455mmol) were added, and the reaction was stirred for 1 hour. The reaction was quenched

Osmium tetroxide (1.00 ml of 2.595 wt/v, dissolved in water (5 ml) and extracted with ether or tert-butanol) was added dropwise to the solution (1 Oml). The organic layer was washed with a 2M stirred aqueous solution of pyrazole from Example 64 with hydrochloric acid (30ml). Neutral acid (3.00g, 9.2mmol) and sodium periodate (4.93g, extracted with solid sodium carbonate and 23.mmol) in acetone (90ml) and water (30ml) with ether (3 (20ml). The ether layers were combined at room temperature. After 5 minutes, the formation was dried over magnesium sulfate, filtered, and all the white precipitate and the suspension were stirred and concentrated under reduced pressure. Unpurified for another 3 hours. The solid was removed, the film product was purified using column poisoning and the filtrate was concentrated by flash chromatography on silica gel using reduced pressure. the title phase was separated, the compound (21 mg) was dried over magnesium sulfate as a colorless oil, filtered and concentrated under reduced pressure to give intermediate aldehyde (Kk, 2H), 2.58 (k, 2H), 2.80 (t, 2H), 3.38 ( t, 2H), 3.81

An aliquot of aldehyde (250 mg, 0.765 mmol) was dissolved in (t, 2H), 4.18 (t, 2H), 6.78 (s, 2H), 7.02 (s, 1H). ly in tetrahydrofuran (5 ml) and stored in an atmosphere. NRMS (thermospray): t/2 (MNU | 372. ferric nitrogen, in a separate flask, anhydrous trichloride Example 56 cerium (377 mg, 1.53 mmol) was added to the solution, 4-Ц4 -(3,5-Dichlorophenoxy)-3-methyl-1H- miscible, methylmagnesium bromide (0.51 ml of pyrazol-5-ylylmethylumorpholine

3M solution in ether, 1.53 mmol) in tetrahydrofuran (3ml) at room temperature in a nitrogen atmosphere. The mixture was stirred at room temperature for 1.5 hours and aldehyde in tetrahydrofuran was added dropwise. The mixture was stirred for 12 hours, and the reaction was then quenched with 1M sodium chloride, sodium triflate Preparation 15 (282mg, // Morpholine (140μl, 1.59mmol) was added once, 0.500mmol) was dissolved in methanol (3 ml) and one bromide pog to vv OO Oz mmol portionwise at room temperature was added chlorobromide. at room temperature. (18mg, 0.025mmol). The mixture was heated at 502C in

The mixture was heated at 507C for 1 hour, cooled to room temperature in a carbon monoxide atmosphere (345kPa, 50Opsi) and concentrated for 10 hours. The reaction was cooled to the desired temperature. 5ml), glacial acetic acid (1.0ml) and water lactate to give the title compound (0.5ml) and stirred at room temperature (bomg) as a colorless oil for 12 hours. The solvent was removed in a flow "H-NMR (400 MHz , СОСИ3): 652.13 (s, ЗН), 2.42 of nitrogen obtaining a yellow solid and non- (m, 4Н), 3.38 (s, 2Н), 3.64 (m, 4Н), 6, 79 (c2H), 7.02 the purified product was purified using a column (c, 1H). flash chromatography on silica gel using

NRMS (thermal spray): t/g2 (MH" | 342. using as an eluent

Example 57 dichloromethane:acetonitrile (95:5, v/v) and then 4-(3,5-Dichlorophenoxy)-3-methyl-5-(2-methyl-dichloromethane:acetonitrile (90:10, v/v)) ode - 1H-imidazol-1-yl)umethyl|-1H-pyrazole giving the title compound (bmg) as a colorless oil. - "H-NMR (ZO0MHZ, SOSIz): 6-1.13 (t, ZN), 2.41 "di! (k, 2H), 3.44 (w s, 1H), 3.94 (s, ЗН), 4.23 (m, 4H), ray t 6.87 (s, 2H), 7.09 (s , 1H). - dream NRMS (thermal spray): t/2 (MH) 391. no and Example 59 1-Ш(4-(3,5-Dichlorophenoxy)-3-methyl-1 H-

Sodium hydride (6095 dispersion in oil, 32 mg, pyrazol-5-yl|methyl)-1H-1,2,4-triazole

0.800 mmol) was added to a stirred solution of 2-methylimidazole (b5 mg, 0.800 mmol) in

M,M-dimethylformamide (ml) at 07C in an atmosphere of nitrogen. The mixture was stirred for 10 min and then bromide Preparation 8 -8-O (100mg, 0.261mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding a 1M aqueous solution of Preparation 8 bromide suspension (100mg, sodium hydroxide (5ml) and the mixture was concentrated to 0.264mMmol), 1,2,4-triazole (92mg, 1.32mmol) and under reduced pressure. A solution of the residue in sodium ethyl carbonate (140 mg, 1.32 mmol) in toluene acetate (20 mL) was washed with water (10 mL) and saturated (5 mL) was heated at 10072 for 12 hours. with an aqueous solution of sodium chloride (1 Oml), the suspension was cooled to room temperature, dried over magnesium sulfate, filtered and ture was added and a 1 M aqueous solution of hydroxide was added, concentrated under reduced pressure to obtain sodium (5 ml). The mixture was extracted with ethyl acetate to give a brown oil. The crude product was purified (3 (20 ml) and the combined organic phases were dried using column flash chromatography on magnesium sulfate, filtered and concentrated using silica gel as an eluent. 4.5:0.5, by volume) lo. The crude product was purified by obtaining the title compound (10 mg) as a colorless oil by column flash chromatography on silica gel using dichloromethane as an eluent. ): b-2.14 (c, ZN), 2.35 tan:methanol:ammonia (95:4.5:0.5, by volume) obtained (c, ZN), 4.89 (c, 2H), 6.68 (c, 2H), 6.78 (c, 1H), 6.82, giving the title compound (62mg) as a free amine (zo0mgz, SOSi): 6-2, 16 (c, ZN), 525. z - ' 3). Otche, "M, at t/x МН" 337. p 29) 6.70 (s, 2H), 7.04 (s, 1H), 7.89 (s, 1H), 8.04 s, 1H) "Hn-pidaael opetanoyloxy)-3-ethyl-5-methoxy HPMS (thermal spray): t/ (MH-| 324.

Example 60 3-((3,5-Diethyl-1H-pyrazol-4-yl)oxy|benzonitrile

Hydrazine hydrate (153 mcg, 3.14 mmol) was added to a stirred solution of B-diketone Pry- A saturated solution of ammonia in methanol (2.3 mL) of preparation 9 (771 mg, 3.14 mmol) in ethanol (1 b mL) and added to the ester of Example 63 (75 mg, the resulting solution was heated with reflux 0.229 mmol) in a bottle at room temperature for 12 hours. After cooling, the bottle was then closed and heated, and the mixture was concentrated under reduced pressure and 757 °C for 17 hours. After cooling, the residue was purified using a column at room temperature, the mixture was concentrated by flash chromatography on silica gel using reduced pressure, obtaining a creamy solid or in quality eluent pentane:ethyl acetate (75:25, substance. The crude product was purified to volume) obtaining the compound indicated in the title by column flash chromatography on silica (712 mg) as a yellow solid, mp 81-kageli using as an eluent, dichloro- 8476. methane, then dichloromethane:methanol (9911,

IN-NMR (400MGu, SOSI»z): 6-1.15 (t, 6H), 2.47 vol.) obtaining the indicated compound (k, 4H), 7.11 (m, 2H), 7.24 (d, 1H), 7.35 (t, 1H). ku (49mg) as a white solid, mp. 159-

NRMS (thermal spraying): t/z2 (МН"| 242. 16076.

Microanalysis: Found: C, 69.03; H, 6.43; M, IN-NMR (400 MHz, SOSI»z): 6-1.10 (t, ZN), 1.17 17.20. Si4Ni5MzOz:0.13H2O is necessary C, 69.02; H, (t, ZN), 2.44 (k, 2H), 2.53 (k, 2H), 4.69 (c, 2H), 5.44 6.31; M, 17,2590. (shs, 1H), 6.22 (w s, 1H), 7.14 (m, 2H), 7.31 (d, 1H),

Example 61 7.40 (t, 1H). 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazole-4-HPLC (thermal spray): mp/z2 (MH" | 299. yl|oxybenzonitrile Microanalysis: Found: C, 64.20; H, 6.12; M, dk 18.79. Si6NivMaO" required C, 64.41; H, 6.08; M, 18.7895. od Example 63 and Ethyl I4-(3-cyanophenoxy)-3,5 -diethyl-1 H- 7 pyrazol-1-yl|Iacetate not - M in, sn

The pyrazole of Example 60 (200mg, 0.829mmol) and 2-chloroethylamine hydrochloride (144mg, 1.24mmol) 4 were heated as a melt at 1507C for 17 hours--7 days. After cooling, the solid was dissolved in saturated aqueous sodium hydrogen carbonate (15 ml) and extracted with dichloromethane. A solution of ethyl hydrazinoacetate (in 8 mg, (2 x 10 ml). The combined organic phases were washed with 2M 0.571 mmol) in ethanol (2, 0ml) was added to dilute hydrochloric acid (20ml) and a stirred aqueous solution of B-diketone. The prepared layer was neutralized with solid sodium carbonate and sodium 9 (140mg, 0.571mmol) and triethylamine (8µl, extracted with dichloromethane (3x 10ml). The combined 0.628ml) in ethanol (1.0ml) and the resulting organic phase solution were dried over magnesium sulfate, heated under reflux, filtered and concentrated under reduced pressure for 18 hours. After cooling, the mixture concentrates and pressures, yielding an orange gum. The crude shaft was separated under reduced pressure and the residue was separated, the product was purified using a column flush between dichloromethane (20ml) and water (1Oml). Using organic chromatography on silica gel, the overnight layer was separated, washed with a saturated eluent of dichloromethane:methanol (90:10) with an aqueous solution of sodium chloride (10 ml), then dichloromethane:methanol:ammonia (90:9:1, vol. containers) were dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (124 mg). Unclean - like pale yellow oil. The resulting product was purified using column H-NMR (400 MGu, SOCIz): b-1.11 (m, 6H), 2.41 flash chromatography on silica gel using (k, 2H), 2.52 (k, 2H) , 3.18 (t, 2H), 4.04 (t, 2H), 7.15 or as an eluent pentane:ethyl acetate (75:25, (m, 2H), 7.29 (d, 1H), 7 .38 (t, 1H). volume) and then ethyl acetate, obtaining the specified

NRMS (thermal spray): t/2 (MNU 285. in the title compound (131 mg) as a yellow oil.

Example 62 "H-NMR (400 MHz, SOCI3): 6-1.08 (m, 6H), 1.25 2-I4-(3-Cyanophenoxy)-3,5-diethyl-1H-pyrazole- (t, ZNU , 2.40 (m, 4H), 4.20 (k, 2H), 4.77 (s, 2H), 7.12 1-yl)acetamide (m, 2H), 7.23 (d, 1H) , 7.34 (t, 1H).

NRMS (thermal spraying): t/2 (MH) 328.

Example 64 1-Allyl-4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole c o se si sn, her o, o. --

WHAT IS THE UNIVERSITY

M well all: thanks no

Sodium hydride (6095 dispersion in oil, 77Omg, obtained by a method similar to the method, 19.2 mmol) was added to the stirring solution of Example 65 using an acceptable yield, allyl bromide (1.70 ml, 19.2 mmol) and pyrazoline amine and bromide Preparation 8.

Example C (5.00g, 17.5mmol) in M.M.

WHAT ABOUT : Iryklad analytical data of nitrogen. The reaction was heated to room temperature. . the mixture was quenched by adding water (100 ml) and the aqueous phase (Also ZN), 2.47 (d, 2H), 3.73 (s, 2H), 6.62 (s, extracted with ether (2x50 ml). The combined organic 1 inst.. N IN with 00. The nb phases were washed with water (00 ml) and saturated 5-th imnTvo grown in vv with an aqueous solution of sodium chloride (00 ml), dried overnight, Fuvetistn 000 over magnesium sulfate, filtered and concentrated as the volume | oil. The crude product was purified to the extent of saturation - - IN") 355. - i): 5-2, with the help of column flash chromatography at 2 IM) H-NMR (400 MHz, SOS): 5 - 2.08 ( 5 ... /th ZN), 2.22 (s, ZN), 2.31 (m, 8Н), 3.36 (s, silica gel using pen- -- nn, gn as an eluent), vtv (s, 2Н ), 7 (c, 1H). tan:ethyl acetate (80:20, by volume) yield including - TRIBES BB 1 NsyaNMR (abbMigts, SOSIU. 5-5 gave the title compound (5.00g) as a yellow oil. -4 2H), 1.60 (m, 2H), 1.90 (m, 2H), 2.41 (m,

IN-NMR (400 MHz, SOSIzv): 6-1.11 (m, 6H), 2.46 m 2H), 325 (s, 2H), 8.75 (m, 2H), 5.82 (s, (m, 4H), 4.65 (d, 2H), 5.04 (d, 1H), 5.22 (d, 1H), 5.99 | | t 5.vo (o, tn), Vuvu (c, 2 ), bean (o, (m, 1H), 6.79 (s, 2H), 6.99 (s, 1H). s I pUeIMNYA 530. | H-NMR (400 MHz, SOS 8 - 2.08 s,

NRMS (thermal spraying): t/2 (МН 325. sewn ZN), 2.74 (m, 2Н), 3.90 (s, ZN), 34 (m,

Example 65 and " 2H), 3.68 (s, 2H), 6.76 (s, 2H), 6.98 (s,

M-(44-(3,5-Dichlorophenoxy)-3-methyl-1H-TU pyrazol-5-yl|methyl)-M-(4-methoxybenzyl)amine 7 | opemnozva | yum pyuomgi, Sobi: 5 5 20 (o, - ZNU, 2.10 (s, ZN), 2.38 (m, 4H), 3.34 (m, a sn, 2H), 3.38 (s, 2H) . : 5 - 1.92 (s, o sn, - y and ZNU, 2.09 (s, ZN), 2.70 (m, 2H), 3.29 (m, 5-7 sya, 2). 3 ... (400MHz, SOS; 6 - 1.30 (m, 4-Methoxybenzylamine (0.104ml, 0.800mmol) -, vn), tvo (m, vn), tva (o, vn) voi m, y . BN), 2 .70 (m, 2H), 3.34 (s, 2H), 3.71 (m, added in one portion to the solution, which is still chn), bv (s, MH). 698 (s, IN). mixed, bromide Preparation 8 (10Omg, si t/gYIMNYA370. | H-NMR (30OMHz, SOS) 5 - 1.60 (m, 0.265mmol) in isopropanol (2ml) at room temperature ! U -ya 2H), 1.80 (m, 2NU, 2.13 (s, ZN), 2.20 (m, : : : o Y 2H), 2.71 (m, 2H), 322 (m, 1H), 3.83 (s, temperature. The mixture was heated at 507C for 3.39 (s, 2), 6.81 (s, 2H), 7.03 (s, 1 hour, cooled to room temperature) and concentrated at reduced under pressure, extracting yellow oil. The oil was diluted with diethyl ether Example 76 with ether (20ml), washed with saturated 3-Chloro-54(3,5-dimethyl-1H-pyrazole-4) aqueous sodium hydrogencarbonate (5ml) and water, and distilled water. yl)oxy|benzonitrile (5 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The purified product was purified by column flash chromatography on silica gel, using dichloromethane:methanol:ammonia (95:4:1, by volume) as an eluent, obtaining p. un the compound indicated in the title (50 mg) as a colorless and M oil. : .

Hydrazine hydrate (1.1 Oml, 21.9 mol) was added. 71 (c, 2H), 3.80 (c, ЗН), 6.83 (m, 4H) to a stirred solution of B-diketone When

E. a c 1) 7 17 2n ' 'shi'' preparation of 16 (5.50g, 21.9mmol) in glacial acetic acid (c, 1), 717 (m, 2H). vyy acid (22ml) and the resulting solution is mixed

NRMS (thermal spraying): t/2 (MH) 392. : as :

EXAMPLES 66-75 were left at room temperature for 14

Spo as with ova p a hours. The mixture was concentrated under reduced pressure and the residue was purified using column codes of the general formula: flash chromatography on silica gel using dichloromethane as an eluent and then dichloromethane: ethyl acetate (85:15, vol. capacitive)

obtaining the title compound (4.80g) as dichloromethane (50ml), washed with 1M water, yellow solid, mp. 1336-1406. sodium carbonate (20 ml) and saturated water

TN-NMR (400 MHz, SOSI»z): 6-2.09 (s, 6H), 7.02 with sodium chloride solution (20 ml), dried over (m, 1H), 7.10 (m, 1), 7.25 (m, 1H). magnesium sulfate, filtered and concentrated

NRMS (electrospray): t/2 (MH) 248. at reduced pressure. Unrefined product

Microanalysis: Found: C, 57.91; N, 4.03; M, was cleaned with the help of columnar flash chrome - 16.79. C12NioMzOsI must be C, 58.19; H, 4.07; M, tography on silica gel using 16.9795 as a quality. eluent dichloromethane:methanol:ammonia (90:9:1, vol.

Example 77 containers) to give the title compound 3-5-(Aminomethyl)-3-methyl-1H-pyrazole-4- (40mg) as a white foam. yl|oxy)-5-chlorobenzonitrile 1N-NMR (300MHZ, SOCI»z): b-2.14 (s, ЗН), 2.40 cm (m, 4Н), 2.83 (m, 4Н), 3 .38 (c, 2H), 7.09 (c, 1H), 7.16 (c, 1H), 7.30 (c, 1H).

In nn, NRMS (thermal spray): m/2 (MH) 332. and Example 79 uch 3-Xpor-5-((5-((4-cyanobenzyl)amino|methyl)-3- ne sh- methyl-1H- pyrazol-4-yl)/oxy|benzonitrile

Bromide Preparation 18 (30Omg, 0.800mmol) was added to a saturated solution of ammonia in isopropanol (30ml) at 0°C. The reaction was stirred for 2 hours and allowed to slowly warm to room temperature. The mixture was concentrated and under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (50 ml). Dichloromethane (50 ml) Example 77 The methane solution was diluted with a 1 M aqueous solution of magnesium sulfate (vm) dichloromethane sodium carbonate ml), dried over sodium sulfate, filtered, concentrated in methane (zml), stirred in a nitrogen atmosphere under reduced pressure, obtaining the product indicated in the title at room temperature for 3 days. Mix the compound (220mg) as a white foam. was concentrated under reduced pressure and the crude "H-NMR (400MGu, SOSI"): 6-2.14 (s, ЗН), 3.79 the product was purified using a column (с, 2Н), 7.08 (IN, c), 7.16 (1Н, с), 7.31 (1Н.с). flash chromatography on silica gel and using

HPMS (thermal spray): t/7 (MH 263. using methanol:ethyl acetate (5:95, volume) as an eluent, obtaining a foam. The foam was dissolved in

Example 78 ethanol (ml), sodium borohydride (5mg, 1H-pyrazol-4-yl|oxy)benzonitrile was added in one portion at room temperature. 1.3 mmol) and the reaction was stirred for 30 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane PE (20 ml). The resulting solution was washed with 1M aqueous solution

sodium carbonate solution (1 Oml) and saturated aqueous sodium chloride solution (1 Oml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product t-Butyl 1-piperazinecarboxylate (1.17g , purified using a flash chrome column, 3 mol) was added in one portion to the solution; 00 dichloromethane methanolamiach BT oo which is stirred, bromide Preparation 18 and y Da (500mg, 1. mol) in isopropanol (20ml) as indicated. in the title compound at room temperature. The mixture was heated at 607C for 1 hour, cooled to room temperature and concentrated at reduced (c, In), 738 (d), 7 .60 (day). " " b pressure, obtaining a yellow oil. The oil was dissolved " NRMS (thermospray); t/x IMNYA 378 in dichloromethane (100 ml) and the resulting solution was washed with 1 M aqueous sodium carbonate (2 O ml) and Z'Hpornv- (Z methyl-5-(4-(methylsulfonyl)-1- saturated aqueous solution of sodium chloride piperazinyl|meth Ilu-1H-pyrazole-4- (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The purified product was purified by column flash chromatography on silica gel using dichloromethane:methanol:ammonia (95:41, by volume) as an eluent, obtaining a yellow foam . The foam was dissolved in dichloromethane (1 mL), the resulting solution was cooled to 0°C, and trifluoroacetic acid (2 mL) was added. Reaction Methanesulfonyl chloride (19 μL, 0.240 mmol) was allowed to warm to room temperature and was added dropwise to the solution, which was stirred. for 24 hours. The mixture is developed, the amine of Example 78 (8Omg, 0.240mmol) and triethylamine (45μL, 0.288mmol) in dichlorometa- (m, 4H), 3.36 (m, 6H), 3.64 (s, ЗН), 7.02 (m, 1), no (Смл) at room temperature in an atmosphere of 7.10 (m, 1Н), 7.25 (m, 1НН). The reaction was stirred for 30 minutes by HPMS (thermal spray) : t/2 (MH) 390. and then concentrated under reduced pressure to give a yellow oil Example 83. The crude product 4-I(14-(3-Xpor-5-cyanophenoxy)-3-methyl-1 H flash pyrazole-5-chromatography on silica gel using dichloromethane and then dichloromethane:methanol:ammonia (95:4:1, by volume) as the yl|methyl)amino)methyl|Ibenzenesulfonamide eluent, obtaining the U specified in the title compound (65mg) as a white foam. in

IN-NMR (400 MHz, SOSIz): b-2.14 (s, ZN), 2.51 o |») (m, 4H), 2.72 (s, ZN), 3.12 (m, 4H) , 3.39 (s, 2H), 7.08 t (m, 1H), 7.13 (m, 1H), 7.26 (s, 1H). everything

NRMS (thermal spraying): t/2 (МН 410. no

Example 81 Triethylamine (125 μl, 0.8 bO0mmol) was added 3-Xpor-5-((5-(C4-(methoxyacetyl)-1-) in one portion to a stirred suspension, piperazinyl|methyl)-3-methyl-1-H -pyrazole-4- hydrochloride of 4-aminomethylbenzenesulfonamide yl)oxy|benzonitrile (144mg, 0.590mmol) and bromide Preparation 18 (100mg, 0.270mmol) in isopropanol (5ml) at room temperature under a nitrogen atmosphere. The reaction was heated at 70" C for 1 hour and then heated, cooled to room temperature

U was concentrated under reduced pressure and crude

And the product was purified using column chromatography and flash chromatography on silica gel using

M-Benzyl-M'-cyclohexylcarbodiimide was added to dichloromethane as an eluent, and then dichloromer (624 mg, 1.3 mmol/g, 0.480 mmol) was added to methane:methanol:ammonia (90:91, by volume) to obtain one portion to a stirred solution or foam. The foam was further purified using methoxyacetic acid (37µl, 0.480mmol) and a Rpepotepech Ipa C18 column and using the amine of Example 78 (8µg, 0.240mmol) in dichloromethane as eluent with diethylamine:methanol (0.1:9911, methane (zml) at at room temperature in atmos-volumetric) obtaining the nitrogen sploufer specified in the title. The reaction was stirred for 1 cu (mg) as a white foam.

HOURS The reagent on the polymer was removed by filtration. The filtrate was concentrated at reduced 3.27 (s, 2H), 3.62 (s, 2H), 3.79 (s, 2H), 7.17 (s, 1H),

PRESSURE And the crude product was purified using 7.21 (s, 1H), 7.40 (m, ZN), 7.77 (d, 2H). by column flash chromatography on silica gel HPMS (thermospray): t/2 (MH) 432. using as an eluent dichloromethane:methanol:ammonia (95:4:1, by volume) obtaining 4-(3.5 -Dichlorophenoxy)-5-(methoxymethyl)-3- the title compound (45 mg) as a white foam. methyl-1H-pyrazole

IN-NMR (400MHz, SOSI"): b-2.11 (s, ЗН), 2.38 (m, 4Н), 3.37 (m, 7Н), 3.51 (m, 2Н), 4, 04 (c, 2H), si 7.04 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H).

NRMS (thermal spraying): t/2 МН") 404. more

Example 82 Fr. t- t

Methyl 4-(4-(3-chloro-5-cyanophenoxy)-3-methyl-iso. LV 1H-pyrazol-5-yl|methyl)-1-piperazinecarboxylate M a sn o Tetrakis(triphenylphosphine)palladium (bOmg) to- t A was given in one portion to the solution that was mixed/ |; bromide Preparation 8 (590 mg, p = 1.5 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) at room temperature. The mixture was heated at 80°C in a carbon monoxide atmosphere

Methyl chloroformate (19μl, 0.240mmol) (690kPa, 100psi) for 18 hours. The reaction was added dropwise to the solution, which was stirred at room temperature and concentrated, of the amine of Example 78 (8mg, 0.240mmol) and stirred under reduced pressure to obtain cinnamic triethylamine (45μl, 0.288mmol) in dichloromethane oil. . The oil was dissolved in dichloromethane (ml) at room temperature in an atmosphere (10 bml) and the resulting solution was washed with nitrogen water. The reaction was stirred for 90 minutes (5 bml), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure and evaporated under reduced pressure. Not getting yellow oil. The crude product, the purified product was purified by column flash chroma flash chromatography on silica gel, tography on silica gel using ether as eluent, obtaining dichloromethane as eluent and then dichloromethane as the title compound (110 mg) as bezbutane:methanol:ammonia (95:4:1, by volume) to give an oil. the title compound (55 mg) as a white foam. H-NMR (400 MHz, SOS); 6-2.15 (s, ZN), 3.34 "H-NMR (400MHz, SOSIz): b-2.09 (s, ZN), 2.34 (s, ZN), 4.35 (s, 2H), 6.83 (s, 2H), 7.03 (s, 1H).

NRMS (thermal spraying): t/2 (МН) 287. si p

Example 85

3-tert-Butyl-4-(3,5-dichlorophenoxy)-5-methyl-K cm 1H-pyrazole b and Ff and to M 1-(3-"Dimethylamino)propyl)-3-ethylcarbodiimido o to (9Zmg, 0.490 mmol) was added in one portion to a stirred solution of the amine of Example 109 (120 mg, 0.440 mmol) and 4-cyanobenzoic acid (71 mg, 0.490 mmol) in dichloromethane (5 ml) at room temperature temperature in a nitrogen atmosphere

Dione mixture Preparation 19 (1.00g, stirred for 20 minutes and then washed with 5.68mmol), 3,5-dichlorophenol (930mg, washed with 1M aqueous sodium hydroxide solution 5.68mmol), cesium carbonate (1.85g, 5, 68mmol) and (10ml), 1M aqueous hydrochloric acid, acetone (20ml) was heated under reflux (10ml) and water (1Oml). The organic layer was dried for 18 hours. After cooling over magnesium sulfate, it was filtered and evaporated - the solid substance was removed by filtration and filtered under reduced pressure, obtaining a yellow foam. the waste was concentrated under reduced pressure. The crude product was purified using the copper compound was dissolved in ethanol (20 ml), hydrazine hydrate (284 mg, 5.68 mmol) was obtained by flash chromatography on silica gel, and the mixture was heated at 607C for 1 hour using dichloromethane . After mixing with octane:methanol:ammonia (95:41, v/v), the resulting mixture was concentrated under reduced pressure to give the title compound (110 mg) as a white foam. pressure, the residue was purified using a column Co-IN-NMR (400 MHz, SOSI"): b-2.09 (s, ЗН), 4.91 flash chromatography on silica gel used (d, 2Н), 6.74 (s , 2H), 6.95 (s, 1H), 6.98 (d, 1H), 7.65 using ethyl acetate:pentane (25:75, (d, 2H), 7.77 (d, 2H) as an eluent ). volume) obtaining the compound indicated in the title - NRMS (thermal spray): t/g (MMNA" | 418. cu (200 mg) as a yellow oil. Example 88

IN-NMR (400 MHz, SOS"): b-1.30 (c, 9H), 2.06 3-Cyano-M-(4-(3,5-dichlorophenoxy)-3-methyl- (c, Н) , 6.81 (s, 2H), 7.02 (s, 1H). 1H-pyrazol-5-yl|methyl)benzamide

NRMS (thermal spray): t/2 (MH) 299. compound 86 and 4-(3,5-Dichlorophenoxy)-3-ethyl-5-methyl-1H- - 8 cm pyrazole with 1-( 3-Dimethylamino)propyl)-3-ethylcarbodiimide (9 mg, 0.490 mmol) was added in one portion to a stirred solution of the amine of Example 109 (120 mg, 0.440 mmol) and 3-cyanobenzoic acid (71 mg, 0.490 mmol) in dichloromethane (5 ml) at room

A mixture of dione Preparation 50 (4.50g at room temperature under a nitrogen atmosphere. Reaction 30.8mmol), 3,5-dichlorophenol (5.00, stirred for 10 minutes and then washed- 30.mmol), cesium carbonate (10.0g, 30.8mmol) and om), M, Mo with aqueous hydrochloric acid of acetone (40ml) was heated from the back of the refrigerator (toml) and a saturated aqueous solution of sodium chloride for hours. After cooling and dusting, the solid substance was removed by filtration and sodium chloride was filtered. hydrazine hydrate (1.00 mL, 30.mmol) was added to the column and the mixture was heated at 60°C for 1 hour. 4:1, by volume) pressure, and the residue was purified using a column of III Dy 100 flash chromatography on silica gel using ethyl acetate:pentane (20:80, 1H) as the eluent to obtain the title compound (100 mg) . and "in volumes, receiving the specified in the title of the word TSN ov t ЧО

In pits (vom, SOS): b-1.18 (t, ZN), 2.11 pe 1.95 (d, 1H), 7.99 (s, not a (s, ZNU, 2.53 (k .

HPMS (thermal spray): t/z2 (MH"U | 271. ppm 5-Dichlorophenoxy)-3-methyl-1H- 4 Cyano-M-(4-(3.5-dichlorophenoxy)-3-methyl- pyrazole-5- yl|methyl)-M-(3-pyridinylmethyl)amine 1H-pyrazol-5-ylmethylbenzamide c 9 cm o sh--O io su o v i o y

Fo - Yin can't do it

A mixture of /Z-pyridinecarboxaldehyde (55MmgG, Amine Preparation 20 (127mg, 0.870mmol) 0.514mmol), replacement of Example 109 (14Omg, was added in one portion to the solution that was mixed- 0.514mmol), magnesium sulfate (500mg) and dichlor- is mixed, bromide Preparation 18 (100mg, methane (5ml) was stirred under nitrogen atmosphere 0.271mmol) in isopropanol (5ml) at room temperature for 18 hours. temperature The mixture was heated at 5072 during

Triacetoxyborohydride was added in one portion over 12 hours, cooled to room temperature, sodium (163 mg, 0.771 mmol) was added, and then Odertic acid (3 drops) was concentrated under reduced pressure. After 5 minutes, the mixture is chewed with yellow butter. The oil was dissolved in 1M chlorine and filtered. The filtrate was washed with 1M aqueous hydrous acid and the aqueous solution was washed with sodium carbonate solution (10ml), water (10ml) and ethyl acetate (10ml). A solid carbo- and a saturated aqueous solution of sodium chloride was added until the end of gas release! The mixture (10 ml) was dried over magnesium sulfate, filtered, extracted with ethyl acetate (3 (20 ml). The combined volumes were concentrated under reduced pressure, and the organic phases were dried over magnesium sulfate, yielding a clear oil. The crude product was filtered and concentrated under reduced pressure, purified with the help of column flash chromatography. the title compound tan:methanol:ammonia (95:4:1, v/v) to give (bOmg) as a colorless oil the title compound (45mg) as a colorless

IN-NMR (400 MHz, SOSI"): 6-2.09 (s, ZN), 3.66 oil. (s, 2H), 3.74 (s, 2H), 6.75 (s, 2H), 6.97 (s, 1H), 7.17 "H-NMR (Z00MGu, SOSi3): 6-2, 14 (с, ЗН), 2.17 (m, 1Н), 7.55 (d, 1Н), 8.49 (m, 2Н). (с, ЗН), 3.45 (с, 2Н), 3 .55 (c, 2H), 7.05, (c, 1H), 7.14

NRMS (electrospray): t/z2 (МН 363. (s, 1Н), 7.31 (m, ЗН), 7.59 (d, 2Н).

Example 90 HPMS (thermal spray): t/2 (MH) 392. 3-(5-(4-Acetyl-1-piperazinyl)methyl|-3- Example 92 methyl-1H-pyrazol-4-yloxy)-5-chlorobenzonitrile 3-Chloro-5-(5-((4-cyanobenzyl)(2-hydroxyethyl)amino|methyl)-3-methyl-1H-pyrazol-4-cmyl)oxy|benzonitrile

Sumy, Fr. d. sut s v no uch

M-Acetylpiperazine (104mg, 0.810mmol) was added in one portion to a stirred solution of bromide Preparation 18 (100Omg, Amine Preparation 21 (153mg, 0.870mmol) 0.271mmol) in isopropanol (5ml) at room temperature was added one portion to the over-temperature solution. The mixture was heated at 502 during stirring, bromide Preparation 18 (100mg, 1 hour, cooled to room temperature- 0.271mmol) in isopropanol (5ml) at room temperature and concentrated under reduced pressure or temperature. The mixture was heated at 5072 while chewing yellow oil. The crude product was purified for 12 hours, cooled to room temperature, evaporated using a flash column and concentrated under reduced pressure or chromatography on silica gel using yellow chewing oil. The oil was dissolved in a 1M water quality eluent dichloromethane:methanol:ammonia solution of sodium hydroxide and the resulting (95:41, by volume) solution indicated in the title was stirred at room temperature to give the compound (9mg) as a colorless oil. within 1 hour. The aqueous solution was extracted by "H-NMR (С300МГц, СОСИ3"): 6-2.08 (с, ЗН), 2.16 with ethyl acetate (З (20 ml) and combined organic phases (с, ЗН), 2.43 ( m, 4H), 3.42 (m, 4H), 3.55 (m, 2H), dried over magnesium sulfate, filtered and 7.08 (s, 1H), 7.16 (s, 1H), 7, 31 (c, 1H) was concentrated under reduced pressure

NRMS (thermal spraying): t/:2 (MH) 374. purified using column flash chrome-

Example 91 tography on silica gel using as

3-Chpor-5-(5-((4- eluent dichloromethane:methanol:ammonia (95:41, ob'-cyanobenzyl) (methyl)amino|methyl)-3-methyl-1H-) receiving indicated in the title the compound pyrazol-4-yl)oxy|benzonitrile (20 mg) as a colorless oil.

IN-NMR (z00Mhz, SOSI»z): b-2.14 (s, ЗН), 2.71 (m, 2H), 3.50 (s, 1H), 3.58 (s, 2H), 3 .67 (m, 2H), 3.72 (s, 2H), 6.99 (s, 1H), 7.09 (s, 1H), 7.31 (s, 1H), 7.41 (d, 2H), 7.58 (d, 2H).

NRMS (thermal spraying): t/2 (MH) 422.

Example 93 Me. see

C-Chloro-5-((3-methyl-5-|(2-methyl-1H-imidazol-1-yl)umethyl|-1H-pyrazol-4-yloxy)benzonitrile Go iodine and sleep more - 2x - in soybeans "about 1000 MN s.n. not t. Hydrazine hydrate (110 μl, 2.24 mmol) was added to the stirred solution of B-diketone.

A suspension of bromide Preparation 18 (100 mg, Preparation 24 (550 mg, 2.04 mmol) in glacial acetic

0.2 bmol), /2-methylimidazole (11 mg, in acid (ml) and the resulting solution was mixed with 1.55 mmol) and sodium carbonate (143 mg, dissolved at room temperature for 1 1.35 mmol) in toluene (5 ml) was heated at 10070 hours. The mixture was concentrated under reduced pressure for 12 hours. The suspension was cooled to pressure and the residue was purified using a column at room temperature, 1M aqueous solution of flash chromatography on silica gel using sodium hydroxide (zml) was added, and the mixture was stirred using pentane:ethyl acetate (60:40, for 1 hour) as an eluent . The mixture was extracted with ethyl acetate (volumetric) to obtain the title compound (Z (20ml) and the combined organic phases were dried (350mg) as a yellow solid, mp 142- over magnesium sulfate, filtered and concentrated at 1442С . were collected under reduced pressure to obtain a white solid. 1N-NMR (SO0MHZ, SOSI"): 6-1.21 (d, 6H), 2.09 r. The crude product was purified by (c, ЗН), 2.90 ( sept, 1H), 7.40 (s, 2H), 7.60 (s, 1H). using column flash chromatography on HPMS (thermospray): t/g (MH") 267. silica gel using breath as an eluent. Example 96 lormethane:methanol:ammonia (95:4.5:0.5, v/v) 5-C1-(2-Hydroxyethyl)-3-isopropyl-5-methyl- giving the title compound (77mg) as 1H- pyrazol-4-yl|oxy) and zophthalonitrile white solid, m.p. 212-21426. with.

IN-YAME (z00MHz, SOSI»z): b-2.14 (s, ZN), 2.33 on (s, ZN), 4.92 (s, 2H), 6.76 (s, 1H), 6.79 (s, 1H), 6.86 (s, 1H), 7.27 (s, 2H). 4 rn"

NRMS (thermal spraying): t/2 (MH) 328. sa

Example 94 "I 2-(4-(3,5-Dichlorophenoxy)-3-methyl-5-(|(3-pyridinylmethyl)amino|methyl)-1H-pyrazol-1- sn,yl)ethanol Tetrabutylammonium fluoride ( 0.28 ml of a 1.0 M solution in tetrahydrofuran, 0.280 mmol) was added in one portion to a stirred solution of io, I -O- pyrazole Preparation 25 (bOmg, 0.140 mmol) in 3 4 / dichloromethane (5 ml) at room temperature. -- The reaction was stirred for 12 hours and concentrated under reduced pressure to obtain a colorless oil. The crude product was purified

Tetrabutylammonium fluoride (0.5d8ml 1.0M dissolved by column flash chromatography in tetrahydrofuran, 0.580mmol) was added to silica gel using as an eluent a portion of ethyl acetate (20:80, vol.) capacity) to give the amine Preparation 22 (150mg, 0.290mmol) was added to the title compound (3mg) as a white solid in dichloromethane (5ml) at room temperature. substance

The reaction was stirred for 12 hours and con- NMR (400 MHz, SOS"): 6-1.17 (d, 6H), 2.08 was centered under reduced pressure to obtain (c, ЗН), 2.76 (sept, 1Н ), 3.52 (m, 2H), 4.10 (m, 2H), colorless oil. The crude product was purified 7.40 (c, 2H), 7.59 (c, 1H). by column flash chromatography on HPMS (electrospray): t/2 (MH 311. silica gel using as an eluent dich- Microanalysis: Found: C, 65.44; H, 5.87; M, lormethane:methanol:ammonia (95 :4:1, by volume) obtained - 17.91. C17NizvMaO2 required C, 65.79; H, 5.85; chewing the title compound (100 mg) as M, 18.0595. colorless oil. Example 97

IN-NMR (400 MHz, SOSI"): 6-2.07 (s, 3H), 3.65 3-(3,5-Dichlorophenoxy)-2-ethyl-b,7- (s, 2H), 3, 76 (c, 2H), 3.96 (m, 2H), 4.24 (m, 2H), 6.76 dihydropyrazolo|1,5-a|pyrazin-4-(5H)-one (c, 2H) , 7.02 (s, 1H), 7.26 (m, 1H), 7.59 (d, 1H), 8.50 a. and (m, 2H).

NRMS (thermal spraying): t/2 МН") 407. and: и

Example 95 d 5-((3Z-Isopropyl-5-methyl-1H-pyrazol-4- -- B,yl)uoxy|isophthalonitrile -

Lithium diisopropylamide (18.0 ml of a 1.5 M solution in cyclohexane, 27.0 mmol) was added dropwise to a stirred solution of pyrazole.

preparation of 26 (12.3g, 24.6mmol) in tetrahydrofur- Microanalysis: Found: C, 53.79; N, 4.88; M, early (120 ml) at -78"C in a nitrogen atmosphere. Reaction 13.14. Si4Ni5Si2MzO is necessary C, 53.86; H, 4.84; tion was stirred for 14 hours, slowly M, 13.4695. heated to room temperature and carefully extinguished Example 99 with a saturated aqueous solution of 3-(3,5-Dichlorophenoxy)-2-ethyl-5-methylammonium chloride (20 ml). ,5-a|pyrazine under reduced pressure and the residue was dissolved in dichloromethane (200 ml). The resulting solution was washed with a saturated aqueous solution of ammonium chloride (100 ml), dried over magnesium sulfate, filtered and 4. concentrated at under reduced pressure to obtain a white solid. Grind the solid substance. with a mixture of dichloromethane and pentane (100 ml and 100 ml) to give the title compound. Methyl iodide (11 μl, 0.176 mmol) was added (2.63 g) as a white solid, mp 220-223". , (k, 2H), 3.60 (m, 2H), 4.24 (t, 2H), 7.00 (s, 2H), 7.26 O, 160 mmol) in M,M-dimethylformamide (2 ml) at (c, 1H), 8.15 (c, 1H). at room temperature in a nitrogen atmosphere. The reaction

NRMS (thermal spraying): t/2 IMMNA") 343. stirred for 3 hours and then concen-

Microanalysis: Found: C, 51.52; N, 3.98; M, plowed under reduced pressure. The remaining solution is 12.74. Si4NziSiOMzO" must be C, 51.55; N, 4.02; in ethyl acetate (20 ml), washed with 1 M aq

M, 12.88965. potassium carbonate solution (2 ml), dried over

Example 98 with magnesium sulfate, filtered and concentrated 3-(3,5-Dichlorophenoxy)-2-ethyl-4,5,6,7- under reduced pressure. The crude product tetrahydropyrazolo(1,5-α|pyrazine) was purified by column flash chromatography on silica gel using dichloromethane:methanol (98:2, v/v) as an eluent to obtain the title compound (18 mg) as a colorless butter.

Single IN-NMR (400 MHz, SOSI»z): 6-1.11 (t, ЗН), 2.42 -y (m, 5Н), 2.84 (t, 2Н), 3.37 (s, 2Н ), 4.11 (t, 2H), 6.77 and M (c, 2H), 6.98 (c, 1H).

Borane (2.00 mL of a 1.0 M solution in tetrahydrofuran) was added to a stirred solution of the pyrazole of Example 97 (326 mg, 4- ((3-(3,5-Dichlorophenoxy)-2-ethyl-b,7- 1.00 mmol) in tetrahydrofuran (1 Oml) at room temperature in nitrogen atmosphere. The reaction with yl)umethyl|benzonitrile was heated under reflux for 5 hours and borane (3.00 mL of a 1.0 M solution in tetrahydrofuran, 3.00 mmol) was added. The reaction was heated under reflux for 14 hours and borane was added (2.00 ml of a 1.0 M solution in tetrahydrofuran, 2.00 mmol). The reaction was heated under reflux for 3 hours, and 4-cyanobenzyl bromide (35 mg, 0.176 mmol) was added borane (2.00 ml of a 1.0 M solution in tetrahydrofuran carbonate, 2.00 mmol) was added to a stirred solution. The mixture was cooled to potassium (24 mg, 0.17 mmol) and the amine of Example 98 at room temperature, 2 M hydrogen chloride was added(Bomg, 0 160 mmol) in MM-dimethylformamide acid (10 ml) and the mixture was heated with the reverse (2 ml) at room temperature in an azo-cooler for 1 hour. Cool the mixture. The reaction was stirred for 14 hours and stirred to room temperature and concen- then concentrated under reduced pressure. Blockages at reduced pressure. The residue was dissolved, the excess was dissolved in ethyl acetate (20ml) and obtained in dichloromethane (40ml), washed with 1M aqueous solution, washed with 1M aqueous potassium carbonate solution (30ml), dried over potassium carbonate (15ml), dried over magnesium sulfate, magnesium was filtered and concentrated, filtered and concentrated under reduced pressure. Unrefined product under pressure. The crude product was purified by flash column flash chromatography on silica gel using as an eluent dichloromethane' methanol (982, vol), lormethane:methanol (98:22, vol) volumes) then dichloromethane:methanol (95:5, v/v) giving the title compound (bbmg) as a white solid, then dichloromethane:methanol:ammonia (90:9:1, v/v, substance, mp 149-1502С . them) obtaining the title compound "H-NMR (400MHz, SOSIv): 6-1.13 (t, ЗН), 2.44 (219mg) as a white solid, Tpl. 76-7720. (k, 23), 2.92 (t, 2H), 3.42 (s, 28), 371 (s, 2n), 413

H-NMR (400MHz, SOSIz): 6-1.10 (t, ЗН), 2.42 (t, 2Н), 6.74 (s, 2Н), 6.97 (s, ТН), 7.42 (d, 2H), 7.60 (Kk, 2H), 3.24 (t, 2H), 3.80 (s, 2H), 4.05 (t, 2H), 6.76 (d, 2n) (c, 2H), 6.95 (c, 1H). ! ; . in

NRMS (thermal spraying): t/g (MH) 312. at that (MH 427.

3-(3,5-Dichlorophenoxy)-2-ethyl-5-(4-12,31. С1и4Ни7О02Мз3О» necessary C, 50.92; H, 5.19; methoxybenzyl)-4,5,6,7-tetrahydropyrazolo |1.5- M, 12.73905. α|pyrazine Example 103 with 2-I4-(3,5-Dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1H-pyrazol-1-yl--ethylamines; -K Y yod t sn, o. - / o o. with M--sv, - 4-Methoxybenzyl chloride (24 μl, 0.176 mmol) n zi M was added to the stirred solution, potassium carbonate (24 mg, 0.176 mmol) and the amine of Example Hydrogen chloride (0.50 ml of a 4.0 M solution in 98 (50mg, 0.160mmol) in M,M-dimethylformamide dioxane, 2.00mmol) was added to a solution (bml) of the pyrazole of Example 136 (bomg, tu) which (bml) at room temperature in an azo-miscible atmosphere was stirred for 14 hours and 0.130 mmol) in dioxane (0.5 ml) at room temperature, then potassium carbonate /(12 mg, temperature in a nitrogen atmosphere. The reaction was stirred - 0.088 mmol) and 4-methoxybenzyl chloride (12 μl, stirred for 2 days and concentrated at 0.088 mmol). The reaction was stirred under constant pressure. The residue was dissolved in hours and then concentrated under reduced pressure in dichloromethane (20 ml) and the resulting brine solution. The residue was dissolved in ethyl acetate (20ml) and washed with 1M aqueous potassium carbonate solution, the resulting solution was washed with 1M aqueous solution (10ml), dried over magnesium sulfate, potassium carbonate filter (20ml), dried over sulfonate and concentrated under reduced pressure. The magnesium was filtered and concentrated while the purified product was purified using a flash under reduced pressure. The crude product was purified by chromatography on silica gel using dichloromethane:methanol.ammonia silica gel as an eluent using dichloromethane:methanol.ammonia silica gel as an eluent (99:91, by volume) obtaining the indicated in the title lormethane:methanol (99:11, by volume ) to give the compound (32mg) as a colorless oil. the title compound (50mg) as colorless "H-NMR (400MGu, SOCI3): 6-1.10 (m, 6H), 2.42 oil. (Kk, 2H), 3.15 (t, 2H), 3.40 (k, 2H), 4.11 (t, 2H), 429 "H-NMR (400MHz, SOSIZz): b-1.13 (t, ЗН), 2.45 (s, 2H), 6 .79 (c, 2H), 6.98 (c, 1H). (Kk, 2H), 2.92 (t, 2H), 3.44 (s, 2H), 3.60 (s, 2H), 3.80 NRMS (thermal spraying): t/2 МН") 358. ( c, ZN), 4.10 (t, 2H), 6.77 (c, 2H), 6.85 (d, 2H), 7.00 EXAMPLES 104-106 (c, 1H), 7.23 (d , 2H).Compounds of the following grouped Examples

NRMS (thermal spraying): t/: (МН) 432. units of the general formula:

Example 102 and (1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-5-yl|methanol in ono M Usch o. was obtained by a method similar to sobu of Example 103 using acceptable noses M mn, starting materials.

Hydrogen chloride (0.50 mL of a 4.0 M solution in diocpotai nRMe knagittdani sani, 2.00 mmol) was added to a solution of the pre- (starting pi xho shi miscible, pyrazole of Example 135 (8bmg, material) 0.200 mmol) in dioxane ( 0.5 ml) at room temperature - 104 pg NAMES 386. | H-NMR (400 MHz, SOSi): 6 temperatures in a nitrogen atmosphere. The reaction mixture was stirred for 24 hours and concentrated under reduced pressure. The residue was dissolved in (c, 18), 7.415 (c, 1H), 7.42 (c, dichloromethane (20 ml) and the resulting solution was washed with 1H). Microanalyses: Found: C, washed with 1M aqueous solution of potassium carbonate Batv; H, BOB M, 786, (10 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using dichloromethane:methanol (99:1, v/v) as eluent to give the title compound (4mg) as a white solid, mp 105-107.

IN-NMR (400 MHz, SOSI»z): b-1.10 (t, ZN), 2.42 (Kk, 2H), 2.55 (s, 2H), 3.13 (t, 2H), 4 .13 (t, 2H), 4.37 (s, 2H), 6.79 (s, 2H), 6.98 (s, 1H).

NRMS (thermal spraying): t/2 (MH) 330.

Microanalysis: Found: C, 50.61; H, 5.23; M,

at room temperature in a nitrogen atmosphere. The reaction of the TV. The mixture was stirred for 3 hours and the mixture was concentrated (example SOXH 5 1.10 (t, ЗН), 2я2 (Kk, stirred under reduced pressure. The remaining solution was 142) - ( Си 2ну, 31 (t, 2Н), 3 ,55 (c, 2H), ly in dichloromethane (5 Oml) and the resulting solution 3.60 (c, 2H), 3.75 (c, ЗН), 407 was washed with 1 M aqueous solution of potassium carbonate (6 an), 6l7Z (b , 2H), 679 (d, (ZOml), dried over magnesium sulfate, filtered

Mmiykhanal Znvsche S. was collected and concentrated under reduced pressure. Non-vVYAV: NN. 567 M. 1188, the purified product was purified using a flash

SynySiMoO2 0 (023s of chromatography on silica gel using in the necessary C, 56.94; H, 5.69; M, the quality of the eluent dichloromethane:methanol:ammonia - white - (90:91, by volume) obtaining indicated in the title 106 pug MH " 444. "H-NMR (400 MHz, SOS 5 - (Example 110, ZNU, 2it (k, 2), 316 (t, compound (b4mg) as a colorless oil. 143) -uhk z» 2n), ZVO (c . 897. (c, ZN), 2.45 (k, 2H), 2.69 (t, 2H), 3.20 (t, 2H), 3.27 in the muscles of the back (m, 2H), 3, 65 (c, 2H), 4.15 (t, 2H), 6.91 (c, 1H), 6.81 v Ba Novo and vo, (c, 2H), 7t.02 (c, 19).

СхниСмеО»О 22СНСЈ NRMS (thermal spraying): t/2 (MNU)| 414. necessary C, 57.84; H, 510; M, Pry klad 1 09 15296. I4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl|methanamine hydrobromide

Example 107 2-I5-(4-Acetyl-1-piperazinyl)methyl|-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl|stylamine mn, weight g siv ./ sn, no M shk bromide Preparation 8 (500mg, 1.30mmol) and Mn were added in portions to a saturated solution of ammonia in isopropanol (5HOml) at 0"C. The reaction was stirred for 2 hours and left slowly

Trifluoroacetic acid (1 mL) was added to warm to room temperature. A mixture of a stirred solution of the pyrazole of Example was concentrated under reduced pressure to give 139 (150 mg, 0.28 mmol) in dichloromethane (2 mL) while the solid was triturated with diethyl ether at room temperature under a nitrogen atmosphere. The reaction yielding the title compound (340 mg) was stirred for 3 hours and the mixture concentrated as a white solid. dug under reduced pressure. Solvent residue - IN-NMR (400 MHz, SOSI"): 6-2.38 (s, ZN), 4.78 l in dichloromethane (20 ml) and the resulting solution (s, 2H), 6.88 (s, 2H) , 7.19 (c, 1H). washed with 1 M aqueous solution of potassium carbonate HPMS (thermospray): t/2 (MH 272. (ZOml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Ne- M-(4-(3,5- Dichlorophenoxy)-3-methyl-1H-purified product was purified using flash pyrazol-5-yl|methyl)-M-(4-fluorobenzyl)amine chromatography on silica gel using dichloromethane:methanol:ammonia (90: 91, by volume) obtaining the title compound (10 mg) as a colorless oil. r. -73-

IN-NMR (400 MHz, SOSI»z): b-1.11 (t, ZN), 2.05 y (s, ZN), 2.32 (m, AN), 2.42 (k, 2H), 3.13 (m, 2H), 3.33 si (s, 2H), 3.34 (m, 2H), 3.52 (m, 2H), 4.15 (t, 2H), 6.73 o (c, 2H), 6.97 (c, 1H). Sodium triacetoxyborohydride (Zbmg,

NRMS (thermal spraying): t/g (MH) 440. 0.160 mmol) was added in one portion to the solution

Example 108 of the miscible pyrazole of Example 109

M-(2-(C1-(2-Aminoethyl)-4-(3,5- (15Omg, 0.400mmol), 4-fluorobenzaldehyde (11mg, dichlorophenoxy)-3-ethyl-1H-pyrazole-5- O,O08Ommol) ) and acetic acid (dropwise) in dichloroylmethyl)amino)ethylacetamide methane (15 ml) at room temperature under a nitrogen atmosphere. The reaction was stirred for 4 hours and then concentrated under reduced pressure.

Z, sn, ku. The crude product was purified by flash chromatography on silica gel using dichloromethane:methanol:ammonia (90:91, v/v) as eluent to give the title compound (bmg) as a colorless oil. sn IN-NMR (z300MHz, SOSI»z): 6-2.17 (s, ZN), 3.67

Trifluoroacetic acid (1 ml) was added to (c, 2H), 3.73 (c, 2H), 6.81 (c, 2H), 6.99 (c, 2H), 7.02 a stirred solution of pyrazole of Example (c, 1H), 7.22 (c, 2H). 141 (122 mg, 0.24 mmol) in dichloromethane (2 ml) by HPMS (electrospray): t/2 (M-NUYA | 378.

Example 111 in Article 4-I414-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-ylmethyl)amino)methyl|-benzonitrile Io; corner s, si Ge) s

Ho Ko Fr. 4-Cyanobenzylamine (155 mg, 1.17 mmol) was added in one portion to a stirred solution of the bromide of Example 144 (100 mg, 0.300 mmol)

Sodium triacetoxyborohydride (216 mg, in isopropanol (1 Oml) at room temperature. 1.09 mmol) was added in one portion to its solution. (c300mg, 0.850mmol), 4-cyanobenzaldehyde was added under reduced pressure to give yellow (117mg, 0.850mmol) and acetic acid (dropwise) into the oil. The crude product was purified from dichloromethane (25ml) at room temperature using a column flash chromatography under a nitrogen atmosphere. The reaction was stirred through silica gel using breath as an eluent for 14 hours and then washed with 1 M aqueous solution of chloromethane:methanol:ammonia (95:4:1, by volume) or sodium carbonate (2 (10ml) and saturated chewing the compound indicated in the title (97mg) as an anhydrous sodium chloride solution (1Oml), dried the colored oil over magnesium sulfate, filtered and concentrated. (с, ЗН), 3.66 shafts at reduced pressure . The crude product (c, 2H), 3.79 (c, 2H), 3.84 (c, ЗН), 7.02 (c, 1H), 7.13 was purified using flash chromatography on (c, 1H)U , 7.31 (c, 1H), 7.37 (d, 2H), 7.58 (d, 2H). silica gel using as an eluent breath-HPMS (thermospray): t/z MH") 392. lormethane:methanol:ammonia (95:4:1, by volume) obtaining Example 114 chewing the compound indicated in the title (10mg) as without - 3-Chloro-5-(C1-(2-hydroxyethyl)-3,5-dimethyl-1H- colored oil. pyrazol-4-yl|!oxy)dbenzonitrile

IN-YAME (z00MHz, SOSI"): 6-2.16 (s, ZN), 3.70 st (s, 2H), 3.85 (s, 2H), 6.78 (s, 2H), 7 ,01 (c, 2H), 7.35. (d, 2H), 7.58 (d, 2H). Co,

NRMS (electrospray): t/2 (MH) 387. in y

Example 112 3-Xpor-5-(1,3,5-trimethyl-1H-pyrazol-4-monoyl)oxy|benzonitrile ne cm 2-Hydroxyethylhydrazine (1.80 g, 24.0 mol) was added to a stirred solution of B-diketone Preparation 16 (5.80g, 23.0mmol) in 4 glacial acetic acid (ZOml) and the resulting solution was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and the resulting brown oil was purified

Methylhydrazine (250 mg, 5.17 mol) was added by flash column chromatography to a stirred solution of B-diketone on silica gel using as an eluent the preparation of 16 (1.00 g, 3.97 mmol) in ice-cold ethyl acetate ( 50:50, v/v) to formic acid (1 Oml) and the resulting solution afforded the title compound (4.80 g) as a yellow solid at room temperature for 2 days. substance, Tpl. 114-11670.

The mixture was concentrated under reduced pressure and H-NMR (Z00MGu, SOS): b-2.04 (s, ЗН), 212 the obtained orange oil was purified with the help of nut st t 4.08 (m, 4Н), 7, 03 (c, 1H), 7.15 by flash column chromatography on silica gel; d; using pen-NRMO (thermo-spraying) in the romato and eluent; t/g2 (MH 292. tan:ethyl acetate (50:50, by volume)) giving the compound (500 mg) as a white solid. 14.14. SlaNi" Mass required C, 57.69; H, 4.84; substance, Mpl. 114-1162С. M, 144095. "H-NMR (ZO0MHC, SOCI3): 6-1.85 (s, ZN), 1.87 Example 15 (s, zn), 3.61 (s, zn), 6.88 (s, 1n), 6.98 (s, 1n), 71 Z-Chlor-5-( 5-((4-cyanobenzyl)amino|methyl)-1- (c, 1H). (2-tihydroxyethyl)-3-methyl-1H-pyrazole-4-

NRMS (thermal spraying): t/x (MNU 262. ilioxy)benzonitrile

Microanalysis: Found: C, 59.48; H, 4.60; M, cm 15.88. SizNi2MzOSI must be C, 59.66; N, 4.62; M, 16.0695. I'm Kut

Example 113 paradise

C-Chloro-5-I(5-((4-cyanobenzyl)amino|methyl-1,3-dimethyl-1H-pyrazol-4-yl)oxy|benzonitrile mono 4-Cyanobenzylamine (131 mg, 0.910 mmol) was added to the stirred solution of pyrazole methylrondini ol) obtained soluble 0001 . . . . m. (Me diketone) methylpyrrolidine (1 Oml) and the resulting solution was heated to 55 pr of BBBGrU for 3 hours. The mixture of concen- (Preparation 43) (thermal spraying) 5 "1.10 (m, 6H), 2.39 (k, crushed under reduced pressure and the obtained brown- 2H), 2.49 (k, 2H), 4.04 (m, 4H), 6.85 (dd, 1H), neve oil was dissolved in acetic acid (10 ml) and 6.99 (s, 1H), 7.00 (dd, 1H). Microanalysis: heated at 40"С for 6 hours. The mixture con pressure and the unpurified product was purified using a column column. ammonia (t, ЗН), 2.34 (s, ЗН), 2.89 (k, 2Н), 2.50 (k, (95:41, by volume)) obtaining the title compound (5 mg) as a white solid substance. 119 EMO topics zi: NAM? (bo Me, ZsOob;

H-NMR (ZO0OMHC, SOS"): 6b-2.05 (s, ЗН), 3.04 (Preparation 45) (electrospray) 5 - 1.13 (m, ВН), 2.40 (s, 2Н) , 3.91 (s, 2Н), 3.99 (t, 2Н), 4.32 (m, 2Н), 7.06 (k 2Ну ), 411 (m, (s, 1H), 7.11 (s, 1H), 7.33 (s, 1H), 7.46 (d, 2H), 7.62 YAN), 7.40 (s . ; H, 5.85; M,

NRMS (thermal spraying): t/2 (MMa" | 444. Vovchi. Tl. 120-121 S.

Example 116 120 SI t/gImMnUz2o. NMR (400 MHz, SOS): 4-I(C4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H- (Preparation 46) (thermal spraying) 5 « 1.08 (m, 6H), 2.39 (k, pyrazol-5-yl|methyl)amino)methyl|benzamide 2H), 2.50 (k, 2Нu 401 (m, 2H), 408 (m, 2H), s 7.03 (c, 1) 7.13 (c, 1), 724 (c, 1H). s Microanalysis; Found: C, 59.67; H, 5.71; oh p a ol

H, 5.67; М.

Amine Preparation 55 (150 mg, 0.800 mmol) of the general formula: was added to a stirred solution of pyrazole Preparation 18 (100 mg, 0.270 mmol) and triethylamine (81 mg, 0.800 mmol) in isopropanol (Oml) and M,M-dimethylformamide (ml) and the resulting solution was heated at 60"C for 3 hours. --7

The mixture was concentrated under reduced pressure and the resulting brown oil was dissolved in ethyl acetate (20 ml). The solution was washed with a 1 M aqueous solution of sodium carbonate (2 (1 Oml) and saturated with an aqueous solution of sodium chloride (10 ml) obtained by a similar method, the solution of Example 76 was dried using acceptable magnesium sulfate, filtered and concentrated - starting diketone and hydrazine The crude product was purified by means of flash chromatography on Example Me ARMS Analytical data silica gel using dichloromethane:methanol:ammonia (90:91, by volume) as an eluent, or ortminnoya with jiame (600 MP; sosyuu;

MG) as without (Preparation 43) (thermal spraying) 5 with 1.18 (t, 6H), 2.47 (k, chewing the compound indicated in the title ( zn), 685 (dd, 10), 698 (s, 1H ). 7.01 (dd, colored oil, etc.). .

IN-NMR (300 MHz, SOSIzv): 6-2.16 (s, ZN), 3.68 122 CM | p/gIMNYagv?7. |NYAMRO (400,000 Mgu, 0 SOS) (s, 2H), 3.82 (s, 2Hn), 7.05 (s, 1Hn), 7.13 (s, 1H), 7.28 (Preparation 45) (thermal spraying) 5 -: 1.20 (BN, m), 2.47 (k, (c, 1), 7.32 (d, 2H), 7.76 (d, 2H). 123 tu» IMN' T 256. miy nin 5 her sroi) . . - ts, iv):

NRMS (electrospray): t/2 (МН"| 396. (Preparation 44) (electrospray) 5 - 1.17 (t, 6Н), 2.34

EXAMPLES 117-120 (c, ZN), 2.48 (k, 4H), 6.92 (c, 1H), 6.96 (c,

Compounds of the following grouped Prepositions - 1n), background (c, tn). units of the general formula: 124 si t/g (mMn)276. | "H-NMR (400 MG, immediately): in (Preparation 46) (thermal spraying) 5 -- 1.18 (t, EN), 2.49 (k,

Go AN), 7.07 (s, 1H), 7.13 (s, 1H), 7.27 (s, 14). сн, EXAMPLES 125-128 o - Compounds of the following grouped Examples in OR of the general formula: с

M. N

CM sn, Y ») was obtained by a method similar to that of Example 114 using an acceptable starting diketone and 2-hydroxyethylhydrazine. - M shh sn,

? (120 mg, 8 5 and kim- example at 00 . alkali p islo prinoy pyrazho shiniy k heated rooms in 5124 sya, mura ish n i do enom 7 o Za ommo t) rat olodzhuval o. Butter

I and l pr lo

And with 30 m mpera, if Mas. in spo o, ij te din, uvalo. y rch y M - nii ho ntr as. And he introduced a wonderful course of poetry and a baronless reception! p atu and be: Oml idro one

PRESENTING inu. per yuch tan (5 mas rokaroe according to the ears of tem erzhu tat ny eny over i tytil od this water, ich y val ory orek yla m us lik ik hl tys et yen y eny l) and dried the lad Zvoryd valy sat 20m l ), ruv i: i na yu ( 20m ent ct ladu and hydrochltic dan chin ali odo iu ( and conc odu

For the legs of the ommyv l), in the natli and pr - sobu y pyraz ss pr rium (20m of oridus su eochishchen s chromium: vyhIDN nRMe MG n), 24 poZhin m "magnesium, sc Ne ova fle in the quality of tt. vnu, 2 3 M isku. K y - le sdyai: a nasal zts s, rofatomum t column tovyuch Al, ob

Application: milled (b 2 x. l en goyu is . (95 ku idny pyrazole YMNYA 299. pvtvelyu 2nu, 243 n vevietnkh. pai down ly stanogamk in spolu ( Weekend whips 2.89 (k, (s, 1NU, 6, pr za ikage nol: vk ke) zn). va!: and ika meta lo is, 2nu, le al sil me ago 04 (t, soe chishchts;, her na an: v'z 16 125 z gnu 4 ynu Melok o aphii normet zanu ZN), 1, sle gr chl vka 79 (Example of tinny (400 8 -1.09 (m, sam gnu to entu dy aslo. 6-1.08 (t, 2H), 4,

MN TV posovi vlyuvy k colorless M SOS b 3.81 (m, tu/x (te (kyu 2H), 3, ), 7.28 (s, Os): EM be MHz, 2 sho si nta in g) as 300 63 (m, 354.

Mt, Mgz, zv (k, 85m MR ( 3, 1H). nya 126 and (vn (400 nu, 2, ( 1nH-Я tn), O (s, /2 M ha) ; moni vv zn M, What ) t - (Example 1 tvo: pochstyutnya (m, 2n). 208 (m ( zn). tto s 2H), dusting) two t'eTMA! (termori k. 2n). Z. s t, ) b, oro il- 4-(3, sya sanitvtK NU so tn), ermoro: Z "ethyl- 2-8, 127 reve oven (m NRMO zh 153 renozel l Istilamine; m, , - nklad 122) Yasya nia) 8 z 106 403 ( t, 2H) PRIKL - Dichlorophadozol-1-yl (Pri ile gnu 5-D Cl a pukh (MN Zo. (thermosp 2nu, 313 (t, 97 (d. 1H)). 2-14-(3.5 (When lNpyr (k.2n), , b. and IN -ethyl-

E hn), dube) il|Estylam ksi)-5-et

Sho 12) ve ip azu) 1 (example of clades (poikats 13 of them) Pr (Pr p 9-131 pova

LADY 12 of them will play

To stupid

With us

Ki i: lyno formulas and kn, general M.

SM M what. but

For the similar and o - Nn bom under exception, I put so sposo or pr) At 1omg, if I put o -- bOmmol (5th: va orylm, 4, inu 50 I will get 76 vyk n bor (1 ,03g, retylam at 1 ish and hydrazine.

Hydrochloric acid and hydrochloric acid were mixed with NRMS tabo Mgc (m, Sum 5) with a carbonate solution - the resulting yield of NAM) was mixed with 1 powder of MH12. , news from henna "aomnole t TM water river (ZOml). solution d and back

Lantvdyu OB 2n), ov 1Nu, gav (Kk pl. inv. traction of food 1M ethano water lfat - vn | 1.58 (m, B (p, 19). Those about ilyali mi» py saturated over su and pony 129 2nu , 7, I zd )i si pr - d) s, their OZ, ml on neck and eyes

Seaghttvaniya BA | t.

SYAMR) p i i k e her ve tya soplnlenn) sg, a layer of sodium ali and cinnamon graphi n ent

IN extra: | : U v e to lu t/g (M! (el (s, ZN), microanalysis of orid; тru zhan oma і e x) on), 1.84 yin) Msogni M. chl niyu, fil u toy flash chr quality voluminous (p. 8; H, 574; agniyu, sku. . Z

And 56 18; Y , M and 6) in . ; g 130 And it is said: S, 68, it is necessary and helpful. (93:61 and (76dm u. 53) Zn: Nemo oo. Tl. zh ado tovu ak luk bar (Preparation 1972. St. tv. M, 1999 shchaly z vykorys nolami ovku spo. as without " ; H, 5 ,75; - I . and ol riv vv, 55; their eli "purpose; title ome - h SOS kag etan iv ioiz y, t, vi-63 es. Mgts, (m. orm azan regional, plylenya, 115 ihl i vk nym (main K, nMR ionization) in, d yuch y shen -1.16 ny, 1. zp I, .no .E1, ov w

TIM OV ivpesraov d) sk tyl. VB-15 covid ТZ) Av Main t, tavnu tvo tv tv tv t) 2. main g

IRg (s, 2H), asl 400 y, t, 313 Aries tav nem MR ( ny, NU, Z, (osn y, s, tya as. IN-Y novnyy Kk, 2 10 ny, preparation 54) lo ) 16 (non-basic, t, 2H), beat the main s, ry H), ' ne иY, t, "o, sno - s, typ-on) 2.60 ( eosovn y, t, 2H) 7.02 ( o new, 1-(1-me 2H), 3.19 (n new, c, 2H), 7.27 (os iethyl- 2H), 10 (neon, c, 1n), ' -3,5- d H), 4, eosno y, p, 1300. 132 noxy) 2H), 6.85 (n snovnyi 1nH). /72 (MN iklad rfe 2H), 6, (neo yy, s, i): t il-

Pr ichlorphazol 7.02 novnen-3-eth 4-(3,5-D )-1H-pyr 1n), 81 o thermally stable enoxy)ethidinyl 1H), 7, MS (terichlorph 3-az a HP 135 4 -(3,5-d iklad 2-I sn, ) tert-ol. Ohm -

M-en, 0.33 e that id o solution p 4 eg oZch 'vet ld orma yy d that perafor portion ni val oda to

5-(Hydroxymethyl)-1H-pyrazol-1-yl|ethyl carbamate of ethyl iodide (1.75 ml) at room temperature under a nitrogen atmosphere. The reaction was heated at 40°C for 1 day and then cooled to room temperature. The mixture was filtered and the remaining solid was washed with dichloromethasone (1 mL). The filtrate was concentrated under reduced atmospheric pressure. .

A solution of the pyrazole of Example 97 (1.96 g, in the title compound (bOmg) as a colorless oil. b.00 mmol) in concentrated hydrogen chloride H-NMR (400 MHz, SOCIzv): 6-1.15 (m, 6H), 1 .44 lots (5Oml) were heated under reflux (c, ЗН), 2.45 (k, 2H), 3.45 (k, 2H), 3.58 (m, 2H), 4.18 for 20 hours. The reaction was cooled to (m, 2H), 4.29 (s, 2H), 5.26 (m, 1H), 6.92 (s, 2H), 7.00 room temperature and concentrated at (s, 1H ). under reduced pressure. The residue was dissolved in dioxane HPMS (electrospray): t/2 |MMa") 480. (VOml) and water (bOml), added /di-t- Example 137 butyl dicarbonate (1.44g, 6.6Omol) and hydrocarbo-tert-Butyl 2-I5-(bromomethyl)-4-(3,5- sodium nate (1.26 g, 15.0 mmol) and the reaction of peremi-dichlorophenoxy)-3-ethyl-1H-pyrazol-1- at room temperature for three days. The reaction was concentrated under reduced pressure. A solution of the residue in dichloromethane (300 ml) was washed with 2M aqueous hydrochloric acid (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. A solution of the crude product in tetrahydrofuran (5 Oml) was cooled to -40°C in a nitrogen atmosphere and triethylamine (0.79 ml, 5.68 mmol) and isopropyl chloroformate (5.68 ml, 1.0 M) were added dropwise. solution in toluene, 5.68 mmol). is stirred, sodium triphenylphoride (537mg, 14.2mmol) and then sphine (820mg, 3.12mmol) and imidazole (213mg, water (3 drops) were added and the reaction was stirred at 0С 3.12mmol) in dichloromethane (15ml) at room temperature. for 1 hour and at room temperature under a nitrogen atmosphere. Then to the reaction for 14 hours. The mixture was concentrated by adding a solution of the alcohol of Example 135 (1.12 g, under reduced pressure and a solution of the residue in dichloromethane- 2.60 mmol) in dichloromethane (5 ml). The reaction mixture (100 ml) was washed with water (100 ml), dried and stirred at room temperature for 2 hours. of magnesium, filtered and concentrated, diluted with dichloromethane (50 ml), washed under reduced pressure. The crude product was washed with a saturated aqueous solution of chloride and purified using flash chromatography on tritium (20 ml), dried over magnesium sulfate, distilled using silica gel as an eluent and concentrated under reduced pressure. lormethane:methanol (97:3, v/v) to give the crude product was purified using the title compound (1.37 g) as a white foam. flash chromatography on silica gel using

IN-NMR (400 MHz, SOSI"): 6-1.10 (t, ЗН), 1.37 or as an eluent dichloromethane:methanol (98:22, (с, 9Н), 2.40 (k, 2Н) . (m, 1H), 6.80 (s, 2H), 6.97 cu (969mg) as a white foam. (c, 1H). IN-NMR (400 MGu, SOSIz"): 6-1.10 (t, ZN), 1.40

NRMS (thermal spraying): t/g2 (MH) 430. (s, 9H), 2.40 (k, 2H), 3.60 (m, 2H), 4.18 (t, 2H), 427

Example 136 (c, 2H), 4.95 (c, 1H), 6.82 (c, 2H), 7.00 (c, 1H). tert-Butyl 2-(4-(3,5-dichlorophenoxy)-5- HPMS (electrospray): t/2 (MH) 494. (ethoxymethyl)-3-ethyl-1H-pyrazole-1- Microanalysis: Found: C , 46.22; H, 4.89; M, yl|stilcarbamate 8.44. Si9Nha«VgSMzOz required C, 46.27; H, 4.90; c with M, 8.5295.

Example 138

Io; o tert-Butyl 2-(5-(aminomethyl)-4-(3,5-4-bHn, dichlorophenoxy)-3-ethyl-1H-pyrazol-1- and yl|stylcarbamate praa ne y,

Everything is not a dream, eh

Silver (I) oxide (210mg, 0.900mmol) was added in one portion to a stirred solution of alcohol of Example 135 (129mg, 0.300mmol) in iodine iodine chn, in! (c) - o y -8x - y y shi o sn, nu ka M ne -e sn, that ko,

The bromide of Example 137 (444mg, 0.900mmol) was added to a saturated solution of ammonia in isopropyl pyrazole (23mg, 0.330mmol) and diisopropylethylamine (17Zmk, a portion to a stirred solution, bromide 1.00mmol) was added at room temperature temperature The reaction of Example 137 (148 mg, 0.300 mmol) and the hydride was stirred for 5 hours, and then the concentrate (6095 dispersion in oil, 13.2 mg, 0.330 mmol) was distilled under reduced pressure. The crude sample in M,M-dimethylformamide (2 ml) at room temperature was purified by means of flash chromatography at room temperature in a nitrogen atmosphere. The reaction was stirred on silica gel as an eluent for 5 hours, quenched with water (1.00 ml) and dichloromethane:methanol (95:5, by volume) obtained and concentrated under reduced pressure. The residue or the title compound (359 mg) was dissolved as white in dichloromethane (3 mL) and a solid was obtained. Tpl. 112-11476. the solution was washed with a 1 M aqueous solution of carbonate

IN-NMR (400 MHz, SOSIv): 621.11 (t, ЗН), 1.40 potassium (100 ml), dried over magnesium sulfate, (c, 9Н), 2.40 (k, 2Н), 3.55 (m, 2H), 3.73 (s, 2H), 4.18 was filtered and concentrated at reduced (t, 2H), 5.60 (s, 1H), 6.77 (s, 2H), 6.98 (c, 1H). 7 pressure. The crude product was purified using

NRMS (thermal spray): t/z MH") 429. flash chromatography on silica gel using

Example 139 using as an eluent dichloromethane:methanol tert-Butyl 2-15-K4-acetyl-1- (98:22, by volume) obtaining indicated in the title piperazinyl)methyl/|-4-(3,5-dichlorophenoxy) -3- compound (125 mg) as a colorless oil. ethyl-1H-pyrazol-1-yl|styl carbamate 1N-NMR (400MHz, SOCI3"): 6-1.13 (t, ЗН), 1.44 si in o (c, 9H), 2.42 (k, 2H), 3.52 (m, 2H), 4.26 (t, 2H), 5.18 g - (s, 2H), 5.48 (s, 1H), 6.16 (s, 1H), 6.73 (s, 2H), 7.00 (s, 1H), 7.18 (s, 1H), 7.45 (s, 1H). in mi NRMS (thermal spray): t/z: (MH"| 480. : a Example 141 sh- / d tert-Butyl 2-15-(Ce- m ee (acetylamino)ethyl|amino)methyl)-4-( 3,5- sn, ne, dichlorophenoxy)-3-ethyl-1H-pyrazol-1- con, yl|stylcarbamate ne

M-Acetylpiperazine (42mg, 0.330mmol) in M,M- and dimethylformamide (tIml) was added to a solution, stirring H, of the bromide of Example 137 (148mg, K sn,

0.000 mmol) and diisopropylethylamine (57 μl, 0.330 mmol) in M, M-dimethylformamide (2 ml) at F; room temperature. The reaction was stirred with water for 5 hours and the mixture was concentrated under reduced pressure. A solution of the residue in dichloromethane sn, with uko (30 ml) was washed with 1M aqueous solution of potassium carbonate sn, that potassium (10 ml), dried over magnesium sulfate, c, filtered and concentrated under reduced o M-Acetylethylenediamine (153 mg, 1.50 mmol) in pressure The crude product was purified using isopropanol (1 ml) was added to the solution used for flash chromatography on silica gel, the bromide of Example 137 (148 mg, using dichloromethane:methanol 0.30 mmol as an eluent) and diisopropylethylamine (57 μl, (98 :2, by volume) to give the title compound (150 mg) as a colorless oil (0.330 mmol) in isopropanol (2 mL) at room temperature. temperature The reaction was stirred for 5 "H-NMR (400 MHz, SOSIv): 6-1.15 (t, ЗН), 1.42 hours and the mixture was concentrated at reduced (s, 9Н), 2.06 (s, ЗН), 2 ,44 (m, 6H), 3.32 (s, 2H), 3.47 pressure. Solution of the residue in dichloromethane (zbml) (m, 2H), 3.60 (m, 2H), 3.65 (m, 2H), 4.23 (m, 2H), washed with 1M aqueous potassium carbonate solution 5.89 (s, 1H), 6.76 (s, 2H), 7.02 (s, 1H). (20ml), dried over magnesium sulfate, filter-

NRMS (thermal spraying): t/g2 (MH) 540. shafts I were concentrated under reduced pressure. Not-

Example 140 purified product was purified by flash tert-Butyl 2-I4-(3,5-dichlorophenoxy)-3-ethyl chromatography on silica gel using in 5-(1H-pyrazol-1-ylmethyl)-1H-pyrazol-1- as eluent dichloromethane:methanol (90710, v/v) ethyl carbamate, then dichloromethane:methanol:ammonia (90:91, v/v) to give the title compound (122 mg) as a colorless oil.

IN-NMR (400 MGu, SOS"): b-1.13 (t, ZN), 1.42

(c, 9H), 1.94 (d, 3H), 2.44 (k, 2H), 2.74 (m, 2H), 3.35 ethanol (4 ml) and with intensive stirring (m, 2H), 3.58 (m, 4H), 4.19 (m, 2H), 5.68 (s, 1), sodium borohydride (18 mg, 0.480 mmol) was added. 6.77 (s, 2H), 7.00 (s, 1H), 7.65 (s, 1H). After the addition is complete, the reaction is stirred

NRMS (thermal spraying): t/2 (MN) 514. poured for 4 hours and then water was added

Example 142 (2ml). The mixture was concentrated under reduced tert-Butyl 2-(4-(3,5-dichlorophenoxy)-3- pressure and the residue was dissolved in dichloromethane ethyl-5-|(4-methoxybenzyl)amino|methyl)-1H- (5Oml). The resulting solution was washed with 1 M aqueous pyrazol-1-yl)ethyl carbamate solution of potassium carbonate (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography for 4 hours, silica gel using dichloromethane:methanol (99:1, vol.) as an eluent, then dichloromethane M in methane:methanol (95:5, vol. "capacitive") receiving in-

M gezan in the title compound (120 mg) as a colorless drug, that, in oil.

Con, IN-NMR (400MGu, SOSIz"): 6-1.10 (t, ЗН), 1.35 ne (s, 9Н), 2.40 (k, 2Н), 3.55 (m, 2Н) , 3.58 (s, 2H), 3.76 4-Methoxybenzaldehyde (4bml, 0.380 mmol), (s, 2H), 4.16 (m, 2H), 5.45 (s, 1H), 6.73 (c, 2H), 6.98 amine of Example 138 (172 mg, 0.400 mmol) and sulfate (c, 1H), 7.32 (d, 2H), 7.55 (d, 2H). magnesium (200 mg) was mixed in dichloromethane HPMS (thermospray): t/g2 (MH) 544. (4 ml) at room temperature for 4 days. Example 144

The mixture was filtered and the filtrate was concentrated under 3-(5-(Bromomethyl)-1,3-dimethyl-1H-pyrazole-4-) under reduced pressure to obtain a yellow oil. Masyl|oxy)-5-chlorobenzonitrile was dissolved in methanol (4 ml) and sodium borohydride (18 mg, 0.480 mmol) was added with vigorous stirring. After completion of the addition of iodine, the reaction was stirred for 4 hours and then water (2 ml) was added. The mixture was concentrated at the end of Eq. under reduced pressure and the residue was dissolved in dichloromethane (5 mL). The resulting solution was washed with a 71 M aqueous solution of potassium carbonate M-Bromosuccinimide (34 Ωg, 1.90 mmol) was added (20 ml), dried over magnesium sulfate, filtered to a stirring solution, pyrazole was added and concentrated under reduced pressure. The purified product of Example 112 (500 mg, 1.90 mmol) in tetrachloride was purified by flash carbon (1 Oml) and azobisisobutyronitrile (20 mg) chromatography on silica gel using dichloromethane:methanol (99:1, 99:1, The reaction was heated under reflux (mh) and then dichloromethane:methanol (95:5, v/v for 1 hour, cooled to room temperature) to give the title compound at reduced temperature (142mg) as a colorless oil pressure. The crude product was purified using

IN-NMR (400 MHz, SOSIv"): 6-1.10 (t, ЗН), 1.40 by flash column chromatography on silica gel (с, 9Н), 2.42 (m, 2Н), 3.55 (m , 5H), 3.66 (c, 2H), 3.77 using pen- (c, 2H) as an eluent, 4.15 (m, 2H), 6.11 (c, 1H), 6.74 ( s, 2H), 6.80 tan:ethyl acetate (80:20, by volume) to obtain (d, 2H), 7.00 (s, 1H), 7.11 (d, 2H). of the title compound (340mg) as a white solid

NRMS (thermal spraying): t/z: (МН"| 549. substance, Tpl. 76-78.

Example 143 IN-NMR (z00MHz, SOS"): 6-2.03 (s, ZN), 3.45 tert-Butyl 2-I5-Sh(4- (s, ZN), 4.32 (s, 2H ), 7.12 (c, 1H), 7.19 (c, cyanobenzyl)amino|methyl)-4-(3,5-dichlorophenoxy)-1H), 7.34 (c, 1H).

3-ethyl-1H-pyrazol-1-yl|stylcarbamate HPMS (thermal spray): t/2 (MH) 342. s Example 145 in 3-(3,5-Diethyl-1-methyl-1H-pyrazol-4-ut yl)oxy|benzonitrile

SM

7 sleep, now with | sn, che) in sn, and Phi is not She

A mixture of 4-cyanobenzaldehyde (5mg, 0.38 mmol), the amine of Example 138 (172 mg, sodium hydride (6095 dispersion in oil, 22 mg, 0.400 mmol), magnesium sulfate (200 mg) and dichloro-0.53 mmol) was added to the pyrazole solution, methane (4 ml) was mixed at room temperature with 60 (100 mg, 0.4 mmol) and methyl iodide raturi for 4 days. The mixture was filtered and the filtrate (34 μl, 0.53 mmol) in dimethylformamide (1.5 ml) was concentrated under reduced pressure at 0°C in a nitrogen atmosphere. The reaction was left to obtain a yellow oil. The oil was dissolved in me- heated to room temperature and mixed

fell for 4 hours. The reaction was quenched with water and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (1 mL), and the organic phase was washed with water (2 O (1 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The oil that poured was washed, purified by means of flash chromatography. containers) obtaining the specified Hydrazine hydrate (39095, 8.00 mmol) was added to the title compound (b5 mg) as a colorless oil. was added to the enol solution from Preparation 60 (2.477, "H-NMR (400 MHz, SOCIv): 6-1.09 ( t, ЗН), 1.12 6.69 mmol) in acetic acid (5 ml) in an atmosphere of 7.38 (m, 4H). heating for 18 hours, the mixture was concentrated

NRMS (electrospray): t/2 (МН 256, under reduced pressure and purified using

IMMa" | 278. flash chromatography on silica gel using

Microanalysis: Found C, 70.15; H, 6.78; M, or as an eluent pentane-ethyl acetate (70:30 16.42. Si5Ni5MzO-O,ovnho is necessary C, 70.17; H, was replaced by 50:50, by volume) obtaining an index of 6.74; M, 163795. zan in the title compound (5.8g) as a yellow oil.

Example 146 IN-NMR (400MHz, SOS"): 6-1.13 (t, ЗН), 2.41 3-(I35-Diethyl-1-(2-methoxyethyl)-1H-pyrazole-4- (Kk, 2H), 2.67 (t, 2H), 3.62 (t, 2H), 4.48 (s, 2H), 6.79 yl|oxy)benzonitrile (m, TN), 6.98 (m, 2H), 7.24 (m, 5H). that NRMS (electrospray): t/2 (M-NU | 364.

Microanalysis: Found C, 66.96; H, 5.62; M, at 11.25... Sgi1NgoMzO2B.0.60H2O is necessary C, 67.04; / sn, H, 5.68; M, 11,1796. Example 148 3-(|3-Ethyl-5-(2-hydroxyethyl)- se x 1H-pyrazol-4-yl|oxy)-5-fluorobenzonitrile m x E cm sn, sna on

Sodium hydride (6095 dispersion in oil, 22 mg, 0.54 mmol) was added to a solution of pyrazole of Example 60 (100 mg, 0.41 mmol) and 1-bromo-2-methoxyethane (51 μl, 0.54 mmol) in dimethylformamide (1.5 ml) at 0"C in a nitrogen atmosphere. The reaction was allowed to warm to room temperature, stirred for 4 hours. The reaction Ferric chloride (11) (9.30 g, 57.5 mmol) was quenched with water and the solvent was removed by reducing to a solution of pyrazole of Example 147 (2.10 g, under constant pressure. The residue was partitioned between ethyl acetate 5.75 mmol) in dichloromethane (30 ml) in the atmosphere (20 ml) and water (10 ml), and the organic phase was washed with nitrogen at room temperature. After mixing with water (2 x 10 ml), drying over magnesium sulfate and washing for 20 minutes, the mixture was diluted with air and concentrated under reduced pressure. The oil that was washed with lormethane (50 ml) with water (100 ml) remained and was purified using flash cooling - then with a saturated aqueous solution of ethylenediamine- matography on silica gel using sodium tetraacetate (7Oml ), dried over a sulfa eluent, a solvent gradient of 10095 pentane with magnesium and concentrated under reduced pressure, pressed on 10095 ethyl acetate and finally ethylacetate. The residue was purified using flash tat:methanol (90:10, v/v) to obtain the indicated chromatography on silica gel using the title compound (bbmg) as a colorless oil. the quality of the eluent dichloromethane:methanol (98:2 was replaced by "H-NMR (400 MHz, SOS"): 6-1.09 (t, ZN), 1.12 was added to 95:5, by volume) obtaining the indicated in ( t, 3H), 2.42 (K, 2H), 2.54 (k, 2H), 3.34 (s, 3H), 3.75 gave the title compound (12 g) as a brown oil, which (t, 2H ), 4.16 (t, 2H), 7.11-7.38 (m, 4H). solid on standing.

NRMS (electrospray): t/» (MH) 300, "H-NMR (400MGu, SOSIv): 6-1.16 (t, ZN), 2.44

IMmiMa") 322. (Kk, 2H), 2.63 (t, 2H), 3.82 (t, 2H), 6.82 (m, 1H), 6.98

Microanalysis: Found C, 68.21; N, 7.07; M, (m, 2H). 14.04. Si7NgiMzO" must be C, 67.85; H, 7.12; M, NRMIES (electrospraying): t/2 (MN) 276. 14.0995. Microanalysis: Found C, 60.69; H, 5.12; M,

Example 147 15.08. C14Ni"Mz3O"E must be C, 61.08; H, 5.13; M, 3-(5-(2-(Benzyloxy)ethyl|-3-ethyl-1H-pyrazole- 15.26).

A-yl)oxy)-5-fluorobenzonitrile Example 149 3-(5-2-(4-Cyanophenoxy)ethyl|-3-ethyl-1H-pyrazol-4-yloxy)-5-fluorobenzonitrile

E cm cm yellow oil. o H-NMR (400MHz, SOSIv): 6-1.18 (t, ZN), 2.49

Phi (Kk, 2H), 2.98 (t, 2H), 4.21 (t, 2H), 6.82 (m, ЗН), 6.99 (m, 2H), 7.56 (m, 2H ). et NRMS (electrospray): t/2 (MH) 377. ud EXAMPLES 150-152

Preparation of the following grouped Examples of the general formula 4-Hydroxy-benzonitrile (49mg, 0.41mmol), triphenylphosphine (10mg, 0.41mmol) and diethylazo-dicarboxylate (b5ml, 0.41mmol) were added sequentially to of a solution of the alcohol of Example 148 (74 mg, d. 0.27 mmol) in tetrahydrofuran (2 ml) under a nitrogen atmosphere at 0"C. The reaction was allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated under reduced pressure and purified by with the help of flash chromatography- was obtained by a method similar to sporaphy on silica gel using Example 149 as an eluent using acceptable toluene: ethyl acetate (75:25, by volume) or aryl alcohol as starting material. chewing the compound indicated in the title ( 50 mg) as

Example Starting material Analytical data m cm 150 148 "H NMR (400 MHz, SOS): 5 18

OBO oh sn, 2.89 (t, 2H), 4.18 (t, 2H), 6.83 (m, -K- 1n), 699 (m, 4H), 804 (m, 1H). that J

NRMS (thermal spraying): t/x M

ИМН"1367. сн, t AKA znaj zves zn of the pyrazole of Example 153 (50 mg, 2nu 72 (m. Nu TIV (m, 1H)U O, 1Zmmol) in dichloromethane (5 ml) in an evaporative atmosphere of a lot of nitrogen at room temperature. After mixing,

Zv. After boiling for 30 minutes, the mixture was diluted with

Gaya 148! "NMR (200MGu, SOSC) 5 - 1.20 with lormethane (20ml), washed with water (100ml) uv! (g, ZN), 253 (k, 2H), 298 (t, ZN), | then saturated aq. sodium tetraacetate solution (20 ml), dried over magnesium sulfate to НО ОО НРМС volume of magnesium and concentrated under reduced pressure (thermospraying): put (МН) ku. The residue was purified using flash zvv. chromatography on silica gel using dichloromethane:methanol (98:2 substituted

These compounds were purified on silica gel (95:5, v/v) to give the title compound (20 mg) as a white solid. loghexane-ethyl acetate (75:25 then 66:34 then IN-NMR (400MGu, SOS"): 6-1.19 (t, ЗН), 2.51 50:50, volume) was replaced by ethyl acetate and in ( Kk, 2H), 2.69 (t, 2H), 3.88 (t, 2H), 7.40 (s, 2H), 7.59 ends ethyl acetate:methanol (90:10, by volume). (c, 1H).

Example 153 HPMS (electrospray): t/2 (MH) 283. 5-((5-(2-(benzyloxy)ethyl|-3-ethyl-1H-pyrazole- Example 155 4-yloxy)isophthalonitrile 3-C5- (Aminomethyl)-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl|oxy)-5-chlorobenzonitrile

MS. SM BA; yo Yam and

Mn o.

From uch not yet MM on sn, Protected alcohol from Preparation 31 (10Omg,

Hydrazine hydrate (177 μl, 3.6 mmol) was added 0.233 mmol) and tert-butylammonium fluoride (36 μmol) to a solution of crude enol from the Preparation of a 1 M solution in tetrahydrofuran, 0.3 mmol) pe- 61 (917 mg, 2.40 mmol) in acetic acid (1 ) was stirred in dichloromethane (5 ml) under a nitrogen atmosphere at room temperature. After the temperature in a nitrogen atmosphere for 3 hours. stirring for 18 hours, the mixture was concentrated under reduced pressure and purified under reduced pressure, and the residue was dissolved in methanol (2 ml) and with the help of flash chromatography on silica gel it was purified on a column filled with Vopavishe 5СХ using pentane as an eluent :cyclohexane polymer with a sulfonic acid (75:25, volume) fixed on it was replaced by toluic acid, the column was washed with methanol (2 ol: ethyl acetate (50:50, volume) obtaining pro- (3ml) removing impurities and 2M aqueous ammonia product, which was further purified by precipitating the product. This technique was repeated by HPLC using an Oemiovia column twice, obtaining the title compound sotbri-gr SZ3O 50x4 bmm Zmcm and using (40mg) as a colorless oil. the quality of the eluent gradient of solvents 5:95 0.190 IN-NMR (400MGu, SOSIz): 6-1.99 (s, ЗН), 3.85 aqueous trifluoroacetic acid in water: acetonitrile (t, 2H), 4.02 (s, 2H), 4.32 (t, 2H), 7.22 (s, 1H), 7.28, obtaining the indicated in the title compound (5 mg) as (c, 1H), 7.47 (c, 1H). colorless oil. NRMS (thermal spraying): t/2 (MH) 309.

IN-NMR (400 MGu, SOS"): 6-1.18 (t, ZN), 2.44 Microanalysis: Found C, 53.32; H, 5.17; M, (Kk, 2H), 2.77 (t, 2H), 3.63 (t, 2H), 4.52 (s, 2H), 7.30 16.38. Si5Ni5SIMAO»-1.85CHzZON is necessary C, (m, 7H), 7.55 (s, 1H). 53.40; H, 5.55; M, 16.77905.

NRMS (electrospray): t/2 (МН"| 231, Example 156

IMMa"| 253. 5-(1-Allyl-3-tert-butyl-5-methyl-1H-pyrazole-4-

Example 154 yl)oxy|isophthalonitrile 5-(3-Ethyl-5-(2-hydroxyethyl)-1H-pyrazole-4-cm yl|oxy)isophthalonitrile

On t not a dream

Sodium hydride (6095 dispersion in oil, 120mg, H, 6.02; M, 16.41965. 33.15mmol) was added to a solution of pyrazole (800mg, 2.80mmol) and allyl bromide (345mg, 5- C1-(2-Aminoethyl)-3-tert-butyl-5-methyl-1H- 2.80 mmol) in dimethylformamide (30 ml) at room temperature in a nitrogen atmosphere and the reaction cm stirred for 3 hours. The reaction was diluted with ethyl acetate (5O0ml), washed with distilled water (2x5Oml), then with a saturated aqueous solution of sodium chloride (5Oml), and the organic phase was concentrated under reduced pressure. The remaining oil was purified by flash chromatography. raffia on silica gel using diphenylphosphorylazide (305 mg, 1.10 mmol) as an eluent, the gradient of pentane solvents was replaced, dissolved in tetrahydrofuran (5 ml) and added to ethyl acetate:pentane (20:80, by volume) to obtain - to the pyrazole solution of Example 157 (180 mg, or the title compound (600mg) as a bezba- 0.55mmol), triphenylphosphine (291mg, 1.10mmol) oil. and diethylazodicarboxylate (193mg, 1.10mmol) in "H-NMR (400MGu, SOSIv): 6-1.21 (c, 9H), 1.96 in tetrahydrofuran (20ml) in a nitrogen atmosphere at (c, ЗН), 4, 66 (s, 2H), 5.04 (d, 1H), 5.24 (d, 1H), 5.98 at room temperature. The reaction was stirred (m, 1H), 7.37 (s, 2H), 7, 57 (c, 1H) for 18 hours, then triphenylphos was added

NRMES (thermal spray): t/2 (MN) 322. fin (291 mg, 1.10 mmol) and the reaction was stirred

Microanalysis: Found C, 70.79; H, 6.29; M, for another 18 hours. Then water was added 17.11. Si9NgomaO.0.05SNeSi is necessary C, 70.48; H, (180 μl, 10 .Omol) and the reaction was stirred pro- 6.24; M, 172695. for a period of 64 hours. The solvent was removed under

Example 157 5-(3-tert-Butyl-1-(2-) under pressure and the remaining white paste, hydroxyethyl)-5-methyl-1H-pyrazole-4- was purified by means of flash chromatography on silica gel using yl|oxyisophthalonitrile in quality eluent dichloromethane:methanol:0.88 ammonia (95:4.5:0.5, by volume) yielding the title compound (55 mg) as a solid, colorless oil. (z00Mhz, SOS"): 6-1.22 (s, 9H), 1.78 er (s, 2H), 2.03 (s, ZN), 3.18 (t, 2H), 4.05 ( m, 2H), 7.38 and (s, 2H), 7.58 (s, 1H), which NRMS (thermal spray): t/2 (MH) 324.

Sodium periodate (1.00g, 4.60mmol), tetrao- Microanalysis: Found C, 64.46; H, 6.48; M, osmium oxide (1.595 solution in tert-butanol, 190mg, 20.47. SiNgM5O-0.20SNeSi» required C, 64.22; 0O.02mmol) and pyrazole of Example 156 (boOmg, H, 6.34; M, 20.5795, 1.86 mmol) was dissolved in acetone (9 ml) and water (3 ml) Example 159 in a nitrogen atmosphere at room temperature, and 3-1І3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole- reaction stirred for 5 hours. Acetone 4-yl|oxy)-5-(1H-1,2,4-triazol-1-yl)benzonitrile was removed under reduced pressure and the residue of the extract was triturated with ethyl acetate (30 ml). The organic phase was washed with water (2 (30 ml) and then with a saturated aqueous solution of sodium chloride (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude aldehyde was dissolved in methanol (15 ml) and borohydride was added in portions sodium chloride (84 mg, 2.22 mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 3 hours and the solvent was removed under reduced pressure. Cesium carbonate (179 mg, 0.55 mmol) was added under reduced pressure. The residue was partitioned between ethyl acetate and of a solution of 1Ni1,2,4triazole (38mg, 0.55mmol) in volume (1Oml) and water (1Oml) and the organic phase of pro-dimethylsulfoxide (1ml) in a nitrogen atmosphere while washing with water (2x10ml) then saturated water at room temperature and the reaction was stirred with a solution of sodium chloride (1 Oml), dried over 10 minutes. Then aryl fluoride with magnesium sulfate was added and concentrated under reduced pressure. The remaining oil was purified by in dimethyl sulfoxide (ml) and the reaction heats up using flash chromatography on silica gel at 1007C for 18 hours. After cooling, using a gradient as an eluent, the reaction was diluted to room temperature. The organic phase was washed with saturated title compound (250 mg) as a colorless oil. aqueous solution of sodium chloride (15 ml), dried

IN-NMR (400 MHz, SOSIz"): 6-1.17 (s, 9H), 1.98 over magnesium sulfate, concentrated at low- (s, 3H), 3.67 (s, 1H), 4.04 (m, 4H), 7.35 (c, 2H), 7.54 under reduced pressure and the residue was purified using (c, 1H). flash chromatography on silica gel using

NRMS (thermal spray): t/z: (МН 325. or as an eluent a gradient of dichloro-

Microanalysis: Found C, 64.30; H, 6.10; M, methane:methanol (98:2 was replaced by 90:10, volume - 16.35. StivNhoMaO».0.20SNegSiI2 required C, 64.04; them) obtaining the title compound

(67.5 mg) as a white solid, mp. 122-12476. The combined organic extracts were dried over sulfate

IN-NMR (400 MHz, SOSIz): 6-1.10 (m, 6H), 2.39 magnesium, concentrated under reduced pressure and (Kk, 2H), 2.51 (k, 2H), 3.61 (sh c, 1H), 4.04 (m, 2H), the residue was purified using flash chromatography - 4.07 (m, 2H), 7.10 (c, 1H), 7.52 (c, 1H), 7, 60 (s, 1H), raffia on silica gel using 8.07 (s, 1H), 8.54 (s, 1H) as an eluent. ent gradient of dichloromethane:methanol solvents

NRMS (thermal spraying): t/2 МН") 353. (100:0 was replaced by 93:7, by volume) obtaining

Microanalysis: Found C, 60.69; H, 5.83; M, the title compound (241mg) as a white foam. 22.98. SivNhoMvO".0.08SNesSi2 is necessary С, 60.46; IN-NMR (400MHz, SOSIz"): 6-1.10 (m, 6H), 2.39

H, 5.66; M, 23,40905. (Kk, 2H), 2.49 (k, 2H), 3.68 (shs, 1H), 4.04 (m, 4H),

EXAMPLES 160-162 5.59 (shs, 1H), 5.88 (shs, 1H), 6.71 (d, 1H), 7.11 (m,

Compounds of the following grouped Examples 2Hn). general formula NRMS (thermal spraying): t/2 (MH) 322. a syu Microanalysis: Found C, 57.91; H, 6.32; M, 12.56. SivNgoeMzOz.0.13C H2cSiI2.0.12H20 is necessary for C, 57.91; H, 6.18; M, 12.5695. that m EXAMPLES 164-167 em XM o Compounds of the following grouped Examples iv, general formula were obtained by a method similar to that of Example 159 using an acceptable sn, heterocycle as starting material. --

Example Me (Initial Analytical data tm i en 160162) oi N-NMR (400 MHz, SOS: 6 -1.70 (m, 6H), sn, ze 2.89 (k, 2H), 2.52 (k, 2H), 362 (she, 1H), 4.02 | obtained by a method similar to spo- (ban), zhov (t, 2H), bah (d, ZNU Ty (b, sobu) of Example 163 using an acceptable

Ti tlev, ah te tTNU tlo (y, RH), protected alcohol as a starting material

Tpl. 169-170 "b. NRMS sh r d r y ! (thermal spraying): whip (MN 379.

Microanalysis: Found C, 65.68; H, 5.98; M, Example ma Analytical data 14.81. SiNaM"Oze0.09СНСЙ" is necessary C, (Starting material 65.61; H, 5.79; M, 14.5195. yours also) and Y 164765 e 7N NMR (400 MHz, SOS): 5 -1.13 (m . "I 2.54 (k, 2H), 3.65 (shs, 18), 4.07 (t, 2H), 411 (t, 2H), 2.40 (Kk, 2H), 2.51 (Kk , 2H), 3.56 (t, 1H), 4.04 gH), 407 (m, 2H), 7.20 (s, 1H), 7.65 (s, 6.51 (s, 1H) , 7.00 (c, 1H), 7.56 (c, 1H), 7.63 (c, 1H). 7.74 (m, 7 " shk " shchi " (c, 1H), 7.90 ( s, 1H). NRMS (electrospray): fluff

NU 785 (b NU 798 (b, 1NU NRMO MN" Зз52, (MMma")| 374. VRMS: (MN) Found! (thermospraying): t/x (MN) 353, VRMO: 3B2,1770. SiNoaM5O" necessary 352,1768.

МН" 353.1722. SiNMeO; necessary 1657 (66) ri "H NMR (400MGu, SOSIv): 5 2110 (m, BNO), 2.40 (k, 2H), zvaltvh С 2.50 (k, 2H) ,, 4.00 (t, 2H), 4.06 (t, 2H), 6.24 (t, 1H), 162 (62) s H NMR (400 MHz, SOS): 5 -1.10 (m, 6H), in (d, 1H), 718 (d, 2H), 7.24 (d, 1H), 7.0 (s, 1H), well | am kan), vi (kN), 8.62 (t, 1H), 404 7.88 (i, 1). HRMS (electrospray): tu» MH") (m, 2H), 4.07 (m, 2H), 7.08 (s, 1H), 7.80 (s, 379, (MMa" | 401. VRMS: (MH) Found 379.1766. ! 2H). 7.87 (s, 1NU 8.02 (s, 1H). NRMO XiaNoazMaOz required 379.1765 (MMa") Found (thermospray): t/2 (MH") 353. VRMS: 401.1585. Sea/NegM«OzMa necessary 401.1584.

ІМН") 353.1719. SivNoMeOg is necessary 1667467) SS "NMR (400 MHz, SOSIv): 5 -1.10 (m, 6Н), 2.41 (k, 2Н), 353.1720. below 2.51 (Kk, 2H), 4.01 (t, 2H), 4.06 (t, 2H), 7.07 (d, 1), 7.13 (s, 1H), 7.22 ( m, 1H)), 7.52 (s, 1H), 7.85 (s, 1H), 7.88 (s, 4 . . s. . 1). YARMO (electrospraying): t/2 IMN")Z80,

Both compounds were isolated from one reaction PMima"i 402. VRMS: (MH) Found 380.1722. starting from the 1,2,3-triazole of Example 161, which are SiNaMnO»z necessarily C80.1717. more polar. Example 163 3-13,5-Diethyl- 1- tag (vv) ON the basis of MR (vomgc, bro) 6 nty (m, VN), 2roya (c, ЗН), 2-.-1 H-piazol-4-yl|oxy)-5-Y 2 ... .64 (s, 1H), 6.81 (s, 1H), 6.01 (s, 1H), 6.99 (s, fluorobenzamide 1H). HRMS (electrospray): t/2 (MH"Z96, ( MMma") 418. VRMS: (MN) Found 3962027. and 001000 nenia

Mn, sn, 4 4 Dichloromethane:methanol (99:11 replaced by 80:20, by volume) was the eluent used for purification by flash column chromatography of these en M oon compounds. The eluent used for the purification of the protected alcohol from Preparation 64 (432 mg, purification by flash column chromatography of this extract) and the p-toluenesulfone compound was dichloromethane:methanol (99:1 replace- (30, mg , 0, mmol) were dissolved in methanol (ml) and diluted to 98:2, by volume) were stirred in a nitrogen atmosphere at room temperature Example 168 for 18 hours. The solvent gave 5-(3-Cyclopropyl-5-ethyl- 1-(2-Hydroxyethyl)- was added under reduced pressure and the residue was partitioned with 1H-pyrazol-4-yl|oxy)isophthalonitrile between saturated aqueous sodium bicarbonate solution (20ml) and dichloromethane (20ml). The aqueous phase was extracted with dichloromethane (10ml) and 'is-

Mo cm Example 170 5-C5-Eethyl-1-(2-hydroxyethyl)-3-isopropyl-1H-pyrazol-4-yl|oxy)isophthalonitrile o Mo cm and M in (o. sn,

Example 169 5-(C5-Cyclopropyl-3-ethyl-1-(2-pdroxyethyl)-1,1H-pyrazol-4-yl|Ioxyisophthalonitrile sn,

Mo cm 2-(2-Bromothoxy)tetrahydropyran (91 μl,

0.bommol) was added to the pyrazole solution. Example 131 (153 mg, 0.55 mmol) was dissolved in dimethylformamide (4 ml) at room temperature in

Then sodium hydride (6095 dispersion in oil, 24 mg, 0.6 mmol) was added under a nitrogen atmosphere, and the reaction was stirred at room temperature for 3 hours. The mixture was diluted with water (50 ml) and

Potassium carbonate (9.1 mg, 0.1 mmol) and 2-(2-) were extracted with ethyl acetate (2 x 50 ml). The combined bromomethoxy)tetrahydropyran (9 ml, 0.61 mmol) organic extracts were washed with saturated aqueous and successively added to the pyrazole solution with sodium chloride solution ( 3 mL), dried over a plate, 129 (152 mg, 0.55 mmol) was dissolved in magnesium dimethyl sulfate, concentrated under reduced ethylformamide (4 mL), and the reaction was heated at 3570 °C pressure, and the residue was purified under a nitrogen atmosphere for 5 hours. I use the initial flash chromatography on silica gel - the material still remained, so the temperature was adjusted with toluene"ethyl acetate (85:15, heated to 802C and the reaction was stirred against volume) as an eluent, obtaining individual isomers as colorless for another 18 hours. The reaction was cooled to room temperature, sodium hydride was added. and p-toluenesulfonic acid (4 mg, stirred at room temperature, 0.02 mmol) was dissolved in methanol (5 ml) and stirred for 1 hour. The mixture was diluted with water (50 ml) and washed in a nitrogen atmosphere at room temperature, extracted with ethyl acetate ( 2 x 50 Oml). Combined flasks for 18 hours. The solvent was removed, the organic extracts were washed with saturated aqueous under reduced pressure, and the residue was partitioned between sodium chloride solution (30 ml), dried over water (30 ml) and dichloromethane (30 ml). Aqueous magnesium sulfate, concentrated p The lower phase was extracted with dichloromethane (20 ml) under reduced pressure, and the residue was purified using the following organic extracts were dried over sulfate flash chromatography on silica gel using magnesium, concentrated under reduced pressure, and pentane:cyclohexane (75: 25, the remaining oil was purified using bulk) to give a mixture of regioisomers (239 mgH). flash chromatography on silica gel using

Regioisomers (239 mg, 0.55 mmol) and p- or as an eluent toluene"ethyl acetate (66:34, toluenesulfonic acid (10 mg, 0.05 mmol) by volume) to obtain the title compound were dissolved in methanol (5 ml) and mixed in ku (39 mg) as oil, in a nitrogen atmosphere at room temperature, by H-NMR (400 MGu, SOSIv): 6-1.05 (t, ZN), 1.14 after 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated 4.06 (m , 4H), 7.38 (c, 2H), 7.58 (c, 1H). aqueous solution of sodium bicarbonate (20 ml) and HPMS (electrospray): t/2 (MH) 325. dichloromethane (Zbml). The organic phase was dried Example 171 over magnesium sulfate, concentrated under reduced pressure, and the remaining oil was purified by pyrazol-4-yl| )isophthalonitrile by flash chromatography on silica gel using toluene:ethyl acetate (50:50, v/v) as eluent to give two products as colorless oils.

The less polar fraction (Example 168) - 34 mg І І "H-NMR (400 MHz, SOSIv): 6-0.76 (m, AN), 1.05 not M (t, ЗН), 1.45 (m, 1Н ), 2.48 (k, 2H), 3.39 (she, 1), n - 4.02 (m, 4H), 7.39 (s, 2H), 7.56 (s, 1H). and He

NRMS (electrospray); t/2 (M-NU 921. The more polar isomer (isomer 2) from Example

The more polar fraction (Example 169) - mg 170 (55 mg, 0.1 Zmmol) and p-toluenesulfonic acid H-NMR (400 MHz, SOCI3): 6-0.62 (m, 2H), 0.78 lot (Zmg , 0.01 mmol) was dissolved in methanol (5 ml) (m, 2H)U, 1.18 (t, ZNU, 1.46 (m, 1H), 2.38 (k, 2H), 3.42 and stirred in nitrogen atmosphere at room temperature (shs, 1H), 4.02 (m, 2H), 4.21 (t, 2H), 7.38 (s, 2H), temperature for 18 hours. Solvent of issue - 7.51 (s , 1H) was poured under reduced pressure and the residue was separated

NRMS (electrospray): t/2 (MH) 323, between water (30ml) and dichloromethane (30ml). Water

IMNI 321. phase was extracted with dichloromethane (20 ml) and

The resulting organic extracts were dried over sulfate under reduced pressure and the remaining brown oil, magnesium, was concentrated under reduced pressure and purified by flash chromatography on the remaining oil, purified by silica gel using dichloromethane as the eluent. :methanol:0.88 ammonia (95:5:0.5, by volume) or as an eluent toluene"ethyl acetate 66:33, obtaining the title compound (25 mg) by volume) obtaining the title compound white solid. ku (339mg) as a white solid. 1N-NMR (400 MHz, SOCI3): 6-1.12 (m, BN), 2.39

IN-NMR (400 MGu, SOS"): 6-1.08 (t, ZN), 1.13 (k, 2H), 2.51 (k, 2H), 3.61 (m, 2H), 4, 20 (m, 2H), 4.78 (d, 6H), 2.49 (k, 2H), 2.97 (sept, 1H), 3.59 (t, 1H), (s, 2H), 5 .42 (s, 1H), 7.40 (s, 2H), 7.59 (s, 1H). 4.06 (m, 4H), 7.37 (s, 2H), 7.57 (s, 1H). Microanalysis: Found C, 50.33; N, 5.07; M,

NRMS (electrospray): t/2 (МН 325. 20.60. C17NhoMeOz35.0.95Н20 is necessary С, 50.35;

Example 172 H, 5.44; M, 20.7295. 2-I4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H- Example 174 pyrazol-1-ylphenylethylcarbamate M-(2-I(I4-(3,5-Dicyanophenoxy)-3,5-diethyl -1 H- ne cm pyrazol-1-yl|ethyl)-2-methoxyacetamide sn, o, sn, sani i s - -

M M to . more often and about X-

Sleep

Trichloroacetyl isocyanate (4 mL, 0.38 mmol) was added to the alcohol solution from Example 119. The amine from Example 127 (100 mg, 0.32 mmol), hydrogen (100 mg, 0.32 mmol) was dissolved in dichloromethane. rochloride//// 1- (3-dimethylaminopropyl)-3- (3.2 ml) in a nitrogen atmosphere at 02С. After permethylcarbodiimide (b3mg, 0b, 35mmol) and M, M- stirring for 2 hours, dichloromethane was removed, dimethylaminopyridine (43mg, 0.35mmol) was added under reduced pressure and methanol was added to a solution of 1-methoxyacetic acid (27μl, (1.6ml), water (1.6ml) and potassium carbonate (134mg, 0.35mmol) in dichloromethane (10ml) under 0.96mmol atmosphere) and the reaction was stirred under nitrogen at room temperature. The reaction takes 2 hours. Methanol was removed under reduced pressure, stirred for 18 hours, concentrated under reduced pressure, and the residue was extracted with dichloromethane (3 under reduced pressure and the remaining yellow oil (10 ml). The combined organic extracts were dried over purified by flash chromatography on magnesium sulfate, concentrated at reduced silica gel using breathing pressure as an eluent and the remaining solid, lormethane:methanol:0.88 ammonia (95:5:0.5, by volume) was purified by flash chromatography to obtain the title compound (32 mg) as silica gels using as eluent dich- colorless oil, lormethane:methanol (98:2, v/v) obtaining H-NMR (400 MHz, SOSiv): 6-1.11 (t, ZN), 1, 16 the title compound (bOmg) as a white solid (t, ЗН), 2.38 (k, 2Н), 2.47 (к, 2Н), 3.41 (с, ЗН), 3.77 substance. ( vd, son go s (m, 2H), 7.19 (she, 1H),

IN-NMR (400 MHz, SOSIz): 6-1.10 (m, 6H), 2.39 " " SH " " (k, 2H), 2.48 (k, 2H), 4.26 (m, 2H ), 444 (m, 2H), 4.62 NRMO (thermal spraying): t/: IMNYA 382. (shs, 2H), 7.41 (s, 2H), 7.58 (s, 1H). Microanalysis: Found C, 61.26; H, 6.18; M,

NRMS (thermal spraying): t/g2 (MH) 354. 17.59. SgoNgzim5Oz.0.60H2gO is necessary С, 61.24;Н,

Microanalysis: Found C, 60.00; H, 5.55; M, 6.22; M, 17.8575. 19.82. SivNt9M5Oz.0.23EOAs is necessary C, 60.30; Example! 75

H, 5.67; M, 18,5895. 5-C1-(3-Azetidinyl)-3,5-diethyl-1H-pyrazole-4-

Example 173 yl|oxy)isophthalonitrile

M-(2-I(I4-(3,5-Dicyanophenoxy)-3,5-diethyl-1 N-m cm pyrazol-1-ylphiethylsulfamide)

Mo. he is a guest and

Goy des" (c) M r De c, yin, r Protected amine from Preparation 69 (178mg,

He 0.42 mmol) was dissolved in 4M hydrochloric acid

Sulfamide (3 mg, 0.32 mmol) was added to in dioxane (ml) and dioxane (ml) and the reaction of the intermediate solution of the amine from Example 127 (100 mg, 0.32 mmol) was stirred at room temperature for 18 hours and dissolved in dioxane (0.5 ml) hours in a nitrogen atmosphere. The solvent was removed under reduced pressure at room temperature. The reaction was heated at reflux and the residue was partitioned between dichloromethane 100"C for 18 hours, cooled to room temperature (20ml) and saturated aqueous bicarbonate solution at room temperature and partitioned between sodium ethyl acetate (20ml). The organic phase was dried over sul- (115ml) and water (15 ml). The organic phase was dried with magnesium foil, concentrated under reduced magnesium sulfate, concentrated under reduced pressure. It was purified using flash chromatography

raffia on silica gel using as an eluent, using flash chromatography on silica gel, a gradient of dichloromethane solvents as an eluent, using a gradient of solvent:methanol:0.88 ammonia (100:0:0, then 98:2:0, then ethyl acetate:pentane) (20:80, v/v) 95:5:0 then 95:5:0.5 then 90:10:1 then 80:20:1, replaced by ethyl acetate:methanol (90:10, v/v (vessels) receiving the indicated in the header of the columns) then dichloromethane:methanol:0.88 ammonia (ZZmg) as a white solid. (90:10:11 then 80:20:11, volumetric) obtaining

NMR (400MGu, SOS"): 6-1.05 (t, ЗН), 1.11 gave the title compound (170mg) as a yellow solid (t, ЗН), 2.44 (m, 4Н), 3 .85 (m, 2H), 4.38 (m, 2H), 5.05 substance. (m, 1H), 7.37 (s, 2H), 7.56 (s, 1H). IN-NMR (400MHz, SOSIz): 6-1.10 (m, 6H), 2.39

NRMS (electrospray): t/z2 (MH 322. (Kk, 2H), 2.49 (k, 2H), 3.80 (s, ЗН), 7.40 (s, 2H), 7.56 (s ,

Microanalysis: Found C, 65.87; H, 5.94; M, 1nH). 20.98. SiovNi»M50.0.38H2O is necessary C, 65.87; H, NRMS (electrospray): t/2 (MH) 281. 6.07; M, 21.0495. Microanalysis: Found C, 68.41; H, 5.71; M,

Example 176 19.93. SivieNieMaO is necessary C, 68.55; H, 5.75; 5-1I3,5-Diethyl-1-(3-hydroxypropyl)-1 H-M, 19.99965. pyrazol-4-yl|oxy)hisophthalonitrile EXAMPLES 178-180

Mo. cm Compounds of the following grouped Examples of the general formula hu Mo ne. and where sn, he | Ot

Protected alcohol from Preparation 70 (215mgH, 0O.5Zmmol) and p-toluenesulfonic acid (10mg,

0.05 mmol) was dissolved in methanol (2 ml) and mixed, stirred in a nitrogen atmosphere at room temperature, obtained by a method similar to sporulation for 18 hours. The solvent was removed from Example 177 using an acceptable under reduced pressure and the residue was separated between alkyl halide as starting material. water (1Oml) and dichloromethane (1Oml). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain the compound (148 mg) indicated in (Starting material under the title) as a pale yellow solid. 1.08 (t, ZN), 1.12 (t, substance, Tpl. 93-95" S. ZN), 2.40 (k, 2H), 2.54 (k, 2H), 8.34 ( s, ZN), 3.75 (t,

IN-NMR (400 MHz, SOSIz): 6-1.11 (m, 6H), 2.04 2H), 417 (t, 2H), 7.38 (s, 2H), 7.56 (s, IN) . NRMS (tt, 2H), 2.37 (k, 2H), 2.53 (k, 2H), 3.06 (t, 1H), 3.69 (electrospray): t/x (МН"1325, | MMa") 347. (dt, 2H), 4.18 (t, 2H), 7.38 (s, 2H), 7.58 (s, 1H). Microanalysis: Found S, bu; H, 6.17; M, 17.08.

NRMS (electrospray): t/2 МН") 325, peda

IMMa" | 347. 1792122) "NMR (200MHz, SOSI"): 5 2 1.10 (m, 6H), 1.98 (tt,

Microanalysis: Found C, 66.27; H, 6.27; M, drinkable | 2H), 2.38 (KN), 2.51 (k, 2H), 2.76 (t, 2H), 4.09 (t, 17.00. C, 66.28; H, 6, 24; Nu 788 (b, NU TB? (b, LV). NRMO

M 7 vo and same (electrospraying): t/g2 МН) 324. Microanalysis:

Found C, 64.86; H, 8.51; M, 20.79.

When treasure 177 | C, 84.79 is necessary for t sipenyuutnya; M, 6.69; M, 5-((3,5-Diethyl-1-methyl-1H-pyrazol-4-20995.yl)uoxy|isophthalonitrile 1803152) but N-NMR (ab, SOS: 5 109 (t, ZNU ZY, m . about ZN), 2.41 (k, 2H), 2.47 (k, 2H), 3.79 (s, ZN), 4.82 (s, keshe (electrospray): t/2 (MH) 339. Microanalysis:

CH Found C, 63.58; H, 5.35; M, 16.35.

Ge) SivNieMaOze0.10H20 is necessary C, 63.56; H, 5.39; ---shezhkhto M, 16.4795. r 1 Two reagents were heated together in the form of a solution, melting at 1607"C for 24 hours, and the reaction

Sodium hydride (6095 dispersion in oil, ZZmg, treated by separating between dichloromethane and na- 0.82 mmol) was added to a solution of pyrazole. of hydrogen chloride (3 ml) at 0"C in a nitrogen atmosphere and the reaction was stirred with peracid and basifying the aqueous phase with carbonate for 10 minutes. Sodium methoxide was added. After extraction with dichloromethane, orthyl iodide (117 mg, 0.82 mmol) and the reaction mixed phase dried and concentrated to give the crude product at room temperature for 18 hours. The reaction was quenched with water (0.2 ml) and concentrated 2Eluent used for purification under reduced pressure. The residue was separated by flash column chromatography between dichloromethane (5 ml) and water (5 ml) and the organic compound was dichloromethane:methanol:0.88 ammonia phase was removed using a 5 μm Frito (95:5:0.5 was replaced by 80:20:1, volume) UMpaytap RTEE cartridge , then concentrated with the eluent used for purification under reduced pressure. The residue was purified by flash column chromatography.

Example 181 -sh- nm 2-I4-(3,5-Dicyanophenoxy)-3,5-diethyl-1 H- sh. Pyrazole from Preparation 75 (320mg, 0.9immol) and amine from Preparation 80 (b8Omg, sn, 4.61mmol) were refluxed in isopropanol (5ml) for 1 ,5 hours. Solvent - KM was removed under reduced pressure and the residue

M y- was purified by means of flash chromatography on sn. about silica gel using breath as an eluent

The ester from Example 180 (200 mg, 0.59 mmol) in chloromethane:methanol:0.88 ammonia (95:5:0.5, by volume) was dissolved in a 2M methanolic ammonia solution (5 mL) to give a product that was further purified by to- and the reaction was stirred under a nitrogen atmosphere with the help of preparative HPLC using 756 for 18 hours. The mixture was concentrated in a column of Vemeiyozvii sotri-gr C30 50x4 bmm Zmkm and under reduced pressure and the residue was purified using a gradient as an eluent with the help of flash chromatography on silica gel with 5:95 0.195 aqueous trifluoroacetic acid as an eluent using a gradient of soluble in acetonitrile acetonitrile (0-min. 95:5 substitutes dichloromethane:methanol:0.88 ammonia (95:5:0.5, shafts at 50:50; 6-7 min. 50:50; 7-7.1 min. 50:50 by volume) obtaining the indicated in the title was diluted for 5:95; 7.1-8 min. 5:95) obtaining the indicated ku (bmg). in the title compound (Z38mgHg). "H-NMR (400MHz, SOS"): 6-1.10 (t, ZN), 1.15 IN NMR (400MGu, COzO0): 6-2.14 (s, ZN), 410 (t, ZN) , 2.44 (k, 2H), 2.54 (k, 2H), 4.69 (s, 2H), 5.55 (s, 2H), 4.34 (s, 2H), 7.03 ( m, 1H), 7.10 (s, 1H), 7.25 (shs, 1H), 6.22 (she, 1H), 7.38 (s, 2H), 7.59 (s, 1H). (m, 1H), 7.54 (t, 1H), 7.64 (d, 1H), 7.92 (d, 1H), 7.97

NRMS (electrospray): t/2 (M-NU | 322. (c, 1H).

Microanalysis: Found C, 68.41; H, 5.71; M, NRMO (electrospraying): t/: (MH") 380. 19.93. Sti6NieMaO required C, 68.55; H, 5.75; M, Microanalysis: Found C, 51.32; H, 3.91 ; M, 19.99965. 13.69. SgoNiviM5O2E-1.00СЕ3СО2Н-1.10Н20 necessary

Example 182 bottom C, 51.49; H, 4.16; M, 13.6595. 5-(13,5-Diethyl-1-(hydroxymethyl)-1H-pyrazole-4- EXAMPLES 184-188 yl|oxy)isophthalonitrile Compounds of the following grouped Examples

Mo of the general formula cm sn, "t

MN

- o sn, ns

Formaldehyde (3795 solution in water, obtained by a method similar to 253 µl, 3.14 mmol) was added to the pyrazole solution of Example 183, using as starting materials pyrazole (P) and amine from Example 122 (440 mg, 1.65 mmol) in ethanol (AND). (ml) and the reaction was stirred at 807C for 18 hours. After cooling to room temperature, the solvent was removed from the solvent under reduced pressure. in ! | and the remaining yellow solid was dissolved in a solution of KES and partitioned between ethyl acetate (15 ml) and water (1 ml) and | ! Y a ma, ani, Zak (in ani Ya i. ZNU in id, the organic phase was removed. The aqueous phase was washed with : E Я. The nitrates were dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound (490 mg ) as a white solid substance- ! 14 h nshsh shi shi Bikini ia vny (t, ZN), 2.39 (k, 2H), 2.61 (k, 2H), 5.49 (s, 2H), 5.68 | | ! B ra: PIV x Zdya ie, ZNU ALREADY b, nyu! (shs, 1H), 7.40 (s, 2H), 7.56 (s, 1nH). and | I ! m, from En, adt nu tativ, tNM

NRMS (thermal spraying): t/ (МН 267. | | | | pet t yayu

Microanalysis: Found C, 64.28; H, 5.52; M, 1 | with dnchyurayutltyak che MN theo 18.47. SivbNieMlO2.0.15H20 is necessary C, 64.27; N, V : and i : | nvrovkyachih dehyudnyu b, BD NI 5.49; M, 18,2495. ; : and ! GE joint school

Example 183 w | g ro 3-((4-(3-cyano-5-fluorophenoxy)-3-methyl-1H-PO p en vylan pyrazol-5-yl|methyl)amino)methyl I|benzamide z 3871 8 a Tpl, 989 -101 50. H NMR (400 MGU, IN-NMR (400 MHz, SOSIz): 6-0.77 (m, 4H), 0.85 "i SOS: 5 - 204 (s, ZN), 3.62 ( s, 2H), (m, 4H), 1.59 (m, 2H), 7.44 (s, 2H), 7.59 (s1H). t/:2 (MNU| 291. tvo s yn tv s. tn). NRMS Microanalysis: Found C, 69.90; H, 4.85; M, (thermal spraying): pug (MN 396. 19.18. Si7Ni4Ma0 .0.1020 is necessary C, 69.90; H,

Microanalysis: Found C, 56.98; H, 4.90; M, 19, 1895. y o) zhk si; pvobhlno Example 190 svt; nadi: M vd. | 5-43,5-Dicyclopropyl-1-trihydroxyethyl)-1 n- pvyatt 771755 27 N'AMRIOU MG, SOC 5-20, pyrazol-4-yl|Ioxy)isophthalonitrile and F MH, | ЗН), 2.30 (s, ЗН), 3.65 (s, 2Н), 3.80 (s, ms. SM 2Н), 6.85 (s, 1Н), 6.95 (s, 1Н) , 7.10 (s, 1NU, 7.30 (d, 2H), 7.70 (d, 2H). NRMS (electrospray): t/2 MH") 376, g

IM -1 374. Microanalysis: Found C, io) - 6559; ON. 565; OM, 0189, 65.51; N, 5.77; M, 182295.

Аеаюваютютетю, 2-Hydroxyethylhydrazine (84mg, 1.1Omol)

VT oTNu BO Tu UBB NU VO was added to the diketone solution from Preparation 82

PI (294mg, 1.00mmol) in acetic acid (1Oml) in vvi: N.O alu; M, i8v8. nitrogen atmosphere at room temperature. After

SooNivMnOs»1 TO is necessary C, stirring for 64 hours, a mixture of concen-av non, tvo». was treated under reduced pressure and the residue was partitioned between dichloromethane (25 ml) and saturated sodium bicarbonate solution (25 ml) for the purification of this compound. preparative HPLC. The organic phase was dried over magnesium sulfate, the eluent used for purification was concentrated under reduced pressure, and the residue was purified by flash column chromatography using dichloromethane:methanol:0.88 ammonia silica gels using dichloromethane:methanol:0.88 ammonia as an eluent. 5:0.5 was replaced by 90:10:1, by volume). lormethane:methanol (99:1 was replaced by 95:5, vol.

From the crystallized product was contaminated, the product was triturated with dichloromethane containing (137 mg) as a white solid to give the title compound, M.p. 115-11776. traces of methanol. It was filtered and filtered. IN-NMR (400 MHz, SOSIz): 6-0.67 (m, 2H), 0.80 rat was concentrated under reduced pressure and poured (m, 4H), 0.85 (m, 2H) , 1.52 (m, 2H), 3.39 (she, 1), the shock was purified using flash chromatography 4.05 (m, 2H), 4.22 (t, 2H), 7.42 (s, 2H ), 7.58 (s, 1H). using dichloromethane as an eluent, NRMS (thermospray): t/2 (MH) 355. tan:methanol:0.88 ammonia (90:10:11, by volume) order- Microanalysis: Found C, 67.63; H, 5.55; M, chewing the compound indicated in the title. 16.35. Sti9NiviM4O".0.17Н20 is necessary C, 67.63;Н, "The column used for the preparation of 5.48; M, 16.60905. tive HPLC was GIMA C18 10μm Example 191 150х21 2mm. 5-C1-(2-Aminoethyl)-3,5-dicyclopropyl-1H-

Example 189 pyrazol-4-yl|oxy)hisophthalonitrile 5-I(3,5-Dicyclopropyl-1H-pyrazol-4-Mo cm yl)uoxy|isophthalonitrile t. Go;

What; She and M

2-chloroethylamine hydrochloride (192 mg, 1.65 mmol) and pyrazole of Example 189 (440 mg,

Hydrazine hydrate (13 µl, 2.75 mmol) was added 1.50 mmol) was heated as a melt at 16072 pro- to a solution of the diketone from Preparation 82 (735 mg, over 18 hours. The residue was partitioned between dichloro- 2.50 mmol) in acetic acid (25 ml) in an atmosphere methane (25 ml) and 10965 aqueous solution of carbon dioxide at room temperature. After mixing potassium (25 ml). The organic phase was dried over a bath for 64 hours, the mixture was concentrated with magnesium sulfate, concentrated under reduced pressure, and the residue was separated under reduced pressure. The residue was purified using dichloromethane (25 ml) and saturated aqueous flash chromatography on silica gel using sodium bicarbonate. (25ml). The organic phase or dichloromethane: methanol: o, 88 as an eluent was dried over magnesium sulfate, ammonia was concentrated (95:5:0 was replaced by 95:5:0.5, volume) under reduced pressure and the residue was purified to obtain the title compound (9.2 mg) was obtained as a solid by flash chromatography on silica gel, m.p. 175-17776. using dichloromethane as an eluent. H-NMR (400MHz, SOSIv): 6-0.70 (m, 2H), 0.79 tan:methanol (98:22 was replaced by 96:4, volume) (m, 4H ), 0.88 (m, 2H), 1.57 (m, 1H), 1.66 (m, tn), obtaining the title compound (47Zmg) 3.46 (t, 2H), 4.41 ( t, 2H), 7.62 (s, 2H), 7.58 (s, 1H). as a white solid, m.p. 168-170260.

Example 192, the factor was removed under reduced pressure, the residue 3-13-cyclopropyl-1-(2-hydroxyethyl)-5-methyl- was dissolved in ethanol (11 ml) and hydrazine-1H-pyrazol-4-yl|oxy)-5- methylbenzonitrile wire (114 μl, 2.35 mmol). The thin white suspension was not stirred for 18 h. at room temperature in a nitrogen atmosphere, methanol was added

C (Oml) and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The organic phase was extracted with 2M aqueous hydrochloric acid (20 ml) and the aqueous phase was washed with dichloromethane (5 (1 Oml),

Example 193 | alkalized with 1M aqueous sodium hydroxide and

3-((5-cyclopropyl-1-(2-hydroxyethyl)-3-methyl) was extracted with dichloromethane (5 mL). The organic 1H-pyrazol-4-yl|oxy)-5-methylbenzonitrile phase was dried over magnesium sulfate and concentrated cm of the shaft at reduced pressure, obtaining the specified in

The title compound (135mg) is available as a yellow oil. 4 with IN-NMR (400 MHz, SOSIz): 6-0.70 (m, 4H), 1.56 g (m, 1H), 2.06 (s, ZN), 2.30 (s, ZN), 3.10 (t, 2H), 3.97 v (t, 2H), 6.87 (s, 1H), 6.92 (s, 1H), 7.05 (s, 1H).

M NRMS (electrospray): t/2 (MN) 297.

On Microanalysis: Found C, 63.81; H, 6.51; M, 2-Hydroxyethylhydrazine (3261.4.80 mmol) to 17.30. С17Нг2М20.0.36СНегСИ is necessary C, 63.78; H, added to the diketone solution from Preparation 86 6.39; M, 17, 1495. (1.00g, 4.37mmol) in acetic acid (10ml) in a nitrogen atmosphere at room temperature. After 3-((3-Diclopropyl-o-methyl-1H-pyrazole-4-) stirring for 18 hours, the concenyl)oxy|-5-methylbenzonitrile mixture was stirred under reduced pressure and the orange oil, n.o. cm that remained, was purified by means of flash chromatography on silica gel using ethyl acetate:pentane (50:50 replaced by 100:0, volume) in H as eluent, obtaining two pale yellow oils.

Less polar fraction (Example 192) - 419mg "H-NMR (400MGu, SOCI3): 6-0.69 (m, 2H), 0.82 Hydrazine hydrate (Zimcl, 0.b4mmol) add- (m, 2H), 1 ... , 4.22 (t, 2H), 6.88 (s, 1H), (150mg, 0.58mmol) in acetic acid (1.3ml) in 6.94 (s, 1H), 7.08 (s, 1H) in a nitrogen atmosphere at room temperature. After

NRMES (thermal spraying): t/2 (MN) 298. stirring for 24 hours, a mixture of concen-

Microanalysis: Found C, 68.29; H, 6.51; M, were poisoned under reduced pressure and the residue was purified - 13.92. C17NioMzO" must be C, 68.67; H, 6.44; M, by means of flash chromatography on silica gel using as an eluent

The more polar fraction (Example 193) - 201 mg of pentane:ethyl acetate (60:40 was replaced by 40:60, "H-NMR (400MGu, SOCI3): 6-0.75 (m, 4H), 1.58 vol.) obtaining the title compound (m, 1H), 2.07 (s, ЗН), 2.35 (s, ЗН), 3.45 (she, 1Н), ku (140mg). 4.00 (m, 4H), 6.92 (s, 1H), 7.00 (s, 1H), 7.10 (s, 1H). "IN-NMR (400MHz, SOCIz): 6-0.60 (m, 4H) , 1.69

NRMIES (thermal spraying): t/2 (МН) 298. (m, 1Н), 2.09 (s, ЗН), 2.34 (s, ЗН), 6.95 (s, 1Н), 6.99

Microanalysis: Found C, 68.44; H, 6.49; M, (CH), 7.10 (c, 1H). 13.95. C17H19Mz3O2 must be C, 68.67; H, 6.44; NRMS (thermal spraying): t/2 (MNU 254.

M, 14, 1395. Microanalysis: Found C, 68.35; H, 6.13; M,

Example 194 15,10. Si5Ni5M3O.0.29EOAc is necessary C, 68.72; 3-I(Z-Diclopropyl-1-(2-aminoethyl)-5-methyl-1H-H, 6.32; M, 1488965. pyrazol-4-yloxy|-5-methylbenzonitrile Example 196 ve cm 3-41- (3-Aminopropyl)-3,5-diethyl-1H-pyrazol-4-yl(oxy)-5-methylbenzonitrile

Alcohol from Example 192 (140mg, 0.47mmol), triphenylphosphine (309mg, 1.18mmol) and phthalimide (174mg, 1.18mmol) were dissolved in tetrahydrofuran, 3-chloropropylamine hydrochloride (b2mg, (9ml) at 0C in a nitrogen atmosphere and during 10 0.48 mmol) and pyrazole of Example 123 (113 mg, minutes added diisopropylazodicarboxylate 0.44 mmol) were heated as a melt at 15072 pro- (232 μl, 1.18 mmol) in tetrahydrofuran (2 ml). over 18 hours. After cooling the remains

The reaction was allowed to warm to room temperature, purified by flash chromatography on peratures and stirred for 18 hours. Dissolve silica gel using breath as an eluent

lormethane:methanol:0.88 ammonia (98:2:0 was substituted for 2 and acceptable aryl alcohols as starting materials for 95:5:0.5, by volume). Contaminated oil that materials. remained, was dissolved in acetone (3 ml) and tartaric acid (54 mg, b, 44 mmol) was added, the mixture was heated to dissolution and cooled. filtered and washed with its F.1H) 749 (dD. IN), 7.53 (M, 3M), 7.82 (M, 1H), 84 (M, with acetone (1 Oml) to give 1H indicated in the title). NRMS (thermal spray); fluff (MH" 311. the compound (127 mg) as a white solid, which was Htv5 Z "N'MR (400 MHz, SOS 5 - 119, OH), 2.48 kN), tartrate salt. | "o 2.51 (k , 2H), 4.03 (m, 2H), 4.10 (m, 2H), 7.06 (o, 1H), 7.22

IR NMR (400 MHz, sorzob): 6b-1.05 (m, bH), (m, NU, 7.38 (t, 1H), 7.42 (m, 1H), 7.69 (d, 1H) , 7.79 (s, 207 (m, 2H), 237 (k, 2H), 2.53 (s, ЗН), 2.57 (k, 2H), Minin non 2.99 (t, 2H), 4.15 (t, 2H), 4.38 (s, 2H), 6.89 (s, 1H), flat sky C, dark background M, 7.01 (s, 1H), 7.19 (s , 1H).8.635.

NRMS (thermal spraying): t/2 (MH) 313.

Microanalysis: Found C, 56.81; H, 6.57; M, p and presentation 200 12.06. С22НзоМаО; necessary C, 57.13; H, 6.54; Reiki V. Dzh(1 H-pyrazop-1-iluphenoxy|-Z B-

M, 12, 1195. ethyl-yH-pi shchy

Example 197 diethyl 1H-pyrazol-1-ylethanol 3-1H3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole at sleep; -

M nu som Men Protected alcohol from Preparation 88 (254mg,

Cesium carbonate (700 mg, 2.14 mmol) was added (00.5 mmol) and p-toluenesulfonic acid (10 mg, to a stirred solution of 2-methoxy-5-0.05 mmol) was dissolved in methanol (4 ml) and mixed, p. shunted in a nitrogen atmosphere at room tempe- cyanophenol (285 mg, 2.15 mmol) and dione Preparation against o. hours The solvent was removed by dissolving 2 (348 mg, 2.15 mmol) in acetone (2 mmol) under reduced pressure, and the residue was partitioned between room temperature and covered with a saturated aqueous solution of sodium bicarbonate and I (20 ml) and dichloromethane (20 ml). Aqueous phase at room temperature. The mixture was concentrated with dichloromethane (10 ml) and the combined organic extracts were dried in dichloromethane and overnight extracts were dried over magnesium sulfate, removed using a 5-MKM frit card, concentrated under reduced pressure, and purified by 100 ml of RTEE. then it was concentrated by means of flash chromatography on silica gel, using a reduced pressure gradient as an eluent. The residue was dissolved in vinegar and , ! . Dichloromethane:methanol (100:0 replaces the acid (5.4 ml) and added 2-hydroxyethylhydrazine and I and I at 93:7, by volume) to obtain the indicated total ) in a nitrogen atmosphere at room temperature the compound (5 mg) as a white solid at room temperature. After mixing against Tpl. 108-1102C for 18 hours, the mixture was concentrated at lower H-NMR (400MHz, SOSIz"): 6-1.11 (m, 6H), 2.46 nom of pressure. The remaining orange oil, (k, 2H), 2.53 it is! tone) 407 is zn) in 44 was purified by means of flash chromatography on (p. 2), 716 (p, 2), 7 68 (c zn) 7 02 (c 2n) shk silica gel using as an eluent gra-' NRMS ( elect o sputtering) in: t/ IMYA 393 dient solvents ethyl acetate:pentane (25:75 (MmMach | 415 ror I " were replaced by 50:50, volume) obtaining indicated in Microanalysis: Found C, 63.62; H, 611; M of the title compound (182 mgH). and "Dy da da, "H-NMR (400 MHz, SOSIzv): b-1.10 (m, 6H), 2.39 no and volume alvsto ovoNesiv necessary C, 63 .63; (Kk, 2H), 2.51 (k, 2H), 3.71 (shs, 1H), 4.00 (s, ЗН), ' p ikla r 4.08 (m, 2H), 4 .09 (m, 2H), 6.89 (s, 1H), 6.99 (d, 1H), 248 slot IZ "rtor-5-M1 H-pyrazole-i - 7.32 (d, 1H). !'

HPMS (thermal spray): t/z (MH 316. Iluphenoxy) 71 H-pyrazol-1-yl)ethanol

Microanalysis: Found C, 64.57; H, 6.73; M, "Phi 13,15. C17NaiMzOz necessary C, 64,74; H, 6,71; M E

M, 13, 3295.

EXAMPLES 198-199 sn,

Compounds of the following grouped Examples -sh- of the general formula no. The protected alcohol from Preparation 89 (38.bmg, -sh-O 0.09mmol) and p-toluenesulfonic acid (3.5MmgH, not zm M oon 0O.01mmol) were dissolved in methanol (ml) and mixed, stirred in a nitrogen atmosphere at room temperature, obtained by a method similar to Raturi's method for 18 hours. The solvent was removed

Example 197 using B-diketone Prigo under reduced pressure and the residue was separated between

1095 with an aqueous solution of potassium carbonate (4 ml) and the reaction was allowed to warm to room temperature with dichloromethane (4 ml). The aqueous phase was extracted with peratures and stirred for 18 hours. Dichloromethane (1 ml) and the combined organic extracts were removed under reduced pressure, the residue was dried over magnesium sulfate, the concentrate was dissolved in ethanol (25 ml) and hydrazine was added under reduced pressure and purified using , 6.25 mmol). The suspension was mixed by flash chromatography on silica gel for 4 hours at 45"C in an nitrogen atmosphere, using a melting gradient as an eluent, concentrated under reduced pressure and dichloromethane:methanol (99:11) factors, the residue was dissolved in methanol. The pass solution - by 98:2, by volume) obtaining the title indicated by passing through a TLC column, using the compound (23mg) as a white solid, mp 120-methanol eluent, to remove impurities, 12276. then 2M methanolic ammonia solution for wash-

IN-NMR (400MHz, SOCI3): 6-1.14 (m, 6H), 2.46 va of the product. The product was then purified with the help of flash chromatography on aluminum oxide ( , 1H), 6.49 (c, 1H), 7.09 (c, 1H), 7.12 (c, 1H), 7.71 using dichloromethane (c, 1H) as an eluent, 7.86 ( with, 1H). tan:methanol:0.88 ammonia (90:10:11, by volume) obtained

NRMS (electrospray): t/2 (MMa") 367. chewing the title compound (212mg) as

VRMO: IMNUAYAI Found 345.1717. butter.

SivNg2EMaO" is necessary 345.1722. IN-NMR (400MHz, SOSIzv): 6-1.12 (m, 6H), 2.43

Example 202 (Kk, 2H), 2.54 (k, 2H), 3.21 (t, 2H), 4.07 (t, 2H), 6.43 3-1Y3,5-Diethyl-1-(2 -hydroxyethyl)-1H-pyrazole- (m, ЗН). 4-yl|oxy)-5-methoxybenzonitrile Microanalysis: Found C, 59.78; H, 6.50; M, but-9 cm 14.35. Si5NioB2Mz3O.0.026H2O is necessary C, 60.05;

H, 6.56; M, 14, 0195.

Goy; Example 204 ev 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl|oxy)-5-fluorobenzamide

On E

Protected alcohol from Preparation 90 (40mg, Mn, 1.00mmol) and p-toluenesulfonic acid (19mg,

0.1 mmol) was dissolved in methanol (1 mmol) and stirred again in a nitrogen atmosphere at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between Mn, saturated aqueous solution of sodium bicarbonate Alcohol from Example 163 (142mg, 0.44mmol), (20ml) and dichloromethane (20ml). The aqueous phase of extr- triphenylphosphine (346 mg, 1.32 mmol) and phthalimide was treated with dichloromethane (40 ml) and the combined organic (194 mg, 1.32 mmol) was dissolved in tetrahydrofuran overnight extracts were dried over magnesium sulfate, (v ml) at 0"C in under a nitrogen atmosphere and concentrated under reduced pressure and purified for 10 minutes, diisopropylazodicarboxylate was added using flash chromatography on silica gel (260 μl, 1.32 mmol) in tetrahydrofuran (1 ml), using dichloromethane as an eluent. The reaction was allowed to warm to room temp. 97:3, by volume) obtaining the specified temperature and stirred for 18 hours. Dissolve the title compound (174 mg) as an oil. The factor was removed under reduced pressure, the residue

IN-NMR (400MHz, SOSIz): 6-1.09 (m, 6H), 2.40 was dissolved in ethanol (Uml) and hydrazine hydride (Kk, 2H) was added, 2.49 (k, 2H), 3, 78 (s, ZN), 4.04 (m, 2H), 4.08 rat (107 μl, 2.2 mmol). The suspension was stirred (m, 2H), 6.66 (s, 1H), 6.71 (s, 1H), 6.79 (s, 1H). for 4 hours at 45"C in a nitrogen atmosphere,

NRMS (electrospray): t/2 (MH) 316. concentrated under reduced pressure and the residue

Microanalysis: Found C, 63.63; H, 6.76; M, was dissolved in methanol. The solution was passed through 13.06. C17H21MzOz.0.08СНосСи" is necessary C, 63.68; column with a polymer with a fixed sulfone

H, 6.68; M, 13.04965. It is acid using as an eluent meta-

Example 203 nol, to remove impurities, then 2M methanol-2-I4-(3,5-difluorophenoxy)-3,5-diethyl-1H-nol ammonia solution for washing the product. pyrazol-1-yl|ethylamine The product was then purified using flash chromatography

E E matography on aluminum oxide using as an eluent dichloromethane:methanol:0.88 ammonia and/or (90:10:11, by volume) obtaining the title compound (bOmg) as an oil. t IN-NMR (400 MHz, SOSIz): 6-1.11 (m, 6H), 2.43 at (Kk, 2H), 2.53 (k, 2H), 3.17 (t, 2H), 4 .05 (t, 2H), 6.01 with M mn, (shs, 1H), 6.25 (she, 1H), 6.75 (d, 1H), 7.16 (m, 2H).

Alcohol from Example 38 (371mg, 1.25mMmolL), VRMSO: IMNYA Found 321.1718. triphenylphosphine (984 mg, 3.75 mmol) and phthalimide SivNa1EMaO" is necessary 321.1722. (552 mg, 3.75 mmol) was dissolved in tetrahydrofuran Example 205 (20 ml) at 0"C in a nitrogen atmosphere and within 10 minutes 3-((3-Isopropyl-5-methyl-1H-pyrazol-4-yl)oxy|- was added 5-methylbenzonitrile diisopropylazodicarboxylate (7 µl, 3.75 mmol) in tetrahydrofuran (2 mL).

Well, dilute solutions of acid and condensing reagents (3x17Oml) in a 96-well plate and the mixture was shaken for 14 hours at room temperature. The solvent was removed under reduced pressure, and the mixture was dissolved in dimethylsulfoxide (500 μl) and purified by HPLC (Madedep Svav(2) 150x10 mm column; a mobile phase gradient of 5:95 (volume) - 95:5 was used (volumetric)

Hydrazine hydrate (100 μl, 2.10 mmol) was added to acetonitrile: (0.195 trifluoroacetic acid in water) to a solution of the diketone from Preparation 91 (544 mgH, di). 2.1 mmol) in acetic acid (1 mmol) in the atmosphere. Retention time: 5.69 minutes. nitrogen at room temperature. After stirring for 64 hours, the mixture was concentrated Example 208 under reduced pressure and the residue was purified by do- / 144(3,5-Dichlorophenoxy)-3-methyl-1H- pyrazole - by means of flash chromatography on silica gel using 5-yl|acetonitrile as an eluent with pentane:ethyl acetate with sa (66:34, by volume) obtaining the title compound (308 mg) as a pale yellow oil. see

IN-NMR (400MGu, SOSIz"): 6-1.22 (d, 6H), 2.09 d (s, ZN), 2.56 (s, ZN), 2.84 (m, 1H), 6 .91 (c, 1H), 6.94 uch (son, 7.11 (C, 1H).

NRMS (thermal spraying): t/g2 (МН 256. no

Example 206 Pyrazole Preparation 8 (1.00g, 2.600mmol) in 3-(1-(2-Aminoethyl)-3-isopropyl-5-methyl-1H-tetrahydrofuran (10ml) was added one portion of pyrazol-4-yl |oxy)-5-methylbenzonitrile to a solution of sodium cyanide (284 mg, 5.20 mmol) in water (1 mL) at room temperature. The reaction was heated at 80°C for 14 hours and cooled to room temperature. The solvent was removed under reduced pressure and the resulting

The brown solid was dissolved in dichloromethane (5 Oml) and water (5 Oml). The organic layer was separated, washed with water (5 Oml), and then with a saturated aqueous solution of sodium chloride

The pyrazole of Example 205 (7mg, 0.27mmol) and hy- (30ml) were dried over magnesium sulfate, filtered, 2-chloroethylamine hydrochloride (38mg, 0.33mmol) was collected and the solvent was removed under reduced pressure, heated as a melt at 15076 for 18 h - obtaining a brown solid. Product of dynamite. The residue was cooled and purified by flash chromatography on silica gel using silica gel as an eluent using tan:ethyl acetate (50:50, by volume) as an eluent, obtaining the following: dichloromethane:methanol: 0.88 ammonia (95:5:0.5, the title compound as a yellow, solid liquid) giving the title compound wine (500 mg), mp. 150-1522C. (25m0). "H-NMR (400 MHz, SOSIv): 6-2.17 (s, ZN), 3.56

IN-NMR (400 MHz, SOCI3): 6-1.18 (m, 6H), 2.06 (s, 2H), 6.77 (s, 2H), 7.02 (s, 1H). (с, ЗН), 2.35 (с, ЗН), 2.79 (m, 1Н), 3.19 (m, 2Н), 4.04 NRMS (thermal spraying): t/2 (MNU | 282. ( m, 2H), 6.89 (s, 1H), 6.97 (s, 1H), 7.12 (s, 1H). Example 209

NRMS (electrospraying): Ittp/7 |MNU| 300. 1-4C4-(3,5-Dichlorophenoxy)-3-methyl-1H-

Example 207 | pyrazol-5-ylidetyl)piperidine 2-I4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl|-M-(2-pyridinylmethyl)acetamide also F, -- note M well "u. Standard solutions: Acid Preparation a 92 (bvOmg, 2.1 mmol) and hexafluorophosphate 1H-poch benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium

CH (761mg, 3.233mmol) was separately dissolved in M,M-dimethylacetamidlriethylamine (96:4) (2 (17 ml).

Standard solutions: Acid Preparation 4 Piperidine (Zmg, 0.03 mmol) was treated with sta- (800 mg, 2.33 mmol), hexafluorophosphate 1n-ndartic acid solutions and condensing benzotriazol-1-yl)-M,M,M',M'- tetramethyluronium agents (250 μl each) in a 96-well plate (822 mg, 3.50 mmol) and diisopropylethylamine (60 mg, and the mixture was shaken for 14 hours at 802C. 4.6 ppm) were separately dissolved in M, M. The solvent was removed under reduced pressure and su-dimethylformamide (3 (13ml). Treated 2- the mixture was dissolved in dimethylsulfoxide (500μl) and (methylamino)pyridine (Zmg, 0.029mmol) was purified by HPLC (MadeiiIep Sziv(2) 150x10mm column

ka; a mobile phase gradient was used, 5:95 o cm (v/v) - 95:5 (v/v) acetonitrile:(0.1905 trifluoroacetic acid in water). h

Holding time: 4.7 minutes. 4

NRMS (electrospraying): t/2 (MH) 368. -sh

EXAMPLES 210-217

The compounds of the following grouped Examples are not of the general formula: were obtained by a method similar to the method of Example 218 using an acceptable amine. and retention/min tu/h (MN sts 219 42 367 ie ny DY SY web y ge obtained by a method similar to the method of nn Н

Example 209 using acceptable amines. I I nih you hold/min those/x (MN ,

SASHA o Y 213 and 458 a 214 and By 424 seter nie I 215 and 53 458

And 229 with and ET for chlorobenzyl)amino|methyl)-3-methyl-1H-pyrazole-4- and sv cm ha 281 5 43 Sv? yo, Moss: and WE

MN vi 232 b 15 438 not M 233 o, for

Standard solutions: Bromide Preparation 18 (8500 mg, 2.30 mmol) was dissolved in M: methyl pyrrole 554 : 37 2-Chlorobenzylamine (19 mg, 0.133 mmol) in a 96-well plate was treated with bromide solution

Preparation 18 (5001 μl) and the mixture was shaken with water for 14 hours at 80°C. The solvent was removed under reduced pressure and the mixture was dissolved in dimethicone sulfoxide (500 μl) and purified by HPLC (Madeiiep Sv(2) 150x10mm column We used a gradient of the mobile phase, 5:95 (by volume) - 95:5 in I and Ii (volume) acetonitrile: (0.190 trifluoroacetate in water).

Holding time: 5.3 minutes. | ; (7-- shi skin

NRMS (electrospray): t/2 (MH) 386. zd and i5 z

EXAMPLES 219-249 - m I

Compounds of the following grouped Examples of the same general formula:

2 and what is the name Wet aluminum oxide was obtained by adding / and water (ml) to aluminum oxide and grade according to Broz sh-- - 15 55 kman (5g). To a stirred solution of sulfide from Example 250 (134 mg, 040 mmol) in 525:55,355 dichloromethane (2 ml) was added wet aluminum oxide (400 mg), followed by OhopefF (123 mg, 5ai; 15,255 0.4 mmol ) and the mixture was heated with the reverse coolant: NI lynk. After 1 hour, a second portion of Ohope (123 mg, 0.40 mmol) was added, and the mixture was heated with draft for another 2 hours. After cooling to room temperature, the reaction mixture was filtered and

b) the obtained solids were washed with dichloromethane (20 ml). The filtrate was concentrated and purified by means of flash chromatography on silica gel (7 and using dichloromethane:methanol (gradient from 99:1 to 90:10, by volume) as eluent) and 4 to obtain the title compound (92 mg ) as butter.

IN-NMR (400 MHz, SOSIz): 6-1.12 (m, 6H), 2.44 385 (Kk, 2H), 2.53 (k, 2H), 2.73 (s, ЗН), 4 ,06 (m, 2H), 4.18

NRMS (electrospray): t/2 (Ma-Ma") 370.

Example 252

Example 250 | | 3-C3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole-

C-4(3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl|oxy)-5-(methylsulfonyl)-benzonitrile 4-yl|oxy)-5-(methylsulfanyl)- benzonitrile P st cm not cm b

SN and; Sn (o) - o is, A.

The protected alcohol from Preparation 93 (687mg, to a stirred solution of sulfide with 1.65mmol) and p-toluenesulfonic acid (32mg, Example 250 (13µg, 0.4mmol) in dichloromethane 0.17mmol) were dissolved in methanol (1bml) and per- (2 ml) at -78C, a solution of meta- was mixed in a nitrogen atmosphere at room temperature, chloroperoxybenzoic acid (138 mg 5Ovag.95 rature. After 4 hours, a second portion of the mixture, 0.4 mmol) in dichloromethane (2 ml) was added. Cold-toluenesulfonic acid (32 mg, 0.17 mmol). the chewing bath was removed and the mixing solution

After 18 hours, the solvent was removed at room temperature for 4 hours. The mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate (20 ml) and sodium bicarbonate (bml) and extracted with dichloromethane (20 ml). The aqueous phase was extracted with methane (3x5ml). The combined organic components with dichloromethane (400 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated. The crystals were dried over magnesium sulfate, concentrated. H-NMR analysis (400 MHz, SOSIv) showed that the mixture was present under reduced pressure! Purified with the help of the desired product and the sulfoxide from Example 251. by flash chromatography on silica gel. The crude mixture of products was dissolved in dichloromethane using Dichloromethane (2 ml) was used as an eluent, it was cooled to -78"C and tan:methanol (9773, volume) was added to it, obtaining the indicated meta-chloroperoxybenzoic acid

(487mg) as a white solid (138mg 5Owag.9o mixture, 0.4mmol) in wine dichloromethane. Tpl. 7270. (2 ml). The cooling bath was removed and the mixture "H-NMR (400MGu, SOSIv): 621.14 (m, 6H), 2.44 was stirred at room temperature through (k, 2H), 2.49 (s, ЗН), 2, 53 (k, ZN), 4.08 (m, 2H), 4.14 gm 1 hour. The mixture was quenched by adding saturated (m, 2H), 6.84 (s, 1H), 7.00 (s, 1H) , Tlo (c), which aqueous solution of sodium bicarbonate (bml) and extra-

NRMO (electrospraying); td IMN 1332. were washed with dichloromethane (Z (5 ml). The combined organic

Microanalysis: Found C, 61.36; H, 643; M, chny components were dried over magnesium sulfate and iron Ov necessary C, 61.61; H, 6.39; M, concentrated. The crude product is a mixture of eyes. separated by means of flash chromatography on

Example 251, | Kageli using dichloro-o 3-13,5-Diethyl-1-(2-tihydroxyethyl)-1H-pyrazole-methane:methanol (98:2, by volume) as an eluent, obtaining 4-1oxy)-5-( methylsulfinyl)-benzonitrile indicated in the title compound contaminated meta-

It is chloroperoxybenzoic acid. Dimethylsulfoxide (ZOmcl,

Oh, 4 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 15 minutes. The mixture was quenched by adding 1090 aqueous solution of potassium carbonate (10 ml) and dichlor- | Priledne Rapvyt | And 70000000 lneluician years of methane evaporated. The remaining aqueous mixture, 254 SNSNAMNMe | HO NMR (400 MHz, SOS): 5 2 1.13 (m, VN), extracted with diethyl ether (2 (10 ml) and ethyl acetate, 49 known with acetate (1 ml). The organic components were combined 2n). vlv (c, IN). 68 (c, IN), 682 (o. 1H), were collected, dried over magnesium sulfate and concentrated by NRMS (HIAT); (MN"Y 359 VRMS: (MN'Y were obtained an unpurified mixture of products, which 3552088. SeachoO" is necessary 359.2078. was purified by means of flash chromatography on ro snasomny K po i pav v in, silica gel using as an eluent breath sonie chiv yan la (nnrmins t, lormethane:methanol (98:2, v/v)) obtaining 6.42 (broad s, 1H), 6.69 (s, 1H), 6.85 (s, indicated in the title compound (26mg) as a white solid 2H). NRMS (HIAT); powder 359 (MH) substance. Mpl. 13320. 258 87 SPSNOSN" | NAM (400 MHz, SOS: 5 - 1.12 (m, VN), "H -NMR (400MGu, SOSIv): 6-1.10 (m, 6H), 2.39 ani asan vi syu, vit, (k, 2H), 2.51 (k, 2H), 3.06 (s, ZN), 4.05 (m, 2H), 4.10 tova about KO NRMS (m, 2H), 7.39 (s, 1H), 7.67 (s, 1H), 7.84 (s, 1nH ). (electrospraying): t/2 360 (MN") VRMS:

NRMS (electrospray): t/2 (Ma-Ma") 385. МН" 380920. SyeNaeMO, necessary

VRMSO: IMNU) 364,1329. StivNgoMeO2g is needed, 3641326.

Example 253 Example 257 3-1Y3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-4-yl |oxy)-5-(2-(dimethylamino)ethoxy|-benzonitrile yl|oxy)-5-methoxybenzonitrile but? om od sn, ivu sn, Yi sn,

Oi va pra mai - and Alcohol from Example 202 (87mg, 0.28mmol),

To a stirred solution of protected triphenylphosphine (220 mg, 0.84 mmol) and alcohol phthalimide from Preparation 94 (180 mg, 0.39 mmol) in (124 mg, 0.84 mmol) dissolved in tetrahydrofuran, methanol (aml) was added para- (Bml) at 0"C in a nitrogen atmosphere and toluene sulfonic acid (89 mg, 0.47 mmol) was added dropwise to diisopropyl azodicarboxylate (165 μl,

After 18 hours at room temperature, dissolve 0.4 mmol) in tetrahydrofuran (1 ml). The reaction factor was evaporated under reduced pressure and allowed to warm to room temperature, and the shock partitioned between dichloromethane (5 mL) and 1095 was stirred for 18 hours. The solvent is an extractive solution of potassium carbonate (ml). Water was added under reduced pressure, the remaining solvent phase was separated and extracted with dichloromethane in ethanol (bml) and hydrazine hydrate was added with tan (zml). Organic components were combined (bZmkl, 1.4 ommol). The suspension was stirred, dried over magnesium sulfate and concentrated for 48 hours at room temperature under reduced pressure. The crude product was concentrated under a nitrogen atmosphere, purified by pressure flash chromatography, and the residue was dissolved in methanol. The silica gel solution, using breath as an eluent, was passed through a column using lormethane:methanol (95:5, vol.) and then methanol as an eluent, to remove impurities, dichloromethane:methanol:ammonia (80:20:11, vol. containers) then a 2M solution of ammonia in methanol, for washing, obtaining the title compound (bZmg) as a product. The product was then purified using oil. flash chromatography on silica gel using H-NMR (400 MHz, SOCIv); 61.13 (m, 6H), 2.43 using dichloromethane:methanol (m, 8H), 2.52 (k, 2H) as an eluent , 2.85 (m, 2H), 3.81 ,,, (broad (95:5) then dichloromethane:methanol:0.88 ammonia with, 1H), 4.08 (m, 6H), 6.70 ( c, 1H), 6.78 (c, 1H), 6.81 (90:10:11, v/v) to give the title compound (67mg) as an oil.

NRMO (CHIAT): t/x (MNU 373. "H-NMR (400MHz, SOSIv): 6-1.13 (m, 6Н), 2.19

VRMS: (MH 373.2234. SgoNgoMaOz is necessary (broad c, 2H), 2.43 (k, 2H), 2.54 (k, 2H), 3.19 (t, 373.2234. 2H), 3, 60 (c, ZN), 4.06 (t, 2H), 6.68 (c, 1H), 6.73 (c,

EXAMPLES 254-256 1H), 6.80 (s, 1H).

Compounds of the following grouped Examples NRMS (electrospray): t/2 315 (MN) of the general formula: VRMS: |MN.) 315.1819. С17Н2зМаО», I need SN 315.1816.

C Example 258 and 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yloxy)-5-(1H-pyrazol-1-yl)benzonitrile in M vn "it was obtained by a method similar to the method of om

Example 253 using as a starting material, a real acceptable protected alcohol (RA) from Preparation 95-97. 7 in s,

Alcohol from Example 164 (162mg, 0.4bmmol),

Triphenylphosphine (362mg, 1.38mmol) and phthalimide in cm (20mg, 1.38mmol) were dissolved in tetrahydrofuran (dml) at 0"C in a nitrogen atmosphere and diisopropylazodicarboxylate (272μl, rai 1.38mmol) in tetrahydrofuran (Iml) was added dropwise. The reaction U was left to warm to room temperature and the flow of MOn EC was stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved. The stirred solution was protected in ethanol (dFml) and hydrazine hydrate (85mg, 0.21mmol) from Preparation 99 (112μl, 2.3mmol). The suspension was stirred in methanol (0.5ml) was added vapor- over 48 hours at room temperature to toluenesulfonic acid (4mg, 0.02mmol). Che- atmosphere of nitrogen, concentrated under reduced pressure for 5 hours, the reaction mixture was concentrated under pressure, and the residue was dissolved in methanol. The solution under reduced pressure, dissolved in dichloromethane, was passed through a 5CX column using in (20 ml), washed with a saturated solution of bicarb-quality eluent methanol, for you addition of impurities, sodium nitrate (20 ml), dried over magnesium sulfate, then a 2M solution of ammonia in methanol for washing and concentrated under reduced pressure. No product. The product was then purified using the purified product mixture was purified using flash chromatography on silica gel using flash chromatography on silica gel using dichloromethane:methanol as an eluent or pentane:ethyl acetate (60:40 (95:25) then dichloromethane) as an eluent :methanol:0.880 ammonia followed by 40:60, v/v) to give (90:10:11, v/v) the title compound (54 mg) as a white solid. of the compound (62mg) as an oil. IN-NMR (400 MHz, SOSIz"): b-2.19 (s, ZN), 2.45

IN NMR (400MHz, COzO0): b-1.15 (m, 6bH), (its 1), 410 (m, 2H), 4.20 (m, 2H), 6.87 (d, 2.46 ( k, 2H), 2.63 (k, 2H), 3.13 (t, 2H), 4.13 (t, 2H), 1H), 6.96 (s, 1H), 7.05 (d, 1H). 6.54 (s, 1H), 7.17 (s, 1H), 7.69 (s, 1H), 7.72 (s, 1H), NRMS (HIAT): t/2 330 (MH") 7 .82 (s, 1H), 8.32 (s, 1H). Microanalysis: Found C, 51.38; H, 3.52; M,

NRMO (KHAT): t/:2 351 (MN) 12.37. Si4Ni1BaMzO" must be C, 51.07; H, 3.37;

VRMS: IMNU) 351, 1929. Si9Hg2MaO" is necessary M, 12.7690. 351, 1928. Example 261

Example 259 5-(3,5-Diethyl-1-(2-K2-

3,5-Dichlorophenyl-3-methyl o 5-(3-methyl-1,2,4-methoxyethoxy)methoxy|ethyl)-1H-pyrazole-4-oxadiazol-5-yl)umethyl|-1H-pyrazole -4-yl ether yl)oxy)isophthalonitrile si sv, Me. CM; And | sn, o-en,

To a stirring solution of alcohol (5.0 g,

To a stirred solution of acid. (100 mg, 0.3 mmol) from Preparation 92 in dime-pe mol) From Griclad 119 In tetrahydrofuran, tylformamide (2 ml) was added in one portion (b5 mp) while carbonyldiimidazole (59 mg, 0.3 mmol) was also added. After 30 minutes at room temperature, methoxyethoxymethyl chloride (2.39 mL, 20.94 mmol) was added (12)-, followed by sodium hydride (838 mg of bovagyu dispersion

M'-hydroxyethaneimidamide (27 mg, 0.5 mmol) and the reaction in oil, 20.94 mmol. After 10 minutes, the reaction mixture was stirred at room temperature; the mixture was heated at 50 C for 18 hours. Writing for 3 hours. A second portion was added to cool to room temperature, a mixture of carbonyldiimidazole (59mg, 0.3bmmol) and the mixture was diluted dropwise (3ml) with saturated aqueous heated at 100"C for 12 hours. After ammonium chloride solution. The mixture was concentrated, cooled to room temperature, added - under reduced pressure, the residue was separated between water (30 ml) and the mixture was extracted with ethyl acetate-dichloromethane (250 ml) and water (200 ml). The aqueous volume (3 (20 ml). The combined organic components of the phase were separated! magnesium and concentrated with tan (150 ml). The organic components were combined under reduced pressure to obtain a brown powder, dried over magnesium sulfate and concentrated. The crude product was purified by fractions under reduced pressure. The crude product was purified by flash chromatography on Silica gels were purified using flash chromatography using ethyl acetate:pentane as an eluent, silica gels using air (30:70, by volume) as an eluent. rusting the title lormethane followed by dichloromethane:methanol (99:1, the compound (40mg) as a pale yellow oil. by volume) obtaining the compound specified in the title - "H-NMR (400 MHz, SOSI"): 5-2.12 (c, ZN), 2.29 cu (5.38 g) as a colorless oil, (c, ZNU , 4.08 (s, 2H), 6.74 (s, 2H), 6.98 (s, 1H). H-NMR (400MHz, SOCI3): 6-1.10 (m, 6H), 2, 39

NRMS (electrospray): t/x 339 (MH) (k, 2H), 2.55 (B, 2H), 3.38 (s, ЗН), 3.51 (m, 2H), 3.56

Example 260 (m, 2H), 3.93 (t, 2H), 4.20 (t, 2H), 4.66 (s, 2H), 7.38

3-Fluoro-5-(11-(2-hydroxyethyl)-5-methyl-3- (c, NO CHAT. tu» 399 (MNU (trifluoromethyl)-1H-pyrazol-4-yl|Ioxybenzonitrile) Microanalysis: Found C, 62.11; H, 6.67; M, 13.51. SgiNovMm«O4--0.43H2O required C, 62.09; H,

6.67; M, 13.7995. m cm

Example 262

3-Cyano-5-1H3,5-diethyl-1-(2-hydroxyethyl)-1H- sn

He) t M o 0 HM on nn sna To a stirring solution of pyrazole from 9 -- Preparation 103 (8Omg, 0.19mmol) in methanol pe -i M on (ml) was added para-toluenesulfonic acid: (4mg, 0 .02 mmol). After 5 hours at room temperature

To a stirring solution of pyrazole, the reaction mixture was concentrated at (bomg) from Preparation 100 in dichloromethane (4ml) under reduced pressure and the residue was divided between dich- added aluminum trichloride (134mg, Tmmol). lormethane (20 ml) and water (20 ml). Organic

After 18 hours, ice was added, the mixture was neutralized, the component was dried over magnesium sulfate, and the lily of the valley was centered under reduced pressure using a saturated aqueous solution. Unrefined sodium bicarbonate was diluted with water (30 ml) and the product mixture was purified using a flash and extracted with dichloromethane (2x4O0 ml). Organic chromatography on silica gel using the components were combined, dried over sulfate quality eluent dichloromethane:methanol (magnesium gradient and concentrated under reduced pressure. from 100:0 to 95:5, by volume) obtaining the indicated in

The crude product mixture was purified to afford the title compound (44 mg) as a white solid. by flash chromatography on silica gel using H-NMR (400 MHz, SOSIv): 6-1.11 (t, ZN), 1.46 using dichloromethane:methanol (d, ZN) as an eluent, 2.54 (k, 2H), 4.10 (k, 2H), 4.17 (k, 2H), 4.79 (95:5, by volume) obtaining indicated in the title (k, 1H), 7.44 (c, 2H ), 7.57 (s, 1H). compound (27 mg) as colorless crystals. NRMS (HIAT): t/ 327 (MNU)

IN-NMR (400MHz, SOSIz): 6-1.10 (m, 6H), 2.40 Example 265 (k, 2H), 2.52 (k, 2H), 4.07 (m, 4H), 7 .25 (c, 1H), 7.60 3-(I3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole- (c, 1H), 7.65 (C1H). 4-yl|oxy )-5-(5-trifluoromethyl-1,2,4-oxadiazole-3-

NRMS (HIAT): t/2 329 (MH) yl)benzonitrile

Example 263 o--k 5-C5-Ethyl-3-(1-hydroxyethyl)-1H-pyrazol-4-vo-K |. sp yl|oxy)isophthalonitrile

SM sn.

What's in the dream, sir. vgt M on son To a miscible solution of pyrazole with i m Preparation 105 (235mg, 0.46bmmol) in dichloro-

Aluminum trichloride was added to NH methane (2 ml).

To a stirred solution of pyrazole (37 µg, 2.86 mmol). The reaction mixture was stirred from Preparation 102 (219 mg, 0.57 mmol) in tetrahydrofuran at room temperature for 48 hours, dropfuran (2.5 ml) was added saturated aqueous, diluted with water (bml) and extracted with sodium carbonate dichloromethane (0.5 ml ). Tanom reaction mixture (bml). The organic component was concentrated-stirred at room temperature under reduced pressure and purified with the help of 4 hours and then heated with reverse cooling flash chromatography on silica gel for 18 hours. The reaction mixture was concentrated using dichloromethane as an eluent under reduced pressure and the tan:methanol residue (gradient from 99:1 to 80:20, by volume) was divided between dichloromethane (20 ml) and water, after which dichloromethane:methanol:0, 88 ammonia (20 ml). The organic phase was dried over sulfate (80:20:11, by volume) to obtain contaminated magnesium and concentrated under reduced pressure. of the title compound (44 mg) as white

The crude product mixture was purified using a solid substance. The product was further purified by HPLC flash chromatography on silica gel using a Rpepotepeh Hypa Siv column using dichloromethane:methanol 150x21.2 mm as an eluent and using as an eluent (gradient from 100:0-90:10, by volume) obtaining a gradient solvents 5:95 0.195 aqueous trifluoroacetate in the title compound (bZmg) as a white solid fatty acid in acetonitrile:acetonitrile (0-1 min. substance. 80:20; 1-7 min. 80:20 was replaced by 0:100; 7- 12 min. "H-NMR (400 MGu, SOSiv): 6-1.21 (t, ZN), 1.51 0:100; 12-12, 1 min. 0:100 was replaced by 80:20; 12.1- ( d, ЗН), 2.54 (Кк, 2Н), 4.89 (к, 1Н), 7.25 15 min. 80:20) obtaining the solution specified in the title (с, 2Н), 7.43 (с, 1H) onion (38 mg) as a white solid.

NRMS (HIAT): t/2 283 (MN) Retention time 5.7 minutes.

Example 264 HPMS (electrospray): m/z2 422 (MH) 5-(C5-Ethyl-3-(1-hydroxyethyl)-1-(2- EXAMPLES 266-268 hydroxyethyl)-1H-pyrazole-4- Compounds of the following grouped Examples of yl|oxy)isophthalonitrile of the general formula:

Tetrahydrofuran (2 ml) was added to preparation 115 (250 mg, 1.6 mmol) and pyrazole from Preparation 18 (155 mg, 0.42 mmol) in isopropanol (bml). Soon, the mish was heated with a reflux condenser. for 2 hours, after which the reaction mixture was concentrated under reduced pressure. Unpurified M product was purified using flash chroma- was obtained by a method similar to the method of tography on silica gel using as

Example 265 using an acceptable eluent dichloromethane:methanol:0.88 ammoniacal alcohol (RA) from Preparations 106-108. (85:15:11, by volume) obtaining a contaminated sample of the title compound. The product will be cool in the future! raprim | And | 00 Analtinidani | was purified by HPLC using a column 1701 esery mn 0 Rpepotepech Hypa Ca) 10μM 150x21.2MmM and extracted 567 7 Retention time 55 waves HPMS using as an eluent a solvent gradient of 5:95 0.195 aqueous trifluoroacetic acid in 1 er acetonitrile:acetonitrile ( 0-min 95:5 was replaced (electrospraying); t/g 396 (MN) by 0:100; 6-10 min 0:100) obtaining the title compound (6b5mg) as an almost white solid

Example 269 iron. 5-I(4-(3-Xpor-5-cyanophenoxy)-3-methyl-1H- Retention time: 3.40 minutes pyrazol-5-yl|methyl)amino)methyl|nicotinamide IN NMR (40 ohms, COzOb) : 6-2.14 (s, ZN), 4.21 o kn, (s, 2H), 4.50 (s, 2H), 7.19 (s, 1H), 7.27 (m, 1H) . ) (9, mya / Microanalysis: Found C, 44.56; H, 3.41; M,

And 14.07. С1и9Ни7МеО»СиИ-1,9СЕзСО2Н is necessary С, о- 44.64; H, 3.11; M, 13.70905. ud Example 271 is Di(tert-butyl) 2-I4-(3,5-dicyanophenoxy)-3,5-

Pyrazole from Preparation 18 (210 mg, 0.57 mmol) followed by sodium potassium carbonate (240 mg, 1.70 mmol). The reaction mixture was heated under reflux for 1.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. and the crude product, the mixture was purified using flash flash chromatography on silica gel using dichloromethane 119 (500 mg, 1.60 mmol) in dichloromethane tan:methanol:0, 88 ammonia (95:5:0.5 then 90:10:1 (5ml) was added tetrazole (226mg, 3.20mmol) then 80:20:1, by volume) to give contaminated di-tert-butyl -M,M- a sample of the desired product. Flash chromatography diisopropylphosphoramidite (1.02ml, 3.20mmol). repeated using as an eluent After stirring for 4 hours at chem- dichloromethane:methanol:0.88 ammonia (100:0:0 then at room temperature the reaction mixture was cooled 95:5:0.5 then 90:10:11, vol. containers) while heating to 0"С and portionwise adding metasane in the title compound (10mg) as pale yellow, chloroperoxybenzoic acid (1.0g 5Owag.9o solid. mushi, Zmmol) (CAUTION, EXOTHERMAL) .

IN NMR (400 MHz, SOzOB): 6-2.05 (s, ZN), 3.62 After 10 minutes, the mixture was heated to room temperature (s, 2H), 3.79 (s, 2H), 7.16 (m, 1H), 7.18 (m, 1n), 7.38 temperature and diluted with dichloromethane (50 ml). (c, 1H), 8.15 (c, 1H), 8.54 (c, 1H), 8.84 (c, 1H). The solution was washed with a saturated aqueous solution

NRMO (HIAT): t/2 419 (Ma-Ma") of sodium carbonate (20 ml) and the aqueous component of

VRMS: (MH 397.1173. C1i9NivMeO»SiI is necessary- cremated and extracted with dichloromethane but 397.1175. (20ml). The combined organic components were washed

Example 270 with a saturated aqueous solution of sodium chloride 2-ICH4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H- (20 ml), dried over magnesium sulfate and concentrated pyrazol-5-yl|methyl)amino)methylisonicotinamide dug under reduced pressure. Uncleaned pro- o. chn, duct mixture was purified using flash chromatography on silica gel using dichloromethane:methanol:0.88 ammonia as the eluent

What m, // (100:0:0 then 99:1:0.1 then 98:2:0.2, volumetric) and! obtaining a sample of the compound indicated in the title -y (6bOmg): - /H axvron IN NMR (400mhz, SOCIz"): b-1.10 (m, 6H), 1.43 to (c, 18H), 2.38 ( k, 2H), 2.55 (k, 2H), 4.26 (m, 4nH),

To a stirred suspension of amine with Addition - 7.38(6.2Н), 7.54(c, 1Н).

NRMS (electrospray): t/2 525 (MN") Example 274

Microanalysis: Found C, 57.77; N, 7.38; M, 5-4113,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole- 10.33. С25На5МаО5Р--Нг2О is necessary C, 57.68; H, 4-yl|oxy)isophthalonitrile benzenesulfonate salt 7.16; M, 10.7690. co. see

Example 272 2-I4-(3,5-Dicyanophenoxy)-3,5-diethyl-1 H- sn, pyrazol-1-yl yl dihydrophosphate oseim mo CM ud n. and ZON - U

M o To a stirred solution of pyrazole from Example 119 (20 g, b5 mmol) in acetone (200 ml) was added benzenesulfonic acid (10.7 g,

To the stirring solution, phos-bdmmol) ester and the mixture was stirred at room temperature from Example 271 (250mg, 0.48mmol) at room temperature for 10 minutes. Trifluoroacetic acid (0.5 ml) was added to the reaction mixture of lormethane (10 ml) at 0"C and the residue was concentrated under reduced pressure. The reaction mixture was recrystallized twice (acetone) to obtain the title compound (16, 2d) as a white powder, it was concentrated for hours under reduced pressure.

The residue was purified by HPLC using a col- IN NMR (400mhz, SOSIv): b-1.05-1.08 (m, 6H), nku Rpepotegeh I ipa Ca(II) 10μM 150x21.2mm and 2.59 (Kk, 2H ), 2.68 (k, 2H), 4.04 (t, 2H), 4.54 (t, 2H), using as an eluent a gradient of 7.35-7.42 (m, ЗН), 7 .55 (c, 1H), 7.64 (c, 1H), 7.986 (d, factors 5:95 0.195 aqueous trifluoroacetic acid 2H). in acetonitrile acetonitrile (0-1.9 min. in 95:5; 2- Microanalysis: Found C, 58.96; H, 5.13; M, 1Ochv. 90:10 was replaced by 30:70; 10.0-13, 8 min. 11.88. SgzNg«MaOv55 necessary C, 58.96; H, 5.16; M, 30:70; 13.8-13.9 min. 30:70 was replaced by 95:5; 11.9695. 13 ,9-15 min 95:5) receiving a sample of the desired product Example 275. This sample was further purified by crystallization of 5-4-(13,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole- using acetonitrile/water to give 4-yl|oxy)isophthalonitrile tosylate salt of the title compound as a white solid - It's my fault, Tpl. 198-19976.

Holding time: 2.31 minutes. dream

IN NMR (400 MHz, COzObB): 6-1.09 (m, 6H), 2.35 seh (kb 23), 261 (Kk, 2H), 428 (m, 4H), 7.55 o -i M on (c, 2H), 7.79 (c, 1H). and.

NRMSO (HIAT): t/2 391 (MN) ze von

Microanalysis: Found C, 50.99; N, 4.92; M, in s and y 14.06. Си7НизМаО5РяН2О is necessary С, 51.13;Н, To a stirring suspension of pyrazole from 5.05: M.14.039. Example 119 (300mg, 1.00mmol) in ethanol (2ml) "Example 273 added p-toluenesulfonic acid (202mg, 5-(13,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole-1.1O0mmol) and the mixture was heated in an oil bath to 4-yl|oxyisophthalonitrile sulfate salt dissolution of solids. The reaction mixture was not cm cooled to room temperature and concentrated under reduced pressure. The residue crys-

Io, sn, lysed (diethyl ether), filtered and recrystallized (isopropyl alcohol)

She obtained the title compound (200 mg) of sheuoHtone as a white solid, m.p. 12070. and; tvo, IN NMR (400 MHz, DMSO-α): b-1.00 (m, 6Н),

To a miscible solution of pyrazole with 2.24 (M, 5H), 2.49 (m, 2H), 4.00 (m, 2H), 711 (d,

Example 119 (200 mg, 0.65 mmol) in acetone (5 ml) 2H), 745 (d, 2H), 7.73 (s, 2H), 8.09 (s, 1H). added sulfuric acid (0.32ml 2M aqueous Microanalysis: Found C, 59.64; H, 5.46; M, solution, 0.b4mmol) and the mixture was stirred at 11.60. SgaNoeMaO55 must be C, 59.74; H, 5.43; M, at room temperature and the solvent was left to 11.6155. steam up The residue was recrystallized (Example 276 toluene/acetone) to give the title compound 5-4(3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazole (160 mg) as a white powder, mp 105 - 4-yl|Ioxy)isophthalonitrile mesylate and salt 11026. Mo cm

IN NMR (400 MHz, SOSI"): 6-1.22 (m, 6H), 2.70 (m, 4H), 4.12 (she, 1H), 4.59 (m, 2H), 4.75 (she, 1H), sn, 7.66 (s, 1H), 7.69 (m, 1H), 2 (s, 1H). at

Microanalysis: Found C, 50.29; H, 4.90; M, he 13.48. Si7NivM«O»-H25O»x is necessary C, 49.99; H, number 4.93; M, 13.72. "vOdMme

To a stirred suspension of pyrazole from IN NMR (400 MHz, CO3O0): 6-1.08 (m, 6Н), 2.32

Example 119 (250 mg, 0.8 mmol) in isopropyl alcohol (Zml) added methanesulfonic acid (m, 2H), 6.93 (s, 1H), 7.05 (s, 1H), 7.18 (s, 1H). lot (52 μl, 0.91 mmol) and the mixture was heated on a NRMS (thermospray): t/2 (free-base bath to dissolve solids. 299

The reaction mixture was cooled to room temperature. Microanalysis: C was found, 51.26; H, 6.36; M, perature and concentrated under reduced pressure 14.08. С17Н25М4О5Р is necessary C, 51.51; H, 6.36; M, up to a volume of 1 ml. The precipitated white solid was 14.1496. washed with cold isopropyl alcohol Example 279 obtaining the title compound (239 mg) 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazole-4-) as a white solid, mp 144-146"60. yl|oxy)-5-methylbenzonitrile (I) tartrate salt

IN NMR (400mhz6y, DMSO-av): 6-1.02 (m, 6H), me. cm 2.32 (Kk, 2H), 2.43 (s, ЗН), 2.52 (m, 2H), 3.73 (m, 2H), 4.02 (m, 2H), 7.75 ( c, 2H), 8.11 (c, 1H). dream

Microanalysis: Found C, 53.20; H, 5.52; M, at 13.68. SivNg22MaO55 must be C, 53.19; H, 5.46; M, 7 - and t, 13.7895. but

Example 277 ! (unosnosnenyusin and 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazole-4- To a stirred solution of amine from Prikyl|oxy)-5-methylbenzonitrile bismesylate salt of Ladu 125 (500 mg , 1.68 mmol) in acetone (15 ml)

(I)-tartaric acid (252 mg, 1.68 mmol) was added to the mixture and the mixture was heated in an oil bath until complete dissolution. The mixture was cooled to room temperature in the dark, and the white precipitate formed was filtered and washed (acetone) to obtain the title compound (515 mg) as a white powder, mp n, m Mne 159-16126. -2805nMe IN NMR (400MHz, COzOb): 6-1.05-1.10 (m, 6Н),

To a stirred solution of amine from Add- 2.32 (c, ЗН), 2.34-2.41 (m, 2Н), 2.53-2.57 (m, 2Н), Ladu 125 (119mg, 0.4 mmol) in ethanol (2 ml) to 3.40 (m, 2H), 4.27 (m, 2H), 4.35 (s, 2H), 6.93 (s, 1H), gave methanesulfonic acid (1.00 ml of 0.84 M 7.05 (c, 1H), 7.17 (c, 1H). solution in ethanol, 0.84 mmol). The reaction mixture HPMS (electrospray): t/2 | Free os- was concentrated under reduced pressure by removing novakNn") 299 some part of ethanol. A mixture of diethyl ether was added. Microanalysis: Found C, 54.80; H, 6.38; M, ether and acetone and a white solid, 12.11. C»iNgvMaO7.0.65H2O required C, 54.81; H, precipitated, filtered and washed (diethyl 6.42; M, 12.1090. ether/acetone) to give the title compound of Example 280 (153 mg) as a white solid, mp 3-(1-(2-Aminoethyl)-9,5-diethyl-1H-pyrazol-4-146-14876.yl|oxy)-5 -methylbenzonitrile succinate salt

IN NMR (400 MHz, COzO0): 6-1.09 (m, 6H), 2.33 me. cm (s, 3H), 2.39 (k, 2H), 2.55 (k, 2H), 2.68 (s, 6H), 3.42 (t, 2H), 4.29 (t, 2H ), 6.93 (s, 1H), 7.06 (s, 1H), 7.19 sn, (s, 1H). Oh

NRMS (thermal spraying): t/2 (Vilna Osnovant 299 neo. - in,

Microanalysis: Found C, 45.83; H, 6.12; M, "noysn,snyubn 11.27. Si9NzoMaO752:0.50Н20 is necessary С, 45.68; To a stirred solution of amine from Prik-

H, 6.25; M, 11,21905. Ladu 125 (235mg, 0.79mmol) in acetone (7ml) to

Example 278 gave succinic acid (9 mg, 0.79 mmol). 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazole-4- After two minutes, the mixture was concentrated to 3 mL of yl|oxy)-5-methylbenzonitrile phosphate salt using a stream of nitrogen, resulting in me cm obtaining white crystals. The precipitate was filtered and washed (acetone) to give the title compound (172 mg) as white crystals, mp another 15526. seh, IN NMR (400mhz, COzO0): 6-1.03-1.07 (m, 6H), sh- r or 2.34 (s, ЗН), 2.40 (k, 2Н), 2.50 (s, AN), 2.59 (k, 2H), well M Mn, 3.34 (t, 2H), 4.23 (t, 2H), 6.95 (s, 1H), 7 ,06 (s, 1H), "NerO, 7.22 (s, 1H).

Phosphoric acid (b3μl, 0.93mmol).Microanalysis: Found C, 60.47; H, 6.77; M, nil then diethyl ether) and dried to give the title compound (265mg) as Example 281 as a white solid, Melting point 210-21126. 3-(1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazole-4-

yl|oxy)-5-methylbenzonitrile (I) citrate salt Example 283

Mo. see 2-I4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazole-

1-yl|Stylamine and 2-I4-(3,5-dichlorophenoxy)-5-ethyl-sn, 1H-pyrazol-1-yl|Stylamine c) He svyren m / " nouosn,konusonIsnsohn What is

Citric acid (900 mg, 0.47 mmol) was added to a stirred solution of amine from Prykshch, min ladu 125 (140 mg, 0.47 mmol) in acetone (Zml). The mixture was stirred until complete dissolution. The mixture was concentrated to 1 ml using a stream of nitrogen and cooled in a refrigerator for ; about 1.5 hours. The precipitate was collected, filtered to obtain M Mn, the title compound (149 mg) as a white pyrazole of Example 42 (1.03 g, 4.00 mmol) and hydroshock, mp. 180-18276. 2-chloroethylamine hydrochloride (510 mg, 4.40 mmol)

IN NMR (400 MHz, СОзОб): 6-1.04-1.07 (m, 6Н), heated as a melt at 1507С for 24 h - 2.35 (s, ЗН), 2.40 (k, 2Н), 2.58 (Kk, 2H), 2.73 (d, 2H), dyn. The reaction was cooled and a solution of the residue in 2.80 (d, 2H), 3.42 (t, 2H), 4.30 (t, 2H), 6.95 (c, 1H), dichloromethane (100 ml) was washed with aqueous 1 M 7.08 (c, 1H), 7.21 (c, 1H). potassium carbonate solution (50 ml), saturated

NRMS (electrospraying): It/72 IV free with sodium chloride solution (50 ml), dry the novice| 299 over magnesium sulfate, filtered and concentrated

Microanalysis: Found C, 56.19; H, 6.20; M, shafts at reduced pressure. Crude product 11.91. SozNzoMaOv is necessary C, 56.32; H, 6.16; M, purified by flash chromatography at 11.42965. silica gel using as an eluent breath

Example 282 lormethane:methanol:ammonia (93:7:1, by volume) obtained 5-(13,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazolizing the compounds indicated in the title (768mg) with an 85:15 4-yl|oxyhisophthalonitrile ratio of regioisomers as a colorless mass

Mo s vn lo.

IN-NMR (400 MHz, SOSIv): 6-1.16 (main, t,

ЗН), 1.16 (minor, т, ЗН), 2.47 (main, к, сн, 2Н), 2.60 (minor, к, 2Н), 3.13 (main, m, о - 2Н) , 3.13 (minor, m, 2H), 4.10 (main, m,

M 2H), 4.10 (minor, m, 2H), 4.24 (main, t,

Well, where are these 2H), 4.24 (minor, t, 2H), 6.85 (main, c, 2-Hydroxyethylhydrazine (8.43ml, 124mmol) 2H), 6.85 (minor, c, 2H), 7 .02 (basic, c, added dropwise to a solution of diketone Pry-1H), 7.02 (non-basic, c, 1H), 7.27 (basic, c, preparation of 45 (30.5g, 113mmol) in 1H acetic acid ), 7.31 (minor, p, 1H). And. (3300 ml) at room temperature in the atmosphere of NRMES (thermospray): t/x MH") 300. nitrogen. The reaction was stirred at room temperature. pressure, obtaining an orange solid in the preparation of the compounds of Examples. It was combined with the orange Preparation 1, a solid from another reaction carried out with 3-(3,5-Dichlorophenoxy)-2,4-pentanedione under similar conditions. The combined crude products was purified by flash column chromatography on silica gel using ethyl acetate:pentane (75:25 v/v) as eluent to give the title compound as a white solid. Proton NMR analysis showed the presence of minor impurities, so the product Z-Chloro-2,4-peythanedione (18 µl, purified using column flash chrome- 1.53 mmol)) was added to the suspension, which was stirred and photographed on silica gel using as of 5-dichlorophenol (250mg, 1.53mmol) and eluent ethyl acetate:ipentane (50:50 v/v) potassium carbonate (233mg, 1.69mmol) in acetone to give the title compound (50g) as (7.7ml) at room temperature temperature in the atmosphere white solid substance, Tpl. 125760. of nitrogen. The mixture was stirred for 30 minutes and

TN-NMR (400 MHz, SOSIv): 6-1.13 (6Н, m), 2.40 was then heated under reflux with pro- (2Н, ю, 2.53 (2Н, ю), 3.53 (1Н, m), 4.11 (AN, m), 7.40 with a draft of 375 hours. After cooling, (2N, s), 7.58 (1 N.s), sodium iodide (230mg, 1.53mmol) was added and the mixture boil-

NRMS (electrospray): t/2 |MNU) 311. li during another 375 hours. After cooling

Microanalysis: Found: C, 65.62; H, 5.85; M, the mixture was again diluted with water (5 ml) and the concentration was 18.04. C17NivMaO" must be C, 65.64; H, 5.84; M, shafts at reduced pressure in the steam trap 18.0595. (Attention: the residue may be lachrymator) by removing acetone. The obtained red aqueous solution was diluted with 2 M hydrochloric acid (5 ml) and 6.17 mmol) was added to the solution, which was stirred and extracted with dichloromethane (3 (1 O ml). It was combined, 4-(3,5-dichlorophenoxy)-3,5 -diethyl-1H- the organic layers were washed with saturated aqueous pyrazole (800mg, 2.81mmol, Example 3) in a dry solution of sodium sulfite (1Oml) and saturated M,M-dimethylformamide (ml) at 0"С in an atmospheric solution sodium chloride (1 Oml), dried under nitrogen. The mixture was stirred for 5 minutes over magnesium sulfate, filtered and evaporated to give off hydrogen and then added under reduced pressure to give red ethyl 4-chloroacetoacetate (0.42ml, 3.09mmol) . oil (344 mg). The crude product was purified by After 30 minutes, the reaction mixture was quenched by adding water (0.5 ml) using flash chromatography on silica gel and concentrated under reduced pressure using pen as an eluent. A solution of the residue in ethyl acetate (5 Oml) protane :ethyl acetate (20:11, by volume) was added to saturated aq. with a solution of zanium chloride in the title compound (118 mg) as a cream of ammonia (20 ml) and water (20 ml), the substance was dried over a solid, Tpl. 91 -9276. fathom magnesium and concentrated under reduced pressure

IN-NMR (400 MHz, SOSIz): 622.04 (s, HV), 6.84 pressure. The crude product was purified using flash chromatography on silica gel using

HPMS (thermal spray): t/2 (MMNA" | 278. using ethyl acetate:pentane as eluent

Microanalysis: Found: C, 50.43; N, 3.84. (30:70, volume) obtaining the indicated in the title

Si NiosSiI2Oz must be C, 50.60; H, 3.86905. compound (1.1 g) as a white solid, mp. 82-

Preparation 2 8476. 4-Chloro-3,5-heptanedione IN-NMR (Zb0Omgz, СОСИ3): b-1.40 (6H, m), 1.26 sn, (ZN, t), 2.44 (AN, ky), 3.47 (2H, s), 4.22 (2H, ky), 4.96 s (2H, s), 6.82 (2H, s), 7.02 (1H, s). o NRMS (thermal spraying): t/2 МН") 413. neo o Microanalysis: Found: C, 55.13; H, 5.34; M,

Chlorotrimethylsilane (29.7 ml, 0.234 mol) to high MvoO is necessary C, 55.22; H, 5.37; M, was added dropwise to a pale yellow, stirring solution of tetrabutylammonium bromide (1.26 g, Preparation 4. 3.9 mmol) in dry acetonitrile (116 bml) at room temperature. 14-(8,5-Dichlorophenoxy).3 ,5-diethyl-T H at room temperature in a nitrogen atmosphere. The resulting pyrazol-1-ylacetic acid solution was cooled with ice and 3,5-heptanedione (10.6 mL, 78.0 mmol) was added dropwise over 5 minutes, and then dry dimethyl sulfoxide (16.6 mL, 0.234 mol) obtaining a yellow xx solution, which was left to slowly heat up to - room temperature, with stirring, over a period of 4 hours. The mixture was diluted with water (1 liter), stirred for 10 min. and then extracted- An aqueous solution of sodium hydroxide (1M, 6.2ml, with ether (1 (500ml, 2 (250ml). The combined ethers b.2mmol) was added dropwise to the solution, the layers were dried over magnesium sulfate, filtered mixed, the ester (2g, 5.6 mmol) of Example 9 was added and concentrated under reduced pressure in tetrahydrofuran (20ml) at 07C. After 1 hour, a yellow oil was obtained. under reduced pressure, aqueous hydrochloric acid (20 ml) was added to obtain the title compound (5.5 g) as intensively stirred. The resulting white pale yellow oil, b.p. 102-1052 C/54 mm Na, the precipitate was collected by filtration, washed with ether containing pr. 1095 of 4,4-dichloro-3,5-heptanedione, which (3 (30ml) and dried in a vacuum gun when microanalysis showed. -1.12 (t, 6H), 2.59 compound as a white solid (1.5g), mp 157- (Kk, AN), 4.77 (s, 0.2H, diketone), 15.50 (with, 0.8Н, 15876. enol). IN-NMR (Zbomgts, SOSIz"): 6-1.13 (6H, m), 2.52

NRMS (thermal spray): t/2 (MMN."| 180 (2Н, ю, 2.60 (2Н, ю), 5.03 (2Н, s), 6.95 (2Н, s), 7.14 for of the title compound and 214 for the de- (TH, c). chlorinated impurity. NRMS (electrospray): t/2 (М-НЯ| 341.

Preparation From Preparation 5

Ethyl 4-I4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-1"8,5-Dichlorophenoxy)2-butanone pyrazol-1-yl|-3-oxo-butanoate c and not. MD in I sleep, 0 p

SHU Cesium carbonate (108g, 0.3Zmol) was added not U. in one portion to the stirred solution,

of 3,5-dichlorophenol (49g, 0.30mol) in acetone for 9 seconds (900ml) at room temperature under a nitrogen atmosphere. To this suspension was added dropwise

Sodium hydride (6095 dispersion in oil, 250mg, 1-bromo-2-butanone (30.bml, 0.30mol) in ace-

toni (ZOOml) and the resulting suspension was heated with (ZOml), dried over magnesium sulfate, filtered and refluxed for 2 hours. It was stirred and concentrated under reduced pressure, and the suspension was cooled to room temperature, forming a yellow solid. Water (200 ml) was added to the crude product and acetone was removed, and the product was purified using a column filter under reduced pressure. The mixture was extracted by dichlorochromatography on silica gel using in methane (2 (300 Oml) and the combined organic phases of the eluent quality pentane ether (90:10, by volume) were dried over magnesium sulfate, filtered and obtaining the title compound (3, 0 g) as concentrated under reduced pressure to obtain a white solid, mp "6070. clear oil. The crude product was purified by INT-NMR (30 Ωmtz, SOCI3): b-2.11 (s, ЗН), 2.43 using a column flash chromatography on (c, ЗН), 2.70 (с, ЗН), 6.78 (с, 2Н), 7.03 (С1Н). ) 299. lormethane:cyclohexane (50:50, by volume) Preparation 8 gave the title compound (b5d) as yellow 1-Acetyl-3-(bromomethyl)-4-(3,5- dichlorophenoxy oil) -5-methyl-1H-pyrazole

IN-NMR (400 MHz, SOSIz"): 6-1.13 (t, ZN), 2.60 a (k, 2H), 4.58 (s, 2H), 6.78 (s, 2H), 7 ,01 (c, 1H).

NRMS (thermal spraying): t/2 (MMNA-| 250.

Preparation 6. 2-(3,5-Dichlorophenoxy)-1-(dimethylamino)-1- o. ve. about penten-3-one -4. ve Bay sn, che. M-Bromosuccinimide (2.70g, 15.0mmol) was added iv to a stirred solution of pyrazole Preparation 7 (3.00g, 10.0mmol) in 1,1,1-trichloroethane (40ml ) at room temperature in a nitrogen atmosphere. The reaction was heated at 807C

Preparation 5 ketone solution (65g, 0.28mol) for 1 hour and then added azobisisobu- in M,M-dimethylformamidedimethylacetal (75ml, thyronitrile (2mg) and the reaction mixture was heated pro-

0.5 bmol) was heated at 100C. using a draft of another 3 hours. The reaction was cooled to room temperature in a Dean-Stark funnel for 10 hours. The reaction at room temperature and the solid removed were cooled and concentrated under reduced filtration. The filtrate was concentrated under pressure to obtain a brown oil. Uncleaned under low pressure! the obtained yellow oil was dissolved in ethyl acetate (100 ml), the product was purified using a column flash. Ethyl acetate was washed by chromatography on silica gel using a 1 M aqueous solution of sodium carbonate as an eluent, pentane: ethyl acetate (90:10, volume (30 ml), water (30 ml) and saturated aqueous solutions) and then pentane: ethyl acetate (60 :40, by volume) nom of sodium chloride (Zbml), dried over sulfa- receiving the title compound (55 g) as volume of magnesium, filtered and concentrated to a yellow oil that solidified on standing. The obtained yellow solid was washed with potash pentane under reduced pressure to obtain a yellow solid. The crude product was purified by addition (100 ml) and dried to give the silica compound indicated in the title by flash column chromatography (28 g) as a yellow solid, m.p. 96- gels using 972C as an eluent. pentane:ethyl acetate (90:10, by volume) to obtain

IN-NMR (400 MHz, SOSIz): 6-0.98 (t, ЗН), 2.30 yellow solid washed with cold (w s, 2H), 2.94 (s, 6H), 6.77 (c, 2H), 6.95 (c, 1H), with ice-cold ether (20 ml) to give 7.24 (c, 1H). well, in the title, the compound (2.3g) as a white solid

NRMS (thermal spraying): t/2 (MINA) 288. wine, Tpl. 111-11970.

Preparation 7 IN-NMR (Zb00Omgz, СОСИ3): 622.10 (s, ЗН), 2.73 1-Acetyl-4-(3,5-dichlorophenoxy)-3,5- (s, ЗН), 4.73 (c, 2H), 6.86 (c, 2H), 7.11 (CH). dimethyl-1H-pyrazole NRMES (thermal spray): t/2 (MH) 379.

Preparation 9 iodine 4-(3-Cdianophenoxy)-3,5-heptandione o "ХА - o o not sn,

Sodium hydride (6095 dispersion in oil, b84mg, 0.17, 1mmol) was added to a stirred solution of acetyl chloride (1.21ml, 17.1mmol) and pyra-B-diketone mixture Preparation 2 (1.79g, of Example 53 (400, 15 mmol) in MM- 11.0 mmol), 3-cyanophenol (1.31 g, 11.0 mmol), dimethylformamide (2 mmol) at 0 b in an atmosphere of cesium carbonate (3.58 g, 11.0 mmol) ) and acetone nitrogen. The reaction was stirred at 0°C for 1 hour (44 ml), heated under reflux and then quenched by adding water (100 ml). Within 2 hours. After cooling, the condensed layer mixture was extracted with ether (2 x 50 ml). The mixture was concentrated under reduced pressure and the residue of the separated organic phase was washed with water (30 ml) and partitioned between dichloromethane (50 ml) and water (25 ml). saturated aqueous solution of sodium chloride

The organic layer was separated, washed with dichloromethane (5 Oml) at room temperature in a nitrogen atmosphere saturated with an aqueous solution of sodium chloride. The reaction was stirred thoroughly (25 ml), dried over magnesium sulfate, filtered for 1 hour and then poured into water (5 Oml). It was torn off and concentrated under reduced pressure, the organic layer was separated, dried over a yellow oil. The crude product was purified by magnesium phosphate, filtered and concentrated under reduced pressure using a flash column. The crude product was purified by chromatography on silica gel using ethyl acetate:pentane (10:90, volume-silica gel using foams as an eluent) with the help of column flash chromatography as an eluent, obtaining the title compound tan:ethyl acetate (50:50, volume) yielding (1.10 g) as a yellow oil. of the title compound (1.20 g) as colorless

IN-NMR (400 MHz, SOSIz): 6-1.04 (t, 6H), 2.49 oil. (Kk, 4H), 7.16 (m, 2H), 7.30 (d, 1H), 7.39 (t, 2H), 14.51 IN-NMR (400 MHz, SOSIz): 6-1.49 (c, 9H), 3.06 (c, 1H). (c, ЗН), 3.50 (td, 1Н), 3.60 (dd, 1Н), 3.80 (m, 4Н),

NRMS (thermal spray): t/2 (MMNA" | 263. 4.26 (w s, 1H), 4.39 (m, 2H).

Preparation 10 HPMS (thermal spraying): t/2 (MMNAa" | 313. tert-Butyl C-(hydroxymethyl)-4- Preparation 12 morpholine carboxylate Methyl-2-(3,5-dichlorophenoxy)-3-

M oxopentanoat o s y on "AZ su o y yo

Borane (38.1 mL of a 1.0 M solution in tetrahydrofuran, 38.1 mmol) was added dropwise to a stirred suspension of 3-Methyl-2-chloro-3-pentanoate (25.0 g morpholinecarboxylic acid (1.00g, 7.63mmol) in 152mmol), 3,5-dichlorophenol (24.6g, 152mmol), tetrahydrofuran (50ml) at room temperature, cesium carbonate (54.47, 16b7mmol) and acetone in the atmosphere nitrogen The reaction was heated under reflux (500 ml) with a mouth-refrigerator and the reaction became homogeneous within 2 hours. After cooling, the mixture was stirred and heated for 12 hours. The reaction was concentrated under reduced pressure, and the residue was cooled to room temperature and partitioned between dichloromethane (100 mL) and water, concentrated under reduced pressure to give a con- (50 mL). The organic layer was separated, and oil was dissolved. The residue was dissolved in a 1 M sodium hydroxide solution saturated with an aqueous chloride solution and stirred at tri (25 ml), dried over magnesium sulfate at room temperature for 5 days. After filtration and concentration under reduced pressure, di-tert-butyl dicarbonate (1.66 g, obtaining an orange oil. Crude product, 7.6 mmol) was added, and the reaction was stirred for 12 hours and purified using a flash column. The reaction was diluted with ether (100 ml). Using organic chromatography on silica gel, the overnight layer was separated, washed with saturated eluent pentane:toluene (90:10, by volume) with an aqueous solution of sodium chloride (10 ml), obtaining the title compound (40.0 g) as dried over magnesium sulfate, filtered and rose oil. concentrated under reduced pressure. Crude H-NMR (z00mhz, SOSIv): 6-1.16 (t, ZH), 2.60 The product was purified using a column (m, 28), 3.77 (s, ZH) 513 (s, 1H ), 6.84 flash chromatography on silica gel using (c2H), 7.10 (c, 1H). or as an eluent pentane:ethyl acetate (50:50, NRMES (thermospray): t/2 (MMN") 308. vol.) and then ethyl acetate to obtain the indicated Preparation 13 in the title compound (1.30g) as a colorless oil. o04 -(3,5-Dichlorophenoxy)-5-ethyl-2-(2-

1N-NMR (400mg, SOCI3): 6-1.48 (s, 9H), 2.05 hydroxyethyl)-2,4-dihydro-ZN-pyrazol-3-one (s, 1H), 3.19 (pc , 1H), 3.47 (td, 1H), 3.60 (dd, 1H), c 3.87 (m, 6H).

NRMS (thermal spraying): t/2 (MH) 218.

Preparation 11 o tert-Butyl. 3-(methylsulfonyl)oxy|methyl)-m 4-morpholinecarboxylate neo. in M he what. A solution of 2-hydroxyethylhydrazine (4.30g,

But oto 56.7mmol) in glacial acetic acid (2.0ml) 7 o was added to a stirred solution, ketoes- and o--y--sn, ter Preparation 12 (15.0g, 51.5mol) in ice-

C |. acetic acid (M0Oml) and the resulting solution was stirred at room temperature for

Triethylamine (1.15 mL, 8.29 mmol) was added over 48 hours. The mixture was concentrated dropwise to a stirred solution under the head pressure and the crude product was purified by Preparation 10 (1.20g, 5.52mmol) and the anhydride using column flash chromatography on methanesulfonic acid (1.44g, 5, 52 MMOLl) in silica gel using as an eluent

chloromethane:methanol (95:5, v/v) to give the title compound (10.1g) as a colorless oil using dichloromethane as eluent to give the title compound (5.10g) as an oil. purple oil.

IN-NMR (400 MHz, SOS"): 6-1.02 (t, ZN), 2.29 TN-NMR (Zbomgz, SOSIv): 6-0.01 (s, 6H), 0.86 (m, 2H), 3.63 (m, 2H), 3.80 (m, 2H), 6.92 (s, 2H), (s, 9H), 1.17 (t, ЗН), 2.45 (k , 2H), 4.01 (m, 2H), 4.14 7.21 (s, 1H). (m, 2H), 6.84 (s, 2H), 7.08 (s, 1H).

NRMS (thermal spraying): t/2 (MH) 317. NRMS (thermal spraying): t/2 MH") 563.

Microanalysis: Found: C, 48.86; N, 4.44; M, Preparation 16 9.01. SizNi"M2gOzSO" must be C, 49.23; H, 4.45; 3-(1-Acetyl-2-oxopropoxy)-5-

M, 8,839. chlorobenzonitrile

Preparation of 14 I 2-(2-tert-Butyl(dimethyl)silyl|oxy)ethyl)-4-(3,5-dichlorophenoxy)-5-ethyl-2,4-dihydro-3H-pyrazol-3-one

Mixture of 3-chloro-2,4-pentanedione (6.7 g, 50.0 mmol), phenol Preparation 36 (7.67 g,

M in 50.00 mmol), cesium carbonate (18.0 g, 55.4 mmol) and neon, acetone (40 ml) were heated under reflux for 2 hours. The reaction was cooled 54, O0mmol) was added in one portion to the solution, dimethylformamide (bml) and acetone (ZOml) and the stirred reaction, pyrazole Preparation 13 was heated at 707C for another 12 hours. After (14.3g, 45.Omol) and imidazole (3.98g, 58.5mMmMol) in cooling, the solid was removed by filtration

M,M-dimethylformamide (90ml) and obtained by breaking up and dissolved in 1M aqueous hydrogen chloride and stirred at room temperature pro-acid (150ml). The resulting solution was extracted with draft for 48 hours. The mixture was separated between ethyl acetate and dichloromethane (Z (100 ml) and the combined organics were separated, dried over magnesium sulfate, sodium chloride (30 ml), dried over sulfate, filtered and concentrated under reduced magnesium, filtered and concentrated under reduced pressure. The crude product was purified under assisted pressure, obtaining the title compound (5.50 g) as a brown solid by column flash chromatography on silica gel, using dichloromethane:methanol (95:5, by volume) as an eluent. obtaining the specified "H-NMR (300 mg, SOCI3): 6-2.04 (s, 6H), 7.13 in the title compound (9.56g) as a colorless oil. (s, 1H), 7.19 (s, 1H), 7.35 (c, 1H), 14.40 (CH).

IN-NMR (400 MHz, SOSIz): 6-0.15 (s, 6H), 0.94 Preparation 17 (s, 9H), 1.16 (t, ЗН), 2.45 (m, 2H), 3 .94 (m, 4H), 6.85 3-|1-Acetyl-3,5-dimethyl-1H-pyrazole-4- (c, 2H), 6.97 (c, 1H). yl)oxy|-5-chlorobenzonitrile

NRMS (thermal spraying): t/2 (МН) 431. si

Microanalysis: Found: C, 52.87; H, 6.52; M, 6.46. CiaNgvM2gOzSi25i is necessary C, 52.90; H, 6.54; not her

M, 6.4990.

Preparation 15 9 Chi 1-(2-tert-Butyl(dimethyl)silyl|oxy)ethyl)-4-(3,5-dichlorophenoxy-3-ethyl-1H-pyrazol-b-yl trite- fluoromethanesulfonate Sodium hydride ( 6095 dispersion in oil, 840 mg, 21.0 mmol) was added to a stirring solution of acetyl chloride (1.50 ml, 21.0 mmol) and pyrochlore of Example 76 (4 , 80g, 19.4mmol) in M,M-s / and lower dimethylformamide (20ml) at 0"C under an atmosphere of nitrogen. The reaction was stirred at 0"C for minutes and then quenched by adding water (200ml) The reaction mixture was extracted with ethyl acetate (3

Phenyltriflamid (3.70g, 10.5mmol) was added (120ml). The combined organic phases were washed in one portion to a stirred solution with water (50 mL) and a saturated aqueous solution of chloropyrazole Preparation 14 (4.10 g, 9.50 mmol) sodium chloride (50 mL), dried over magnesium sulfate ( 1.60 ml, 11.4 mmol) in dichloromethane, filtered and concentrated under reduced pressure (20 ml) at room temperature under atmospheric pressure to give a yellow solid. nitrogen The reaction was stirred for 2 hours and the crude product was purified with co- then poured into water (50 ml). The organic layer of flash chromatography on silica gel was separated, dried over magnesium sulfate, using dichloromethane as an eluent, filtered and concentrated under reduced pressure by chewing the title compound (5.00 g) as white pressure. The crude product was purified using a solid substance, Tpl. "6026. by column flash chromatography on silica gel

TN-NMR (400 MHz, SOSIz): b-2.06 (s, ЗН), 2.38 Preparation 20 (s, ЗН), 2.65 (s, ЗН), 6.99 (m, 1Н), 7 .08 (m, 1H), 7.29 4-(Methylamino)methyl|benzonitrile (m, 1H). that

NRMS (thermal spraying): t/2 |MNU) 290. МН

Preparation 18 3-(1-Acetyl-3-(bromomethyl)-5-methyl-1H-pyrazol-4-yl|oxy)-5-chloro-benzonitrile can be

4-Cyanobenzaldehyde (12.0 g, 92.0 mmol), mes-n, tylamine (9 ml of a 2.0 M solution in tetrahydrofuran, 137 mmol) and magnesium sulfate (45 g) were mixed in dichloromethane (30 ml) at room temperature under sleep, within 5 days. The mixture was filtered and the filtrate

M-Bromosuccinimide (4.60 g, 25.6 mmol) was added and concentrated under reduced pressure to obtain a stirring solution of pyrazole. A yellow oil. The oil was dissolved in the methanol of cooking 17 (5.00g, 17.Zmmol) in 1,1,1- (200ml) and carefully with intensive stirring trichloroethane (7Oml) and azobisisobutyronitrile were added to the bath sodium borohydride /(4.10g, (20mg) at room temperature in an atmosphere of 109 mmol). After completion of the addition of nitrogen reaction. The reaction was heated at 802C for 3 hours, stirred for 1 hour, and the mixture was concentrated and then cooled to room temperature under reduced pressure. The remainder of the resolution. A second portion of Mn was added in a 1M aqueous solution of sodium bromosuccinimide hydroxide (2.00g, 11.2mmol) and the reaction mixture (200ml) and the mixture was stirred at room temperature; the mixture was heated at 802C for another 4 hours. period for 1 hour. The resulting solution

The reaction was cooled to room temperature, extracted with dichloromethane (2 (200 ml) and combined and concentrated under reduced pressure, and the obtained organic phases were dried over magnesium sulfate. The yellow oil was purified using a column, filtered and concentrated under reduced pressure. flash chromatography on silica gel at the applied pressure, obtaining the title compound using pentane:dichloromethane (13.4 g) as a pale yellow oil as an eluent. (25:75, by volume) obtaining the title compound "H-NMR (30 ohm , SOCIz): 6-1.46 (s, 1H), 2.46 compound (2.30g) as a white solid, mp 122- (s, 3H), 3.82 (s, 2H), 7, 47 (d, 2H), 7.64 (d, 2H). 12326. NRMS (electrospray): t/2 (MNU | 147.

NMR (Zb0omtz, SOSIz): b-2.10 (s, ЗН), 2.74 Preparation 21 (s, ЗН), 4.73 (s, 2Н), 7.12 (s, 1Н), 7 .22 (c, 1H), 7.39 4-((2-Hydroxyethyl)amino|methylubenzonitrile (c, 1H). he

Preparation 19 p

Z-Chloro-5,5-dimethyl-2,4-hexanedione dn sn, sn, o niub bo om

Chlorotrimethylsilane (26.8 ml, 0.21 mol) to a mixture of 4-cyanobenzaldehyde (at, added dropwise to a pale pale solution. which 107 mmol), ethanopamine (6.56 g, 10 mmol) and toluene (1.13 g, tetrabutylammonium bromide) was stirred. , beer (100 ml) was heated with the return of the refrigerator

3.5 mol) in dry acetonitrile (100 mol) under reflux for 14 hours using a nozzle at room temperature in a nitrogen atmosphere. Oder- Dean-Stark for water removal. The reaction cooled solution was cooled with ice and chewed drop by drop to room temperature! 5,5-dimethylhexane was added to the concentrate under reduced pressure for 5 minutes, yielding yellow 2-4-dione (10.0g, 70.4mmol) and then dry dimethyl oil. The oil was dissolved in dichloromethane (200 ml), the sulfoxide (14.7 ml, 0.21 mol) was cooled to 0°C, and triethylamine (16.3 ml, 117 mmol) and chloromethyl were added dropwise to the solution, which was allowed to slowly heat up to room temperature. temperature during mixing of silanes. (14.9 ml, 11 7 mmol). White formed within 3 hours. The mixture was diluted with water to precipitate and then stirred for 1 hour (1000 ml) and stirred for 10 minutes. and then the mixture was filtered. The filtrate was concentrated by extracting with ether (1 (500 ml, 2 (250 ml). Combined under reduced pressure, obtaining an orange solid, the ether layers were dried over magnesium sulfate, a substance (25.0 g). The orange solid was filtered and concentrated under reduced pressure) in methanol (200 ml) and carefully under high pressure, obtaining a yellow oil. Crude borohydride was added to thorough stirring, and the product was purified by distillation under reduced pressure of tritium (4.50, 122 mmol). After completion, obtaining the title compound (10, 0g) as an addition, the reaction was stirred for ! pale yellow oil, Bp. 220-2252C./vOmm No. hours and the mixture was concentrated at reduced "H-NMR (400mg, SOCIz): b-1.25 (s, 9H), 2.39 pressure. The residue was dissolved in a 1M aqueous solution (c, ZH), 5.10 (c, 1H) sodium hydroxide (200 ml) and the mixture was stirred

NRMS (thermal spraying): t/g (MMNA" | 194. at room temperature for 1 hour.

The resulting solution was extracted with dichloromethane

(3 (200 ml) and the combined organic phases were dried over the reaction, stirred at room temperature with magnesium sulfate, filtered and concentrated for 2 hours. The mixture was diluted with water under reduced pressure. The crude product (200 ml), stirred for 10 min. and then purified with column flash chrome- was extracted with ether (Z (100 ml). The combined ether tographies on silica gel using as layers were dried over magnesium sulfate, filtered-eluent dichloromethane:methanol:ammonia (95:41, washed and concentrated under reduced pressure by chewing a yellow oil. The crude product was purified (12.07) as a pale yellow oil, which solidified on column flash standing to give a yellow solid, Tp. chromatography on silica gel using in " 6076. qualities of the eluent pentane:ethyl acetate (98:2, vol.

TN-NMR (30 ohms, SOCI3): b-1.84 (s, 2H), 2.84 them) obtaining the title compound (t, 2H), 3.68 (t, 2H), 3.89 (s , 2H), 7.45 (d, 2H), 7.65 (2.00g) as a colorless oil. (d, 2H). IN-NMR (400 MHz, SOSIv): 6-1.15 (d, 6H), 2.29

NRMS (thermal spraying): t/z2 (МН 177. (с, ЗН), 3.25 (sept, 1Н), 15.60 (с, 1Н).

Preparation of 22 NRMS (thermal spraying): t/2 (MMNA" | 180.

M-11-(2-Tsret- Preparation 24

Butyl(dimethyl)silyl|oxy)ethyl)-4-(3,5-5-(1-Acetyl-3-methyl-2-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl|methyl)u - oxobutoxy) isophthalonitrile

M-(3-pyridinylmethyl)amine

And so

M, g o - zom x

Kk - Sh o. mixture of dione Preparation 23 (1.12g, 6.94mmol), phenol Preparation 39 (1.00g, 3-(Methylamino)pyridine (327mg, 3.04mmol) 6.94mmol), cesium carbonate (2.25g . room temperature and concentrated at temp. The mixture was heated at 507C under reduced pressure to obtain a brown solid for 1 hour, cooled to room temperature. The solid was dissolved in 1M water and concentrated under reduced pressure with hydrochloric acid (5Oml) and the solution was extracted with orange oil. The crude product was washed with dichloromethane (Z (30 ml). The combined organic phases were purified using a column flash chroma, the phases were washed with saturated aqueous tography on silica gel using a sodium chloride solution (30 ml), dried over the eluent dichloromethane:methanol:ammonia (95 :41, volume with magnesium sulfate, filtered and concentrated) to give the title compound under reduced pressure. The crude product (5mg) as a colorless oil was purified by column flash chromium-"H-NMR (400mg, SOCI3): 6 -0.15 (s, 6H), 0.77 tography on silica gel using (s, 9H) as a quality, 2.02 (s, ЗН), 3.64 (s, 2H), 3.70 (s, 2 ), 3.95 pentanoethyl acetate eluent (90:10, volume) (t, 2H), 4.17 (t, 2H), 6.75 (c, 2H), 6.97 (c, 1H), 7 ,15 to give the title compound (580mg) (dd, 1H), 7.53 (d, 1H), 8.47 (m, 2H) as a yellow solid.

NRMS (thermal spraying): t/2 (MN) 521. IN-YAME (Zbomgts, SOSIz): 6-1.08 (d, 6Н), 2.02

Preparation 23 (s, ZN), 2.24 (sept, 1H), 7.47 (s, 2H), . 7.63 (s, 1H),

C-Chloro-5-methyl-2,4-hexanedione 14.71 (s, 1H). not NRMS (electrospray): t/2 (M-NU| 269. sn, Preparation 25 s 5-(1-(2-CChtert- o Butyl(dimethyl)silyl|oxy)ethyl)-3-isopropyl-5- what o methyl-1H-pyrazol-4-yl|Ioxyxophthalonitrile

Chlorotrimethylsilane (13.4 mL, 105 mmol) was added dropwise to a pale yellow moving solution of tetrabutylammonium iodide (566 mg, 1.53 mmol) in dry acetonitrile (10 mL) at room temperature under a nitrogen atmosphere. The obtained solution was cooled with ice and added dropwise with NaCl, 5-methylhexane-2,4-dione (4.50g, 35.1mmol) was added over 5 minutes, and then dry dimethylsulphate was added. .

2-bromomethoxy-t-butyldimethylsilane is stirred for one hour. Then tetrabutylammonium bromide (566bmg, 1.75mmol) and (gtomg, T.2mmol) and pyrazole of Example 95 were added in one portion

(250mg, 0.930mmol) in M,M-dimethylformamide (5ml) at 0"C under a nitrogen atmosphere. The reaction was warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched by adding water (500ml) and the aqueous phase was extracted with ethyl acetate (3 (30 mL). The combined organic phases were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by chlorine -butyldimethylsilane (1.93 g, using column flash chromatography at 12.vmmol) was added in one portion to the solution, silica gel using as eluent a pen-stirring, pyrazole of Example 1 (3.50 g, tan:ethyl acetate (80:20, vol. capacity) receiving the indicated- 11.6mmol) and imidazole (1.03g, 15.1mmol) in M,M-zane in the title compound (bOmg) as colorless dimethylformamide (23ml) at room temperature under a nitrogen atmosphere. Reaction stirred "H-NMR (400 MHz, SOCIz): 6-0.02 (s, 6H), 0.85 for 2 days and added water (200 ml). Aqueous ( s, 9H), 1.19 (d, 6H), 2.09 (s, 3H), 2.79 (sept, 1H), the phase was extracted with diethyl ether (3 (200 ml) 3.99 (m, 2H), 4.10 (m, 2H), 7.39 (s, 2H), 7.57 (s, 1H). and the combined organic phases were washed with water

NRMS (electrospray): t/2 (MH) 425. (2x5Oml) and a saturated aqueous solution of chloride

Preparation 26 of sodium (2x50ml), dried over magnesium sulfate, di(tert-Butyl)-2-I4-(3,5-dichlorophenoxy)-3- filtered and concentrated under reduced ethyl-1H-pyrazol-1-yl|ethylimidodicarbonate and pressure The crude product was purified using (tert-butyl)/2-(4-(3,5-dichlorophenoxy)-5-ethyl flash chromatography on silica gel using 1H-pyrazole-1-ylethylimidodicarbonate using pentane as an eluent: ethyl acetate a and c (80:20, v/v) to give the title compound (4.82 g) as a colorless oil.

Y o B above (sn) 201 (s, Z), 205 (s, ZM), 388 (K, 22), 402 o o o o s, 9H), 2.01 (s, ZH), 2.05 (c, ZN), 3.88 (k, 2H), 4, kla | ut (k, 2H), 6.76 (c, 2H), 6.88 (c, 1H). on and M NRMS (thermal spraying): t/2 (МН) 415.

Preparation 28 5-(Bromomethyl)-1-(2-Quaternary butyl(dimethyl)silyl|oxy)ethyl)-4-(3,5-

Di-tert-butyl dicarbonate (14.0 g, 64.2 mmol) and dichlorophenoxy)-3-methyl-1H-pyrazole 4,4-dimethylaminopyridine (63 mg, 5.14 mmol) were added in portions to a stirred solution of the seven amines of Example 283 (7.72 g, 25.7 mmol) in acetonitrile (128 ml) at room temperature under a nitrogen atmosphere. The reaction was stirred for 14 hours and concentrated under reduced pressure. le owl

The solution of the residue in dichloromethane (300 ml) was washed with water (100 ml), dried over magnesium sulfate, and the crude product was purified. 27 (1007, 2bmmol) tetrachlorothane:methanol (991, by volume) obtaining the indicated carbon numbers (Toml) ! azobisisobutyronitrile' and p. (20 mg) at room temperature in an atmosphere of the title compound without nitrogen in an 85:15 ratio. The reaction was heated with reverse cooling of repoivomers, Yak levova. full tank for 5 hours, then cooled to zn), 15 (minor t, ЗН) 152 (main, s, room temperature and filtered. Filtrate 18Н), 1.52 (minor, s, 18Н), 2.47 (main , k, was concentrated under reduced pressure and crude 2Н), 2.56 (minor, к, 2Н), 4.00 (main, t, the product was purified using a column 2Н), 400 (minor, t 2Н), 424 (main, flash chromatography on silica gel using 2Н), 424 (minor, 2Н), in 85 (main, with dichloromethane:methanol:ammonia 2Н as an eluent), in 85 (minor, с n), 700 ( main, with (97:2.5:0.5, by volume) obtaining the specified

TNU, 7.00 (minor, s, 1H), 7.21 (main, s, tricky compound (300mg) as a colorless oil. 18), 725 (minor and 1n). shi shk H-NMR (300 MHz, SOSIz): 6-0.04 (s, 6H), 0.82 "NRMS (thermal spray): t/MH" 500. (s, ZNO, 2.02 (s, ZNO) , 3.96 (m, 2H), 4.22 (m. 2H), 4.1

Microanalysis: Found: C, 54.94; H, 6.26; M, (c, 2H), 6.81 (c, 2H), T1 (c, 1H). . 8.27. SzzNai SIMzO5 must be C, 55.20; H, 6.24; M, demo (thermal spraying); td |МН"1 495. wat o cho is otvet. Butypidimethylsilyloxyethyl) 4 Butyl(dimethyl)silyl|oxy)ethyl)-3,5-dimethyl-1 H-(3,5-dichlorophenoxy)-3,5-dimethyl- 1 H-pyrazole pyrazol-4-yloxyiu 5-chlorobenzonitrile cm Hesk iodine y

I nd y y ; -x ran sn, not M in re sn, still he, -K

Chloro-t-butyldimethylsilane (2.78g, 18.5mmol) was added in one portion to the solution, the bromide of Preparation 30 (1.59g, 3.26mmol) was stirred, the pyrazole of Example 114 (4.89g, was added to a saturated of a solution of ammonia in isopropanol (16.8 mmol) and imidazole (1.48 g, 21.8 mmol) in M,M-panol (30 ml) at 0°C. The reaction was stirred with dimethylformamide (30 ml) at room temperature for two hours and left slowly heating in a nitrogen atmosphere. The reaction was stirred to room temperature. The mixture was concentrated for 3 days and water (200 ml) was added. The aqueous phase was under reduced pressure and the resulting yellow phase was extracted with diethyl ether (3 (200 ml), the oil was dissolved in dichloromethane (50 ml ).The solution and the combined organic phases were washed with water, washed with a 1M aqueous solution of sodium carbonate (2x5Oml) and a saturated aqueous solution of triium chloride (2 (20ml) and a saturated aqueous solution of sodium chloride (2x50ml), dried over magnesium sulfate, sodium chloride (homl), dried over magnesium sulfate, filtered and concentrated at po nizhno nia, filtered ! concentrated under pressure. The crude product was purified under reduced pressure to obtain the title compound (1.00 g) as a yellow oil by flash chromatography on silica gel. using dichloromethane as an eluent gives H-NMR (z00mg, SOSIv): 6--0.23 (c, BN), 0.62 or the compound indicated in the title (5.60g) as yellow (c, ЗН), 1 .22 (c, 2H), 1.82 (c, ZN), 2.56 (c, 2H), 3.78 oil. ot 4.02 (m, 2H), 6.85 (s, 1H), 6.96 (s, 1H), 7.06

IN-NMR (400 MHz, SOSIz): b--0.02 (s, 6Н), 0.82 s, y | and (s, 9H), 2.02 (s, ЗН), 2.12 (s, ЗН), 3.97 (k, 2Н), 4.06 HRMS (thermal spray): t/2 (МН) 421. (m, 2H), 7.02 (s, 1NU, 7.11 (s, 1H), 7.24 (s, 1H). Preparation 32

NRMS (thermal spray): t/z (MH" | 408. 1-Bromo-3-xpro-5-methoxybenzene

Microanalysis: Found: C, 58.95; H, 6.96; M, and oon, 10.22. SgoNgvMzO»siIvi needs C, 59.13; H, 6.95;

M, 10, 3595.

Preparation of 30 Ve 3-|5-(Bromomethyl)-1-(2-Tret-Sodium methoxide (2.20 ml of 4.5M solution in methyl(dimethyl)silyl|oxy)ethyl)-3-methyl-1H-tanol . cm (2d8ml) at room temperature in a nitrogen atmosphere. The reaction was heated with reflux

It was heated for 3 days and cooled to room temperature. The mixture was concentrated at

Mosen, under reduced pressure and the resulting yellow oil were dissolved in dichloromethane (3 mL). The resulting solution was washed with water (2 (20 ml) and dried over

M-Bromosuccinimide (2.44 g, 13.7 mmol) was added with magnesium sulfate, filtered and concentrated to a stirred solution of pyrazole under reduced pressure. The crude product of preparation 29 (5.56 g, 13./7 mmol) in tetrachloride was purified by column flash chromium-carbon (5 Oml) and azobisisobutyronitrile (20 mg) using tography on silica gel at room temperature under a nitrogen atmosphere. cyclohexane eluent, obtaining the specified

The reaction was refluxed to afford the compound (302 mg) as a colorless oil. for 1 hour, cooled to room H-NMR (400 MHz, SOS): 6-3.77 (s, ЗН), 6.82 temperature and concentrated at reduced (s, 1), 6.94 (s, 19), 7.09 (p. 19). about pressure The crude product was purified using Microanalysis: Found: c, Zv; N, 2.75. by column flash chromatography on silica gel STNeVGSIO, it is necessary C, 37.96; H, 2.7396. using as an eluent pen- Preparation 33 . tan:dichloromethane acetate (75:25, v/v) gave 3-Fluoro-5-methoxybenzonitrile chewing the title compound (3.00 g) as a colorless oil.

IN-NMR (Zbomgz, SOSIz): b--0.02 (s, 6H), 0.83 (s, 9H), 2.04 (s, ЗН), 3.97 (k, 2H), 4, 25 (m, 2H), 4.43 (s, 2H), 7.09 (s, 1H), 7.18 (s, 1H), 7.33 (s, 1H). Sodium methoxide (1.50 ml of a 4.5M solution in me-

NRMES (thermal spraying): t/2 (MH") 486. ethanol, 7.10 mmol) was added dropwise to the spray

Preparation of 31, a stirred form of 3,5-difluorobenzonitrile 3-(5-(Aminomethyl)-1-(2-Ctret- (1.00g, 7.Ommol) in N,M-dimethylformamide butyl(dimethyl)silyl|oxy )ethyl)-3-methyl-1H-(Zbml) at 02C in a nitrogen atmosphere. The reaction with pyrazol-4-yl|oxy)-5-chlorobenzonitrile was heated to room temperature and

stirred for 14 hours. The cleavage reaction on silica gel using ether (40 ml) as an eluent was washed with water (Z (100 ml) and cyclohexane-ethyl acetate (95:5, by volume) with a saturated aqueous solution of sodium chloride to obtain the title compound (380 mg ) (100 ml), dried over magnesium sulfate, filtered as a yellow oil, poured and concentrated under reduced pressure. Non-IN-NMR (Zbomgc, SOCIz): 6-3.82 (ZH, s), 7.04 purified product purified by flash (c, 1H), 7.12 (c, 1H), 7.23 (c, 1H) chromatography on silica gel using in Microanalysis: Found: C, 57.50; H, 3.63; M , the quality of the eluent cyclohexane-ethyl acetate (95:5, 8.16. C8vNeMoSi! required C, 57.33; H, 3.61; volume) obtaining the compound indicated in the title - M, 8.369o. ku (418mg) as yellow butter Preparation 36

1N-NMR (40 ohms, SOSI"): b-3.84 (s, ZN), 6.82 C-Chloro-5-hydroxybenzonitrile (dd, 1H), 6.95 (dd, 1H), 6.96 ( with, 1H). and he

NRMS (thermal spraying): It/2 (MMNAa" | 169.

Microanalysis: Found: C, 63.46; H, 3.95; M, 9,14. SvaNeMOg is necessary C, 63.58; H, 4.00; M, 9,279. see

Preparation 34 Boron trichloride (26.Oml of a 1.0M solution in the breath

C-Fluoro-5-hydroxybenzonitrile lormethane, 26.0 mmol) was added dropwise to

E. of a stirred solution of the nitrile of Preparation 35 (1.80g, 10.0mmol) and tetrabutylammonium iodide (4.36g, 11.0mmol) in dichloromethane (50ml) at -18°C. The reaction was allowed to warm to room temperature and stirred for 14 h

Boron trichloride (1.65 ml of a 1.0 M solution in dychidine. The reaction was cooled to 0C, carefully lormethane, 1.65 mmol) was added dropwise to quenched with ice and diluted with dichloromethane of a stirred solution, nitrile Preparation- (100 ml). The organic phase was washed with water (3 nya 33 (100 mg, 0.6 mmol) and tetrabutyl iodide (40 ml) and a saturated aqueous solution of ammonium chloride (268 mg, 0.728 mmol) in sodium dichloromethane (3 ml) (40 ml), dried over magnesium sulfate, at -78"C. The reaction was allowed to heat up to 0"C, filtered and concentrated under reduced pressure, stirred for 2 hours and then left under pressure. The crude product was purified by warming to room temperature and the mixture was used for flash chromatography on silica gel for 14 hours . The reaction was cooled with cyclohexanone as an eluent to 0"C, carefully quenched with ice, and then concentrated under reduced pressure to obtain ethyl acetate (80:20, by volume). The residue was dissolved in the title compound (900 mg) as white twerly in ether (40 ml) and the resulting solution was washed with water (3 (40 ml) and a saturated aqueous solution of "H-NMR (400 MHz, dedDMSO): b-7.12 (m, 2H), sodium chloride ( 40 ml), dried over magnesium sulfate 7.38 (c, 1H), 10.65 (c, 1H), filtered and concentrated at poney- Microanalysis: Found: C, 54.76; H, 2.81; M, the wife of pressure. The crude product was purified at 8.94. C7NaMOSI needs C, 54.75; H, 7" 2.63; M, by means of flash chromatography on silica gel 9.129. using cyclohexane as an eluent. Preparation 37 san:ethyl acetate (90:10, by volume) obtaining the indicated 1,3-dibromo-5-methoxybenzene in the title, the compound (50 mg) as a white solid, Vu.

TN-NMR (30 ohms, SOCI3): β-5.81 (s, 1H), 6.80 (9, (dd, 1H), 6.94 (dd, 1H), 6.95 (s, 1H).

Microanalysis: Found: C, 60.99; N, 3.01; M, Ve and 10,16. C"NAMOE is necessary C, 61.32; H, 2.94; M, Sodium methoxide (8.80 ml of a 4.5 M solution in methanol, 10.2295. 41.0 mmol) was added dropwise to the solution

Preparation 35 of a stirred mixture of 3,5-dibromofluorobenzene 3-Chloro-5-methoxybenzonitrile (5.00g, 19.0mmol) in M,M-dimethylformamide (95ml) at 0"С under a nitrogen atmosphere. The reaction was left , were allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution was washed with water (3

Tetrakis(triphenylphosphine)palladium (174 mg, (300 ml) and a saturated aqueous solution of chloride 0.150 mmol) was added in one portion to the sodium solution (3000 ml), dried over magnesium sulfate, well, which is stirred, bromide Preparation 32 was filtered and concentrated at reduced (500 mg , 2.26mmol) and zinc cyanide (14bmg, pressure to give the title compound 1.24mmol) in M,M-dimethylformamide (3ml) at (5.13g) as a white solid. at room temperature in a nitrogen atmosphere. The reaction of IN-NMR (Zbomgc, SOCIz): 6-3.79 (s, ЗН), 7.00 was heated at 100"C for 14 hours and cooled (s, 2Н), 7.26 (s, 1Н). The mixture was concentrated to room temperature. » it is necessary C, 31.62; H, 2.2795.

Preparation 38 ly and cooled to -20"C. Trifluoromethanesulfonic anhydride was added dropwise. 3,5-Dicyanomethoxybenzene was also added

Mo. at. acid (1.01ml, 6b.00mmol). The reaction was left to stand, warmed to room temperature, stirred for 14 hours and carefully poured into water (100 ml). The aqueous phase was extracted with ether (15 Oml) and the organic phase was washed with water (3

Tris(dibenzylidene ketone)dipalladium (6.53g, ml) with 1M hydrochloric acid (with a tovmt of 1.15mmol) was added in one portion to the solution, a 1.0M aqueous solution of stirred sodium carbonate, bromide Preparation 37 (2x75ml), water (75ml) and saturated aqueous solution (38.07, T43mmol) and zinc cyanide (20.0g, in the form of sodium chloride (75ml), dried over sul- 172mmol) in M.M-dimethylformamide (300ml) under magnesium ph, filtered and concentrated at room temperature in a nitrogen atmosphere. The reaction under reduced pressure obtained as indicated in the title was heated at 100 °C for 14 hours and the compound (2.86 g) was obtained as a pale brown oil. juvapa to room temperature. "H-NMR (400mg, SOCIz): b-2.35 (c, 3H), 3.80 water (1500ml) was added and the mixture was extracted with ethyl acetate (c, 3H), 6.60 (c, 1H), 6, 68 (s, 1H), 6.73 (s, 1H). (3 (500ml). The combined organic solutions of the filtrate were prepared and the filtrate was washed with water (500ml), dried, 3-Methoxy-5-methylbenzonitrile over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene (1000 mL) to give the title compound (18.0 g) as a yellow-brown solid.

TN-NMR (30 ohms, SOCI3): 6-3.83 (ZH, s), 7.31 vo (2H, s), 7.48 (1H, s). Triflate Preparation 40 (1.94g, 7.10mmol),

Preparation 39 Dibrombis(triphenylphosphine)nickel (369mg, 3,5-Dicyanohydroxybenzene 0.490mmol), 1,1-bisidiphenylphosphino)ferrocene (33mg, 0.590mmol) and potassium cyanide (1.38g, 21.3mmol) were added sequentially to the suspension, mixed, zinc KieKetF (supplied

Aidagisp spetis! sotrapu as a suspension; 5 g of zinc in

Ge 100 ml of tetrahydrofuran) (74 mg, 1.14 mmol) in

Nitrile Preparation 38 (9.60g, 60.7mmol) of acetonitrile (4ml) at room temperature. aluminum trichloride (32.4 g, 243 mmol) was added in portions to the suspension, which was stirred. The reaction was heated at 7573 for 8 hours and then cooled to room temperature. dichloromethane (250 ml) at 0"C in a nitrogen atmosphere. The mixture was partitioned between ether (200 ml) and water

The suspension was heated to 45"C and stirred with (15 Oml) and the organic phase was separated by washing for 6 days. The reaction was cooled to room temperature with water (2 (100 ml) and saturated water temperature and carefully poured onto ice (450 ml). sodium chloride (75 ml), dried over sul-

Concentrated magnesium chloride was added dropwise, filtered and concentrated under acid (450 ml) and the resulting suspension was stirred under reduced pressure for 10 minutes at room temperature to obtain a pale brown oil. The crude product was purified using The resulting solid was collected by flash chromatography on silica gel using filtration, washed with water and dried using pentane:ethyl acetate as an eluent with phosphorus pentoxide to obtain (85:15, by volume) the title compound (7.83 g) as a yellow-brown compound (815mg) as a white solid. a solid substance containing approximately 1195 ir- NMR (400 MHz, SOSIz): 6-2.34 (s, ZN), 3.80 of the starting material according to "H-NMR and microanalysis. (s, ZN), 6, 93 (s, 1H), 6.94 (s, 1H), 7.04 (s, 1H).

IN-NMR (400 MHz, SOSIz): 6-7.36 (m, 2H), 7.56 Preparation 42 (m, 1Hn). 3-Hydroxy-5-methylbenzonitrile

Preparation 40 nos on

3-Methoxy-5-methylphenyl trifluoromethanesulfonate

Her sc o--ato Boron trichloride (17.6 ml of a 1.0 M solution in the breath

Neo. o pormethane, 17.6 mmol) was added dropwise to a stirred solution of the nitrile of Preparation 41 (86 mg, 5.88 mmol) and tetrabutylammonium iodide (2.61 g, 7.05 mmol) in dichloromethane (50 mL) but at -78"C. The reaction was left to warm to room

Trifluoromethanesulfonic acid anhydride at room temperature and stirred for 20 (2.02 ml, 12.0 mmol) was added dropwise up to minutes. The reaction was cooled to 0"C, the stirred solution was carefully quenched with ice and diluted with methylphenol dichloromethane (1.50g, 10.9mmol) in pyridine (100ml). The organic phase was separated, dried (20ml) at -202С in a nitrogen atmosphere. The reaction was poured over magnesium sulfate, filtered and concentrated at 0С, stirred for 90 minutes under reduced pressure. The crude product was purified by means of flash chromatography on silica gel using pentane:ethyl acetate (90:10, volume pentane:ethyl acetate (50:50, volume) as eluent) or them) to give the title compound by chewing the title compound (677mg) as (9.33g) as a yellow oil. white solid. IN-NMR (400 MHz, SOS"): keto and eno-

IN-NMR (400 MHz, SOSIz): 622.32 (s, ЗН), 5.05 lin form with a predominant enol content (s, 1Н), 6.88 (s, 1Н), 6.90 (s, 1Н) , 7.04 (p. 1H). component; signals of enol 0-1.00 (m, 7H), 1.60

Preparation 43-46 (m, 1H), 2.25 (m, 2H), 5.59 (s, 1H), 15.62 (s, 1H);

Compounds of the following grouped Preparations signals ketoform 5-1.00 (m, 7H), 2.01 (m, 1H), general formula: 2.52 (m, 2H), 3.68 (s, 2H). i NRMS (electrospray): t/2 (M-NU | 139.

Microanalysis: Found: C, 68.35; N, 8.72.

SvNigO" must be C, 68.55; H, 8.6395. see Preparation 48

The compound of the following grouped Preparations o of the general formula: was obtained by a method similar to the method o o

Preparation C, using an acceptable method, obtained starting phenol and chloride using a method similar to that of Preparation 2. Preparation 47 using an acceptable keto acid and carboxylic acid as starting materials

Pi V PILNO AND MY (Phenol Me) 4Z (Phenop E t/2 (MH) 281. "NAIMR (300 MHz, SOS"): 6 - 1.05

Same ET Retet 7.03 (6, 19), 7.04 (m, 1H). Re t/2 MAN" 141. | "H-NMR (400 MGu, (electrospray) 44 (phenol t/x (M-H' 258. "H-NMR (400 MHz, SOSv); 6 - 109 SOSIv): keto and enol forms are present

Preparation 42) (electrospray) | (t, 6H), 2.32 (k, 4H), 2.37 (s, ЗН), with a predominant enol content of 5 x 1.12 (m, 6.96 (s, 1H), 6.97 (s, 1H), 7.15 (c, | 18H, keto and enol), 2.32 (m, 4H, keto and 1H), 14.50 (c, 1H). and ХХ and enol), 2.49 ( m, 2H, keto and enol), 3.61 (s, 4BiPhenOL OM tuye IMON'CH269. | H-NMR (300 MHz, SOS 5-09 2H, keto), 549 (s, 1H, enol), 15, 52 (p.

Preparation 39) (electrodispersion) | (m, bH), 2.30 (m, 4H), 7.42 (s, 2H), 1H, enol) Microanalysis: Found: C, 46 (Phenol a pug|MH'280. | H-NMR (200 Mchs, SOSK 5 - 1.08 67.57; H, 9.926.

Preparation 36) (thermal spraying) | (m, VN), 2.31 (k, 4H), 7.12 (s, 1H),

Preparation 49-51

Compounds of the following grouped Preparations

Preparation of 47 of the general formula: 1-Cyclopropyl-1,3-pentanedione i

UA o o was obtained by a method similar to this method

A suspension of magnesium (1.83g, 75.0mmol) was stirred in methanol (85ml) under reflux as the starting material. in a dark refrigerator for 90 minutes. The suspension was cooled to room temperature and a solution of 3-ketopentanoic acid in PO (17.4 g, 150.0 mmol) in methanol (15 ml) was added. White su- and cyclore te monli?a | NMR (400 MHz, SOS TLO, the suspension was dissolved to obtain a pale yellow sample of phen 47) 2H), 15.90 (s, 1H). rank. The reaction was stirred at room temperature for 1 hour and then concentrated (thermal spraying was used). , under reduced pressure, obtaining a pale yellow commercially 2H), 15.40 (c, 1H), a solid, which was dissolved in M,M-"diketoyu dimethylformamide (50 ml). In a separate flask, carvia and TS) dark, | (Preparation (electrospray) | (m, 9H), 2.64 (k, ЗН), 320 (m, sions) was added to the solution that stirred, cyclopropyl pancarboxylic acid (6.46 g, 75.0 mmol) in M,M-dimethylformamide (150 mL) at room temperature under nitrogen atmosphere. The reaction was stirred Preparations 52-54 for 90 minutes and then Compounds were added dropwise of the following grouped Preparations, the magnesium salt was obtained earlier. The reaction of the alternating formula: was stirred for 3 days and then poured into 1.0 M cm hydrochloric acid (150 ml). The aqueous phase was extracted with ether (3x2 00ml) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using flash 59 was obtained by a method similar to that of sodium (249mg, 10.8mmol) was added to benzob. in a nitrogen atmosphere and the permeation reaction 39. was carried out for 30 minutes. Then methyl acrylate (25.9 ml, 259 mmol) was added dropwise and the reaction was stirred at room temperature (Dicotone Mo) for 18 h. After quenching with saturated aqueous 52 ChcycloRg| ЭЙ t/7|М-Н" 282. H-NMR (400 MHz, СОСиЬу 0.83 . . . (Preparation (electrospray) | (m. 2Н), 1.12 (t, ZNU, 1.21 (m, 2Н) , ammonium chloride solution (200 ml), the mixture was extracted 49) 1.78 (m, 1H), 2.29 (k, 2H), 7.49 (e), washed with ethyl acetate (2 (30Oml) and combined organic! 2H), 7.61 (c, 1H), 14.87 (c, 19). The overnight extracts were washed with a saturated aqueous solution of sodium chloride (100 ml), dried over tet over magnesium sulfate and concentrated at - hl IB; tim ova; NYEME (106 MAZ; SBS TO5 pressure. The remaining oil was dissolved in (Preparation (electrospraying) | (m, 9H), 2.23 (k, 2), 2.58 (m , 18), ethanol (300 ml) and 1M aqueous sodium hydroxide solution (300 ml) was added dropwise. After three hours, the ethanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane

Preparation 55 (200 ml). The aqueous phase was then acidified with 2M aqueous 4-(Aminomethyl)benzamide hydrochloric acid (150 ml), extracted with dichloromethane (2 (250 ml), and the combined organic extracts were dried over magnesium sulfate and

Me, concentrated under reduced pressure. The remaining oil was dissolved in 1095 aqueous solution

Powder of potassium hydroxide (340 mg, bmol) of potassium carbonate (300 ml), washed with diethyl was added in one portion to the solution, which was ether (300 ml) and the aqueous phase was acidified to stir, 4-(aminomethyl)benzonitrile (200 mg, RNI using concentrated hydrogen chloride 1 .5 mmol) in 2-methyl-2-propanol (20 ml) at boiling acid. The mixture was then extracted with dichloromethane under a nitrogen atmosphere. The reaction was heated with nom (2 (300 ml) and the combined organic extracts under reflux for 30 minutes and was washed over magnesium sulfate and concentrated when cooled to room temperature. gave the compound (44 4g) as a colorless oil. The product was purified by flash chroma- "H-NMR (300 MHz, SOCI3): 6-2.67 (t, 2H), 3.89 tography on silica gel using (t . 42)-1-(Benzyloxy)-5-hydroxy-4-hepten-3-one (150 mg) as a white solid. AD

IN-YAMER (Zbomgts, SOSIz): 6-3.85 (s, 2H), 7.43 no. ch o (d, 2H), 7.82 (d, 2H). what

NRMS (thermal spraying): t/2 (MH) 151.

Preparation 56 Magnesium suspension (1.74g, 71.bmol) in meta-

Z-Oxopentanoic acid (85 ml) was heated under reflux with stirring in a nitrogen atmosphere for another 1.5 hours, cooled to room temperature, and B-keto acid from Preparation 56 was added

Sodium hydroxide (54 g, 1.35 mol) was added (16.6 g, 14 mmol). The reaction was stirred in portions to a solution of methyl ester with 3-oxo for 1.5 hours, and the solvent was removed under reduced pentanoic acid (80 g, 0.62 mol) under tetrahydrogen pressure, obtaining the magnesium salt of the acid as furan (30 Oml) and water ( ZOOml) at 0"C. The reaction gave a white solid. Meanwhile, the acid was allowed to warm to room temperature and Preparation 57 (12.9g, 71.6mmol) was dissolved in stirred for 18 hours. The reaction mixture was mixed with dimethylformamide (1500ml) and washed with diethyl ether (500 ml) in portions under atmospheric pressure, and concentrated carbonyldiimidazole (12.8 g, 78.6 mmol) was added under nitrogen at room temperature, and the phase was acidified to pH at 0"C. This mixture was washed with hydrochloric acid (140 ml). Aqueous was stirred for 1 hour and mag- phase was extracted with dichloromethane (2 (30 Oml) and the nium salt obtained above as a solution in dimethyl- the combined organic extracts were dried over sul- tylformamide (5 Oml). under reduced pressure and the reaction was allowed to stir under pressure to afford the title compound at room temperature for 18 h. The mixture (44g) as a white solid was concentrated under reduced pressure and an orange

IN-NMR (400mhz, SOSIz"): 6-1.12 (t, 3H), 2.59 The oil was dissolved in dichloromethane (300ml), washed (k, 2H), 3.49 (s, 2H). were washed with 0.M aqueous hydrochloric acid

Preparation 57 (250ml) containing methanol (1Oml) and an aqueous phase

C-(Benzyloxy)propanoic acid was separated and extracted with dichloromethane

AFZXH (2 (300 ml). The combined organic extracts were washed with a saturated aqueous solution of chloride

The solution (30 mL) containing methanol (20 mL) was dried over magnesium sulfate and concentrated at

low pressure The orange oil was purified using cyclohexane:pentane (10:90, v/v) as an eluent by flash chromatography on silica gel to give the title compound using cyclohexane (5.80 g) as an eluent as an orange oil. sodium:ethyl acetate (80:20, v/v) to give the title compound (12.0 g) as an orange ma - (k, 2H), 2.59 (t, 2H), 3.75 (t, 2H), 4.45 (s, 2H), 6.92 slo. (m, 1H), 7.02 (m, 2H), 7.29 (m, 5H), 14.50 (s, 1H).

IN-NMR (400 MHz, SOSIz"): b-1.17 (t, ZN), 2.33 NRMS (electrospray): t/2 (MMa") 392. (Kk, 2Н), 2.58 (t, 2H), 3.76 (t, 2H), 4.53 (s, 2H), 5.57 Preparation 61 (s, 1H), 7.13 (m, 5H). 5-41 E)-1-IZ3 -(Benzyloxy)propanoyl|-2-

HRMS (electrospray): t/2 |MMa") 257. hydroxy-1-butenyl)oxy)isophthalonitrile

Microanalysis: Found C, 71.77; H, 7.74.

Si"NigOz is necessary C, 71.76; H, 7.69905. sha and: o

Preparation of 59 she (4E)-1-(Benzyloxy)-4-chloro-5-hydroxy-4-Mo hepten-3-one OO oo sn

In Go, . . . . Sodium hydride (6095 dispersion in oil, 412 mg, 12.3 mmol) was added to the solution, which was stirred

Trimethylsilyl chloride (10 mL, 51.3 mmol) was added, phenol from Preparation 39 (1.48 g, was added to a solution of enol from Preparation 58, 10.3 mmol) in tetrahydrofuran (70 mL) in atmos- (4.0 g, 17. mmol) in acetonitrile ( 25ml) in a nitrogen atmosphere at room temperature. After nitrogen vaporization at 02С. Then, dimethyl was added, stirring for 30 minutes, enoloxide (33.bml, 51.3mmol) was added, followed by tert- from Preparation 59 (2.76g, 10.3mmol) and the reaction of butylammonium bromide (275mg, 0.85mmol) and the reaction stirred for 18 hours. It was carefully mixed at 02C for 2 hours. The mixture was given water (100ml) and 2M aqueous hydrogen chloride solution, diluted with water (100ml), extracted with diethyl sulfate (1Oml) and the mixture was extracted with ethyl acetate and ether (100ml) and the organic phase was washed (2 (150Oml). The organic part was combined, saturated aqueous solution of sodium chloride, washed with a saturated aqueous solution of chloride (5 Oml), dried over magnesium sulfate and concentrated sodium (100 ml), dried over magnesium sulfate and crushed under reduced pressure. The rose oil was concentrated under reduced pressure. The residue was purified using a flash Chromatography was purified using flash chromatography on silica gel using as an eluent cytography on silica gel using loghexane:ethyl acetate (80:20, by volume) as an eluent (pentaneethyl acetate 90:10, by volume) to obtain the compound indicated in the title (3.76g) as pink to give the title compound (1.00g) as an oil. yellow oil. "IN-NMR (400mhz, SOSIz"): b-1.17 (t, ZN), 2.62 NRMEUS ( thermal spraying): t/2 (МН) 375. (k, 2Н), 2.96 (t, 2Н), 3.79 (t, 2H), 4.57 (s, 2H), 7.12 Preparation 62 (m, 5H), 15.49 (s, 1H). 3-(1-(2-Quarter-

HPMS (electrospray): t/g2 (MPa 291. Butyl(dimethyl)silyl|oxy)ethyl)-3,5-diethyl-1 H-

Preparation of 60 pyrazol-4-yl|oxy)-5-fluorobenzonitrile

3-4(1E)-1-3-(benzyloxy)propanoyl|-2-E cm hydroxy-1-butenyloxy)-5-fluorobenzonitrile (o, es rya e. -- M"

B dach i, St

IR sleep, but before"

Sodium hydride (6095 dispersion in oil, (1.92g, but sn, 48.0mmol)) was added to the stirred solution- Imidazole (477mg, 7.02mmol) and triturate chloride, phenol from Preparation 34 (8.80g , butyl-dimethylsilyl (977mg, 6.48mmol) followed by 48.0mmol) in tetrahydrofuran (450ml) under atmospheric conditions was added to the alcohol solution from Example under nitrogen at room temperature. After stirring 117 (1.65 g, 5.40 mmol) in dimethylformamide for 1 hour, enol (1 mL) was added at room temperature in an atmosphere

Preparation of 59 (12.9g, 48.0mmol) and reaction with nitrogen. The reaction was stirred for 18 hours and stirred for 64 hours. The mixture was diluted with water (100 ml) and extracted with water (200 ml) and 2M aqueous hydrochloric acid-diethyl ether (4 (50 ml). The combined organic compounds (40 ml) were extracted with ethyl acetate (2 extracts were dried over magnesium sulfate, concentrated 15 Oml) and the combined organic extracts were washed under reduced pressure and the residue was purified with a saturated aqueous solution of sodium chloride using flash chromatography on silica (100 ml), dried over magnesium sulfate and condensed gel using as an eluent, under reduced pressure An orange oil, dichloromethane:methanol (99:11, v/v) was obtained.

TN-NMR (400 MHz, SOCI3): 6-0.03 (s, 6H), 0.84 O.75 mmol) dissolved in dimethylsulfoxide (s, 9H), 1.10 (m, 6H), 2.42 (k , 2H), 2.56 (k, 2H), 4.00 (ml) and the reaction was heated at 1007C for 18 (t, 2H), 4.09 (t, 2H), 6.86 (d, 1H), 6.99 (m, 2H). hours After cooling to room temperature

NRMS (thermal spray): t/2 (MH) 419. the reaction was diluted with water (7 ml) and extracted

Microanalysis: Found C, 62.73; H, 7.83; M, washed with diethyl ether (12 ml) the organic phase 9.75. | Cg22NzaEMz3O251-0.06СНоСиИ» must be C, washed with a saturated aqueous solution of chloride 62.68; N, 7.66; M, 9.94905. sodium (3.5 ml), dried over magnesium sulfate,

Preparation 63 was concentrated under reduced pressure and the residue 3-((3,5-Diethyl-1-I(I2-(tetrahydro-2H-pyran-2-) was purified by flash chromatography on yloxy)ethyl|-1H-pyrazole-4- ilux)-5-silica gels using graphofluorobenzonitrile dichloromethane:methanol as an eluent (99:1 v/v was replaced by 95:5 v/v) to obtain the unexpected title compound (108 mg) as io/sn, oil. d IN-NMR (400 MHz, SOSIz"): 6-1.12 (m, 6H), 1.56 -8 (m, 6H), 2.44 (k, 2H), 2.59 (k, 2H), 3.48 (m, 1H), 3.69 re (m, 1H), 3.79 (m, 1H), 4.08 (m, 1H), 4.20 (t, 2H), 4 .54 ) with (s, 1H), 6.72 (d, 1H), 7.15 (m, 2H). with NRMS (thermal spraying): t/2 МН") 406.

Microanalysis: Found C, 60.57; H, 6.97; M, p-toluenesulfonic acid (32mg, 9.97. C21iNgvEMz3O4:0.08SNegsSi2:0.32H20, 0.17 mmol) was added to the alcohol solution with Pryk-C, 60.57; H, 6.94; M, 10.0596. 117 (5.04g, 16.mmol) and dihydropyran Preparation 65 , , (7.57ml, 8.mmol) in dichloromethane (b5ml) at 000 8-(48,5-Diethyl-1-|2-(tetrahydro-2H- pyran-2- at room temperature under nitrogen.The reaction of yloxy)ethyl/|1H-pyrazol-4-yloxy)-5-(1H-pyrazole-) was stirred for 2 hours, but the starting material of 1-yl)benzonitrile still remained because an aliquot of p-toluenesulfonic acid (284 mg, U cm 1.49 mmol) was added and the reaction was stirred for 1 hour. The mixture was diluted with diethyl ether (9 mL) and washed with a mixed aqueous solution (water (5 mL), a saturated aqueous solution of sodium chloride (25 mL), and a saturated aqueous solution of sodium bicarbonate (25 mL)). The aqueous phase was extracted, washed with diethyl ether (2 (boml), and the combined organic extracts were dried over magnesium sulfate, and concentrated under reduced pressure, and the residue Cesium carbonate (269 mg, 0.82 mmol) was added and purified by flash chromatography on to a solution of pyrazole (51 mg, 0.75 mmol) in dry silica gel using dimethyl sulfoxide (ml) as an eluent under a nitrogen atmosphere with the title compound (6.31 g) as an oil for 15 minutes. Then aryl fluoride was added

IN-NMR (400mhz, SOSIz): 6-1.08 (m, 6H), 1.52 Z Preparation 63 (291mg, 0.75mMmol) soluble (m, 6H), 2.39 (k, 2H), 2.54 (k, 2H), 3.45 (m, 1H), 3.64 in dry dimethyl sulfoxide (1 ml) and the reaction (m, 1H), 3.75 (m, 1H), 4.06 (m , 1H), 4.17 (t, 2H), 4.51 were heated at 1007s for 18 hours. After (c, 1n), 6.82 (d, 1), 7.22 (m, 2H). cooling to room temperature reaction

NRMS (thermal spray): t/2 (MH) 388. diluted with water (7 ml) and extracted with diethyl

Preparation with 64% ether (1O0ml). The organic phase was washed with 3-((3,5-Diethyl-1-(2-(tetrahydro-2H-pyran-2- saturated aqueous solution of sodium chloride yloxy)ethyl|-1H-pyrazol-4-yloxy)-5- ( Zml), dried over magnesium sulfate, concentrated with fluorobenzamide under reduced pressure, and the residue was purified by flash chromatography on silica gel using a dichloromethane:methanol gradient of various factors as an eluent (100:0 was replaced by 90:10 , volume) obtaining the compound (55 MmgH) indicated in the above.

In IN-NMR (400 MHz, SOSIz"): 6-1.13 (m, 6H), 1.58 em dc (m, 6H), 2.44 (k, 2H), 2.60 (k, 2H) , 3.49 (m, 1H), 3.69: o (m, 1H), 3.80 (m, 1H), 4.10 (m, 1H), 4.21 (t, 2H), 4, 55 (s, 1H), 6.50 (s, 1H), 6.98 (s, 1H), 7.57 (s, 1H), 7.63 (s, 1H), 7.72 (s, 1H ), 7.89 (c, 1H).

Cesium carbonate (269 mg, 0.82 mmol) was added HRMSO (thermospray): t/2 (MH"| 436, to a solution of 3-methyl-3-pyrazolip-b-one (74 mgG, Mpa") 458. 0.75 mmol) in dimethylsulfoxide (1 ml) in atmo- VRMS: IMNT Found 436.2352. SgaNzoM5Oz under nitrogen at room temperature and the reaction must be 436.2343 stirred for 15 minutes. Then added IMMa-"| Found 458.2168. Cg"NhoM5OzMa was not aryl fluoride from Preparation 63 (291 mg, 458.2162 is obtained.

Preparations 66-68 phase was removed using 5 μM fritova-

Obtaining the following grouped prepared cartridge UMpaytap RTEE, then concentrations of the general formula were carried out under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of

For example, ethyl acetate: pentane (20:80, then 25:75, 6. then 34:66, then 50:50, then 75:25, then 100:0, -8- volume) factors were replaced by ethyl acetate: methanol en M o (1071, volume) then dichloromethane:methanol:0.88 o ammonia (90:10:11, then 80:20:11, volume) obtain (u; or the compound indicated in the title (189 mg) as a pale yellow oil was carried out according to a method similar to the "H-NMR" method (400 MHz, SOCI3): b-1.03-1.17 (m, vH),

Preparation of 65 using an acceptable 1.49 (s, 9H), 2.39-2.52 (M, 4H), 4.32 (m, 2H), 4.50 heterocycle as starting material. (m, 2H), 4.94 (m, 1H), 7.38 (s, 2H), 7.56 (s, 1H).

NRMS (thermal spraying): p/2 (MN) 422,

Preparation of Mo Analytical data IMMa" | 444. tires Microanalysis: Found C, 65.08; H, 6.49; M, preparation of Me) 16.48. С2зН27М50з3:0.18Н20 necessary С, 65.04;Н, 66 ( 63) CE "H NMR (400 MHz, SOSIvu: 5 2 1.13 (m, EN), 1.63 6.49; M, 16.4995. zi y (m. 6H), 2.44 (k, 2H), 2.60 (k, 2H). 3.46 (m, 1H), 3.67 (m, 1H), 3.79 (m, 1H), 408 (m, 1H), 420 (t, 2H), 4.53 Preparation 70 (s, 1H), 6.26 (t, 1H), 6.64 (d, 1NU, 7.17 (s, 1H), 7.21 5-(13.5- Diethyl-1-3-(tetrahydro-2H-pyran-2- (b, NU 784 (b, 1), TA (t, NU NRMO yloxy)propyl|-1H-pyrazole-4- (thermal spraying): fluff ( МН) 463, (МИМа") 485. iluxiisophthalonitrile

VRMS: IMN'Y Found 4632353. SzhNaMaOh This; required 463.2340 (MMa" Found 4852166. 00 shedeetite 67 (63) Co "nH NMR (400 MHz, SOSIv): 6 with 1.10 (m, BN), 1.56 d ny (m, 6H), 2 .41 (k, 2H), 2.56 (k, 2H), 3.44 (m, 1H), 3.64 -- m, 1H). 3.75 (m, 1H), 4.05 (m, 1H), 4.17 (t, 2H), 4.50 is - 7.00 and t 7.08 m well 720 m like that: -7 (s, 1H), 7.84 (s, 1H), 7.86 (s, 1H). NRMS sn, o (thermal spraying): fluff (MH") 464, |MMa") 496.

VRMS: MH") Found 4642297. SeNumeOz Sodium hydride (6095 dispersion in oil, ZZmg, required 4642293 IMMa" Found 486.2113, 0.82mmol) was added to the pyrazole solution Prykniy nin sos5-t bottom tIV ladu 122 (200mg, 0.75 mmol) in dimethylformamide

Sk (m, OH), 2.29 (s, ЗН), 2.98 (k, 2Н), 2.58 (k, 2Н), 343 (Змл) at 0"С in a nitrogen atmosphere and the reaction of

Fin), abs (m, zn), 366 (s, zn), 379 (m, 1H), stirred for 10 minutes. 2-(3- 404 (m, 1NU, 415 (t, 24), 4.50 (s, 1H), 5.59 (s, 1H), bromo-propoxy)tetrahydropyran (184mg, thermally annealing IMN 80 Gmychat) was added 0.2 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with water (0.2 mL) and concentrated under reduced pressure. The residue was partitioned between dichloromethane and raffia during purification of this compound was used (5ml) and water (5ml) and the organic phase was removed with dichloromethane:methanol (99:11 was replaced by 95:5, using a 5MKM fritted volume cartridge).

Preparation 69 | wife pressure. The residue was purified by tert-Butyl 3-I4-(3,5-dicyanophenoxy)-3,5- flash chromatography on silica gel using diethyl-1H-pyrazol-1-yl|-1-azetidinecarboxylate or a gradient of ethyl solvents as eluent -

Mo. cetate:pentane (20:80, then 25:75, then 34:66, then 50:50, then 75:25, then 100:0, by volume) sc, replaced by ethyl acetate:methanol (10:1 , volume

(Ho) about them) then dichloromethane:methanol:0.88 ammonia-I sn, (90:10:1, then 80:20:1, by volume) obtaining including 0-(-sn, the title compound (238 mg) as a pale yellow solid, oil.

Sodium hydride (6095 dispersion in oil, ZZmg, 1.63 (m, 2H), 1.66-1.88 (m, 2H), 2.15 (dd, 2H), 2.38 0О.82mmol) was added to of pyrazole solution Prik- (k, 2H), 2.53 (k, 2H), 3.37-3.55 (m, 2H), 3.75-3.90 (m, Ladu 122 (200mg, 0.75mmol ) in dimethylformamide 2H), 4.11 (m, 2H), 4.56 (m, 1H), 7.37 (C, 2H), 7.55 (s, (3ml) at 0"С in a nitrogen atmosphere and the reaction was stirred for 10 minutes. 3-Iodo-NRMS (electro): t/x (MH 409, MMA" 421. tert-butyl azetidine-1-carboxylic acid was added. Microanalysis: Found C, 66.59; H, 6.91; M, ester (234 mg, 0.82 mmol) and the reaction was stirred for 13.40. SisHgvM«Oz'0.36H2O required C, 66.57; H, at room temperature for 18 hours. 6.98; M, 13.5095.

The reaction was quenched with water (0.2 ml) and concentrated Preparation 71 under reduced pressure. The residue was divided between 3-(1-Acetyl-3,5-dimethyl-1H-pyrazole-4-dichloromethane (5 ml) and water (5 ml) and organic yl)oxy|-5-fluorobenzonitrile iodine 1 pc (Starting material for the preparation of Me) with 72139) CM | Tpl. 204-206 "S. "H NMR (400 MHz, SOSI"): 5 " 2.06 (s, o. o ZN), 2.38 (s, ZN), 2.66 (s, ZN), 7 .33 (c, 2H), 7.58 (c, 1H). at -4 NRMS (thermospray): pug МН" 281. Microanalysis: but with Senem.О»0.30NIO necessary C, 63.06; H, 445; M,

Phenol from Preparation 34 (10.0g, 72.7mmol), - 19.6196.

Z-chloro-2,4-pentanedione (7.10 g, 72.7 mmol) and carbo- | from the rear 1 Bave 0. "H NMR (400 MHz, SOXH 8 7 205 (o, . . : ЗН), 2.33 (s, ЗН), 2.38 (s, ЗН), 2.66 (s, ЗН), 6.88 (c, 1H), sodium cesium (23.6g, 72.9mmol) was heated from reverse (c, IN), 712 (C, IN). HRMS (thermodissolving): in a refrigerator in acetone (100 ml ) in the atmosphere - MH") 270. Microanalysis: Found C, 86.67; H, 5.71; M, ri of nitrogen for 2 hours. The reaction was cooled at 165.25. SivNi"MeO" must be C, 66.9; H, 5.61; M, 15.6095. to room temperature, slowly added 1M 7A" (Commercial) HO) Mpl. 131-133 20. I NMR (400 MHz, SOS): 5 2 2.13 (s, aqueous hydrochloric acid (50 Oml) and a mixture of ext. ) NEMO perioaroylation). pu MH t was treated with ethyl acetate (3 (100 ml). United Microznals: Found C, 657; H, 5/1; M, 16233. organic extracts were dried over magnesium sulfate. BlueMzO" necessary C, 85, 87; H, 5.13; M, 144695. and concentrated under reduced pressure. The remaining oil was dissolved in methanol. The product was purified using a column (100 ml), hydrazine (5.3 ml, 109 mmol) was added ) and flash chromatography on silica gel using - the reaction was stirred at room temperature or as an eluent ethyl acetate: pentane (10:90, in a nitrogen atmosphere for 2 hours. Solvent of bulk). was removed under reduced pressure and the remaining solution 2 The product was purified using column was dissolved in dimethylformamide (50 ml) at 0"C. After flash chromatography on silica gel, acetyl chloride (5.1 ml, 72.0 mm ol), or as an eluent ethyl acetate:pentane (10:90, after which portions of sodium hydride (6095 dispersion was replaced by 20:80, by volume). in oil, 2.8 g, 72.0 mmol). The reaction was stirred Preparation 75 for 15 minutes and Na was added. 3-(1-Acetyl-3-(bromomethyl)-5-methyl-1H-ammonium chloride solution (50 ml), and the reaction was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (3 (100 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give an oil. After settling for 18 hours, a solid was formed from the oil, 5- 4, which was removed by filtration, was washed with diethyl ether (50 ml) to give the indicated compound (3.507) as a white solid, pyrazole from Preparation 71 (1.00 g, 3.6 mmol) , SOSIv): b-2.06 (c, ZN), 2.37 was dissolved in carbon tetrachloride (20 ml) and ro (c, ZN), 2.65 (c, ZN), 6.81 (d, 1H) .

NRMO (thermal spraying); that MH 273. about 2,2:-azobisisobutyronitrile (ZOmg) and the reaction of heating

Microanalysis: Found C, 61.62; N, 4.44; M, o: 15.09. Si4H12MzO»E must be C, 61.53; N, 4.43; M, shafts at 9572 during ! hours The reaction 3895 was cooled to room temperature, concentrated Preparations 72-74 under reduced pressure and purified by

Compounds of the general formula were grouped by flash chromatography on silica gel using ethyl acetate (80:20, v/v) as eluent to give the title compound (1.30 g) as a pale yellow oil. rai o H-NMR (400 MHz, SOS): 6-2.05 (s, ZN), 2.69 -- m-4 (s, ZN), 4.68 (s, 2H), 6.89 (d, 1H), 6.99 (s, 1H), 7.08 a sn (d, 1H). but from NRMS (thermal spraying): t/2 (M-V/NU| 272. obtained by a method similar to the Microanalysis method: Found C, 45.08; H, 3.14; M,

Preparation 71 using acceptable 11.44. С14НииВГИМзО»2Е-1.05Н2О is necessary C, 45.31; phenol as a starting material. H, 3.56; M, 11.32905.

Preparation 76-78 (m, 1H), 8.12 (m, 1H), 8.18 (s, 1H). p cm Preparation 80

Y Y 3-(Aminomethyl)benzamide n. Mn, (e) - rya

M sn, o sv,

Ve Nitrile from Preparation 79 (6.4g, 43.8mmol)

Obtaining the following grouped Preparations were suspended in acetic acid (bOml) and added to the general formula 1095 palladium on charcoal (100 mg). The reaction was hydrogenated in cm under hydrogen boOpsi pressure at room temperature and stirring for 18 hours. There was n, the starting material, so another aliquot of 1095 palladium on charcoal (500 mg) was added and the procedure was repeated. The reaction mixture was filtered through sem sn, Agroseyi, washed with acetic acid and the filtrate and. concentrated under reduced pressure. Remainder. and. was azeotroped with toluene and purified using a method similar to that described in flash chromatography on silica gel using

In the preparation of 15, using an acceptable eluent, dichlormerazop as a starting material. tan:methanol:0.88 ammonia (100:0:0 was replaced by 90:10:11 then 85:15:1.5, by volume) to obtain the indicated (Starting material given in the title compound (5.3g) as a colorless cooking oil. 7672) SM | Tal. 132-134 "0. "H NMR (400 MHz, SOSIzu: 5 - 2.06 (s, ZN), IN-NMR (400 MHz, COzO0): 6-3.83 (s, 2H), 7.39 2.66 (s, ZNU , 4.67 (s, 2H), 7.40 (s, 2H), 7.63 (s, 1H). Microanalysis:

SEN ef and necessary S, 47.92; H, 3.45; M, 14.9095. 773 KE ka "S. NMR (400 MHz, SOS 5 - 2.052, ZN), 2-Xpor-1,3-dicyclopropyl-1,3-propanedione 2.35 (s, ZN), 2.70 (s , ZNU, 4.70 (s, 2H), 6.95 (s, 1H), 6.99 (s, 1H), which

SieNioVIM3O2»0.40H2O must be C, 50.69; H, 4.20; M, 11.8295. 7874) H | Tll. 120-124 "S. I NMR (400 MHz, SOSIv): 6 « 2.05 (s, ЗН), and 0000 ШМИ zrimethyl silt chloride vom 130 mmol) pava pi testa was added to a solution of tert-butylammonium bromide peobndo S. oh nVVk Mast (0.70g, 2, 17 mmol) in acetonitrile (50 ml) in an atmosphere of 4 .. sh . ' sphere of nitrogen at 0"C. Then added 1,3-

An aliquot of 2,2-dicyclopropyl-propane-1,3-dione (pos: azobisisobutyronitrile (ZOmg)) was added to this reaction and the mixture was boiled UKO98155438) (6.62, 43 BMMOL) in acetonitrile for another 2 hours. . (15 ml) followed by drops of dimethyl sulfoxide

The product was purified by column (9.25 mL, 130 mmol) and the reaction was allowed to warm to room temperature for 4 hours. or as an eluent a gradient of ethyl solvents - The mixture was diluted with water (75 Mml), extracted with acetate: pentane (0100 then 2:98 lotim 5:95 then diethyl ether (3 (35 ml) and combined organic 10:90 then 15:85 then 30:70, by volume). And the extracts were dried over magnesium sulfate and concentrated

The product was purified using column distillation under reduced pressure. The residue from flash chromatography on silica gel was used with the help of flash chromatography on silica as eluent ethylacetate:pentane (10:90 kagel used as eluent was replaced by 20:80, by volume). pentane:diethyl ether (95:5, by volume) obtained

Preparation 79 of the title compound (3.76 g) as an oil,

Z-Cyanobenzamide which was an 80:20 mixture of the enol'keto form. cm TN-NMR (400 MHz, SOS"): 6-1.02 (m, 4H), 1.17 (m, 4H), 2.24 (m, 0.2H), 2.39 (m, 0, 8H), 5.05 (s, 0.2H), 16.34 (s, 0.8H).

Microanalysis: Found C, 57.59; H, 5.89. o Mn SeNiSO»:0.02SNeSi» is necessary C, 57.92; N, 5.94. 0.88 Ammonia solution (ZOml) was slowly added Preparation 82 to a solution of 3-cyanobenzoyl chloride / (10Hg, 5-(2-Cyclopropyl-1-(cyclopropylcarbonyl)-2- 60.3mmol) in dichloromethane (100ml) at 0"C in oxoethoxy|isophthalonitrile under a nitrogen atmosphere and the reaction was stirred for 20 minutes. The mixture was filtered and the solid was washed with water (50 mL) then with diethyl ether (50 mL), azeotroped with toluene and dried under vacuum to give the title compound (9 g) as a white solid.

TN-NMR (400 MHz, SOS"): 6-7.62 (m, 1H), 7.86

Cesium carbonate (1.97g, 6.06bmmol) was added to a stirred solution of phenol (200ml) and portionwise under a nitrogen atmosphere at 0" melting 39 (0.865g, 6.00mmol) in acetone (24ml) was added carbonyldiimidazole (22.4g, 138mmol). under a nitrogen atmosphere under reflux with reflux. This mixture was stirred for 1.5 hours with a stirrer. After stirring for 5 hours, the pyrite salt obtained above was added as a solution in minutes, diketone was added from Preparation 81 dimethylformamide (10 Oml) at 0"С. The reaction was (1.12 g, 6.00 mmol) in acetone (bml) and the reaction was allowed to stir at room temperature for 4 hours. After cooling for 92 hours, the mixture was poured into 2M, the mixture was diluted with water (25 ml) and acetone-derived hydrochloric acid (85 ml), then dissolved under reduced pressure. The aqueous phase was diluted with water (17 Oml). The mixture was extracted with diethyl ether, acidified with 2 M aqueous hydrochloric acid ether (6 (200 ml) and combined organic extracts, extracted with dichloromethane (5 ml) and the extract was washed with a saturated aqueous solution, the overnight phase was dried over magnesium sulfate and sodium chloride (3x200ml), dried over sulfa- concentrated under reduced pressure. The remaining volume of magnesium and concentrated under reduced pressure- was purified by flash chromatography on ku. The remaining orange oil was purified on silica gel using as an eluent gram- by flash chromatography on silica gel dient of solvents pentane-ethyl acetate (95:5 replaced by using as eluent foamed to 90:10 then 80:20, volume) obtained: diethyl ether (100:0 replaced by 90:10, or specified in title compound (1.03g) as a white then 80:20, v/v) to give the indicated solid, which existed as an enol tau- compound (7.39g) as a yellow oil. tomer, mp 135-137 ". IN-NMR (40 ohms, SOSIz): 6-0.83-0.95 (m, 2H),

IN-NMR (400 MHz, SOSIz"): 6-0.93 (m, 4H), 1.19 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H), 2.00 (c, ZN). (m, 4H), 1.74 (m, 2H), 7.53 (s, 2H), 15.25 (s, 1H). NRMS (electrospray): t/2 (MMa" | 149.

NRMS (electrospray): t/2 (M-N"U) 293. Preparation 85

Microanalysis: Found C, 69.18; N, 4.82; M, 2-Chloro-1-cyclopropyl-1,3-butanedione 9.35. C17H14M2Oz must be C, 69.38; N, 4.79; M, 9,529.

Preparation 83 AK 3-Oxobutanoic acid a o Trimethylsilyl chloride (18.9 ml, 174 mmol)

CH was added to a solution of tert-butylammonium bromide (932 mg, 2.89 mmol) in dry acetonitrile (50 ml)

Sodium hydroxide (37.9g, 0.947mol) was dissolved in a nitrogen atmosphere at room temperature and in water (770ml) and methyl was added to the solution. The mixture was cooled to 0°C. Then the wild ester of 3-oxo-butanoic acid (100 g, ketone from Preparation 84 (7.3 g, 57.9 mmol) in ace-0.86 b1 mol) was added at room temperature during tonitrile (Zbml), after which it was added dropwise for minutes. The reaction was stirred for 18 hours with dry dimethyl sulfoxide (12.3 mL, 174 mmol). hours, quenched with ammonium sulfate (700g) and slowly The reaction was stirred at 07C for 1.5 hours, acidified with a solution of concentrated hydrogen chloride, and the mixture was diluted with water (500ml), extracted acid (21.5ml) in water (250ml), cooled filled with diethyl ether (2 x 200 ml and 100 ml) and washed with ice. The reaction mixture was extracted, the diethylated organic extracts were dried over sulfate with ether (6 (200 ml), and the combined organic magnesium salts were concentrated under reduced pressure. The extracts were dried over magnesium sulfate and concentrated. The remaining oil was purified using obtaining the indication of flash chromatography on silica gel used in the title compound (58.2 g) as pale yellow or as an eluent pentanedietyl ether (100:0 oil, which was a mixture of keto:enol tautomers. was replaced by 95:5, then 90 :10, volumetric) received

IN-NMR (400 MHz, SOCI3): 6-2.00 (s, ZH-enol), chewing the title compound (5.76g) as free- 2.30 (s, ZH-keto), 3.51 ( c, 2H-keto), 5.02 (c, 1H- colored oil. enol). IN-NMR (400 MHz, SOSIz): b-0.99-1.08 (m, 2H),

Preparation 84 1.15-1.20 (m, 2H), 2.27 (s, ЗН), 2.38-2.46 (m 1). 1-Cyclopropyl-1,3-butanedione NRMS (electrospray): t/2 (M-H"U) 159.

Preparation 86 3-P-(Cyclopropylcarbonyl)-2-oxopropoxy|- ne 5-methylbenzonitrile

Magnesium (3.04g, 125mmol) was suspended in methanol (145ml) and heated with reflux under stirring in a nitrogen atmosphere; under pressure for 1 hour, cooled to room temperature, and a cooled solution of B-keto acid from Preparation 83 (25.5 g, 250 mmol) in methanol (25 ml) was added dropwise. The reaction of the mixture - Cesium carbonate (2.45 g, 8.30 mmol) and phenol from the shaft for 1 hour at room temperature - Preparation 42 (1 g, 7.50 mmol) was added to the solution, the solvent was removed under reduced pressure of the stirred solution, the diketone from the preparation - receiving the magnesium salt of the acid. At the same time, 85 (1.3 g, 8.30 mmol) in acetone (44 mL) in acyclopropane carbonate (9.91 mL, under nitrogen at 60°C and the reaction was stirred at 125 mmol) was dissolved in dimethylformamide for 5 hours. cooling mixture ha-

forces with water and acetone were removed under reduced Preparation 89 pressure. The aqueous phase was acidified with 1 M aqueous chloro-3,5-Diethyl-4-3-fluoro-5-(1H-pyrazole-1-hydrochloric acid), extracted with ethylacetylphenoxy|-1-(2-(tetrahydro-2H-pyran-2 - volume and the organic phase was dried over methyloxy)ethyl|-1H-pyrazolium sulfate and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel using pentane:ethyl acetate (85:15, v/v) as eluent to give the title compound (1.03 g) as a pale red solid substance o -th

TN-NMR (400 MHz, SOS"): 6-0.85 (m, 2H), 1.12 XM o (m, 2H), 1.86 (m, 1H), 1.94 (s, ЗН), 2.95 (s, ZN), 6.99 m (m, 2H), 7.10 (s, 1H). dream

NRMS (electrospray) t/z2 (M-N"U | 256.

Preparation 87 and Cesium carbonate (538mg, 1.65mmol) was added to pet Al 000 lo rogmn pyrazole (volume, 1 vommol) in the soma

E dimethyl sulfoxide (2 ml) in a nitrogen atmosphere at

E at room temperature and the reaction was stirred for 15 minutes. Then added aryldiphto-sn. ried from Preparation 87 (57Omg, 1.50mmol) in su- o. - hum dimethyl sulfoxide (2 ml) and the reaction was heated at 100"C for 18 hours. After

M cooling to room temperature reaction sn. It was diluted with water (20 ml) and extracted with diethyl ether (2 (20 ml). The organic phase was washed with p-Toluenesulfonic acid (with a saturated aqueous solution of sodium chloride 1.89 mmol) added to the alcohol solution with Prik- (1 ml), dried over sulfate magnesium, concentrate 38 (5.6g, 18.9mmol) and dihydropyran (8.62ml) were dissolved under reduced pressure. A small amount of the starting material remained, so the residue was dissolved in dichloromethane (75ml) at dimethyl sulfoxide (12 ml) was added at room temperature, peremipyrazole (510 mg, 7.50 mmol) was added to the reaction, after which the carbonate was stirred for 2 hours, diluted with diethyl cesium (2.5 g, 7 mmol) and the reaction was heated with ether (100 mmol ) and washed with mixed water at 100"C for 18 hours. After cooling to sodium chloride, the reaction was diluted with water and sodium bicarbonate (zoml); united and sodium chloride solution (10 ml), dried over organic extracts dried over magnesium sulfate with magnesium sulfate, concentrated under reduced pressure, concentrated under reduced pressure and increased pressure and the residue was purified using the residue purified using flash chromatography flash chromatography on silica gel using - raffia on silica gel using as eluent a gradient of dichloro-eluent dichloromethane:methanol (98:2, volume) methane:methanol (100:0 was replaced by 964, volume - obtaining the compound indicated in the title ( 6.31d) like them). Two fractions were obtained, the first of which was oil. ' all 1. k- a separate product (less polar) and another mixture (m in) 240 o o vB(k on) Kui her tn) uv2 two products. The second fraction was purified according to the new (m, 1n), 373 (m In) 4 05 (m 1n) 416 (t 2n), 4 50 using dichloromethane as an eluent, 1), in 39 (m zn). " " shu " shi tan: acetonitrile (93:7 was replaced by 90:10, obje- (s, NRMS " and " t/x IMNYA Z81 mnykh) obtaining a more polar product. and (thermal spraying); tug I and I in. Less polar product-Preparation 88

Microanalysis: Found C, 62.16; N, 6.92; M, (254M) 7.16. СгоНовМ2Оз.0.09СНосСиИ" is necessary C, 62.18; H-NMR (400 MHz, SOSIv); 6-1.11 (m, 6H), 1.50

H, 6.80; M, 7.22. (m, 6H), 2.46 (k, 2H), 2.58 (k, 2H), 3.43 (m, 1H), 3.64

Preparation 88 | (m, NU, 3.75 (m, 1H), 4.04 (m, 1H), 4.18 (t, 2H), 4.50 o 48,5-Di(1Hpyrazol-1 ylylphenoxy) 3, 5- (c, 1H), 6.42 (c, 2H), 7.15 (c, 2H), 7.67 (c, 3H), 7.90 diethyl-1-|(2-(tetrahydro-2H -pyran-2-yloxy)ethyl|- (c, 2H). 1H-pyrazole HPMS (electrospray): m/7 (MH) 477, c - IMMa"I 499.

Ul Z VRMS: (MN) Found 477.2612.. SovNzzMvOz m is necessary 477.2609. tho; sn, More polar product - Preparation 89 o. (37.7mg) - TN-NMR (400mhz, SOSIz): 6-1.11 (m, 6H), 1.46 - M o (m, 6H), 2.43 (k, 2H), 2.57 (k, 2H), 3.43 (m, 1H), 3.64 b (m, 1H), 3.75 (m, 1H), 4.05 (m, 1H), 4.17 (t, 2H ), 4.51 sn, (s, 1H), 6.42 (m, 2H), 7.07 (m, 2H), 7.66 (s, 1H), 7.82 - (s, 1H).

NRMS (thermal spray): t/2 (MH) 429. β-yl|acetic acid

Preparation 90 s a 3-((3,5-Diethyl-1-I(I2-(tetrahydro-2H-pyran-2- phylloxy)ethyl|-1H-pyrazol-4-yloxy)-5- methoxybenzonitrile b on sn , slya not SM -. YN not"

Pyrazole of Example 208 (400 mg, 1.41 mmol)

It was stirred at 110"C for 14 hours in 100 ml of concentrated hydrochloric acid (20 ml). The mixture was cooled to room temperature and

At ( y; the solvent was removed under reduced pressure to obtain a yellow solid. The solid

Sodium methoxide (2595 wt./vol. in methanol, dissolved in dichloromethane (50 ml) and 1 M aqueous 23 0 ml, 1.00 mmol) was added dropwise to hydrogen chloride (500 ml) and the organic layer of the aryl fluoride from Preparation 63 (387 mgH, The organic part was washed with 1.00 mmol) and dimethylformamide (5 ml) at room temperature with 1 M aqueous hydrochloric acid (50 ml) at room temperature under a nitrogen atmosphere. The reaction was washed over magnesium sulfate, filtered and stirred for 5 hours, diluted with water, the factor was removed under reduced pressure to obtain (10 ml) and extracted with diethyl ether (50 ml). taking the title compound (400 mg) as a pale organic phase was dried over magnesium sulfate, a yellow solid, mp. 156-15870. concentrated under reduced pressure and the residue 1H NMR (400 MHz, COzO0): 6-2.02 (s, ЗН), 4.89 was purified by flash chromatography to (s, 2H), 6.82 (s, 2H), 7.02 (s, 1H). silica gel using as an eluent dich- NRMS (thermospray): t/2 МН") 303. lormethane:methanol (97:3, by volume) obtaining Microanalysis: Found C, 47.50; H, 3.50; M, the title compound (400 mg) as an oil. 9.46. Si2NiOSiM2Oz required C, 47.86; H, 3.35; M,

IN-NMR (400 MHz, SOSIz"): 6-1.09 (m, 6H), 1.49 9.300. (m, 6H), 2.41 (k, 2H), 2.55 (k, 2H), 3.46 (m, 1H), 3.66 Preparation 93 (m, 1H), 3.77 (m' ks, 4H), 4.07 (m, 1H), 4.19 (t, 2H), 3-((3,5-Diethyl-1-(2-(tetrahydro-2H-pyran-2- 4.52 (m, 1H), 6.66 (s, 1H), 6.69 (s, 1H), 6.77 (s, 1H). yloxy)ethyl|-1H-pyrazol-4-yloxy)-5-

HPMS (thermal spray): t/g2 (MH) 400. (methylsulfanyl)benzonitrile

Microanalysis: Found C, 65.59; H, 7.32: M, us cm 10.42... SgoNgoMzO4.0.04СН2Si" is necessary C, 65.71

IN, 7.28; M, 104395. z

Preparation 91 o. - 3-(1-Acetyl-3-methyl-2-oxobutoxy)-5-methylbenzonitrile se Mo o o z

Ns. o c. Sodium thiomethoxide (180 mg, 2 mmol) was added to a stirred solution of aryl fluoride with

Preparation of 63 (774 mg, 2.00 mmol) in dimethylformamide (1 Oml) at room temperature in

Cesium carbonate (1.50g, 4.61mmol) and phenol under a nitrogen atmosphere. The reaction mixture was stirred

Preparation 42 (609 mg, 4.61 mmol) was added over 5 hours and then heated at 10070 to a stirred solution of the diketone with Preparation 18 hours. A second portion of thiome 23 (750mg, 4.61mmol) in acetone (23ml) in sodium oxide (30mg, 1mmol) and the reaction mixture under a nitrogen atmosphere at 502С was added and the reaction was stirred and heated at 10072 for another 5 hours. After 3 hours. After cooling the reaction mixture to room temperature, the mixture was quenched with water (10 ml) and acetone was removed by diluting with water (100 ml) and extracted under diethylated pressure. The aqueous phase was extracted with ether (2 x 50 ml). The organic phase was dried over lormethane (4 (25 ml) and the combined organics were extracted with magnesium sulfate, concentrated under reduced pressure, dried over magnesium sulfate and under reduced pressure, and the residue was purified using concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using by means of flash chromatography using dichloromethane:methanol (97:3, using silica gel as eluent pen-volume) as an eluent, obtaining the indicated in the title spolutane: ethyl acetate (90:10, volume) obtaining in the (700mg) as an oil. gives the title compound (544mgH). "H-NMR (400mg, SOCI3): 6-1.14 (m, 6H), 1.52 "H-NMR (400mg, SOCI3): 6- 1.10 (m, 6H), 209 (m, 6H), 2.44 (k, 2H), 2.49 (s, ЗН), 2.59 (k, ЗН), 3.50 (s, ЗН ), 2.42 (s, ЗН), 2.69 (m, МН), 7.00 (m, 1Н), 3.70 (m, 1Н), 3.80 (m, 1Н), 4.10 (m, tn), (c2n), 7.19 (s, 1H). 4.23 (m, 2H), 4.55 (m, 1H), 6.82 (s, 1H), 7.01 ( with,

NRMS (thermal spray): t/2 (MMH| 277. 1Н), 7.09 (s, 1Н).

Preparation 92 NRMO (XI;Tya): t/y IMNYA 416.

I4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazole-

Preparation 94 97 (63) СНеСНоОСН; | "H NMR (400 MHz, SOSIv): 6 g 1.10 (m, 6H), 1.50 (m, 3-13,5-Dethyl-142-(tetrahydro-2n-pyrano- pninyloxy)ethyl| -1H-pyrazol-4-yloxy-5-(2-2n), 4.52 (s, 1H), 6.70 (s, 2H), 6.79 (s, 18).HPRS (dimethylamino)ethoxy| benzonitrile for spectrospraying) pit 465 (MY" BRME: MN che shchi sm sn, Preparation 98 oy 5-Methyl-1-(2-(tetrahydro-2H-pyran-2-y -3- -1n- -A- rene poksm )etm 3-(trifluoromethyl)-1H-pyrazol-4-ol "o z t o

Sodium hydride (Zbmg o) was added to a stirred solution of /-M,M-ve with M dimethylethanolamine (33ml, 0.833mmol) in dimes and ethylformamide (2ml). To the stirred solution, 1-(2- bovag .95 dispersion in oil, 0.90 mmol).After 10 hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1 N- minutes, a solution of aryl fluoride from Prigoto-pyrazol-4-ol (60 mg, 2.8 mmol; Kepkum Nokoka) was added - 63 (291mg, 0.75mmol) in dimethylformamide Avapi Sagawa Koduo Simiva Zpogeikai, 1988, (2ml) and the reaction mixture was stirred at room temperature (51,139-49) in dichloromethane (1Oml) and ethyl acetate for 18 hours. The mixture was dissolved (4 ml) with para-toluenesulfonic acid dily 1095 aqueous solution of potassium carbonate (27 mg, O0.14 mmol), then 3,4-dihydro-2H-pyran (12 ml) and extracted with diethyl ether (2 (with 40 µl, 3.7 mmol ). The reaction mixture was stirred (7 ml). The combined organic components were dried at room temperature for 3 hours and over magnesium sulfate and concentrated under reduced pressure. was purified using flash chromatography on chromatography on silica gel using pentane:ethyl acetate (60:40, volume-lormethane:methanol (gradient from 99:1 to 90:10, gradient from 99:1 to 90:10, ) yielding the title compound voluminous) yielding the title compound (560 mo as a white solid. ku (180 mg) as an oil. H-NMR (40Omhz, SOCI3): 0-1.60 (m, 6H), 2.23 "H-NMR (400 MHz, SOCIz): 6-1.09 (m, 6H), 1.50 (s, ЗН), 3.44 (m, 1H), 3.60 (m, 1H), 3.72 (M, 1H), (m, vn), 2.39 (k, 2n), 2.47 (s, vn), 2.55 (k, 2n), 2, 87 4.04 (m, 1H), 418 (m, 2H), 4.50 (broad c, 1nH). (m, 2n), 3.47 (m, 1n), 3.67 (m, 1n), 3.78 (m, 19), NRMO (electrospray): t/: IM-NU 293. 4.05 ( M, 1H), 4.17 (m, 4H), 4.52 (m, 1H), 6.70 (C, 2H), Preparation 99 6.79 (sn). | "Z-Fluoro-5-(o-methyl-1-(2-"tetrahydro-2H-

NRMS (electrospray): t/g (MNU) 457. pyran-2-yloxy)ethyl-3-(trifluoromethyl)-1H-

VRMS: |MNU| 457.2810.. SovNztMaOx must be pyrazol-a-yl|oxy)benzonitrile 457.2810. and

Preparation 95-97

Obtaining the following grouped Pryhotura /; of the general formula m o

Shk and form of St. de

To a stirred solution of sn pyrazole (214 mg, 0.7 mmol) from Preparation 98 in dimethylformamide (0.7 mL) was added 3.5 m HM in difluorobenzonitrile (304 mg, 2.2 mmol) and sodium carbonate , 73 potassium (Z04mg, 2.2mmol). The reaction mixture was heated at 907"C for 7 hours. After cooling by a method similar to the heating method to room temperature, added

Preparation of 94 using acceptable saturated aqueous solution of sodium chloride (20ml) and alcohol as starting material. the mixture was extracted with ethyl acetate (20 ml). Orga-

Gtonryan Tknianniant night component was separated, washed 1 "Vakhidnny catednyat 7 ; : a saturated aqueous solution of sodium chloride

MLN tents Zurvtn V Ak K U VV (20 ml), dried over magnesium sulfate and concentrated

MB melennkh removed the znzaya tm Odesa ruvali at reduced pressure. Unpurified prochni, ZZhv zh "No, KV Zh, ChK, dobyn, YAN Atduct was purified using flash chromatography and TENU Ya st, ZNM bis, ZNU, toiv, janv skh on silica gel using as an eluent and: (I know MRMKI flelectropokhtizechkyah zp IN) Fa I pentane: ethyl acetate (80:20, by volume) obtaining: | ! mom yaEan SmMin" nebu: the compound indicated in the title (267 mg) as a colorless shik shi NEK Bora Z oil;

Ivanh, what, shh zha. them, YAN), Z, them, Nu 35 them, 1IN-NMR (400MHz, SOS"): 6-1.61 (m, bN), 2.18 tn zvo, YAN, aa ik. ЗР, яв их, ZNO, AB (in, (c, ЗН), 3.48 (m, 1Н), 3.64 (m, 1), 3.75 (m, 1),

VN was eaten by ZK, but in the afternoon there is. TNB? 4.30 (t, 2H), 4.50 (wide c, 1H), 6.85 (d, 1H),

I know; TN), tya b ZNK ba ve ZK NRMO 6.94 (c, 1H), 7.05 (d, 1H). ' N Z iyapestrorozpypenvnyau: fluff Here KK YAM: IM ! | fmvon oinu mys nesbbkidn ZeZoni, I NRMS (electrospraying): t/2 (M-NYA | 412.

KOM TM A AKA A nya Preparation 100

3-Cyano-5-|(3,5-diethyl-1-(2-((2- using dichloromethane as an eluent: methanol methoxyethoxy)methoxy|ethyl)-1H-pyrazole-4- (100:0, 99 :1, then 98:2, by volume) to give the yl)oxy|benzamide of the title compound (2.67g) as a white solid. (t, ЗН), 1.19 y (t, ЗН), 2.43 (k, 2Н), 2.72 (с, ЗН), 3.85 (к.2Н), 7.38 сн, о- - (s, 2H), 7.81 (s, 1H). b / sn, NRMS (electrospray): t/2 331 (MAM). - Preparation of 102 chad 5-C1-Acetyl-3-(1-bromethyl) -5-ethyl-1H-, , pyrazol-4-yl|oxy) isophthalonitrile

To a stirred solution of pyrazole with m cm

Example 261 (193mg, 0.49mmol) in tetrahydrofuran (2ml) was added with a 2M aqueous solution of sodium hydroxide (8.7μl, 0.49mmol) and the CH reaction mixture, heated at 65"C for 24 hours. After cooling (after cooling to room temperature, a second portion of a 2M solution of sodium hydroxide was added (8.7 μl, 0.49 mmol) and the mixture was heated at 6570 for 24 hours. An aqueous solution of BE and sodium hydroxide (100 μl) was added and the mixture was heated at pyrazole solution from Preparation 101 (881 mg, 652C for 24 hours. The reaction mixture concen- 2.8 mmol) in carbon tetrachloride (12 ml) was denatured under reduced pressure, diluted with water, bubbling a stream of nitrogen through the solution of pro- (75 ml) , neutralized to and pH7 using draft for 20 minutes. M-bromosuccinimide 2M solution of aqueous hydrochloric acid and extra- (763mg, 4.28mmol) were added, after which DIVM (ZOmg) and reacted with dichloromethane (2x25ml). Combined orgatsin the mixture was heated at 857°C for 4 hours, overnight components were dried over sulfate m of magnesium and After cooling to room temperature, it was concentrated under reduced pressure to obtain a mixture concentrated under reduced pressure, and the crude product, which was purified using the quality of the eluent dichloromethane:methanol to pentane:ethyl acetate (gradient from 1000 to (100:0, 98:2, 96.5:3.5 then 95:5, volume) obtaining- 67:33, volume) obtaining the compound (348 mg) indicated in the title and dulayihm v za, v J as a colorless oil. butter in the title, the compound (bomg) as without "H-NMR (400 MHz, SOSI"): 6-1.10 (t, ZN), 2.00

IN-NMR (400 MHz, SOSIz"): 6-1.10 (m, 6H), 2.40 (d, ZN), 2.70 (s, ZN), 2.80 (m, 2H), 4, 95 (k, 1H), 7.42 (k, 2H), 2.55 (k, 2H), 3.36 (s, ЗН), 3.50 (k, 2H), 3.59 (s.2H ), 7.60 (S.1H). | and (k, 2H), 3.94 (k, 2H), 4.20 (k, 2H), 4.64 (s, 2H), 7.30 NRMS (electrospray): t/2 283 (МН. ( s, 1NU, 7.59 (s, 1H), 7.70 (s, 1H). Preparation 103

Preparation 101 5-(C5-Ethyl-3-(1-hydroxyethyl)-1-|2-(tetrahydro-5-(1-Acetyl-3,5-diethyl-1H-pyrazol-4-yl)). - ok- 2H-pyran-2 yloxy)ethyl 7H-pyrazol-isophthalonitrile and luxy)isophthalonitrile cm Mo. sy ) sn, | sleep about that (Fi sn o,

Well, M

To a stirred solution of pyrazole with

Example 122 (3.0 g, 11.3 mmol) in dimethylformaldehyde. To a stirred solution of pyrazole with amide (45 ml) at 02C, acetyl chloride of Example 263 (197 mg, 0.70 mmol) in dimethylformamide (1.2 ml, 17.0 mmol) was added. ), after which amide hydride (3ml) was added at 0°C in portions of /2-(2- sodium (678 mg of bOwag.obs dispersion in oil, bromethoxy)tetrahydro-2H-pyran o (Po5 μl, 17.0 mmol). The cooling bath was removed and 0.7 mmol) after which sodium hydride (31 mg, the reaction mixture was stirred at room temperature - 0.77 mmol). After 15 minutes, the cooling temperature for 40 minutes. The reaction was quenched, the bath was removed, and the mixture was stirred at room temperature by adding a saturated aqueous solution of ammonium chloride for 60 hours. The reaction mixture (4 ml) and concentrated under reduced pressure was quenched by adding a saturated aqueous solution to obtain an orange residue. This material was ammonium chloride (0.5 mL) and then concentrated by partitioning between ethyl acetate (200 mL) and water under reduced pressure. Unrefined product (200ml). The organic component was washed with water, purified by flash chromatography on silica gel (100 ml), saturated with an aqueous solution of chloride, using sodium disodium (75 ml) as an eluent, and then dried over maglor methane:methanol sulfate (gradient from 100:0 to 95:5, and then concentrated under reduced pressure.

The crude product mixture was purified using (in 4mg) as a white foam, which turned into a weak flash chromatography on silica gel used on standing. "H-NMR (400 MHz, SOSIv): 6-1.11 (t, ZN), 1.45

(d, 3H), 1.65 (m, 6H), 2.59 (k, 2H), 3.50 (m, 1H), 3.70 silica gel chromatography using v (m, 1H), 3.81 (m, 1H), 4.11 (m, 1H), 4.25 (t, 2H), 4.56 quality of eluent dichloromethane:methanol (gradient (m, 1H), 4.76 (m, 1), 7 .40 (c, 2H), 7.55 (c, 1H). from 100:0 to 90:10, by volume) obtaining the specified

NRMS (electrospray): t/2 411 (MNY. in the title compound (259 mg) as a colorless oil.

Preparation 104 IN-NMR (400 MHz, SOS"): b-1.14 (m, 6Н), 2.46

3-Cyano-5-(3,5-diethyl-1-(2-((2- (Kk, 2H), 2.59 (k, 2H), 3.39 (c, Н), 3.53 ( k, 2H), 3.59 methoxyethoxy)methoxy|ethyl)-1H-pyrazole-4- (Kk, 2H), 3.95 (k, 2H), 4.29 (k, 2H), 4.68 ( c, 2H), 7.34 yl)oxy|-M'-hydroxybenzenecarboximidamide (c, 1H), 7.87 (c, 1H), 8.04 (c, 1H). no. m HRMSO (HIAT): t /:2 532 (МН) sk Preparation 106-108 nm Obtaining the following grouped Preparations, vans of the general formula . -sn,

To a stirred solution of pyrazole with o /

To Example 261 (1.5 g, 3.7 mmol) in ethanol (7.5 ml) was added a solution of sodium carbonate (200 mg, 1.88 mmol) and hydroxylamine hydrochloride (262 mg, carried out by a method similar to method 33.7 mmol) in water (7.5 ml). After mixing Preparation 105, using an acceptable reaction acid chloride for 5 hours at room temperature as an acylating agent instead of the tritium mixture, the mixture was concentrated under reduced pressure of fluoroacetic anhydride. and the residue was partitioned between dichloromethane (50 mL) and water (40 mL). The aqueous phase was separated and extracted with dichloromethane (ZOml). Organic compounds "NMR (200 MHz, SOXH 5 - 1.14 (m, 6), gav (k, 2H), 2.58 (k, the components were combined, dried over sulfate 2H), 2.67 (s, Н ), 3.39 (s, ZNU, 3.55 (k, 2H), 3.59 (k, 2H), 3.95 (k, 2H), magnesium and concentrated under reduced pressure.

The crude product mixture was purified with the help of C, BOI found; H, 627; M, 15.38. Semy" i 02NYU flash chromatography on silica gel used C, 59.94; H, 6,476; M, 151996. using dichloromethane:methanol as an eluent 107 EHI'N-NMR (400 MHz, SOCXH 5 - 144 (m, OH), 1.44 (t, ЗН), 2.45 (Kk (gradient from 100: 0 to 96:4, by volume) obtaining 2H). 59 (k, 2H), (s, 1H). HRMS (electrospray): t/: 492 (M i Ma"; not oil. x 108 "H NMR (400 MHz, SOS"): 6 - 1711 (m, 6H), 1.49 (d, OH), 2.44 (k, "H-NMR (400 MHz, SOCI3): 6-1.11 (m, 6H), 2.42 2H), 2.49 (k , 2H), 3.30 (sept, 1H), 3.39 (s, ЗН), 3.54 (m, 2H), 3.59 (m, (Kk, 2H), 2.58 (k, 2H ), 3.41 (s, ЗН), 3.59 (m, 4Н), 3.95 2Н), 3.95 (t, 2Н), 4.23 (t, 2Н), 4.91 (s, 2H), 7.22 (m, 1H), 7.83 (m, (t, 2H), 4.17 (t, 2H), 4.61 (s, 2H), 4.77 (wide s, 1H ), 8.02 (m, 1H). NRMS (electrospray): fluff 506 (M -- Ma") 2H), 7.38 (m, 1H), 7.49 (m, 2H). | rakovnany sir - nevi 6.76; M, 14.62... SoNazimeOv

NRMS (electrospraying): t/z2 432 (МН. ее пт т

Microanalysis: Found C, 57.50; H, 6.71; M, 16.01. Cg/NgvMaOl-0.4H2O must be C, 57.50; H, Preparation 109 6.85; M, 15.9695. Ethyl z-(Ctret-

Preparation of 105 butoxycarbonyl)amino|methyl)nicotinate 3-(3,5-Diethyl-1-(2-(2- with methoxyethoxy)methoxy|ethyl)-1H-pyrazol-4-srayl)oxy|-5- (5-(trifluoromethyl)-1,2,4-oxadiazol-3-o Y o yl|Ibsenzonitrile 2 se-, I st | To the stirring solution, ethyl 5- and M cyanonicotinate (3.0 g, 17.0 mmol ; Appaiep Oeg

Spethier, 1959, 621, 106-136) in ethanol (200 ml) sv o-on, concentrated hydrochloric acid was added - | i- (Z4ml) followed by 590 palladium on charcoal (Z30Omg). The reaction mixture was stirred at room temperature in a hydrogen atmosphere (5Opsi) for 18

To a stirred solution of amidoxime from hours. The reaction mixture was filtered through

Preparation of 104 (300mg, 0.7Omol) in Agrose!F pyridine and concentrated under reduced pressure

Three mL) of trifluoroacetic anhydride was added to the mixture with little stirring and the crude product was purified using

I carry: p In the flash chromatography on silica gel, I use the reaction mixture of dichloromethane:methanol:0.880 as an eluent at room temperature for 2 hours and heated at 110 C for 18 hours. ammonia (gradient from 95:5:0.5 to 85:5:1.5, volume)

After warming to room temperature, the intermediate amine (2.1 g) was obtained as a yellow mass. The mixture was concentrated under reduced pressure to give a cloudy solid. This material (21g of the residue was divided between 2M aqueous solution of He) 11.7mmol) was suspended in dichloromethane (22ml), (bml) and dichloromethane (bml). Triethylamine (1.8 ml, 13.0 mmol) was added to the organic phase, after which it was separated and concentrated under reduced pressure with di-tert-butyl dicarbonate (2 mg, 13 mmol). pressure The residue was purified using a flash. After 48 hours, the reaction mixture was diluted with

lormethane (50ml) and washed with water (50ml). 7.5 (wide s), 7.59 (wide s), 8.14 (wide

The organic component was dried over sulfate c), 8.31 (m, 1H), 8.72 (m, 1H), 8.90 (m, 1H). magnesium and concentrated under reduced pressure and HPMS (electrospray): t/2 152 (MH") then purified by flash chromatography. HPMS: IMNYA 152.0819. C7Ni0M2O is necessary on silica gel using dichloromethane as an eluent: 152.0818 methanol:0.88 ammonia (gradient from Preparation 112 100:0:0 to 95:5:0.5, v/v) to give the indicated Ethyl 2-(tert- in the title compound (2.0g) as a yellow oil. butoxycarbonyl )amino|methyl)uizonicotinate 1TH-NMR (400 MHz, SOCI»z): b-1.40 (m, 12H), 4.42 OO lOH, (m, 4H), 8.22 (s, 1H), 8 .71 (c, 1H), 9.12 (c, 1H).

NRMO (HIAT): t/2 279 (M-NU) sia

Preparation 110 5-((third- 4)

Butoxycarbonyl)amino|methyl)nicotinic acid 0

Х Х To the stirring solution, ethyl 2- neo Hn) ! 100 g of cyanoisonicotinate (2.00 g, 11 mmol, .. Mea. - Spet., 1976, 19, 483) in ethanol (20 ml) was added to a 2 M aqueous solution of hydrochloric acid (7.5 ml)

To the stirred solution of the ester with 595 palladium on charcoal (200 mg) was added. Reaction preparation of 109 (2.00g, 7.10mmol) in TM aqueous solution was stirred at room temperature with sodium hydroxide solution (15ml, 15mmol) added under a hydrogen atmosphere (bOpsi) for 48 hours. poured methanol (15 ml). Mix the reaction mixture - the mixture was filtered through Agrosey! and lily of the valley filtrate at room temperature for 18 h and centrifuged under reduced pressure. The remainder of the vessels, after which methanol was removed by azeotropic distillation using reduced pressure. The aqueous solution was washed with toluene under reduced pressure. To a solution containing diethyl ether (2 x 25 ml), cooled to stirring, the residue (3.00 g) in dichloromethane

OS and neutralized to pH 7 by adding 2M aqueous (22ml), triethylamine (4.6ml, 33mmol) and hydrochloric acid solution (7.5ml) were added. The mixture con- after which di-tert-butyl dicarbonate (2.62 g, concentrated under reduced pressure to obtain 12.0 mmol). After stirring for 1 yellow oil (1.51g). hours at room temperature reaction mixture

IN NMR (400 MHz, (C03)250): 6b-1.37 (s, 9H), diluted with dichloromethane (100 ml) and washed with 4.16 (d, 2H), 7.51 (m, 1H), 8.07 (c, 1H), 8.50 (c, 1H), water (50 ml). The organic component was washed with 8.88 (c, 1H). saturated aqueous solution of sodium chloride

NRMO (HIAT): t/2 251 (M-N"U) (5Oml), dried over magnesium sulfate and concentrated

Preparation 111 was carried out under reduced pressure to obtain a brown oily solid. The crude product was purified using flash chromatography on silica gel using as an eluent

Dichloromethane:methanol:0.98 ammonia (98:2:0.2 and then 97:3:0.3, by volume) was used to obtain the

To a stirred solution of the acid the title compound (2.20 g) as a yellow oil.

Preparation of 110 (770mg, 3.100mmol) in dime- IN-NMR (400mg, SOCI3): 6-1.38 (t, ЗН), 1.45 carbonyldiimide (c, 9Н), 4, 38 (k, 2H), 4.50 (m, 2H), 5.50 (broad c, sol (b0Omg, 3.70 mmol). After 10 minutes, add 1H), 7.73 (d, 1H), 7 .81 (c, 1H), 8.65 (d, 1H). or 0.80 ammonia (Iml). After another 1 hour HRMS (electrospray): t/72 281 (MH) the reaction mixture was concentrated under reduced Preparation 113 pressure and the residue was purified by flash 2-((tert-chromatography on silica gel using in Butoxycarbonyl)amino|methyl)isonicotinous /- acid-quality eluent dichloromethane:methanol:0.88 ammonia lot (gradient from 95:5:0.5 to 80:20:1, by volume) peel- o; he chewing Bos-protected intermediate. Trifluoroacetic acid was added to a stirred solution of this material in dichloromethane (20 ml). - o. sn, acid (bml). After 18 hours, a second portion of trifluoroacetic acid (bml) was added, and the reaction mixture was stirred at room temperature. To the stirred solution, the ester with Pry- for 24 hours. The solution was concentrated while preparing 112 (1.50 g, 35 mmol) in methanol under reduced pressure, obtaining an oily solution (1O0ml), a 1M aqueous solution of hydroxide was added to the excess, which was purified using flash sodium chromate (1Oml). After 1 hour, the reaction mixture was cooled to 02С and neutralized by adding eluent dichloromethane:methanol:0.88 ammonia 2M aqueous solution of hydrochloric acid (5 ml) (100:0:0, then 90:10:1, then 80:20:1, by volume) The reaction mixture was concentrated under reduced pressure to obtain the of the title compound (650 mg) pressure and the residue was purified by flash as a yellow oil, chromatography on silica gel using in 'H NMR (400 mg, (CO3)250): 6b-4.11 (c, 2H), eluent quality dichloromethane:methanol: 0.880 ammonia

(80:20:11, by volume) to give the title compound (1.30 g) as a yellow foam. trituration with diethyl ether (10 ml) obtaining

IN NMR (400 MHz, COzO0): 6-1.43 (s, 9H), 4.36, a sample of the desired product (1.0 g) as a white powder (s, 2H), 7.68 (m, 1H), 7.91 (s, 1H), 8.47 (m, 1H). shock.

NRMS (electrospray): t/2 251 (M-NU) IN NMR (400 MHz, O6-DMSO): 6b-1.39 (s, 9Н),

VRMS: (MNYA | 253.1179. Si2Ni7M2Ox4 required 4.25 (m, 2H), 7.44 (m, 1H), 7.61 (m, 1H), 7.66 (broad- 253.1183 s, 2H), 8.21 (wide c, 1H), 8.59 (d, 1H).

Preparation 114 NRMS (electrospray): t/2 250 (M-NU) tert-Butyl I(4-(aminocarbonyl)-2- Microanalysis: Found C, 57.26; H, 6.86; M, pyridinylmethylcarbamate 16.65 C12H17Mz3Oz must be C, 57.36; H, 6.82; M, o NN, 16.7290.

Preparation 115

Zh 2-(Aminomethyl)isonicotinamide oh, luky o onov, | I:

To a stirred solution of acids with and Mn,

Preparation 113 (1.93, 520 mmol) in dichloromethane was added to a stirred solution of pyridine in tylformamide (Toml) and I was added. after that, trifluoroacetic acid (15 ml) was added to the 1-(3-thane) hydrochloride (5 mL). After stirring at room temperature, dimethylaminopropyl)-3-ethylcarbodiimide (1.20 g, heated for 18 hours) the reaction mixture - 6.20 mmol). After 1 hour, 0.880 ammonia was added, centrifuged under reduced pressure, and the reaction mixture was purified under reduced pressure and washed azeo-50-X8-200 using as an eluent water after ru p U U U What 0.880 amiocomethanol:water (5:5:90, by volume) by tropical distillation using toluene under reduced pressure to obtain the title compound (265 mg) under reduced pressure, obtaining a yellow semisolid as a white solid Crude the product was purified by H NMR (400 MgC Oe-DMsSO): 5-2.1 (broad with the help of flash chromatography on silica gel, 1H), 34 (broad with 1n), C 85 (gn in 7.57 ( m using dichloromethane 1H as an eluent), 7.60 (broad s, 1H), 7.80 (m, 1H), 8.16 (shitane:methanol:0.88 ammonia (95:5:0 .5, by volume) oky c, 1H), 8.59 (m, 1H) obtaining the title compound (1.1g) as p NRMS (HIAT): v/v 152 (MN) a clear oil that crystallized when standing And!

Computer typesetting by T. Chepelev Signature Circulation 26 approx.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, str. Urytskogo, 45, Kyiv, MSP, 03680, Ukraine

SE "Ukrainian Institute of Industrial Property", str. Glazunova, 1, Kyiv - 42, 01601