UA91415C2 - Pyrazoles as 11-beta-hsd-1 - Google Patents

Abstract

Provided herein are compounds of the formula (I) as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome.

Description

approach to the treatment of diabetes. In addition to the biochemical data discussed above, there are data from transgenic mice as well as small clinical trials in humans that support the therapeutic potential of 11p8-H5O1 inhibition.

Experiments on transgenic mice show that modulation of the activity of 118-H5OYI can lead to beneficial therapeutic effects in diabetes and metabolic syndrome. For example, if the 118-H5O1 gene is deleted in mice, fasting does not lead to the usual increase in the content of ibRavse and FEPKG, and the animals are not prone to hyperglycemia caused by stress or obesity. In addition, in animals deprived of this gene, in which obesity was induced with the help of a feed diet containing a lot of fats, a significantly lower fasting blood glucose content was observed than in normal animals with the same body weight (U. Koiyemizem ei aI. Rgos. May, Asad. Osi. OBA 1997, 94, 14924). It was also established that mice deprived of 11p8-H5O1 have a better lipid profile, insulin sensitivity and glucose tolerance (M. M. Mopopei and U. VI. Spet. 2001, 276, 41293). The effect of overexpression of the 118-H5O1 gene in mice was also investigated. In these transgenic mice, there is an increased activity of 118-H5YUOI in adipose tissue and increased obesity of internal organs, which is associated with metabolic syndrome. Corticosterone content is increased in adipose tissue, but not in serum, and mice show an increased degree of obesity, especially when fed a high-fat diet. Mice fed a low-fat diet exhibit hyperglycemia and hyperinsulinemia, as well as glucose intolerance and insulin resistance (N. Mazi?gaki and I. Zsiepse, 2001, 294, 2166).

The effects of the non-selective 11β-hydroxysteroid dehydrogenase inhibitor, carbenoxolone, have been studied in small clinical trials in humans. In one study, it was established that carbenoxolone leads to an increase in the sensitivity to insulin of the body as a whole, and this increase is attributed to a decrease in glucose production in the liver (V. A. UMaiYiKeg ei aiYi. U. Siip. EpaosgipoY. Meiyar. 1995, 80, 3155). In another study, in diabetics, but not in healthy people, after stimulation with glucagon, reduced glucose production and reduced glucogenesis were observed (A.S. In addition, it was established that carbenoxolone improves cognitive ability in healthy elderly people, as well as in those suffering from type 2 diabetes (T. S. Zapaeer v. a. Rgos. Mai). Asad si OBA 2004, 101, 6734).

A number of nonspecific inhibitors of 118-H5O1 and 118-H5O2 have been identified, including glycyrrhetinic acid, abietic acid, and carbenoxolone. In addition, a number of selective inhibitors of 118-H5O1 were discovered, including chenodeoxycholic acid, flavanone, and 2'-hydroxyflavanone (5. Oiedetgisn ei ai. Yeshig. 9). Epaoshypoi. 2000, 142, 200 and V. A. 5. 5spmvigeg eyi a!. My. SeiI. Epdosiipoi. 2003, 212, 41).

The art requires 118-H5O1 inhibitors that are effective in the treatment of diseases such as type II diabetes and metabolic syndrome. In addition, in this field of technology, 118-H5OI inhibitors are needed, having values of ICzo less than about 1 µm.

One embodiment of the present invention relates to a compound of formula (1): wherein: (8)

Kk, MAV.

M ()

K. I

Kk,

Vi stands for hydrogen;

Ag means adamantane, unsubstituted or substituted by a hydroxy group, an oxy group, a halogen group, an amino group, lower. alkyl-acylamino group or lower. alkylsulfonylamino group;

Az means lower. alkyl, branched or unbranched, halogen, halogen-lower. alkyl, 3- - 8--lene heteroaryl containing 1-3 heteroatoms selected from the group consisting of M, O and 5, which may be unsubstituted or substituted by halogen or lower. alkyl, -MH(CHa On, -MH(CHa)pOsSnHz, -MHNH(SnHz)", -"MH(CHg) ps NzZOH, -

Mn(CHz(CHupOsnH), -"MH(CHz(CHng on, -MSnHgsn(CHzUH, -MH(CHnagzpO(CHg)pCHz, -M(CHneCHz)g9, -"CH2)OH, - (CHNaOO(CHaO)pCHz . includes M, O, and 5, which may be unsubstituted or substituted by lower alkyl, hydroxy, hydroxyphenyl, -(CHg)y-phenyl, -CHNa(CHo)OH or halogen;

Wa means lower. alkyl, branched or unbranched, unsubstituted or substituted by a hydroxy group, - (CH3)t-(C3Cv)-cycloalkyl, unsubstituted or substituted by a hydroxy group or lower. alkyl, haloalkyl, hydroxyalkyl, -(CHn)pO(CHno)CH3, /-«(CHna)zpOo(CHna)pO(CHnao)CH3, /-(CHgaspOoC(CH3)iz or -CH(CH3)x(CHnoz po a saturated heterocyclyl ring containing 4-6 atoms, 1-2 of which are selected from the group consisting of M, o and 5;

Az means hydrogen or lower. alkyl, unsubstituted or substituted by halogen; and n is 0, 1, 2 or 3; t is equal to 0, 1 or 2; and p is equal to 1, 2 or 3; and to its pharmaceutically acceptable salts.

Another embodiment of the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of a compound of the formula! or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

Another embodiment of the present invention relates to a method of treating a metabolic disorder, which includes the step of administering a therapeutically effective amount of a compound of formula I! to the patient who needs it.

The present invention relates to 118-H5OO1 inhibitors. In a preferred embodiment, the present invention relates to pharmaceutical compositions comprising pyrazoles of formula I:

Kk, MAV.

KD ()

K. I

Kk, as well as their pharmaceutically acceptable salts, which are applicable as 118-H5OT inhibitors.

It should be understood that the terminology used in the present invention is intended to describe preferred embodiments and is not intended to be limiting. In addition, although techniques, devices, and materials similar to or equivalent to those described in the actual invention may be used in the practice or testing of the valid invention, the preferred methods, devices, and materials are described below.

In the present invention, the term "aryl" is used to denote a mono- or polycyclic aromatic ring system in which the rings may be carbocyclic; or in which the rings may contain one or more atoms selected from the group consisting of o, 5 and M, commonly referred to as heteroaryl rings. Examples of aryl groups are phenyl, pyridyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, cinnolinyl, furyl, imidazo(|4,5-z|pyridinyl, imidazolyl, indolyl, isoquinolinyl, isoxazolyl, naphthyl,

M,7Inaphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, purinyl, pyridazinyl, pyrazolyl, pyrido(2,3-4|pyrimidinyl, pyrimidinyl, pyrimido(4,5-4|Ipyrimidinyl, pyrrolo(2,3-4|pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, etc.

As used in the present invention, the term "alkyl" means, for example, a branched or unbranched, cyclic or acyclic, saturated or unsaturated (eg, alkenyl or alkynyl) hydrocarbyl radical, which may be substituted or unsubstituted. A cyclic alkyl group is preferably present

Сз-Си2, preferably С5-Сио, preferably С5-С7. The acyclic alkyl group is preferably C1-Cio, preferably C-Cv, preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (including n-pentyl and isopentyl), preferably methyl. Therefore, it should be understood that the term "alkyl" as used in the present invention includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched ), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl, and substituted cycloalkynyl.

The term "heterocyclyl" means a saturated or partially unsaturated 5- or b-membered ring which may contain 1, 2 or 3 atoms selected from the group consisting of nitrogen, oxygen and/or sulfur. Examples of heterocyclyl rings include piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl.

As used in the present invention, the term "lower alkyl" means, for example, a branched or unbranched, cyclic or acyclic, saturated or unsaturated (eg, alkenyl or alkynyl) hydrocarbyl radical in which the cyclic lower is indicated. the alkyl group is C3, C1, C5, C1, C1, C1, C1 or C, preferably C3, C1, C1, C1 or C; and in which the acyclic lower is specified. the alkyl group is Si, C", Cz, Ca, Sv, Sv or

C, preferably - C, C", C3, C, for example, methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl). Therefore, it should be understood that the term "lower alkyl" when used in the present invention includes lower. alkyl (branched or unbranched), lower. alkenyl (branched or unbranched), lower. alkynyl (branched or unbranched), cyclic lower. alkyl, cyclic lower. alkenyl and cyclic lower. alkynyl

Alkyl and aryl groups can be substituted or unsubstituted. If they are substituted, they will usually contain, for example, 1-3 substituents, preferably 1 substituent. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (eg, substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (for example, trifluoromethyl); oxygen-containing groups such as alcohol (e.g., hydroxyl, hydroxyalkyl, aryl(hydroxy)alkyl), ether (e.g., alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehyde (e.g., carboxaldehyde), ketone (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl , arylalkylcarbonyl, arylcarbonylalkyl), acidic (e.g., carboxy group, carboxyalkyl), acid derivatives such as ester groups (e.g., alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy group, alkylcarbonyloxyalkyl), amide (e.g., aminocarbonyl, mono- or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl), carbamate (for example, alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or dialkylaminocarbonyloxy group, arylaminocarbonyloxy group) and urea (for example, mono- or dialkylaminocarbonylamino group or arylaminocarbonylamino group); nitrogen-containing groups such as amino groups (for example, amino-, mono- or dialkylamino group, aminoalkyl, mono- or dialkylaminoalkyl), azide, cyano groups (for example, cyano group, cyanoalkyl), nitro group; sulfur-containing groups, such as thiol, simple thioether, sulfoxide and sulfonic (for example, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more, preferably one heteroatom (for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl,

isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, and carbolinyl).

Below alkyl groups can be substituted or unsubstituted, preferably unsubstituted. If they are substituted, they will usually contain, for example, 1-3 substituents, preferably 1 substituent.

As used in the present invention, the term "alkyl" means, for example, alkyl-O- and "alkyl" means, for example, alkyl-CO-. Alkoxyl substituents or substituents containing an alkyl fragment may be substituted, for example, by one or more alkyl groups.

As used in the present invention, the term "halogen" means, for example, a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical and more preferably a fluorine or chlorine radical.

As used in the present invention, the term "a pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of a compound of formula (I). Salts can be obtained from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrogen chloride, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucilaginous, nitric, oxalic, pamoic, pantothenic, phosphoric, amber, sulfuric, tartaric, oxalic, p-toluenesulfonic, etc. Especially preferred are fumaric, hydrogen chloride, hydrogen bromide, phosphoric, succinic, sulfuric and methanesulfonic acids. Acceptable salts with bases include alkali metal salts (eg sodium, potassium), alkaline earth metal salts (eg calcium, magnesium) and aluminum salts.

Compounds of the formula | include their pharmaceutically acceptable esters. "Pharmaceutically acceptable esters" are derivatives of compounds of the general formula (I) by functional groups, which are readily capable of being converted into the original compounds. Examples of such compounds include physiologically acceptable and metabolically labile esters such as methoxymethyl ethers, methylthiomethyl ethers and pivaloyloxymethyl ethers.

In addition, the scope of the valid invention includes any physiologically acceptable equivalents of compounds of the general formula (I), similar to metabolically labile esters, which are capable of forming the original compounds of the general formula (1).

More specifically, for example, pharmaceutically applicable esters are compounds of formula I, in which, for example, the hydroxy group can be esterified. Examples of such esters are formate, acetate, propionate, butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate, and M,M-dimethylaminoacetate.

Compounds of the formula | may contain one or more asymmetric carbon atoms and may exist as optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. Optically pure forms can be obtained, for example, by separating the racemates, using asymmetric synthesis or asymmetric chromatography (chromatography using chiral sorbents or eluents). The present invention includes all these forms.

It should be understood that for the compounds of the general formula I proposed in the actual invention, it is possible to synthesize derivatives by functional groups and obtain derivatives that are readily capable of being transformed into the original compounds.

Physiologically acceptable and metabolically labile derivatives, which are capable of forming starting compounds of the general formula I, are also included in the scope of the present invention.

Preferred is the compound of formula I, in which

C: stands for unsubstituted adamantane; and

Az means lower. alkyl, branched or unbranched, halogen, halogen-lower. alkyl, 3- - 8--lene heteroaryl containing 1-3 heteroatoms selected from the group consisting of M, O and 5, which may be unsubstituted or substituted by halogen or lower. alkyl, -MH(CHa On, -MH(CHa)pOsSnHz, -MHNH(SnHz)", -"MH(CHg) ps NzZOH, -

Mn(сНзуСНапоснН», -МН(СНз(СНоНно) MosnsНn(СнНзЗОН, -МН(СНг)зО(СНг)оСНз, -М(СНеСНавз)», -"СНа)сОН, - (СНа)пО(СНаг)пСНз, or a 3- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms selected from the group consisting of M, O and 5 which may be unsubstituted or substituted by lower alkyl, hydroxy, hydroxyphenyl, -(CHg)p-phenyl, -"СНе)пОН or a halogen.

Also preferred is the compound of formula I, in which

Ag means adamantane substituted with a hydroxy group, a halogen, an amino group, an acetylamino group, or a methanesulfonylamino group; and

Az means lower. alkyl, branched or unbranched, halogen, halogen-lower. alkyl, 3- - 8--lene heteroaryl containing 1-3 heteroatoms selected from the group consisting of M, O and 5, which may be unsubstituted or substituted by halogen or lower. alkyl, -"MH(CHg OH, -MH(CHg)zpOsSnHz, -MNHON(CHh)", MH(ISHg) С НЗзOH, -

Mn(CH3)(CHpOsnH», -MH(CH3CHnagzone, -MSnHgsn(CHnz3H, -MH(CHg)zpO(CHag)pCH3, -M(CHnegSnH3)g, -""CHag)oOH, - (CHa)pO(CHag )pCH3, or a 3- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms selected from the group consisting of M, O, and 5, which may be unsubstituted or substituted by lower alkyl, hydroxy, hydroxyphenyl, -( CHg)p-phenyl, -(CHg)OH or halogen.

Also preferred is the compound of formula I, in which

C: stands for unsubstituted adamantane; and

Wa means lower. alkyl, branched or unbranched, -(CH8)t-(C3-C5)-cycloalkyl, unsubstituted or substituted by hydroxy or lower. alkyl, haloalkyl, hydroxyalkyl, -(СНа)пО(СНо)СНЗ3, /- (СнапО(СНао)пО(СНг) СН, ««"СНg)pos(СН3)з or -»СН(СН3)г(СНа) pONn

Another preferred object of the present invention is a compound of formula I, in which

Ag means adamantane substituted with a hydroxy group, a halogen, an amino group, an acetylamino group, or a methanesulfonylamino group; and

Wa means lower. alkyl, branched or unbranched, -(CHe)t-(C3-C6)-cycloalkyl, unsubstituted or substituted by hydroxy or lower. alkyl, haloalkyl, hydroxyalkyl, -(СНо)пО(СНа)пСНЗ3, /-

(Snazpo(CHnao)pOo(CHgo) ps Hz, ""CHnazpoCs(CHz)z or -CH(CHz)x(CHg On.

Another preferred object of the present invention is a compound of formula !, in which H2 is trans-hydroxyadamantane.

Also preferred is a compound of formula I in which Az represents a trifluoromethyl group.

Another preferred object of the present invention is a compound of formula I, in which Az means a pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholine group.

Preferred is the compound of formula I, in which Ba means cyclopropyl, tert-butyl, -CH(CH3)2CHegOH, methyl, -

CEz or the group -"СНг)оСЕ", in which n is equal to 1 or 2.

Also preferred is the compound of formula I, in which H5 is a trifluoromethyl group.

Also preferred is a compound of formula I selected from the group consisting of methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; Trans-1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; adamantane-2-ylamide of 2'-methyl-2'H-1,3|bipyrazolyl-4"-carboxylic acid; adamantane-2-ylamide of methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; adamantane-2- 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ylamide; adamantane-2-ylamide tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide; trans-1-tert-butyl- 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide cis-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide; (B-hydroxyadamantan-2-yl)-amide trans-2' -methyl-2' H-/1,3|bipyrazolyl-4"-carboxylic acid; adamantane-2-ylamide of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; adamantane-2-ylamide methyl-5-(4-methylpiperazin-1-yl)-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide 5-(2-hydroxyethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide methyl-5-(1,2,4H-pyrazol-1-yl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide methyl-5-pyrrolidin-1-yl-1H-pyrazole-4 -carboxylic acid; adamantane-2-ylamide 5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide 5-(4-hydroxypiperidin-1-yl) )-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide 5-(2-hydroxyethyl)-methylamino|-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide 5-(2-Hydroxypropylamino)-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide methyl-5-morpholin-4-yl-1H-pyrazole-4-carboxylic acid; adamantane-2 -ylamide of 5-(2-methoxyethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide of 5-isopropylamino-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2- 5-(4-Hydroxymethylpiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide; adamantane-2-ylamide 5-(4-benzylpiperazin-1-yl)-1-methyl-1H-pyrazole-4-carbonate slots; 5-(B-3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide; adamantane-2-ylamide of 5-diethylamino-1-methyl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide tert-butyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid; 5-|4-(2-hydroxyethyl)-piperazin-1-yl|-1-methyl-1H-pyrazole-4-carboxylic acid adamantanilamide; adamantane-2-ylamide 5-(2-methoxyethyl)-methylamino|-1-methyl-1H-pyrazole-4-carboxylic acid; adamantan-2-ylamide 2'-tert-butyl-2'H-1,3bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-chloro-1H -pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-tert-butyl-2'H-(1,3bipyrazolyl-4"-carboxylic acid; adamantan-2-ylamide tert- butyl-5-chloro-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide tert-butyl-5-(3-hydroxypyrrolidin-1-yl)-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide tert-butyl-5-(4-hydroxypiperidin-1-yl)-1H-pyrazole-4-carboxylic acid; 5-azepan-1-yl-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide acid; adamantane-2-ylamide methyl-5-thiomorpholin-4-yl-1H-pyrazole-4-carboxylic acid; adamantane-2-ylamide tert-butyl-5-piperidin-1-yl-1H-pyrazole-4- carboxylic acid; trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (B-fluoroadamantan-2-yl)-amide; trans-M-(4-aminoadamantan-1-yl)-acetamide ; trans-M-(4-aminoadamantan-1-yl)-methanesulfonamide; (5-acetylaminoadamantan-2-yl)-amide trans-2'-methyl-2'H-|1,3 |bipyrazolyl-4"-carboxylic acid; Trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide; trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-methanesulfonylaminoadamantan-2-yl)-amide; Trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide; trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-methanesulfonylaminoadamantan-2-yl)-amide; Trans-2'-tert-butyl-2'H-1,3-bipyrazolyl-4"-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide; (5-methanesulfonylaminoadamantan-2-yl)-amide trans-2'- tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-1-methyl-5-piperidin-1-yl-1H-pyrazole -4-carboxylic acid; trans-2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (B-methanesulfonylaminoadamantan-2-yl)-amide;

Trans-1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; Trans-1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; Trans-1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide; trans-1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide; trans-1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (b-hydroxyadamantan-2-yl)-amide; Trans-5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; (B-hydroxyadamantan-2-yl)-amide trans-2'-cyclohexyl-2' H-(1,3|bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-5- chloro-i-cyclohexyl-1H-pyrazole-4-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclohexyl-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid acid; (B-hydroxyadamantan-2-yl)-amide trans-2"-(tetrahydropyran-4-yl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2- yl)-amide of trans-5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-cycloopentyl-2'H-I 1,3 |bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclopentyl-2'"H-(1,3|bipyrazolyl-4-carboxylic acid; (b-hydroxyadamantane-2 -yl)-amide trans-5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-2'-(cis-4 -hydroxycyclohexyl)-2"H-(1,3bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-ka carboxylic acid; Trans-I-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; trans-1-(cis-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (b-hydroxyadamantan-2-yl)-amide; trans-1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (b-hydroxyadamantan-2-yl)-amide; (B-hydroxyadamantan-2-yl)-amide trans-2-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans -1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-(2-methoxyethyl)-2'H-I( 1,3|bipyrazolyl-4"-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-2'-(2-(2-methoxyethoxy)-ethyl|-2'H-Y 1,3bipyrazolyl-4 "-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl) trans-2'-(Z-methoxypropyl)-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid amide; (5-acetylaminoadamantan-2-yl)-amide trans-2'-(Z- methoxypropyl)-2'H-(1,3|bipyrazolyl-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; ( B-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-cyclopropyl-2' H-(1,3|bi pyrazolyl-4"-carboxylic acid; Trans-4-chloro-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (b-hydroxyadamantan-2-yl)-amide; (b-hydroxyadamantan-2-yl)-amide trans-1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl- 1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2- trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid yl)-amide; (5-acetylaminoadamantan-2-yl)-amide trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4 -carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'- cyclobutyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2g--tert-butyl-4-methyl-2'H-(1, 3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-tert-butyl-4-chloro-2 H-P1, 9|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-4-bromo-2'-tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-acetyl aminoadamantan-2-yl )-amide trans-2'-tert-butyl-4-chloro-2'H-20 (1,3|bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-4-chloro -2'-cyclobutyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclopropyl-2'H-(/1,3bipyrazolyl -4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-4-chloro-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid and (5-acetylaminoadamantan -2-yl)-amide of trans-4-chloro-2'-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid.

Also preferred is a compound of formula I selected from the group consisting of (B-hydroxyadamantan-2-yl)-amide trans-2'-tert-butyl-2'H-(1,3bipyrazolyl-4"-carboxylic acid; (B -hydroxyadamantan-2-yl)-amide 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-methyl-5-pyrrole -1-yl-1H-pyrazole-4-carboxylic acid; adamantan-2-ylamide 2'-methyl-2'H-1,3|bipyrazolyl-4"-carboxylic acid; adamantan-2-ylamide 1-methyl-5 -trifluoromethyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2 -yl)-amide cis-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-methyl-2' H-/1 ,3|bipyrazolyl-4"-carboxylic acid;

(B-hydroxyadamantan-2-yl)-amide 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; adamantan-2-ylamide 2'-tert-butyl-2'H-1,3bipyrazolyl-4"-carboxylic acid; and (B-hydroxyadamantan-2-yl)-amide 1-tert-butyl-5-chloro-1H- pyrazole-4-carboxylic acid.

Another preferred object of the present invention is a compound of formula I, said compound being selected from the group consisting of (5-acetylaminoadamantan-2-yl)-amide trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acids; (5-acetylaminoadamantan-2-yl)-amide trans-2'-tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (5-methanesulfonylaminoadamantan-2-yl)-amide trans- 2'-tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-ethoxymethyl-1H-pyrazole -4-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans -1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5- (5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-cyclohexyl-2'H-(1,3|bipyrazolyl-4 "-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclohexyl-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl )-amide trans-2"-(tetrahydropyran-4-yl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-cyclic Opentyl-2'H-/I1 ,3bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclopentyl-2'"H-(1,3|bipyrazolyl-4-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-2" -(cis-4-hydroxycyclohexyl)-2"H-(1,3bipyrazolyl-4"-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-(cis-4-hydroxycyclohexyl)-5-trifluoromethyl -1H-pyrazole-4-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (B- hydroxyadamantan-2-ylamide trans-2'-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-(2 -methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (5-acetylaminoadamantan-2-ylamide trans-2-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2'-(3-methoxypropyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl) trans-2'-(3-methoxypropyl)-2'H-(1,3|bipyrazolyl-4-carboxylic acid amide; (B-hydroxyadamantan-2-yl)-amide trans c-1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; Trans-5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide; (B-hydroxyadamantan-2-yl)-amide trans-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-4- chloro-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4 -carboxylic acid; (b-hydroxyadamantan-2-yl)-amide trans-1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid; (B-hydroxyadamantan- trans-1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 2-yl)-amide; (B-hydroxyadamantan-2-yl)-amide trans-1-cyclobutyl-5-trifluoromethyl-1 N-pyrazole-4-carboxylic acid; trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide; (5-acetylaminoadamantan-2-yl)-amide trans-5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclobutyl-2'H-(1,3|bipyrazolyl-4" -carboxylic acid; (B-hydroxyadamantan-2-yl)-amide trans-2g--tert-butyl-4-methyl-2'H-(1,3|bipyr azolyl-4"-carboxylic acid; (B-Hydroxyadamantan-2-yl)-amide trans-2'-tert-butyl-4-chloro-2' N-(1,93-bipyrazolyl-4"-carboxylic acid; (5-acetylaminoadamantan-2-yl)-amide trans-2'-tert-butyl-4-chloro-2'H-(1,9|bipyrazolyl-4"-carboxylic acid; and (5-acetylaminoadamantan-2-yl)-amide trans-4-chloro-2' -cyclobutyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid.

Also preferred is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

Also preferred is a method of treating a metabolic disorder comprising the step of administering a therapeutically effective amount of a compound of formula I to a patient in need thereof.

Also preferred is a method of treating diabetes, obesity or metabolic syndrome which comprises administering an effective amount of a compound of formula I.

Another preferred object of the present invention are compounds of formula I intended for use as a therapeutically active substance.

Also preferred are the compounds of formula I intended for the preparation of medicinal products intended for the treatment of a metabolic disorder.

It is preferable to use the compound of formula I! for the preparation of medicinal products intended for the treatment of diabetes, obesity or metabolic syndrome.

General synthesis of the compounds proposed in the actual invention o o o o o ee n OH, Pdrolysis Mmv,v,

YAM " ON,

AH --t; | Ov, v sya-ya A -- Ky v; ok, "M Kk, M V x

Кк Кк 2 3 5 4 1 eМНнМН, 8) о о о о я ов вы о, s і-- ря х or о х pa 20 2s ha

Scheme 1

One general approach to the synthesis of the compounds of the present invention is shown in Scheme 1. In this scheme, a complex B-ketoester of Formula 2 is converted to a compound of Formula 3, wherein X is dialkylamino (such as dimethylamino) or lower. an alkoxy group (such as an ethoxy group) and then a compound of the formula C is reacted with hydrazine to obtain a compound of the formula 4. Then the ester protecting group in the compound of the formula 4 is cleaved off and the resulting carboxylic acid is reacted with an amine of the formula HMA" to obtain the desired compound of the formula 1 The reaction of a compound of formula 2 to obtain a compound of formula C can be carried out under conditions that are well known in the art. For example, when X is dimethylamino, a compound of formula C can be prepared by treating a compound of formula 2 with dimethylacetal of M,M-dimethylformamide in an inert solvent such as an aromatic hydrocarbon (eg, toluene) at a temperature of from about 50 to about 100°C. Examples of the conditions for carrying out this reaction are given in the literature, for example, in the publications of N. N. UU/azzegtapp ei ai. Tekigapeadgop G. ei. 1984, 25, 3743-3746, in 5. Seiip ei ai. Zupipeviv 1983, 566-568, and in 9. bmeiye eyi a. 5upipevziv 1990, 70-72. In the case where X represents an ethoxy group, the compound of formula C can be obtained by treating the compound of formula 2 with triethylorthoformate in the presence of acetic anhydride under reflux. Examples of conditions for this reaction given in the literature, for example, in the publications of Y. Siaizep Peridz, App. Spec. 1897, 297, 1-18; in Her.

Stotbie ei ai. U. Spet. boss. ReikKkip Tgapv. And 1979, 464-471; in M. 5. 5. Raiapki yei ai. U. Med. Spent 2000, 43, 3995-4004; and in M. T. Neitego's a). Temapnedhop 2002, 58, 8581-8589.

Another general approach to the synthesis from intermediate 4 is also presented in Scheme 1. In this method, as described (PCT Ipi. Arry. 2003051820), when the X-dimethylamino group is commercially available, the ethyl ether of 3-dimethylaminoacrylic acid (formula 25) is treated with trifluoroacetic anhydride in toluene and obtain an intermediate product described by formula 2c. Treatment of the intermediate product of the formula 2c with alkylhydrazine gives compounds of the general formula 4.

The reaction of the compound of formula 3 with hydrazine can be carried out under various conditions. For example, a compound of formula C can be reacted with hydrazine or with an addition salt of hydrazine with an acid in an inert solvent such as an alcohol (eg, ethanol). In the case when the acid addition salt of hydrazine is used, the reaction is then carried out in the additional presence of a base, such as a tertiary alkylamine (for example, triethylamine or diisopropylethylamine). The reaction is usually carried out at a temperature of from about -20 to about 807C.

Examples of conditions for carrying out this reaction are given in the literature, for example, in the publications of U. A. Vesk eyi ai. 9.

Self-employed. Spent 1987, 24, 739-740; in S. Mepogli vy a). U. Neiegosusi. Spent 1987, 24, 1669-1676; in ER. V. Research Institute of AI. PCT Ipi. Arri. UUO 2003051845; in E. And atbregii eyi a. GROWTH of Ipi. Arri. UMO 2002044133; in N. 5pitoyugti her a. O5 4,792,565; and in N. ONKI heri a. Visogd. Honey. Spent GI hey. 2002, 12, 3191-3193.

The cleavage of the compound of formula 4 with the formation of the corresponding carboxylic acid is carried out under conditions that are well known in the field of organic synthesis, many of which are described in the publication "Rgoyesiime Sptocirv ip Ogdapis

Zupipeviv" | T. MU. Sgeepe apa R. skh. M. M/iiv, 2pa Edyop, dopp Ulieu 5 bopv, M.U. 1991). For example, in the case when

Ba means methyl or ethyl, the reaction can usually be carried out by treating the compound with one equivalent of an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide, preferably lithium hydroxide, in a suitable solvent such as a mixture of tetrahydrofuran, methanol and water. The reaction can be carried out at a temperature of from about 0°C to about room temperature, preferably at about room temperature. In another example, when Ba represents a group that can be cleaved in an acidic medium, such as a tert-butyl group, the ether can be treated a strong inorganic acid such as a hydrohalic acid such as hydrogen chloride or hydrogen bromide or a strong organic acid such as a halogenated alkanecarboxylic acid such as trifluoroacetic acid and the like.

The reaction is usually carried out in the presence of an inert organic solvent (such as dichloromethane) and at a temperature of from about 0°C to about room temperature, preferably at about room temperature. , which can be cleaved off by catalytic hydrogenation, and with the additional condition that the latter part of the molecule is stable under such conditions, the reaction can be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium on carbon in the presence of an inert solvent (eg, an alcohol such as ethanol) at about room temperature and atmospheric pressure.

Carboxylic acid compound of structure 4, in which HB. means hydrogen, with an amine of the NMA structure," according to Scheme 1, can be carried out by methods well known to one of ordinary skill in the art. For example, the transformation can be carried out by reacting a carboxylic acid of structure 4, in which Ba is hydrogen, or a corresponding derivative thereof, such as an activated ether, with an amine of the structure HMA:A" or the corresponding addition salt with an acid (e.g., hydrochloride), if necessary, then in the presence of a coupling reagent, many examples of which are well known in peptide chemistry. The reaction is usually carried out by treating the carboxylic acid of structure 4, in which Ba is hydrogen, with the hydrochloride of the amine of structure

HMA" in the presence of a suitable base such as diisopropylethylamine, a coupling reagent such as O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate or T5TI and optionally additionally in the presence of a substance that increases the reaction rate , such as 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole, in an inert solvent such as a chlorinated hydrocarbon (eg dichloromethane) or

M,M-dimethylformamide or M-methylpyrrolidinone, at a temperature from about 0"C to about room temperature, preferably at about room temperature. Alternatively, the reaction can be carried out by converting the carboxylic acid of formula 4, in which Ba" is hydrogen, into an activated an ester derivative, such as an M-hydroxysuccinimide ester, followed by its reaction with an amine of the structure HMA" or with the corresponding addition salt with an acid. This sequence of reactions can be carried out by the reaction of a carboxylic acid of formula 4, in which Na is hydrogen, with M-hydroxysuccinimide in the presence of a coupling reagent such as M,M'-dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran at a temperature of from about 0°C to about room temperature. The resulting M-hydroxysuccinimide ester is then treated with an amine of the structure HMA:P" or the corresponding addition salt with an acid, in the presence of a base such as an organic base (e.g., triethylamine or diisopropylethylamine, etc.) in a suitable inert solvent such as M,M-dimethylformamide, at about room temperature.

The sequence of reactions shown in scheme 1 can also be carried out using solid-phase synthesis, in the case where X means an amino group bound to the polymer. In this methodology, the compound of formula 2 is treated with M-formylimidazole dimethylacetal bound to a polymer with an amine, such as an aniline-functionalized cellulose derivative (for example, 4-aminophenylsulfonylethoxycellulose manufactured by Iopiozogo,

Ovii pai Iaret, Slesp Veribiis) in the presence of an acid catalyst such as camphorsulfonic acid in an inert solvent such as M,M-dimethylformamide at a temperature of about 80°C to obtain compounds of formula 3 in which X represents a bound with an aniline polymer. The compound of formula C is then converted to the compound of formula 4 by treatment with hydrazine in an inert solvent such as an alcohol (e.g., isopropanol) at a temperature near the boiling point of the solvent. Examples of conditions for this reaction are given in the literature, e.g., publication I . Oye I osa eyi a. U. Sotr. Speth. 2003, 5, 465-471. c) o o IT i, mA,

A uv me, chn

In MA, I, | M. in-ya

M 3 x

IS

B t 1

Scheme 2

A pyrazole-4-carboxamide of formula 1, in which H5 is hydrogen, can be obtained according to scheme 2, according to which a p-ketoamide of formula b is converted to a compound of formula 7, in which X is a dialkylamino group (such as a dimethylamino group) or lower. an alkoxy group (such as an ethoxy group) and then a compound of formula 7 is reacted with hydrazine to give a compound of formula 1. A compound of formula 6 can be reacted to give a compound of formula 7 under conditions well known in the art. For example, when X is dimethylamino, a compound of formula 7 can be prepared by treating a compound of formula 6 with dimethylacetal of M,M-dimethylformamide in an inert solvent such as an aromatic hydrocarbon (eg, toluene) at a temperature of from about 50 to about 100°C. . Examples of conditions for this reaction are given in the literature, for example, in the publications of V. 2irei ei ai. 9. Negegosushi. Spet. 1991, 28, 1731-1740; in 0. E. 5eii» eiii a). Temapedgop I eiii. 1995 , 36, 1413-1416; in A.M. Wata Rao and a. Temanedgoop II. 1990, 31, 1439-42; and in R. Kosiepe5ki and a. Temanedgoop Gay. 1988, 29, 4481-4. In when X is an ethoxy group, the compound of formula 7 can be obtained by treating the compound of formula 6 with triethylorthoformate in the presence of acetic anhydride under reflux. Examples of the conditions for this reaction are given in the literature, for example, in the publication of N. Oyemagei A. U. Speth. bos. 1961, 3254-3260.

The reaction of the compound of formula 7 with hydrazine can be carried out under various conditions. For example, a compound of formula 7 can be reacted with hydrazine or an addition salt of hydrazine with an acid in an inert solvent such as an alcohol (eg, ethanol). In the case when the acid addition salt of hydrazine is used, the reaction is carried out in the additional presence of a base, such as a tertiary alkylamine (for example, triethylamine or diisopropylethylamine). The reaction is usually carried out at a temperature of from about -20 to about 807C.

Examples of the conditions for conducting this reaction are given in the literature, for example, in the publications of A. Kh. Viooga.

Mea. Spent Gay. 1998, 8, 2787-2792; in T. A. Eitaai! her a. swarms 9). Snet 2002, 76, 945-952 Spetisa! Arzigasiv AM 2002:501464; and in S. Siasoteiia ei a). Yeshig U. Oga. Spent 2003, 537-541.

The sequence of reactions shown in Scheme 2 can also be carried out in the case where X is aniline. Thus, a compound of Formula 7 can be prepared from a compound of Formula 6 by treatment with M-(Alkoxymethylene)aniline, optionally in the presence of an inert solvent such as kerosene, at an elevated temperature such as from about 125 to about 140°C. Example Conditions the conduct of this reaction are given in the literature, for example, in the publications of E. V. Oaip Spect. Veg. 1902, 35, 2496-2500; in R. V. Oaipz eyi a). U. At. Spect. bos. 1909, 31, 1148-1157; in R. V. Oaiipz eg a. 9). At. Spec. bos. 1918, 40, 562-569; and in O. 5. Moirei5 Spec. Veg. 1981, 114, 3471-3484.

The compound of formula 7 can then be converted to the compound of formula 1 by treatment with hydrazine in an inert solvent such as ethanol at a temperature near the boiling point of the solvent. Examples of the conditions for conducting this reaction are given in the literature, for example, in EP publications. V. Yuaip5 ei ai. 9). At. Spent boss. 1909, 31, 1148-1157; in RV Oaipe yei ai. 9. At. Spent boss. 1916. 38, 1515; in R. V. Oaipv vy a. 9). At. Spent boss. 1918, 40, 562-569; and in A. M. Voghizemisp eyi a. OKgaip5kKii Kpitispezkii 7pygpa! 1986, 52, 641-7 Spetisai! Abzigasiv AM 1987: 458919.

Ma o o snzona » o vnnmn Not even that Cat who -808- - -- 6 more vo00-- m o 8 9 "7 1

Scheme Z

Compounds of the present invention wherein H5 is lower. alkyl, including lower. haloalkyl, such as trifluoromethyl, can be obtained by the reactions shown in Scheme 3. In this procedure, which for the case where 5 is trifluoromethyl, is described in EP 1067121A2, an alkyl cyanoacetate such as ethyl cyanoacetate is treated with an ester such as ethyl trifluoroacetate in the presence of a base , such as sodium ethoxide in ethanol. The resulting sodium salt adduct 10 is then treated with an alkylhydrazine such as methylhydrazine to effect a cyclization to 5-amino-1-alkylpyrazole 11. The 5-amino group can then be converted to another group, such as a halide (see below). oh oh

M not uya RMnMv, but p tobomoh then sv - I - 5 sh mn, ---- x ml y I th 12 13 14

Scheme 4

As shown in scheme 4, the derivative of 1-alkyl-5-pyrrolylpyrazole-4-carboxylic acid of formula 14 can be obtained using as a starting material the ester of 3-alkoxy-2-cyanoacrylic acid of formula 12 by reaction with hydrazine of the formula АМНМН» and obtain an intermediate 5-aminopyrazole of formula 13, which can then be reacted with 2,5-dimethoxytetrahydrofuran to give 5-pyrrolylpyrazole of formula 14. It can be converted into the carboxamide of the present invention by reactions analogous to those discussed above for scheme 1. The annulation reaction, which leads to the formation of the pyrazole, can usually be carried out by treating a 3-Alkoxy-2-cyanoacrylate ester of formula 12 (such as 3-ethoxy-2-cyanoacrylic acid ethyl ester) with a hydrazine of the formula AMNMH" in an inert solvent such as ethanol at boiling 'yatinni with reflux refrigerator. Further annulation to form the pyrrole ring is usually carried out by heating the intermediate 5-aminopyrazole with 2,5-dimethoxytetrahydrofuran in an organic acid such as acetic acid at a temperature of about 1007°C. An example of conditions suitable for carrying out this reaction is given in the literature, e.g. , in the publication of M. Correi ai. 9. Neiegosusi. Spets. 2001, 38, 1045-1050.

Additional examples of methods for obtaining 5-amino-1-arylpyrazole-4-carboxylates are given in publications .. zZmeik Neiegosusieev 1984, 22, 2513-2516; at 9. VA. VeskK ei ai. uU Self-employed. Spent 1987, 24, 267-270; and in T.

Ye erbeg! z ei ai. Viogd. Honey. Spent And hey. 2000, 10, 821-826. The carboxylate of formula 14 can then be hydrolyzed to the corresponding carboxylic acid and introduced into a coupling reaction with an amine of the formula HMA:Ag using methods similar to those discussed above for the conversion of the carboxylate of formula 4 into the compound of formula 1 proposed in the present invention. o - o I- o o o lettre brom, o and password MA, MAV, poh ZHETNH po M--e You LIVE po k p Kk Kk 16 17 18

Scheme 5

As shown in Scheme 5, the 1-alkyl-5-arylpyrazole-4-carboxylic acid derivative of formula 18 can be prepared using the 5-aminopyrazole-4-carboxylate of formula 15 as starting material by diazotization of the amino group in the presence of a halogenating reagent such as copper bromide ( AND). The reaction is usually carried out by treating a compound of formula 15 with an alkyl nitrite such as tert-butyl nitrite or isoamyl nitrite in an inert solvent such as a halogenated hydrocarbon (e.g. carbon tetrachloride) at about 50°C in the presence of a source of bromine such as bromine bromide copper(I), dibromomethane or bromoform.

Alternatively, chlorination can be carried out at the C-5 position by replacing the bromine source with a chloride source such as copper(I) chloride. The conditions suitable for carrying out this reaction are given in the literature, for example, in the publications of U. V. Vesk apa M. R. Gupsp 05 4620865 and in N. Migikaja OR 2002003410. The conversion of the complex ester of the formula 16 into the amide of the formula 17 is similar to the conversion of the compound of the formula 4 into the compound of formula 1, discussed above, and it can be carried out according to similar reactions. The conversion of a compound of formula 17 to a compound of formula 18 of the present invention can be carried out by a Suzuki reaction with an organoboronic intermediate such as an arylboronic acid or an ester thereof, a reaction well known to one of ordinary skill in the art. For example, the reaction can usually be carried out by reacting a compound of formula 17 with an arylboronic acid in a conventional inert solvent, such as a polar aprotic solvent (eg, M,M-dimethylformamide), or a simple ether (eg, dioxane) or water, in the presence of a catalytic amount of the complex palladium(0) (e.g. tetrakis(triphenylphosphine)-palladium(0)) or a compound that can be reduced to palladium(0) (e.g. palladium(I) acetate or bis(triphenylphosphine)-palladium(I) chloride ), optionally additionally in the presence of a catalytic amount of a phosphine ligand, such as tri-o-tolylphosphine or tri-tert-butylphosphine, or alternatively in the presence of a previously prepared palladium(0) complex with a phosphine ligand such as bis(tri- cyclohexylphosphine)-palladium, and in the presence of an inorganic base, for example, an alkali metal carbonate, bicarbonate, hydroxide or phosphate (for example, potassium phosphate or sodium carbonate or sodium hydroxide) at a temperature of from about room temperature to approx

1007C, and preferably from about room temperature to about 50"C. The conditions suitable for carrying out this reaction are given in the literature, for example, in the publication of H.-U. UMapd apa K. Sgohipdeg Teigapedgop

Gene. 2000, 41, 4713-4716. The starting substance of the formula 15 can be obtained from the ester of 3-alkoxy-2-cyanoacrylic acid of the formula 12 by reaction with alkylhydrazine according to reactions similar to those described above for obtaining the compound of the formula 13. Conditions suitable for carrying out this reaction are given in the literature, for example, in publications R. Vopaamagiiyi eyi ai. U. Med. Spent 2002, 45, 4875-4887; in 5. Zopepope ei ai. Visogd. Honey. Spent And hey. 2001, 11, 2529-2531; in M. Korrei ai. U. Neiegosusi. Spent 2001, 55, 1045-1050; and in R. bepesi eyi ai. Have a drink

Sottype 1999. 29, 311-341 3 b 3 g Z MA, A, Z MA, A,

Scheme 6

As shown in scheme b, it is possible to replace 5-bromopyrazole of structure 21 with amines upon heating with microwave radiation to obtain a compound of general structure 22. and c; o, Lya y man, dme x y M N tyh M x V, 7 v, "my, v v 23 24

Scheme 7

As shown in Scheme 7, a compound of formula 24, wherein Bi is lower. alkyl, can be prepared from a compound of formula 23 by reaction with a strong base (such as sodium hydride) in an inert solvent (such as dimethylformamide) at room temperature to produce the corresponding anion. Then it is introduced into the reaction with the lower one without separation. with an alkyl halide of the formula NIH, also at room temperature, and obtain the desired compound of the formula 24, in which Bi means lower. alkyl

Techniques suitable for obtaining many p-ketoesters of formula 2 are known from the literature. A list of many of these methods is given in the publication "Sotrgepepvime Ogdapis Tgapeioptaiyope: A Szcide yuyu Eipsiyopai!

Stocyr Rgeragayopv" | V. S. IGagosk, MSN RybiizPpegv, Ips. Mem Khoik, 19891, for example, on p. 685, 694-695 and 768.

Additional examples of synthesis techniques suitable for obtaining many B-ketoesters of formula 2 are given in the publication "Aimapsei Ogdapis Spetivigu" (U. Magsn, Zga Eaiiop, dopp UMieu b Bop5, Ips. Mem Moik, 1985) on pp. 437-439 and 823-824. In addition, more than 100 B-ketoesters of formula 2 are listed as being commercially available in

Amayarie Spetis! of Oigesiog, which is well known to those skilled in the art of organic synthesis. about; ono si pa «g nov, r o 6 o o v; he, 26 2

Scheme 8

One example of a method for obtaining a B-ketoether of formula 2 is shown in Scheme 8. Meldrum's acid (25) is treated with an acyl chloride of the formula AzSOCI in an anhydrous inert solvent such as a halogenated hydrocarbon (eg, methylene chloride or dichloroethane). The reaction is carried out in the presence of an anhydrous organic base such as pyridine, triethylamine or diisopropylethylamine at about room temperature. Conditions suitable for carrying out this reaction are given in the literature, for example, in the publication of N.

Etiyepaz her a. U. Ogd. Spent 2001, 26, 6756-6761. The resulting intermediate of formula 26 is then heated with an alcohol of formula HO, either using the alcohol as a solvent (for example, when the alcohol is methanol or ethanol) or in an inert solvent such as benzene (for example, when the alcohol is benzyl alcohol or tert-butyl alcohol). The reaction is usually carried out at a temperature of from about 60 to about 80"C. Conditions suitable for carrying out this reaction are given in the literature, for example, in the publication of U. Oikam ei a). U. Ogud. Spet. 1978, 43, 2087-2088 he o

NMA. And oh

E. Eh at 172

Here. in

Ge) at 26 27

Scheme 9

B-Ketoamides of formula 27 can be obtained from the intermediate of formula 26 by treatment with a stoichiometric amount of the amine of formula HMA:A" in a suitable inert solvent such as toluene under reflux. The conditions suitable for carrying out this reaction are given in the literature, for example, in the publication P. 5 Rak ei a. Zupipeziz 1992, 1213-1214.

Sources of monosubstituted hydrazines of formula 5

Many monosubstituted hydrazines of formula 5 are commercially available or are prepared by one of the many synthetic techniques well known in the organic chemistry field described above.

More than 100 hydrazines, some of which can be used in the actual invention as compounds of formula 5, are sold by such firms as Aidgisp Spetisai, Ips., MimatsyKe, UMI; TSI Ateigisa, Ropapa, OV; I apsavzieg Zupipeviv tsa, Iapsazpige, OK; ABOY Ips., Mezhagk, OE; Vuap osiepiyis, Ii oi Raite5, 5C; OaKmooy Rgodysiv, Ips., M/evi

Soishtbria, 5C; Aa Aezai, UMaga NiyiYi, MA. Many other examples are given in the publication of Amaiarije Spetis!5

Oigesiogu (MY. Iptogptaiop buvzietv, Zap I eapago, SA) or 5sigipaeg (Spetisa! Arvigasiv Zegmiise5, Soishtryv,

ON).

Many methods of obtaining hydrazines are known and their overview is given in the publication "Te Spetivigu oi She

Nuagago, Ago, apa Agohu Stgotsrv. Rap 1" Y. Titrepake apa u. 5iomuei!; 5. Raiai Ed.; dhopp UMieu 5 ope, CY.

Hopaop 1975, 69-107). In addition, several methods of obtaining substituted hydrazines are given in the publication of Sh.

Vadpagzzop Spe. wasps Neu. 2001, 30, 205-213.

In addition to the methods described in detail below, the following methods can be used to obtain alkylhydrazines: the reaction of an aldehyde or ketone with a hydrazide followed by reduction and hydrolysis (СН 307629, Spet. ABrv. 51: 25623; M.I. SPaiyi a. U Ogd . Spet. 1981, 46, 5413-5414); Hoffman's reaction of urea (9. Migei and A. Temapedgop 1987, 43, 891-894); electrophilic amination of alkylamine: (S. R. Atsagiei apa 1. n.

Oiatopa u). At. Spent boss. 1954, 76, 4869-4871; A. Kolyaga eyi ai. Have a drink Sottype 1995, 25, 3805-3812); reaction

Mitsunobu alcohol with M-tert-butoxycarbonylaminophthalimide with subsequent hydrolysis (M. Vgo55e ei a).

Temgapedtop Hey. 2000, 41, 205-207); conversion of alkylamine into the corresponding M-alkylsydnon with further hydrolysis (U. Ryddeg ei ai. U. At. Spets. bos. 1955, 77, 1843-1848); reaction of alkyl bromide with diethyl ether

M'-isopropylidenephosphorohydrazinic acid or diphenylphosphinic acid hydrazide with subsequent removal of the protective group (5. 2amzhadki ei a). bupipeziz 1987, 485-487; V. MioikozheKka apa 7. 2miyeeggak

Teganedop Hey. 1978, 19, 4731-4734).

N

- ---I--how - -і6 Kk Men, 16-Х 28 5 іо-О0То5 29

Io-5SN., 30

Scheme 10

A monosubstituted hydrazine of formula 5 can be obtained by nucleophilic substitution of the compound with a suitable leaving group, 5 as shown in Scheme 10. Suitable leaving groups are compatible with the reaction conditions used to prepare the compounds of the present invention. Examples of such groups are p-toluenesulfonate (OTo5) or halogen groups, including bromide, chloride and fluoride, preferably bromide or chloride. For example, a compound of structure 5 can be prepared from a compound of structure 28 by treating a halogenated compound of formula 28 with hydrazine hydrate in an alcoholic solvent such as methanol, ethanol, or 1-butanol at about room temperature or at the boiling point of the solvent used.

Alkyp -Mn, --ia Alkyl -MNMn, 29 5 (B-alkyl)

Scheme 11

Alkylhydrazines of formula 5 can be prepared from the corresponding amino-containing structure 29 as shown in Scheme 11. The reaction can be carried out by treating the amino-containing structure 29 with hydroxylamine-O-sulfonic acid in ice water in the presence of an inorganic base such as potassium hydroxide, and water.

The synthesis is carried out at approximately the boiling point. Hydroxylamine-O-sulfonic acid is commercially available.

Alternatively, the compound of structure 5 can be prepared by slow addition of chloroamine to the amine of structure 29 in the presence of potassium hydroxide. The resulting mixture is kept for several hours and filtered, if necessary to purify the reaction mixture from amine hydrochloride and/or ammonium chloride that has precipitated. Alkylhydrazine of structure 5 is purified by distillation. Chloroamine can be obtained by reacting chlorine with ammonia. 6) о c) в ие ныши про зо 31 32

H

Inn and Kk, A --- wounds about k-Mm-Mn, SIN 33 5

Scheme 12

Some alkylhydrazines of structure 5 can also be prepared from the ketone or aldehyde of structure 30 according to scheme 12 by forming the tert-butyl alkylidene carbazate of formula 32, which can then be reduced and hydrolyzed to give the hydrochloride compound of formula 5. The first reaction can be carried out by treating the carbonyl of formula 30 with tert-butyl carbazate of formula 31 in an inert solvent such as hexane under reflux for a short time. The resulting intermediate 32 can then be reduced with diborane in tetrahydrofuran in an anhydrous medium at about room temperature to give the intermediate carbazate of formula 33. Hydrolysis of the carbazate of structure 33 can be carried out in a dilute acid such as hydrochloric acid at about 100°C to give the alkylhydrazine hydrochloride of formula 5 An example of the use of this technique for obtaining alkylhydrazines is given in the publication of M. I. SzNaii, Eiya! 9). Ogd. Spets. 1981, 46, 5413.

Scheme 13

Scheme 13 shows a general method for the synthesis of many alkylhydrazine derivatives that are not commercially available. Tert-butyl isopropylidene carbazate is alkylated in an alkaline medium, for example, treated with potassium hydroxide and alkyl halides in toluene at 80"C in the presence of an interphase catalyst, such as tetrabutylammonium bisulfate. After alkylation, the isopropylidene protecting group and the Bos protecting group are removed by acid hydrolysis and the desired hydrazine is obtained in the form Hydrochloride. The preparation of tert-butylisopropylidene carbazate, as well as its alkylation, are described in the publication of Zupiei 2004, 2355-2356. 16) "МН, рі n.ММмН, Х --й --- К-МНМН,

Kk; him in; in 36 5

Scheme 14

Alternatively, alkylhydrazines of formula 5 can be obtained from a ketone or aldehyde of formula 30 according to scheme 14 by obtaining an intermediate hydrazone of formula 36 followed by a reduction reaction to give compounds of structure 5. Compounds of general structure 36 can be obtained by reacting an aldehyde or ketone (structure 30) with with an excess of hydrazine hydrate in a solvent such as methanol, ethanol, isopropanol or dioxane at the boiling point of the solvent.

Hydrogenation of the hydrazone intermediate of structure 36 can be carried out using palladium hydroxide or palladium on a support (e.g., activated charcoal) as a catalyst, in an alcoholic solvent (e.g., methanol, ethanol) in the presence of acetic acid at about room temperature under a pressure of 60 lb -force/inch".

J. re no

M. 20 o'clock conc. NOI, Nn ek spe k z. paid p" snn, 37 ZV 5

Scheme 15

In an additional method of synthesis, the Vos group-protected amine of formula 37 is used as a starting material, which is treated with MOBE4 in the presence of pyridine in an aprotic solvent such as acetonitrile, and M-nitroso-M-Bos-alkylamine of formula 38 is obtained. After treatment with M-nitroso -M-Bos-alkylamine of the formula 38 with concentrated NCI and powdered activated zinc at a low temperature, such as -78°C, in a solvent such as methanol, to obtain an alkylhydrazine of the formula 5 (Scheme 15). This technique is described in the scientific literature (A. Kyapo, ei ai., Temzapedop Gei. 2000, 41, 9575-9579).

Many amines of the formula NMA" are commercially available and known to those skilled in the art. In addition, there are many methods of synthesizing amines of the formula NMA" known to a person of ordinary skill in the art.

Many of these methods are indicated in the publications "Tpe Spetivigu oi She Atipo Stoyr" |M. 5. sirzop; 5. Raiai Ea.; add

UMieeu 5 Bopv, TSI. I Opadop 1968, 37-77|, in "Admapseda Ogdapis Spetivigu" U. Magsp, Zga Eaiiop, dopp U/ieu 4 Bopv,

Ips. Mem Moik, 19851, on pp. 1153-1154, and in "Sotrgepepvime Ogdapis Tgapviogptaiyyope: And (zcide Yuyu Eipsiiopai!

Stotsir Rgeragayopvg" IV. S. I agosk, MSN Rybiizpegv, Ips. Mem Hogk, 19891 on p. 1061-1063. In one example of obtaining an amine of the formula NMAiAg2, a solution of oxime obtained from (1H8)-(-)-camphor in alcohol , such as amyl alcohol, is treated with sodium added in small portions over a long period of time, such as about 4 hours. The reaction is carried out at the boiling point of the solvent and the product is (-)-endobornylamine hydrochloride, a compound of the formula HA", in which Bi is hydrogen and HB" means a bornyl fragment. The exact conditions for carrying out this reaction are given in the literature, for example, in the publication of I. A. Radieye and A. R. Ooenpeg, g. 9. Og9d. Spet. 1980, 45, 5105-5113. 1-Hydroxyadamantan- The 4-one reacts with hydroxylamine hydrochloride in boiling ethanol in the presence of aqueous sodium hydroxide to give 1-hydroxyadamantan-4-one oxime, which is then reduced with lithium aluminum hydride in an inert solvent such as tetrahydrofuran under reflux to give 4-aminoadamantan-1-ol, which is usually isolated and characterized as the hydrochloride. The conditions for carrying out these reactions are given in the literature, for example, in the publication of N. M/. SeiShk apa u. I. M. A. Zspiaitapp Teiganeadgop 1968, 24, 5369-5377.

It is also possible to obtain cis- and trans-isomers of 4-aminoadamantan-1-ol using a 3-step technique.

First, commercially available 1-hydroxyadamantan-4-one is reacted with (5)-(-)-1-phenylethylamine under reductive amination conditions (sodium triacetoxyborohydride in acetic acid and dichloromethane at room temperature for 12 hours or longer). Then cis- and trans-isomers of the reductive amination product of 1-phenylethylamine can be separated chromatographically. The cis- and trans-isomers of 4-aminoadamantan-1-ol are then obtained under different hydrogenolysis conditions, as shown in Scheme 16 below.

о и Mavn(odsu 7 dr Mono m Da (in) z" with 75 t ng, 1095 РІС methanol, yumn t-ra, 12 h o trans cis m 42

Scheme 16

Derivatives of the hydroxyadamantanamides can be prepared as shown below in Scheme 17. The tertiary hydroxy group in 43 can be replaced by fluorine with a suitable reagent such as (diethylamino)-sulfur trifluoride (DETS) in a non-polar solvent such as methylene chloride. Compound 43 can also be converted to an amine in two steps involving a Ritter-type reaction with chloroacetonitrile followed by thermolysis with thiourea to give compound 45. By a similar Ritter reaction, compound 43 can be converted to the M-acetyl derivative 46. on ua! 9ae DAST

MN sn, Fr

F -- 4

M, Mn

M t, / in M 43 ts and sn.sM, H.O, m 1. SISN,SM, H,8O,, snIon sneon 2. Thioserea, 9) heating Min.

NM about ra

Mn

MN. they are about, Kk

МН 46 y) yuyu

Kk 45

Scheme 17

As shown in Scheme 18, the intermediate Trans-M-(4-aminoadamantan-1-yl)-acetamides (ie 49) can be obtained.

Protection of the primary amino group of trans-41 followed by a Ritter reaction gives intermediate 48, which is deprotected to give trans-M-(4-aminoadamantan-1-yl)-acetamide 49. Alternatively, compound 49 can be obtained directly from trans-41 (intermediate 2) by heating with a nitrile in trifluoroacetic acid followed by hydrolysis in an alkaline medium. da Ethos-O8y da vsm - A o Нn --- '(-А---- -2-k nem he base of ttosy" OH o ASONIN, BO, mice 41 1. VSM, SESOON 2. man o Piperidine o p pi

Ethos" does NOT blow nm shk 48 49

Scheme 18

As shown in Scheme 19, trans-N-(4-aminoadamantan-1-yl)y-methanesulfonamides (ie: 53) can also be obtained. The intermediate adamantyl alcohol 47, which contains the EMOS protective group, can be converted into the intermediate chloromethylacetamide 50 by the Ritter reaction. The reaction of 50 with thiourea when heated in an alcohol solvent and acetic acid gives amine 51. The conditions for the reactions of the transformation of 47 into 51 are given in the literature (Ugdepvopv, A. ; Katsyzv, M.; KaimipvnN, 1I.; Shosha, M.A. bZupipeziv 2000, 12, 1709-1712). Sulfonylation of 51 in alkaline medium using a suitable sulfonyl chloride, such as methanesulfonyl chloride, followed by deprotection affords trans-N-(4-aminoadamantan-1-yl)y-methanesulfonamide 53.

sisn,sM o H hun nu tu" ON ASON/NIO, Ethos" Y son / BONN 47 50 50, n de EYude water base uv B tost mn ne - 5 55725 ros KY ZV 51 52

Piperidine, O dmenya mV 53

Scheme 19

Trans-M-(4-aminoadamantan-1-yl)-acetamides (ie 49), Trans-M-(4-aminoadamantan-1-yl)-methanesulfonamides (ie: 53) or trans-4-aminoadamantan-1-ol (intermediate 2) can then be coupled with a suitable pyrazole carboxylic acid such as 54 to give the intermediate adamantyl amides 55. Chlorine substitution in 55 can be carried out with various nucleophilic reagents such as pyrazole or substituted pyrazole in alkaline media upon heating and get the product 56. x to y and t and y

M, | --- «Н-«А«-яХщН----- / n

What are you doing?

Kk Ts

Kk x - n,-on, -MNSOK, 54 55 -MNBOZHV. h

M. nn o the basis of MN

M

Ts 1

Kk Ma 56

Scheme 20

As shown in Scheme 21, 1-alkyl-5-methoxymethylpyrazole-4-carboxylic acids 60 can be obtained from 1-alkyl-5-methylpyrazole-4-carboxylic acid ester 57 by bromination with M-bromosuccinimide to give the intermediate bromomethyl derivative 58. Example conditions, suitable for carrying out this bromination reaction, given in the literature (Vesk, 9. ei a!., U. Negegosusi. Spet. 1987, 24, 693-695). Substitution of bromine for a suitable alkoxy group and simultaneous transesterification can be carried out by heating intermediate 58 in an alcoholic solvent with the appropriate sodium salt. An example of the conditions for carrying out this transformation is given in the literature (Opodega, a. ei ai. Ogdapis I eyege 2005, 18, 4029). If sodium alkoxide is not commercially available, it can easily be obtained by treating a suitable alcohol with sodium hydride. Hydrolysis of the ester group in 59 gives the acid intermediate boO, which can then be introduced into the coupling reaction with trans-M-(4-aminoadamantan-1-yl)-acetamides (i.e. 49), trans-M-(4-aminoadamantan-1-yl )y-"methanesulfonamides (ie: 53) or trans-4-aminoadamantan-1-ol (intermediate 2) and obtain compounds of the structure 61. o o o) / I-bromosuccinimide Mast, new

M X p M X an her her 7 in vo vot 57 58 59 x zad Z go) MAO x We

M. in M Kh i r;

Kk ov, V ok, 60 61

Xx - H, -OH, -MNSOK, -MNVO,K

Scheme 21

As shown in Scheme 22, substituted isoxazoles of structure 65 can be prepared using compound 62 as a starting material. Heating compound 62 with the appropriate hydrazine 5 followed by hydrolysis of the ester group affords the carboxylic acid intermediate 64. Compound 64 can then be introduced into the coupling reaction with trans-M -(4-aminoadamantan-1-yl)y-acetamides (i.e. 49), trans-M-(4-aminoadamantan-1-yl)-

methanesulfonamides (ie: 53) or trans-4-aminoadamantan-1-ol (intermediate product 2) and obtain compounds of structure 65. 9) IF) s / Maon or x Masgovn o pon - ch-o H 7m X Z 7 kl mnunoi in 62 63 o n on as o at s shin

And about Ov

Kk E M-o 64 65 х- Н,-ОН, -МНСОВ, -МН5ЗО,К

Scheme 22

In a final but non-limiting example of the synthesis of an amine of the formula NMAIAg, the secondary amine can be prepared by reductive amination, which is well known to those of ordinary skill in the art of organic synthesis, in which the amine is treated with a ketone to produce an imine, which is reduced by one of a variety of reducing reagents. Numerous examples of the conditions that can be used to carry out this reaction are given in the publication "SotrgeNepvime Ogdapis Tgapvioptaiope: A Sycyde o Bipsiyope! Sgotsr Rgeragayopv"

IA. S. Gatyusk, MSN Rybiivpegv, Ips. Mem Hogk, 19891 on p. 421-423. For example, the amine and ketone can be treated with a reducing agent such as tetrabutylammonium cyanoborohydride in an inert solvent such as a halogenated hydrocarbon (eg, dichloromethane) in the presence of a methanolic solution of hydrochloric acid at about room temperature.

The starting substances of formula 12 are usually obtained by treating cyanoacetate with trialkyl orthoformate in the presence of an acid anhydride catalyst, such as acetic anhydride, at 80-1607C. The conditions for conducting such reactions are given in the literature, for example, in the publications of V. sch. dhopez 9). At. Spent boss. 1952, 74, 4889-4891; in M. 9. Syzask ei ai. IN). Spent boss. C 1971, 1501-1507; and in O. AsKeptapp ei aiI. 05 4,277,418.

In carrying out the method proposed in the present invention, an effective amount of any of the compounds proposed in the present invention, or a combination of any of the compounds proposed in the present invention, or a pharmaceutically acceptable salt thereof, is administered by any of the usual and acceptable routes, known in the art, individually or in combination. Thus, the compounds or compositions can be administered orally (e.g., buccally), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., via suppositories or douches), transdermally (e.g., via dermal electroporation) or by inhalation (e.g. by aerosol), and in solid, liquid or gaseous dosage form, including tablets and suspensions. Administration can be carried out in the form of a single dosage form during continuous therapy or in the form of a single dosage form as needed.

The therapeutic composition can also be an oil emulsion or dispersion together with a lipophilic salt, such as a pamoic acid salt, or a long-acting biodegradable formulation for subcutaneous or intramuscular administration.

Pharmaceutical carriers suitable for the preparation of compositions can be solid, liquid or gaseous; thus, the compositions can be tablets, pills, capsules, suppositories, enteric-coated powders or otherwise protected preparations (for example, bound with ion-exchange resins or placed in lipid-bilious vesicles), long-acting preparations, solutions, suspensions , elixirs, aerosols, etc. The carrier may be selected from a variety of oils, including petroleum and animal, vegetable and synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are the preferred liquid carriers, especially (isotonic to blood) for injection solutions.

For example, drugs for intravenous administration include sterile aqueous solutions of the active ingredient(s), which are prepared by dissolving the solid active ingredient(s) in water to obtain an aqueous solution and sterilizing the solution. Suitable pharmaceutical inert excipients include starch, cellulose, talc, glucose, lactose, gelatin, maltose, rice flour, chalk, silicon dioxide, magnesium stearate, sodium stearate, glycerin monostearate, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, ethanol, etc. . Conventional pharmaceutical additives, such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for regulating osmotic pressure, buffers, etc., can be introduced into the composition. Suitable pharmaceutical carriers and compositions prepared using them are described in the publication

Vetipdyup'z Rpagptaseciisa! bsiepsez Bu E. MU. Mapip. Such compositions in any case contain an effective amount of the active compound together with a suitable carrier so as to produce a suitable dosage form suitable for administration to the recipient.

The dosage of a compound of the present invention depends on a number of factors, such as, for example, the route of administration, the age and body weight of the subject, and the pathological condition of the subject to be treated, with the ultimate decision being made by the treating physician or veterinarian. . Such an amount of the active compound, determined by the treating physician or veterinarian, is called the "effective amount" in the actual invention and in the claims. For example, the dose of a compound of the present invention is usually in the range of about 1 to about 100 ug per day.

The present invention is further described by the following examples, which are intended to be illustrative and not to limit the scope of the present invention.

Examples

Reagents were purchased from Aiaigpsny, Bidta, Mauridde, Admapsey SpettTesp, and Iapsaziei or other suppliers listed below and used without further purification. LC/MS (liquid chromatography/mass spectroscopy) spectra were recorded using the following systems. The system for obtaining mass spectra includes the spectrometer Misgotavzv Riayopt II: ER ionization in the mode of positive ions (mass range: 150-1200 at. mass unit). Simultaneous chromatographic separation was carried out using the following system for HPLC (high-performance liquid chromatography): a set of columns E5 Ipaivilevs

Spgotedaropa M/A C-18 Zy 120A (3.2(ZOmm); 5 mobile phase A: water (0.0295 TFA (trifluoroacetic acid) and phase B: acetonitrile (0.0295 TFA); gradient mode from 1095 V to 9095 V during the test, the time to establish the equilibrium of the test, the flow rate 2 ml/min.

Separation by means of supercritical liquid chromatography was carried out using the system

Mesheg-Toiiedo Mipidgat under the following typical conditions: 100 bar, 30"C, elution at a rate of 2.Oml/min., a 12 mm AO column with 4096 MeoN in supercritical liquid CO." In the case of the analysis of substances with basic amino groups, 0.295 isopropylamine was added to the modifying methanol .

Obtaining preferred intermediate products for synthesis

Intermediate 1: 4-Aminoadamantan-1-ol (cis/trans mixture)

KMAI, O, (5 wt.» of catalyst)

MN,on NOI - Nv pound-force"") MN. o maonam) won TON dsavtod, with

Z dune 8 i

Stage 1: 5-Hydroxyadamantan-2-onoxime 5-Hydroxy-2-adamantanone (15g, 90.2mmol, SAB5 4: 20098-14-0, purchased from the TSI company) was dissolved in EYN (100ml) and added to a solution of hydroxylamine hydrochloride ( 10 g, 143, 9 mmol) in zinc. Mahon (8Oml). The mixture was heated at 1007C for 2 hours. EN was evaporated and water and dichloromethane were added. The resulting mixture was stirred for 1 hour. and then filtered. The solid was collected. The resulting mixture was separated.

The aqueous layer was additionally extracted twice with dichloromethane. The combined organic phases were concentrated under high vacuum. The resulting residue was combined with the solid obtained by filtration.

Crystallization from EtOAc gave 5-hydroxyadamantane-2-onoxime (12g, 73905). Mass spectrum: t/2: 182 (M'n1).

Stage 2: 4-Aminoadamantan-1-ol

AP/A25 Oz (2.3g, 5wt.do, 1.1mmol) was added to a mixture of 5-hydroxyadamantane-2-onoxime (10g, 55mmol) in

EUN (110 ml) into the apparatus and Parra for hydrogenation. The hydrogenation reaction was carried out in a Parr hydrogenation apparatus at a hydrogen pressure of 55 psi at 507C for 48 hours. The disappearance of the starting substance and the formation of the product were recorded using LC-MS. The mixture was filtered through celite and concentrated in vacuo to dryness to give 4-aminoadamantan-1-ol (about 9 g of 98905), which was used in the next step without further purification. Mass spectrum: t/2: 168.1 (M-n1).

Intermediate product 2: 4-Aminoadamantan-1-ol (trans) ayuvme, Go ru enlaidevni, he V NO (bbpound- «e And during the night re and Fen ny and tire and o

Stage 1. 4-(8-1-Phenylethylamino)-adamantan-1-ol

Palladium hydroxide on carbon (2.54g, 5Omas.9o water, 20oMas.9o Ra on a dry matter basis, 4.8mmol) was placed in a Parr apparatus (350O0ml) under a nitrogen atmosphere. 5-hydroxy-2-adamantanone (15 g, 90.2 mmol), aluminum isopropoxide (18.43 g, 90.2 mmol), (5)-(-)-1-phenylethylamine (99-95, 9995

EN (enantiomeric excess), 10.94 g, 90.mmol) and toluene (150 ml). The mixture was shaken vigorously for several minutes and then hydrogenated with Na (55 psig?) for 5 h. at room temperature. Then they added yin. Mason's solution (200 ml) and the reaction mixture were thoroughly mixed. After filtration through celite and washing with MeOHN, the filtrate was concentrated to remove organic solvents. The remaining alkaline aqueous mixture was extracted with dichloromethane (3x200ml).

The combined organic phases were concentrated using a laboratory vacuum line and then under high vacuum to give 4-(5-1-phenylethylamino)-adamantan-1-ol (21.65g, 8895) as an oil. The trans/cis ratio for the crude substance according to 1H NMR data is 100:5. Mass spectrum: t/7: 272.2 (M-1).

Stage 2. 4-Aminoadamantan-1-ol (trans) 1095 Palladium on charcoal (1.7g, 1.6mmol) was carefully added to a 350ml Parr apparatus. A solution of trans-4-(5-1-phenylethylamino)-adamantan-1-ol (obtained in the previous step, without further purification, 21.65g, 79.8mmol) in ethanol (150ml) was carefully added to the Parr apparatus under an argon atmosphere. The reaction mixture was hydrogenated in a Parr apparatus with H0 (55 psi) at room temperature overnight.

The reaction mixture was filtered through celite under argon, the celite was washed with ethanol and the combined filtrates were concentrated under high vacuum to give a sticky solid (15g). Acetonitrile (boml) was added and the solution was lyophilized to obtain trans-4-aminoadamantan-1-ol (13.8 g, quantitative yield) as a powdery substance. Mass spectrum: t/2: 168.1 (M-n1).

A preferred method for obtaining intermediate 2 using 5-hydroxyadamantan-2-one as a starting material is described below.

Stage 1: 4-Aminoadamantan-1-ol

5-Hydroxyadamantan-2-one (15g, 90.24mmol, Ipiegpaiopa! breccia) and Ra/C (1.498g, Oedivzza 19985880, 595, 5095 water) were added to the Parr reactor, followed by a solution of ammonia in methanol (7n, 300 .4 ml, 2.1 mol). A hydrogen pressure equal to 200-250 lbf/inch was created in the reactor and maintained for 18 hours. Then the mixture was filtered through a layer of celite and concentrated in vacuo to obtain 4-aminoadamantan-1-ol (15.15 g,

4/-trans/cis according to NMR-O2O) in the form of a white solid. This substance was used directly without additional purification.

Stage 2: trans-4-Aminoadamantan-1-ol hydrochloride 4-Aminoadamantan-1-ol (15.15g, 90.58mmol in the form of a 4/1 "trans/cis" mixture) was suspended in methanol and cooled to 0"C. Slowly added trimethylsilyl chloride (12.1 bml, 95.11 mmol), maintaining the internal temperature below 7"C. The resulting mixture was stirred at 07C for an hour. and then heated to room temperature and refluxed for 2 hours. The suspension was cooled to room temperature and stirred for 1 hour. Then the solid was filtered and dried at 607"C in a vacuum for 18 hours. trans-4-Aminoadamantane-1-ol hydrochloride (12.7g) was obtained as a white solid (95.1595 purity according to gas chromatography, pure trans-isomer according O2O NMR data).

Intermediate 3: 1-Methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid

To a solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid ethyl ether (20g, 91.2mmol; manufactured by the company Viiyi Raik Tsa., Satyoga, Sogpmai, OK) in methanol (10Oml) and GION (2.4 g, 100 mmol) was added to water (100 ml). The reaction mixture was stirred at reflux for 4 hours. and then concentrated under reduced pressure to remove methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (9 ml) and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid, which was used without further purification.

Intermediate product 4: Ethyl-3-M,M-dimethylamino-2-trifluoroacetyl acrylate with parts of ODU all Х Oe po Х M " all ev, -- | ГО !

Trifluoroacetic anhydride (10.1 g, 48/1 mmol) for about 20 min. was added dropwise to a mixture of ethyl-M,M-dimethylaminoacrylate (6.9g, 48.2mmol) and toluene (10ml), which was cooled in an acetone-ice bath (approximately -10°C). The reaction mixture was then allowed to warm to room temperature temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL) and water (8 O mL). The mixture was stirred for 15 minutes and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane.

The combined organic phases were dried in vacuo and purified by chromatography on silica gel eluting in a gradient mode with a mixture of 0-4095 ethyl acetate/hexane, then 4095 ethyl acetate/hexane and obtained ethyl-3-

M,M-dimethylamino-2-trifluoroacetyl acrylate 10.2 g, 89965).

Intermediate 5: Cyclopropyl hydrazine hydrochloride

LANGUAGE, sope. NSI rom vos sl ru-prya Mov district o

Stage 1. M-(tert-Butoxycarbonyl)-cyclopropylamine

A solution of di-tert-butyl dicarbonate (43.7 g, 200 mmol) in dichloromethane (100 ml) was added to a solution of cyclopropylamine (12.4 g, 252.2 mmol) in dichloromethane (5 mL) at 0"C in an ice-water bath. Then the reaction mixture stirred at room temperature for 18 h. The solvent was evaporated in vacuo to give M-(tert-butoxycarbonyl)-cyclopropylamine (31 g, 99905).

Stage 2. M-Nitroso-M-(tert-butoxycarbonyl)-aminocyclopropane

Nitrosonium tetrafluoroborate (9.32g, 79.8mmol) was carefully added in several portions to a cooled (-30"С) solution of M-(tert-butoxycarbonyl)-cyclopropylamine (9.57g, 60.9mmol) and anhydrous pyridine (11.7ml) in dry acetonitrile (150 ml). The solution was stirred at -30"C for 30 minutes. and then at 0"C for 2 hours.

Ice water and EtOAc were added, and the organic phase was separated and quickly washed with 1N. NSI for removing pyridine. The organic phase was washed with sodium chloride. MansCO3 and brine, dried (Md5oOa), filtered and evaporated in a high vacuum at a water bath temperature below 40"C, and obtained

M-nitroso-M-(tert-butoxycarbonyl)-aminocyclopropane (12.1 g, quantitative yield) as an oil.

Stage 3. Cyclopropyl hydrazine hydrochloride

M-Nitroso-M-(tert-butoxycarbonyl)-aminocyclopropane (12g - 60.9 mmol) was dissolved in Meon (bobml) and cooled to -78"C in an acetone/solid carbon dioxide bath. At -78"C with stirring until the reaction concentrated NSI (54 ml) was slowly added to the mixture. Then activated zinc (33.7 g, 51 bmmol; activated powder of nanoparticles produced by Aiagisp) was slowly added to the reaction mixture with stirring at -78°C. The reaction mixture was stirred at -78°C for 8 hours. The reaction mixture was then filtered through Celite. The filtrate was concentrated in a high vacuum at a water bath temperature below 40°C, and crude cyclopropylhydrazine hydrochloride was obtained as a sticky semi-liquid substance.

Intermediate product 6. 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid oo pevom, v cen o ni veorov « roya, SEC z ve g -- vv I , A A

Stage 1. Ethyl ether of 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Triethylamine (2.2 g, 21.7 mmol) and cyclopropylhydrazine hydrochloride (intermediate 5, without further purification; O, Aug, 7 4 mmol) were sequentially added to a solution of ethyl 3-M,M-dimethylamino-2-trifluoroacetylacrylate (intermediate 4, 1.76g, 74mmol) in ethanol (12ml). The resulting suspension was thoroughly mixed and, divided into 3 equal portions, placed in 10 ml test tubes for treatment with Regzop microwave radiation! Spetizigu (Vioiade AV, Zuedep). The test tubes were covered with membranes and treated with microwave radiation with a power of 150 W using Regzop! Spettivigu Mystozhame

Zupipeviziz zuviet (Vioiade AB, bmuedep) at 1607°C for 30 h. The reaction mixtures from these three tubes were combined and the ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, concentrated in vacuo, and purified by chromatography on silica eluting in a gradient mode with a mixture of 0-2090 ethyl acetate/hexane, then 20905 ethyl acetate/hexane and obtained the ethyl ether of 1-cyclopropyl-5-trifluoromethyl-1H- of pyrazole-4-carboxylic acid (140mg, 895) Mass spectrum: t/g: 249.1 (MAT).

Stage 2. 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

GION (16 mg, 0.67 mmol) was added to a solution of 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (14 mg, 0.5 mmol) in NaOH (2 mL) and water (2 mL). The reaction mixture was stirred at reflux overnight and then the solution was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the solution was acidified to pH2 with concentrated NOSI. Then the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (13mg, quantitative yield), which was used without further purification.

Intermediate 7: 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (9) - Pon o MeonH/water mouth AD

E -m E m"

M E and - -

PON (0.54g) was added to a solution of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (5g, 21.2mmol, purchased from Viope) in CH2OH (45ml) and water (A5ml , 22.5 mmol).

The reaction mixture was stirred at reflux for 4 hours. and then the solution was concentrated under reduced pressure to remove methanol.

The residue was diluted with water and the solution was acidified to pH2 with concentrated HCl.

Then the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4.02 g, 8095), which was used without further purification.

Intermediate product 8. 2'-Methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid) i o no od ---------- well ih u m" ham

Stage 1. Ethyl ether of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid

To a mixture of tert-butyl nitrite (29.5 ml, 248 mmol), copper chloride (17.6 g, 177 mmol) and anhydrous acetonitrile (490 ml) in portions over 30 minutes. 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ether (25 g, 148 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 1 hour, then at 657C for 1 hour. Then the mixture was poured into a . HCl (b0Oml) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were concentrated in vacuo and the crude residue was purified by flash chromatography eluting in a gradient mode with a mixture of 0-2095 ethyl acetate/hexane, then 2095 ethyl acetate/hexane and 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester was obtained (18g, 6495).

Stage 2. Ethyl ether of 2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

Sodium hydride (6095 in oil; 767 mg, 19 mmol) was added to a solution of pyrazole (1.36 g, 20 mmol) in dry

DMF (dimethylformamide) (40 ml) in a nitrogen atmosphere at 0"C in an ice-water bath and the mixture was heated at 407 for 1 hour. 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ether (1, 89g, 10 mmol) and the mixture was heated at 1007C overnight and then cooled. Water and ethyl acetate were added, the organic layer was separated and the aqueous phase was extracted three times with EOAc. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography on dioxide silicon by elution in a gradient mode with a mixture of 0-2090 ethyl acetate/hexane, then 2095 ethyl acetate/hexane, and 2-methyl-2'H-1,3-bipyrazolyl-4"-carboxylic acid ethyl ester was obtained (0.2 g, 990).

Stage 3. 2'-Methyl-2'H-/P1,3|bipyrazolyl-4"-carboxylic acid

To a solution of 2'-methyl-2'H-Y1,3|bipyrazolyl-4"-carboxylic acid ethyl ether (340 mg, 1.54 mmol) in

GION (41mg, 1.71mmol) was added to SNZON (5ml) and water (55ml). The reaction mixture was stirred at reflux for 4 hours. and then the solution was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the solution was acidified to pH2 with concentrated NOI. Then the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 2'-methyl-2'H-H1,3|bipyrazolyl-4"-carboxylic acid (30mg, quantitative yield), which was used without further purification.

Intermediate product 9. 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid maords

SM pyati holoyudilkoOs 7th and M - n --i nikom during the night nan her o sov Z solo go 8)

Sean sys in meoninyu yur -- stu ---- Sho s X snsm approx

Stage 1. Ethyl ester of 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid

A solution containing tert-butylhydrazine hydrochloride (10 g, 80.3 mmol), ethyl (ethoxymethylene) cyanoacetate (13.6 g, 80.4 mmol) and anhydrous sodium acetate (8.2 g, 100 mmol) in 100 ml of ethanol was stirred and boiled Refrigerated for 16 hours. The solution was poured into ice water. The separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were successively washed with water and saturated brine and dried over sodium sulfate. The solvent was removed in vacuo and 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester was obtained (13Hg, 7795).

Stage 2. Ethyl ether of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid

To a mixture of tert-butyl nitrite (7.2 ml, 60.5 mmol), copper(!) chloride (4.6 g, 48.5 mmol) and anhydrous acetonitrile (120 ml) in portions over 30 min. 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ether (8.4 g, 39.6 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 1 hour, then at 657"C within 1 hour Then the mixture was poured into the bn. NSI (120 ml) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. Then the combined organic phases were concentrated in vacuo, the crude residue was purified by flash chromatography eluting in a gradient mode with a mixture of 0-2090 ethyl acetate/hexane, then 2095 ethyl acetate/hexane to obtain ethyl ether 1-tert-butyl-5-chloro- 1H-pyrazole-4-carboxylic acid (5.5g, 3995).

Stage 3. 1-tert-Butyl-5-chloro-1H-pyrazole-4-carboxylic acid

GION (0.63g, 26.3mmol) was added to a solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid ethyl ether (5g, 21.7mmol) in methanol (50ml) and water (30ml) . The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure to remove methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (4 ml) and extracted with ethyl acetate. The organic extracts were evaporated in vacuo to give 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (4g, 9195), which was used without further purification.

Preparation of the preferred compounds proposed in the present invention

Example 1 (5-Hydroxyadamantan-2-yl)-amide methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid

He is about the aunt

DIPEA o no and MN, Ddhm/dMF se u

M her (FI x no Y M o;

Example 1 1-Methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (intermediate 3, Zvmg, 0.2 mmol) was dissolved in a mixture of dry dichloromethane (3.2 ml) and dry DMF (0.dml ). DIPEA (isopropylethyl ether) (0.14 ml, 0.1 mmol) and T5TI (72 mg, 0.22 mmol) were added to the resulting mixture. After stirring the mixture for a while. the appearance of an active ester was detected using LC-MS. Then 4-aminoadamantan-1-ol (ZZmg, 0.2 mmol) was added. After another 2 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by reverse phase HPLC with C-18 in a gradient mode of 10-10095 acetonitrile/water and the compound of example 1 was obtained: (B-hydroxyadamantan-2-yl)-amide 1-methyl-5 -pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (44mg, 6595). Mass spectrum: t/27: 341.2 (Mt).

Example 2 (B-Hydroxyadamantan-2-yl)-amide of trans-1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid, our solution: not trans cis

Example 2

Methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (intermediate 3, 2.66 g, 13.9 mmol) was dissolved in a mixture of dry dichloromethane (40 ml) and dry DMF (100 ml). DIPEA (14.5 ml, 83.2 mmol) and T5TIi (5.02 g, 15.2 mmol) were added to the resulting mixture. After stirring the mixture for 1 hour. the appearance of an active complex ester was detected using LC-MSO. Then 4-aminoadamantan-1-ol (2.32 g, 13.9 mmol) was added. Still through

2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in a vacuum and purified by preparative HPLC with reversed phase C-18 in gradient mode 25-3595. The compound of example 2, trans-1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide, which is eluted as the second peak corresponding to the mass spectrum, was isolated with t/2-:341.2 (M1).

Example C

Adamantane-2-ylamide of 2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

Go tatu in DIPEA Ok o

LE a dkhm/dMmF da and sha --- Lk

Ti and Ne and M m and S

Example C 2-Methyl-2'"H-I1,3bipyrazolyl-4"-carboxylic acid (intermediate 8, 50mg, 0.2b6mmol) was dissolved in a mixture of dry dichloromethane (3.2ml) and dry DMF (0.8ml) . DSHEA (0.23ml, 1.3mmol) and T5TI (9Zmg, 0.2v8mmol) were added to the resulting mixture. After stirring the mixture for 1 hour. the appearance of an active ester was detected using LC-MS. Then 2-aminoadamantane hydrochloride (58 mg, 0.31 mmol) was added. After another 2 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane.

The combined organic phases were dried in vacuo and purified by preparative reversed-phase HPLC

C-18 in a gradient mode of 10-10095 acetonitrile/water and obtained adamantan-2-ylamide 2'-methyl-2'H-

1,9-bipyrazolyl-4"-carboxylic acid (65 mg, 7795). Mass spectrum: t/2: 362.2 (M--1).

Example 4

Adamantane-2-ylamide methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (g) what is DUMidMme?

M z. ON 7 M and m on shchh

Gee And you are in!

Example 4

Methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (77 mg, 0.4 mmol, SABY: 119083-00-0, purchased from Viopeia) was dissolved in a mixture of dry dichloromethane (3.2 ml) and dry DMF (0. 8ml). DIPEA (0.28ml, 1.bmmol) and T5TY (145mg, 0.44mmol) were added to the resulting mixture. After stirring the mixture for 1 hour. the appearance of an active complex ester was detected using LC-MOS. Then 2-aminoadamantane hydrochloride (75 mg, O0.4 mmol) was added. After another 2 hours. water was added and the organic layer was separated.

The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in vacuo and purified by reverse phase HPLC C-18 in a gradient mode of 10-10095 acetonitrile/water to give adamantane-2-ylamide 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carbon acid (85mg, 6595). Mass spectrum: t/l: 328.2 (Mt).

Example 5

Adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid and DIPEA what no dk: oh bass son No I Y

I'm full

Example 5 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (b4 mg, O0.4 mmol, SABY: 54367-66-7, purchased from the company

Oakzhoa) was dissolved in a mixture of dry dichloromethane (3.2 ml) and dry DMF (0.8 ml). DIPEA (0.28 ml, 1.6 mmol) and TT (145 mg, 0.44 mmol) were added to the resulting mixture. After stirring the mixture for an hour. the appearance of an active complex ester was detected using /LC-MSO. Then 2-aminoadamantane hydrochloride (75 mg, O0.4 mmol) was added. After another 2 hours. water was added and the organic layer was separated.

The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in vacuo and purified by reverse phase HPLC with C-18 in a gradient mode of 10-10095 acetonitrile/water to give adamantane-2-ylamide. 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 6095). Mass spectrum: t/2: 2941 (MAT).

Example 6

Adamantane-2-ylamide of tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid in the composition of DIPEA (in;

Residential complex

Example 6

Tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate 7, bimg, 0.26bmmol) was dissolved in a mixture of dry dichloromethane (3.2ml) and dry DMF (0.vml). DIPEA (0.23 ml, 1.3 mmol) and T5TI (9 mg, 0.28 mmol) were added to the resulting mixture. After stirring the mixture for an hour. the appearance of an active complex ester was detected using LC-MOS. Then 2-aminoadamantane hydrochloride (58 mg,

Oh, sorry). After another 2 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried in vacuo. It was purified by reverse phase HPLC with C-18 in a gradient mode of 10-10095 acetonitrile/water to give adamantane-2-ylamide 1-tert-butyl-

B-trifluoromethyl-1H-pyrazole-4-carboxylic acid (62mg, 6595). Mass spectrum: t/2: 370.2 (M'-1).

Examples 7 and 8

Trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide and cis-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide on tvtu vech, DhMidmo pa de zhk -- 5 4-- - - i -i n k М Н - s uzi Ж THE ЖЖ in -Ж trans cis

Example 7 Example 8

Tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate 7, 3.28g, 13.9mmol) was dissolved in a mixture of dry dichloromethane (40ml) and dry DMF (10ml). DIPEA (14.5 ml, 83.4 mmol) and T5TY (5 g, 16.7 mmol) were added to the resulting mixture. After stirring the mixture for 2 hours. the appearance of an active ester was detected using LC-MSOS. 4-aminoadamantan-1-ol (2.32 g, 13.9 mmol) was added. In another 4 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane.

The combined organic layers were dried in vacuo and purified by chromatography on silica eluting in a gradient mode with a mixture of 0-6095 ethyl acetate/hexane, then 6095 ethyl acetate/hexane to give (5-hydroxyadamantan-2-yl)-amide cis-1 -tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (example 8, 1.75 g, 33905) and (5-hydroxyadamantan-2-yl)-amide. trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (example 7, 0.85g, 1695). The trans isomer eluted after the cis isomer. Both compounds were characterized using mass spectra: t/2: 386.2 (М--1).

Example 9 (B-Hydroxyadamantan-2-yl)-amide of trans-2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid)

M --- mk | GT yam | In trans cis

Example 9 2-Methyl-2'"H-I1,3bipyrazolyl-4"-carboxylic acid (intermediate 8, 296mg, 1.54mmol) was dissolved in a mixture of dry dichloromethane (24ml) and dry DMF (bml). DSHEA (1 bml, 9.2 mmol) and T5TI (556 mg, 1.6v8 mmol) were added to the resulting mixture. After stirring the mixture for 1 hour. the appearance of an active ester was detected using LC-MS. 4-Aminoadamantan-1-ol (258 mg, 1.54 mmol) was added. After another 2 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in vacuo and purified by preparative HPLC with reversed-phase C-18 in a gradient mode of 15-2095 acetonitrile/water and obtained first (5-hydroxyadamantan-2-yl)-amide cis-2'-methyl- 2'"H-(1,3|bipyrazolyl-4"-carboxylic acid (100 mg, 1995, mass spectrum: t/7: 342.2 (Ma1)), and then (5-hydroxyadamantan-2-yl)- amide of trans-2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid).

Example 10

5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide

O BE DIYPEA yur -a DhMidMe and o EE z ni E si i" ne ve

Example 10 5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (91 mg, O0.4 mmol, SABI: 128455-63-0, purchased from Maubrgidde) was dissolved in a mixture of dry dichloromethane (3 .2ml) and dry DMF (0.vml). DSHEA (0.28 ml, 1.6 mmol) and T5TIi (145 mg, 0.44 mmol) were added to the resulting mixture. After stirring the mixture for a while. the appearance of an active ester was detected using LC-MS. Then 2-aminoadamantane hydrochloride (75 mg, O0.4 mmol) was added. After another 2 hours. water was added and the organic layer was separated.

The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in vacuo and purified by reverse phase HPLC with C-18 in a gradient mode of 10-10095 acetonitrile/water to give adamantane-2-ylamide. 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (55 mg, 3895). Mass spectrum: t/2: 362.1 (M-n1).

Example 11

Adamantane-2-ylamide of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid

LVPEA mesh sim her gu s s

Example 10 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (b9mg, O04mmol, SABYA: 27006-82-2, purchased from Maubridde) was dissolved in a mixture of dry dichloromethane (3.2ml) and dry DMF (0.8 ml). DIPEA (0.28 ml, 1.6 mmol) and T5TY (145 mg, 0.4 mmol) were added to the resulting mixture. After stirring the mixture for 1 hour.

the appearance of an active complex ester was detected using /LC-MSO. Then 2-aminoadamantane hydrochloride (75 mg, O0.4 mmol) was added. After another 2 hours. water was added and the organic layer was separated.

The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in vacuo and purified by reverse phase HPLC with C-18 in a gradient mode of 10-10095 acetonitrile/water to give adamantane-2-ylamide 5-chloro-1,3-dimethyl-1H-pyrazole-4 -carboxylic acid (72mg, 5895). Mass spectrum: t/72: 308.1 (MAT).

Example 12

Adamantane-2-ylamide cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid and Košcha no Dhm/dme Ga M in 8066-O-m are

With M

And her "7 Ge

Example 12 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate 6, 20 mg, 0.09 mmol) was dissolved in a mixture of dry dichloromethane (1 bml) and dry DMF (0.2 ml). DIPEA (O0.Timl, 0.57 mmol) and T5TI (ZZmg, 0.11 mmol) were added to the resulting mixture. After stirring the mixture for Thd. the appearance of an active complex ester was detected using LC-MOS. Then 2-aminoadamantane hydrochloride (17mg,

Oh, my God). After another 2 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried in vacuo and purified by chromatography on silica eluting in a gradient mode with a mixture of 0-4095 ethyl acetate/hexane, then 4095 ethyl acetate/hexane to give adamantane-2-ylamide 1-cyclopropyl-5-trifluoromethyl- 1H-pyrazole-4-carboxylic acid (18mg, 5695). Mass spectrum: t/7: 354.2 (M--1).

Example 13 (5-Hydroxyadamantan-2-yl)-amide cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid o ono Mn, DPE ev - ra Ddhmidme o

M M

But with

Sui ke

Example 13 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate b, 100 mg, 0.45 mmol) was dissolved in a mixture of dry dichloromethane (4 ml) and dry DMF (1 ml). was added to the resulting mixture

DIPEA (0.5 ml, 2.9 mmol) and T5TY (165 mg, 0.5 mmol). After stirring the mixture for 2 hours. the appearance of an active ester was detected using LC-MSOS. Then 4-aminoadamantan-1-ol (77mg,

Oh, 4bmmol). In another 4 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a gradient mode of 10-10095 acetonitrile/water and obtained (B-hydroxyadamantan-2-yl)-amide. 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (79mg, 4895.

Mass spectrum: t/2: 370.2 (M'-1).

Example 14

Adamantane-2-ylamide methyl-5-(4-methylpiperazin-1-yl)-1H-pyrazole-4-carboxylic acid

Her SI / more

Mk h

A solution of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (Example 5, 59mg; 0.20mmol) and 1-methylpiperazine (0.47ml; 4.2mmol) in M-methylpyrrolidinone ( O0.9ml) was heated at 230"C in a hermetic container by microwave radiation for 2 hours. The mixture was allowed to cool to room temperature and the crude product was purified using reversed-phase HPLC to obtain adamantane-2-ylamide methyl-5-(4-methylpiperazine-1 -yl)-1H-pyrazole-4-carboxylic acid (41mg, 5795) as an off-white solid, EP-MSVR t/e calcd for CoHzM5O (MH) 358.2602, found 358.2597.

Example 15

Adamantane-2-ylamide 5-(2-hydroxyethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid (o) and

M sleep

M

And

Go)

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 59mg; 0.20mmol) and ethanolamine (0.20ml; 3.3mmol) with microwave radiation according to the method described in example 14, step 2, after purification by reversed-phase HPLC gave adamantane-2-ylamide 5-(2-hydroxyethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid (26bmg, 4195) as a white powder substances ER-MSVR t/e calculated for Сч17Н27МаО» (Ма-НУ) 319.2129, found 319.2127.

Example 16

Adamantane-2-ylamide methyl-5-(1,2,4|griazol-1-yl-1H-pyrazole-4-carboxylic acid (c)

M sha in M "a

AI mod

Heating a mixture of adamantane-2-ylamide, 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88mg; 0.300mmol), triethylamine (0.22ml; 1.5bmmol) and 1,2,4 -triazole (0.21 g; 3.00 mmol) by microwave radiation for 4 hours. according to the method described in example 14, after purification by reverse-phase HPLC gave adamantane-2-ylamide 1-methyl-5-(1,2,4A|griazol-1-yl-1H-pyrazole-4-carboxylic acid ( 11mg, 1195) in the form of an almost white powdery substance. EP-MSVR t/e calculated for С17Нг22МвО (М-АНУ) 327.1928, found 327.1924.

Example 17

Adamantane-2-ylamide of methyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid c) and

M o /4 " M

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.00 mmol) and pyrrolidine (0.25 ml; 3.00 mmol) with microwave radiation according to the method described in Example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 1-methyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid (bOmg, 6195) as an off-white powdery substance.

ER-MSOSVR t/e calculated for StioNgoMm4O (MAN) 329.2336, found 329.2334.

Example 18

Adamantan-2-ylamide 5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid

M

Wed a

M

/ m

Co

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.3 mmol) and 0-3-pyrrolidinol (0.25 ml; 3.0 mmol) with microwave radiation according to the method described in example 14, after purification by reverse-phase HPLC gave adamantane-2-ylamide 5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (b8mg, 6695 ) in the form of an almost white powdery substance. EP-MSVR t/e calculated for C1i9NhoMaO" (M--NU) 345.2285, found 345.2281.

Example 19

Adamantane-2-ylamide of 5-(4-hydroxypiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (9) and

M

2pR-

M

Shk, 8)

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.0 mmol) and 4-hydroxypiperidine (0.31 ml; 3.0 mmol) by microwave radiation according to the method , described in Example 14, after purification by reversed-phase HPLC gave adamantan-2-ylamide 5-(4-hydroxypiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (87 mg, 8195) in in the form of an almost white powdery substance. ER-MSVR t/e calculated for SgoNziMaO" (Ma-NU) 359.2442, found 359.2437.

Example 20

Adamantane-2-ylamide of 5-|(2-hydroxyethyl)-methylamino|-1-methyl-1H-pyrazole-4-carboxylic acid (c) and

M

M

Here it is

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.3 mmol) and 2-(methylamino)-ethanol (0.25 ml; 3.0 mmol) by microwave radiation according to the method 5 described in example 14, after purification by reversed-phase HPLC gave 5-|(2-hydroxyethyl)-methylamino|-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (29mg, 2995). in the form of an almost white powdery substance. ER-MSVR t/e calculated for SivNgoMaO" (MAN") 333.2285, found 333.2282.

Example 21

Adamantane-2-ylamide 5-(2-hydroxypropylamino)-1-methyl-1H-pyrazole-4-carboxylic acid

M x M to -5

I know

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.33 mmol) and 1-amino-2-propanol (0.25 ml; 3.0 mmol) by microwave radiation according to the method described in example 14, after purification by reversed-phase HPLC gave 5-(2-hydroxypropylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (b5mg, 6595) in in the form of an almost white powdery substance. ER-MSVR t/e calculated for SivNgoMaO" (MN) 333.2285, found 333.2282.

Example 22

Adamantane-2-ylamide of methyl-5-morpholin-4-yl-1H-pyrazole-4-carboxylic acid (c)

M pi /y M ko

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88mg; 0.3Omol) and morpholine (0.2bml; 3,Omol) with microwave radiation for 4 hours. according to the method described in example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 1-methyl-5-morpholin-4-yl-1H-pyrazole-4-carboxylic acid (7bmg, 7495) in the form of almost white powdery substance. ER-MSVR t/e calculated for C1i9NoaMaOg (MH) 345.2285, found 3452282.

Example 23

Adamantan-2-ylamide 5-(2-methoxyethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid) and p

M br" and ; c) x

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88mg; 0.30mmol) and 2-methoxyethylamine (0.2bml; 3.0mmol) by microwave radiation according to the method , described in example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 5-(2-methoxyethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid (b5mg, 6595) as an almost white powder substances ER-MSVR t/e calculated for SivNgoMaO" (M--NU) 333.2285, found 333.2282.

Example 24

Adamantane-2-ylamide of 5-isopropylamino-1-methyl-1H-pyrazole-4-carboxylic acid

M c) ve / r her

Heating a mixture of adamantane-2-ylamide, 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (Example 5, 88 mg; 0.300 mmol), triethylamine (0.44 mL; 3, Immol) and 2-aminoisobutyric acid ( 320mg; C3.1mmol) by microwave radiation for two hours. according to the method described in example 14, after purification by reverse-phase HPLC gave 5-isopropylamino-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (28 mg, 2995) as an almost white powdery substance. ER-MSOVR t/e calculated for SiviNgoiMm«O (MAN) 317.2336, found 317.2334.

Example 25

Adamantane-2-ylamide methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 8 in 8 mg; 0.3 mmol) and piperidine (0.31 ml; 3 mmol) with microwave radiation according to the method described in example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid (52 mg, 5190) as an off-white powder.

ER-MOSVR t/e calculated for SgoNzi MO (Manu) 343.2493, found 343.2489.

Example 26

Adamanthan-2-ylamide 5-(4-hydroxymethylpiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid

M o

I x r

WITH

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.3 mmol) and piperidine (0.31 ml; 3.1 mmol) with microwave radiation according to the method described in example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 5-(4-hydroxymethylpiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (40 mg, 3695) as almost white powdery substance. ER-MSVR t/e calculated for SgiNzzMaO" (MN) 373.2598, found 373.2597.

Example 27

Adamanthan-2-ylamide 5-(4-benzylpiperazin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid

M

9) that / re

M M

BACKGROUND

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 8a8mg; 0.3Omol) and M-benzylpiperazine (0.54ml; 3.Omol) by microwave radiation according to the method , described in Example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 5-(4-benzylpiperazin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 3895) in in the form of an almost white powdery substance. ER-MSVR t/e calculated for SgviNz5M5O (MAN") 434.2915, found 434.2910.

Example 28

Adamantan-2-ylamide 5-(B-3-hydroxyscrolidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid

M

/x not; IS

Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (Example 5, 88 mg; 0.3 mmol) and (A)-(-)-3-hydroxypyrrolidine (0.2 bml; Z, Immol) by microwave radiation according to the method described in example 14, after purification by reversed-phase HPLC gave adamantan-2-ylamide 5-(B-3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol- 4-carboxylic acid (5 mg, 5495) in the form of an almost white powdery substance. EP-MSVR t/e calculated for C1i9NhoMaO" (MaH") 345.2285, found 345.2283.

Example 29

Adamantane-2-ylamide of 5-diethylamino-1-methyl-1H-pyrazole-4-carboxylic acid

M o

Mr

AND

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, 88 mg; 0.3 mmol) and diethylamine (0.32 ml; 3 mmol) with microwave radiation according to the method described in example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 5-diethylamino-1-methyl-1H-pyrazole-4-carboxylic acid (1bmg, 1695) as an off-white powdery substance. EP-MS (electrospray ionization mass spectroscopy) t/e calculated for Si19NziMaO (MANNU) 331, found 331.

Example 30

Adamantane-2-ylamide tert-butyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid

Mn o) sho

WITH

Heating a mixture of adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (10mg;

0.3 mmol) and pyrrolidine (0.25 ml; 3.0 mmol) by microwave radiation according to the procedure described in Example 37, step 5, after purification by reversed-phase HPLC gave adamantane-2-ylamide 1-tert-butyl-5- piperidin-1-yl-1H-pyrazole-4-carboxylic acid (14 mg, 1695) as a white solid. ER-

MOVR (high-resolution mass spectroscopy with electrospray ionization) t/e calculated for

Sg2NzaMmaO (MAN) 371.2806, found 3712801.

Example 31

5-|4-(2-hydroxyethyl)-piperazin-1-yl|-1-methyl-1H-pyrazole-4-carboxylic acid adamantanilamide

M o / h

M GT Fr

Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (Example 5, 88 mg; 0.3 mmol) and 1-(2-hydroxyethyl)-piperazine (0.38 ml; C, immole) by microwave radiation according to the method described in example 14, after purification by reverse-phase HPLC gave adamantanilamide 5-I4-(2-hydroxyethyl)-piperazin-1-yl|-1-methyl-1H-pyrazole-4-carbon acid (71 mg, 61905) in the form of an almost white powdery substance. EP-MSVR t/e calculated for Cg2g1iNzaM5O" (Man) 388.2707, found 388.2702.

Example 32

Adamantane-2-ylamide 5-|(2-methoxyethyl)-methylamino|-1-methyl-1H-pyrazole-4-carboxylic acid

M o kA

M y -

Heating a mixture of adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (Example 5, 88 mg; 0.3 mmol) and (2-methoxyethyl)u-methylamine (27 bmg; 3.0 mmol) with a microwave by radiation according to the method described in example 14, after purification by reversed-phase HPLC gave adamantan-2-ylamide 5-(2-methoxyethyl)-methylamino|-1-methyl-1H-pyrazole-4-carboxylic acid (b1mg, 5995 ) in the form of an almost white powdery substance. ER-MSVR t/e calculated for C1i9NziMaO" (MEN) 347.2442, found 347.2438.

Example 33

Adamantane-2-ylamide of 2'-tert-butyl-2'H-Y,3Ibipyrazolyl-4"-carboxylic acid 7 ra "mo zo sy sr z g, healing M Y; H a " y

Example 33

In a test tube for treatment with microwave radiation Regzop! Spetivine (Vioiade AV, bmedep) was thoroughly mixed with adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (example 36, 100 mg, 0.3 mmol), pyrazole (41 mg, 0.6 mmol ), KE (35 mg, 0.0 mmol) and DMSO (dimethyl sulfoxide) (2 ml).

The test tube was covered with a membrane and treated with microwave radiation with a power of 150 W using Regzop! Spetiziu Misgozhame Zupipevziz zuziet (Vioiade AV, Zmedep) at 230"C for 20 minutes.

The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, concentrated in vacuo and purified using a preparative method

HPLC with reverse phase C-18 in a gradient mode of 10-10095 acetonitrile/water and obtained 2'-tert-butyl-2'H-/1,3bipyrazolyl-4"-carboxylic acid adamantane-2-ylamide (45mg, 4195). Mass spectrum: t/2: 368.2 (Mt).

Example 34 (B-Hydroxyadamantan-2-yl)-amide of trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid: Mn, DIPEA Z Ua Z fa

Yes, yes, trans cis

Example 34 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (intermediate 9.2 g, 9.87 mmol) was dissolved in a mixture of dry dichloromethane (40 ml) and dry DMF (100 ml). DIPEA (10.3 ml, 59.1 mmol) and T5TIi (3.6 g, 10.9 mmol) were added to the resulting mixture. After stirring the mixture for 2 hours. the appearance of an active ester was detected using LC-MS. Then 4-aminoadamantan-1-ol (1.65 g, 9.9 mmol) was added. In another 4 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried in a vacuum. The crude mixture was first purified by chromatography on silica eluting in a gradient mode with a mixture of 0-6090 ethyl acetate/hexane, then 6095 ethyl acetate/hexane, and further purified by preparative reverse-phase C-18 HPLC in a gradient mode of 25-5095 acetonitrile/ water and obtained (5-hydroxyadamantan-2-yl)-amide cis-1-tert-butyl-

B-chloro-1H-pyrazole-4-carboxylic acid (example 34, 900mg, 2695, mass spectrum: t/7: 352.2 (M1)), and then (5-hydroxyadamantan-2-yl)-amide trans -1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (1400mg, 4095).

Example 35 (B-Hydroxyadamantan-2-yl)-amide of trans-2'-tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (c) before I point

M Y N , Gak man, dMmF Kk n n

I'm with! hl --shi i WHAT

Example 35

Sodium hydride (6095 in oil; 420 mg, 10.5 mmol) was added to a solution of pyrazole (714 mg, 10.5 mmol) in dry

DMF (140 ml) in a nitrogen atmosphere at 0"C in an ice-water bath and the mixture was heated at 40"C for an hour.

Trans-5-chloro-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ether (5-hydroxyadamantan-2-yl)-amide was added (Example 34, 1.89 g, 5.4 mmol) and the mixture was heated at 1107"C overnight and then cooled.

Water and ethyl acetate were added, the organic layer was separated and the aqueous phase was extracted three times with EtOAc.

The combined organic phases were concentrated in vacuo and the residue was purified by preparative HPLC with reverse phase C-18 in a gradient mode of 10-10095 acetonitrile/water to give (5-hydroxyadamantan-2-yl)-amide trans-2'-tert- butyl-2'H-1Y1,3bipyrazolyl-4"-carboxylic acid (500mg, 2495). Mass spectrum: t/2: 384.2 (MAT).

A preferred technique for obtaining (5-hydroxyadamantan-2-yl)-amide trans-2'-tert-butyl-2'H-(1,3|bipyrazolyl-4-carboxylic acid) using ethyl 3,3-diethoxypropionate as a starting material is described below.

VSH ton Oxalyl chloride, DMF o ra sud sk ti skopu X sion on

Pyrazole, MaOH, MMP, etc

Stage 1: Ethyl ether of 2-formyl-3-oxopropionic acid

Ethyl 3,3-diethoxypropionate (100 g, 525.7 mmol) was dissolved in THF (tetrahydrofuran) (ZbOml) at room temperature. Ethyl formate (175.1 ml, 2.1 mol) was added at room temperature. The solution was cooled in an ice bath to 0"C and through the dropping funnel slowly for 300 minutes, maintaining the internal temperature below 5"C, IVyOK (1M solution in THF, 1.156ml, 1.156 mol) was added. The color immediately changed from colorless to dark orange. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was stirred at room temperature for 18 hours.

The reaction mixture was concentrated in vacuo and the solvent was removed. The remaining brown solution, containing a white solid, was cooled in an ice bath and hydrochloric acid (b.v., 200 ml) was added until pH-Z was established, maintaining the internal temperature below 20"C. The resulting bright yellow suspension was then heated to room temperature. temperature and stirred for 1h. Another 700ml of solvent was removed in vacuo at room temperature. Water (400ml) was added to dissolve all the white solid and ethyl acetate (500ml) was added and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted once with ethyl acetate (200ml). The combined organic extracts were washed once with brine (100 ml).

After drying over Mo5O" and concentration in a vacuum, 2-formyl-3-oxopropionic acid ethyl ether (75.85 g) was obtained in the form of a yellow oil.

Stage 2: 1-tert-butyl-1H-pyrazole-4-carboxylic acid Formyl-3-oxopropionic acid ethyl ester (75.85g, 525.6mmol) was dissolved in ethanol (1L) at room temperature. At room temperature, tert-butylhydrazine hydrochloride (65.5g, 525.6mmol) was added and the temperature of the reaction mixture was gradually raised to 32°C. Then the container was placed in an ice bath for re-cooling to 20°C. It took about an hour to completely dissolve tert-butylhydrazine. The solution was stirred at room temperature for The reaction mixture was cooled in an ice bath. Sodium hydroxide (4N, 152.4g) was added to neutralize the hydrochloric acid. Then most of the ethanol was removed in vacuo and methanol (300ml) was added, followed by an additional amount of sodium hydroxide (4N, 304.8g, 1.05mol).

The internal temperature was gradually raised to 32°C. The reaction vessel was then placed in a water bath to re-cool to room temperature, and the reaction mixture was stirred at room temperature for 18 hours. Methanol (300ml) was then removed in vacuo, keeping the temperature of the water bath below 30°C. WITH. Then the reaction mixture was cooled to 0"C and, maintaining the internal temperature below 15"C, slowly added hydrochloric acid (bl., 190ml). The pH value of the solution was adjusted to 2.

The resulting suspension was stirred in an ice bath for 2 hours. and the solid was filtered. After drying at 60"C in a vacuum for 2.5 days, 1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) was collected in the form of an almost white solid. The mother liquor was extracted three times with dichloromethane (200 ml x 3 .

The combined organic layer was washed once with brine (100 ml) and dried over magnesium sulfate. After concentration in vacuum and drying, 16.5 g of a yellowish solid was collected. The crude material was crystallized from hot iso-propyl acetate (25 mL) and heptane (25 mL). After cooling to room temperature, the solid substance was filtered and the precipitate on the filter was washed with a mixture of iso-propyl acetate and heptane (1/1 (vol./vol., 14 ml)) and dried in an oven at 60"C in a vacuum for 5 hours. The second portion was collected 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7g) as a white solid.

Step 3: 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid Tert-butyl-1H-pyrazole-4-carboxylic acid (5g, 29.73mmol) was dissolved in tetrahydrofuran (50ml) at room temperature. n-butyllithium (2.5 M solution in hexane, 29.73 mL, 74.33 mmol) was added to a separate container and cooled to -157C. A solution of 1-tert-butyl-1H-pyrazole-4-carboxylic acid was added dropwise to the n-butyllithium solution, maintaining the internal temperature below -10"C. The total time of addition was 30 minutes. The resulting brown suspension was stirred and kept at a temperature of -10 to -157"C for 40 minutes. Then the reaction mixture was cooled to a temperature from -15 to -20"C. A solution of hexachloroethane (14.08g, 59.46bmmol) in tetrahydrofuran (50ml) was added dropwise, maintaining the internal temperature below -107C. The complete addition time was 20 minutes.

After addition, the obtained dark brown solution was stirred at a temperature from -10 to -1570 for ЗОхв. and heated to room temperature for 1 hour. Then the reaction mixture was cooled to 1572 °C and water (50 ml) was slowly added, maintaining the internal temperature below 20 °C. 120 ml of organic solvents were distilled off under reduced pressure at 25 °C in a water bath, which resulted in the formation of a suspension.

Heptane (5 bml) was added, resulting in the formation of a clear brown biphasic solution. After stirring at room temperature for 15 min. the aqueous layer (pH-11.8) was separated. The organic layer was extracted once with Mahon (Tn., 20 ml). The combined aqueous phase was washed with heptane (25 ml) and cooled in an ice bath. Hydrochloric acid (b.n.) was added to bring the pH value to 2, maintaining the internal temperature below 20"C. The suspension was stirred in an ice bath at 0-57 for 1 hour and the solid was filtered and washed with water (40ml). After drying in vacuum at 60"C for 18 hours. 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5.28 g) was obtained as a light yellow solid.

Step 4: trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

Tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5g, 24.67mmol) was suspended in toluene (50ml) at room temperature. Dimethylformamide (12 μl) was added and the reaction container was placed in a water bath. To the suspension drop by drop for 10 minutes. oxalyl chloride (3.3 ml, 37 mmol) was added. There was a slight heating and the internal temperature rose from 23"C to 21"C. The suspension was stirred at room temperature for 5 hours. Toluene (25 ml) was removed under vacuum at a water bath temperature equal to 210" to remove excess oxalyl chloride. Tetrahydrofuran (25 ml) was added to the resulting solution of acyl chloride in toluene and a transparent dark orange solution was formed. In a separate container for the reaction, trans-4 was added -aminoadamantan-1-ol hydrochloride (5.28g, 25.9mmol, intermediate 2) and sodium hydroxide solution (In., 49.34ml, 49.34mmol) and obtained a cloudy solution. This solution was placed in a water bath. The solution obtained above of acyl chloride was added to the aqueous solution through the dropping funnel for 20 minutes, maintaining the internal temperature below 2570. After the addition, the resulting suspension was stirred at room temperature for 18 hours. The solid substance was filtered and dried at 60"C in a vacuum for 18 hours. Trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (5.92 g) was collected as a white solid. Heptane (5 Oml) was added to the mother liquor and the resulting suspension was stirred at room temperature for an hour. The solid was filtered again. After drying at 60"C in a vacuum for 18 hours, 1.7 g of the second portion was collected. According to the data

HPLC purity was 96.92965.

Stage 5: trans-2'-tert-butyl-2'H-Y1,3-bipyrazolyl-4"-carboxylic acid (B-Hydroxyadamantan-2-yl)-amide tert-butyl -5-chloro-1H-pyrazole-4-carboxylic acid (20g, 56.84mmol) and pyrazole (7.74g, 113.7mmol) were added to M-methylpyrrolidinone (4000ml) and stirred at room temperature. Sodium hydroxide solution ( 5095, 18.19 g, 227 4 mmol).The suspension was heated at 120"C and a yellowish solution was obtained. Then the reaction mixture was heated at 1207"C for 100 hours. Pyrazole (3.87 g, 56.84 mol) and sodium hydroxide solution (5095, 4.55 g, 56.84 mmol) were added. The reaction was allowed to continue at 120 "C for 2 hours. Then the reaction mixture was cooled to 5"C in an ice bath.

Water (500 ml) and saturated ammonium chloride solution (500 ml) were added, maintaining the internal temperature below 20 °C. The resulting suspension was stirred in an ice bath for 2 hours, and then the solid was filtered and washed with water (300 ml) and dried in an oven at 50 "C in a vacuum for 18 hours.

(5-Hydroxyadamantan-2-yl)-amide of trans-2'-tert-butyl-2'H-Y1,3-bipyrazolyl-4-carboxylic acid (16.81 g) was obtained as a white solid.

Example 36

Adamantane-2-ylamide of tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid o tetu with sh: tone BU t

Zh NS I p

Example 36

Tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (intermediate 9, 0.5 g, 2.47 mmol) was dissolved in a mixture of dry dichloromethane (12 ml) and dry DMF (3 ml). DIPEA (2.bml, 14.9 mmol) and TT (0.9 g, 2.7 mmol) were added to the resulting mixture. After stirring the mixture for an hour. the appearance of an active ester was detected using LC-MS. Then 2-aminoadamantane hydrochloride (0.44 g, 2.34 mmol) was added. After another 2 hours. water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane.

The combined organic phases were dried in vacuo and purified by preparative reversed-phase HPLC

C-18 in a gradient mode of 10-10095 acetonitrile/water and obtained adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (65O0mg, 8395). Mass spectrum: t/7: 336.2 (M--1).

Example 37

Adamantane-2-ylamide tert-butyl-5-(3-hydroxypyrrolidin-1-yl)-1H-pyrazole-4-carboxylic acid

Mn td x stu v

Steps 1 - 3: 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid was obtained according to the methods described above for intermediate 9.

Stage 4: Preparation of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide

When stirring to a solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (3.040g; 15.0mmol) in a mixture of M,M-dimethylformamide/methylene chloride (ratio 1:4, 20ml) at room temperature diisopropylethylamine (21.2 ml; 120.4 mmol) was added. Then T5TI (5.420 g; 18.0 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. and then 2-adamantylamine hydrochloride (2.844 g; 15.0 mmol) was added. The mixture was stirred over the weekend at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting clear yellow resin was triturated with diethyl ether to obtain adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (4.02g, 8090) as a white powdery substance.

Stage 5: Preparation of 1-tert-butyl-5-(3-hydroxypyrrolidin-1-yl)-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide

A mixture of adamantane-2-ylamide of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (example 36, 101 mg;

0.00 mmol) and pyrrolidine-Z-ol (y/-) (0.25 ml; 3.00 mmol) in M-methylpyrrolidinone (ml) at 2507C were heated in a sealed container with microwave radiation for 4 hours. The mixtures were allowed to cool to room temperature and the crude product was purified by reversed-phase HPLC to give 1-tert-butyl-5-(3-hydroxypyrrolidin-1-yl)-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide ( 25mg, 2295) in the form of an almost white solid. EP-MSVR t/e calculated for Сg2Нз5МаО» (MAN) 358.2602, found 358.2602.

Example 38

Adamantan-2-ylamide tert-butyl-5-(4-hydroxypiperidin-1-yl)-1H-pyrazole-4-carboxylic acid "Mn td i gino X-

Heating a mixture of adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (Example 36, 101 mg; 0.00 mmol) and piperidin-4-ol (30 mg; 3.00 mmol) with microwave radiation according to the procedure described in example 37, step 5, after purification by reversed-phase HPLC gave adamantane-2-ylamide 1-tert-butyl-5-(4-hydroxypiperidin-1-yl)-1H-pyrazole-4-carbon acid (14 mg, 1295) in the form of an almost white powdery substance. EP-MSVR t/e calculated for Cg2gziNz7MaO" (Ma-H") 357.2649, found 357.2650.

Example 39

Adamantane-2-ylamide of 5-azepan-1-yl-1-methyl-1H-pyrazole-4-carboxylic acid chn x

M

Heating a mixture of adamantane-2-ylamide, 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, bomg; 0.20 mmol) and azepane (0.2 ml; 2.0 mmol) at 250"C with microwave radiation according to the method described in example 14, after purification by reversed-phase HPLC gave adamantane-2-ylamide 5-azepan-1-yl-1-methyl-1H-pyrazole-4-carboxylic acid (41 mg, 5895) in the form of almost white powdery substance. EP-MSVR t/e calculated for SgiNzzMaO (MH) 357.2649, found 3572644.

Example 40

Adamantane-2-ylamide methyl-5-thiomorpholin-4-yl-1H-pyrazole-4-carboxylic acid chn tr x goi 5

Heating a mixture of adamantane-2-ylamide of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (example 5, bomg; 0.20 mmol) and thiomorpholine (0.20 ml; 2.00 mmol) at 250"C with microwave radiation according to the method described in example 14, after purification by reverse-phase HPLC gave adamantane-2-ylamide 1-methyl-5-thiomorpholin-4-yl-1H-pyrazole-4-carboxylic acid (15 mg, 2195) as a light - a brown powdery substance. EP-MSOVR t/e calculated for CizNgoMaO5 (M--H") 361.2057, found 361.2053.

Example 41

Adamantane-2-ylamide tert-butyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid chn td x stu

Heating a mixture of adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (example 36, 101 mg; 0.3 mmol) and piperidine (0.300 ml; 3.0 mmol) by microwave radiation according to the method , described in example 37, step 5, after purification by reversed-phase HPLC gave 1-tert-butyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid adamantane-2-ylamide (19 mg, 1695) in the form of an almost white powdery substance. ER-MSVR t/e calculated for SgZiNz7MaO (MAN) 385.2962, found 385.2958.

Example 42 (5B-Fluoroadamantan-2-yl)-amide trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid /4 and : E

F n 2 ke

Stage 1: Preparation of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

When stirring, to a mixture of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (3,000 g; 11.4 mmol) in a mixture of methanol/water (ratio 1:11, 500 ml) at room temperature, hydroxide was added lithium (0.383 g; 16.0 mmol). The mixture was refluxed for 2 hours, then allowed to cool to room temperature and concentrated to approximately half of the initial volume. The resulting mixture was acidified with the help of other NSI to -rni and extracted with methylene chloride.

The extracts were dried over sodium sulfate, filtered and concentrated to obtain 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2.47 g, 9290).

Stage 2: Preparation of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)y-amide

When stirring to a solution of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2.334 g; 9.88 mmol) in a mixture of M,M-dimethylformamide/methylene chloride (ratio 1:4, 15 ml) at room temperature temperature, diisopropylethylamine (9.00 ml; 51.13 mmol) was added. Then T5TI (5.420 g; 18.0 mmol) was added.

The resulting mixture was stirred at room temperature for 2 hours. and then 2-adamantylamine (1.654g; 9.89mmol) was added. The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was successively washed with 0.5N. NSI, saturated with sodium bicarbonate solution then brine, was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as a light brown solid. Purification by column chromatography (NedibZer-1209d silica gel, 1095--1009o ethyl acetate/l-hexane) gave the desired trans-isomer of (5-hydroxyadamantan-2-yl)-amide 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4 -carboxylic acid (1.23g, 3290) as a white solid. The resulting clear yellow resin was triturated with diethyl ether to obtain adamantane-2-ylamide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (4.02g, 8095) as a white powdery substance. The cis isomer was also isolated (1.58 g, 4195).

Stage 3: 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (X-Fluoroadamantan-2-yl)-amide

When stirring to a solution of (5-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (trans-isomer) (bOmg, 0.1bmmol) in dry to methylene chloride (2 ml), cooled to 0"C in a nitrogen atmosphere, DETS reagent was added dropwise using a syringe. Then the mixture was allowed to warm to room temperature. After 1 hour, the reaction was stopped with a saturated solution of sodium bicarbonate (0.5 ml). The resulting mixture was diluted with methylene chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product. of 4-carboxylic acid (28mg, 4590) as a white solid, EP-MSVR t/e calculated for Sti9NovigaMzO (M.H) 385.2962, found 385.2963.

Example 43 trans-M-(4-Aminoadamantan-1-yl)-acetamide (8) pouave n

Stage 1: trans-(5-hydroxyadamantan-2-yl)-carbamic acid 9UN-Fluoren-9-yl methyl ester

To a suspension of 4-aminoadamantanol hydrochloride (intermediate 2, 26.48 g; 130.0 mmol) in dichloromethane (800 ml) was added triethylamine (92.0 ml; 656.8 mmol). To this mixture in portions within 15 minutes. added EMOS-

O5y (65.78 g; 195 mmol). The resulting suspension was stirred in an argon atmosphere at room temperature.

After 20 hours triethylamine (28 g; 199 mmol), EMOS-O5y (21.92 g; 65 mmol) and dichloromethane (30 mmol) were added.

Another 20 hours later. the reaction mixture was cooled to 0"C and 4N. HCl (400ml) was slowly added with stirring and allowed to warm to room temperature. The organic phase was separated and successively washed with water (300ml), saturated sodium bicarbonate solution (300ml) and saturated sodium chloride solution (300ml) . The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain 86.8 g of crude product. This substance was triturated twice with hexane (2 x 300 mL) and the solid was filtered and washed several times with hexane (total of 30 mL) and air-dried to obtain 40 ,bg 9H-fluoren-9-ylmethyl ester of trans-(5-hydroxyadamantan-2-yl)-carbamic acid as an off-white solid.

Stage 2: 9H-Fluoren-9-yl methyl ester of trans-(5-acetylaminoadamantan-2-yl)-carbamic acid

When stirring to a suspension of 9H-fluoren-9-ylmethyl ester of trans-(5-hydroxyadamantan-2-yl)-carbamic acid (11.69g; 30, mol), acetonitrile (23ml) and glacial acetic acid (30ml), cooled to 0"С, concentrated sulfuric acid (30ml) was slowly added over 20 minutes. Then the mixture was allowed to warm to room temperature and stirred for 30 hours, and then stored in the freezer overnight (20 hours). Then the reaction mixture was poured into the crushed ice/water mixture (500 ml) and allowed to warm to room temperature for 2 hours. The resulting mixture was extracted with ethyl acetate. The extract was successively washed with water, a saturated solution of sodium bicarbonate and finally with a saturated solution of sodium chloride. Then the extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain 10 23g of trans-(5-acetylaminoadamantan-2-yl)-carbamic acid 9nH-fluoren-9-ylmethyl ether in the form of a yellow foamy substance.

Step 3: trans-M-(4-Aminoadamantan-1-yl)-acetamide

Piperidine (8 ml) was added to a solution of trans-(5-acetylaminoadamantan-2-yl)carbamic acid 9H-fluoren-9-ylmethyl ether (10.21 g; 23.7 mmol) in dry dimethylformamide (30 ml) while stirring.

After 45 minutes the reaction mixture was concentrated in vacuo. The resulting residue was suspended in water (100 ml) and stirred at room temperature for 1 hour. The resulting suspension was filtered and the solid was washed with 100 ml of water. The combined filtrates and washing solutions were transferred to a separatory funnel and washed with diethyl ether. Then the aqueous phase was concentrated in a vacuum and a viscous liquid was obtained, which was lyophilized to obtain 3.28 g of trans-M-(4-aminoadamantan-1-yl)-acetamide as a pale yellow solid. This substance was used without further purification.

A preferred procedure for the preparation of trans-M-(4-aminoadamantan-1-yl-acetamide) using trans-4-aminoadamantan-1-ol hydrochloride (intermediate 2) is described below.

Step 1: M-(5-acetylaminoadamantan-2-yl)-2,2,2-trifluoroacetamide trans-4-Aminoadamantan-1-ol hydrochloride (120g, 589.1mmol) was added to the reaction vessel, followed by acetonitrile ( 1.5 l) and trifluoroacetic acid (1 l, 12.85 mol). After stirring at room temperature, the reaction mixture was concentrated in vacuo for 6 days. Then the contents were dissolved in ethyl acetate (4 L), successively washed with a saturated solution of sodium bicarbonate (2 x L) and water (1 x L). Then the organic phase was separated and filtered through a funnel with a porous filter. The filtrate was concentrated in vacuo and 150 g of solid was obtained. This solid was dissolved in ethyl acetate (Tl) and stirred for 1 hour. After concentration, the solvent was replaced by heptane (Tl) and the resulting suspension was filtered.

The solid was washed with a solvent mixture of ethyl acetate-heptane (1/4, 5000 ml). Then the solid substance was filtered and dried in an oven at 45"C in a vacuum for 18 hours to obtain M-(5-acetylaminoadamantan-2-yl)-2,2,2-trifluoroacetamide (135g) as a white solid.

Step 2: M-(4-Aminoadamantan-1-yl)-acetamide hydrochloride

M-(5-Acetylaminoadamantan-2-yl)-2,2,2-trifluoroacetamide (135g, 443.mmol) was added to the reaction vessel, and then ethanol (2L) and sodium hydroxide (37g, 913.8mmol) were added. . The reaction mixture was heated at 50-557C and stirred over the weekend. The reaction mixture was then allowed to cool to room temperature and glacial acetic acid (100 mL, 1.748 mol) was added. The resulting mixture was then concentrated in vacuo to give a white solid. The solid was suspended in ether (1 L) and stirred for 1 h. Then the solid was filtered, washed with ether (200 ml) and dried in an oven at 45"7C for 18 hours, and 240 g of solid was obtained. The solid was dissolved in methanol (500 ml). With stirring, hydrochloric acid (4 N solution in dioxane, 500 ml) was added, and then 2 L of ether was added dropwise.The mixture was then concentrated in vacuo to give a white solid.

The solid was dissolved in methanol (1 L) and stirred for 1 hour. The solid was filtered and discarded. The filtrate was concentrated in vacuo until it began to crystallize (about 500 mL). The light suspension was transferred to a container. With stirring, ether (2 L) was added dropwise and a thick suspension of a white solid was obtained. The solid was filtered and washed with ether. After drying in an oven at 457C for 18 hours. M-(4-aminoadamantan-1-yl)-acetamide hydrochloride (96bg) was obtained as a white solid.

Example 44 trans-M-(4-Aminoadamantan-1-yl)u-methanesulfonamide o.,0 "The same

Nn

Stage 1: 9H-Fluoren-9-yl methyl ester of trans-(5-(2-chloroacetylamino)-adamantan-2-yl|-carbamic acid

Upon stirring to a mixture of 9H-fluoren-9-ylmethyl trans-(5-hydroxyadamantan-2-yl)-carbamic acid (11.69g; 30.0mmol), chloroacetonitrile (20ml) and glacial acetic acid (25ml) cooled to 0"C, concentrated sulfuric acid (25ml) was added. The resulting mixture was allowed to warm to room temperature. After 7 hours, the mixture was placed for storage in a freezer at -207C overnight and then allowed to warm to room temperature for two hours. Then the reaction mixture was poured into crushed ice/water (b0O0ml) mixture and allowed to warm to room temperature for 10 min with stirring. The mixture was then extracted with ethyl acetate (550ml). The extract was washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was then dried over sulfate of sodium, filtered and concentrated in a vacuum to obtain 6.18 g of 9H-fluoren-9-ylmethyl ether /trans-(5-(2-chloroacetylamino)-adamantan-2-yl|-carbamic acid in the form and yellow foamy substance.

Stage 2: 9H-Fluoren-9-yl methyl ester of trans-(5-aminoadamantan-2-yl)-carbamic acid

When stirring, thiourea (206 mg; 206 mg; 2.67 mmol), and then glacial acetic acid (2 ml). The resulting solution was heated at 80"C in a sealed test tube for 21 hours and then it was kept for 72 hours at room temperature. Then the mixture was concentrated to half the volume in a stream of dry nitrogen and then suspended in diethyl ether and the solid was filtered. The solid was washed with diethyl ether and obtained 1.14 g of trans-(5-aminoadamantan-2-yl)-carbamic acid 9H-fluoren-9-ylmethyl ether as a white solid.

Stage 3: trans-(5-methanesulfonylaminoadamantan-2-yl)-carbamic acid 9H-fluoren-9-yl methyl ester

While stirring, a saturated solution of sodium bicarbonate (75 ml) was added to a solution of trans-(5-aminoadamantan-2-yl)carbamic acid 9H-fluoren-9-ylmethyl ether (991 mg; 2.33 mmol) in ethyl acetate (100 ml) and then water (25ml). Then for 5 min. methanesulfonyl chloride (2.0 ml; 25.7 mmol) was added dropwise and stirring was continued for 1.5 h. Then sodium carbonate (5.83g) was slowly added to the reaction mixture, followed by methanesulfonyl chloride (2.0ml) and the mixture was stirred for 20h. at room temperature. The slow addition of sodium carbonate (18.2 g) and then methanesulfonyl chloride (4.0 ml) was repeated and the mixture was re-stirred for 24 hours. at room temperature. The organic layer was washed several times with Zn. with a solution of hydrochloric acid, and then with a saturated solution of sodium bicarbonate and finally with a saturated solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 722 mg of crude product as an off-white solid. The crude product was further purified by chromatography (IZCO Sotrapiop system, A5-409d column with silica gel; eluent: ethyl acetate/hexane; 0-10095 gradient mode; flow rate dOml/min.) and bbomg of 9H-fluoren-9-yl methyl ether was obtained trans-(5-methanesulfonylaminoadamantan-2-yl)-carbamic acid in the form of a white foamy substance.

Step 4: trans-M-(4-Aminoadamantan-1-yl)y-methanesulfonamide

Piperidine (1.00 ml) was added to a solution of 9H-fluoren-9-yl methyl ether of trans-(5-methanesulfonylaminoadamantan-2-yl)-carbamic acid (1.73 g; 3.71 mmol) in M,M-dimethylformamide (4 ml). . The mixture thickened after a few minutes, and another 4 ml of dimethylformamide and 1.0 ml of piperidine were added to facilitate mixing. The resulting suspension was stirred at room temperature for 2 hours. and then concentrated in vacuo. The residue was partitioned between diethyl ether and water. Then the aqueous layer was concentrated in vacuo under heating and the light yellow oily residue was lyophilized to obtain 741 mg of trans-M-(4-aminoadamantan-1-yl)y-methanesulfonamide as a pale yellow solid.

Example 45 (5-Acetylaminoadamantan-2-yl)-amide of trans-2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid th

MN

IZ) /x

Su - k

When stirring to a solution of (5-hydroxyadamantan-2-yl)-amide of trans-2'-methyl-2'H-Y1,3bipyrazolyl-7-carboxylic acid (10 mg; 0.300 mmol; obtained in example 9) in acetonitrile ( Concentrated sulfuric acid (0.10 ml) was added dropwise to glacial acetic acid (0.1 ml) and glacial acetic acid (0.1 ml) cooled to 0 °C. Then the ice bath was removed and the mixture was allowed to warm to room temperature. After 4 hours, glacial acetic acid was added (0.5ml) and concentrated sulfuric acid (0.50ml) and the mixture was stirred for 700h at room temperature. The reaction mixture was then concentrated under a stream of dry nitrogen to remove acetonitrile and then ice (15ml) was added to the reaction mixture. The mixture was stirred for 1h .at room temperature.

Then the mixture was filtered and the white solid was washed several times with saturated sodium bicarbonate solution and then with water and the solid was air-dried overnight to obtain 9 mg of (5-hydroxyadamantan-2-yl)-amide trans-2'-methyl-2'H -Y1,3bipyrazolyl-4"-carboxylic acid as a white solid. EP-MSVR t/e calculated for SgoNgvMeOgoMa (M--Ma") 405.2009, found 405.2007.

Example 46 (5-Acetylaminoadamantan-2-yl)-amide of trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid

Mn

Mn o

Gu Xi M

To a solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (intermediate product 9; 134 mgHg;

0.bbmmol) in M,M-dimethylformamide (1.0ml) was added M,M-diisopropylethylamine (0.63ml; 3.bOmole), and then

T5TY (253 mg; 0.4 mmol). After an hour added trans-M-(4-aminoadamantan-1-yl)y-acetamide (obtained in example 43; 125 mg; 0.bOmole) and the mixture was stirred for 18 hours. at room temperature. Then the reaction mixture was concentrated in a stream of dry nitrogen, dissolved in ethyl acetate and successively washed with 0.5N. hydrochloric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer was dried (sodium sulfate), filtered and concentrated to give a crude light solid. The crude product was purified by reversed-phase HPLC to obtain 104 mg of trans-1-tert-butyl-5-chloro (5-acetylaminoadamantan-2-yl)-amide. oro-1H-pyrazole-4-carboxylic acid as a white solid. EP-MSVR t/e calculated for СгоНзоМаО2СИ (МН) 393.2052, found 393.2053.

Example 47 (5-Methanesulfonylaminoadamantan-2-yl)-amide of trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid

Would "V. about Mn

MA

(9) ear

H

Compound 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (intermediate 9; 10Omg;

0.5 mmol) and trans-M-(4-aminoadamantan-1-yl)y-methanesulfonamide (obtained in example 44; 11 mmol; 0.45 mmol) using LTPC according to the method described in example 46, after purification with

Reversed phase HPLC afforded trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid bZmg (5-methanesulfonylaminoadamantan-2-yl)-amide as a white solid. ER-MSVR t/e calculated for

StieNzoMmaOzSI5 (MAN Manu) 429.1722, found 429.1722.

Example 48 (5-Acetylaminoadamantan-2-yl)-amide trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid oem

Mn ze

E x / r

E M

AND.

Compound 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate 7; 52 MmgH;

0.2bmmol) and trans-M-(4-aminoadamantan-1-yl)y-acetamide (obtained in Example 43; 125mg; 0.bOmmol) using T5TI according to the method described in Example 46, after purification by HPLC with reverse phase gave 4 mg of trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide as a white powdery substance. ER-MSVR t/e calculated for

С21НзоМаО2 with (MANNU) 4272316, found 427.2314.

Example 49 (5-Methanesulfonylaminoadamantan-2-yl)-amide of trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid vUry ra o MH

MN r

IS

Gh

E M

What?

The combination of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate 7; b2mg; 0.22mmol) and trans-M-(4-aminoadamantan-1-yl)y-methanesulfonamide (obtained in example 44; b1 mg; 0.25 mmol) using T5TiO according to the method described in example 46, after purification by reversed-phase HPLC gave 44 mg of (5-methanesulfonylaminoadamantan-2-yl)-amide trans-1-tert-butyl-5 - trifluoromethyl-1H-pyrazole-4-carboxylic acid in the form of a white powdery substance. ER-MSVR t/e calculated for SgoNzoMaozEz5 (MAN) 463.1985, found 463.1982.

Example 50 (5-Acetylaminoadamantan-2-yl)-amide trans-2'-tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid sh--K

МН ух

Su

AND.

When stirring, pyrazole (1.255 g; 18.0 mmol) was added to a suspension of sodium hydride (b01 mg; 15.03 mmol) in M,M-dimethylformamide (25.0 ml) under an argon atmosphere at room temperature. After the release of water was stopped, the aqueous mixture was heated at 40"C in a sealed high-pressure test tube for an hour. Trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide was added (obtained in example 46; 589 mg; 1.50 mmol) and the resulting mixture was heated at 110"C in a sealed high-pressure test tube for 17 hours. Then the reaction mixture was concentrated under vacuum under heating. The residue was suspended in water (5 Oml) and acidified to pH-1 using 1N. hydrochloric acid and diluted with 100 ml of water. Then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and 593 mg of (5-acetylaminoadamantan-2-yl)-amide trans-2'-tert-butyl-2'H-

I,Z'bipyrazolyl-4"-carboxylic acid in the form of an almost white powdery substance. EP-MSVR t/e calculated for SgzNzzMeO" (MaANU) 425.2660, found 425.2660.

Example 51 (5-Methanesulfonylaminoadamantan-2-yl)-amide of trans-2'-tert-butyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid o

And nki

Mn (9) /x a

J

The reaction of trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-methanesulfonylaminoadamantan-2-yl)-amide (obtained in Example 47; 50 mg; 0.12 mmol) with an excess of pyrazole (102 mg; 1.47 mmol) and sodium hydride (50 mg; 1.24 mmol) according to the method described in example 50, and extraction of the acidified aqueous mixture with methylene chloride followed by trituration of the crude product with diethyl ether gave 51 mg of (B-methanesulfonylaminoadamantan-2-yl)-amide trans -2'-tert-butyl-2'H-I1,3bipyrazolyl-4"-carboxylic acid in the form of an almost white powdery substance. EP-MSVR m/e calculated for SggNzzMeOz5 (MH) 461.2330, found 461.2329.

Example 52 (5-Acetylaminoadamantan-2-yl)-amide of trans-1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid

MN

(9) /x

Stage 1: trans-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

Compound 1-methyl-5-chloro-1H-pyrazole-4-carboxylic acid (SABZHYA 54367-66-7, purchased from the company

Oakjoody; 2.00 g; 12.46 mmol) and trans-4-aminoadamantan-1-ol (intermediate 2; 2.84 g; 14.00 mmol) using T5TI according to the method described in example 46, after trituration of the crude product with diethyl ether gave 1.44 g ( Trans-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid 5-hydroxyadamantan-2-yl)amide as a white solid.

Stage 2: trans-1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

A mixture of trans-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (500 mg; 1.62 mmol) and piperidine (1.29 ml; 13.0 mmol) in M -methylpyrrolidinone (1 Oml) was heated by microwave radiation at 250"C in a hermetic high-pressure test tube for 30 minutes. The mixture was allowed to cool to room temperature and a large part of the excess piperidine was removed under high vacuum. The resulting solution was purified by reversed-phase HPLC and 545 mg (5 -hydroxyadamantan-2-yl)-amide of trans-1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid in the form of a white powdery substance.

Stage 3: Trans-1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid (5-Acetylaminoadamantan-2-yl)-amide

When stirring to a solution of trans-1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (7Omg; 0.20mmol) in acetonitrile (1 ,Oml) and glacial acetic acid (0.20ml) at room temperature was added dropwise concentrated sulfuric acid (0.4Oml). After 22 hours the reaction mixture was neutralized with a saturated solution of sodium bicarbonate. Then the mixture was extracted with ethyl acetate and the extract was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by reversed-phase HPLC to obtain 35 mg of trans-1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide as a white powdery substance . ER-MSVR. t/e calculated for Cg2NzaM5O" (MAN) 400.2707, found 400.2708.

Example 53 (5-Methanesulfonylaminoadamantan-2-yl)-amide of trans-2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

M nm

Mn o

Su - k

Stage 1: Trans-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (X-Methyladamantan-2-yl)-amide

Compound 1-methyl-5-chloro-1H-pyrazole-4-carboxylic acid (SABAB54367-66-7, purchased from the company

Oakmjos; vOomg; 0.50 mmol) and trans-M-(4-aminoadamantan-1-yl)y-methanesulfonamide (obtained in example 44; 110 mg; 0.45 mmol) using T5TI according to the method described in example 46, after purification of the crude product using Reversed phase HPLC afforded trans-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid bomg(5-methyladamantan-2-yl)-amide as a white solid.

Stage 2: trans-2'-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (5-Methanesulfonylaminoadamantan-2-yl)-amide

The reaction of trans-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (5-methyladamantan-2-yl)-amide (46mg;

0.12 mmol) with an excess of pyrazole (71 mg; 1.02 mmol) and sodium hydride (3 mg; 0.97 mmol) according to the method described in example 50, and extraction with an acidified mixture of water and methylene chloride followed by trituration of the crude product with diethyl ether gave 4 mg ( 5-methanesulfonylaminoadamantan-2-yl-amide trans-2'-methyl-2'H-Y1,3Ibipyrazolyl-4"-carboxylic acid in the form of an almost white powdery substance. EP-MSNR (low resolution mass spectroscopy with electrospray ionization) t/e calculated for SizH27MvOz5 (M--H") 419, found 419.

Example 54 (B-Hydroxyadamantan-2-yl)-amide of trans-1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid

Ki

AH

Stage 1: 2-dimethylaminomethylene-3-oxobutyric acid methyl ester

A solution of methyl acetoacetate (5.0 ml, 46.3 mmol) and dimethyl acetal of M,M-dimethylformamide (6.8 ml, 47.95 mmol) was heated at 807 °C for 2.3 h. Then the reaction mixture was cooled to 25 °C and then concentrated in vacuo and 2-dimethylaminomethylene-33-oxobutyric acid methyl ester (7.43 g, 9495) was obtained as a red-black solid. This substance was used without further purification.

Stage 2: 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester

A solution of 2-dimethylaminomethylene-3-oxobutyric acid methyl ether (7.43g, 43.40mmol) in absolute ethanol (7/Oml) was treated with tert-butylhydrazine hydrochloride (5.52g, 44.29mmol) and sodium acetate (4.42g, 53 .88 mmol). The resulting mixture was heated at 907"C for 18 hours. Then the reaction mixture was cooled to 25"C. The reaction mixture was poured onto ice, washing with dichloromethane (50 ml). The mixture was transferred to a separatory funnel and the layers were shaken and separated. The aqueous layer was additionally extracted with dichloromethane (1x5Oml). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (x5Oml), water (x5O0ml) and a saturated aqueous solution of sodium chloride (1x5Oml), dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography using 12SO SotrbiBiavzna (column 1209; 0-1095 ethyl acetate/hexane) gave 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (6.04g, 7190) as a yellow oil.

Stage 3: 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid

A solution of 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ether (2.0g, 10.19mmol) in methanol (6b, 9ml), cooled to 0"C, was treated dropwise with 4N aq. sodium hydroxide solution (5.1 mL, 20.4 mmol). The reaction mixture was allowed to slowly warm to 25"C. The reaction mixture was stirred at 2570 overnight. The reaction mixture was then concentrated in vacuo to remove methanol. The residue was diluted with water (25 ml) and then extracted with ethyl acetate (1x25 ml). Then the aqueous layer was acidified to pH-1 Zn. aqueous solution of hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and hexane, and then dried under vacuum to give 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid (1.43g, 7895) as a white solid.

Stage 4: trans-1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

A solution of 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 2.74 mmol), trans-4-aminoadamantan-1-ol hydrochloride (590 mg, 2.89 mmol), 1-hydroxybenzotriazole (450 mg, C3.3Mmol) and O-(benzotriazol-yl)-M,M,M,M'-tetramethyluronium hexafluorophosphate (1.25g, 3.29mmol) in M,M-dimethylformamide (8.00ml, 0.34M) in cooled to 0"C under a nitrogen atmosphere and stirred at 0"C for 35 minutes. Then, the reaction mixture was treated dropwise with M,M-diisopropylethylamine (1.9 ml, 10.90 mmol) using a dropping funnel. The reaction mixture was allowed to gradually warm to 25°C. The reaction mixture was stirred at 2570 overnight. The reaction mixture was then cooled to 0°C and treated dropwise with 2N. aqueous sodium hydroxide solution (4.2 ml, 8.40 mmol). The resulting mixture was allowed to gradually heat up to 25"7C during

Then the reaction mixture was treated with dichloromethane (25 ml). The resulting solution was stirred at 2570 for another 1.5 hours. The reaction mixture was then partitioned between water (25 ml) and dichloromethane (25 ml).

The aqueous layer was additionally extracted with dichloromethane (25 ml). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (1x25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography using a SotbribBiabey IZSO (column 409; 50-10095 ethyl acetate/hexane) gave trans-1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide ( 75.3 mg, 890) as a white solid. ER--MOSVR t/e calculated for C19NhoMzO2 (M-ANU) 332.2333, found 332.2333.

Similarly received:

From the methyl ester of 4-methoxy-3-oxobutyric acid: (5-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-

B5-methoxymethyl-1H-pyrazole-4-carboxylic acid as a light brown solid (494.bmg, 58.290). ER--MSVR t/e calculated for SgoNziMzOz (Ma-NU) 362.2438, found 362.2437.

From the methyl ether of 4,4,5,5,5-pentafluoro-3-oxopentanoic acid: (5-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-pentafluoroethyl-1H-pyrazole-4-carboxylic acid acid as a white solid (13.1mg, 2995). ER--MSVR t/e calculated for SgoNovE5MzO" (MN) 436.2018, found 436.2018.

From the methyl ester of 5-methoxy-3-oxopentanoic acid: trans-1-tert-butyl-5-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide in the form of almost white solid (389mg, 4790).

ER"-MOSVR t/e calculated for С21НЗЗМ3ОЗ (МН) 376.2595, found 376.2595.

From the methyl ester of 3-oxohexanoic acid: trans-1-tert-butyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide as an almost white solid (698.2 mg, 81,690). EP--MSVR t/e calculated for SgiNzzMzO" (M-A-H") 360.2646, found 360.2645.

From the methyl ester of 3-oxopentanoic acid: trans-1-tert-butyl-5-ethyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide as an almost white solid (683.9 mg, 77,990). EP-MSVR t/e calculated for SgoNziMzO" (M--H") 346.2489, found 346.2490.

From the methyl ester of 4-methyl-3-oxopentanoic acid: trans-1-tert-butyl-5-isopropyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide as a white solid (94 .5 mg, 2895). ER--MSVR t/e calculated for SgiNzziMzO" (MAN) 360.2646, found 360.2646.

Example 55 (5-Hydroxyadamantan-2g-yl)-amide of trans-1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid for

And x dl

Stage 1: 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester

A solution of 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (3.38g, 17.22mmol) (as described in Example 54, step 2) in carbon tetrachloride (12.2ml, 1, 41M) at 2573 was treated with M-uccinimide (3.10 g, 17.41 mmol). The reaction vessel was equipped with a reflux condenser. The installation was wrapped with aluminum foil and then illuminated with a 250W sunlight lamp

According to Then the reaction mixture was filtered and washed with carbon tetrachloride. The filtrate was transferred to a separatory funnel and washed with water (500 ml) and a saturated aqueous solution of sodium chloride (1x50 ml).

The organics were dried over magnesium sulfate, filtered, washed with carbon tetrachloride and concentrated in vacuo to give a clear yellow oil.

Chromatography using IZCO SotriBiazp (column 1209, 0-1095 ethyl acetate/hexane) gave 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester (4.51g, 9595) as a clear oil. The substance was used without additional purification.

Stage 2: 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester

A solution of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ether (220 mg, 0.79 mmol) in ethanol (4.0 mL, 0.2 M) was treated with sodium ethoxide (65.4 mg, 0.96 mmol) ). The reaction mixture was heated at 90"C and stirred at this temperature for 2.5 hours. Then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (75 ml) and water (50 ml). The organic substances were washed with a saturated aqueous solution of sodium bicarbonate (1x5 Oml) and with a saturated aqueous solution of sodium chloride (1x5Oml), dried over magnesium sulfate, filtered and concentrated in a vacuum to obtain 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ether (102.8 mg, 5190) in the form orange oil.The substance was used without further purification.

Stage 3: 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid

A solution of 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ether (99.8 mg, 0.39 mmol) in methanol (0.5 mL) and water (0.5 mL) at 2573 was treated with hydroxide monohydrate lithium (20.2 mg, 0.4 vmmol).

The container for carrying out the reaction was equipped with a reflux condenser and then heated at 100" for 2 hours. Then the reaction mixture was concentrated in a vacuum. The resulting residue was acidified to pH-1 with an aqueous solution of hydrochloric acid. A cloudy mixture was formed. The substance was alkalinized by treatment with a 1N aqueous solution of hydroxide sodium. This solution was extracted with ethyl acetate (1x10ml). These organics were discarded. The aqueous layer was re-acidified to pHN with another aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (2x10ml). These organics were dried over magnesium sulfate, filtered and concentrated in vacuum to give 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (77.5 mg, 8795) as a yellow solid, which was used without further purification.

Stage 4: trans-1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid

A solution of /1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (76.8 mg, 0.3 mmol), trans-4-aminoadamantane-1-ol hydrochloride (71.3 mg, 0.35 mmol), 1-hydroxybenzotriazole (55.8 mg, 0.41 mmol) and O-(benzotriazol-y-yl)-M,M,M,M'-tetramethyluronium hexafluorophosphate (155.1 g, 0.40 mmol) in M,M-dimethylformamide (1, 0ml, 0.34M) in a nitrogen atmosphere was cooled to 0"C and stirred at 0"C for

35 minutes Then the reaction mixture was treated dropwise with M,M-diisopropylethylamine (0.23 ml, 1.34 mmol). The reaction mixture was allowed to gradually warm to 25°C. The reaction mixture was stirred at 257°C overnight. Then the reaction mixture was cooled to 0°C and treated dropwise with 2N. aqueous solution of sodium hydroxide (0.55 ml, 1.1 mmol). The resulting mixture was allowed to gradually heat up to 257C for 5 hours. Then the reaction mixture was treated with dichloromethane (5 ml). The resulting solution was stirred at 257C for another 1.5 hours. The reaction mixture was then partitioned between water (25 ml) and dichloromethane (25 ml). The aqueous layer was additionally extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium chloride (1 x 25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography using IZSO Sotbribiaz (column 49, 0.5-495 methanol/dichloromethane) gave trans-1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (66.2mg, 5290) as an off-white solid. EP"-MSVR t/e calculated for Sg1iNzzMzOz (MAN) 376.2595, found 376.2595.

Similarly received:

From the methyl ether of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid and propan-2-ol: (5-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-isopropoxymethyl -1H-pyrazole-4-carboxylic acid as a white solid (274.7mg, 6895). EP--MSVR t/e calculated for Cg2Hza5MzOz (MH?) 390.2751, found 390.2751.

From the methyl ether of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid and 2-methylpropan-1-ol: (B-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5 -isobutoxymethyl-1H-pyrazole-4-carboxylic acid as an almost white solid (130.5 mg, 4190). ER--MOVR t/e calculated for SgzNz7MzOz (MaNU) 404.2908, found 404.2905.

From the methyl ether of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid and cyclopropylmethanol: (b-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-cyclopropylmethoxymethyl-1H- pyrazole-4-carboxylic acid as a white solid (153.4 mg, 6195). ER--MOVR t/e calculated for SgzNaz5MzOz (MN) 402.2751, found 402.2753.

Example 56 (5-Acetylaminoadamantan-2-yl)-amide of trans-1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid

M M

0 shk

Stage 1: 1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid Solution of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ether (1.51g, 5.48mmol ) (obtained in example 55, stage 1) in sodium methoxide (23.8 ml, 11.9 mmol, 0.5 M solution in methanol) was heated at 90"C and stirred for 2.5 hours. Then the reaction mixture was concentrated in vacuo. The resulting white the solid was dissolved in water (100ml) and extracted with ethyl acetate (1x150ml). Then the organic matter was washed with a saturated aqueous solution of sodium bicarbonate (1x100ml), water (1x10O0ml) and a saturated aqueous solution of sodium chloride (1x100ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Since it was found that the product did not pass into the organic extracts, the aqueous layers were combined and acidified to pH-1 with a concentrated aqueous solution of hydrochloric acid and then extracted with dichloromethane (1x15Oml). These organics were dried over magnesium sulfate, filtered and concentrated in vacuum and receive 1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (1.03 g, 8890) was obtained as a white solid. The substance was used without additional purification.

Stage 2: trans-1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (5-Acetylaminoadamantan-2-yl)-amide

A solution of / 1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (317.9mg, 1.4O9mmol) in dichloromethane (8.5ml, 0.18M) was treated with M,M-diisopropylethylamine (1, 6 ml, 9.8 mmol) and M,M,M'M'-tetramethyl-O-(M-succinimidyl)-uronium tetrafluoroborate (539.5 mg, 1.79 mmol). The resulting mixture was stirred at 25°C for 2 h. Then the reaction mixture was treated with trans-M-(4-aminoadamantan-1-yl)-acetamide hydrochloride (476 8 mg, 1.94 mmol) (obtained in Example 43). The reaction mixture was stirred at 25"C during the night. The reaction mixture was then partitioned between water (100 ml) and dichloromethane (100 ml).

The aqueous layer was additionally extracted with dichloromethane (1 x 100 ml). The combined organic layers were washed with water (4x100ml) and saturated aqueous sodium chloride solution (1x100ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography using IZCO SotbriRiazp (column 409, 0.5-595 methanol/dichloromethane) afforded (5-acetylaminoadamantan-2-yl)-amide. trans-1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (428.7 mg, 71905) as a white solid. ER--MOVR t/e calculated for

Sg2NzaMaOz (MN) 403.2704, found 403.2706.

Example 57 Trans-1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5-Acetylaminoadamantan-2-yl)-amide (9) and ah as

M M

N m ho

J

Stage 1: Ethyl ester of 3-dimethylamino-2-(5-methylisoxazole-3-carbonyl)-acrylic acid

A solution of 5-methylisoxazole-3-carboxylic acid (3.5g, 27.53mmol) in dichloromethane (27.53ml, 1.0M), cooled to 0"C, was treated with oxalyl chloride (5.63ml, 63.33mmol, 98905), and then a few drops

M,M-dimethylformamide. The reaction mixture was stirred at 0"C for 300 minutes. Then it was allowed to gradually warm up to 25"C. The reaction mixture was stirred at 25"C overnight. The reaction mixture was then concentrated in vacuo and then dried under high vacuum for 1.5h. The resulting solid was then dispersed in toluene (21.2ml, 1.3M) at 25"C and then treated dropwise with a solution of ethyl-(3-dimethylamino)-acrylate (3.98 g, 27.81 mmol) in triethylamine (8.02 ml, 57.55 mmol). The resulting black reaction mixture was heated at 120°C overnight. The reaction mixture was then cooled to 25°C and then partitioned between water (1500ml) and dichloromethane (3x1000ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 3-dimethylamino-2-(5-methylisoxazole-3-carbonyl)-acrylic acid ethyl ester (presumably quantitative yield, 27.53 mmol) as a black oil .

The substance was used without additional purification.

Stage 2: 1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester

A solution of 3-dimethylamino-2-(5-methylisoxazole-3-carbonyl)-acrylic acid ethyl ether (27.53 mmol) in absolute ethanol (41.7 ml) was treated with tert-butylhydrazine hydrochloride (3.57 g, 28.63 mmol) and sodium acetate (2.80 g, 34.13 mmol). The resulting mixture was heated at 907"C for 18 hours. Then the reaction mixture was cooled to 25"C. The reaction mixture was diluted with water (200ml) and then extracted with dichloromethane (3x150ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester (7.37tg, 9695) in the form of a black solid. The substance was used without additional purification.

Stage 3: 1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid

A solution of 1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester (7.37g, 26.59mmol) in methanol (17.7ml, 1.5M), cooled to 0"C, treated dropwise with 4N aqueous sodium hydroxide solution (13.3ml, 53.15mmol). The reaction mixture was allowed to slowly warm up to 25"C. The reaction mixture was stirred at 257°C overnight. The reaction mixture was then concentrated in vacuo to remove methanol. The residue was diluted with water (150 mL) and then extracted with dichloromethane (3x150 mL). These organic substances were discarded. The aqueous layer was then acidified to pH-1 with 2N aq. solution of hydrochloric acid.

This solution was extracted with a solution of 90/10 dichloromethane/methanol (33x150 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-tert-butyl-5-(5-methylisoxazole-

C-yl)-1H-pyrazole-4-carboxylic acid (5.42 g, 8295) as a brown solid. The substance was used without additional purification.

Stage 4: trans-1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5-Acetylaminoadamantan-2-yl)-amide

A solution of 1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (350 mg, 1.40 mmol) in dichloromethane (7.9 mL, 0.18 M) was treated with M,M- diisopropylethylamine (1.9 mL, 8.6 mmol) and M,M,M',M'-tatreiMathyl-O-(M-succinimidyl)-uronium tetrafluoroborate (507 2 mg, 1.6 mmol). The resulting mixture was stirred at 257"C for 2 hours. Then the reaction mixture was treated with trans-M-(4-aminoadamantan-1-yl)-acetamide hydrochloride (446.7 mg, 1.82 mmol) (obtained in example 43). The reaction mixture was stirred at 25 "With during the night. Then the reaction mixture was partitioned between water (150ml) and dichloromethane (3x100ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.

Vioiade chromatography (40M column, 2-495 methanol/dichloromethane) gave (5-acetylaminoadamantan-2-yl)-amide trans-1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H- pyrazole-4-carboxylic acid (330.8 mg, 5490) as an almost white solid. ER--MSOVR t/e calculated for Cg24NzziM5Oz (M-ANU) 440.2656, found 440.2656.

Similarly received:

From 1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid and trans-4-aminoadamantan-1-ol: (B-hydroxyadamantan-2-yl)-amide . trans-1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid as an off-white solid (193.4mg, 6095). ER--MOVR t/e calculated for Cg2NzoMaOz (MH) 399.2391, found 399.2387.

Example 58 (5-Hydroxyadamantan-2-yl)-amide of trans-1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid

? WITH

M

M GSU-si

J

Stage 1: 2-(5-chloroisoxazole-3-carbonyl)-3-dimethylaminoacrylic acid ethyl ester

A solution of 5-chloroisoxazole-3-carboxylic acid (791 mg, 5.43 mmol) (preparation is described in UUO 03093250

A2) in dichloromethane (27.2 ml, 0.2 M), cooled to 0"C, was treated with oxalyl chloride (0.71 ml, 8.15 mmol, 98905), and then with several drops of M,M-dimethylformamide. The reaction mixture was allowed to gradually warm to 25"S. The reaction mixture was stirred at 25°C overnight. The reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in dichloromethane and re-concentrated twice to remove the remaining oxalyl chloride. The residue was then dissolved in dichloromethane (1 bml, 0.34 M) and treated dropwise with a solution of ethyl 3-(dimethylamino)-acrylate (0.79g, 5.51mmol) in triethylamine (1.bml, 11.47mmol).

The resulting red-orange reaction mixture was heated at 60°C overnight. The reaction mixture was then cooled to 25°7°C and then partitioned between water (50ml) and dichloromethane (100ml). Then the organic substances were washed with water (500 ml) and a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated in a vacuum. Chromatography using Vioiade (column

OM, 50-6090 ethyl acetate/hexane) gave 2-(5-chloroisoxazole-33-carbonyl)-3-dimethylaminoacrylic acid ethyl ester (300 mg, 2095) as a red oil.

Stage 2: 1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

A solution of 2-(5-chloroisoxazole-3-carbonyl)-3-dimethylaminoacrylic acid ethyl ether (294.8 mg, 1.0 mmol) in absolute ethanol (1.4 ml, 0.77 M) was treated with tert-butylhydrazine hydrochloride (137.8 mg, 1 .10 mmol) and sodium acetate (108.bmg, 1.32 mmol). The resulting mixture was heated at 907C overnight. Then the reaction mixture was cooled to 25"7C and concentrated in vacuo. The reaction mixture was partitioned between water (200 ml) and dichloromethane (2 x 5 Oml). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo Chromatography with Vioiade (column 405, 6095 ethyl acetate/hexane) followed by chromatography with ISO

Solvent Riazp (column 49, 0-2095 ethyl acetate/hexane) gave 1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (67 Ag, 2195) as a yellow oils

Step 3: 1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid

A solution of 1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ether (55.3 mg,

0.18 mmol) in absolute ethanol (0.9 ml, 0.2 M) was treated with a 2 M aqueous solution of lithium hydroxide (0.18 ml, 0.37 mmol). The reaction mixture was stirred at 25°C for 1.5 hours and then heated at 100°C for 1 hour. The reaction mixture was then allowed to cool to 25°C and stirred at 257°C overnight. The reaction mixture was then concentrated in vacuo. The residue was treated with water and then acidified to pH-1 1N. aqueous solution of hydrochloric acid. The precipitate formed was collected by filtration, washed with water and hexane and dried under vacuum to give 1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (38.7mg, 7790 ) in the form of an almost white solid.

Stage 4: trans-1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

A solution of 1-tert-butyl-5-(5-chloroisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (36.2 mg, 0.1 mmol) in dichloromethane (0.54 mL) and N,M-dimethylformamide ( 0.13 mL) at 257°C was treated with M,M-isopropylethylamine (0.18 mL, 1.033 mmol) and M,M,M'/M'-tetramethyl-O-(M-succinimidyl)uronium tetrafluoroborate (48.3 mg, 0 ,1 bmmol).

The resulting mixture was stirred at 25"C for 6.5 hours. Then the reaction mixture was treated with trans-4-aminoadamantan-1-ol hydrochloride (intermediate 2; 35.3 mg, 0.17 mmol). The reaction mixture was stirred at 25"C overnight. Then the reaction mixture was partitioned between water (25 ml) and dichloromethane (3x25 ml). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (1 x 25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography using IZCO Solvent (column 449, 0-44-10095 ethyl acetate/hexane) afforded (5-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-(5-chloroisoxazol-3-yl)- 1H-pyrazole-4-carboxylic acid (12.8 mg, 2395) as an almost white solid.

ER"-MSOSVR t/e calculated for SgiH27SIMAOz (Ma-NU) 419.1845, found 419.1844.

Example 59 (B-Hydroxyadamantan-2-yl)-amide of trans-5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid

A t "on / m si

Stage 1: 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester

Cyclohexylhydrazine hydrochloride (3.057g, 20.29mmol, CA y24214-73-1, purchased from Aiagsp) was combined with ethyl-(ethoxymethylene)-cyanoacetate (3.390g, 20.04mmol) and anhydrous sodium acetate (2.080g, 25, 3bmmol) in 30ml of ethanol. The mixture was heated at 70"C for 16 hours, then cooled to room temperature and concentrated. The residue was partitioned between methylene chloride and water. The separated aqueous phase was extracted with a second portion of methylene chloride. The organic phases were successively washed with water and brine and then combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting in a gradient mode with a mixture of 25-7090 ethyl acetate/hexane to give 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.42g, 9290 ).Mass spectrum: t/7: 238.1 (MN).

Stage 2: 5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester

Copper(I) chloride (2.500 g, 25.25 mmol) was suspended in 7.0 ml of cold (ice/acetone bath) anhydrous acetonitrile. Tert-butyl nitrite (5.75 mL, 9095, 43.5 mmol) was added, followed by a suspension of 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ether (4.408 g, 18.58 mmol) in 27.0 mL acetonitrile. The mixture was stirred at room temperature for 45 minutes. and then at 70"C for 1.25 hours. The mixture was cooled to room temperature, slowly added to bn. HCl (17.5 ml) and then extracted with methylene chloride. The organic phase was successively washed with water and brine. The aqueous phases were back-extracted with a second portion of methylene chloride. These the two organic phases were combined, dried over sodium sulfate, and concentrated in vacuo.The crude residue was chromatographed by flash chromatography eluting with a gradient of 10-5095 ethyl acetate/hexane to give 5-chloro-1-cyclohexyl-1H-ethyl ether of pyrazole-4-carboxylic acid (1.98g; 4295).Mass spectrum: t/2: 257.3 (MH).

Stage 3: 5-Chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid

5-Chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ether (1.969 g, 7.67 mmol) was dissolved in methanol (11.5 ml). Lithium hydroxide (0.250 g; 10.44 mmol) and water (11.5 ml) were added. The mixture was heated at 80-8570 for 1.5 hours. cooled to room temperature and concentrated in vacuo to remove methanol.

The residue was diluted with tetrahydrofuran and re-concentrated to ensure complete removal of methanol. Then the residue was diluted with water and acidified with BN. NSI (1.80ml) to pH 2g-2.5. the solid that settled from the solution was collected by filtration, washed with water and dried under reduced pressure at 1002 to give 5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (1.676g, 9695) which was used without further purification . Mass spectrum: t/2: 229.0 (MAN).

Step 4: (5-Hydroxyadamantan-2-yl)-amide trans-5-chloro-i-cyclohexyl-1H-pyrazole-4-carboxylic acid 5-Chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (0.152 g, 0.6 ppm) was dissolved in a mixture of dry

of M,M-dimethylformamide (2.bml) and dry methylene chloride (0.7ml). M,M-isopropyl-M-ethylamine (0.91 ml, 5.2 mmol) and T5Ti (0.238 g, 0.79 mmol) were added to the solution, and the solution was stirred under an argon atmosphere for

Z, Bhod. LC-MS then indicated the formation of an active ester and trans-4-aminoadamantane-1-ol hydrochloride (0.136g, 0.67mmol, intermediate 2) was added. Stirring was continued at room temperature in an argon atmosphere for 44 hours. The reaction mixture was added to water and extracted twice with methylene chloride. The organic phases were combined and washed twice with water and then with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography eluting in a gradient mode with a mixture of 60-10095 ethyl acetate/hexane. Fractions containing the product were concentrated in vacuo and the residue was triturated with a mixture of ethyl acetate-hexane to obtain trans-5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide as of a white solid (0.179g, 7190) MSVR (ER) t/e calculated for SgoNgvSIMzO" (MN) 378.1943, found 378.1943.

Example 60 (B-Hydroxyadamantan-2-yl)-amide of trans-2'-cyclohexyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid y; a: t. "on hy y me (B- Trans-5-chloro-i-cyclohexyl-1H-pyrazole-4-carboxylic acid hydroxyadamantan-2-yl)-amide (117mg, 0.3100mmol, example 59) and pyrazole (bbmg, 0.969mmol) were combined in 1- methyl-2-pyrrolidinone (2.1 ml). 5095 aqueous solution of sodium hydroxide (135 mg, 1.688 mmol) was added and the mixture was heated at 1207C for 10-11 hours.

The mixture was cooled in an ice water bath and water (2.62 ml) and a saturated aqueous solution of ammonium chloride (2.62 ml) were successively added. After a short period of time, a clear solution was formed and then the product settled. After stirring in the cold for 1.5 hours. the solid substance was collected by filtration, washed with water and dried in a high vacuum at 100"C to obtain (5-hydroxyadamantan-2-yl)-amide trans-2'-cyclohexyl-2'"H-I(1,3bipyrazolyl-4"- of carboxylic acid (107.5mg, 8590). MSVR(ER) t/e calculated for

SgzNaiM5O" (MN) 410.2551, found 410.2550.

Example 61 (5-Acetylaminoadamantan-2-yl)-amide of trans-5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (c) about their "

5-Chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (0.213 g, 0.93 mmol, obtained in example 59, stage

C) was dissolved in a mixture of dry M,M-dimethylformamide (3.bml) and dry methylene chloride (0.9ml). M,M-diisopropyl-M-ethylamine (1.25 ml, 7.22 mmol) and T5TI (0.334 g, 1.11 mmol) were added, and the solution was stirred at room temperature under an argon atmosphere for 1 h. Then LC-MS indicated the formation of an active ester.

Trans-N-(4-aminoadamantan-1-yl)-acetamide (0.194 g, 0.93 mmol, obtained in example 43) was added.

Stirring was continued at room temperature overnight. The reaction mixture was added to water and extracted twice with methylene chloride. Each organic phase was washed with water and brine. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography eluting in a gradient mode with //-0-4095 methanol/methylene chloride. Fractions containing the product were concentrated in vacuo. The residue was crystallized from a hot mixture of ethyl acetate/lexane and dried in a high vacuum at 100"C to obtain trans-5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide as white solid (0.194g, 5095). MSVR (ER) t/e calculated for Cg2NziSiMaOg" (MH) 419.2209, found 419.2207.

Example 62 (5-Acetylaminoadamantan-2-yl)-amide trans-2'-cyclohexyl-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid ram

N n- t y

M. (5-Acetylaminoadamantan-2-yl)-amide of trans-5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (151 mg, 0.362 mmol, example 61) and pyrazole (77 mg, 1.131 mmol) was combined in 1-methyl-2-pyrrolidinone (2.4 ml).

5095 aqueous solution of sodium hydroxide (158 mg, 1.975 mmol) was added and the mixture was heated at 1207C for 11 hours. The mixture was cooled in an ice water bath and water (3.2 ml) and a saturated aqueous solution of ammonium chloride (3.2 ml) were added. After a short period of time, a clear solution was formed and then the product settled.

The mixture was stirred in the cold for -2 hours. and then the solid was collected by filtration, washed with water and dried in a high vacuum at 1007C to obtain (5-acetylaminoadamantan-2-yl)-amide trans-2'-cyclohexyl-2'"H-(1,3|bipyrazolyl-4- carboxylic acid (139.1mg, 8495).

Sg25NzaMvO" (MAN) 451.2816, found 451.2816.

Example 63 (5-Hydroxyadamantan-2-yl)-amide of trans-2"-(tetrahydropyran-4-yl)-2'H-/1,3|bipyrazolyl-4"-carboxylic acid , oh oh

Stage 1: M'-(tetrahydropyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ether

Tetrahydro-AN-pyran-4-one (1.002g, 10.01mmol, CA5 2529943-42-8, purchased from RiiKa) was combined with tert-butyl carbazate (1.322g, 10.00mmol) in hexane (10ml). The mixture was heated in an oil bath at 65-70" for 75 minutes. A new precipitate began to settle from the solution until the carbazate completely went into solution. The mixture became very thick due to the solid precipitate. It was diluted with an additional amount of hexane and heated for another 15 minutes. The mixture was cooled to room temperature and concentrated in vacuo. Isopropanol was added to the residue and the mixture was vigorously stirred for 5 min. and then diluted with ether and cooled. The solid was collected by filtration and dried in vacuo to give M'-(tetrahydropyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ether 1.326g , 6290).The second portion (0.373g, 1795) was collected from the uterine solution.

Stage 2: (Tetrahydropyran-4-yl)-hydrazine hydrochloride tert-Butyl ether M'-(tetrahydropyran-4-ylidene)-hydrazinecarboxylic acid (5.210 g, 24.32 mmol) was dissolved in a mixture of dry tetrahydrofuran (22 ml) and dry methanol (30 ml ). Sodium cyanoborohydride was added to the resulting solution, which led to violent gas evolution. After gas evolution stopped, the mixture was refluxed for 5-10 minutes. After cooling to room temperature NSI (10.5 ml) was slowly added and then the mixture was refluxed for 20 min. After cooling to room temperature, the solvent was removed in vacuo. The residue was triturated with hot isopropanol and then cooled to room temperature, diluted with ether and cooled. The solid was collected by filtration and found to be the reduced material, but the protecting groups were incompletely removed. The solid was dissolved in the same THF-methanol mixture and treated with the help of bn. NSI (10.5 ml) under reflux for another 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove a small amount of undissolved matter. The filtrate was then concentrated in vacuo. Isopropanol was added to the residue and a solid quickly began to crystallize from solution. After cooling overnight, ether was added and then further cooled. The solid was then collected by filtration, washed with ether and dried in vacuo to give (tetrahydropyran-4-yl)-hydrazine hydrochloride (2.22g, 6095).

Stage 3: 5-Amino-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (Tetrahydropyran-4-yl)-hydrazine hydrochloride (1.975g, 12.94mmol), ethyl-(ethoxymethylene) -cyanoacetate (1.958g, 11.57mmol) and sodium acetate (1.370g; 16.70mmol) were combined in ethanol (1bml). The mixture was heated at 80-857C for 17 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue partitioned between methylene chloride and water. The organic phase was separated and washed with water and then brine. Each aqueous phase was subjected to back extraction with methylene chloride. These two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude substance was purified by flash chromatography eluting with a mixture of 60-10095 ethyl acetate/hexane to obtain 5-amino-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.554g, 9295) .

Stage 4: 5-chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

(Midinium chloride) (1.700g, 17.17mmol) was suspended in cold (ice water bath) acetonitrile (5ml).

Tert-butyl nitrite (2.35 ml, 9095, 17.80 mmol) was added to the suspension, and then a solution of 5-amino-1-(tetrahydropyran-4-yl)-1nH-pyrazole-4-carboxylic acid ethyl ether (3.157 g, 13.19 mmol) in acetonitrile (19 mL). The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. and then at 707C for 1 hour. The reaction mixture was cooled to room temperature and added to bn. NSI (12.5 ml). After stirring for 15 min. the mixture was extracted with methylene chloride. The organic phase was successively washed with water and brine. Then each aqueous phase was repeatedly washed with one portion of methylene chloride. These two organic phases were combined, dried over sodium sulfate and concentrated.

Purification by flash chromatography with gradient elution with 40-10095 EtOAc-hexane gave 5-chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.205g, 6390).

Mass spectrum: t/2: 259.30 (MN).

Stage 5: 5-chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid

5-Chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ether (2.194 g (9895), 8.31 mmol) was dissolved in methanol (12.5 ml). Lithium hydroxide (0.274 g, 11.44 mmol) and water (12.5 mL) were added and the mixture was heated at 80°C for 1 h. After cooling to room temperature, the mixture was concentrated to remove methanol. Tetrahydrofuran was added to the residue and it was removed in vacuo to provide complete removal of methanol. The aqueous residue was treated with BN NOSI (1.88 mL), resulting in the precipitation of a dense milky white solid. The solid was collected by filtration, washed with water, and dried under high vacuum under heating to give 5-chloro-1 -(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid (1.900g, 9995). Mass spectrum: t/7: 231.30 (M.H).

Stage 6: (5-Hydroxyadamantan-2-yl)-amide. trans-5-chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid 5-Chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid (124.5 mg , 0.540 mmol) was dissolved in a mixture of dry M,M-dimethylformamide (2.1 ml) and dry methylene chloride (0.5 ml). M,M-diisopropyl-M-ethylamine (0.75 ml, 4.335 mmol) and T5TI (193 mg, 0.644 mmol) were successively added to the solution. In 2 hours LC-MS indicated the formation of an active ester. Trans-4-aminoadamantane-1-ol hydrochloride (113.Omg, 0.555 mmol, intermediate 2) was added and the mixture was stirred at room temperature under an argon atmosphere for 45 hours. The reaction mixture was added to water and extracted twice with methylene chloride. These two organic layers were combined and washed twice with water and then once with brine, dried over sodium sulfate and concentrated. Flash chromatography with elution in a gradient mode with a mixture of 5-1090 methanol-methylene chloride followed by crystallization from a mixture of ethyl acetate-hexane gave (5-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-(tetrahydropyran-4-yl) -1H-pyrazole-4-carboxylic acid (138 mg (purity 9695), 65905).

MOVR (ER) t/e calculated for SizNagvSIMzOz (Ma-NU) 380.1736, found 380.1733.

Stage 7: (5-Hydroxyadamantan-2-yl)-amide trans-2'-(tetrahydropyran-4-yl)-2'H-(1,3bipyrazolyl-4"-carboxylic acid (5-Hydroxyadamantan-2-yl) -amide of trans-5-chloro-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid (78.3 mg, 9695, 0.198 mmol) was combined with pyrazole (4 mg, 0.67 mmol) and 5095 aqueous solution of sodium hydroxide (105.Omg, 1.313 mmol) in 1-methyl-2-pyrrolidinone. The mixture was heated at 1207C for 12h and then stirred at room temperature for 2h. The resulting thick heterogeneous mixture was successively treated with water (1.74ml) and saturated aqueous ammonium chloride solution (1.74 mL). A clear solution formed shortly before the solid began to re-set out of solution. The mixture was stirred in the cold for 2 h and then filtered, washed with water and dried under high vacuum under heating to give ( Trans-2'-(tetrahydropyran-4-yl)-2'H-(1,3bipyrazolyl-4-carboxylic acid 5-hydroxyadamantan-2-yl)-amide (59.3 mg, 7395). MSVR (ER) t/ is calculated for Сg2Н hM5Oz (MN) 412.2343, found 412.2343.

Example 64 (B-Hydroxyadamantan-2-yl)-amide of trans-5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid

M

And so on

Stage 1: tert-butyl ether of M'-cyclopentylhydrazinecarboxylic acid

Cyclopentanone (5,000 g, 59.44 mmol; SAB Ya120-92-3, purchased from Aiagpsp) was dissolved in hexane (9 mL). Tert-butyl carbazate (7.860 g, 59.47 mmol) was added and the mixture was heated at 65-707"C for an hour.

The mixture was cooled and concentrated in vacuo. The residue was dissolved in a mixture of isopropanol (25ml) - ether (25ml) - hexane (50ml) and cooled. The crystalline substance was collected by filtration and M'-cyclopentylhydrazinecarboxylic acid tert-butyl ether (5.51g; 4790) was obtained. A second portion (2.62 g, 2290) was collected from the mother's solution.

Stage 2: Cyclopentylhydrazine hydrochloride tert-butyl ether of M'-cyclopentylhydrazinecarboxylic acid (5.448g, 27.48mmol) was dissolved in dry tetrahydrofuran (25ml) and dry methanol (34ml). Sodium cyanoborohydride (2.044 g, 32.53 mmol) was added in portions, and then the mixture was refluxed in an argon atmosphere for 1 hour. After cooling to room temperature, bn was added. NS! (12 ml) and the mixture was refluxed for 1.5 hours. At this point, NMR of the aliquots showed that there was still a certain amount of the substance with the BOS protecting group. They added an additional number of bn. NSI and the mixture were boiled under reflux for another 10 minutes. and then it was cooled to room temperature and stirred overnight. The mixture was filtered to remove undissolved matter, concentrated and azeotroped three times with toluene to remove water. The residue was dissolved in hot isopropanol, cooled to room temperature, diluted with ether and cooled. Filtration gave cyclopentylhydrazine hydrochloride (3.903g, 10395) which was used without any further purification.

Stage 3: 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester

Cyclopentylhydrazine hydrochloride (1.000g, 7.32mmol), ethyl-(ethoxymethylene)cyanoacetate (1.026g, 6.btmmol) and anhydrous sodium acetate (0.644g, 7.85mmol) were combined in ethanol (10mL) and heated at 707 for 8 p.m. After cooling to room temperature, the ethanol was removed in vacuo and the residue partitioned between methylene chloride and water. The organic phase was successively washed with water and brine. Each aqueous phase was back-extracted with one portion of methylene chloride. These two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography eluting with a mixture of 10-4095 EtOAc/hexane gave 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.170g, 7395). Mass spectrum: t/7: 2241 (MAN).

Stage 4: 5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester

5-Amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ether (1.164 g, 4.96 mmol) was dissolved in acetonitrile (10.00 ml). Copper chloride (0.722 g, 7.29 mmol) and glacial acetic acid (0.0 ml, 10.4 mmol) were added and the mixture was cooled in an ice water bath. The first portion of tert-butyl nitrite (0.29 ml, 90956, 2.20 mmol) was added. The cooling bath was removed and the mixture was allowed to warm to room temperature.

A second portion of tert-butyl nitrite (0.58 mL, 4.39 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was diluted with ethyl acetate. After vigorous mixing, the layers were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated. Purification by flash chromatography with gradient elution with 20:80 ethyl acetate-hexane gave 5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.710g; 6195). Mass spectrum: t/7: 243.1 (MAN).

Stage 5: 5-Chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid

5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ether (0.710 g, 2.93 mmol) was dissolved in methanol (4.3 ml). Water (4.3 mL) and lithium hydroxide (0.097 g, 4.05 mmol) were added and the mixture was heated at 807°C for 2 h. After cooling to room temperature, the methanol was removed in vacuo. Tetrahydrofuran was added to the residue and then it was removed in vacuo to provide complete removal of methanol.

The residue was diluted with water and processed using BN. NSI up to 2-3, which led to precipitation of a milky white solid. The solid was collected, washed with water and dried using a laboratory vacuum line at 457C to give 5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (0.580g, 9190).

This substance was used without any additional purification.

Step 6: (5-Hydroxyadamantan-2-yl)-amide trans-5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid 5-Chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ( 0.225g, 1.05mmol) was dissolved in dry M,M-dimethylformamide (4.0ml) and dry methylene chloride (1.0ml). M,M-diisopropyl-

M-ethylamine (1.45ml, 8.38mmol) and T5TI (0.359g, 1.19mmol) and stirring was continued at room temperature under an argon atmosphere for 2.5h. and then LC-MS indicated the completion of the activated ester formation reaction. Trans-4-aminoadamantane-1-ol hydrochloride (0.224g, 1.10mmol, intermediate 2) was added and the mixture was stirred at room temperature under argon overnight. The reaction mixture was added to water and extracted twice with methylene chloride. Each organic phase was washed with water and then with brine. These two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography (when eluting in a gradient mode with a mixture of 50-10095 ethyl acetate-hexane) followed by crystallization from a mixture of ethyl acetate-hexane gave (5-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-cyclopentyl- 1 H-pyrazole-4-carboxylic acid (0.174g, 4695). MSVR (ER) t/e calculated for C1i9NgvSIMzO»2 (Ma-NU) 3641787, found 3641785.

Example 65 (B-hydroxyadamantan-2-yl)-amide of trans-2'-cyclopentyl-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid

IN

(B-Hydroxyadamantan-2-yl)-amide of trans-5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (137mg, 0.37bmmol, example 64) was combined with pyrazole (82.8mg , 1.216 mmol) and 5095 with an aqueous solution of sodium hydroxide (164 mg, 2.050 mmol) in 1-methyl-2-pyrrolidinone (2.5 ml) and heated at 1207C for 11 hours. Then the mixture was cooled to room temperature and stirred for 8 hours. Water (3.0 ml) and a saturated aqueous solution of ammonium chloride (3.0 ml) were successively added. A clear solution was formed shortly before the solid began to settle out of solution again. The mixture was stirred in an ice water bath for 2 hours. and then filtered, washed with water and dried in a high vacuum at 1007C to obtain (5-hydroxyadamantan-2-yl)-amide of trans-2'-cyclopentyl-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid (126.5 mg, 8490).

MOVR (ER) t/e calculated for Сg2НоМ5О» (MAN) 418.2213, found 418.2213.

Example 66 (5-Acetylaminoadamantan-2-yl)-amide of trans-2'-cyclopentyl-2'H-/I1,3|bipyrazolyl-4"-carboxylic acid

M epi t 7

M. m s, o

Stage 1: (5-Acetylaminoadamantan-2-yl)-amide trans-5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid 5-Chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (0.334 g, 1.5 mmol obtained in example 64, stage 5) was dissolved in dry M,M-dimethylformamide (b,00 ml) and dry methylene chloride (1.5 ml). M,M-isopropyl-M-ethylamine (2.15 ml, 12.4 mmol) and T5TiO (0.563 g, 1.87 mmol) were successively added to the solution, and the stirring was continued at room temperature under an argon atmosphere for 1 h. and then LC-MS indicated the completion of the activated ester formation reaction. Trans-M-(4-aminoadamantan-1-yl)-acetamide (0.330 g, 1.58 mmol, obtained in example 43) was added and the mixture was stirred at room temperature for 22 hours. The reaction mixture was added to water and extracted twice with methylene chloride. These two organic phases were combined, washed twice with water and once with brine, dried over sodium sulfate and concentrated. The crude substance was purified by a combination of flash chromatography and crystallization from a hot mixture of methylene chloride-ether-hexane to obtain trans-5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (0.417g, 6695). MSVR (ER) t/e calculated for SgiNgoSIMAO" (M-ANU) 405.2052, found 405.2052.

Stage 2: (5-Acetylaminoadamantan-2-yl)-amide trans-2'-cyclopentyl-2'H-Y1,3|bipyrazolyl-4"-carboxylic acid (5-Acetylaminoadamantan-2-yl)-amide trans-5 -chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (150.0mg, 0.33mmol) was combined with pyrazole (69.2mg, 1.016mmol) and 5095 aqueous sodium hydroxide solution (148mg, 1.850mmol) in 1-methyl-2-pyrrolidinone (2.2 mL). The mixture was heated at 1207 C and then cooled to room temperature and stirred for 5 h. Water (2.8 mL) and saturated aqueous ammonium chloride solution (2.8 mL) were added to the thick mixture . A clear solution was observed shortly before the solid substance began to settle again from the solution. The mixture was stirred in a bath for 1.5 hours and then filtered, washed with water and dried in a high vacuum at 100"C. The crude solid was recrystallized from a mixture of methylene chloride-ether-hexane and obtained (5-acetylaminoadamantan-2-yl)-amide trans-2'-diclopentyl-2'H-1,3-bipyrazolyl-4"-carboxylic acid (103 mg, 7195). MSVR (ER) t/e calculated for Sg«Hz2MevOg (MH) 437.2660, found 437.2660.

Example 67 (b-hydroxyadamantan-2-yl)-amide of trans-5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid

In he

Stage 1: tert-butyl ether M'-I4-(tert-butyldimethylsilanyloxy)-cyclohexylidene|-hydrazinecarboxylic acid tert-butyldimethylsilyloxycyclohexanone (3.146g, 97906, 13.36bmmol, SAB y555145-45-4, purchased from Aiagsa) was dissolved in hexanes (24 ml).

Tert-butyl carbazate (1.80 g, 9895, 13.35 mmol) was added and the mixture was heated at 707C for

According to After cooling to room temperature, a white solid precipitated from the solution. The solid substance was collected by filtration, washed with hexane and dried to give M-I(4-(tert-butyldimethylsilanyloxy)-cyclohexylidene-hydrazinecarboxylic acid tert-butyl ether (4.12g, 9095).

Stage 2: 4-Hydrazinocyclohexanol hydrochloride tert-Butyl ether M'-(4-(tert-butyldimethylsilanyloxy)-cyclohexylidene|-hydrazinecarboxylic acid (4.103g, 11.998mmol) was dissolved in dry tetrahydrofuran (11.5ml) and dry methanol (15.0ml ). Sodium cyanoborohydride (0.945g, 14.29mmol) was added in portions. After gas evolution stopped, the mixture was refluxed for 1.5h. At this point, a little more sodium cyanoborohydride (0.047g, 0.75mmol) was added and boiled refluxing was continued for another 30 min to ensure completion of the reaction. After cooling to room temperature, sodium chloride (10 mL) was added, resulting in the precipitation of a white solid. The mixture was heated at 70°C for 2 h and then cooled to room temperature temperature and stirred for 12 h. The reaction mixture was concentrated and subjected to azeotropic distillation with toluene to remove almost all water. The residue was then dissolved in hot isopropanol and recooled to at room temperature. The insoluble matter was removed by filtration. The filtrate was diluted with ether and cooled. The substance fell out of solution as an oil/resin. The mother liquor was removed by decantation. The oil/resin was then washed with ether and dried in vacuo to give 4-hydrazinocyclohexanol hydrochloride (1.920g, 9690). A second portion (0.261g, 1395) was collected from the mother liquor. The yield was more than theoretical due to the presence of the included solvent and a small amount of impurities. The substance was used without any additional purification.

Stage 3: 5-amino-1-(4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester

Hydrazinocyclohexanol hydrochloride (1.920 g, 9.79 mmol) was dissolved in hot ethanol and then cooled slightly. Ethyl-(ethoxymethylene)-cyanoacetate (1.520 g, 8.98 mmol) and anhydrous sodium acetate (2.013 g, 24.54 mmol) were added and the mixture was heated at 707C for 15 hours. After cooling to room temperature, the mixture was partitioned between methylene chloride and water. The aqueous phase was washed with a second portion of methylene chloride. These two organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. Flash chromatography with elution in a gradient mode with a mixture of /-0-2095 methanol/ethyl acetate separated a significant part of the cis-trans mixture of isomers. After chromatography, the pure fractions of each isomer were combined and crystallized from a mixture of EA-hexane to obtain 5-amino-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.511g, 23905 (portion 1); 0.121g, 595 (portion 2)) and 5-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ether (0.625g, 2895).

Stage 4: 5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester

Copper(I) chloride (126mg, 1.273mmol) and tert-butyl nitrite (18µl, 1.364mmol) were combined with acetonitrile (2.0ml) in the cold (ice water bath). 5-amino-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ether (230 mg, 0.908 mmol) was added in portions. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. and then at 70"C for 30 minutes. After cooling to room temperature, the mixture was treated with BN NOSI (0.9 ml) and extracted four times with methylene chloride. The organic phases were combined, washed with water and brine, dried over sodium sulfate and concentrated in Purification by flash chromatography eluting with 50-10095 ethyl acetate/hexane gave 5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester (137mg, 5590).

Stage 5: 5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid

Chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester (183 mg, 0.631 mmol) was dissolved in methanol (1.2 ml). Lithium hydroxide (20.8 mg, 0.869 mmol) and water (1.2 mL) were added and the mixture was heated at 80°C for 1 h. The reaction mixture was concentrated and then re-concentrated from tetrahydrofuran to ensure complete removal of methanol. The residue was diluted with water and treated with bn

NSI (160 μl), which led to the precipitation of a solid substance. The solid was collected by filtration, washed with water and dried under high vacuum at 507C to give 5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid (140 mg, 9195). Mass spectrum: t/72: 245.0 (MN).

Stage 6: trans-5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid /(5-Hydroxyadamantan-2-yl)y-amide

Chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid (52.4 mg, 0.214 mmol) was dissolved in dry M,M-dimethylformamide (0.vml) and dry methylene chloride (0.2ml). M,M-diisopropyl-M-ethylamine (0.30 ml, 1.734 mmol) and TT (7 mg, 0.242 mmol) were successively added to the solution, and stirring was continued at room temperature for 1 h. and then LC-MS indicated the completion of the activated ester formation reaction. Trans-4-aminoadamantane-1-ol hydrochloride (45 mg, 0.22 mmol, intermediate 2) was added and stirring was continued at room temperature under argon overnight. The reaction mixture was added to water and extracted twice with methylene chloride. These two organic phases were combined, successively washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (eluting with 0-20956 methanol-ethyl acetate) followed by crystallization from hot ethyl acetate-hexane gave (5-hydroxyadamantan-2-yl)-amide. trans-5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid (42.4 mg, 6595). MSVR (ER) t/e calculated for

SgoNgvSIMzOz (MAN) 394.1892, found 394.1894.

Example 68 (5-Hydroxyadamantan-2-yl)-amide of trans-2'-(cis-4-hydroxycyclohexyl)-2'"H-(1,3|bipyrazolyl-4"-carboxylic acid; and

M Kh "y, 1-2

Trans-5-chloro-1-(cis-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid (b-hydroxyadamantan-2-yl)-amide (143 mg, 9795, 0.352 mmol, example 67) was combined with pyrazole (75mg, 1.102mmol) and 5095 aqueous sodium hydroxide solution (156bmg, 1.950mmol) in 1-methyl-2-pyrrolidinone (2.4ml). The mixture was heated at 1207 for 12 hours. and then stirred at room temperature for 5 hours. Then the mixture was cooled in an ice water bath. Water (3.Oml) and a saturated aqueous solution of ammonium chloride (3.Oml) were successively added.

The reaction mixture briefly turned into a clear solution and then the product precipitated from the solution. After mixing in the cold for 2 hours. the solid substance was collected by filtration, washed with water and dried in a high vacuum at 100°C to obtain (5-hydroxyadamantan-2-yl)y-amide trans-2'-(cis-4-hydroxycyclohexyl)-2'H-(1, 3-bipyrazolyl-4"-carboxylic acid (115 mg, 7790). MSVR (ER) t/e calculated for

SgziNzai M5Oz (MAN) 426.2500, found 426.2500.

Example 69 (B-hydroxyadamantan-2-yl)-amide of trans-1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid in; and

M. E

Stage 1: 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

Cyclopentylhydrazine hydrochloride (0.250g, 1.83mmol, example 64, stage 2), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxobutyric acid ethyl ether (0.403g, 1.6v8mmol) and anhydrous sodium acetate (0.163g, 1.99 mmol) were combined in ethanol (2.5 ml) and heated at 707C for 17 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back-extracted with a second portion of methylene chloride. These two organic phases were combined, dried over sodium sulfate and concentrated in vacuo.

Purification by flash chromatography with gradient elution with 10-4095 ethyl acetate-hexane gave 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.244g, 5295). Mass spectrum: t/2: 2771 (MAN).

Stage 2: 1-Cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Ethyl ether of cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.237g, 0.858mmol) was dissolved in methanol (2.00ml). Water (2.0 mL) and lithium hydroxide (0.027 g, 1.127 mmol) were added and the mixture was heated at 80°C for 2 h. After cooling to room temperature, the methanol was removed in vacuo. THF was added to the residue and then removed in vacuo to ensure complete removal. of methanol. B. NCI (0.2 mL) was added to the aqueous residue until pH 2-3 was established, resulting in the precipitation of a white solid. The solid was collected by filtration, washed with water, and dried under high vacuum at 1007 to give 1-cyclopentyl-5- trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.134 g, 63905).

Stage 3: trans-1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

Cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (125 mg, 0.504 mmol) was dissolved in dry

M,M-dimethylformamide (2.0 ml) and dry methylene chloride (0.5 ml). M,M-diisopropyl-M-ethylamine (0.70 ml, 4.046 mmol) and TT (181 mg, 0.601 mmol) were sequentially added to the solution, and stirring was continued at room temperature for 1 h. and then LC-MS indicated the completion of the activated ester formation reaction. Trans-4-aminoadamantane-1-ol hydrochloride (107.8 mg, 0.529 mmol, intermediate 2) was added and stirring was continued at room temperature under argon for 17 h. The crude reaction mixture was added to water and extracted twice with methylene chloride. Each organic phase was successively washed with water and brine. These two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography followed by crystallization from ethyl acetate-hexane gave trans-1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (13Zmg, 6695). MSVR (ER) t/e calculated for SgoNovEzMzO" (M--NU) 398.2050, found 398.2050.

Example 70 (5-Hydroxyadamantan-2-yl)-amide of trans-1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid in; and m "on

ME

Fi

Stage 1: 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

Cyclohexylhydrazine hydrochloride (0.276g, 1.59mmol, CA 824214-73-1, purchased from AIAPSNP), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxobutyric acid ethyl ether (0.459g, 1.67mmol) and anhydrous sodium acetate (0.188 g, 2.29 mmol) was combined in ethanol (2.9 ml) and heated at 707C for 15 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back-extracted with a second portion of methylene chloride. These two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography with gradient elution with 5-4095 ethyl acetate-hexane gave 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (0.270g, 5595). Mass spectrum: t/2: 291.3 (MN).

Stage 2: 1-Cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Ethyl ether of cyclohexyl-5-trifluoromethyl-5-pyrazole-4-carboxylic acid (0.265 g, 0.91 mmol) was dissolved in methanol (1.4 ml). Water (1.4 mL) and lithium hydroxide (0.029 g, 1.21 mmol) were added and the mixture was heated at 80°C for 1.5 h. After cooling to room temperature, the methanol was removed in vacuo.

Tetrahydrofuran was added to the residue and then removed in vacuo to ensure complete removal of methanol. bn NSI was added to the water until the pH was set at 2-3, which led to the precipitation of a solid substance. The solid was collected by filtration, washed with water and dried in a high vacuum at 1007C to give 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.206g, 8695). Mass spectrum: t/l: 263.3 (MN).

Stage 3: trans-1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

Cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (196 mg, 0.747 mmol) was dissolved in dry

M,M-dimethylformamide (2.9 ml) and dry methylene chloride (0.7 ml). M,M-diisopropyl-M-ethylamine (1.00 ml, 5.78 mmol) and T5TI (270 mg, 0.897 mmol) were sequentially added to the solution, and the stirring was continued at room temperature under an argon atmosphere for 1 h. and then LC-MS indicated the completion of the activated ester formation reaction. Trans-4-aminoadamantane-1-ol hydrochloride (1b0mg, 0.785mmol, intermediate 2) was added and stirring was continued at room temperature overnight. The crude reaction mixture was added to water and extracted twice with methylene chloride. Each organic phase was successively washed with water and brine. These two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography followed by crystallization from ethyl acetate-hexane gave trans-1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (208 mg, 6790 ). MSVR (ER) t/e calculated for SgiHgvEzMzO" (M--H") 412.2207, found 412.2206.

Example 71 (5-Hydroxyadamantan-2-yl)-amide trans-1-(cis-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ra

M "on chi

IS

? he

Stage 1: Ethyl ether of 1-(4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 4-Hydrazinocyclohexanol hydrochloride (0.255g, 1.53mmol, obtained in example 67, stage 2), ethyl ether of 2- Dimethylaminomethylene-4,4,4-trifluoro-3-oxobutyric acid (0.272g, 1.14mmol) and anhydrous sodium acetate (0.256g, 3.12mmol) were combined in ethanol (2.0ml) and heated at 70"С under an argon atmosphere for 14 h. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The aqueous phase was washed a second time with methylene chloride. The two organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (when eluting in the gradient mode with a mixture of 40-10095 ethyl acetate-hexane) led to the successful separation of cis-trans isomers and obtained ethyl ether cis-1-(4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4- carboxylic acid (96.1 mg, 2795) and ethyl ether of trans-1-(4- hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (63.5 mg, 18905).

Stage 2: cis-1-(4-Hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Ethyl ester of cis-1-(4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (94.7 mg, 0.309 mmol) was dissolved in methanol (0.5 ml). Lithium hydroxide (10.3 mg, 0.430 mmol) and water (0.5 mL) were added and the mixture was heated at 807°C for 1 h. After cooling to room temperature, methanol was removed in vacuo. Tetrahydrofuran was added and removed in vacuo to ensure complete removal of methanol. The residue was diluted with water and acidified with normal HCl (75 μl; pH 1.5-2). The solid substance that settled from the solution was collected by filtration, washed with water and dried in a high vacuum at 50"C to obtain cis-1-(4 -hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (70mg; 8195). Mass spectrum: t/72: 279.1 (M.N).

Stage 3: (5-Hydroxyadamantan-2-yl)-amide trans-1-(cis-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid cis-1-(4-Hydroxycyclohexyl)-5 -trifluoromethyl-1H-pyrazole-4-carboxylic acid (6b7mg, 0.241mmol) was dissolved in dry M,M-dimethylformamide (1.00ml) and dry methylene chloride (0.2ml). M,M-diisopropyl-M-ethylamine (0.33 mL, 1.907 mmol) and T5TI (82 mg, 0.272 mmol) were sequentially added to the solution, and stirring was continued at room temperature under an argon atmosphere for 1 h. and then LC-MS indicated the completion of the activated ester formation reaction. Trans-4-aminoadamantane-1-ol hydrochloride (50 mg, 0.245 mmol, intermediate 2) was added and stirring was continued at room temperature under argon overnight. The crude reaction mixture was added to water and extracted twice with methylene chloride. These two organic phases were combined and successively washed with water and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography (when eluting in a gradient mode with a mixture of 0-2095 methanol-ethyl acetate) followed by crystallization from a mixture of ethyl acetate-ether gave (5-hydroxyadamantan-2-yl)-amide trans-1-(cis-4-hydroxycyclohexyl) )-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (44.9 mg, 4395). MSVR (ER) t/e calculated for Sg1iNgvEzMzOz (M.--H") 428.2156, found 4282157.

Example 72 (5-Hydroxyadamantan-2-yl)-amide trans-1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazol-4-carboxylic acid rheone

IS

With him

Stage 1: trans-1-(4-Hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Ethyl ether of trans-1-(4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (62.3 mg, 0.203 mmol, obtained in example 71, stage 1) was dissolved in methanol (0.3 ml). Lithium hydroxide (7.1 mg, 0.297 mmol) and water (0.3 mL) were added and the mixture was heated at 807°C for 1 h. After cooling to room temperature, methanol was removed in vacuo. Tetrahydrofuran was added and removed in vacuo to ensure complete removal of methanol. The residue was diluted with water and acidified with the help of the NOSE.

The solid initially settled out of solution, but then quickly turned into an oil/resin. The mixture was extracted twice with methylene chloride. These two organic phases were combined, washed with water, dried over sodium sulfate and concentrated to give trans-1-(4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (35.8 mg; 6395). Mass spectrum: t/2: 277.1 (M-H).

Stage 2: (5-Hydroxyadamantan-2-yl)-amide trans-1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid trans-1-(4-Hydroxycyclohexyl)-5 -trifluoromethyl-1H-pyrazole-4-carboxylic acid (31.bmg, 0.114mmol) was dissolved in dry M,M-dimethylformamide (0.5ml) and dry methylene chloride (0.1ml). M,M-diisopropyl-h-ethylamine (155 μl, 0.89 mmol) and T5TO (39 mg, 0.1300 mmol) were sequentially added to the solution, and stirring was continued at room temperature in an argon atmosphere for 5 hours. Trans-4-aminoadamantane-1-ol hydrochloride (24 mg, 0.118 mmol, intermediate 2) was added and stirring was continued at room temperature under an argon atmosphere for 23 h. The crude reaction mixture was added to water and extracted twice with methylene chloride. These two organic phases were combined and successively washed with water (3x) and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography with gradient elution with a mixture of 0-2095 methanol-ethyl acetate followed by crystallization from a mixture of ethyl acetate-ether gave (5-hydroxyadamantan-2-yl)-amide trans-1-(trans-4-hydroxycyclohexyl)- 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (30.4 mg, 6395). MSVR (ER) t/e calculated for SgiNgvEzMzOz (MANNU) 428.2156, found 428.2156.

Example 73 (B-hydroxyadamantan-2-ylamide of trans-2'-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

O on t What h

M. m "y and re;

Stage 1: Preparation of (2-methoxyethyl)-hydrazine

1-bromo-2-methoxyethane (4.00 ml, 42.44 mmol) was added dropwise over 20 minutes to a solution of hydrazine monohydrate (22 ml, 453.5 mmol) in ethanol (7 ml) at 0"C in an ice-water bath. Then the reaction the mixture was allowed to warm to room temperature and was stirred for 40°C and then heated at 45°C for 12 hours in a preheated oil bath. Then the reaction mixture was cooled to room temperature and concentrated to remove ethanol. The remaining aqueous layer was extracted with methylene chloride (2x100ml) and diethyl ether (2x100ml). The organic layers were combined and dried over anhydrous NaCl, filtered and concentrated to obtain (2-methoxyethyl)-hydrazine as a colorless oil (2.35 g, 61905).

Stage 2: Preparation of 5-amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

Ethyl-(ethoxymethylene)-cyanoacetate (4.40g, 26.48mmol) was added to a solution of (2-methoxyethyl)-hydrazine (2.35g, 26.07mmol) in ethanol (40ml). The solution was refluxed in a preheated oil bath (9072) for The reaction mixture was cooled to room temperature and concentrated to remove ethanol. The residue was dissolved in methylene chloride ("10 Oml) and washed with water (1 Oml) and brine (10 ml). The organic layer was dried over anhydrous Ma5O4, filtered and concentrated in vacuo to obtain 5-amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.3g, 9595) in the form of an orange oil, which was used without additional cleaning. Mass spectrum: t/2: 214.0 (M-n1).

Stage 3: Preparation of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

To a mixture of tert-butyl nitrite (5.3 ml, 40.10 mmol), anhydrous copper(!) chloride (4.10 g, 41.41 mmol) and anhydrous acetonitrile (100 ml) for 10 min. 5-amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ether (17.8 g, 83.4 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 1 hour, then at 60 "C within 2 hours. and then stirred at room temperature overnight.

Then the mixture was cooled to room temperature and carefully poured into a 6.On. aqueous solution of NSI (100 ml).

The aqueous phase was extracted with methylene chloride (3x30 Oml). The combined organic extracts were combined, dried over anhydrous Mag25O4, filtered and concentrated in vacuo to give 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ether as an orange oil (4, bg, 8095), which was used without additional purification. Mass spectrum: t/2: 233.0 (Mt).

Stage 4: Preparation of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid

To a solution of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ether (4.6 g, 19.77 mmol) in methanol (32 ml) and water (332 ml) was added lithium hydroxide (1.10 g , 26.22 mmol). The reaction mixture was stirred at reflux for 1 h. and then the solution was concentrated under reduced pressure to remove methanol. Then the residue was carefully acidified with 6.0N. aqueous solution of NOSI.

The resulting mixture was extracted with methylene chloride (33x50 ml). The combined organic extracts were dried over anhydrous Ma5O, filtered and concentrated in vacuo to give 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid as a white solid (1.27g, 3195) . Mass spectrum: t/72: 205.3 (M--1).

Stage 5: Preparation of trans-5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid 5-Chloro-1-(2-methoxyethyl)-1H (5-hydroxyadamantan-2-yl)-amide -pyrazole-4-carboxylic acid (1.270 g, 6.207 mmol) was dissolved in a mixture of dry methylene chloride (5 ml) and dry M,M-dimethylformamide (bml). Diisopropylethylamine (9, 0ml, 51.67mmol) and O-(M-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2.30g, 7.6b4mmol) were added to the solution.

The solution was stirred at room temperature for 4 hours, after which LC-MS analysis of an aliquot indicated complete conversion to activated ether. Then, trans-4-aminoadamantan-1-ol hydrochloride (obtained from intermediate 2, 1.30 g, 6.382 mmol) was added. The solution was stirred for 24 hours, after which the reaction was quenched with water (20 ml). The aqueous layer was extracted with methylene chloride (2 x 50 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product. The crude substance was purified by column chromatography on silica gel (gradient elution from ethyl acetate to 1090 methanol/ethyl acetate) to give (5-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-(2-methoxyethyl)- 1H-pyrazole-4-carboxylic acid as an almost white solid (0.756g, 34.595). ER-MSVR t/e calculated for

Si7Nga«SIMzOz (MAN) 353.1579, found 353.1576.

Stage 6: Obtaining (5-acetylaminoadamantan-2-ylamide trans-2'-(2-methoxyethyl)-2'Y-Y1,3bipyrazolyl-4"-carboxylic acid

To a solution of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (0.177g, 0.500mmol) and pyrazole (0.280g, 4.113mmol) 6095 sodium hydride (0.160 g, 4 mmol) was added to dry M,M-dimethylformamide (2 bml). The solution was heated at 120"C in a preheated oil bath for 20 hours. The solution was cooled to room temperature and the reaction was stopped with water (ml) and an aqueous solution

MNASI (Iml). Since precipitation did not occur, the aqueous phase was extracted with methylene chloride (2x50 ml).

The organic extracts were combined, dried over anhydrous Ma»5O», filtered and concentrated in a vacuum under heating (100°C) to remove excess M,M-dimethylformamide. The product was purified using column chromatography on silica gel (when eluting with a mixture of 590 methanol/ methylene chloride) and obtained (B-hydroxyadamantan-2-yl)-amid. trans-2'-(2-methoxyethyl)-2'H-I(1,3bipyrazolyl-4-carboxylic acid in the form of a white solid (0.125g, 6595). ER-MSVR t/e calculated for СгоНг7М5Оз (МН) 408.2006, found 408.2003.

Example 74 Trans-1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (B-hydroxyadamantan-2-yl)-amide

He did. , x - p; sv, re)

Stage 1: Preparation of (2-methoxyethyl)-hydrazine

1-bromo-2-methoxyethane (4.00 ml, 42.44 mmol) was added dropwise over 20 minutes to a solution of hydrazine monohydrate (22 ml, 453.5 mmol) in ethanol (7 ml) at 0"C in an ice-water bath. Then the reaction the mixture was allowed to warm to room temperature and was stirred for 40 °C and then heated at 45 °C in a preheated oil bath for 12 hours. Then the reaction mixture was cooled to room temperature and concentrated to remove ethanol. The remaining aqueous layer was extracted with methylene chloride (2x100ml) and diethyl ether (2x100ml). The organic layers were combined and dried over anhydrous NaCl, filtered and concentrated to obtain (2-methoxyethyl)-hydrazine as a colorless oil (2.35 g, 61905).

Stage 2: Preparation of 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a solution of (2-methoxyethyl)-hydrazine (0.104, 1.15 mmol) in ethanol (2 mL) was added ethyl 3-H,K-dimethylamino-2-riftoacetylacrylate (intermediate 4, 0.261 mg, 1.09 mmol). The resulting solution was treated with microwave radiation at 160"C for 0.5 h. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. The residue was dissolved in methylene chloride (50 ml) and washed with water (20 ml) and brine (10 ml). The organic layer was dried over anhydrous Ma5O4, filtered and concentrated in vacuo to obtain 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (296.1 mg, 9995) as a brown oil, which was used without further purification.

Stage 3: Preparation of 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Lithium hydroxide (0.072g, 1 .73 mmol). The reaction mixture was stirred at reflux for 2 hours. and then the solution was concentrated under reduced pressure to remove methanol. Then the residue was carefully acidified with 6b,0n. aqueous solution of NOSI.

The resulting mixture was extracted with methylene chloride (3x25 ml). The combined organic extracts were dried over anhydrous Mod5O, filtered and concentrated in vacuo to give 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as an orange oil (0.183g, 7195), which used without additional purification. Mass spectrum: t/7: 239.0 (Ma1).

Stage 4: Preparation of trans-1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 1-(2-Methoxyethyl)-5-trifluoromethyl-1H (5-hydroxyadamantan-2-yl)-amide -pyrazole-4-carboxylic acid (0.180g, 0.756bmmol) was dissolved in a mixture of dry methylene chloride (4ml) and dry M,M-dimethylformamide (1ml). To the solution was added diisopropylethylamine (1.1 mL, 3.3 mmol) and O-(M-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.280 g, 0.93 mmol). The solution was stirred at room temperature for 1 h, after which the LC-MS analysis of an aliquot indicated complete conversion to activated ether. Then trans-4-aminoadamantan-1-ol hydrochloride (intermediate 2, 0.160g, 0.785mmol) was added. The solution was stirred for 24 hours, after which the reaction was quenched with water (20 ml). The aqueous layer was extracted with methylene chloride (2 x 50 ml). The organic extracts were combined and washed with water (2 x 20 ml) and brine (20 ml), dried over anhydrous Mo5O»4, filtered and concentrated in vacuo to obtain a crude substance in the form of an orange oil. The crude substance was purified by column chromatography on silica gel (gradient elution from methylene chloride to 5905-1090 methanol/ethyl acetate) and obtained (5-hydroxyadamantan-2-yl)-amide trans-1-(2-methoxyethyl)-5- trifluoromethyl-1H-pyrazole-4-carboxylic acid as a white solid. (0.073g, 2595). ER-MSVR t/e calculated for SivNag"EzMzOz (MaN") 410.1662, found 410.1662.

Example 75 (5-Acetyl aminoadamantan-2-ylamide trans-2"-(2-methoxyethyl)-2'H-(/1,3|bipyrazolyl-4"-carboxylic acid o o ak

M. y and "M U che what

Stage 1: (2-Methoxyethyl)-hydrazine

1-bromo-2-methoxyethane (18.8 ml, 0.20 mol) was added dropwise over 20 minutes to a solution of hydrazine monohydrate (89.4 ml, 8.00 mol) in ethanol (120 ml) at 0"C in an ice water bath. Then the reaction mixture was allowed to warm to room temperature and was stirred for 40 hours and then heated at 45"C in a preheated oil bath for 12 hours. Then the reaction mixture was cooled to room temperature and concentrated to remove ethanol. The remaining aqueous layer was extracted with methylene chloride (2x100ml) and diethyl ether (2x100ml). The organic layers were combined and dried over anhydrous Ma»5O, filtered and concentrated to give (2-methoxyethyl)-hydrazine as a colorless oil (8.0 g, 5090).

Stage 2: 5-amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

To a solution of (2-methoxyethyl)hydrazine (9.0g, 99.9mmol) in ethanol (170ml) was added ethyl-(ethoxymethylene)-cyanoacetate (14.36g, 84.9mmol). The solution was refluxed in a preheated oil bath (9072) for 24 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. The residue was dissolved in methylene chloride (100ml) and washed with water (1Oml) and brine (1O0ml). The organic layer was dried over anhydrous Mag5O", filtered and concentrated in vacuo to give 5-amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ether (17.8g, 9895) as a red oil, which used without additional purification. Mass spectrum: t/2: 214.0 (M--1).

Stage 3: 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

To a mixture of tert-butyl nitrite (17.6 ml, 133.4 mmol), anhydrous copper(I) chloride (13.55 g, 136.9 mmol) and anhydrous acetonitrile (160 ml) for 10 min. 5-amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ether (17.8 g, 83.4 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 1 h, then at 70 "C within 2 hours. Then the mixture was cooled to room temperature and carefully poured into a 6.On. aqueous solution of NSI (85 ml). The aqueous phase was extracted with methylene chloride (3x150 ml).

The combined organic extracts were combined, dried over anhydrous Mag2504, filtered and concentrated in vacuo to give the crude material as a green oil. The product was purified by column chromatography on silica gel (eluting with a mixture of ethyl acetate/hexane in a gradient mode from 3:7 to 1:0) and 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carbonate ethyl ether was obtained acid in the form of light yellow oil (8.51 g, 4495). Mass spectrum: t/7: 233.0 (M--1).

Stage 4: 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid

Lithium hydroxide (1.21 g, 50.4 mmol). The reaction mixture was stirred at reflux for 1 h. and then the solution was concentrated under reduced pressure to remove methanol. Then the residue was carefully acidified with 6b,0n. aqueous solution of NSI. The resulting mixture was extracted with methylene chloride (33x50 Oml). The combined organic extracts were dried over anhydrous Mag50O4, filtered and concentrated in vacuo to give 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid as a white solid (6.93g, 9295). Mass spectrum: t/2: 205.3 (Ma1).

Stage 5: (5-Acetylaminoadamantan-2-yl)-amide trans-5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid 5-Chloro-1-(2-methoxyethyl)-1H- pyrazole-4-carboxylic acid (178 mg, 0.870 mmol) was dissolved in a mixture of dry methylene chloride (ml) and dry M,M-dimethylformamide (3.5 ml). M,M-diisopropylethylamine (1.2 mL, 7.00 mmol) and O-(M-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (289 mg, 0.960 mmol) were added to the solution.

The solution was stirred at room temperature for 4 hours, after which LC-MS analysis of an aliquot indicated complete conversion to activated ether. Then trans-m-(4-aminoadamantan-1-yl)-acetamide (obtained in Example 43, 200 mg, 0.9600 mmol) was added. The solution was stirred for 24 hours, after which the reaction was quenched with water (20 ml). The aqueous layer was extracted with methylene chloride (2 x 50 ml).

The organic extracts were combined, dried over anhydrous Ma»5O», filtered and concentrated in vacuo to give a crude substance. The crude substance was purified by column chromatography on silica gel (gradient elution from methylene chloride to 495 methanol/methylene chloride) and obtained (5-acetylaminoadamantan-2-yl)y-amide trans-5-chloro-1-(2-methoxyethyl) -1 H-pyrazole-4-carboxylic acid as an almost white solid (174mg, 5095). ER-MSVR t/e calculated for C1i9H27SIMAOz (M-ANU) 395.1842, found 395.1845.

Stage 6: (5-Acetylaminoadamantan-2-ylamide trans-2-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

To a solution of trans-5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (116 mg, 0.300 mmol) and pyrazole (2 mg, 0.90 mmol) an aqueous solution of sodium hydroxide (0.100 ml, 1.20 mmol, 5095 wt/wt) was added to M-methylpyrrolidinone (1.5 ml). The solution was heated at 120"C in a preheated oil bath for 12 hours. The solution was cooled to room temperature and the reaction was stopped with water (ml) and an aqueous solution of MNAeCl (ml). Since precipitation did not occur, the aqueous phase was extracted with methylene chloride (2x50ml). Organic extracts of were combined, dried over anhydrous Mag5O, filtered and concentrated in a vacuum under heating (100°C) to remove excess MMR. The product was purified by column chromatography on silica gel (eluting with a mixture of 595 methanol/methylene chloride) and obtained (5-acetylaminoadamantan-2-ylamide trans-2-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4" -carboxylic acid as a white solid (77mg, 6095). In some cases, residual MMP was removed by heating at 100"C under high vacuum or by dissolving the residue in ethyl acetate, washing with water, drying over anhydrous Mag25O4, filtering and concentrating in vacuo EP - MSVR t/e calculated for

Sg2NzoMvOz (MA-H") 427.2452, found 4272451.

Example 76 (b-hydroxyadamantan-2-yl)-amide of trans-2-(2-(2-methoxyethoxy)-ethyl/|-2'H-(1,3bipyrazolyl-4"-carboxylic acid)

On t Shchi sh.

M chu o7 Y Me

Co

Stage 1: (2-(2-Methoxyethoxy)-ethyl|-hydrazine

1-(2-bromoethoxy)-2-methoxyethane (13.6 ml, 0.100) was added dropwise over 20 minutes to a solution of hydrazine monohydrate (44.00 ml, 1.00 mol) in ethanol (75 ml) at 0"C in an ice-water bath. Then the reaction mixture was allowed to warm to room temperature and was stirred for 5 min. and then heated at 40" in a preheated oil bath for 12 h. Then the reaction mixture was cooled to room temperature and concentrated to remove ethanol. The remaining aqueous layer was extracted with methylene chloride (2x100ml) and diethyl ether (2x100ml). The organic layers were combined and dried over anhydrous Mag25O4, filtered and concentrated to give (2-(2-methoxyethoxy)-ethyl|-hydrazine as a light yellow oil (10.29g, 8590).

Stage 2: Ethyl ester of 5-amino-1-I(I2-(2-methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid

Ethyl-(ethoxymethylene)-cyanoacetate (6.43g, 37.99mmol) was added to a solution of (2-(2-methoxyethoxy)-ethyl|-hydrazine (6b.0g, 44.7mmol) in ethanol (//ml). refluxed in a preheated oil bath (9072) for 24h. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. The residue was dissolved in methylene chloride (U10Oml) and washed with water (20ml) and brine (10ml). Organic layer dried over anhydrous Ma5O4, filtered and concentrated in vacuo to obtain 5-amino-1-(2-(2-methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid ethyl ether (10.38g, 9995) in the form of an orange oil, which was used without further purification, Mass spectrum: t/2: 258.0 (M--1).

Stage 3: 5-chloro-1-(2-(2-methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid ethyl ester

To a mixture of tert-butyl nitrite (8.5 ml, 64.5 mmol), anhydrous copper(I) chloride (6.54 g, 66.1 mmol) and anhydrous acetonitrile (d80 ml) was added ethyl ether 5-amino-1-(2-(2 -methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid (10.38g, 40, Zmmol) for 10 min. at 0"C. The reaction mixture was stirred at room temperature for Mh., then at 70"C for 2h. Then the mixture was cooled to room temperature and carefully poured into a 6.0N aqueous solution of HCl (45ml).The aqueous phase was extracted with methylene chloride (3x150ml).

The combined organic extracts were combined, dried over anhydrous Mag2504, filtered and concentrated in vacuo to give the crude oil. The product was purified by column chromatography on silica gel (eluting with a mixture of ethyl acetate/hexane, in a gradient mode from 1:3 to 1:0) and obtained ethyl ether 5-chloro-1-|2-(2-methoxyethoxy)-ethyl|- 1 H-pyrazole-4-carboxylic acid in the form of light yellow oil (3.43 g, 3095). Mass spectrum: t/27: 277.0 (M--1).

Step 4: 5-chloro-1-(2-(2-methoxyethoxy)-ethyl-1H-pyrazole-4-carboxylic acid

To a solution of 5-chloro-1-I(2-(2-methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid ethyl ether (3.43 g, 12.39 mmol) in methanol (12 ml) and water (12 ml) lithium hydroxide (415 mg, 17.3 mmol) was added. The reaction mixture was stirred at reflux for 1 h and then the solution was concentrated under reduced pressure to remove methanol. The residue was then carefully acidified with a 6b.0N aqueous solution of NOSI.

The resulting mixture was extracted with methylene chloride (3x50ml). The combined organic extracts were dried over anhydrous Ma5O, filtered and concentrated in vacuo to give 5-chloro-1-(2-(2-methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid as a white solid ( 2.65 g, 8695). Mass spectrum: t/2: 249.0 (M.-1).

Stage 5: (5-Hydroxyadamantan-2-yl)-amide trans-5-chloro-1-(2-(methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid 5-Chloro-1-|2-( 2-methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid (497 mg, 2.00 mmol) was dissolved in a mixture of dry methylene chloride (2 ml) and dry M,M-dimethylformamide (3 ml). M,M-diisopropylethylamine was added to the solution (2.8 mL, 16.0 mmol) and O-(M-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (722 mg, 2.40 mmol). The solution was stirred at room temperature for 1 h, then subjected to LC -MS analysis of an aliquot indicated complete conversion to the activated ester. Trans-4-aminoadamantane-1-ol hydrochloride (Intermediate 2, 489 mg, 240 mmol) was then added. The solution was stirred for 24 h, then quenched with water (20 mL). Aqueous layer extracted with methylene chloride (2x5Oml). The organic extracts were combined and washed with water (2x20ml) and brine (20ml), dried over anhydrous Mag25O4, filtered and concentrated in vacuo to obtain a crude substance Well. The crude substance was purified by column chromatography on silica gel (with gradient elution from ethyl acetate to 5905 and then to 1095 methanol/ethyl acetate) to obtain (5-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-(2 -(Methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid as a white solid (4bO0mg, 5895).ER-MSVR t/e calcd for CioHgvSIM2Ox4 (MH) 398.1841, found 398.1842.

Stage 6: trans-2-(2-(2-methoxyethoxy)-ethyl|-2'H-P1,3bipyrazolyl-4"-carboxylic acid (5-Hydroxyadamantan-2-yl)y-amide.

To a solution of 5-chloro-1-(2-(methoxyethoxy)-ethyl|-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (200 mg, 0.500 mmol) and pyrazole (103 mg, 1 .6 mmol) in M-methylpyrrolidinone (3 ml) was added an aqueous solution of sodium hydroxide (0.200 ml, 3.79 mmol, 5095 wt./wt). The solution was heated at 120"C in a preheated oil bath for 24 hours. The solution was cooled to room temperature and the reaction was stopped with water (2 ml) and an aqueous solution of MNACI (2 ml). Since precipitation did not occur, the aqueous phase was extracted with methylene chloride (2 x 50 ml). The organic extracts were combined, dried over anhydrous Mag5O", filtered and concentrated in vacuo under heating (100 ) to remove excess MMP.The product was purified by column chromatography on silica gel (eluting with 595 methanol/methylene chloride) to give (5-hydroxyadamantan-2-yl)-amide trans-2-(2-(2-methoxyethoxy)-ethyl /|-2'H-(1,3bipyrazolyl-4"-carboxylic acid in the form of a colorless oil (142mg, 6695). EP-MSVR t/e calculated for Cg22NziM5O4 (M-ANU) 430.2449, found 430.2449.

Example 77 trans-1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (b-hydroxyadamantan-2-yl)-amide

On da xx i r, sv; district

Stage 1: 2-(2-Bromoethoxy)-2-methylpropane

2-bromoethanol (14.1 ml, 200 mmol), methylene chloride (35 ml) and concentrated sulfuric acid (1 ml) were added to a high-pressure apparatus with a stirring rod. The container was cooled to -78"C in a solid carbon dioxide/acetone bath. In a separate container cooled to -78"C, 2-methylpropene (-50ml) was condensed.

Then 2-methylpropene was added to the container containing 2-bromoethanol. The container was sealed and stirred at room temperature for 48 hours. Then the container was cooled to -78"C in a solid carbon dioxide/acetone bath. The container was opened and the mixture was carefully poured into a saturated aqueous solution of sodium bicarbonate (100ml). The aqueous layer was extracted with methylene chloride (2x500ml) and hexane (x50ml). The organic layers were combined , dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2-(2-bromoethoxy)-2-methylpropane in the form of a colorless oil (35g, 9795).

Stage 2: (2-tert-Butoxyethyl)-hydrazine

2-(2-bromoethoxy)-2-methylpropane (12.1 ml, 0.075 mol) was added dropwise over 20 minutes to a solution of hydrazine monohydrate (36.0 ml, 0.750 mol) in ethanol (7 0 ml) at 0"C in an ice water bath ). Then the reaction mixture was allowed to warm to room temperature and was stirred for 5 min. and then heated at 40" in a preheated oil bath for 4 h. Then the reaction mixture was cooled to room temperature and concentrated to remove ethanol. Water (20 ml) was added to the container and the aqueous layer was extracted with diethyl ether (2 x 100 ml). The organic layers were combined and dried over anhydrous Mag250O4, filtered and concentrated to give (2-tert-butoxyethyl)-hydrazine as a colorless oil (6.05g, 6196).

Stage 3: 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether ethyl ether

To a solution of (2-tert-butoxyethyl)-hydrazine (260 mg, 1.96 mmol) in ethanol (4 mL) was added ethyl 3-M,M-dimethylamino-2-rifluoroacetylacrylate (intermediate 4, 400 mg, 1.67 mmol). The solution was refluxed in a preheated oil bath (9072) for 24 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. The residue was dissolved in methylene chloride (50 ml) and washed with water (20 ml) and brine (10 ml). The organic layer was dried over anhydrous

Mag25O4, filtered and concentrated in vacuo to obtain 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (620 mg, »99905) in the form of an orange oil, which was used without additional purification . Mass spectrum: t/2: 309.2 (Mt).

Stage 4: 1-(2-tert-Butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Lithium hydroxide (67 mg, 2 .9 mmol). The reaction mixture was stirred at reflux for 4 hours. and then the solution was concentrated under reduced pressure to remove methanol. Then the residue was carefully acidified with 6b,0n. aqueous solution of NOSI.

The obtained mixture was extracted with methylene chloride (2x30 ml). The combined organic extracts were dried over anhydrous Mag25O4, filtered and concentrated in vacuo to give 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a red oil (425mg, 75905), which used without additional purification.

Stage 5: (5-Hydroxyadamantan-2-yl)-amide trans-1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 1-(2-tert-Butoxyethyl)-5- trifluoromethyl-1H-pyrazole-4-carboxylic acid (425mg, 1.51mmol) was dissolved in a mixture of dry methylene chloride (1.5ml) and dry M,M-dimethylformamide (bml). M,M-diisopropylethylamine (2.1 ml, 12.0 mmol) and O-(M-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (548 mg, 1.82 mmol) were added to the solution. The solution was stirred at room temperature for 1 h, after which the LC-MS analysis of an aliquot indicated complete conversion to activated ether. Then, trans-4-aminoadamantane-1-ol hydrochloride (intermediate 2, 370 mg, 1.82 mmol) was added. The solution was stirred for 24 hours, after which the reaction was quenched with water (20 ml). The aqueous layer was extracted with methylene chloride (2x5 Oml). The organic extracts were combined and washed with water (2x20ml) and brine (20ml), dried over anhydrous Mag25O4, filtered and concentrated in vacuo to obtain a crude substance. The crude substance was purified by column chromatography on silica gel (gradient elution from methylene chloride to 595 to 1095 methanol/methylene chloride) and obtained (5-hydroxyadamantan-2-yl-amide trans-1-(2-tert-butoxyethyl)- 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a white solid The white solid was recrystallized from hot diethyl ether, methylene chloride and methanol (99/1/0 1) to give the desired product as a white solid (135mg, 2195).EP-MSVR t/e calculated for СхиНзоРзЕзоз (МН) 430.2312, found 430.2314.

Example 78 (5-Hydroxyadamantan-2g-yl)-amide of trans-2'-(3-methoxypropyl)-2H-/1,3bipyrazolyl-4"-carboxylic acid 9 n to CL on

AND

M. m m t to

Stage 1: hydrazine carboxylic acid tert-butyl ether To a solution of tert-butyl carbazate (10.0 g, 75.6 mmol) in acetone (75 ml, 1.0 mol) anhydrous magnesium sulfate (2.0 g) and 10 drops of glacial acetic acid were added. The solution was refluxed for 5 hours in a preheated oil bath (857C). The solution was cooled to room temperature, filtered and concentrated in vacuo to obtain hydrazinecarboxylic acid tert-butyl ether as a white solid (12.0g, 9295).

Mass spectrum: t/l2: 173.3 (M'-1).

Stage 2: M'-isopropylidene-M(3-methoxypropyl)-hydrazinecarboxylic acid tert-butyl ether

Powdered potassium hydroxide (1.98g, 35.3mmol) and tetrabutylammonium hydrosulfate (904mg, 2.72mmol) were added to a solution of hydrazinecarboxylic acid tert-butyl ether (4.67g, 27.16bmmol) in toluene (90ml). The solution was heated at 507C in a preheated oil bath for 45 minutes. 1-bromo-33-methoxypropane (3.67 mL, 32.wbmmol) was added dropwise. Then the solution was heated at 80"C for

The solution was cooled to room temperature and washed with water (Zh 150 ml) until a neutral reaction of the aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give M'-isopropylidene-M-(3-methoxypropyl)-hydrazinecarboxylic acid tert-butyl ether as a viscous oil (6.49g, 9895), which was used without additional cleaning. Mass spectrum: t/2: 245.4 (Mt).

Stage 3: (3-Methoxypropyl)-hydrazine dihydrochloride

To a solution of M'-isopropylidene-M-(3-methoxypropyl)-hydrazinecarboxylic acid tert-butyl ether (6.49g, 26.bmmol) in tetrahydrofuran (50ml) was added 2.00n. hydrochloric acid (27 ml). The solution was refluxed (-80°C) in a preheated oil bath for 10 h. The solution was cooled to room temperature and concentrated in vacuo to remove tetrahydrofuran. Toluene (200 mL) was added to the aqueous layer and water was removed by vacuum concentration. (this procedure was repeated 2 more times) and (3-methoxypropyl)-hydrazine dihydrochloride (4.65 g, 96905) was obtained as a light yellow sticky solid, which was used without further purification.

Stage 4: 5-amino-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester

Ethyl-(ethoxymethylene)-cyanoacetate (3.89g, 23, 0 mmol). The solution was refluxed in a preheated oil bath (9072) for 24 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. The residue was dissolved in methylene chloride (7100 ml) and washed with water (30 ml). The organic layer was dried over anhydrous Mag25Ox, filtered and concentrated in vacuo to obtain 5-amino-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ether (5.01g, 96905) in the form of an orange oil, which used without additional purification. Mass spectrum: t/2: 228.4 (M--1).

Stage 5: 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester

Anhydrous copper(!) chloride (3.73 g , 37.7 mmol) and acetic acid (2.6 ml, 46.0 mmol). The mixture was cooled to 0"C in an ice-water bath, after which tert-butyl nitrite (4.9 mL, 36 b, dmmol) was added over 10 min. The solution was allowed to warm to room temperature and stirred for 4 h. 6.0 n was carefully added to the solution . hydrochloric acid (20 ml). The aqueous layer was extracted with methylene chloride (2 x 100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude substance. The product was purified using column chromatography on silica gel (eluting with a mixture of ethyl acetate /hexane, 11) and obtained 5-chloro-1-(33-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.71 g, 3095) in the form of an orange oil. Mass spectrum: t/2: 247 ,3 (M'-1).

Stage 6: 5-chloro-1-(33-methoxypropyl)-1H-pyrazole-4-carboxylic acid

Lithium hydroxide (235 mg , 9.8 mmol). The reaction mixture was stirred at reflux for 1 h. and then the solution was concentrated under reduced pressure to remove methanol. Then the residue was carefully acidified with 6.O0N. aqueous solution of NS.

The obtained mixture was extracted with methylene chloride (2x50 ml). The combined organic extracts were dried over anhydrous Ma»5O»x, filtered and concentrated in vacuo to give 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid as an orange solid (1, 35g, 8895). Mass spectrum: t/2: 219.3 (MAT).

Stage 7: (5-Hydroxyadamantan-2-yl)-amide trans-5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid 5-Chloro-1-(33-methoxypropyl)-1H- pyrazole-4-carboxylic acid (500 mg, 2.29 mmol) was dissolved in a mixture of dry methylene chloride (2.3 ml) and dry M,M-dimethylformamide (U9 ml). M,M-diisopropylethylamine (3.2 ml, 18.32 mmol) and O-(M-succinimidyl)1,1,3,3-tetramethyluronium tetrafluoroborate (827 mg, 2.75 mmol) were added to the solution. The solution was stirred at room temperature for 1 h, after which the LC-MS analysis of an aliquot indicated complete conversion to activated ether. Trans-4-aminoadamantan-1-ol hydrochloride (intermediate 2, bOmg, 2.97 mmol) was then added. The solution was stirred for 24 hours, after which the reaction was quenched with water (20 ml). The aqueous layer was extracted with methylene chloride (2x5 Oml). The organic extracts were combined and washed with water (2x20ml) and brine (20ml), dried over anhydrous Mag25O4, filtered and concentrated in vacuo to obtain a crude substance. The crude substance was purified by column chromatography on silica gel (gradient elution from 7590 ethyl acetate/hexane to ethyl acetate) and obtained (5-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-(3-methoxypropyl)- 1 H-pyrazole-4-carboxylic acid as a white solid (452mg, 5390). ER-

MSVR t/e calculated for SivNagvSIMzOz (M--NU) 368.1736, found 368.1733.

Stage 8: trans-2'-(3-methoxypropyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (5-Hydroxyadamantan-2-yl)-amide

To a solution of 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (200 mg, 0.544 mmol) and pyrazole (74 mg, 1.09 mmol) in M -methylpyrrolidinone (3.5 ml) was added sodium hydroxide (87 mg, 2.18 mmol) and water (0.1 ml). The solution was heated at 120"C in a preheated oil bath for 16 hours. The solution was cooled to room temperature and the reaction was stopped with water (ml) and an aqueous solution

MNASI (Iml). Since precipitation did not occur, the aqueous phase was extracted with methylene chloride (2x50 ml).

The organic extracts were combined, dried over anhydrous Ma»5O», filtered and concentrated under vacuum with heating (7100 °C) to remove excess MMP. The product was purified by column chromatography on silica gel (eluting with a mixture of 595 methanol/methylene chloride) and obtained (5-Hydroxyadamantan-2-yl)-amide trans-2'-(3-methoxypropyl)-2'H-Y1,3|bipyrazolyl-4"-carboxylic acid as a white solid (108mg, 5095). In some cases, residual MMR was removed by heating at 100"C in a high vacuum or by dissolving the residue in ethyl acetate, washing with water, drying over anhydrous Ma»5Om, filtering and concentrating in vacuum EP-MSVR t/e calculated for Cg21NhoM5Oz (МН) 400, 2343, found 400.2342.

Example 79 (5-Acetylaminoadamantan-2-yl)-amide of trans-2'-(3-methoxypropyl)-2'H-Y1,3|bipyrazolyl-4"-carboxylic acid o

Gee)

Eh

My U t that

Stage 1: (5-Acetylaminoadamantan-2-yl)-amide trans-5-chloro-1-(2-methoxypropyl)-1H-pyrazole-4-carboxylic acid 5-Chloro-1-(2-methoxypropyl)-1H- pyrazole-4-carboxylic acid (obtained in example 78, stage 6; 190mg, 0.872mmol) was dissolved in a mixture of dry methylene chloride (tIml) and dry M,M-dimethylformamide (4ml). Diisopropylethylamine (1.4 mL, 8.0 mmol) and O-(M-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (290 mg, 0.960 mmol) were added to the solution. The solution was stirred at room temperature for 1 h, after which the LC-MS analysis of an aliquot indicated complete conversion to activated ether. Then trans-M-(4-aminoadamantan-1-yl)y-acetamide (obtained in example 43, 200 mg, 0.960 mmol) was added. The solution was stirred for 24 hours, after which the reaction was quenched with water (20 ml).

The aqueous layer was extracted with methylene chloride (2 x 50 ml). The organic extracts were combined, dried over anhydrous Mag25O4, filtered and concentrated in vacuo to obtain a crude substance. The crude substance was purified by silica gel column chromatography (gradient elution from methylene chloride to 595 methanol/methylene chloride) to give (5-acetylaminoadamantan-2-yl)-amide trans-5-chloro-1-(2-methoxypropyl)- 1H-pyrazole-4-carboxylic acid as a loose white solid (200mg, 5695). ER-MSVR t/e calculated for SgoNgoSIMAOz (MAN) 409,2001, found 409,2002.

Stage 2: trans-2'-(3-methoxypropyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (X-Acetylaminoadamantan-2-yl)-amide

To a solution of 5-chloro-1-(2-methoxypropyl)-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (232 mg, 0.57 mmol) and pyrazole (155 mg, 2.27 mmol) in An aqueous solution of sodium hydroxide (0.300 ml, 5.68 mmol, 5095 wt/wt) was added to M-methylpyrrolidinone (2.5 ml). The solution was heated at 120"C in a preheated oil bath for 24 hours. The solution was cooled to room temperature and the reaction was stopped with water (ml) and an aqueous solution of MNACI (ml). Since precipitation did not occur, the aqueous phase was extracted with methylene chloride (2x50ml). Organic extracts of were combined, dried over anhydrous Mag5O, filtered and concentrated in a vacuum under heating (7100°C) to remove excess MMR. The product was purified by silica gel column chromatography (eluting with a mixture of 590 methanol/methylene chloride) and obtained (5-acetylaminoadamantan-2-yl)-amide. trans-2'-(3-methoxypropyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid as a white solid (17Omg, 6995). In some cases, residual MMPs were removed by heating at 100"C in high vacuum or by dissolving the residue in ethyl acetate, washing with water, drying over anhydrous Mag25O4, filtering and concentrating under vacuum.

SgzNzaMvOz (MN) 441.2609, found 441.2609.

Example 80 (B-hydroxyadamantan-2-yl)-amide of trans-1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid java same M "on

MN and EN

To

Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (intermediate 6, 291mg, 1.33mmol) was dissolved in a mixture of dry dichloromethane (12ml) and dry DMF (3ml) and T5TI (481mg, 1.bmmol) was added.

Then DIPEA (1.4 ml, vmmol) was added to the above mixture. After stirring the mixture for 2 hours. trans-4-aminoadamantane-i-ol (268mg, 1.bmmol, intermediate 2) was added. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane.

The combined organic layers were dried under vacuum. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a gradient mode of 10-10095 acetonitrile/water to obtain (5-hydroxyadamantan-2-yl)y-amide. trans-1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (254mg, 5295). MSNR t/y: calculated for SivNggEzMzO" (М--Н) 370.2, found 370.2.

Example 81 (B-Hydroxyadamantan-2-yl)-amide of trans-5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid a

M h m i i

And so

Stage 1: Synthesis of a mixture of ethyl ether of 5-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid and ethyl ether of 3-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid

A mixture containing cyclopropylhydrazine hydrochloride (intermediate 5, without further purification; 3.65g, 33.67mmol), ethyl-(ethoxymethylene)-cyanoacetate (5.69g, 33.67mmol) and anhydrous sodium acetate (2.03g, 33, 67 mmol) in bOml of ethanol was stirred and refluxed overnight. The solution was cooled to room temperature and water and dichloromethane were added. The separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were successively washed with water and brine and dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude residue was purified by flash chromatography eluting with a gradient of 0-290 methanol/dichloromethane to give a mixture of 5-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ether (eluted first ) and 3-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ether (eluted a little later) (2 isomers: total 2.03 g, 3195), which was used as a mixture without additional separation. MSNR t/2 calculated for SeNizMzO" (MN) 196 1, found 196.1.

Stage 2: Synthesis of a mixture of 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ether and 3-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ether

To a mixture of tert-butyl nitrite (2.033 ml, 15.38 mmol), copper(I) chloride (1.52 g, 15.38 mmol) and anhydrous acetonitrile (30 ml) at 0"C was added a solution of a mixture of ethyl ether 5-amino-1- cyclopropyl-1H-pyrazole-4-carboxylic acid and 3-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (obtained in the last step) in anhydrous acetonitrile (20ml). The reaction mixture was stirred at room temperature for h. and then at 60"C for 2 h. The mixture was cooled to room temperature and poured into bn.

NSII (20 ml) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. Then the combined organic phases were concentrated in vacuo, the crude residue was purified by flash chromatography eluting in a gradient mode with a mixture of 10-2095 ethyl acetate/hexane, then 2095 ethyl acetate/hexane and obtained the ethyl ether of 5-chloro-1-cyclopropyl-1H- pyrazole-4-carboxylic acid (eluted first, 296mg, 1395) and 3-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ether (eluted later, 159mg, 795). MSNR t/2 calculated for SeNiiSIM2gO" (MAN) 2151, found 215.1.

Stage 3: Synthesis of 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid

GION (40mg, 1.66bmmol) was added to a solution of 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ether (296mg, 1.3v8mmol) in methanol (15ml) and water (15ml). The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure to remove methanol. The residue was diluted with water, acidified to pH-2 with concentrated HCl and extracted with ethyl acetate.

The organic extracts were evaporated in vacuo to give 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (242 mg, 9395), which was used without further purification.

Stage 4: Synthesis of (5-hydroxyadamantan-2-yl)-amide trans-5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Chlorocyclopropyl-1H-pyrazole-4-carboxylic acid (242mg, 1.3 mmol) was dissolved in a mixture of dry dichloromethane (dml) and dry DMF (2 ml) and T5TI (318 mg, 1.56 bmmol) was added. Then DIPEA (1.44 ml, 7.8 mmol) was added to the specified mixture. After stirring the mixture for 2 hours. trans-4-aminoadamantane-1-ol hydrochloride (318mg, 1.5bmmol. intermediate 2) was added. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a gradient mode of 10-9095 acetonitrile/water to give (5-hydroxyadamantan-2-yl)-amide trans-5-Chloro-1-cyclopropyl-1H-pyrazole-4 -carboxylic acid (200mg, 4695). MSNR t/2 calculated for

Si7Ng22S1M3O" (MAN) 336 1, found 336 1.

Example 82 (B-Hydroxyadamantan-2-yl)-amide of trans-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

I

M. m N

Mo;

Dove

Sodium hydride (6090 dispersion in mineral oil; 115mg, 2.83bmmol) was added to a solution of pyrazole (195mg, 2.86bmmol) in dry DMF (25ml) under a nitrogen atmosphere at 0"C in an ice water bath and the mixture was heated at 40 "C within an hour. Trans-5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (120 mg, 0.33 mmol) was added and the mixture was heated at 1107 for 48 hours. and then cooled.

Then DMF was evaporated under vacuum, water and ethyl acetate were added. The organic layer was separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were concentrated in vacuo and the residue was purified by preparative HPLC with reverse phase C-18 in a gradient mode of 10-60905 acetonitrile/water to give (5-hydroxyadamantan-2-yl)-amide trans-2-cyclopropyl-2 of Н-/1,3|bipyrazolyl-4"-carboxylic acid (126mg, 9595). MSNR t/2 calculated for СоНг5М5О» (М--Н) 368.2, found 368.2.

Example 83 (5-Hydroxyadamantan-2-yl)-amide of trans-4-chloro-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid a/y I

M. | IN

M

And the beginning

Sodium hydride (6095 in oil; 57 mg, 1.43 mmol) was added to a solution of 4-chloropyrazole (148 mg, 1.43 mmol) in dry DMF (25 mL) under a nitrogen atmosphere at 0"C in an ice-water bath, and the mixture was heated at 40 "C within 1 hour. Trans-5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (bomg, 0.1 mmol) was added and the mixture was heated at 1107C overnight and then cooled. Then DMF was evaporated under vacuum, water and dichloromethane were added. The organic layer was separated and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were concentrated in vacuo and the residue was purified by preparative HPLC with reverse phase C-18 in a gradient mode of 10-9095 acetonitrile/water to give (B-hydroxyadamantan-2-yl)-amide trans-4-chloro-2 of '-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid (56 mg, 7795). MSNR t/2 calcd. for C0H2SIM5O" (M--H) 402.2, found 402 2.

Example 84 (5-Hydroxyadamantan-2-yl)-amide of trans-1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid aa

M "i

Mi 7 Shchi "ME N

FO

Stage 1: Synthesis of cyclopropylmethylhydrazine

Bromomethylcyclopropane (7.5 g, 55.6 mmol) was added dropwise to hydrazine hydrate (13.9 g, 277 mmol) with stirring at room temperature for 20 min. Stirring was continued at room temperature for an hour. Then the mixture was heated to 507C and stirred for 1 hour. The reaction mixture was cooled to room temperature and extracted three times with ether. The ether layers were combined and concentrated in vacuo to give cyclopropylmethylhydrazine (3.2 g, 6790) as a colorless oil, which was used without further purification.

Stage 2: Synthesis of 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether

Triethylamine (0.35 mL, 2.52 mmol) and cyclopropylmethylhydrazine (72 mg, 0.84 mmol) were sequentially added to a solution of ethyl 3-IR,K-dimethylamino-2-trifluoroacetylacrylate (intermediate 4, 200 mg, 0.84 mmol) in ethanol ( 4ml) in a test tube for treatment with microwave radiation with a volume of 1Oml Regzop! Spetizigu (Vioiade AV, Zmzhedep). The test tube was covered with a membrane and treated with microwave radiation with a power of 150 W using Regzop! Spetivzigu Misgozhame Zupipevziz buviet (Vioiade AV, Zmedep) at 1607"C for 30 minutes. The ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, concentrated in vacuo , and purified by reversed-phase C-18 HPLC in a gradient mode of 10-9095 acetonitrile/water and obtained 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (120 mg, 5495). MSNR t/ 2 calculated for C11Ni4EziM2O2 (Mk) 263.1, found 263.1.

Stage 3: Synthesis of 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

To a solution of 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (120mg, 0.4bmmol) in methanol (5ml) and water (Xml) was added PON (1Zmg, 0.54mmol). The reaction mixture was stirred at reflux overnight and then the solution was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the solution was acidified to pH-2 with concentrated HCl. Then the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo to give 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (100 mg, 9395), which was used without further purification.

Stage 4: Synthesis of trans-1-CDiclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)y-amide

Cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.4 mmol) was dissolved in a mixture of dry dichloromethane (12 ml) and dry DMF (3 ml) and T5TI (151 mg, 0.52 mmol) was added. Then DIPEA (0.45 ml, 2.58 mmol) was added to the above mixture. After stirring the mixture for 2 hours. trans-4-aminoadamantan-i-ol (87 mg, 0.5 mmol, intermediate 2) was added. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane.

The combined organic layers were dried under vacuum. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a 2-6095 acetonitrile/water gradient to obtain (5-hydroxyadamantan-2-yl)y-amide trans-1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole- 4-carboxylic acid (26mg, 1695). MSNR t/2 calculated for Sti9NgaEzMzO" (М--Н) 384.2, found 384 2.

Example 85 (5-Hydroxyadamantan-2-yl)-amide of trans-1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid i; M, "he

M | EN fe on

Stage 1: Synthesis of tert-butyl ether M'-(2-hydroxy-1,1-dimethylethyl)-hydrazinecarboxylic acid about eEO (9) M OS. then CT about about

M ia rei xx -- - Residential complex

Kk me o -e

Solution M-(tert-butoxycarbonyl)-3-(4-cyanophenyl)-oxaziridine (СА5 4: 150884-56-3), purchased from the company

Asgov, 5.17 g, 21 mmol) in anhydrous diethyl ether (20 ml) at room temperature was added to a solution of 2-amino-2-methylpropanol. Diethyl ether was evaporated under reduced pressure and the residue was purified by flash chromatography eluting in a gradient mode with a mixture of 3-590 methanol/dichloromethane to obtain M'-(2-hydroxy-1,1-dimethylethyl)-hydrazinecarboxylic acid tert-butyl ether ( 1.63 g, 4090), which was used without additional purification.

Stage 2: Synthesis of 2-hydrazino-2-methylpropane-1-ol trifluoroacetate

СсЕ, сСОоОН about the same nd dhm enye se: about (9)

Trifluoroacetic acid (4 ml) was added to a solution of M'-(2-hydroxy-1,1-dimethylethyl)-hydrazinecarboxylic acid tert-butyl ether (490 mg, 2.4 mmol) in dichloromethane (4 ml). The mixture was stirred at room temperature for an hour. The reaction mixture was concentrated in vacuo to obtain 2-hydrazino-2-methylpropan-1-ol trifluoroacetate (52 mg, quantitative yield), which was used without further purification.

Stage 3: Synthesis of 1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether. Carving of computer bus BOM baking and on on

Triethylamine (1.6 mL, 12 mmol) and 2-hydrazino-2-methylpropan-1-ol trifluoroacetate (520 mg, 2.4 mmol) were sequentially added to a solution of ethyl 3-M,M-dimethylamino-2-trifluoroacetylacrylate (intermediate 4, 574 mg, 2.4 mmol) in ethanol (dml) in a tube for treatment with microwave radiation with a volume of 25 ml

Regzopa! Spetivzigu (Vioiade AV, buedep). The test tube was covered with a membrane and treated with microwave radiation with a power of 150 W using Regzop! Spetizigu Misgomame Zupipeviz buviet (Vioiade AV,

Zmedep) at 1607"C for 1 h. The ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the aqueous phase was extracted three times with dichloromethane. The organic layers were combined, concentrated in vacuo and purified by flash chromatography at elution in a gradient mode with a mixture of 0-40905 ethyl acetate/hexane, then 4095 ethyl acetate/hexane and obtained 1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (328mg, 4995). MSNR t/2 calculated for C11Ni5EzM2gOz (МН) 281 1, found 281.1.

Stage 4: Synthesis of 1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

To a solution of 1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (328 mg, 1.17 mmol) in methanol (5 mL) and water (mL) was added GION ( Z4mg, 1.4mmol). The reaction mixture was stirred at reflux overnight and then the solution was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the solution was acidified to pH-2 with concentrated HCl. Then the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (280 mg, 9595), which was used without further purification.

Stage 5: Synthesis of (5-hydroxyadamantan-2-yl)-amide trans-1-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 1-(2-Hydroxy- 1,1-dimethylethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (280 mg, 1.1 mmol) was dissolved in a mixture of dry dichloromethane (12 ml) and dry DMF (3 ml) and added

TT (403 mg, 1.3 mmol). Then DIPEA (1.2ml, 6.bmmol) was added to the above mixture. After stirring the mixture for 2 hours. trans-4-aminoadamantan-1-ol (217 mg, 1.3 mmol, intermediate 2) was added. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a gradient mode of 10-4095 acetonitrile/water to give (5-hydroxyadamantan-2-yl)-amide trans-1-(2-hydroxy-1,1-dimethylethyl) -5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (230 mg, 5295). MSNR t/2 calculated for C1i9NovEziMzOz (MAN) 402.2, found 402.2.

Example 86 (5-Hydroxyadamantan-2-yl)-amide of trans-1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid a ; M, She m | N

H

Stage 1: Synthesis of methyl ester of 2-cyclopropanecarbonyl-3-dimethylaminoacrylic acid оо mmео оо ох . -k --j yr

MmeO that 7

A mixture of 3-cyclopropyl-3-oxopropionic acid methyl ether (15 g, 0.1 mmol) and M,M-dimethylformamide dimethyl acetal (14.7 ml, 111 mmol) was heated at 757C for 2 hours. The crude mixture was concentrated under high vacuum and crude 2-cyclopropanecarbonyl-3-dimethylaminoacrylic acid methyl ether (20.4 g, 9195) was obtained, which was used without further purification.

Stage 2: Synthesis of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester

Triethylamine (4.8 mL, 34.2 mmol) and tert-butylhydrazine hydrochloride (1.4 g, 11.4 mmol) were sequentially added to a solution of the crude methyl ether of 2-cyclopropanecarbonyl-3-dimethylaminoacrylic acid (2.4 g, 11.4 mmol) in ethanol (24 mL ). The resulting suspension was thoroughly mixed and, divided into 2 equal portions, placed in 2 test tubes with a volume of 25 ml for treatment with Regzop microwave radiation! Spitiwig

Vioiade AV, Zmzhedep). The test tubes were covered with membranes and treated with microwave radiation with a power of 150 W using Regzop! Spetivzigu Misgozhame Zupipevziz buviet (Vioiade AV, Zmedep) at 1607C during ZOkhv. The reaction mixtures from these two test tubes were combined and the ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water and the aqueous phase was extracted three times with dichloromethane.

The organic phases were combined, concentrated in vacuo, and purified by silica chromatography, eluting in a gradient mode with a mixture of 10-2095 ethyl acetate/hexane, then 2095 ethyl acetate/hexane, and obtained methyl ether 1-tert-butyl-5-cyclopropyl- 1H-pyrazole-4-carboxylic acid (921mg, 3695). MSNR t/2 calculated for Si2NivM2O" (MN) 223.1, found 223.1.

Stage 3: Synthesis of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid

GION (119 mg, 4.97 mmol) was added to a solution of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ether (921 mg, 4.14 mmol) in methanol (15 mL) and water (15 mL). The reaction mixture was stirred at reflux overnight and then the solution was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the solution was acidified to pH2 with concentrated HCl. Then the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (789mg, 9295), which was used without further purification.

Stage 4: Synthesis of trans-1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)y-amide

Tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (200mg, 0.9bmmol) was dissolved in a mixture of dry dichloromethane (8ml) and dry DMF (2ml) and T5TI (349mg, 1.16bmmol) was added. Then DIPEA (ml, 5,/bmmol) was added to the above mixture. After stirring the mixture for 2 hours. trans-4-aminoadamantane-1-ol hydrochloride (236 bmg, 1.1 bmmol, intermediate 2) was added. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a gradient mode of 2-70905 acetonitrile/water to give (trans-5-hydroxyadamantan-2-yl)-amide trans-1-tert-butyl-5-cyclopropyl-1 N-pyrazole-4-carboxylic acid (129mg, 3895). MSNR t/2 calculated for

SgiNzi MzO" (MAN) 358.3, found 358.2.

Example 87 (B-Hydroxyadamantan-2-yl)-amide of trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid o a

I) z lo i J

M o 1. mavnusm mMeonlgF hexane M-m o 2. NS Mm-m te shksvch n t Gdya U o her o

Stage 1: Synthesis of tert-butyl ether of M'-cyclobutylidene-hydrazinecarboxylic acid

The reaction mixture of cyclobutanone (15 g, 214 mmol) and hydrazinecarboxylic acid tert-butyl ether (28.3 g, 214 mmol) in hexane (225 ml) was refluxed for 2 hours. After cooling, the resulting precipitate and solid were filtered under vacuum. Isopropanol (10ml) and hexane (100ml) were added to the solid and the mixture was dried in a rotary evaporator under vacuum until a suspension was formed. After filtration, the solid was washed twice with hexane and dried under vacuum to give tert-butyl ether

M'-cyclobutylidenehydrazinecarboxylic acid (32 g, 8190) as a white solid, which was used without further purification.

Stage 2: Synthesis of cyclobutylhydrazine hydrochloride

Sodium cyanoborohydride (360mg, 133mmol) was added to a mixture of tert-butyl ether of M'-cyclobutylidene-hydrazinecarboxylic acid (2g, 10.8mmol) in anhydrous methanol (12ml) and anhydrous THF (9ml).

The reaction mixture was refluxed for 30 minutes. and then cooled to room temperature and stirred for 20 min. Bn was added dropwise to the reaction mixture. NSI (4, bml). Then the mixture was refluxed for 30 minutes. The mixture was cooled and the salts were removed by filtration. The resulting filtrate was concentrated in a vacuum. The residue was dispersed in isopropanol and cooled in an ice water bath. Then hexane was added and the mixture was dried in a rotary evaporator under vacuum until a suspension was formed. After filtration and washing with hexane, cyclobutylhydrazine hydrochloride (1.26 g, 9590) was obtained as a white solid and was used without further purification.

Stage 3: Synthesis of 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether

M o o

Triethylamine (0.35 mL, 2.52 mmol) and cyclobutylhydrazine hydrochloride (200 mg, 0.84 mmol) were sequentially added to a solution of ethyl 3-M,M-dimethylamino-2-fluoroacetylacrylate (intermediate 4, 200 mg,

O, in 4 mmol) in ethanol (4 ml) in a tube for treatment with microwave radiation with a volume of 1 Oml Reggopai

Spetivigu (Vioiade AV, Zmzhedep). The test tube was closed with a membrane and treated with microwave radiation with a power of 150 W using Regzop! Spetivznu Misgozhame Zupipev's busiet (Vioiade

AB, Zmedep) at 160"C for 30 min. The ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the aqueous layer was extracted three times with dichloromethane. The organic layers were combined, concentrated in vacuo, and purified by HPLC with reversed phase C-18 in a gradient mode of 40-8095 acetonitrile/water and obtained 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (117mg, 5395). MSNR t/2 calculated for C11Ni14EziM2O" ( M...) 263.1, found 263.1.

Stage 4: Synthesis of 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

PON (1 mg, 0.54 mmol) was added to a solution of 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ether (117 mg, 0.45 mmol) in methanol (5 mL) and water (mL). The reaction mixture was stirred at reflux overnight and then the solution was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the solution was acidified to pH-2 with concentrated NOSI. Then the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (9Zmg, 8995), which was used without further purification.

Step 5: (5-hydroxyadamantan-2-yl)-amide. trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

Cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (7mg, 0.3mmol) was dissolved in a mixture of dry dichloromethane (3ml) and dry DMF (2ml) and T5TI (205mg, 0.6mmol) was added. Then DIPEA (0.32ml, 1.8bmmol) was added to the above mixture. After stirring the mixture for 2 hours. trans-4-aminoadamantane-1-ol hydrochloride (77 mg, 0.38 mmol, intermediate 2) was added. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were concentrated in vacuo. The crude mixture was purified by preparative HPLC with reverse phase C-18 in a gradient mode of 10-7595 acetonitrile/water and obtained (5-hydroxyadamantan-2-yl-amid. trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4 -carboxylic acid (54 mg, 4595). MSNR t/g calculated for Sti9HgaEzMzO" (M--H) 384.2, found 384 2.

Example 88 (5-Acetylaminoadamantan-2-yl)-amide of trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid o 6)

Cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (example 87, stage 4, 100mg, 0.4mmol) was dissolved in a mixture of dry dichloromethane (8ml) and dry DMF (2ml) and 5TI (285mg, 0.95mmol) was added ). Then DIPEA (0.45 ml, 2.58 mmol) was added to the above mixture. After stirring the mixture during added trans-M-(4-aminoadamantan-1-yl)y-acetamide (107 mg, 0.5 mmol, obtained in example 43). After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were concentrated in vacuo. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a gradient mode of 10-9095 acetonitrile/water and obtained (5-acetylaminoadamantan-2-yl)-amide. trans-1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (104 mg, 57965). MSNR t/2 calculated for SgiNa7EzMaO" (М--Н) 425 2, found 425.2.

Example 89 (5-Acetylaminoadamantan-2-yl)-amide of trans-5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid H 4 si

Stage 1: Synthesis of cyclobutylhydrazine 1. mavn., seven meonlgF 2. NSI m-K o-4- 3. ME m-mn, poi --

Sodium cyanoborohydride (10.3g, 156bmmol) was added to a mixture of tert-butyl ether of M'-cyclobutylidene-hydrazinecarboxylic acid (24g, 130mmol) in anhydrous methanol (1800ml) and anhydrous THF (120ml).

The reaction mixture was refluxed for one hour. and then cooled to room temperature and stirred for ЗОхв. Bn was added dropwise to the reaction mixture. NSI (5 bml). Then the mixture was refluxed for 1 hour. The mixture was cooled and the solid was removed by filtration. The resulting filtrate was concentrated in a vacuum. The residue was treated with triethylamine to form a slightly alkaline mixture and the mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo to give crude cyclobutylhydrazine (11 g, 9890) as an oil, which was used without further purification.

R o and vEyunosh o vo

EOo sooKk 5 d M Ko

Circle (in) o sis! Wow, that's snsm ana, oh,

Separation into meonine du pot Eh -- zh lk si mya si mya

Stage 2: Synthesis of a mixture of 5-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether and 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether

A mixture containing crude cyclobutylhydrazine (obtained in the last step, without further purification; 3.5g, 40.8mmol) and ethyl-(ethoxymethylene)-cyanoacetate (6.9g, 40.mmol) in ethanol (140ml) was stirred and boiled refluxed overnight. The solution was cooled to room temperature and the mixture was diluted with water and dichloromethane. The separated aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with water and brine and then dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude residue was purified by flash chromatography eluting in a gradient mode with a mixture of 0-296 methanol/dichloromethane to obtain a mixture of 5-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether (eluted first) and 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether (eluted a little later) (2 isomers: total 5.4 g, 6395), which was used as a mixture without additional separation. MSNR t/2 calculated for StioNizMzO" (M-А-Н) 210.1, found 2101.

Stage 3: Synthesis of 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether and 3-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether

A mixture of 5-amino-1-cyclobutyl-1H-pyrazole ethyl ether was added to a mixture of tert-butyl nitrite (5.1 ml, 38.7 mmol), copper(!) chloride (3.6 g, 38.7 mmol) and anhydrous acetonitrile (100 ml) -4-carboxylic acid and 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether (obtained at the last stage, without additional purification) in anhydrous acetonitrile (HO0ml) at 0"C. The reaction mixture was stirred at room temperature for an hour and then at 60"C for 2 hours. The mixture was cooled to room temperature and then poured into the bn. NSI (5 bml) and extracted with dichloromethane. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were then concentrated in vacuo, the crude residue was purified by flash chromatography eluting in gradient mode with a mixture of 10-2095 ethyl acetate/hexane, then 2095 ethyl acetate/hexane. The desired fractions were concentrated in a vacuum and dried in a vacuum to obtain 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether (eluted first, b610mg, 10.395) and 3-chloro-1-cyclobutyl-1H ethyl ether -pyrazole-4-carboxylic acid (eluted later, 147mg, 2.595). MSNR t/2 calculated for SiONiZSIM2gOg" (M--H) 229.1, found 229.1.

Stage 4: Synthesis of 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid

To a solution of 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ether (182mg, 0.79mmol) in methanol (8ml) and water (dml) was added PON (23Zmg, 0.9bmmol). The reaction mixture was stirred at reflux for 4 hours. and then concentrated under reduced pressure to remove methanol. The residue was diluted with water, acidified to pH2 with concentrated HCl and extracted with ethyl acetate.

The organic layer was evaporated in vacuo to give 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid (148 mg, 9495), which was used without further purification.

Stage 5: Synthesis of (5-acetylaminoadamantan-2-yl-amide trans-5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid 5-Chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid (74 mg , 0.37 mmol) was dissolved in a mixture of dry dichloromethane (8 mL) and dry DMF (2 mL) and T5TI (245 mg, 0.81 mmol) was added. Then DIPEA (0.39 mL, 2.22 mmol) was added to the above mixture. After stirring the mixture trans-M-(4-aminoadamantan-1-yl)-acetamide (92 mg, 0.44 mmol, obtained in Example 43) was added over 2.5 hours. After stirring overnight, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane . The combined organic layers were concentrated in vacuo. The crude mixture was purified by preparative reverse-phase C-18 HPLC in a 10-9095 acetonitrile/water gradient to give (5-acetylaminoadamantan-2-yl)-amide trans-5-chloro -1-cyclobutyl-1H-pyrazole-4-carboxylic acid (120mg, 8390).

MeENR t/2 calculated for SgoN27SIMAO" (MAN) 391.2, found 391.2.

Example 90 (5-Acetylaminoadamantan-2-yl)-amide of trans-2'-cyclobutyl-2'H-Y1,3|bipyrazolyl-4"-carboxylic acid o o

M. "AK

M | N

MV; to

Sodium hydride (6095 dispersion in mineral oil; 58 mg, 1.44 mmol) was added to a solution of pyrazole (98 mg, 1.44 mmol) in dry DMF (18 mL) under a nitrogen atmosphere at 0"C in an ice-water bath, and the mixture was heated at 40 "C within 1 hour. Trans-1-5-chlorocyclobutyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (700 mg, 0.18 mmol) was added and the mixture was heated at 1107C for 48 hours. and then cooled to room temperature. Then DMF was evaporated under vacuum, water and ethyl acetate were added.

The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC with reverse phase C-18 in a gradient mode of 10-9095 acetonitrile/water. The desired fractions were concentrated in vacuo and dried in vacuo to obtain (5-acetylaminoadamantan-2-yl)-amide of trans-2'-cyclobutyl-2'H-N1,3-bipyrazolyl-4"-carboxylic acid (38mg, 5095). MSNR t/2 calculated for SgzNzoMevO" (MN) 423.3, found 423.2.

Example 91 (B-Hydroxyadamantan-2-yl)-amide of trans-2'-tert-butyl-4-methyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid)

M. ton / N on - V , it man, dMF sa y n si chho - sh-

Sodium hydride (6095 dispersion in mineral oil; 180mg, 4.6bmmol) was added slowly to a solution of 4-

of methylpyrazole (380 μl, 4.6 mmol) in dry DMF (30 ml) at 0"C in an ice-water bath. The mixture was stirred in an argon atmosphere for 17 hours and then the mixture was heated at 40"C for 1.5 hours. Trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (Example 34, 200 mg, 0.57 mmol) was added and the mixture was heated at 1107C overnight for From days and then it was cooled. The solvent was removed in vacuo. The resulting mixture was diluted with water and extracted with chloroform (2x). The organic layers were combined and washed with water (3x), then with a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting mixture was purified by column chromatography using silica gel and eluting with a mixture of 660-709 ethyl acetate in petroleum ether. The desired fractions were concentrated in vacuo and trans-2'-tert-butyl-4-methyl-2'H-1,3-bipyrazolyl-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide was obtained as a white solid ( 5Zmg, 2395); ER(u) -MSVR t/2 calculated for Сg2НзиМ5О» (М-А-Н) 398.2551, found 398.2546.

Example 92 (5-Hydroxyadamantan-2g-yl)-amide of trans-2'-tert-butyl-4-chloro-2'H-N,3-bipyrazolyl-4"-carboxylic acid

And a

M 7 - n

M sub

And M

This compound was obtained by a method similar to that described in example 91 (previous example), with the exception that 4-chloropyrazole was used instead of 4-methylpyrazole and trans-2'-tert-butyl (5-hydroxyadamantan-2-yl)-amide was obtained -4-chloro-2'H-/1,3bipyrazolyl-4-carboxylic acid (5395) as an almost white solid; MSNR t/2 calculated for C21Ng8SIM5O" (MAN) 418.20, found 418.33.

Example 93 (5-Hydroxyadamantan-2-yl)-amide of trans-4-bromo-2'-tert-butyl-2'H-Y,3bipyrazolyl-4"-carboxylic acid

With a

M. "he and she

M | IN

M

WHAT

And Me

This compound was obtained by a method similar to that described in example 91, with the exception that 4-bromopyrazole was used instead of 4-methylpyrazole and (5-hydroxyadamantan-2-yl)-amide trans-4-bromo-2'-tert-butyl was obtained -2'H-/1,3bipyrazolyl-4"-carboxylic acid (2395) in the form of a white solid; ER(yu) -

MOVR t/2 calculated for SgiNgvVIi M5O" (MN) 462.1499, found 462.1497.

Example 94 (5-Acetylaminoadamantan-2-yl)-amide trans-2'-tert-butyl-4-chloro-2'H-/1,3|bipyrazolyl-4"-carboxylic acid c) o) 7 a "n -, mi N

M

I

M--

Sodium hydride (6095 in oil; 220 mg, 5.5 mmol) was slowly added to a solution of 4-chloropyrazole (710 mg, b, Ummol) in dry DMF (40 mL) at 0°C in an ice-water bath. The mixture was stirred under an argon atmosphere for 10 min. and then the mixture was heated at 40"C for 2 hours. Trans-1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (2700 mg, 0.69 mmol) was added and the mixture was heated at 1107 overnight for 2 days and then cooled. The solvent was removed in vacuo. The resulting mixture was diluted with water and extracted with ethyl acetate (2x). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The solid was dispersed in ether and filtered and dried under high vacuum to give (5-acetylaminoadamantan-2-yl)-amide trans-2'-tert-butyl-4-chloro-2'IN-

1,9-bipyrazolyl-4-carboxylic acid as a white solid (237mg, 7495); ER(yaU -MSVR t/: calculated for SgzNai SIMeO" (MAN) 459.2270, found 459.2268.

Example 95 (5-Acetylaminoadamantan-2-yl)-amide of trans-4-chloro-2'-cyclobutyl-2'H-/1,3-bipyrazolyl-4"-carboxylic acid

Gee) oh ah! tk

M | N

M o-a o

Sodium hydride (6095 in oil; 49mg, 1.23mmol) was added to a solution of 4-chloropyrazole (126mg, 1.23mmol) in dry DMF (16bml) under a nitrogen atmosphere at 0"C in an ice water bath and the mixture was heated at 40 "C within 1Th. Trans-1-5-chlorocyclobutyl-1H-pyrazole-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (bOmg, 0.15 mmol) was added and the mixture was heated at 1107C for 48 hours. and then cooled to room temperature. Then DMF was evaporated under vacuum, water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC with reverse phase C-18 in a gradient mode of 10-9095 acetonitrile/water. The desired fractions were concentrated in a vacuum and dried in a vacuum to obtain trans-4-chloro-2'-cyclobutyl-2'H-1,3-bipyrazolyl-4-carboxylic acid (5-acetylaminoadamantan-2-yl)-amide (42 mg, 6295). MSNR t/2 calculated for SgzNgoSIMvO" (M) 456.2, found 456.2.

Example 96 (5-Acetylaminoadamantan-2-yl)-amide trans-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid o (a; a " m | H H

M what; where

This compound was obtained similarly to the preparation of (5-hydroxyadamantan-2-yl)-amide trans-2'-cyclopropyl-2'H-

I,Z'bipyrazolyl-4"-carboxylic acid (example 82), with the exception that intermediate product 2 was replaced by trans-M-(4-aminoadamantan-1-yl)-acetamide (obtained in example 43).

Example 97 (5-Acetylaminoadamantan-2-yl)-amide of trans-4-chloro-2-cyclopropyl-2'H-(1,3|bipyrazolyl-4"-carboxylic acid

Ge) 8)

Mi N y y What-ah

To

This compound was obtained similarly to the preparation of trans-4-chloro-2'-cyclopropyl-2'H-(1,3|bipyrazolyl-4-carboxylic acid) (5-hydroxyadamantan-2-yl)-amide (Example 83), according to with the exception that intermediate 2 was replaced by trans-M-(4-aminoadamantan-1-yl)-acetamide (obtained in example 43).

Example 98 (5-Acetylaminoadamantan-2-yl)-amide of trans-4-chloro-2'-(2-methoxyethyl)-2'H-(1,3|bipyrazolyl-4"-carboxylic acid) In

M M

- yo sh-oh

This compound was obtained similarly to the preparation of trans-2'-(2-methoxyethyl)-211/-(11,3bipyrazolyl-4"-carboxylic acid (5-acetylaminoadamantan-2-ylamide (Example 75), with the exception that pyrazole was replaced by 4- chloropyrazole.

Example 99

The study of the compounds proposed in the actual invention was carried out

Inhibition of 118-H5O1 ip myo by the compounds of the present invention has been demonstrated using the cell assay methods described below:

Research Nek man:

NEK-293 cells, stably transfected with the full-length 11-strand human NOUO1 cDNA, were propagated and diluted with MDES medium with a high glucose content (Ipigodep Ca 11995-065), to which 1090 was added

FtTS (fetal calf serum) (Ipuygodep Sai 10082-147), penicillin/streptomycin (1 µg/ml) and genecitin (1 µg/ml). The day before the analysis, cells were extracted from the vials using a trypsin/EDTC (ethylenediaminetetraacetic acid) mixture, centrifuged and washed with medium for Petri dishes (MDES with a high glucose content, without phenol red; Ipigodep Sai 21063-029, with the addition of 295 purified with charcoal FTS; Setipi Sai Ag2311R). From a suspension containing 250,000 cells/ml of suspension in a medium for Petri dishes, 200 μl of cells were seeded into each well of a 96-well coated plate (VioSoai Saii 356461) and grown overnight at 37°C. in DMSO, was added to the medium for Petri dishes, to which BSA was added (final concentration 2 mg/ml). The final concentration of DMSO was 195. The medium was aspirated from the plates and the compounds in the medium were added to each well. The plates were incubated at 37"C for 1 hour. , so that the compounds get into the cells. Then 1 μl of substrate (cortisone) was added to each well (final concentration 100 nM) and incubated for 1 hour. at 37"C. Then the plates were transferred to ice and 8 omcl of the medium was transferred to a 96-well plate and stored at -307C.

Quantitative determination of cortisol in media with cells was carried out using competitive EGISA with the help of EGISA-Gidni (Tgorikh Say T10206/E!. 10054), anti-cortisol EIIA antibodies (Azzau Oezidpv, Ips.

Sai80-1148), and the cortisol-enzyme conjugate (Azzau YuOevidpe, Ips. Saii 80-1147). 384-well plates (Rysop Sai3988) were coated overnight at 4"C with an anti-mouse IgG (bidta Ca M-1397) suspended in 0.995 Mass (5 mg/ml), 500 μl per well. The plates were washed with ZFf ( phosphate-buffered saline), 0.190 PuEEP-20, then washed with Z3FF only. Plates were blocked with blocking buffer (Thorikh Saiy AI0O75) for 2 h at room temperature. Then plates were washed as described above. Samples for analysis were thawed, diluted 1: 4 in MDES, 2 mg/ml BSA, 195 DMSO, and 24 μl were transferred to wells of a 384-well plate that had been previously coated and various amounts of cortisol standard were added.12 μl of cortisol conjugate and 12 μl of anti-cortisol were added to each well.

EIA antibodies and incubated for 2 hours. at room temperature on an orbital tablet shaker. The wells were then freed by inversion, then washed three times with 100 μl of wash buffer (Thorikh), and then 2 times with 100 μl of assay buffer (Thorikh). BoOmcl SOR-B5BTANV (Tgorikh) was added to each well and incubated for 10 minutes. at room temperature.

Chemiluminescence was recorded using the M Neadegh Mission (Reikip EIteg). Cortisol content in each sample was obtained by interpolation using a standard curve obtained using known amounts of cortisol. The value of ISzo was calculated with the help of the software for approximating the curves of XI RIS (085).

Study of OUR man:

Cells:

NAPE cells stably transfected with human 11-8-H5OY cDNA (pitNaPE) were maintained in Dulbecco's modified essential medium (MDES) 41095 fetal bovine serum (FBS) containing penicillin (100 Mo/ml) and streptomycin (100 μg/ml), geneticin (80 Ωkg/ml) and I-glutamine (2 mm) at 37"C in a humid atmosphere (9595 air, 595 COg).

Preparation of cells for research:

Cells QUESTION at 8095 fusion in a mattress with an area of 225 cm? washed with ZfF, then separated with a warm trypsin/EDTC mixture. Cells were counted and resuspended in modified Dulbecco's phenol red-free essential medium (MDES) containing 290 purified serum at a concentration of 100,000 cells in 200 μL and plated in wells of a 96-well culture plate (precoated with polylysine) . Cells were incubated overnight at 37"C in a humid atmosphere (9595 air, 596 CO"2). Study of steroid conversion:

Transformation studies were performed 1 day after seeding in 96-well plates. The medium was removed and replaced with 100 μl of Dulbecco's modified essential medium containing no phenol red (MDES) containing 2 mg/ml bovine serum albumin (BSA) 195 DMSO or the test compound dissolved in DMSO.

Cells were incubated with the test compound for 10 min. At 37"C in a humid atmosphere (9595 air, 595 CO). Cortisone was added to a final concentration of 200 nM after 10 minutes, and the cells were incubated for 120 minutes at 37"C in a humid atmosphere (9595 air, 595 CO).

The reaction was stopped by transferring 80 μl of medium into an empty 96-well plate. The samples were stored at -2076 before determination of cortisol concentration using EI ISA.

The results of cell studies showing inhibition of 118-HOO1 ip myo by typical compounds of the present invention are shown below.

Table:

Our NaPE

An example of Le | Name You NEK (IS55, mk M) | here it is

MKM) (5-hydroxyadamantan-2-yl)-amide 1-methyl-3-pyrrol-1-yl-1H- 0.0399 d pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide 2 trans -1-methyl-5-pyrodo-i-yl-iH- |) 0.0222 dn of pyrazole-4-carboxylic acid adamantane-2-ylamide 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid /0, 18858 dn of adamantan-2-ylamide 1-tert-butyl-5-trifluoromethyl-1 H- 0.0098 dn pyrazole-4-carboxylic acid (5-hydroxyadamantan-2-yl)-amide trans- 1-tert-butyl- 5-

I trifluoromethyl- I H-pyrazole-4- 0.6009 dicarboxylic acid (5-hydroxyadamantane-2-1l3-amide cis-1-tert-butyl-3- trifluoromethyl- I H-pyrazole-4- 0.0202 dn carboxylic acid acid (5-hydroxyadamantane-2-1l)-amide trans-2'-methyl-2 H-

I1.3"|bipyrazolyl-1"-carboxylic acid 0.0386 dn adamantane-2-ylamide 1-r cyclopropyl-5-trifluoromethyl- 0.0222 di

I H-pyrazole-4-carboxylic acid adamantane-2-ylamide 1-methyl-5- 14 (4-methylpiperazin-1-yl)-1H- 0.0233 dn pyrazole-4-carboxylic acid

And adamantane-o-ilamide 1-methyliyaa o | ! 22 morpholin-4-ia5 1 H-trazol-d» 00166 | of carboxylic acid | : zadamantan-2-ylamide 5-(2-23 and methoxystylamino)-I-methyl-1H- 0.075, Di! ztnrazol-I-carboxylic acid! ! ! t | what! with adamantane-o-ipamide 5-0" | : methozhxistyl)-methylamino|-1- | and ! 32 rubber 100262 days

And methyl-PPreprazole-Y-carbonov | and and | acid | : adamantane-2-ylamide 2'-trecht- ! ! 43 butyl-O NAPI.Z'ibipyrazolyl-i- 0 0.0068 | days of carboxylic acid - ! in pis klin CO nt is it piv tin about the question of Minko and Mivin :(3-hydroxyadamantai-y-ily-amim 14 | I-tert-butyl-5-chlorao-1H- | 0.0192 I 00056

And pyrazole-d-carboxylic acid | and HER

G | (5-hydroxylamantane-d-yl)i-amide trans-- -tert-butna-2 - what else |trans-? tregbuti? NU | 0.029 Soda5

Ha biturazolil-i "carbon | ! : ((5chdroxydamantania-iinamide - trans-d'-methylya"N. ay pt : rano Mety yo, - 100482 000539

IZ Tbinirazolyl-I -carboxylic acid; ! and (5-apetilamivodamantan-2-L)- | | ! - med trane-I-tert-butyl-i- | ; 46 (al tranet treoutne - 10.0662 | 00085 and chloro-1Nepyrazole-I-carboxylic acid

Ezacetylaminozlamantaneisi)n and amide tris-i-tert-butyls" ! ; 48 -amyltrane-I trevue 0.0181 00003 : and trifluoromethyl Nprazol-! skharboney kisletio 0 ! ((5-anethylaminogdamantan-g-i l)- : : iamid trane-? -tert-butylod C- ! ! ho samil trans? stret-futia? M- | 9.0238 vd : | PA Ozpyrazolyl-K -carbonova ! ; : - methanesulfonylamine amide: 53 yl)yl-amide trans-2 "methyl-2 H- 00769 0.006

EP. bipyrazolyl-4-carbon (5-hydroxyadamantan-2-yl)-amide ans-5-chloro-1-(2-73 trans-5-chloro-1507 0.0229 0.0006 methoxyethyl)-1H-pyrazole-4- carboxylic acid (5-hydroxyadamantan-2-yl)-amide trans-2"-|2-(2-methoxyethoxy)- 76 rans-2 |2(o-methoxyethoxy). | dru 0.0153 ethylI-2"H- (1,3"|bipyrazolyl-4"-carboxylic acid (5-hydroxyalamantan-2-1l)-amide trans-1-(2-tert-butoxyethyl)-5-71 rane-I-(2-tert-butoxyethyl) -5- | du 0.0046 trifluoromethyl- I H-pyrazole-4- carboxylic acid

DN - no data.

It should be understood that the valid invention is not limited to the preferred embodiments of the valid invention described above, since there may be 5 changes made to the preferred embodiments included in the scope of the appended claims.