JP2010525020A - Heterocyclic compounds with affinity for muscarinic receptors - Google Patents

Abstract

本発明は、式（Ｉ）の複素環式化合物あるいはその製薬学的に許容され得る塩、溶媒和物又は水和物に関し、式中、−複素環は２個の二重結合を含んでなり、それらは破線（−−−）により示されるいくつかの位置に存在することができ；−複素環は２個のヘテロ原子を含有し、−ＷはＮ又はＮＨであり；−ＹはＣＨ、Ｏ又はＮＨであり、ここでＹがＯである場合、Ｘ_１はＣＨであり、且つＸ_２は残基Ｃ−Ｚ−Ｒ２又はＣ−Ｒ３であり、ここでＺはＮＨ、Ｏ又はＳであり；そしてＹがＣＨ又はＮＨである場合、Ｘ_１及びＸ_２の１つはＣＨ又はＮであり、他は残基Ｃ−Ｚ−Ｒ２又はＣ−Ｒ３であり、ここでＺはＮＨ又はＳであり；−Ｒ１は構造（ａ）、（ｂ）及び（ｃ）から選ばれ：−Ｒ２は、場合により独立してハロゲン、ヒドロキシ、シアノ、オキソ、（Ｃ_１−Ｃ_６）アルコキシ、（Ｃ_１−Ｃ_６）アルキルチオ、（Ｃ_１−Ｃ_６）アルケニルオキシ、（Ｃ_１−Ｃ_６）アルケニルチオ、（Ｃ_１−Ｃ_４）アルコキシ（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_５−Ｃ_７）シクロアルキル、５−員不飽和複素環（場合によりハロゲンで置換されていることができる）、フェニル、フェニルオキシ及びフェニルチオから選ばれる１個もしくはそれより多い置換基で置換されていることができる（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_２−Ｃ_１０）アルケニル及び（Ｃ_２−Ｃ_１０）アルキニルから選ばれ、ここでフェニル基は場合によりハロゲンで置換されていることができるか；あるいは−Ｒ２は式（Ｉａ）を有する基のＺａ−記号において置換されている非分枝鎖状（Ｃ_２−Ｃ_８）アルキルであり、ここでＸ_１がＣＨ又はＮである場合、Ｘ_１ａはＣＨ又はＮであり、且つＸ_２ａはＣ−Ｚａ−であるか、あるいはＸ_１がＣ−Ｚ−Ｒ２である場合、Ｘ_１ａはＣ−Ｚａ−であり、且つＸ_２ａはＣＨ又はＮであり；そして記号Ｗａ、Ｙａ及びＺａならびに置換基Ｒ１ａは前に記号Ｗ、Ｙ及びＺならびに置換基Ｒ１に関して定義したと同じ意味を有し、且つ独立して選ばれず、記号Ｗａ、Ｙａ及びＺａならびに置換基Ｒ１ａのそれぞれは、式（Ｉ）の構造の他の部分中の記号Ｗ、Ｙ及びＺならびに置換基Ｒ１とそれぞれ同じ記号及び置換基を示し；−Ｒ３は場合により独立してハロゲン、ヒドロキシ、シアノ、（Ｃ_１−Ｃ_６）アルコキシ、（Ｃ_１−Ｃ_６）アルキルチオ、（Ｃ_１−Ｃ_６）アルケニルオキシ、（Ｃ_１−Ｃ_６）アルケニルチオ、（Ｃ_１−Ｃ_４）アルコキシ（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_５−Ｃ_７）シクロアルキル、場合によりハロゲンで置換されていることができる５−員不飽和複素環、フェニル、フェニルオキシ及びフェニルチオから選ばれる１個もしくはそれより多い置換基で置換されていることができる（Ｃ_４−Ｃ_１０）アルキル、（Ｃ_２−Ｃ_１０）アルケニル及び（Ｃ_２−Ｃ_１０）アルキニルから選ばれ、ここでフェニル基は場合によりハロゲンで置換されていることができる。本発明の化合物はムスカリン性受容体に親和性を有し、ムスカリン性受容体が媒介する疾患及び状態の処置、軽減又は予防において使用することができる。
【選択図】 なし[Chemical 1]

The present invention relates to a heterocyclic compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the -heterocycle comprises two double bonds. , They can be present at several positions indicated by the dashed line (---); the -heterocycle contains 2 heteroatoms, -W is N or NH; -Y is CH, O or NH, where Y is O, X ₁ is CH and X ₂ is the residue C—Z—R 2 or C—R 3, where Z is NH, O or S And when Y is CH or NH, one of X ₁ and X ₂ is CH or N and the other is the residue C—Z—R 2 or C—R 3, where Z is NH or S -R1 is selected from structures (a), (b) and (c): -R2 is optionally independently halogen, hydroxy, Ano, oxo, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkenyloxy, (C ₁ -C ₆ ) alkenylthio, (C ₁ -C ₄ ) alkoxy _{1 selected from} (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy and phenylthio Selected from (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl and (C ₂ -C ₁₀ ) alkynyl, which may be substituted with one or more substituents, wherein the phenyl group is optionally it can be substituted by halogen; or -R2 is unbranched substituted in Za- symbol group having the formula (Ia) (C ₂ C ₈₎ alkyl, wherein when _{X 1} is CH or N, _{X 1} a is CH or N, and either _{X 2} a is a C-Za -, or _{X 1} is C-Z- If it is R2, _{X 1} a is a C-Za -, and _{X 2} a is CH or N; and the symbol Wa, Ya and Za and substituents R1a symbols W before, Y and Z and the substituents Having the same meaning as defined for R1 and not being independently selected, the symbols Wa, Ya and Za and the substituent R1a respectively represent the symbols W, Y and Z in other parts of the structure of formula (I) and each with a substituent R1 shows the same symbols and substituents; -R3 is independently optionally halogen, hydroxy, _{cyano, (C} 1 -C _{6) alkoxy, (C} 1 -C ₆₎ alkylthio, _{(C 1} - C ₆₎ alkenyloxy, C ₁ -C _{6) alkenylthio, (C} 1 -C ₄₎ alkoxy _(C 1 -C _{4) alkoxy, (C} 5 -C ₇₎ cycloalkyl may optionally be substituted by halogen 5- membered (C ₄ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl and (C) which may be substituted with one or more substituents selected from unsaturated heterocycles, phenyl, phenyloxy and phenylthio _2- C ₁₀ ) alkynyl, wherein the phenyl group can be optionally substituted by halogen. The compounds of the present invention have affinity for muscarinic receptors and can be used in the treatment, alleviation or prevention of diseases and conditions mediated by muscarinic receptors.
[Selection figure] None

Description

FIELD OF THE INVENTION The present invention relates to novel heterocyclic compounds having affinity for muscarinic receptors, pharmaceutical compositions containing the compounds and the treatment, alleviation of or diseases or conditions mediated by muscarinic receptors. It relates to the use of said compounds for the manufacture of a medicament for prevention.

BACKGROUND OF THE INVENTION Muscarinic cholinergic receptors mediate the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Muscarinic receptors comprise five distinct subtypes designated as muscarinic M1, M2, M3, M4 and M5 receptors. Each subtype has a unique distribution in the central and peripheral nervous system. The M1 receptor is expressed primarily in the cerebral cortex and appears to be involved in the control of higher cognitive functions; the M2 receptor is a major subtype found in the heart and is included in the control of heart rate The M3 receptor is widely expressed in many peripheral tissues and appears to be involved in gastrointestinal and urinary tract irritation and sweating and salivation; the M4 receptor is present in the brain and has locomotion and antipsychotic effects; M5 receptors are located in the brain and can be involved in psychotic conditions such as compound addition and schizophrenia. In view of the important physiological roles attributed to each of the muscarinic receptor subtypes, extensive efforts have been made to create new compounds that exhibit selective agonistic or antagonistic properties (eg, US Pat. Non-patent document 1; Non-patent document 2; Patent document 3; Non-patent document 3; Non-patent document 4; Non-patent document 5;

  A well known example of an M1 / M4 preferred muscarinic receptor agonist is the thiadiazole compound xanomeline, which has desirable aspects in preclinical studies but exhibits undesirable side effects in clinical studies (eg, non-patented See review by ref. 7 and US Pat. No. 6,057,049), which seems to be related to activity mediated by M2 receptors (eg heart rate effect). Furthermore, xanomeline has a relatively low (in vitro) metabolic stability. Xanomeline-related compounds are further disclosed in US Pat. However, representative compounds exhibit undesirable side effects, which appear to be related to activities mediated by M2 and M3 receptors (eg, heart rate effect and salivation, respectively).

  Further research continues to develop therapeutics with selective M1 / M4 distribution, but this has not yet yielded successful candidates. Accordingly, there is a need for new selective compounds having the desired properties.

European Patent No. 0296721 European Patent No. 0316718 US Pat. No. 5,527,813 US Pat. No. 5,376,668

Sauerberg, P.A. et al. Author, J.H. Med. Chem. , Vol. 35, no. 22, 1992, 2274-2283 Ward, J .; S. et al. Author, J.H. Med. Chem. , Vol. 35, no. 22, 1992, 4011-4019 Zlotos, D.M. P. et al. Author, Exp. Opin. Ther. Patents, Vol. 9, no. 8, 1999, 1029-1053 Plate, R.A. , Et al. Author, Bioorg. Med. Chem. 4, 1996, 227-237 Plate, R.A. , Et al. Author, Bioorg. Med. Chem. 8, 2000, 449-454 Del Guide, M.M. R. et al. Author, Arch. Pharm. Med. Chem. 336, 2003, 143-154 Egglen, R .; M.M. Written, Progress in Medicinal Chemistry, 43, 2005, p. 105-136

DESCRIPTION OF THE INVENTION This time, formula (I)

[Where:
The heterocycle comprises two double bonds, which can be present in several positions indicated by dashed lines (---);
The heterocycle contains 2 heteroatoms;
-W is N or NH;
-Y is CH, O or NH, where when Y is O, X ₁ is CH and X ₂ is the residue C-Z-R2 or C-R3, where Z is NH And when Y is CH or NH, one of X ₁ and X ₂ is CH or N and the other is the residue C—Z—R 2 or C—R 3, where Z is NH or S;
-R1 is selected from structures (a), (b) and (c):

-R2 is independently halogen, optionally, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy, (C} 1 -C ₆ ) Alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle (optionally substituted with halogen) ), (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl and (C ₂ -C), which may be substituted with one or more substituents selected from phenyl, phenyloxy and phenylthio ₁₀ ) selected from alkynyl, wherein the phenyl group may optionally be substituted with halogen;
Alternatively, -R2 is the formula (Ia)

The unbranched substituted in Za- symbol groups having _(C 2 -C ₈₎ alkyl,
Here, when X ₁ is CH or N, X ₁ a is CH or N and X ₂ a is C—Za— or when X ₁ is C—Z—R 2, X ₁ a is C-Za- and X ₂ a is CH or N; and the symbols Wa, Ya and Za and the substituent R1a have the same meaning as previously defined for the symbols W, Y and Z and the substituent R1. And each of the symbols Wa, Ya and Za and the substituent R1a is the same as the symbols W, Y and Z and the substituent R1 in the other part of the structure of the formula (I), respectively. And substituents;
-R3 is independently halogen, optionally, hydroxy, _{cyano, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy, (C} 1 -C ₆₎ alkenyl Thio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, From (C ₄ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl and (C ₂ -C ₁₀ ) alkynyl which may be substituted with one or more substituents selected from phenyloxy and phenylthio Wherein the phenyl group can optionally be substituted with a halogen]
Or a pharmaceutically acceptable salt, solvate or hydrate thereof exhibits an affinity for muscarinic receptors, particularly M1 and / or M4 receptors, and modulates muscarinic receptor Have been found to have sexual properties, particularly (partially) operability. Furthermore, the compounds of the present invention exhibit higher (in vitro) metabolic stability than the prior art compound xanomeline.

  The compounds of the present invention are useful for the treatment, alleviation and prevention of diseases and conditions mediated by muscarinic receptors. Preferred compounds are M1 and M4 receptor agonists in the treatment of diseases and conditions mediated by muscarinic M1 / M4, including but not limited to Alzheimer's disease, cognitive impairment, Sjogren's disease, schizophrenia and antinociception. Can be used. In particular, the compounds of the invention can be used for the treatment, reduction or prevention of cognitive and psychotic disorders.

In one aspect of the present invention, compounds, halogen independently is optionally R2, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C ₆ ) _{alkenyloxy, (C} 1 -C _{6) alkenylthio, (C} 1 -C ₄₎ alkoxy _(C 1 -C _{4) alkoxy, (C} 5 -C ₇₎ cycloalkyl, 5- membered unsaturated heterocyclic ring (if (C ₁ -C ₁₀ ) alkyl, which can be substituted with one or more substituents selected from phenyl, phenyloxy and phenylthio, (C _2- C ₁₀ ) alkenyl and (C ₂ -C ₁₀ ) alkynyl, wherein the phenyl group is optionally substituted with halogen (I ). Preferably, halogen is independently optionally is R2, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C ₄₎ alkoxy _(C 1 -C _{4) alkoxy, (C} 5 -C ₇ ) (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C) which may be substituted with one or more substituents selected from cycloalkyl, tetrahydrofuranyl and phenyl ₈ ) Selected from alkynyl, wherein the phenyl group may be optionally substituted with halogen. Particularly preferred is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl optionally substituted with one or more halogens or (C ₁ -C ₆ ) alkoxy. A compound of formula (I) selected from

Further, in one aspect of the present invention, optionally the R3 _(C 5 -C ₇₎ can be substituted with one substituent selected from cycloalkyl or phenyl _(C 4 _{-C 10)} alkyl, Selected from (C ₂ -C ₁₀ ) alkenyl and (C ₂ -C ₁₀ ) alkynyl, wherein phenyl can be optionally substituted by halogen.

  In yet another embodiment of the invention, R1 has the structure (a) or (b), in particular (a).

In another embodiment, the compound is in particular X ₁ is CH, X ₂ is the residue C—Z—R 2 or C—R 3 and Z is O or S, and preferably X ₂ is the residue When it is C—Z—R2, it has the formula (I) where W is N and Y is NH. Z is preferably S.

  In yet another embodiment, Y is O, Z is O or S, and preferably Z is S.

  The term halogen refers to fluoro, chloro, bromo or iodo. Preference is given to fluoro.

The term (C ₁ -C ₁₀ ) alkyl is a branched or unbranched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, n-pentyl, sec -Means pentyl, hexyl, octyl; Especially in the residue C—Z—R 2, when Z is O or S, unsubstituted n-pentyl is a preferred alkyl group. A preferred substituted R 2 alkyl group is ethoxyethyl when Z is O or S and — (CH ₂ ) ₃ CF ₃ when Z is S.

The term (C ₁ -C ₆ ) alkoxy means an alkoxy group having 1 to 6 carbon atoms, wherein the alkyl moiety is as defined above. The term (C ₁ -C ₆ ) alkylthio has a similar meaning. The term _(C 1 -C ₄₎ alkoxy _(C 1 -C ₄₎ alkoxy, alkoxy moiety is substituted with itself also _(C 1 -C ₄₎ alkoxy _(C 1 -C ₄₎ means an alkoxy group To do.

The term (C ₂ -C ₈ ) alkenyl means a branched or unbranched alkenyl group having 2 to 8 carbon atoms, where double bonds are present in various parts of the group For example, vinyl, allyl, butenyl, n-pentenyl, sec-pentenyl, hexenyl, octenyl and the like are meant. In the residue C—Z—R2, when Z is O or S, the preferred alkenyl group is 4-pentenyl and the preferred substituted alkenyl group is 4,4-difluoro-but-3-enyl.

The term (C ₁ -C ₆ ) alkenyloxy means an alkenyloxy group having 1 to 6 carbon atoms, wherein the alkenyl moiety is as defined above. The term (C ₁ -C ₆ ) alkenylthio has a similar meaning.

The term (C ₂ -C ₈ ) alkynyl means a branched or unbranched alkynyl group having 2 to 8 carbon atoms, where triple bonds are present in various parts of the group. For example, ethynyl, propargyl, 1-butynyl, 2-butynyl and the like.

The term (C 5 _{-C 7)} cycloalkyl, a cyclic alkyl group having 5-7 carbon atoms, thus cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

  The term 5-membered unsaturated heterocycle in the definition of R2 has 5 atoms, in which at least one atom is a heteroatom selected from O, N and S and the other atoms are carbon Means a heterocycle that is an atom, wherein the heterocycle further contains at least one double bond. Examples are furanyl and pyrrolyl groups.

  With reference to a substituent, the term “independently” means that the substituents can be the same or different from each other.

  The compounds of the invention can be suitably prepared by methods available in the art and as illustrated in the experimental part of the specification. Several new and useful intermediates have been found for the preparation of the compounds of the present invention.

  Thus, another aspect of the invention is a compound of formula (II)

[Where:
The heterocycle comprises two double bonds, which can be present in several positions indicated by dashed lines (---);
The heterocycle comprises two heteroatoms;
-W ^* is N, NH or N-2- (trimethylsilyl) ethoxymethyl;
-Y ^* is CH, O, N or NR4, wherein R4 is H, 2-(trimethylsilyl) - _{ethoxymethyl,} -SO 2 N _{(CH 3)} is selected from ₂ and -SO ₂ phenyl; wherein Y ^{When *} is O, X ₁ ^* is CH and X ₂ ^* is the residue C—Z ^* —R 2 ^* or C—R 3 ^* , where Z ^* is NH, O or S; And when Y ^* is CH or NH, one of X ₁ ^* and X ₂ ^* is CH or N and the other is the residue C—Z ^* —R 2 ^* or C—R 3 ^* , where Z ^* Is NH or S;
-R2 ^* is one or more than independently optionally halogen, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C ₆₎ alkenyl Oxy, (C ₁ -C ₆ ) alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle (optionally halogen) (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl which can be substituted with phenyl, phenyloxy or phenylthio Wherein the phenyl group can be optionally substituted with a halogen;
Or -R2 ^* is the formula (IIa)

The unbranched substituted in ^Z * a- symbol groups having _(C 2 -C ₈₎ alkyl,
Here, when X ₁ ^* is CH or N, X ₁ ^* a is CH or N and X ₂ ^* a is C—Z ^* a—, or X ₁ ^* is C—Z ^* −. When R2 ^* , X ₁ ^* a is C—Z ^* a— and X ₂ ^* a is CH or N; and the symbols W ^* a, Y ^* a and Z ^* a are the symbols W ^* , Y ^* and Z ^* and and independently have the same meaning as defined not chosen previously with respect to, each of the symbols W ^{* a,} Y * ^a and Z ^{* a} in the other parts of the structure of formula (II) The symbols W ^* , Y ^* and Z ^* are the same as each other;
-R3 ^* is independently halogen, optionally, hydroxy, _{cyano, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy,} (C 1 _-C 6) Alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl can be substituted with one or more substituents selected from phenyloxy and phenylthio _(C 4 _{-C 10) alkyl,} (C 2 _{-C 10)} alkenyl and _(C 2 _{-C 10)} alkynyl Wherein the phenyl group can optionally be substituted with a halogen]
This compound is useful in the preparation of compounds of formula (I) wherein R1 has the structure (a). The preferred substitution pattern in the compound of formula (II) corresponds to the preferred substitution pattern of the compound of formula (I).

  Formula (III)

[Wherein R5 is H and R6 is Br;
Alternatively, a heterocyclic compound in which R5 is —Si (CH ₃ ) ₃ and R6 is Br or —Si (CH ₃ ) ₃ ] is also an embodiment of the present invention, in which R1 has the structure (a) Is useful in the preparation of compounds of formula (I) having

  The compounds of the present invention may contain one or more asymmetric centers and can thus exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional asymmetric centers can exist. Each such asymmetric center independently yields two optical isomers, and all of the possible optical isomers and diastereomers in the mixture and as pure or partially purified compounds are in accordance with the present invention. It is intended to be included within the scope of The present invention is meant to encompass all such isomers of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be performed as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with reagents containing asymmetric centers of known absolute configuration. . If desired, racemic mixtures of the compounds can be separated and the individual enantiomers isolated. By methods well known in the art, for example by coupling a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture followed by standard methods such as fractional crystallization or chromatography. Separation can be accomplished by separating the individual diastereomers.

The mixture may exist as a polymorph and is therefore intended to be included within the present invention. In addition, the compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of the present invention. .

Isotopically-labelled compounds of formula (I) or pharmaceutically acceptable salts thereof, including isotope-labeled compounds of formula (I) that are detectable by PET or SPECT, are also disclosed herein. Included within the scope of the invention. Labeled with [ ¹³ C]-, [ ¹⁴ C]-, [ ³ H]-, [ ¹⁸ F]-, [ ¹²⁵ I]-or other isotopically enriched atoms suitable for receptor binding or metabolic studies. The same applies to the compounds of formula (I).

  The term “pharmaceutically acceptable salt” is used within the scope of sound medical judgment and in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc. It refers to a salt that is suitable to do and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be used in situ when the compounds of the invention are finally isolated and purified, or they can be combined with pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Separately, it can be produced by reacting.

  The compounds of the present invention can be administered enterally or parenterally. The exact dosage and management of these compounds and their compositions depends on the biological activity of the compound itself, the age, weight and sex of the patient, the individual patient's need, pain or need to be administered the drug. Will depend on the degree of health and the judgment of the practitioner. In general, parenteral administration requires lower dosages than other methods of administration that are more adsorbent dependent. However, the dosage for humans is preferably 0.001-10 mg / kg body weight, more preferably 0.01-1 mg / kg body weight. Generally, enteral and parenteral dosages will be in the range of 0.1 to 1,000 mg total active ingredient per day. Agents made using the compounds of the present invention can also be used as adjuvants in therapy. In such cases, the agent is administered in combination treatment with other compounds useful in the treatment of such disease states. Also contemplated in this regard are pharmaceutical combination preparations comprising at least one compound of the invention and at least one other pharmacologically active substance.

See, for example, the standard reference, “Remington, The Science and Practice of Pharmacy” (21 ^st edition, Lippincott Williams & Wilkins, 2005, especially Part 5: Pharmaceutical Manufacture, referred to as Pharmaceutical Manufacture). The compounds can be compressed into solid dosage units, such as pills or tablets, or processed into capsules or suppositories, mixed with a suitable excipient. The compounds can also be applied in the form of solutions, suspensions or emulsions by means of pharmaceutically suitable liquids.

  For the production of dosage units, eg tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically suitable additive which does not interfere with the function of the active compounds can be used.

  Suitable carriers with which the compounds of the present invention can be administered include, for example, lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. A composition for intravenous administration can be, for example, a solution of a compound of the invention in a sterile isotonic aqueous buffer. Where necessary, the intravenous composition can include, for example, solubilizers, stabilizers and / or local anesthetics to reduce pain at the site of infusion.

The pharmaceutical composition of the present invention may be prepared for any route of administration, which comprises at least one compound of the present invention and pharmaceutically acceptable salts thereof in any pharmaceutically suitable. Together with ingredients, excipients, carriers, auxiliaries or vehicles.

  By “pharmaceutically suitable” is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

  In one aspect of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more pharmaceutical compositions of the invention. Written materials, such as instructions for use or notifications in a form prescribed by government agencies that regulate the manufacture, use or sale of pharmaceutical products, are associated with such containers. The notice reflects the approval by the institution of manufacture, use or sale for human or veterinary administration.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention is related. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described in this document. All published documents, patent applications, patents and other cited references referred to in this specification are incorporated herein by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

  The following examples are intended only to further illustrate the invention in more detail, and therefore these examples are not to be construed as limiting or limiting the scope of the invention in any way.

§1. Materials and Methods Nuclear magnetic resonance spectra ( ¹ H NMR and ¹³ C NMR, APT) are obtained in the same solvent at 300 K using a Bruker ARX 400 ( ¹ H: 400 MHz, ¹³ C: 100 MHz) unless otherwise noted. It has been determined. ¹⁹ F NMR and ¹³ C NMR experiments were performed at 11.74 T (499.9 MHz for ¹ H; 125.7 MHz for ¹³ C; 50.7 MHz, 470.4 MHz for ¹⁹ F). This was done on a Varian Inova 500 spectrometer operated with a 5 mm SW probe. Spectra were determined in deuterated chloroform or dichloromethane obtained from Cambridge Isotop Laboratories Ltd. A chemical shift (δ) is shown in ppm from tetramethylsilane (1H, 13C) or CCl 3 F ( ¹⁹ F) to the lower magnetic field. Coupling constant J is indicated in Hz. The peak shapes in the NMR spectrum are represented by the symbols “q” (quartet), “dq” (double quartet), “t” (triplet), “dt” (double triplet), “ It is indicated by “d” (doublet), “dd” (double doublet), “s” (singlet), “bs” (broad singlet) and “m” (multiplet). NH and OH signals were identified after mixing the sample with 1 drop of D ₂ O.

  Flash chromatography refers to purification using the indicated eluent and silica gel (either Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-0.063 mm).

  Column chromatography was performed using silica gel 60 (0.063-0.200 mm, Merck).

  Melting points were recorded on a Büchi B-545 melting point apparatus.

Mass spectra (MS) were recorded on a Micromass QTOF-2 instrument using MassLynx application software for data acquisition and reconstruction. Accurate mass measurements of quasimolecular ions [M + H] ⁺ were performed. Precise mass measurements were performed using a JEOL JMS-SX / SX102A Tandem Mass Spectrometer using a Fast Atom Bombardment (FAB). A resolution of 10,000 (10% valley definition) was used for high resolution FAB mass spectrometry.

  All reactions involving moisture sensitive compounds or conditions were performed under an anhydrous nitrogen atmosphere.

The reaction was monitored by use of thin-layer chromatography (TLC) with the indicated eluent on a silica-coated plastic sheet (Merck precoated silica gel 60 F254). Spots were visualized by UV light (254 nm) or _{I 2.}

  The extinction coefficient was determined using a HP 8453 UV-Vis spectrophotometer.

Analytical high performance liquid chromatography (HPLC) was performed on a C18 column (Inertsil ODS-3, particle size 3 mm; 4.6 mm 50 mm) with the following elution gradient: 2.0 ml min− ¹ . A linear gradient over 5 minutes from a 5% to 95% aqueous solution of CH ₃ CN containing 0.04% HCO ₂ H, followed by 95 minutes of CH ₃ CN containing 0.04% HCO ₂ H for 2 minutes % Aqueous solution. The product was detected at λ = 254 nm.

Liquid chromatography-mass spectrometry (LC-MS), Method A
The LC-MS system consists of two Perkin elmer series 200 micropumps. The pumps are connected to each other by a 50 μl tea mixer connected to a Gilson 215 autosampler. The method is as follows:

Step Total time Flow rate (ul / min) A (%) B (%)
0 0 2000 95 5
1 1.8 2000 0 100
2 2.5 2000 0 100
3 2.7 2000 95 5
4 3.0 2000 95 5

A = 100% water containing 0.025% HCOOH and 10 mmol NH4HCOO pH = + / − 3
B = 100% ACN containing 0.025% HCOOH

The autosampler has a 2 μl injection loop. The autosampler is connected to a Waters Atlantics C18 30 ^* 4.6 mm column containing 3 μm particles. The column is temperature controlled at 40 ° C. in a Perkin Elmer series 200 column oven. The column is connected to a Perkin Elmer series 200 UV meter with a 2.7 μl flow cell. The wavelength is set at 254 nm. The UV meter is connected to a Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters:
Scan range: 150-900a. m. u. Polarity: Positive; Scanning mode: Profile; Resolution Q1: UNIT; Step size: 0.10a. m. u. Time per scan: 0.500 seconds; NEB: 10; CUR: 10
IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10.
Connect the light scattering detector to the Sciex API 150. The light scattering detector is a Sedere Sedex 55 operating at 50 ° C. and 3 bar N ₂ .

  The entire system is controlled by G3 powermac.

Liquid chromatography-mass spectrometry (LC-MS), Method B
The LC-MS system consists of the Agilent series 1100 system consisting of the following parts:
-G1379A degasser-G1312A binary pump The pump is connected to the G1313A ALS autosampler.
The method is as follows:

Step Total time Flow rate A (%) B (%)
(Min) (ml / min)
0 0 1.0 2 98
1 10.5 1.0 98 2
2 18.0 1.0 98 2
3 18.1 1.0 2 98
4 24.0 1.0 2 98

A: acetonitrile containing 0.1% HCOOH or acetonitrile containing 10 mM NH3 B: water containing 0.1% HCOOH or water containing 10 mM NH3

  The autosampler is connected to a Zorbax Extended C18 column 150 × 4.6 mm containing 3.5 μm particles.

  The column is temperature controlled at 35 ° C. in a G1316A Colcomm column oven.

  The column is coupled to a G1315B DAD diode array detector. The wavelength region is set to 220-320 nm. The UV meter is connected to a G1946D MSD mass spectrometer operated in electron spray mode.

The mass spectrometer has the following parameters:
Scanning range: 100-800amu
Polarity: Positive and negative Style: Scan Step size: 0.20
Cycle time: 1.04 seconds% Cycle time: 50%
Dry gas: Nitrogen Gas flow: 10 liters / min Gas temperature: 300 ° C
Nebulizer pressure (Neb. Press): 30 psi
Capillary voltage (capillary Volt.): 3000V

  An Alltech ELSD 2000 detector is connected in parallel with the MSD. Divide the flow after DAD.

The ELSD has the following parameters:
Drying gas: Nitrogen Gas flow: 1.5 liters / min Drift tube temperature: 39 ° C
Impactor: On

§2. Abbreviations n-BuLi n-butyllithium t-BuOH t-butanol dba dibenzylideneacetone DCM dichloromethane DMF N, N'-dimethylformamide DMF-DMA N, N'-dimethylformamide dimethylacetal DMSO dimethyl sulfoxide EtOH ethanol Et2O diethyl ether g gram h Time Me Methyl MeI Methyl iodide MeOH Methanol mg Milligram min Minute ml Milliliter m. p. Melting point c. q. Melting range NBS N-bromosuccinimide NIS N-iodosuccinimide PE Petroleum ether (40-65oC)
Rt retention time (LC / MS)
SEM-Cl (2-chloromethoxy-ethyl) -trimethylsilane TBAF tetrabutylammonium fluoride THF tetrahydrofuran

§3. General Aspects of Synthesis Various synthetic routes for the preparation of the compounds of the invention shown in Formula I have been described and are readily prepared from readily available starting materials. More general information about pyrazole, imidazole and isoxazole, for example: A. Joule, K.M. Mills and G.M. F. Smith, “Heterocyclic Chemistry”, third edition, Stanley Hornes (Publishers) Ltd. , Cheltenham, 1998. Further information on the addition and subsequent removal of protecting groups in organic synthesis is: W. Greene and P.M. G. M.M. Wuts, “Protective Groups in Organic Synthesis”, third edition, John Wiley & Sons, Inc. , New York, 1999.

The choice of a particular method depends on the compatibility of the functional groups with the reagents used, the possibility of using protecting groups, catalysts, activating reagents and coupling reagents and the ultimate present in the final compound being produced. Depends on factors such as structural features.

  In one example of a general method (Scheme 1), nicotinoyl chloride hydrochloride (1) is converted to N-methyl-N-methoxyamide (2) in the presence of a base and reacted with hexyl-lithium. (J. Med. Chem., 35, 1992, 2392-2406) to give 1-pyridin-3-yl-heptan-1-one (3).

Mild α-methyleneation of compound 3 (J. Org. Chem., 71, 2006, 2538-2541) gives 2-methylene-1-pyridin-3-yl-heptan-1-one (4). It is reacted with hydrazine (Synthesis, 1989, 320-321) to give 1- (4-pentyl-3-pyridin-3-yl-4,5-dihydropyrazol-1-yl) -ethanone (5) Gave. Oxidation of 2-pyrazoline to pyrazole can be performed using methods well known to those skilled in the art. Specific conditions are: activated MnO ₂ (EP 0094555) in dichloroethane, giving compound 6, which is deprotected under basic conditions to give compound 7. 3- (4-Pentyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine derivative (9) is derived from compound 8 using CH ₃ I with a pyridine moiety. Was obtained by quaternizing and reducing the corresponding pyridinium salt with NaBH ₄ (Arch. Pharm. Pharm. Med. Chem., 336, 2003, 143-154).

In another example of a general method (Scheme 2), the readily available pyridin-3-yl-acetic acid (10) is converted to the N-methyl-N-methoxyamide derivative (12) which is converted to BuLi and Reaction gives 1-pyridin-3-yl-hexan-2-one (13). Treatment of 13 with N, N-dimethylformamide dimethyl acetal gives enamine (14), which is converted to pyrazole (15). The synthesis of 3- (4-butyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (16) was performed using the two step sequence shown in Scheme 1. ) In Scheme 2.

  In yet another example of a general method (Scheme 3), 3- (4-Bromo-1H-pyrazol-3-yl) -pyridine (20A) or its iodo analog (20B) (Bioorganic & Medicinal Chemistry, 4 , 1996, 227-237) are used as precursors for the synthesis of compounds of general formula I. 20A di-lithio derivative (Bioorganic) prepared on multigram scale by pyrazole-NH deprotonation and bromine-lithium exchange (2,1 eq. N-BuLi, THF, -78 ° C., 2 h). & Medicinal Chemistry, 8, 2000, 2317-2335) with disulfide (eg methyldisulfanylmethane) to give 3- (4-methylsulfanyl-1H-pyrazol-3-yl) -pyridine 21A It is converted to the 1,2,5,6-tetrahydro-1-methylpyridine derivative 22A according to the two-step permutation shown in Scheme 1.

  The formation of anions at the aromatic ortho position used in the synthetic method described in this method is performed according to a general synthetic strategy known as Directed Ortho Metalation (DOM). Within this region, several functional groups known as Directed Metallization Groups (DMG's) were investigated for this purpose.

The dimethylsulfonamido group as a directional metallization group (DMG) at the N ₁ -position of 3-pyridin-3-yl-pyrazole-1-sulfonic acid dimethylamide (23) is Its functionalization is possible (Chem, Ber., 124, 1991, 1639-1650). Produced on multigram scale by α-metalation (1,0 equivalents, t-BuLi, THF, -78 ° C, 1 hour) 23-lithio derivatives, disulfides (eg 1-butyldisulfanylbutane) (J. Org. Chem., 64, 1999, 5366-5370) to give 5-butylsulfanyl-3-pyridin-3-yl-pyrazole-1-sulfonic acid dimethylamide 24, which Protected (25) and converted to the 1,2,5,6-tetrahydro-1-methylpyridine derivative 26 according to the two-step sequence shown in Scheme 1.

Another synthetic route for the preparation of the compounds of the invention shown in Formula I is described in Scheme 4. Introduction of a 2- (trimethylsilyl) -ethoxymethyl group (SEM) as a protecting group (Tetrahedron Letters, 39, 1998, 5171-5174) gave a mixture of compounds 27A and 27B. Subsequent bromine-lithium exchange ((1,1 eq. N-BuLi, THF, -78 ° C., 1 h) and reaction of this 27A / B 4-lithio derivative with S ₈ was carried out by the intermediate 3-pyridine-3 Produces the lithium aryl thiolate (J. Org. Chem., 69, 2004, 3236-3239) of -yl-1- (2-trimethyltyranyl-ethoxymethyl) -1H-pyrazole-4-thiol. This intermediate was captured using 4-bromo-1,1,1-trifluorobutane to give a mixture of 28A and 28B, followed by removal of the SEM protecting group to produce the desired 3- [4- (4 , 4,4-trifluoro-butylsulfanyl) -1H-pyrazol-3-yl] -pyridine 21B, which is 1,2,5,6-tetrahydro-1 according to the two-step sequence shown in Scheme 1. -Conversion to methylpyridine derivative 22B.

In another aspect, 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (20B, Scheme 5) is used as the starting material for the compounds of the invention shown in Formula I. The 4-lithio derivative of the SEM protected derivative 29A / B prepared according to the corresponding compound 27A / B (Scheme 4) is reacted with trimethylborate followed by in situ hydrogen peroxide oxidation (J. Heterocyclic Chem., 31, 1994). , 1377-1380) and the corresponding 3-pyridin-3-yl-1- (2-trimethylsilanyl-1-ethoxymethyl) -1H-pyrazol-4-ol (30, showing one isomer) Gave. Using methods well known in the art, for example by reacting compound 30 with K ₂ CO _{3 in} DMF in the presence of various (aryl) alkyl halides such as (3-bromo-propyl) -benzene. , 4-hydroxy derivative 30 can be alkylated to produce compound 31A (showing one isomer). Subsequent removal of the SEM group yields 3- [4- (3-phenyl-propoxy) -1H-pyrazol-3-yl] -pyridine (32A), which is 1,2, according to the two-step permutation shown in Scheme 1. Conversion was made to 5,6-tetrahydro-1-methylpyridine derivative 33A.

  Scheme 6 shows a two alternative method for the preparation of 3- (4-alkoxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine compounds.

A readily obtainable mixture of SEM protected pyrazoles 29A / B is converted into the effective two-step permutation described in Scheme 1 (quaternization of the pyridine moiety with CH ₃ I and reduction of the corresponding pyridinium salt with NaBH ₄ ) To a 34A / B mixture.

  Methods for the formation of C—O bonds have been reported (eg J. Am. Chem. Soc., 123, 2001, 10770). More precisely, the cross-coupling method catalyzed by CuI / 1,10-phenanthroline (Organic Letters, 4, 2002, 973-976) is used and the 4-iodo-pyrazole analogue (34A / B) is used. It should be possible to perform an effective conversion of the primary alcohol. Subsequent deprotection of compound 35A (representing one isomer) is 3- (4-hexyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (33B). Gave.

  In another synthetic permutation (Scheme 6), C—O bond formation can be performed using the cross-coupling method catalyzed by CuI / 1,10-phenanthroline to produce compound 31G. The synthesis of compound 33G according to the method shown in Scheme 5 is shown in Scheme 6.

  One aspect of the present invention is bis3- (4-alkylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro, which can bind to and activate muscarinic receptors. -1-methylpyridine derivatives (eg Compound 22C, Scheme 7) (J. Med. Chem., 44, 2001, 4563-4576). Introduction of phenylsulfonyl as a protecting group (starting from 20A) was done regioselectively to produce 3- (1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl) -pyridine ( 20A to 36A).

The cross-coupling of aliphatic and aromatic thiols with aryl bromides can be mediated by a Pd ₂ (dba) ₃ / Xantphos catalyst system in refluxing xylene to give the corresponding aryl thioether (Organic Letters, 6, 2004, 4587-4590, Tetrahedron, 61, 2005, 5253-5259).

Using this method, 36A was converted to the protected bis-alkylsulfanyl-pyrazole derivative 37. Removal of the N ₁ -phenylsulfonyl group can be carried out using methods well known to those skilled in the art, for example by reacting compound 37 with potassium hydroxide, optionally in the presence of hydrazine in diethylene glycol. . Quaternization of the (bis) -pyridine moiety with CH ₃ I and reduction of the corresponding (bis) -pyridinium salt with NaBH ₄ gave the pyrazole derivative 22C. Scheme 7 shows another method for the preparation of 3- (4-alkylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine derivatives, and thus Scheme 3 And 4 (respectively 22A and 22B), respectively, the main feature being the availability of the parent thiol.

  Another example of the preparation of compounds of the invention of formula I is shown in Scheme 8.

Direct nitration of the pyrazole derivative 19 (Chem. Ber., 88, 1955, 1577) gives 3- (4-nitro-1H-pyrazol-3-yl) -pyridine (38), which corresponds to the corresponding 3 Reduction to -pyridin-3-yl-1H-pyrazol-4-ylamine (39) and reaction with acid chlorides such as butyryl chloride yielded the amide (40). The subsequent conversion to the 1,2,5,6-tetrahydro-1-methylpyridine derivative 41 was performed according to the two-step sequence shown in Scheme 1. Subsequent LiAlH ₄ reduction of the amide produces butyl- [3- (1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1H-pyrazol-4-yl] -amine (42). Let me.

Scheme 9 shows the preparation of 3- (4-alkynyl (and alkenyl) -1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine derivatives as compounds of formula I. 3- (1-Phenylsulfonyl-4-bromo-1H-pyrazol-3-yl) -pyridine (36A, Scheme 7) or its iodo analog 36B (Scheme 9) is suitable for Sonogashira coupling with terminal acetylene. It is an excellent substrate (Tetrahedron Letters, 38, 1997, 7835-7838, Eur J. Org. Chem., 2006, 3283-3307). Catalytic reaction with PdCl ₂ (PPh ₃ ) ₂ in the presence of CuI and (for example) hex-1-yne (excess Et ₃ N, DMF, 80 ° C., 2 hours) produces compound 43A. Subsequent deprotection (according to Scheme 7), and the two-step permutation shown in Scheme 1, is 3- (4-hex-1-ynyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro. -1-Methylpyridine (45A) was provided.

The scope and reactivity of compound 36A (or 36B) is further illustrated by a Suzuki-Miyaura coupling reaction with (for example) an alkenylboronic acid. Catalytic reaction using Pd (OAc) ₂ and effective S-Phos in the presence of K ₃ PO ₄ and (for example) (E) -hexen-1-ylboronic acid (J. Am. Chem. Soc., 127, 2005) Year, 4685-4696) gave alkenyl 46A. Subsequent deprotection and the two-step permutation shown in Scheme 1 is 3- (4-hex-1-enyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine. (47A) was given.

  In another aspect, 3- (4-iodo-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (48, Bioorganic &) as starting material for compounds of the invention of formula I Medicinal Chemistry 8, 2000, 449-454).

  Referring to Scheme 3, 48 di-lithio derivatives (Bioorganic & Medicinal Chemistry, 8, 2000, 2317-2335) (2,1 eq. N-BuLi, THF, -78 ° C., 2 hours) were converted to disulfides ( For example, 1-butyldisulfanyl-butane) was captured to give the corresponding 3- (4-butylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane 49A.

Scheme 10 shows a method for the preparation of alternative-but still general-3- (4-alkylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane derivatives. Thus, compound 48 was converted by a Pd ₂ (dba) ₃ / Xantphos catalyst system (similar to Scheme 7 but at 120 ° C. in DMF) to provide the corresponding aryl thioether in one step without protection. 49B should be able to be given.

A readily obtainable mixture of SEM protected pyrazoles 50 (one of the isomers) is as described in Scheme 6 but with different conditions and catalysed by CuI / 1,10-phenanthroline. It was converted to a 51A mixture by the cross-coupling method. Subsequent deprotection of 51A is the corresponding 3- (4-butoxy-1H-pyrazol-3-yl)-
1-azabicyclo [2.2.2] octane 52A is provided.

  A further example of the preparation of the compounds of the invention of formula I is shown in Scheme 11.

Easily obtainable 1-aza-bicyclo [3.2.1] octane-6-one (53) (J. Med. Chem., 36, 1993, 683-689) is an effective two-step permutation. Similar to (Bioorganic & Medicinal Chemistry 8, 2000, 449-454), converted to 6- (1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] -6-ol (55) did. Attempts were made to improve the yield of dehydration of the alcohol (55) by acylation (56) (Heterocycles, 24, 1986, 971-977) and subsequent elimination in heat (185 ° C.). Reduction of enamine (57) gave the expected endo 1-azabicyclo [3.2.1] derivative (58). Introduction of pentane-1-thiol via iodination (Bioorganic & Medicinal Chemistry, 4, 1996, 227-237) and Pd ₂ (dba) ₃ / Xantphos catalyst system (according to Scheme 7) (4-Pentylsulfanyl-1-H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane (60A) was obtained.

  Scheme 12 shows yet another example of the preparation of compounds of the invention of formula I.

Commercially available 3-pyridinealdoxime (61) is converted to its chlorohydroxyimino derivative (US 2004/0157900), which is converted “in situ” to nicotinonitrile oxide ( Tetrahedron, 61, 2005, 4363-4371) and reacted with 1,2-bis-trimethylsilanyl-ethyne (Chem. Ber., 107, 1974, 3717-3722), 1,3-dipolar addition ring The product 3- (4,5-bis-trimethylsilanyl-isoxazol-3-yl) -pyridine (62) is obtained. Halogen-induced ipso desilylation yielded the 4-bromo-5-trimethylsilanyl derivative (63). Subsequent desilylation with NH ₄ OH (Chem. Ber., 112, 1979, 2829-2836) yields 3- (4-bromo-isoxazol-3-yl) -pyridine (64).

  The isoxazole-pyridine derivatives 62, 63 and 64 are novel compounds and are therefore embodiments of the present invention.

The introduction of (for example) butane-1-thiol into compound 64 (according to Schemes 7, 10 and 11) via the Pd ₂ (dba) ₃ / Xantphos catalyst system is 3- (4-butylsulfanyl-isoxazole- 3-yl) -pyridine (65A) was provided. The quaternization of the pyridine moiety with preferentially sulfuric acid dimethyl ester and the reduction of the corresponding pyridinium salt with NaBH ₄ gives the corresponding 3- (4-butylsulfanyl-isoxazol-3-yl) -1 , 2,5,6-tetrahydro-1-methylpyridine (66A).

  Scheme 13 shows the preparation of 3- (4-alkynyl (and alkenyl) -isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine derivatives as compounds of formula I.

  3- (4-Bromo-isoxazol-3-yl) -pyridine (64) is an excellent substrate for Sonogashira coupling with (terminal) acetylene using a method analogous to that described in Scheme 9.

  Subsequent conversion of these alkynyl derivatives (Scheme 13, eg 69A) using the quaternization and reduction conditions described in Scheme 12 yields the corresponding 3- (4-alkynyl-isoxazol-3-yl) -1, 2,5,6-tetrahydro-1-methylpyridine derivative (eg 70A) was given.

  The scope and reactivity of compound 64 is further illustrated by the Suzuki-Miyaura coupling reaction with (for example) alkenylboronic acid using the method described in Scheme 9. Subsequent conversion of these alkenyl derivatives (Scheme 13, eg 67A) using the quaternization and reduction conditions described in Scheme 12 provides the corresponding 3- (4-alkenyl-isoxazol-3-yl) -1, A 2,5,6-tetrahydro-1-methylpyridine derivative (eg 68A) was provided.

  The preparation of the compounds of the invention of formula I is further illustrated in Scheme 14.

3-Trimethylstannanyl-pyridine (71) (Eur. J. Org.) Obtained from 3-bromo-pyridine using the Knochel method (Angew. Chem., Int. Ed., 39, 2000, 4414-4435). Chem., 2002, 2126) under the Stille conditions (toluene, 120 ° C., PdCl ₂ (PPh ₃ ) ₂ ), 4,5-dibromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole. (72) (Tetrahedron Letters, 39, 1998, 5171-5174), 3- [5-bromo-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl]- Pyridine (73) is obtained. Introduction of (for example) pentane-1-thiol (according to Scheme 12) with a Pd ₂ (dba) ₃ / Xantphos catalyst system (according to Scheme 12) gave the corresponding 5-pentylsulfanyl-isoxazole derivative (74A). Quaternization of the pyridine moiety (CH ₃ I) and reduction of the corresponding pyridinium salt with NaBH ₄ (75A) and subsequent removal of the SEM group is 3- [5-pentylsulfanyl-3H-imidazol-4-yl] -1,2,5,6-tetrahydro-1-methylpyridine (76A) is produced.

  Instead of converting 74A to 76A, the deprotection of 74B (Scheme 14, compound 77) and subsequent quaternization and reduction is accomplished by the desired 3- [5-hexylsulfanyl-3H-imidazol-4-yl]- 1,2,5,6-tetrahydro-1-methylpyridine (76B) is produced.

§4. Synthesis of specific compounds
N-methoxy-N-methyl-nicotinamide (compound 2, scheme 1)
Nicotinoyl chloride hydrochloride (Compound 1) (10 g, 56 mmol) and 6.28 g N, O-dimethyl-hydroxylamine. HCl (72.8 mmol) was combined in 200 ml dichloromethane. To this mixture was added 18.14 ml of pyridine (within 15 minutes at 0 ° C.). The reaction mixture was subsequently stirred at room temperature for 4 hours. The reaction was concentrated in vacuo. The resulting residue was taken up in dichloromethane and H ₂ O (0 ° C.), washed with 2N NaOH solution followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (MeOH / triethylamine 97/3) gave compound 2 as an oil (6.92 g, 74%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ 8.96 (d, J = 2 Hz, 1 H), 8.69 (d, J = 5 Hz, 2 Hz, 1 H), 8.04 (dt, J = 8 Hz, 2 Hz) , 1H), 7.41-7.32 (m, 1H), 3.56 (s, 3H), 3.40 (s, 3H). (TLC MeOH / triethylamine R _f 0.19).

1-pyridin-3-yl-heptan-1-one (compound 3, scheme 1)
To a solution of compound 2 (1.0 g, 6.02 mmol) in anhydrous THF (15 ml) was added 3.08 ml (7.66 mmol) hexyl-lithium (2.5 M in hexanes) under N _2. At -78 ° C. After the dropwise addition, the resulting solution was stirred at −78 ° C. for 30 minutes. The mixture was allowed to warm to ambient temperature and was poured into NH ₄ Cl solution (10 g in 50 ml H ₂ O, 0 ° C.). Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether / PE 1: 1) to give compound 3 as an oil (0.91 g, 78%).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.78 (d, J = 5 Hz, 2 Hz, 1H), 8.24 (dt, J = 8 Hz, 2 Hz, 1H), 7.47-7.37 (m, 1H), 2.99 (t, J = 7 Hz, 2H), 1.84-1.65 (m, 2H), 1.47-1. 25 (m, 6H), 0.90 (bt, J = 7 Hz, 3H).

2-Methylene-1-pyridin-3-yl-heptan-1-one (compound 4, scheme 1)
To 1 g (5.2 mmol) of compound 3 dissolved in 10 ml of MeOH was added 0.1 ml piperidine, 0.1 ml acetic acid and 3 ml aqueous formaldehyde solution (37% formaldehyde in water). The mixture was heated to reflux for 48 hours. The mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give compound 4 as an oil (1.05 g, 95%).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 8.94 (d, J = 2 Hz, 1H), 8.76 (d, J = 5 Hz, 2 Hz, 1H), 8.05 (dt, J = 8 Hz, 2 Hz, 1H), 7.46-7.35 (m, 1H), 5.94 (s, 1H), 5.64 (s, 1H), 2.48 (bt, J = 7 Hz, 2H), 1 .60-1.25 (m, 6H), 0.99-0.82 (m, 3H).

1- (4-Pentyl-3-pyridin-3-yl-4,5-dihydropyrazol-1-yl) -ethanone (Compound 5, Scheme 1)
Compound 4 (3.37 g, 16.6 mmol) and 5.89 ml of hydrazine hydrate were dissolved in 50 ml of acetic acid and heated to reflux for 1.5 hours. The mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ether / ethyl acetate 1/1) to give compound 4 (amorphous, 2.92 g, 68%).
H-NMR (600 MHz, D ₆ DMSO): δ 8.92 (d, J = 2 Hz, 1H), 8.67-8.64 (m, 1H), 8.07 (bd, J = 8 Hz, 1H) , 7.39-7.36 (m, 1H), 4.04 (t, J = 10 Hz, 1H), 3.96 (dd, J = 10 Hz, J = 5 Hz, 1H), 3, 67-3. 61 (m, 1H), 2.40 (s, 3H), 1.76-1.69 (m, 1H), 1.50-1.42 (m, 1H), 1.39-1.22 ( m, 6H), 0.87 (bt, J = 7 Hz, 3H).

3- (4-Pentyl-1H-pyrazol-3-yl) -pyridine (Compound 7, Scheme 1)
Compound 5 (0.9 g, 3.47 mmol) and 3.01 g MnO ₂ (10 eq) were combined in dichloroethane (100 ml) and warmed to reflux for 2 hours (Dean Stark conditions). Additional MnO ₂ (6.02 g) was added and the mixture was refluxed for an additional 12 hours. The mixture was cooled and filtered and the filtrate was washed thoroughly with dichloroethane / isopropyl alcohol (1/1). The mixture was concentrated in vacuo to give some starting material (5) (TLC ethyl acetate R _f 0.27) and already deacylated product (7) (TLC ethyl acetate R _f 0.12). The contaminated oxidation product (6) (TLC ethyl acetate R _f 0.20) was obtained. This mixture (0.64 g) was used in the next step without further purification.
The material was dissolved in 5 ml EtOH and 5 ml 2N NaOH and the reaction mixture was refluxed for 4 hours. The mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give the title compound (7) as an oil (344 mg, 1.6 mmol, 46% (total)).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 8.88 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 7.92 (dt, J = 8 Hz, 2 Hz, 1H), 7.47 (bs, 1H), 7.38-7.33 (m, 1H), 2.62 (t, J = 7 Hz, 2H), 1.64-1.55 (m, 2H), 1.36-1.28 (m, 6H), 0.85 (bt, J = 7 Hz, 3H).

3- (4-Pentyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 9, Scheme 1)
Iodomethane (0.08 ml, 1.28 mmol) was added to a solution of 7 (130 mg, 0.6 mmol) in acetone (10 ml). After heating for 12 hours, the reaction mixture was cooled and the precipitated crystals were filtered, washed with diethyl ether and dried to give compound 8. To a cooled (−30 ° C.) suspension of this pyridinium iodide derivative (8) in MeOH (15 ml) was added sodium borohydride (90 mg, 2.4 mmol) in small portions. The mixture was allowed to warm to ambient temperature and was poured into saturated NH ₄ Cl solution (0 ° C.). The solvent was (partially) removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH / triethylamine 97/3) to give the title compound 9 (amorphous, 63 mg, 45% (total)).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 7.35 (bs, 1H), 6.07-6.00 (bs, 1H), 3.33-3.25 (m, 2H), 2.64 -2.35 (m, 6H), 2.45 (s, 3H), 1.68-1.50 (m, 2H), 1.41-1.28 (m, 4H), 0.90 (bt , J = 7 Hz, 3H).

N-methoxy-N-methyl-2-pyridin-3-yl-acetamide (compound 12, scheme 2)
To a solution of anhydrous dichloromethane (200 ml) containing compound 10 (15.35 g, 88.4 mmol) was added 14.93 ml (163.3 mmol) oxalyl chloride and a few drops of DMF. The mixture was gently refluxed under N ₂ for 8 hours. The mixture was cooled, concentrated, re-dissolved in dichloromethane and concentrated. The residue was dissolved in 200 ml of anhydrous dichloromethane and 11.09 g (113.7 mmol) of N, O-dimethyl-hydroxylamine. HCl was added. To this mixture (0 ° C.), 2.73 ml of pyridine was added (within 15 minutes). The reaction mixture was subsequently stirred at room temperature for 4 hours. The reaction was concentrated in vacuo. The resulting residue was taken up in dichloromethane and H ₂ O (0 ° C.), washed with 2N NaOH solution followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (ethyl acetate) gave compound 12 as an oil (5.2 g, 33%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.53-8.49 (m, 2H), 7.66 (bd, J = 8 Hz, 1H), 7.29-7.24 (m, 1H) , 3.78 (s, 2H), 3.68 (s, 3H), 3.20 (s, 3H).

1-Pyridin-3-yl-hexan-2-one (Compound 13, Scheme 2)
To a solution of anhydrous THF (15 ml) containing compound 12 (1.0 g, 5.5 mmol) 2.6 ml (6.5 mmol) n-BuLi (2.5 M in hexane) was added under N _2. At -50 ° C. After the dropwise addition, the resulting solution was stirred at −50 ° C. for 30 minutes. The mixture was allowed to warm to ambient temperature and was poured into NH ₄ Cl solution (10 g in 50 ml H ₂ O, 0 ° C.). Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give compound 13 as an oil (0.21 g, 25%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.50 (dd, J = 5 Hz, 2 Hz, 1H), 8.45 (d, J = 2 Hz, 1H), 7.54 (dt, J = 8 Hz, J = 2 Hz, 1H), 7.29-7.24 (m, 1H), 3.70 (s, 2H), 2.50 (t, J = 7 Hz, 2H), 1.62-1.53 ( m, 2H), 1.34-1.24 (m, 2H), 0.9 (bt, J = 7 Hz, 3H).

1-dimethylamino-2-pyridin-3-yl-hept-1-en-3-one (compound 14, scheme 2)
Dry t-BuOH in 13 (2.0 g, 11 mmol) and DMFDMA (2.5 ml, 14.6 mmol) was refluxed for 18 hours under _{N 2.} The solution was allowed to reach room temperature and was subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give compound 14 as an oil (1.85 g, 62%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.51 (dd, J = 5 Hz, 2 Hz, 1H), 8.45 (d, J = 2 Hz, 1H), 7.66 (s, 1H), 7 .53 (dt, J = 8 Hz, J = 2 Hz, 1H), 7.28-7.24 (m, 1H), 2.72 (bs, 6H), 2.20 (t, J = 7 Hz, 2H) 1.54-1.46 (m, 2H), 1.26-1.16 (m, 2H), 0.9 (bt, J = 7 Hz, 3H).

3- (4-Butyl-1H-pyrazol-3-yl) -pyridine (Compound 15, Scheme 2)
Compound 14 (0.95 g, 4 mmol) and 0.46 ml of hydrazine hydrate (9.4 mmol) were dissolved in absolute ethanol (25 ml) and heated to reflux for 2 hours. The mixture was cooled and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give compound 15. (Amorphous, 0.7 g, 85%).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 8.65 (d, J = 2 Hz, 1H), 8.52 (dd, J = 5 Hz, 2 Hz, 1H), 7.72-7.67 (m, 2H), 7.35-7.31 (m, 1H), 2.82 (t, J = 7 Hz, 2H), 1.70-1.62 (m, 2H), 1.42-1.33 ( m, 2H), 0.9 (bt, J = 7 Hz, 3H).

3- (4-Butyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 16, Scheme 2)
Iodomethane (0.9 ml, 14 mmol) was added to a solution of 15 (600 mg, 3 mmol) in acetone (50 ml). After heating for 12 hours, the reaction mixture was cooled and the precipitated crystals were filtered, washed with diethyl ether and dried to give the corresponding pyridinium iodide derivative. To a cooled (−30 ° C.) suspension of this pyridinium iodide derivative in MeOH (100 ml) was added sodium borohydride (0.5 g, 18.9 mmol) in small portions. The mixture was allowed to warm to ambient temperature and was poured into saturated NH ₄ Cl solution (0 ° C.). The solvent was (partially) removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH / triethylamine 97/3) to give the title compound 16 (amorphous, 500 mg, 70% (overall)). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.40 (bs, 1H), 5.78-5.74 (bs, 1H), 3.15-3.05 (m, 2H), 2.71 (Bt, J = 7 Hz, 2H), 2.56 (t, J = 6 Hz, 2H), 2.43 (s, 3H), 2.38-2
. 32 (m, 2H), 1.68-1.60 (m, 2H), 1.43-1.36 (m, 2H), 0.96 (t, J = 7 Hz, 3H).

3- (4-Methylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21A, Scheme 3)
In a solution of anhydrous THF (150 ml) containing compound 20A (3.0 g, 13.4 mmol, prepared according to Bioorganic & Medicinal Chemistry, 4, 1996, 227-237), 2.1 equivalents of n-BuLi. (11.2 ml, 2.5 M in hexane) was added dropwise at −78 ° C. under N ₂ . After the dropwise addition, the resulting solution was stirred at −78 ° C. for 2 hours. At this temperature 1.1 equivalents of methyldisulfanylmethane (1.33 ml) were added and the resulting solution was stirred at −78 ° C. for 1 hour, and then allowed to warm to ambient temperature overnight. The mixture was then quenched with saturated NH ₄ Cl solution at 0 ° C. and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (ethyl acetate) gave compound 21A (oil, 1.71 g, 67%).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.28 (dt, J = 8 Hz, 2Hz, 1H), 7.70 (s, 1H), 7.42-7.33 (m, 1H), 2.38 (s, 3H)

3- (4-Methylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22A, Scheme 3)
2.5 equivalents of iodomethane (1.39 ml, 22.37 mmol) was added to a solution of 21A (1.71 g, 8.95 mmol) in acetone (100 ml) and the mixture was stirred for 18 hours. The precipitated crystals were filtered, washed with diethyl ether and dried to give the corresponding pyridinium iodide derivative. To a cooled (−30 ° C.) suspension of this pyridinium iodide derivative in MeOH (100 ml) was added sodium borohydride (1.35 g, 35.5 mmol) in small portions. The mixture was allowed to warm to ambient temperature and was poured into saturated NH ₄ Cl solution (0 ° C.). The solvent was (partially) removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH) to give the title compound 22A. (Solid, 1.39 g, 74% (as a whole)). Melting point 131.5 ° C. LCMS (Method A); R _t : 0.96 min, ([M + H] ⁺ = 210).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.52 (s, 1H), 6.56-6.46 (bs, 1H), 3.40-3.36 (m, 2H), 2.62 (Bt, J = 6 Hz, 2H), 2.46 (s, 3H), 2.45-2.38 (m, 2H), 2.30 (s, 3H).

3- [4- (4,4,4-trifluoro-butylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22B, Scheme 4)
60% dispersion of NaH in mineral oil (0.54 g, 13.64 mmol) to a solution of anhydrous THF containing Compound 20A (2.79,12.4 mmol) (100 ml), was added under _{N 2} It was. The resulting mixture was stirred at room temperature for 2 hours followed by treatment with 13.64 mmol (2.41 ml) (2-chloromethoxy-ethyl) -trimethylsilane (SEM-Cl). The resulting mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the mixture and the organic layer was washed three times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give a mixture of 27A (main component) and 27B as an oil (3.19 g, 73%). Purification by carefully controlled flash chromatography (diethyl ether / PE 1/1) gave 27B followed by 27A.
Compound 27B (oil). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.15 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.20 (dt, J = 8 Hz, 2 Hz, 1 H), 7.71 (s, 1 H), 7.38-7.34 (m, 1 H), 5.44 (s, 2 H), 3.64 (t, J = 8 Hz, 2 H), 0 .94 (bt, J = 8 Hz, 2H), 0.02 (s, 9H). Compound 27A (oil). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.90 (d, J = 2 Hz, 1H), 8.75 (dd, J = 5 Hz, 2 Hz, 1H), 7.96 (dt, J = 8 Hz, 2 Hz, 1 H), 7.63 (s, 1 H), 7.47-7.42 (m, 1 H), 5.34 (s, 2 H), 3.70 (t, J = 8 Hz, 2 H), 0 .92 (bt, J = 8 Hz, 2H), 0.02 (s, 9H).
Both compounds were confirmed using NOESYPHSW and HMBGCGP analysis.
To a solution of anhydrous THF (50 ml) containing a 27A / B mixture (0.92 g, 2.6 mmol), 1.14 ml (1.1 eq) n-BuLi (2.5 M in hexane) was added dropwise. the _{(N 2} -78 ℃ below). After the addition, the resulting solution was stirred at −78 ° C. for 60 minutes. At this temperature, sulfur powder (2.6 mmol, 0.083 g) was added and the reaction mixture was stirred for an additional 2 hours (−78 ° C.). The reaction was monitored by thin-layer chromatography. After the addition of 4-bromo-1,1,1-trifluoro-butane (1.1 eq, 0.54 ml), the mixture was allowed to warm to ambient temperature (overnight) and saturated NH ₄ Cl solution (0 ° C. ) The solvent was (partially) removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give (mainly) a mixture of 28A and 28B. (Oil, 0.49 g, 45%).
¹ H-NMR (describes data of 28A, 400 MHz, CDCl ₃ ): δ 8.80 (d, J = 2 Hz, 1H), 8.70 (dd, J = 5 Hz, 2 Hz, 1H), 7.96 (Dt, J = 8 Hz, 2 Hz, 1H), 7.68 (s, 1H), 7.48-7.43 (m, 1H), 5.35 (s, 2H), 3.72 (bt, J = 8 Hz, 2H), 2.58 (t, J = 7 Hz, 2H), 2.10-1.97 (m, 2H), 1.71-1.59 (m, 2H), 0.93 (bt , J = 8 Hz, 2H), 0.00 (s, 9H).
To a solution of anhydrous THF (20 ml) containing a 28 A / B mixture (0.49 g, 1.18 mmol), 3.54 ml (3.0 eq) TBAF (1.0 M in THF) under N ₂ was added. Added in. After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography (diethyl ether) to give 3- [4- (4,4,4-trifluoro-butylsulfanyl) -1H-pyrazol-3-yl] -pyridine (21B). It was. (Oil, 0.32 g, 95%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 8.28 (dt, J = 8 Hz, 2 Hz, 1 H), 7.73 (s, 1 H), 7.42-7.37 (m, 1 H), 2.61 (t, J = 7 Hz, 2 H), 2.19-2.08 (m, 2H), 1.75-1.65 (m, 2H).
Using the method described for the conversion of 21A to 22A, compound 21B (0.3 g, 1.49 mmol) was converted to compound 22B. Yield 0.131 g (amorphous, 72% overall). LCMS (Method A); R _t : 1.64 min, ([M + H] ⁺ = 306).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 6.67-6.60 (bs, 1H), 3.43-3.39 (m, 2H), 2.71 -2.62 (m, 4H), 2.49 (s, 3H), 2.48-2.43 (m, 2H), 2.28-2.19 (m, 2H), 1.81-1 .75 (m, 2H).

Bis- [3- (1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1
H-pyrazol-4-yl) -2-sulfanylethyl] -methane (compound 22C, scheme 7)
60% dispersion of NaH in mineral oil (0.73 g, 18.3 mmol) to a solution of anhydrous THF containing Compound 20A (3.71,16.6 mmol) (100 ml), was added under _{N 2} It was. The resulting mixture was stirred at room temperature for 2 hours followed by treatment with 18.3 mmol (2.33 ml) of phenylsulfonyl chloride. The resulting mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the mixture and the organic layer was washed three times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to give 3- (1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl) -pyridine (36A). (TLC ethyl acetate _Rf 0.7) (amorphous, 5.34 g, 89%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.1 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 8.24 (s, 1H), 8 .16 (dt, J = 8 Hz, 2 Hz, 1H), 8.10-8.05 (m, 2H), 7.70 (bt, J = 7 Hz, 2H), 7.62-7.56 (m, 2H), 7.39-7.34 (m, 1H).
To a degassed solution of xylene (20 ml) containing 36 (0.7 g, 1.92 mmol) 0.45 equivalents (0.12 ml, 0.86 mmol) of pentane-1,5-di-thiol And 0.5 equivalents of K ₂ CO ₃ (0.137 g, 0.96 mmol) were added. The resulting mixture was stirred for further 2 hours under N _2. 0.192 mmol of Pd ₂ (dba) ₃ (176 mg) and 0.384 mmol of xantphos (222 mg) were added in succession. After the addition, the resulting solution was refluxed under N ₂ for 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (ethyl acetate) to give compound 37 as an oil (0.46 g, 68%). (TLC ethyl acetate _Rf 0.29).
Compound 37 (0.46 g, 0.65 mmol), _NH 2 _NH 2 in KOH and 1ml of 0.7 g. H ₂ O was combined in diethylene glycol (10 ml) and warmed to reflux under N ₂ for 1 hour. The mixture was cooled, concentrated and re-dissolved in MeOH. Purification by filtration over 5 g of SCX-2 (MeOH followed by 1N NH ₃ / MeOH) followed by flash chromatography (ethyl acetate) yielded bis- [3-pyridin-3-yl-1H-pyrazol-4-yl ) -2-sulfanylethyl] -methane was provided as the 37 deprotected analog (amorphous, 0.23 g, 83%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.15 (d, J = 2 Hz, 2H), 8.57 (dd, J = 5 Hz, 2 Hz, 2H), 8.31 (dt, J = 8 Hz, 2 Hz, 2H), 7.66 (s, 2H), 7.36-7.32 (m, 2H), 2.50-2.42 (m, 4H), 1.34-1.26 (m, 6H).
Using the method described for the conversion of 21A to 22A, the deprotected analog of compound 37 (0.23 g, 0.54 mmol) was converted to compound 22C. Yield 0.2 g (oil, 80% overall). LCMS (Method A); R _t : 1.66 min, ([M + H] ⁺ = 459).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.50 (s, 2H), 6.92-6.85 (bs, 2H), 3.90-3.80 (m, 4H), 3.07 (Bt, J = 7 Hz, 4H), 2.77 (s, 6H), 2.66-2.54 (m, 8H), 1.54-1.43 (m, 6H).

3- (4-Ethylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21D)
Compound according to the method described for the synthesis of compound 21A (see scheme 3) using ethyldisulfanyl-ethane and 3- (4-bromo-1H-pyrazol-3-yl) -pyridine (compound 20A) as disulfide 21D was produced.
Yield: 76%. (oil). LCMS (Method A); R _t : 1.56 min, ([M + H] ⁺ = 206).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.11 (d, J = 2 Hz, 1H), 8.64 (dd, J = 5 Hz, 2 Hz, 1H), 8.18 (dt, J = 8 Hz, 2 Hz, 1 H), 7.71 (s, 1 H), 7.39-7.35 (m, 1 H), 2.64 (q, J = 7 Hz, 2 H), 1.26 (t, J = 7 Hz, 3H).

3- (4-Ethylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22D)
Compound 22D was prepared from compound 21D according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 73% (solid). Melting point 95-97 ° C. LCMS (Method A); R _t : 1.15 min, ([M + H] ⁺ = 224).
¹ H-NMR (mixture of rotational isomers (3/1), mainly describing, 400 MHz, CDCl ₃ ): δ 7.53 (s, 1H), 6.55-6.46 (bs, 1H ), 3.40-3.37 (m, 2H), 2.67-2.60 (m, 4H), 2.46 (s, 3H), 2.43-2.36 (m, 2H), 1.19 (3H).

3- (4-Propylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21E)
The method described for the synthesis of compound 21A using 1-propyldisulfanyl-propane and 3- (4-bromo-1H-pyrazol-3-yl) -pyridine (compound 20A) as disulfides (see Scheme 3) Compound 21E was prepared according to (Flash chromatography conditions ethyl acetate / diethyl ether 5/1).
Yield: 76%. (oil).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.31 (dt, J = 8 Hz, 2 Hz, 1H), 7.68 (s, 1H), 7.39-7.35 (m, 1H), 2.56 (t, J = 7 Hz, 2H), 1.54-1.43 (m, 2H), 0.90 (t, J = 7 Hz, 3H).

3- (4-Propylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22E)
Compound 22E was prepared from compound 21E according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 77% (solid). Melting point 111 ° C. LCMS (Method A); R _t : 1.39 min, ([M + H] ⁺ = 238).
¹ H-NMR (mixture of rotamers 8/1), describing main one, 400 MHz, CDCl ₃ ): δ 7.55 (s, 1H), 6.61-6.55 (bs, 1H) , 3.43-3.39 (m, 2H), 2.68-2.60 (m, 4H), 2.48 (s, 3H), 2.46-2.39 (m, 2H), 1 .58 (dq, J = 7 Hz, 7 Hz, 2H), 0.98 (t, J = 7 Hz, 3H).

3- (4-Butylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21F)
The method described for the synthesis of compound 21A using 1-butyldisulfanyl-butane and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound 20B) as disulfides (see Scheme 3) Compound 21F was prepared according to (Flash chromatography conditions ethyl acetate / diethyl ether 3/1).
Yield: 18.4%. (oil).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.31 (dt, J = 8 Hz, 2 Hz, 1H), 7.68 (s, 1H), 7.39-7.34 (m, 1H), 2.58 (t, J = 7 Hz, 2H), 1.48-1.40 (m, 2H), 1.36-1.25 (m, 2H), 0.90 (t, J = 7 Hz, 3H).

3- (4-Butylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22F)
Compound 22F was prepared from compound 21F according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 73% (amorphous). Compound 22A was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Recrystallization from EtOH / ethyl acetate gave a solid (free base / fumaric acid 1/1), mp 120-121 ° C. LCMS (Method A); R _t : 1.16 min, ([M + H] ⁺ = 252).

3- (4-pentylsulfamoyl phenylsulfanyl -1H- pyrazole-3 -yl) - pyridine (Compound 21G)
The method described for the synthesis of compound 21A using 1-pentyldisulfanyl-pentane and 3- (4-bromo-1H-pyrazol-3-yl) -pyridine (compound 20A) as disulfide (see Scheme 3) Compound 21G was prepared according to
Yield: 71%. (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.32 (dt, J = 8 Hz, 2 Hz, 1 H), 7.66 (s, 1 H), 7.39-7.34 (m, 1 H), 2.57 (t, J = 7 Hz, 2 H), 1.48-1.41 (m, 2H), 1.30-1.14 (m, 4H), 0.81 (t, J = 7 Hz, 3H).

3- (4-Pentylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22G)
Compound 22G was prepared from compound 21G according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 77% (solid). Melting point 100-101 ° C. LCMS (Method A); R _t : 1.67 min, ([M + H] ⁺ = 266).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.51 (s, 1H), 6.56-6.47 (bs, 1H), 3.40-3.36 (m, 2H), 2.65 -2.59 (m, 4H), 2.45 (s, 3H), 2.44-2.38 (m, 2H), 1.57-1.47 (m, 4H), 1.39-1 .24 (m, 4H) 0.88 (t, J = 7 Hz, 3H).

3- (4-Hexylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21H)
The method described for the synthesis of compound 21A using 1-hexyldisulfanyl-hexane and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound 20B) as disulfides (see Scheme 3) Compound 21H was prepared according to
Yield: 37%. (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.62 (dd, J = 5 Hz, 2 Hz, 1H), 8.31 (dt, J = 8 Hz, 2Hz,
1H), 7.70 (s, 1H), 7.40-7.35 (m, 1H), 2.59 (t, J = 7 Hz, 2H), 1.50-1.42 (m, 2H) 1.34-1.12 (m, 6H), 0.81 (t, J = 7 Hz, 3H).

3- (4-Hexylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22H)
Compound 22H was prepared from compound 21H according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 49% (amorphous). LCMS (Method A); R _t : 1.81 min, ([M + H] ⁺ = 280).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.51 (s, 1H), 6.60-6.50 (bs, 1H), 3.40-3.36 (m, 2H), 2.65 -2.59 (m, 4H), 2.45 (s, 3H), 2.44-2.38 (m, 2H), 1.56-1.48 (m, 2H), 1.39-1 .20 (m, 6H) 0.88 (t, J = 7 Hz, 3H).

3- [4- (3-Phenyl-propylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21I)
3-Phenyl-propyldisulfanyl-3-propylbenzene (prepared according to the method described in Tetrahedron Letters, 42, 2001, 6741-6743) and 3- (4-bromo-1H-pyrazol-3-yl) as disulfides Compound 21I was prepared according to the method described for the synthesis of Compound 21A (see Scheme 3) using) -pyridine (Compound 20A). (Flash chromatography conditions (ethyl acetate)). Yield: 22% (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.62 (dd, J = 5 Hz, 2 Hz, 1H), 8.31 (dt, J = 8 Hz, 2 Hz, 1H), 7.69 (s, 1H), 7.40-7.36 (m, 1H), 7.24 (bt, J = 7 Hz, 2H), 7.17 (bt, J = 7 Hz, 1H), 7.04 (bd, J = 7 Hz, 2H), 2.65-2.57 (m, 4H), 1.84-1.75 (m, 2H).

3- [4- (3-Phenyl-propylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22I )
Compound 22I was prepared from compound 21I according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 59% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.51 (s, 1H), 7.30-7.22 (m, 2H), 7.21-7.12 (m, 3H), 6.66 -6.46 (bs, 1H), 3.39-3.34 (m, 2H), 2.70-2.55 (m, 6H), 2.44 (s, 3H), 2.43-2 .36 (m, 2H), 1.89-1.80 (m, 2H).

3- [4- (4,4-Difluoro-bute-3enylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21J)
4- (4,4-Difluoro-but-3-enyldisulfanyl-1,1-difluoro-but-1-ene (Tetrahedron Letters, 42, 2001, 6741-6743) and 3- (4 Compound 21J was prepared according to the method described for the synthesis of Compound 21A (see Scheme 3) using -bromo-1H-pyrazol-3-yl) -pyridine (Compound 20A) (flash chromatography conditions (acetic acid Ethyl)) Yield: 58% (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.62 (dd, J = 5 Hz, 2 Hz, 1H), 8.31 (dt, J = 8 Hz, 2 Hz, 1 H), 7.72 (s, 1 H), 7.42-7.36 (m, 1 H), 4.19-4.06 (m, 1 H), 2.59 (t, J = 7 Hz, 2H), 2.18-2.09 (m, 2H).

3- [4- (4,4-Difluoro-bute-3enylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22J)
Compound 22J was prepared from compound 21H according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 90% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.54 (s, 1H), 6.68-6.44 (bs, 1H), 4.27-4.15 (m, 1H), 3.40 -3.66 (m, 2H), 2.66-2.60 (m, 4H), 2.47 (s, 3H), 2.45-2.38 (m, 2H), 2.22-2 .14 (m, 2H).

3- [4- (3-Phenyl-allylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21K)
3-Diphenyl-allyldisulfanyl-3-allylbenzene (Tetrahedron Letters, 42, 2001, 6741-6743) and 3- (4-bromo-1H-pyrazol-3-yl) -pyridine (compound 20A) as disulfides Used compound 21K according to the method described for the synthesis of compound 21A (see Scheme 3). (Flash chromatography conditions (ethyl acetate)). Yield: 22%. (oil). (TLC ethyl acetate _Rf 0.45).

3- [4- (3-Phenyl-allylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22K)
Compound 22K was prepared from compound 21K according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 72% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.52 (s, 1H), 7.30-7.18 (m, 5H), 6.70-6.20 (bs, 1H), 6.20 −6.07 (m, 2H), 3.37 (d, J = 7 Hz, 2H), 3.33-3.28 (m, 2H), 2.54 (bt, J = 7 Hz, 2H), 2 .40 (s, 3H), 2.39-2.30 (m, 2H).

3- [4-Pent-4-enylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21L)
5-pente-4-enyldisulfanyl-pent-1-ene (Tetrahedron Letters, 42, 2001, 6741-6743) and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound) as disulfides 20B) was used to prepare compound 21L according to the method described for the synthesis of compound 21A (see Scheme 3). (Flash chromatography conditions (ethyl acetate)). Yield: 28%. (oil). LCMS (Method A); R _t : 2.21 min, ([M + H] ⁺ = 246).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.62 (dd, J = 5 Hz, 2 Hz, 1H), 8.31 (dt, J = 8 Hz, 2 Hz, 1H), 7.71 (s, 1H), 7.41-7.35 (m, 1H), 5.73-5.59
(M, 2H), 4.97-4.89 (m, 2H), 2.59 (t, J = 7 Hz, 2H), 2.10-2.03 (m, 2H), 1.61-1 .54 (m, 2H).

3- [4-Pente-4-enylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22L)
Compound 22L was prepared from compound 21L according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 61% (amorphous). LCMS (Method A); R _t : 1.84 min, ([M + H] ⁺ = 264).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.52 (s, 1H), 6.70-6.40 (bs, 1H), 5.81-5.68 (m, 1H), 5.04 -4.94 (m, 2H), 3.40-3.36 (m, 2H), 2.66-2.57 (m, 4H), ｀ 2.45 (s, 3H), 2.45- 2.37 (m, 2H), 2.17-2.09 (m, 2H), 1.66-1.58 (m, 2H).

3- [4- (Furan-2-ylmethylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21M)
Compound 21M was prepared according to the method described for the synthesis of compound 21A (see Scheme 3) using difurfuryl-disulfide and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound 20B). . (Flash chromatography conditions (ethyl acetate)). Yield: 54% (oil).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.59 (dd, J = 5 Hz, 2 Hz, 1H), 8.20 (dt, J = 8 Hz, 2 Hz, 1H), 7.54 (s, 1H), 7.38-7.32 (m, 1H), 7.21-7.19 (m, 1H), 6.16-6.12 (m, 1H), 5.88-5.84 (m, 1H), 3.75 (s, 2H).

3- [4- (Furan-2-yl-methylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22M)
Compound 22M was prepared from compound 21M according to the method described for the synthesis of compound 22A (see Scheme 3).
Yield: 65% (amorphous). LCMS (Method A); R _t : 1.04 min, ([M + H] ⁺ = 276).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 7.36 (s, 1H), 7.33-7.31 (m, 1H), 6.38-6.26 (bs, 1H), 6.24 -6.20 (m, 1H), 5.93-5.90 (m, 1H), 3.78 (s, 2H), 3.30-3.22 (m, 2H), 2.60 (bt , J = 7 Hz, 2H), 2.44 (s, 3H), 2.41-2.33 (m, 2H).

3- (4-Benzylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21N)
Compound 21N was prepared according to the method described for the synthesis of Compound 21A (see Scheme 3) using dibenzyl-disulfide and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (Compound 20B). . (Flash chromatography conditions (ethyl acetate)). Yield: 33%. (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.0 (d, J = 2 Hz, 1 H), 8.58 (dd, J = 5 Hz, 2 Hz, 1 H), 8.10 (dt, J = 8 Hz, 2Hz, 1
H), 7.43 (s, 1H), 7.33-7.28 (m, 1H), 7.17-7.11 (m, 3H), 7.02-6.96 (m, 2H) , 3.72 (s, 2H).

3- (4-Benzylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22N)
Compound 22N was prepared from compound 21N according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 48% (amorphous). LCMS (Method A); R _t : 1.55 min, ([M + H] ⁺ = 286). Compound 22N was reacted with 1 equivalent of fumaric acid in EtOH and concentrated.
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.63 (s, 1H), 7.28 (t, J = 7 Hz, 2H), 7.28 (t, J = 7 Hz, 2H), 7. 24 (bt, J = 7 Hz, 1H), 7.17 (bd, J = 7 Hz, 2H), 6.82-6.79 (bs, 1H), 6.66 (s, 2H), 4.28 ( bd, J = 15 Hz, 1H), 4.05 (dd, J = 16 Hz, 6 Hz, 2H), 3.86-3.80 (m, 1H), 3.55-3.50 (m, 1H), 3.18-3.10 (m, 1H), 2.94 and 2.93 (2 x s, 3H), 2.68-2.46 (m, 2H).

3- [4- (2-Ethoxy-ethylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21O)
1-ethoxy-2- (2-ethoxy-ethyldisulfanyl) -ethane (Tetrahedron Letters, 42, 2001, 6741-6743) and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine as disulfides Compound 21O was prepared according to the method described for the synthesis of Compound 21A (see Scheme 3) using (Compound 20B). (Flash chromatography conditions (ethyl acetate)). Yield: 28%. (oil). LCMS (Method A); R _t : 2.21 min, ([M + H] ⁺ = 246).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.62 (dd, J = 5 Hz, 2 Hz, 1H), 8.33 (dt, J = 8 Hz, 2 Hz, 1 H), 7.75 (s, 1 H), 7.41-7.36 (m, 1 H), 3.46 (t, J = 7 Hz, 2 H), 3.38 (q, J = 7 Hz, 2H), 2.78 (t, J = 7 Hz, 2H), 1.14 (t, J = 7 Hz, 3H),

3- [4- (2-Ethoxy-ethylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22O)
Compound 22O was prepared from compound 21O according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 63% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.56 (s, 1H), 6.70-6.50 (bs, 1H), 3.55-3.43 (m, 4H), 3.40 −3.36 (m, 2H), 2.81 (t, J = 7 Hz, 2H), 2.61 (bt, J = 7 Hz, 2H), 2.46 (s, 3H), 2.44-2 .38 (m, 2H), 1.18 (t, J = 7 Hz, 3H).

3- {4- [2- (2-Methoxy-ethoxy) -ethylsulfanyl] -1H-pyrazol-3-yl} -pyridine (Compound 21P)
1-methoxy-2- {2- [2-((2-methoxy-ethoxy)-as disulfide
Using ethyldisulfanyl] -ethoxy} -ethane (Tetrahedron Letters, 42, 2001, 6741-6743) and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (Compound 20B), Compound 21P was prepared according to the method described for the synthesis (see Scheme 3). (Flash chromatography conditions (ethyl acetate)). Yield: 36%. (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.58 (dd, J = 5 Hz, 2 Hz, 1H), 8.35 (dt, J = 8 Hz, 2 Hz, 1H), 7.78 (s, 1H), 7.39-7.32 (m, 1H), 3.51-3.44 (m, 6H), 3.34 (s, 3H), 2 .78 (t, J = 7 Hz, 2H).

3- {4- [2- (2-methoxy-ethoxy) -ethylsulfanyl] -1H-pyrazol-3-yl} -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22P)
Compound 22P was prepared from compound 21P according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 33% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 6.74-6.69 (bs, 1H), 3.59-3.51 (m, 8H), 3.38 (S, 3H), 2.83 (t, J = 7 Hz, 2H), 2.77 (bt, J = 7 Hz, 2H), 2.55 (s, 3H), 2.52-2.45 (m , 2H).

3- (4-Allylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 21Q)
The method described for the synthesis of compound 21A using 3-allyldisulfanyl-propene and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound 20B) as disulfides (see Scheme 3) Compound 21Q was prepared according to (Flash chromatography conditions (ethyl acetate)). Yield: 27%. (oil).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.29 (dt, J = 8 Hz, 2 Hz, 1 H), 7.70 (s, 1 H), 7.40-7.36 (m, 1 H), 5.77-5.66 (m, 1 H), 4.94 (bdd, J = 11 Hz, 1 Hz, 1H), 4.83 (bdd, J = 17 Hz, 1 Hz, 1H), 3.19 (bd, J = 8 Hz, 2H).

3- (4-Allylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22Q)
Compound 22Q was prepared from compound 21Q according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 17% (amorphous).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 7.52 (s, 1H), 6.62-6.48 (bs, 1H), 5.84-5.74 (m, 1H), 4.98 (Bdd, J = 11 Hz, 1 Hz, 1H), 4.90 (bdd, J = 17 Hz, 1 Hz, 1H), 4.00-3.95 (m, 2H), 3.23 (bd, J = 8 Hz, 2H), 2.61 (bt, J = 7 Hz, 2H), 2.46 (s, sH), 2.44-2.39 (m, 2H).

3- (3-Pyridin-3-yl-1H-pyrazol-4-ylsulfanyl) -propionitrile (Compound 21R)
The method described for the synthesis of compound 21A using 3- (2-cyano-ethyldisulfanyl) -propionitrile and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound 20B) as disulfides. Compound 21R was prepared according to (see Scheme 3). (Flash chromatography conditions (ethyl acetate)). Yield: 62%. (oil).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.20 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.33 (dt, J = 8 Hz, 2Hz, 1H), 7.82 (s, 1H), 7.43-7.37 (m, 1H), 2.76 (t, J = 7Hz, 2H), 2.45 (t, J = 7Hz, 2H).

3- [3- (1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1H-pyrazol-4-ylsulfanyl] -propionitrile (Compound 22R)
Compound 22R was prepared from compound 21R according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 8% (amorphous).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 6.60-6.50 (bs, 1H), 3.40-3.36 (m, 2H), 2.79 (T, J = 7 Hz, 2H), 2.66 (bt, J = 7 Hz, 2H), 2.50 (t, J = 7 Hz, 2H), 2.47 (s, 3H), 2.45-2 .38 (m, 2H).

3- [4- (3-Methyl-butylsulfanyl) -1H-pyrazol-3-yl] -pyridine (Compound 21S)
Describes the synthesis of compound 21A using 3-methyl-1- (3-methyl-butyldisulfanyl) -butane and 3- (4-iodo-1H-pyrazol-3-yl) -pyridine (compound 20B) as disulfides. Compound 21S was prepared according to the method described (see Scheme 3). (Flash chromatography conditions (ethyl acetate)). Yield: 39%. (oil).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.18 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 8.35 (dt, J = 8 Hz, 2 Hz, 1 H), 7.78 (s, 1 H), 7.39-7.35 (m, 1 H), 2.60 (t, J = 7 Hz, 2 H), 1.65 to 1.57 (m, 1H), 1.42-1.33 (m, 2H), 0.81 (d, J = 7 Hz, 6H).

3- [4- (3-Methyl-butylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 22S)
Compound 22S was prepared from compound 21S according to the method described for the synthesis of compound 22A (from 21A) (see Scheme 3).
Yield: 73%. (Amorphous).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 7.5 (s, 1H), 6.60-6.48 (bs, 1H), 3.40-3.36 (m, 2H), 2.66 -2.59 (m, 4H), 2.45 (s, 3H), 2.44-2.39 (m, 2H), 1.72-1.62 (m, 1H), 1.45-1 .39 (m, 2H), 0.86 (d, J = 7 Hz, 6H).

3-Pyridin-3-yl-pyrazole-1-sulfonic acid dimethylamide (Compound 23, Scheme 3)
Compound 19 (3.0 g, 20.7 mmol) and 2.22 ml of phenylsulfonyl chloride (20.7 mmol) were combined in pyridine (100 ml) and stirred at reflux for 18 hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed ₃ times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether / PE 2/1) to give compound 23 (amorphous, 2.86 g, 55%).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.1 (d, J = 2 Hz, 1 H), 8.6 (dd, J = 5 Hz, 2 Hz, 1 H), 8.16 (dt, J = 8 Hz, 2 Hz, 1H), 8.05 (d, J = 3 Hz, 1H), 7.39-7.34 (m, 1H), 6.75 (d, J = 3 Hz, 1H), 3.02 (s, 6H).

5-Butylsulfanyl-3-pyridin-3-yl-pyrazole-1-sulfonic acid dimethylamide (Compound 24, Scheme 3)
To a solution of compound THF (1.0 g, 4 mmol) in anhydrous THF (50 ml) was added 1 equivalent of n-BuLi (2.35 ml, 1.7 M in pentane) at −78 ° C. under N ₂ . It was dripped. After the dropwise addition, the resulting solution was stirred at −78 ° C. for 1 hour. At this temperature 1.1 equivalents of 1-butyldisulfanylbutane (0.79 ml) was added and the resulting solution was stirred at −78 ° C. for 1 hour, and then allowed to warm to ambient temperature overnight. The mixture was then quenched with saturated NH ₄ Cl solution at 0 ° C. and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether / PE 5/1 to ethyl acetate / diethyl ether 1/1) gave compound 24 (oil, 0.93 g, 70%).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 9.1 (d, J = 2 Hz, 1 H), 8.6 (dd, J = 5 Hz, 2 Hz, 1 H), 8.15 (dt, J = 8 Hz, 2 Hz, 1H), 7.39-7.34 (m, 1H), 6.50 (s, 1H), 3.02 (s, 6H), 3.02 (t, J = 7 Hz, 2H), 1 .82-1.67 (m, 2H), 1.60-1.42 (m, 2H), 0.97 (t, J = 7 Hz, 3H).

3- (5-Butylsulfanyl-1H-pyrazol-3-yl) -pyridine (Compound 25, Scheme 3)
Compound 24 (0.92 g, 2.71 mmol) was dissolved in 50 ml n-BuOH. To this solution was added 2 g of KOH dissolved in 50 ml of H ₂ O and the reaction mixture was stirred at room temperature for 18 hours under N ₂ . The reaction mixture was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether / PE 4/1) gave compound 25 (amorphous, 0.44 g. 70%). (TLC ethyl acetate _Rf 0.34).

3- (5-Butylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 26, Scheme 3)
Compound 26 was prepared according to the method described for the synthesis of compound 22A (from 21A). Yield: 70% (amorphous).
¹ H-NMR (200 MHz, CDCl ₃ ): δ 6.27 (s, 1H), 6.22-6.18 (bs, 1H), 3.31-3.27 (m, 2H), 2.82 (T, J = 7 Hz, 2H), 2.58 (bt, J = 7 Hz, 2H), 2.44 (s, 3H), 2.39-2.32 (m, 2H), 1.62-1 .54 (m, 2H), 1.4-1.37 (m, 2H), 0.86 (t, J = 7 Hz, 3H).

3- [4- (3-Phenyl-propoxy) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33A, Scheme 5)
60% dispersion of NaH in mineral oil (3 g, 1.1 eq), compound 20B (18.36 g, 68.74 mmol) in anhydrous THF (100 ml) containing were added under _{N 2.} The resulting mixture was stirred at room temperature for 2 hours followed by treatment with 13.37 ml (1.1 eq) (2-chloromethoxy-ethyl) -trimethylsilane (SEM-Cl). The resulting mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the mixture and the organic layer was washed three times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give a 29A and 29B (variable) mixture as an oil (23.09 g, 83%).
¹ H-NMR (400 MHz, CDCl ₃ ): NMR is very similar to the NMR of a 27 A / B mixture (see Scheme 4). The major isomers (probably 29A) are shown: δ 9.15 (d, J = 2Hz, 1H), 8.65 (dd, J = 5Hz, 2Hz, 1H), 8.17 (dt, J = 8Hz, 2Hz, 1H), 7.74 (s, 1H), 7.39-7.34 (m, 1H), 5.46 (s, 2H), 3.71-3.62 (m, 4H, both isomerism) body), 0.98-0.84 (m, 4H, both isomers), 0.02 (both isomers, Si _{(CH 3)} 3).
To a solution of anhydrous THF (250 ml) containing a 29 A / B mixture (10 g, 25 mmol), 10.5 ml (1.1 eq) n-BuLi (2.5 M in hexane) was added dropwise (N ₂ -78 ° C under). After the addition, the resulting solution was stirred at −78 ° C. for 60 minutes. At this temperature, trimethyl borate (3 eq, 8.50 ml) was added (dropped within 15 minutes) and the reaction mixture was stirred at −78 ° C. for a further 2 hours. The reaction mixture was then allowed to warm to ambient temperature (overnight). The temperature of the reaction mixture was lowered to −10 ° C. and 2.2 ml (1.5 eq) acetic acid was added. Subsequently, 1.1 equivalent of a 30% H ₂ O ₂ solution (2.93 ml) was added dropwise while maintaining the temperature at <−5 ° C. The mixture was allowed to warm to ambient temperature and stirred for an additional 4 hours. To the reaction mixture was added 10 ml H ₂ O followed by ethyl acetate (500 ml). The organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to give 3-pyridin-3-yl-1- (2-trimethylsilanyl-1-ethoxymethyl) -1H-pyrazole-4- All (30) was provided as a (variable) mixture of SEM protected product isomers. (Amorphous, 2.9 g, 40%).
¹ H-NMR (400 MHz, CDCl ₃ , mixture of isomers to 1/1): δ 9.22 and 8.90 (2 x bs, 1H), 8.47-8.18 (m, 2H), 7 .45-7.34 (m, 1H), 7.36 and 7.31 (2 x s, 1H), 5.36 and 5.35 (2 x s, 2H), 3.74-3.69 and 3.64-3.59 (2 x m, 2H), 0.99-0.90 (m, 2H), 0.02 and 0.01 (2 x s, 9H).
To a solution of anhydrous DMF (50 ml) containing compound 30 (2.03 g, 6.98 mmol), 1.5 eq. K ₂ CO ₃ (1.45 g) was added and the mixture was stirred under N ₂ for 1 h. did. After the addition of 3-bromo-propylbenzene (1.1 eq, 1.17 ml), the resulting solution was stirred at 45 ° C. for 18 hours, allowing to reach ambient temperature. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether) to give 31A as a mixture of SEM isomers. (Oil, 1.92 g, 67%).
¹ H-NMR (400 MHz, CDCl ₃ , showing main isomers): δ 8.96 (d, J = 2 Hz, 1H), 8.61 (dd, J = 5 Hz, 2 Hz, 1H), 8.05 (Dt, J = 8 Hz, 2 Hz, 1H), 7.42-7.39 (m, 1H), 7.39 (s, 1H), 7.30-7.14 (m, 5H), 5.37 (S, 2H), 3.98 (t, J = 7 Hz, 2H), 3.74-3.69 (m, 2H), 2.74 (t, J = 7 Hz, 2H), 2.10-2 .02 (m, 2H), 0.98-0.92 (m, 2H), 0.01 (s, 9H).
31A (1.93 g, 4.71 mmol) in anhydrous THF (50 ml) containing, 14.16Ml the TBAF (1.0 M in THF) of (3.0 eq) was added under _{N 2.}
After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give the desired 3- [4- (3-phenyl-propoxy) -1H-pyrazol-3-yl] -pyridine (32A). (Oil, 1.32 g, 73%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.15 (d, J = 2 Hz, 1H), 8.54 (dd, J = 5 Hz, 2 Hz, 1H), 8.24 (dt, J = 8 Hz, 2Hz, 1H), 7.35-7.31 (m, 1H), 7.30-7.25 (m, 2H), 7.22-7.17 (m, 3H), 3.96 (t, J = 7 Hz, 2H), 2.83 (t, J = 7 Hz, 2H), 2.19-2.11 (m, 2H).
Using the method described for the conversion of 21A to 22A (see Scheme 3), compound 32A (0.3 g, 1.49 mmol) was converted to the title compound 3- [4- (3-phenyl-propoxy) -1H. -Pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (33A). Yield: 70% (amorphous, 72%). LCMS (Method A); R _t : 1.52 min, ([M + H] ⁺ = 298).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.31-7.25 (m, 2H), 7.22-7.17 (m, 3H), 7.16-7.11 (bs, 1H) , 6.62-6.44 (bs, 1H), 3.87 (t, J = 7 Hz, 2H), 3.41-3.36 (m, 2H), 2.79 (t, J = 7 Hz, 2H), 2.58 (t, J = 7 Hz, 2H), 2.44 (s, 3H), 2.42-2.35 (m, 2H), 2.11-2.04 (m, 2H) .

3- (4-Hexyloxy-1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33B, Scheme 6)
Using the method described for the conversion of 21A to 22A (see Scheme 3), compound 29A / B was converted to 3- (4-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazole. Conversion to -3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (compound 34A / B).
Yield: 47%. (Amorphous). LCMS (Method A); R _t : 2.66 min, ([M + H] ⁺ = 420) and R _t : 2.74 min, ([M + H] ⁺ = 420).
Compound 34A / B (0.75g, 1.79 mmol), CuI (34 mg, 0.179 _{mmol), Cs 2 CO 3 (1.18g} , 3.58 mmol), 1,10-phenanthroline (0.07 g, 0.358 mmol) and 1-hexanol (5 ml, 40 mmol) were heated at 140 ° C. for 18 hours (under air). The mixture was cooled to room temperature. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / PE 1/1) to give compound 35A as an oil (0.24 g, 34%). LCMS (Method _A); R t: 2.50 ^{min, ([M + H] +} = 394). (TLC ethyl acetate / PE 1/1, R _f 0.07).
To a solution of anhydrous THF (20 ml) containing a mixture of 35A (0.24 g, 0.6 mmol), 1.52 ml (2.5 eq) TBAF (1.0 M in THF) was added under N _2. It was. After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was flash chromatographed (ethyl acetate / MeOH).
(1/1)) to give title compound 33B. (Oil, 0.12 g, 75%). LCMS (Method A); R _t : 1.99 min, ([M + H] ⁺ = 264).
Compound 33B was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (amorphous).
_{^{1 H-NMR (600MHz, D}} 6 DMSO): δ 7.50 (bs, 1H), 6.58 (s, 2H), 6.50 (bs, 1H), 3.88 (t, J = 7Hz, 2H), 3.75 (bs, 2H), 3.02 (bt, J = 7 Hz, 2H), 2.69 (s, 3H), 2.4
8-2.42 (m, 2H), 1.75-1.67 (m, 2H), 1.45-1.38 (m, 2H), 1.36-1.28 (m, 4H), 0.89 (t, J = 7 Hz, 3H).

3- (4-Butyloxy-1H-pyrazol-3-yl) -pyridine (Compound 32C)
Synthesis of Compound 32A using 1-bromo-butane and 3-pyridin-3-yl-1- (2-trimethylsilanyl-1-ethoxymethyl) -1H-pyrazol-4-ol (30) as alkyl halides Compound 32C was prepared according to the method described for (see Scheme 5). Workup and flash chromatography (ethyl acetate / diethyl ether 1/1) gave compound 31C. Yield 30% (oil).
¹ H-NMR (representing main isomer, 400 MHz, CDCl ₃ ): δ 8.9 (d, J = 2 Hz, 1H), 8.6 (dd, J = 5 Hz, 2 Hz, 1H), 8.05 (Dt, J = 8 Hz, 2 Hz, 1H), 7.42 (s, 1H), 7.41-7.37 (m, 1H), 5.37 (s, 2H), 3.98 (t, J = 7 Hz, 2H), 3.74-3.68 (m, 2H), 1.74-1.66 (m, 2H), 1.49-1.39 (m, 2H), 0.92 (t , J = 7 Hz, 3H), 0.02 (s, 9H).
The SEM-isomer mixture was deprotected (TBAF / THF) to give 3- (4-butyloxy-1H-pyrazol-3-yl) -pyridine (32C).
Yield: 70% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.53 (dd, J = 5 Hz, 2 Hz, 1H), 8.23 (dt, J = 8 Hz, 2Hz, 1H), 7.35-7.31 (m, 1H), 7.30 (s, 1H), 3.77 (t, J = 7Hz, 2H), 1.84-1.77 (m, 2H), 1.57-1.47 (m, 2H), 0.98 (t, J = 7 Hz, 3H).

3- (4-Butyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33C)
Using the method described for the conversion of 21A to 22A (see Scheme 3), compound 32C was converted to the title compound (33C).
Yield: 77% (amorphous). LCMS (Method A); R _t : 1.48 min, ([M + H] ⁺ = 236).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.19 (bs, 1H), 6.52-6.42 (bs, 1H), 3.88 (t, J = 7 Hz, 2H), 3.38 -3.44 (m, 2H), 2.57 (t, J = 7 Hz, 2H), 2.44 (s, 3H), 2.41-2.36 (m, 2H), 1.79-1 .71 (m, 2H), 1.53-1.43 (m, 2H), 0.97 (t, J = 7 Hz, 3H).

3- (4-But-3-enyloxy-1H-pyrazol-3-yl) -pyridine (Compound 32D)
4-Bromo-but-1-ene and 3-pyridin-3-yl-1- (2-trimethylsilanyl-1-ethoxymethyl) -1H-pyrazol-4-ol (30) are used as alkyl halides. Compound 32D was prepared according to the method described for the synthesis of compound 32A (see Scheme 5). Workup and flash chromatography (diethyl ether) gave compound 31D. Yield 43% (oil, TLC diethyl ether _Rf 0.37). It was subsequently deprotected (TBAF / THF) to give 3- (4-but-3-enyloxy-1H-pyrazol-3-yl) -pyridine (32D).
Yield: 75% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.15 (d, J = 2 Hz, 1H), 8.58 (dd, J = 5 Hz, 2 Hz, 1H), 8.24 (dt, J = 8 Hz, 2Hz,
1H), 7.35-7.30 (m, 1H), 7.32 (s, 1H), 5.96-5.85 (m, 1H), 5.22-5.11 (m, 2H) 4.02 (t, J = 7 Hz, 2H), 2.62-2.55 (m, 2H).

3- (4-But-3-enyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33D)
Compound 32D was converted to the title compound (33D) using the method described for the conversion of 21A to 22A (see Scheme 3).
Yield: 94% (amorphous). LCMS (Method A); R _t : 1.33 min, ([M + H] ⁺ = 234).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.20 (bs, 1H), 6.60-6.42 (bs, 1H), 5.94-5.83 (m, 1H), 5.19 −5.07 (m, 2H), 3.94 (t, J = 7 Hz, 2H), 3.38-3.33 (m, 2H), 2.59-2.50 (m, 4H), 2 .44 (s, 3H), 2.41-2.36 (m, 2H).

3- (4-Heptyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33E)
Compound 34A / B (0.75 g, 1.79 mmol) (see Scheme 6), CuI (34 mg, 0.179 mmol), Cs ₂ CO ₃ (1.18 g, 3.58 mmol), 1, A mixture of 10-phenanthroline (0.07 g, 0.358 mmol) and 1-heptanol (5 ml) was heated at 140 ° C. for 18 hours (in air). The mixture was cooled to room temperature. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / PE 1/1) to give Compound 35E (35A heptyl analog, Scheme 6) as an oil (0.22 g, 30%). LCMS (Method A); R _t : 2.60 min, ([M + H] ⁺ = 408).
To a solution of anhydrous THF (20 ml) containing a mixture of 35E (0.22 g, 0.54 mmol), 1.35 ml (2.5 eq) TBAF (1.0 M in THF) was added under N _2. It was. After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / MeOH 1/1) to give the title compound 33E. (Oil, 0.08 g, 53%). LCMS (Method A); R _t : 2.23 min, ([M + H] ⁺ = 278).

Compound 33E was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (amorphous).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.37 (bs, 1H), 6.58 (s, 2H), 6.43 (bs, 1H), 3.84 (t, J = 7 Hz, 2H), 3.51 (bs, 2H), 2.77 (bt, J = 7 Hz, 2H), 2.52 (s, 3H), 2.39-2.33 (m, 2H), 1.72 -1.66 (m, 2H), 1.45-1.22 (m, 8H), 0.87 (t, J = 7Hz, 3H).

3- (4-Pent-4-enyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33F)
Compound 34A / B (0.75 g, 1.79 mmol) (see Scheme 6), CuI (34 mg, 0.179 mmol), Cs ₂ CO ₃ (1.18 g, 3.58 mmol), 1, A mixture of 10-phenanthroline (0.07 g, 0.358 mmol) and pent-4-en-1-ol (5 ml) was heated at 140 ° C. for 18 hours (under air). The mixture was cooled to room temperature. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / PE 1: 1) to give compound 35F (35A pent-4-enyl analog, Scheme 6) as an oil (0.41 g, 60%). . LCMS (Method A); R _t : 2.33 min, ([M + H] ⁺ = 378).
To a solution of anhydrous THF (20 ml) containing a mixture of 35F (0.22 g, 0.54 mmol), 1.35 ml (2.5 eq) TBAF (1.0 M in THF) was added under N _2. It was. After the addition, the resulting solution was refluxed for 18 hours, cooled and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / MeOH 1/1) to give the title compound 33F. (Oil, 0.08 g, 53%). LCMS (Method A); R _t : 1.83 min, ([M + H] ⁺ = 248).
Compound 33F was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (amorphous).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.38 (bs, 1H), 6.56 (s, 2H), 6.48-6.44 (m, 1H), 5.88-5. 80 (m, 1H), 5.06 to 4.95 (m, 2H), 3.86 (t, J = 7 Hz, 2H), 3.60 (bs, 2H), 2.86 (bt, J = 7 Hz, 2H), 2.58 (s, 3H), 2.42-2.37 (m, 2H), 2.20-2.15 (m, 2H), 1.83-1.77 (m, 2H).

3- (4-Pentyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 33G, Scheme 6)
Compound 29A / B (1.0 g, 2.49 mmol) (see Scheme 5), CuI (0.05 g, 0.249 mmol), Cs ₂ CO ₃ (1.62 g, 4.98 mmol), A mixture of 1,10-phenanthroline (0.09 g, 0.498 mmol) and pentanol (7 ml) was heated at 140 ° C. for 18 hours (in air). The mixture was cooled to room temperature. Ethyl acetate was added and the organic layer was washed with 5% NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / PE 1: 2) to give compound 31G as an oil (0.24 g, 27%). LCMS (Method A); R _t : 2.76 min, ([M + H] ⁺ = 362).
¹ H-NMR (400 MHz, mixture of isomers, CDCl ₃ ): δ 9.25 and 8.90 (d, J = 2 Hz, 1H), 8.61 and 8.52 (dd, J = 5 Hz, 2 Hz, 1H), 8.28 and 8.06 (dt, J = 8 Hz, 2 Hz, 1H), 7.43 and 7.29 (s, 1H), 7.41-7.37 and 7.35-7.31. (M, 1H), 5.39 and 5.37 (s, 2H), 4.0-3.92 (m, 2H), 3.71 and 3.60 (bt, J = 7 Hz, 2H), 1.88-1.80 and 1.76-1.69 (m, 2H), 1.52-1.25 (m, 6H), 0.97-0.90 (m, 3H).
To a solution of anhydrous THF (25 ml) containing 31G (0.23 g, 0.63 mmol) was added 1.59 ml (2.5 eq) TBAF (1.0 M in THF) under N ₂ . After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give 3- (4-pentyloxy-1H-pyrazol-3-yl) -pyridine 32G. (Oil, 0.14 g, 95%). LCMS (Method A); R _t : 2.27 min, ([M + H] ⁺ = 232).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.53 (dd, J = 5 Hz, 2 Hz, 1H), 8.23 (dt, J = 8 Hz, 2 Hz, 1H), 7.36-7.29 (m, 2H), 3.96 (bt, J = 7 Hz, 2H), 1.87-1.78 (m, 2H), 1.51-1. 34 (m, 6H), 0.94 (t, J = 7
Hz, 3H).
Using the method described for the conversion of 21A to 22A (see Scheme 3), compound 32G was converted to the title compound (33G).
Yield: 85% (amorphous). LCMS (Method A); R _t : 1.83 min, ([M + H] ⁺ = 250).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.19 (bs, 1H), 6.54-6.50 (bs, 1H), 3.88 (t, J = 7 Hz, 2H), 3.40 -3.36 (m, 2H), 2.59 (t, J = 7 Hz, 2H), 2.45 (s, 3H), 2.43-2.37 (m, 2H), 1.81-1 .75 (m, 2H), 1.46-1.34 (m, 4H), 0.93 (t, J = 7 Hz, 3H).

Butyl- [3- (1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1H-pyrazol-4-yl] -amine (Compound 42, Scheme 8)
To a concentrated (10 ml) H ₂ SO ₄ solution containing compound 19 (0.725 g, 5 mmol), a mixture of 5 ml H ₂ SO ₄ and 5 ml HNO ₃ was added dropwise at −10 ° C. under N ₂ . . After the addition, the resulting solution was stirred at room temperature for 3 hours. The mixture was poured into ice followed by 2N NaOH. Ethyl acetate was added and the organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give compound 38 as an oil (0.57 g, 60%).
¹ H-NMR (200 MHz, CDCl ₃ and D ₆ DMSO 1/1): δ 8.9 (d, J = 2 Hz, 1H), 8.7 (d, J = 5 Hz, 2 Hz, 1H), 8.05 (Dt, J = 8 Hz, 2 Hz, 1H), 7.60 (s, 1H), 7.48-7.40 (m, 1H).
Compound 38 (0.37 g, 1.9 mmol) was dissolved in MeOH (containing Pd (OH) _{2 /} C (0.03 g)). Hydrogenation was performed within 3 hours (1 atm) at room temperature. The reaction mixture was filtered, washed with ethyl acetate / MeOH (1/1) and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate followed by ethyl acetate / MeOH 1/1) to give compound 39 as an oil (0.29 g, 95%).
¹ H-NMR (200 MHz, CDCl ₃ and D ₆ DMSO 1/1): δ 9.05 (d, J = 2 Hz, 1H), 8.51 (d, J = 5 Hz, 2 Hz, 1H), 8.09 (Dt, J = 8 Hz, 2 Hz, 1H), 7.43 (s, 1H), 7.37-7.32 (m, 1H).
To a solution of anhydrous CH ₃ CN (15 ml) containing a mixture of compound 39 (0.21 g, 1.3 mmol) and 0.27 ml (1.5 eq) triethylamine, 0.14 ml of butyryl chloride was added to N _2. Added below. After the addition, the resulting solution was stirred at room temperature for 3 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give N- (3-pyridin-3-yl-1H-pyrazole) -butyramide 40 (oil, 0.19 g, 77%). (TLC ethyl acetate _Rf 0.16).
Compound 40 was converted to compound 41 using the method described for the conversion of 21A to 22A (see Scheme 3).
Yield: 65% (amorphous). LCMS (Method _A); R t: 0.73 ^{min, ([M + H] +} = 249).
¹ H-NMR (600 MHz, CDCl ₃ ): δ 8.4 (bs, 1H), 7.5 (bs, 1H), 6.0-5.96 (m, 1H), 3.27 (bs, 2H) ), 2.63 (t, J = 7 Hz, 2H), 2.43 (s, 3H), 2.43-2.37 (m, 2H), 2.32 (t, J = 7 Hz, 2H), 1.76-1.70 (m, 2H), 0.98 (t, J = 7 Hz, 3H).
To a solution of anhydrous THF (25 ml) containing compound 41 (0.27 g, 1.09 mmol), 0.04 g (1.0 eq) LiAlH ₄ was added under N ₂ . After the addition, the resulting solution was refluxed for 18 hours, allowing to warm to ambient temperature. To the reaction mixture was added 0.04 ml H ₂ O, followed by 0.08 ml 2N NaOH and 0.04 ml H ₂ O. The resulting mixture was warmed for 10 minutes (60 ° C.), cooled to room temperature and filtered. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / MeOH 1/1) to give the title compound 42. (Oil, 0.21 g, 95%). LCMS (Method _A); R t: 1.05 ^{min, ([M + H] +} = 235).
¹ H-NMR (600 MHz, CDCl ₃ ): δ 7.1 (bs, 1H), 6.17-6.14 (m, 1H), 3.4-3.37 (m, 2H), 2.99 (T, J = 7 Hz, 2H), 2.64 (t, J = 7 Hz, 2H), 2.48 (s, 3H), 2.47-2.42 (m, 2H), 1.66-1 .60 (m, 2H), 1.47-1.40 (m, 2H), 0.97 (t, J = 7 Hz, 3H).

3- (4-Hex-1-ynyl-1H-pyrazol-3-yl) -pyridine (Compound 44A, Scheme 9)
Using the method described for the conversion of 20A to 36A (see Scheme 7), compound 20B (10.49 g, 38.6 mmol) was converted to 3- (1-phenylsulfonyl-4-iodo-1H-pyrazole- Conversion to 3-yl) -pyridine (36B). Yield 11.65 g (amorphous, 74%). (TLC diethyl ether _Rf 0.4).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.05 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 8.27 (s, 1H), 8 .12 (dt, J = 8 Hz, 2 Hz, 1H), 8.10-8.06 (m, 2H), 7.73-7.67 (m, 1H), 7.58 (bt, J = 7 Hz, 2H), 7.39-7.34 (m, 1H).
To triethylamine (10 ml) and DMF (4 ml) containing 36B (0.97 g, 2.36 mmol) was added 3 equivalents of hex-1-yne (0.81 ml). The resulting mixture was stirred for further 2 hours under N _2. 10 mol% of CuI (45 mg), were added successively 5 mol% of _{PdCl 2 (PPH 3) 2 (} 83mg) and 18 mole% of _PPH 3 _(111mg). After the addition, the resulting solution was warmed at 70 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE (1/1)) to give 3- (1-phenylsulfonyl-4-hex-1-ynyl-1H-pyrazol-3-yl) -pyridine ( 43A) was provided as an oil (0.66 g, 77%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.5-9.2 (bs, 1H), 8.8-8.4 (bs, 1H), 8.34 (bd, J = 8 Hz, 1H) , 8.21 (s, 1H), 8.08-8.04 (m, 2H), 7.67 (bt, J = 7 Hz, 1H), 7.57 (bt, J = 7 Hz, 2H), 7 .41-7.32 (bs, 1H), 2.42 (t, J = 7 Hz, 2H), 1.62-1.53 (m, 2H), 1.49-1.39 (m, 2H) , 0.93 (t, J = 7 Hz, 3H).
Compound 43A (0.66 g, 1.81 mmol), 1.3 g KOH and 2 ml NH ₂ NH ₂ . H ₂ O was combined in diethylene glycol (20 ml) and warmed to reflux under N ₂ for 1 hour. The mixture was cooled, concentrated and redissolved in MeOH. Purification on 25 g SCX-2 (MeOH followed by 1N NH ₃ / MeOH) and subsequent flash chromatography (ethyl acetate) gave the title compound 44A. Yield 0.37 g (90%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.60 (dd, J = 5 Hz, 2 Hz, 1H), 8.34 (dt, J = 8 Hz, 2Hz, 1H), 7.73 (s, 1H), 7.39-7.34 (m, 1H), 2.43 ((t, J
= 7 Hz, 2H), 1.64-1.56 (m, 2H), 1.52-1.42 (m, 2H), 0.94 (t, J = 7 Hz, 3H).

3- (4-Hex-1-ynyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 45A, Scheme 9)
Compound 44A was converted to compound 45A using the method described for the conversion of 21A to 22A (see Scheme 3). Yield: 90% (amorphous). LCMS (Method A); R _t : 1.79 min ([M + H] ⁺ = 244).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 6.78-6.66 (bs, 1H), 3.42-3.38 (m, 2H), 2.59 (Bt, J = 7 Hz, 2H), 2.45 (s, 3H), 2.44-2.37 (m, 2H), 1.62-1.43 (m, 4H), 0.94 (t , J = 7 Hz, 3H).

3- (4-Hept-1-ynyl-1H-pyrazol-3-yl) -pyridine (Compound 44B)
The method described for the synthesis of compound 44A using hept-1-yne and 3- (1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl) -pyridine (36A) (see Scheme 9) Compound 44B was prepared according to (Flash chromatography using diethyl ether) gave 3- (1-phenylsulfonyl-4-hept-1-ynyl-1H-pyrazol-3-yl) -pyridine (43B) as an oil (90%).
^{1 H-NMR (400MHz, CDCl} 3): δ 9.25 (bs, 1H), 8.6 (bs, 1H), 8.34 (bd, J = 8Hz, 1H), 8.21 (s, 1H ), 8.06 (bd, J = 8 Hz, 2H), 7.67 (bt, J = 7 Hz, 1H), 7.57 (bt, J = 7 Hz, 2H), 7.36-7.30 (m) , 1H), 2.42 (t, J = 7 Hz, 2H), 1.63-1.55 (m, 2H), 1.44-1.28 (m, 4H), 0.89 (t, J = 7 Hz, 3H).
Using the method described for the conversion of 43A to 44A (see Scheme 9), compound 43B was converted to the title compound 44B. Yield: 98% (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.59 (dd, J = 5 Hz, 2 Hz, 1H), 8.37 (dt, J = 8 Hz, 2 Hz, 1 H), 7.72 (s, 1 H), 7.38-7.33 (m, 1 H), 2.42 ((t, J = 7 Hz, 2 H), 1.65 to 1.57 (m , 2H), 1.46-1.30 (m, 4H), 0.90 (t, J = 7 Hz, 3H).

3- (4-Hept-1-ynyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 45B)
Compound 44B was converted to compound 45B using the method described for the conversion of 21A to 22A (see Scheme 3). Yield: 44% (amorphous). LCMS (Method A); R _t : 1.84 min, ([M + H] ⁺ = 258).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 6.78-6.66 (bs, 1H), 3.42-3.38 (m, 2H), 2.59 (Bt, J = 7 Hz, 2H), 2.45 (s, 3H), 2.44-2.37 (m, 2H), 1.62-1.43 (m, 4H), 0.94 (t , J = 7 Hz, 3H).

3- (4-Nony-1-ynyl-1H-pyrazol-3-yl) -pyridine (Compound 44C)
Non-1-yne and 3- (1-phenylsulfonyl-4-iodo-1H-pyrazole-
Compound 44C was prepared according to the method described for the synthesis of compound 44A (see Scheme 9) using 3-yl) -pyridine (36B). (Diethyl ether / PE
Flash chromatography using 1/1) gave 3- (1-phenylsulfonyl-4-non-1-ynyl-1H-pyrazol-3-yl) -pyridine (43C) as an oil (80%). (TLC diethyl ether _Rf 0.44).
Using the method described for the conversion of 43A to 44A (see Scheme 9), compound 43C was converted to the title compound 44C. Yield: 78% (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.61 (dd, J = 5 Hz, 2 Hz, 1H), 8.35 (dt, J = 8 Hz, 2 Hz, 1 H), 7.73 (s, 1 H), 7.39-7.34 (m, 1 H), 2.42 ((t, J = 7 Hz, 2 H), 1.65 to 1.56 (m , 2H), 1.47-1.38 (m, 2H), 1.37-1.22 (m, 6H), 0.90 (t, J = 7 Hz, 3H).

3- (4-Nony-1-ynyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 45C)
Compound 44C was converted to Compound 45C using the method described for the conversion of 21A to 22A (see Scheme 3). Yield: 79% (amorphous). LCMS (Method A); R _t : 2.17 min, ([M + H] ⁺ = 286).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 6.74-6.69 (bs, 1H), 3.40-3.36 (m, 2H), 2.58 (Bt, J = 7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1 .39 (m, 2H), 1.36-1.23 (m, 6H), 0.89 (t, J = 7 Hz, 3H).

3- [4- (5-Phenyl-pent-1-ynyl) -1H-pyrazol-3-yl] -pyridine (Compound 44D)
The method described for the synthesis of compound 44A using pent-4-ynylbenzene and 3- (1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl) -pyridine (36B) (see Scheme 9) Compound 44C was prepared according to (Flash chromatography using diethyl ether / PE (1/1)) is 3- [1-phenylsulfonyl-4- (5-phenyl-pent-1-ynyl) -1H-pyrazol-3-yl] -pyridine ( 43D) was provided as an oil (80%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.3 (d, J = 2 Hz, 1H), 8.6 (dd, J = 5 Hz, 2 Hz, 1H), 8.33 (dt, J = 8 Hz, 2Hz, 1H), 8.22 (s, 1H), 8.09-8.05 (m, 2H), 7.68 (bt, J = 8Hz, 1H), 7.57 (bt, J = 8Hz, 2H), 7.35-7.25 (m, 3H), 7.21-7.15 (m, 3H), 2.74 ((t, J = 7 Hz, 2H), 2.42 ((t, J = 7 Hz, 2H), 1.96-1.87 (m, 2H).
(TLC diethyl ether _Rf 0.56).
Using the method described for the conversion of 43A to 44A (see Scheme 9), compound 43D was converted to the title compound 44D. Yield: 86% (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.6 (dd, J = 5 Hz, 2 Hz, 1H), 8.35 (dt, J = 8 Hz, 2 Hz, 1H), 7.74 (s, 1H), 7.40-7.17 (m, 6H), 2.77 ((t, J = 7 Hz, 2H), 2.44 ((t, J = 7 Hz, 2H), 1.99-1.89 (m, 2H).

3- [4- (5-Phenyl-pent-1-ynyl) -1H-pyrazol-3-yl] -1
, 2,5,6-Tetrahydro-1-methylpyridine (Compound 45D)
Compound 44D was converted to compound 45D using the method described for the conversion of 21A to 22A (see Scheme 3). Yield: 95% (amorphous). LCMS (Method A); R _t : 1.99 min, ([M + H] ⁺ = 306).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 7.31-7.18 (m, 5H), 6.79-6.73 (bs, 1H), 3.43 -3.40 (m, 2H), 2.78 (t, J = 7Hz, 2H), 2.60 (bt, J = 7Hz, 2H), 2.45-2.37 (m, 7H), 1 .95-1.87 (m, 2H).

3- [4- (5-Cyclohexyl-pent-1-ynyl) -1H-pyrazol-3-yl] -pyridine (Compound 44E)
The method described for the synthesis of compound 44A using pent-4-ynyl-cyclohexane and 3- (1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl) -pyridine (36B) (see Scheme 9). Compound 44E was prepared according to (Flash chromatography using diethyl ether / PE 1/1) is 3- [1-phenylsulfonyl-4- (5-cyclohexyl-pent-1-ynyl) -1H-pyrazol-3-yl] -pyridine (43E) As an oil (90%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.6 (dd, J = 5 Hz, 2 Hz, 1H), 8.33 (dt, J = 8 Hz, 2 Hz, 1 H), 8.21 (s, 1 H), 8.08-8.04 (m, 2 H), 7.68 (bt, J = 8 Hz, 1 H), 7.57 (bt, J = 8 Hz, 2H), 7.35-7.31 (m, 1H), 2.38 (t, J = 7 Hz, 2H), 1.72-1.55 (m, 6H), 1.31-1.10 ( m, 7H), 0.95-0.8 (m, 2H).
Using the method described for the conversion of 43A to 44A (see Scheme 9), compound 43E was converted to the title compound 44E. Yield: 94% (oil).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (d, J = 2 Hz, 1H), 8.6 (dd, J = 5 Hz, 2 Hz, 1H), 8.35 (dt, J = 8 Hz, 2 Hz, 1H), 7.72 (s, 1H), 7.39-7.34 (m, 1H), 2.40 (t, J = 7 Hz, 2H), 1.73-1.57 (m, 6H), 1.35-1.10 (m, 7H), 0.93-0.75 (m, 2H).

3- [4- (5-cyclohexyl-pent-1-ynyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine (Compound 45E)
Compound 44E was converted to Compound 45E using the method described for the conversion of 21A to 22A (see Scheme 3). Yield: 90% (amorphous). LCMS (Method A); R _t : 2.28 min, ([M + H] ⁺ = 312).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 6.76-6.71 (bs, 1H), 3.41-3.37 (m, 2H), 2.59 (Bt, J = 7 Hz, 2H), 2.45-2.35 (m, 7H), 1.75-1.55 (m, 6H), 1.35-1.10 (m, 7H), 0 .94-0.8 (m, 2H).

3- (4-Hex-1-enyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 47A, Scheme 9)
To toluene (20 ml) containing 36A (0.67 g, 1.84 mmol) (see Scheme 7) 1.5 equivalents of (E) -hexen-1-ylboronic acid (0.35 g) was added. It was. The resulting mixture was stirred under N ₂ for 2 hours. 2 equivalents of K ₃ PO ₄ (0.7
8g) 4 mol% Pd (OAc) ₂ (16.5 mg) and 8 mol% S-Phos (60.4 mg) were added in succession. After the addition, the resulting solution was warmed at 90 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (1-phenylsulfonyl-4-hex-1-enyl-1H-pyrazol-3-yl) -pyridine (46A). As an oil (0.38 g, 61%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.8 (d, J = 2 Hz, 1H), 8.6 (dd, J = 5 Hz, 2 Hz, 1H), 8.15 (s, 1H), 8 .10-8.05 (m, 2H), 7.94 (dt, J = 8 Hz, 2 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (bt, J = 8 Hz, 2H), 7.37-7.33 (m, 1H), 6.19-6.02 (m, 1H), 2.2-2.13 (m, 2H), 1.45-1.29 ( m, 4H), 0.90 (t, J = 7 Hz, 3H).
Compound 46A (0.34 g, 0.97 mmol), 0.7 g KOH and 1 ml NH ₂ NH ₂ . H ₂ O was combined in diethylene glycol (10 ml) and warmed to reflux under N ₂ for 1 hour. The mixture was cooled, concentrated and redissolved in MeOH. Purification on 25 g SCX-2 by filtration (MeOH followed by 1N NH ₃ / MeOH) followed by flash chromatography (ethyl acetate) was purified by 3- (4-hex-1-enyl-1H-pyrazol-3-yl ) -Pyridine (deprotected analog of 46A) was provided. Yield 0.18 g (86%). (TLC diethyl ether _Rf 0.18).
Using the method described for conversion of 21A to 22A (see Scheme 3), 3- (4-hex-1-enyl-1H-pyrazol-3-yl) -pyridine was converted to the title compound 47A. Yield: 50% (amorphous). LCMS (Method A); R _t : 2.30 min ([M + H] ⁺ = 246).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.59 (s, 1H), 6.22 (bd, J = 16 Hz, 1H), 6.03-5.98 (bs, 1H), 5.98 −5.88 (m, 1H), 3.26-3.21 (m, 2H), 2.63 (bt, J = 7 Hz, 2H), 2.44 (s, 3H), 2.43-2 .36 (m, 2H), 2.19-2.11 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, J = 7 Hz, 3H).

3- {4-2 [-(3-Fluoro-phenyl) -vinyl] -1H-pyrazol-3-yl} -1,2,5,6-tetrahydro-1-methylpyridine (Compound 47B)
Toluene (20 ml) containing 36A (0.48 g, 1.32 mmol) (see Scheme 7) was added 1.5 equivalents of (E) -2- (3-fluorophenyl) -vinylboronic acid (0 .33 g) was added. The resulting mixture was stirred under N ₂ for 2 hours. 2 equivalents of _K 3 _PO 4 (0.56g), were added successively 4 mol% of _Pd (OAc) 2 (8.8mg) and 8 mol% of S-Phos (32mg). After the addition, the resulting solution was warmed at 90 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (1-phenylsulfonyl-4- [2- (3-fluoro-phenyl) -vinyl] -1H-pyrazole-3. -Yl) -pyridine (46B) was provided as an oil (0.39 g, 73%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.85 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 8.36 (s, 1H), 8 .13-8.08 (m, 2H), 7.95 (dt, J = 8 Hz, 2 Hz, 1H), 7.72-7.67 (m, 1H), 7.58 (bt, J = 8 Hz, 2H), 7.41-7.37 (m, 1H), 7.33-7.27 (m, 1H), 7.16 (bd, J = 7 Hz, 1H), 7.12-7.07 ( m, 1H), 7.0-6.94 (m, 1H), 6.92 (d, J = 16 Hz,
1H), 6.82 (d, J = 16 Hz, 1H).
Compound 46B (1.06 g, 2.62 mmol), 1.3 g KOH and 2 ml NH ₂ NH ₂ . H ₂ O was combined in diethylene glycol (25 ml) and warmed to reflux under N ₂ for 1 hour. The mixture was cooled, concentrated and redissolved in MeOH. Purification on 25 g SCX-2 by filtration (MeOH followed by 1N NH ₃ / MeOH) and subsequent flash chromatography (ethyl acetate) yields 3- {4- [2- (3-fluoro-phenyl) -vinyl] -1H-pyrazol-3-yl} -pyridine (46B deprotected analog) was provided. Yield 0.42 g (60.4%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.85 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 7.95-7.90 (m, 2H), 7.45-7.41 (m, 1H), 7.32-7.27 (m, 1H), 7.20-7.16 (m, 1H), 7.14-7.09 ( m, 1H), 6.99 (d, J = 16 Hz, 1H), 6.96-6.86 (m, 2H).
3- {4- [2- (3- (Fluoro-phenyl) -vinyl] -1H-pyrazol-3-yl} -pyridine using the method described for the conversion of 21A to 22A (see Scheme 3). Was converted to the title compound 47B. Yield: 67% (amorphous). LCMS (Method _A); R t: 1.79 ^{min, ([M + H] +} = 284).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.78 (s, 1H), 7.31-7.25 (m, 1H), 7.20-7.10 (m, 2H), 7.0 −6.88 (m, 2H), 6.81 (d, J = 16 Hz, 1H), 6.07-6.01 (m, 1H), 3.33-3.25 (m, 2H), 2 .69 (bt, J = 7 Hz, 2H), 2.50-2.42 (m, 5H).

3- (4-Oct-1-enyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 47C)
To toluene (20 ml) containing 36A (0.91 g, 2.5 mmol) (see Scheme 7) 1.5 equivalents of (E) -octen-1-ylboronic acid (0.59 g) was added. It was. The resulting mixture was stirred under N ₂ for 2 hours. 2 equivalents of _K 3 _PO 4 (1.06g), were added successively 4 mol% of _Pd (OAc) 2 (22.4mg) and 8 mol% of S-Phos (82mg). After the addition, the resulting solution was warmed at 90 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (1-phenylsulfonyl-4-oct-1-enyl-1H-pyrazol-3-yl) -pyridine (46C). As an oil (0.31 g, 32%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.85 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 8.15 (s, 1H), 8 .08-8.05 (m, 2H), 7.93 (dt, J = 8 Hz, 2 Hz, 1H), 7.69-7.64 (m, 1H), 7.59-7.52 (m, 2H), 7.37-7.33 (m, 1H), 6.19 (d, J = 16 Hz, 1H), 6.10-6.03 (m, 1H), 2.19-2.12 ( m, 2H), 1.45 to 1.37 (m, 2H), 1.36 to 1.23 (m, 6H), 0.90 (t, J = 7 Hz, 3H).
Compound 46C (0.35 g, 0.89 mmol), 0.7 g KOH and 1 ml NH ₂ NH ₂ . H ₂ O was combined in diethylene glycol (10 ml) and warmed to reflux under N ₂ for 1 hour. The mixture was cooled, concentrated and redissolved in MeOH. Purification on 25 g SCX-2 by filtration (MeOH followed by 1N NH ₃ / MeOH) followed by flash chromatography (ethyl acetate) was purified by 3- (4-oct-1-enyl-1H-pyrazol-3-yl ) -Pyridine (deprotected analog of 46C) was provided. Yield 0.19 g (95%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.85 (d, J = 2 Hz, 1H), 8.65 (dd, J = 5 Hz, 2 Hz, 1H), 7.91 (dt, J = 8 Hz, 2 Hz, 1 H), 7.71 (s, 1 H), 7.41-7.36 (m, 1 H), 6.27 (d, J = 16 Hz, 1 H), 6.07-5.98 (m, 1H), 2.19-2.12 (m, 2H), 1.46-1.38 (m, 2H), 1.37-1.23 (m, 6H), 0.89 (t, J = 7Hz, 3H).
Using the method described for the conversion of 21A to 22A (see Scheme 3), 3- (4-oct-1-enyl-1H-pyrazol-3-yl) -pyridine was converted to the title compound 47C. Yield: 95% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 6.24 (bd, J = 16 Hz, 1H), 6.07-6.02 (m, 1H), 5.98 −5.89 (m, 1H), 3.29-3.25 (m, 2H), 2.63 (bt, J = 7 Hz, 2H), 2.46 (s, 3H), 2.44-2 .38 (m, 2H), 2.18-2.12 (m, 2H), 1.46-1.38 (m, 2H), 1.38-1.24 (m, 6H), 0.91 (T, J = 7 Hz, 3H).

3- (4-Butylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49A, Scheme 10)
To a solution of compound 48 (0.5 g, 1.65 mmol), prepared according to Bioorganic & Medicinal Chemistry, 8, 2000, 449-454, in anhydrous THF (150 ml), 2.1 equivalents of n-BuLi ( 1.39 ml, 2.5 M in hexane) was added dropwise at −78 ° C. under N ₂ . After the dropwise addition, the resulting solution was stirred at −78 ° C. for 1.5 hours. At this temperature, 1.1 equivalents of ethyl disulfanylethane (0.35 ml) was added and the resulting solution was stirred at −78 ° C. for 1 hour, followed by allowing to warm to ambient temperature overnight. The mixture was then quenched with saturated NH ₄ Cl solution at 0 ° C. and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 2N NaOH, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (MeOH) gave the title compound 49A (amorphous, 0.15 g, 35%). Compound 49A was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. (solid). Melting point 162-164 ° C. LCMS (Method A); R _t : 1.62 min, ([M + H] ⁺ = 266).
¹ H-NMR (400 MHz, D ₆ DMSO): δ 7.83 (s, 1H), 6.43 (s, 2H), 3.60-3.39 (m, 3H), 3.25-3. 00 (m, 4H), 2.58 (bt, J = 7 Hz, 2H), 2.10-2.05 (m, 1H), 1.98-1.83 (m, 2H), 1.78- 1.68 (m, 1H), 1.48-1.30 (m, 4H), 0.84 (t, J = 7 Hz, 3H).

3- (4-Pentylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49B, Scheme 10)
Compound 48 dissolved; (13.2 mmol 1.82 g) and pentane-1-thiol (1.53 ml, 12.4 mmol) in DMF in 30 ml (2.50 g 8.25 _{mmol), K} 2 CO 3 The solution was degassed with argon for 45 minutes. To this solution was added Pd ₂ (dba) ₃ (755 mg; 0.83 mmol) and xantphos (953 mg; 1.65 mmol). After the addition, the reaction mixture was heated to 120 ° C. and stirred for 20 hours under N ₂ . The mixture was cooled, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1N NH ₃ / MeOH) and subsequent purification by flash chromatography (EtOH) gave the title compound 49B as an oil. Yield 395 mg (17%). Compound 49B was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (solid). Mp 142-145 ° C.
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.83 (s, 1H), 6.48 (s, 2H), 3.58-3.51 (m, 1H), 3.48-3. 41 (m, 2H), 3.25-3.15 (m, 3H), 3.11-3.03 (m, 1H), 2.61-2.53 (m, 2H), 2.11 2.06 (m, 1H), 1.97-1.85 (m, 2H), 1.77-1.69 (m, 1H), 1.59-1.52 (m, 1H), 1. 48-1.41 (m, 2H), 1.34-1.22 (m, 4H), 0.83 (t, J = 7 Hz, 3H).

3- (4-Methylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49C)
Compound 48 (2.50 g; 8.25 mmol) (see Scheme 10) was dissolved in 30 ml of DMF and the solution was degassed with argon for 45 minutes. To this solution was added NaSMe (867 mg, 12.4 mmol), Pd ₂ (dba) ₃ (755 mg; 0.83 mmol) and xantphos (953 mg; 1.65 mmol). After the addition, the reaction mixture was heated to 120 ° C. and stirred for 20 hours under N ₂ . The mixture was cooled, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1N NH ₃ / MeOH) followed by purification by flash chromatography (EtOH) gave compound 49C (oil). Crystallization from diethyl ether gave the title compound (solid). Mp 145-147 ° C. Yield: 290 mg (16%).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.70 (s, 1H), 3.21-3.12 (m, 1H), 3.10-3.01 (m, 2H), 2. 92-2.85 (m, 1H), 2.81-2.73 (m, 2H), 2.68-2.61 (m, 1H), 2.21 (s, 3H), 1.81- 1.78 (m, 1H), 1.68-1.55 (m, 3H), 1.25-1.18 (m, 1H).

3- (4- Ethylsulfanyl -1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49D)
Compound 49D was prepared according to the method described for the synthesis of compound 49B (see Scheme 10) using ethanethiol as a reagent. Subsequent purification by flash chromatography (EtOH to EtOH / triethylamine 99/1) gave compound 49D.
Yield: 30% (oil).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.69 (s, 1H), 3.16-2.99 (m, 3H), 2.92-2.84 (m, 1H), 2. 80-2.71 (m, 2H), 2.67-2.60 (m, 1H), 2.56-2.51 (m, 2H), 1.78-1.75 (m, 1H), 1.66-1.54 (m, 3H), 1.25-1.18 (m, 1H), 1.08 (t, J = 7 Hz, 3H).

3- (4- Propylsulfanyl -1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49E)
Compound 49E was prepared according to the method described for the synthesis of compound 49B (see Scheme 10) using propane-1-thiol as a reagent. Subsequent purification by flash chromatography (EtOH to EtOH / triethylamine 99/1) gave compound 49E.
Yield: 25% (amorphous)
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.72-7.64 (bs, 1H), 3.16-2.99 (m, 3H), 2.93-2.84 (m, 1H) ), 2.80-2.71 (m, 2H), 2.67-2.60 (m, 1H), 2.54-2.48 (m, 2H +)
DMSO), 1.78-1.75 (m, 1H), 1.66-1.54 (m, 3H), 1.47-1.40 (m, 2H), 1.25-1.18 ( m, 1H), 0.90 (t, J = 7 Hz, 3H).

3- (4-Hexylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49F)
Compound 49F was prepared according to the method described for the synthesis of compound 49B (see Scheme 10) using hexane-1-thiol as a reagent. Subsequent purification by flash chromatography (EtOH) gave compound 49F.
Yield: 25% (oil). Compound 49F was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (solid). Melting point 130 ° C.
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.81 (s, 1H), 6.46 (s, 2H), 3.55 to 3.49 (m, 1H), 3.45-3-3. 39 (m, 2H), 3.22-3.13 (m, 3H), 3.08-3.02 (m, 1H), 2.60-2.52 (m, 2H), 2.09- 2.05 (m, 1H), 1.95-1.83 (m, 2H), 1.75-1.68 (m, 1H), 1.57-1.51 (m, 1H), 1. 46-1.40 (m, 2H), 1.35-1.29 (m, 2H), 1.27-1.17 (m, 4H), 0.83 (t, J = 7 Hz, 3H).

3- (4-Phenethylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 49G)
Compound 49G was prepared according to the method described for the synthesis of compound 49B (see Scheme 10) using 3-phenyl-1-propanethiol as a reagent. Subsequent purification by flash chromatography (EtOH) gave compound 49G.
Yield: 11% (oil). Compound 49G was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (amorphous).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.86 (s, 1H), 7.26 (t, J = 8 Hz, 2H), 7.19-7.14 (m, 3H), 6. 49 (s, 2H), 3.56-3.50 (m, 1H), 3.46-3.39 (m, 2H), 3.24-3.14 (m, 3H), 3.10- 3.03 (m, 1H), 2.66 (t, J = 7 Hz, 2H), 2.60-2.53 (m, 2H), 2.03-2.00 (bs, 1H), 1. 94-1.82 (m, 2H), 1.77-1.68 (m, 3H), 1.56-1.50 (m, 1H).

3- [4- (3-Methyl-butylsulfanyl) -1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane (Compound 49H)
Compound 49H was prepared according to the method described for the synthesis of compound 49B (see Scheme 10) using 3-methyl-1-butanethiol as a reagent. Subsequent purification by flash chromatography (EtOH) gave compound 49G.
Yield: 20% (oil). Compound 49G was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (solid). Melting point 157-159 [deg.] C.
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.83 (s, 1H), 6.47 (s, 2H), 3.56-3.50 (m, 1H), 3.46-3. 40 (m, 2H), 3.24-3.15 (m, 3H), 3.09-3.03 (m, 1H), 2.58 (t, J = 7 Hz, 2H), 2.09- 2.06 (bs, 1H), 1.96-1.84 (m, 2H), 1.76-1.68 (m, 1H), 1.67-1.59 (m, 1H), 1. 58-1.52 (m, 1H), 1.38-1.30 (m, 2H), 0.83 (d, J = 7 Hz, 6H)
.

3- [4- (4,4-Difluoro-but-3- enylsulfanyl) -1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane (Compound 49I)
3-Phenyl-propyldisulfanyl-3-propylbenzene as a disulfide (prepared according to the method described in Tetrahedron letters, 42, 2001, 6741-6743) and 3- (4-iodo-1H-pyrazol-3-yl) Compound 49I was prepared according to the method described for the synthesis of Compound 21A (see Scheme 3) using 1-azabicyclo [2.2.2] octane (see Compound 48, see Scheme 10). Purification conditions were: Prep HPLC (system CHSLCPO2), column: Inertsil ODS-3, 8 μm, eluent 10% / 90% CH ₃ CN / H ₂ O + HCOOH, 50 ml / min LCMS (Method A): R _t : 1.16 ^{minutes, ([M + H] +} = 300). Rate: 4.5% (oil).
¹ H-NMR (600 MHz, CDCl ₃ ): δ 7.63 (s, 1H), 4.24 and 4.17 (ddt, J = 7 Hz, 26 Hz, 3 Hz, 1H), 3.91-3.84 ( m, 1H), 3.51-3.37 (m, 3H), 3.32-3.19 (m, 2H), 3.12-3.03 (m, 1H), 2.57 (t, J = 7 Hz, 2H), 2.23-2.15 (m, 3H), 2.12-2.01 (m, 1H), 2.01-1.89 (m, 2H), 1.61- 1.51 (m, 1H).

3- (4-Butoxy-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 52A, Scheme 10)
A 60% dispersion of NaH in mineral oil (1.5 g, 38 mmol) was added to 3- (4-iodo-1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane (compound 48, To a solution of anhydrous THF (300 ml) containing 9.6 g, 31.7 mmol) was added under N _{2. The} resulting mixture was stirred at room temperature for 2 hours until all solids dissolved. The mixture was treated with 38.4 mmol (6.74 ml) of 2-chloromethoxy-ethyl-trimethylsilane (SEM-Cl) and the resulting mixture was stirred at room temperature for 20 hours, part of the desired product (50). Due to typical quaternization, TBAF (1M solution in THF, 45 ml, 45 mmol) was added and the mixture was stirred at room temperature for 20 h, ethyl acetate was added to the mixture and the organic layer was dissolved in 2N NaOH. And followed by brine, dried _(Na 2 _SO 4), filtered and concentrated to give 3- [4-iodo-1- (2-trimethylsilanyl - ethoxymethyl)-1H-pyrazol-3-yl .] -1-azabicyclo [2.2.2] gave octane (50) yield: 11.6 g, 26.7 mmol, 84% .LCMS (method _B); R t: 3.11 min, ([ M + H] ⁺ = 434).
Compound 50 (2.5 g, 5.77 mmol), CuI (1.37 g, 7.19 _{mmol), Cs 2 CO 3 (3.90g} , 12 mmol), 1,10-phenanthroline (2.60 g, 14. 4 mmol) and butanol (25 ml) were heated in a microwave at 150 ° C. for 4 hours.
The mixture was cooled to room temperature. Ethyl acetate was added and the organic layer was washed with 2N NaOH solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography (gradient EtOH to EtOH / triethylamine 300/1) followed by a second flash chromatography (EtOH / ethyl acetate / triethylamine 25/75/1) to give compound 51A as an oil (0.33 g, 15%). LCMS (Method _B); R t: 3.27 ^{min, ([M + H] +} = 380).
Compound 51A (0.33 g, 0.86 mmol) in anhydrous THF containing (5 ml), was added TBAF in 3.5ml of (1.0M in THF) _{N 2} below. After the addition, the resulting solution was stirred at room temperature for 20 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (gradient EtOH to EtOH / triethylamine 97/3) followed by preparative HPLC purification: PrepHPLC (system CHSLCPO2), column: Inertsil ODS-3, 8 μm. Eluent 10% / 90% CH ₃ CN / H ₂ O + HCOOH, 50 ml / min was performed to give the title compound 52A. (Oil, 0.1 g, 45%). LCMS (Method _A): R t: 1.0 ^{min, ([M + H] +} = 250).
¹ H-NMR (600 MHz, D ₆ DMSO + a few drops of HCOOH): δ 8.63 (s, ˜1H), 7.2 (s, 1H), 3.99-3.93 (m, 1H), 3 .85 (t, J = 7 Hz, 2H), 3.54-3.26 (m, 5H), 3.19-3.12 (m, 1H), 2.36-2.32 (m, 1H) , 2.12-1.95 (m, 3H), 1.76-1.70 (m, 2H), 1.67-1.60 (m, 1H), 1.50-1.42 (m, 2H), 0.98 (t, J = 7 Hz, 3H).

3- (4-propoxy-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 52B)
Compound 52A using propanol and 3- [4-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane (50) Compound 52B was prepared according to the method described for the synthesis of (see Scheme 10). Finishing and flash chromatography (gradient EtOH to EtOH / triethylamine 300/1) followed by a second flash chromatography (EtOH / ethyl acetate / triethylamine 25/75/1) gave compound 51B as an oil (14%) . LCMS (Method _B): R t: 7.15 ^{min, ([M + H] +} = 366). Compound 51A was subsequently deprotected (TBAF / THF) and purified by flash chromatography (gradient EtOH to EtOH / triethylamine 97/3) followed by preparative TLC purification (CH ₃ CN / H ₂ O), The title compound 52B was provided as an oil. (51%). LCMS (Method A); R _t : 0.91 min, ([M + H] ⁺ = 236).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.34 (s, 1H), 3.74 (t, J = 7 Hz, 2H), 3.24-3.19 (m, 1H), 3. 03-2.96 (m, 1H), 2.92-2.87 (m, 1H), 2.86-2.74 (m, 3H), 2.69-2.62 (m, 1H), 1.88-1.84 (m, 1H), 1.67-1.55 (m, 5H), 1.26-1.20 (m, 1H), 0.92 (t, J = 7 Hz, 3H ).

3- (4-Pentyloxy-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane (Compound 52C)
Pentanol (25 ml) and 3- [4-Iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane (50) ( Compound 52C was prepared according to the method described for the synthesis of Compound 52A (see Scheme 10) using 2 g, 4.61 mmol). Finishing and flash chromatography (gradient EtOH to EtOH / triethylamine 300/1) followed by a second flash chromatography (EtOH / ethyl acetate / triethylamine 25/75/1) gave compound 51C as an oil (0.46 g 15%). LCMS (Method B); R _t : 3.30 min ([M + H] ⁺ = 394).
To a solution of SEM-protected pyrazole 51C (0.46 g, 1.2 mmol) in EtOH (5 ml) was added HCl (4M in dioxane, 1 ml, 4 mmol) and the reaction mixture was stirred at 75 ° C. for 20 h. Stir. Subsequent purification by flash chromatography (gradient EtOH to EtOH / triethylamine 97/3) followed by preparative HPLC purification:
PrepHPLC (system CHSLCPO2), column: Inertsil ODS-3, 8 μm. Eluent 10% / 90% CH ₃ CN / H ₂ O + HCOOH, 50 ml / min gave the title compound 52C. (Oil, 60 mg, 19%).
¹ H-NMR (600 MHz, D ₆ DMSO + a few drops of HCOOH): δ 8.65 (s, ˜1H), 7.2 (s, 1H), 3.96-3.90 (m, 1H), 3 .84 (t, J = 7 Hz, 2H), 3.54-3.46 (m, 1H), 3.45-3.26 (m, 4H), 3.19-3.12 (m, 1H) , 2.36-2.32 (m, 1H), 2.12-1.95 (m, 3H), 1.79-1.74 (m, 2H), 1.67-1.60 (m, 1H), 1.45-1.35 (m, 4H), 0.95 (t, J = 7 Hz, 3H).

Exo-6- (1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octan-6-ol (Compound 55, Scheme 11)
A suspension of propargylaldehyde diethyl acetal (14.62 g, 114 mmol) and t-BuOK (14.92 g, 133 mmol) in 350 ml of anhydrous THF was stirred at −10 ° C. for 1 hour under N ₂ . Then 1-aza-bicyclo [3.2.1] octane-6-one (53, J. Med. Chem., 36, 1993, 683-689) (11.92 g. 95 mmol) in 100 ml THF. And the resulting homogeneous reaction mixture was stirred at 0 ° C. for a further 2 hours. The mixture was then quenched with aqueous acetic acid at 0 ° C. and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 2N NaOH, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (dichloromethane / MeOH / NH ₄ OH 93/7 / 0.5) was obtained from 6- (3,3-diethoxy-prop-1-ynyl) -1-azabicyclo [3.2.1] octane. -6-ol (54) was provided as an oil (20.87 g, 86%). LCMS (Method _A): R t: 1.18 ^{min, ([M + H] +} = 254).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.28 (s, 1H), 3.74-3.65 (m, 2H), 3.61-3.52 (m, 2H), 3.45 (D, J = 13 Hz, 1H), 3.12-3.04 (m, 1H), 3.0-2.82 (m, 4H), 2.22-2.18 (m, 1H), 2 .17-2.02 (m, 1H), 1.98-1.89 (m, 1H), 1.71-1.61 (m, 1H), 1.39-1.30 (m, 1H) 1.22 (t, J = 7 Hz, 6H).
Compound 54 (15.39 g, 60.7 mmol) and 7.02 g hydrazine dihydrochloride were combined in EtOH / H ₂ O (3/2, 250 ml) and warmed to reflux under N ₂ for 18 hours. The mixture was cooled, concentrated and re-dissolved in MeOH. Amberlyte IRA-95 (basic) was added to the reaction mixture, followed by stirring at room temperature for 18 hours. The mixture was filtered, concentrated and re-dissolved in MeOH. Filtration over 100 g SCX-2 (MeOH followed by 1N NH ₃ / MeOH) gave the title compound 55 (amorphous). Yield 8.45 g (72%).
¹ H-NMR (600 MHz, D ₆ DMSO + a few drops of CF ₃ COOH): δ 7.70 (d, J = 2 Hz, 1H), 6.42 (d, J = 2 Hz, 1H), 4.24-4 .20 (m, 1H), 3.41-3.31 (m, 4H), 3.25-3.21 (m, 1H), 2.45-2.42 (m, 1H), 2.40 -2.30 (m, 1H), 2.10-2.04 (m, 1H), 1.74-1.64 (m, 2H), the methods used were DEPT, HSQC, COSY, HMBC, ROESY And NOESY.

Endo-6- (1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane (Compound 58, Scheme 11)
Compound 55 (7.83 g, 41 mmol) and 9.81 ml (120 mmol) of pyridine were combined in benzene (150 ml). Acetic anhydride (11.48 ml, 120 mmol) was added and the reaction mixture was warmed to 40 ° C. under N ₂ for 72 hours. The mixture was cooled, concentrated and re-dissolved in MeOH. 100g filtration over SCX-2 of (MeOH and subsequently 1N _NH 3 / MeOH) compound 56 (amorphous, 9.6 g, to 100%), LCMS (method _A): R t: 0.98 min, ([M + H] ⁺ = 236) was obtained and used without further purification.
Compound 56 (1.2 g, 5.1 mmol) was heated under reduced pressure (23 mbar) at 200 ° C. for 5 minutes (in the neat) followed by cooling to room temperature. Purification by flash chromatography (dichloromethane / MeOH / NH ₄ OH 85/15/1) was purified by 6- (1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] oct-6-ene (57 ) As an oil (0.49 g, 49%). LCMS (Method _A): R t: 1.27 ^{min, ([M + H] +} = 176).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.56 (d, J = 2 Hz, 1H), 6.43 (s, 1H), 6.36 (d, J = 2 Hz, 1H), 3.50 −3.45 (m, 1H), 3.06-2.97 (m, 1H), 2.93 (d, J = 10 Hz, 1H), 2.86-2.79 (m, 2H), 2 0.06-1.93 (m, 1H), 1.78-1.72 (m, 1H), 1.49-1.41 (m, 1H).
Compound 57 (3.84 g, 21.9 mmol), 6.9 g ammonium formate (110 mmol) and 20% Pd (OH) ₂ / C (340 mg) were combined in MeOH (150 ml) and warmed to reflux for 1 hour. I let you. The mixture was cooled, filtered, concentrated and re-dissolved in MeOH. Purification by filtration over 40 g of SCX-2 (MeOH followed by 1N NH ₃ / MeOH) and subsequent flash chromatography (MeOH / triethylamine 90/3) gave endo-6- (1H-pyrazol-3-yl)- 1-azabicyclo [3.2.1] octane (58) was obtained (amorphous, 2.8 g, 73%). LCMS (Method _A): R t: 0.80 ^{min, ([M + H] +} = 178).
¹ H-NMR (600 MHz, D ₆ DMSO / CDCl ₃ (1/1)): δ 7.54 (d, J = 2 Hz, 1H), 6.16 (d, J = 2 Hz, 1H), 3.98 -3.92 (m, 1H), 3.90-3.84 (m, 1H), 3.82-3.77 (m, 1H), 3.53-3.48 (m, 1H), 3 .32-3.24 (m, 3H), 2.82-2.77 (m, 1H), 2.03-1.94 (m, 1H), 1.68-1.60 (m, 1H) , 1.58-1.52 (m, 1H), 1.51-1.47 (m, 1H), the methods used are DEPT, HSQC, COSY, HMBC, ROESY and NOESY.

Endo-6- (4-pentylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane (Compound 60A, Scheme 11)
To a solution of 58 (1.49 g, 8.41 mmol) in anhydrous DMF (60 ml) at −10 ° C. was added 2.68 g (10.93 mmol) N-iodosuccinimide. The reaction mixture was stirred at −10 ° C. for 2 hours and at room temperature for 1 hour. The solvent was (partially) removed under reduced pressure. MeOH was added and the resulting reaction mixture was filtered over 120 g SCX-2 (MeOH followed by 1N NH ₃ / MeOH) and endo-6- (4-iodo-1H-pyrazol-3-yl) -1- Azabicyclo [3.2.1] octane (59) was obtained (amorphous, 1.73 g, 67%). LCMS (Method A); R _t : 1.25 min, ([M + H] ⁺ = 304).
¹ H-NMR (600 MHz, D ₆ DMSO + CF ₃ COOH): δ 7.72 (s, 1H), 4.08-4.03 (m, 1H), 3.80-3.75 (m, 1H), 3.73-3.68 (m, 1H), 3.50-3.45 (m, 1H), 3.34-3.25 (m, 3H), 3.04-3.0 (m, 1H) ), 2.24-2.14 (m, 1H), 1.64-1.57 (m, 1H), 1.50-1.42 (m, 1H), 1.22-1.17 (m 1H), the methods used are DEPT, HSQC, COSY, HMBC, ROESY and NOESY.
Compound 59 (0.50 g; 1.65 mmol), K ₂ CO ₃ (0.3 g; 2.14 mmol) and pentane-1-thiol (0.26 ml, 2.06 mmol) were added to 20 ml of xylene / DMF ( 9/1) and the solution was degassed with argon for 45 minutes. To this solution _{Pd 2 (dba) 3 (150mg} ; 0.165 mmol) and Xantphos; a (190 mg 0.33 mmol) was added. After the addition, the reaction mixture was heated to 130 ° C. and stirred for 20 hours under N ₂ . The mixture was cooled, concentrated and re-dissolved in MeOH. Purification on 75 g SCX-2 (MeOH followed by 1N NH ₃ / MeOH) and subsequent flash chromatography (MeOH / triethylamine (97/3)) gave the title compound 60A as an oil. Yield 150 mg (32%). Compound 60A was reacted with 1 equivalent of fumaric acid in EtOH and concentrated (amorphous).
LCMS (Method A); R _t : 1.39 min ([M + H] ⁺ = 280).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.85 (s, 1H), 6.43 (s, 2H), 3.80-3.70 (m, 2H), 3.63-3. 58 (m, 1H), 3.28-3.22 (m, 1H), 3.20-3.19 (m, 3H), 2.82-2.78 (m, 1H), 2.63- 2.55 (m, 2H), 2.12 to 2.01 (m, 1H), 1.65 to 1.56 (m, 1H), 1.50 to 1.44 (m, 2H), 1. 37-1.15 (m, 6H), 0.85 (t, J = 7 Hz, 3H).

Endo-6- (4-butylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane (Compound 60B)
The method described for the synthesis of compound 60A using butane-1-thiol and endo-6- (4-iodo-1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane (50) ( Compound 60B was prepared according to Scheme 11). Compound 60B was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Yield: 49% (amorphous). LCMS (Method _A); R t: 1.71 ^{min, ([M + H] +} = 266).
¹ H-NMR (600 MHz, D ₆ DMSO): δ 7.80 (s, 1H), 6.46 (s, 2H), 3.94-3.89 (m, 1H), 3.86-3. 81 (m, 1H), 3.79-3.74 (m, 1H), 3.45-3.41 (m, 1H), 3.31-3.22 (m, 3H), 2.93- 2.89 (m, 1H), 2.62-2.55 (m, 2H), 2.21-2.11 (m, 1H), 1.66-1.59 (m, 1H), 1. 49-1.42 (m, 2H), 1.40-1.33 (m, 2H), 1.26-1.20 (m, 2H), 0.86 (t, J = 7 Hz, 3H).

3- (4-Bromo-isoxazol-3-yl) -pyridine (Compound 64, Scheme 12)
To a solution of anhydrous THF (250 ml) containing 3-pyridine aldoxime (61) (18.87 g, 154.7 mmol) was added 20.57 g (1.0 eq) N-chlorosuccinimide. After the addition, the resulting solution was stirred at 65 ° C. for 18 hours. The temperature of the reaction mixture was then lowered to −30 ° C. and 1,2-bis-trimethylsilanyl-ethyne was added (26.4 g, 170.4 mmol), keeping the temperature <−25 ° C., followed by triethylamine ( 2 equivalents, 42 ml, dropwise) was added. After stirring for an additional 30 minutes, the mixture was allowed to warm to ambient temperature, diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue is purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (4,5-bis-trimethylsilanyl-isoxazol-3-yl) -pyridine (62) as an oil. (4.45 g, 17%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.70 (dd, J = 5 Hz, 2 Hz, 1H), 8.68 (d, J = 2 Hz, 1H), 7.76 (dt, J = 8 Hz, 2 Hz, 1H), 7.41-7.37 (m, 1H), 0.46 (s, 9H),. 011 (s, 9H
).
To a solution of anhydrous CCl ₄ (80 ml) containing compound 62 (4.45 g, 15.4 mmol) was added (1.1 eq, 1.04 ml) of Br ₂ . After the addition, the resulting solution was stirred at 40 ° C. for 18 hours. The reaction mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether) gave 3- (4-bromo-5-trimethylsilanyl-isoxazol-3-yl) -pyridine (63) as an oil (4.5 g, -100%). .
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.08 (d, J = 2 Hz, 1H), 8.73 (dd, J = 5 Hz, 2 Hz, 1H), 8.14 (dt, J = 8 Hz, 2 Hz, 1H), 7.46-7.41 (m, 1H), 0.40 (s, 9H).
To a solution of EtOH (20 ml) containing compound 63 (4.5 g, 15.4 mmol), 5 ml of 25% NH ₄ OH was added. After the addition, the resulting solution was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether) gave the title compound (64) as an oil (2.76 g, 82%). (TLC diethyl ether _Rf 0.4).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.14 (d, J = 2 Hz, 1H), 8.76 (dd, J = 5 Hz, 2 Hz, 1H), 8.58 (s, 1H), 8 .19 (dt, J = 8 Hz, 2 Hz, 1H), 7.48-7.43 (m, 1H).

3- (4-Butylsulfanyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 66A, Scheme 12)
To a degassed solution of dioxane (40 ml) containing 64 (1.0 g, 4.44 mmol) was added 1.2 equivalents (0.62 ml) butane-1-thiol and 2 equivalents triethylamine (1.52 ml). ) Was added. The resulting mixture was stirred for further 2 hours under N _2. 2.5 mol% of _{Pd 2 (dba) 3 (100mg} ) and 5 mol% of Xantphos a (128 mg) were successively added. After the addition, the resulting solution was stirred at 95 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to give 3- (4-butylsulfanyl-isoxazol-3-yl) -pyridine (65A) as an oil (0.26 g, 25%). (TLC diethyl ether _Rf 0.54).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.24 (d, J = 2 Hz, 1H), 8.72 (dd, J = 5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8 .31 (dt, J = 8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J = 7 Hz, 2H), 1.52-1.43 (m, 2H), 1.39-1.29 (m, 2H), 0.83 (t, J = 7 Hz, 3H).
To a solution of 65A (0.35 g, 1.5 mmol) in acetone (20 ml) was added 1 equivalent of sulfuric acid dimethyl ester (0.14 ml, 1.5 mmol) and the mixture was stirred at room temperature for 18 hours. The precipitated crystals were filtered, washed extensively with diethyl ether and dried to give the corresponding pyridinium sulfate monomethyl ester derivative. To a cooled (−30 ° C.) suspension of this compound in MeOH (25 ml) was added sodium borohydride (0.17 g, 4.5 mmol) in small portions. The mixture was allowed to warm to ambient temperature and was poured into saturated NH ₄ Cl solution (0 ° C.). The solvent was (partially) removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH) to give the title compound 66A (amorphous, 1.09 g, 73% (total)). LCMS (Method _A): R t: 1.58 ^{min, ([M + H] +} = 253).
¹ H-NMR (600 MHz, CDCl ₃ ): δ 8.23 (s, 1H), 7.06-7.04 (m, 1H), 3.40-3.38 (m, 2H), 2.68 (T, J = 7 Hz, 2H), 2.59 (t, J = 7 Hz, 2H), 2.48-2.42 (m, 5H), 1.57-1.51 (m, 2H), 1 .44-1.37 (m, 2H), 0.90 (t, J = 7 Hz, 3H).

3- (4-Hexylsulfanyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 66B)
To a degassed solution of dioxane (30 ml) containing 64 (0.6 g, 2.66 mmol) (see Scheme 12) 1.2 equivalents (0.62 ml) hexane-1-thiol and Two equivalents of triethylamine (0.92 ml) was added. The resulting mixture was stirred for further 2 hours under N _2. 2.5 mol% of _{Pd 2 (dba) 3 (61mg} ) and 5 mol% of Xantphos a (77 mg) were successively added. After the addition, the resulting solution was stirred at 95 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to give 3- (4-hexylsulfanyl-isoxazol-3-yl) -pyridine (65B) as an oil (0.25 g, 37%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.24 (d, J = 2 Hz, 1H), 8.73 (dd, J = 5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8 .31 (dt, J = 8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J = 7 Hz, 2H), 1.52-1.43 (m, 2H), 1.35-1.13 (m, 6H), 0.85 (t, J = 7 Hz, 3H).
To a solution of 65A (0.25 g, 0.95 mmol) in acetone (20 ml) was added 1 equivalent of sulfuric acid dimethyl ester (0.09 ml, 0.95 mmol) and the mixture was stirred at room temperature for 18 hours. The precipitated crystals were filtered, washed extensively with diethyl ether and dried to give the corresponding pyridinium sulfate monomethyl ester derivative. To a cooled (−30 ° C.) suspension of this compound in MeOH (25 ml) was added sodium borohydride (0.144 g, 4 eq) in small portions. The mixture was allowed to warm to ambient temperature and was poured into saturated NH ₄ Cl solution (0 ° C.). The solvent was (partially) removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH) to give the title compound 66B (amorphous, 0.72 g, 65% (total)). LCMS (Method A); R _t : 1.92 min, ([M + H] ⁺ = 281).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.23 (s, 1H), 7.06-7.04 (m, 1H), 3.40-3.38 (m, 2H), 2.67 (T, J = 7 Hz, 2H), 2.59 (t, J = 7 Hz, 2H), 2.48-2.42 (m, 5H), 1.59-1.51 (m, 2H), 1 .41-1.21 (m, 6H), 0.85 (t, J = 7 Hz, 3H).

3- (4-Hex-1-enyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 68A, Scheme 13)
To anhydrous THF (30 ml) containing compound 64 (0.64 g, 2.84 mmol), 1.5 equivalents of (E) -hexen-1-ylboronic acid (0.55 g) was added. The resulting mixture was stirred under N ₂ for 2 hours. 2 equivalents of _K 3 _PO 4 (1.2g), was added 2 mol% of Pd _(OAc) 2 _(13mg) and 4 mol% of S-Phos a (47 mg) successively. After the addition, the resulting solution was warmed at 65 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed with saturated NaHCO ₃ solution and dried (Na ₂ SO ₄ ).
, Filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (4-hex-1-enyl-isoxazol-3-yl) -pyridine (Compound 67A) as an oil. (0.47 g, 69%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.9 (d, J = 2 Hz, 1H), 8.72 (dd, J = 5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8 0.0 (dt, J = 8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 6.11-5.99 (m, 2H), 2.22-2.14 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, J = 7 Hz, 3H).
Using the method described for the conversion of 65A to 66A (see Scheme 12), 3- (4-hex-1-enyl-1H-pyrazol-3-yl) -pyridine (67A) was converted to the title compound 68A. Converted. Yield: 95% (amorphous). LCMS (Method _A): R t: 1.68 ^{min, ([M + H] +} = 247).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.28 (s, 1H), 6.36-6.30 (m, 1H), 6.09-5.93 (m, 2H), 3.46 -3.41 (m, 2H), 2.70 (t, J = 7 Hz, 2H), 2.52 (s, 3H), 2.51-2.45 (m, 2H), 2.21-2 .14 (m, 2H), 1.47-1.31 (m, 4H), 0.92 (t, J = 7 Hz, 3H).

3- (4-Oct-1-enyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 68B)
To anhydrous THF (20 ml) containing 64 (0.49 g, 2.17 mmol) (see Scheme 13) 1.5 equivalents of (E) -octen-1-ylboronic acid (0.51 g) added. The resulting mixture was stirred under N ₂ for 2 hours. 2 equivalents of _K 3 _PO 4 (0.92g), was added 2 mol% of Pd and _(OAc) 2 _(10mg) and 4 mol% of S-Phos (36mg) in succession. After the addition, the resulting solution was warmed at 65 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (4-oct-1-enyl-isoxazol-3-yl) -pyridine (Compound 67B) as an oil. (0.19 g, 34%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.9 (d, J = 2 Hz, 1H), 8.72 (dd, J = 5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 7 .9 (dt, J = 8 Hz, 2 Hz, 1H), 7.45-7.40 (m, 1H), 6.11-5.99 (m, 2H), 2.21-2.13 (m, 2H), 1.46-1.38 (m, 2H), 1.37-1.21 (m, 6H), 0.91 (t, J = 7 Hz, 3H).
Using the method described for the conversion of 65A to 66A (see Scheme 12), 3- (4-oct-1-enyl-1H-pyrazol-3-yl) -pyridine (67B) was converted to the title compound 68B. Converted. Yield: 54% (amorphous). LCMS (Method A); R _t : 2.0 min ([M + H] ⁺ = 275).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.28 (s, 1H), 6.32-6.27 (m, 1H), 6.09-5.93 (m, 2H), 3.37 -3.33 (m, 2H), 2.61 (t, J = 7 Hz, 2H), 2.45 (s, 3H), 2.44-2.39 (m, 2H), 2.20-2 .12 (m, 2H), 1.48-1.38 (m, 2H), 1.37-1.24 (m, 6H), 0.85 (t, J = 7 Hz, 3H).

3- (4-Hept-1-ynyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 70A, Scheme 13)
To anhydrous DMF (20 ml) containing compound 64 (1.08 g, 4.8 mmol) was added 1
. 5 equivalents of hept-1-ynyl-trimethyl-silane (1.21 g), 3 equivalents of KOAc (1.41 g) and 1 equivalent of TBAF (1.0 M in THF) were added. The resulting mixture was stirred for further 2 hours under N _2. 10 mol% of _Pd and (OAc) 2 (108mg) and 20 mole% of _PPH 3 (251 mg) was added and continuously. After the addition, the resulting solution was warmed at 90 ° C. under N ₂ for 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3- (4-hept-1-ynyl-isoxazol-3-yl) -pyridine (69A) as an oil ( 0.34 g, 30%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.3 (d, J = 2 Hz, 1H), 8.7 (dd, J = 5 Hz, 2 Hz, 1H), 8.58 (s, 1H), 8 .34 (dt, J = 8 Hz, 2 Hz, 1H), 7.44-7.39 (m, 1H), 2.42 (t, J = 7 Hz, 2H), 1.65-1.57 (m, 2H), 1.45 to 1.29 (m, 4H), 0.91 (t, J = 7 Hz, 3H).
Using the method described for the conversion of 65A to 66A (see Scheme 12), 3- (4-hept-1-ynyl-1H-pyrazol-3-yl) -pyridine (69A) was converted to the title compound 70A. Converted. Yield: 50% (amorphous). LCMS (Method _A): R t: 1.78 ^{min, ([M + H] +} = 259).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.18-7.13 (m, 1H), 3.41-3.36 (m, 2H), 2.59 (T, J = 7 Hz, 2H), 2.45 (s, 3H), 2.45-2.38 (m, 2H), 1.64-1.55-2.12 (m, 2H), 1 .46-1.30 (m, 4H), 0.91 (t, J = 7 Hz, 3H).

3- [5-Bromo-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl] -pyridine (Compound 73, Scheme 14)
To anhydrous THF (100 ml) containing 3-bromo-pyridine (3.29 g, 20.82 mmol), 1.2 eq of iPrMgCl (12.49 ml, 2M in THF) was added and the resulting mixture was N _2. Stirring for 2 hours (10 ° C.). Subsequently 1.2 equivalents of (CH ₃ ) ₃ SnCl were added and the reaction mixture was stirred at room temperature for 18 hours (under N ₂ ). The reaction mixture was quenched with saturated NH ₄ Cl solution, diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/1) to give 3-trimethylstannanyl-pyridine (71) (3.32 g, 66%). LCMS (Method _A): R t: 2.09 ^{min, ([M + H] +} = 242).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.62 (bs, 1H), 8.52 (dd, J = 5 Hz, 2 Hz, 1H), 7.76 (dt, J = 8 Hz, 2 Hz, 1H) 7.25-7.21 (m, 1H), 0.33 (s, 9H), with Sn satellites at 0.41 and 0.27.
To a solution of 71 (0.82 g, 3.4 mmol) in anhydrous toluene (50 ml), 0.9 equivalent (1.10 g) of 4,5-dibromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H- imidazole (compound 72, LCMS (method _a): R t: 3.60 ^{min, ([M + H] +} = 357)) was added and the resulting mixture was stirred for 2 hours under _{N 2} (room temperature). To this reaction mixture was added 10 mol% PdCl ₂ (PPH ₃ ) ₂ (240 mg). After the addition, the temperature was raised to 100 ° C. and the resulting solution was stirred under N ₂ for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed 3 times with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to give 3- [5-bromo-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl]- Pyridine (73) was provided as an oil (385 mg, 36%). LCMS (Method _A): R t: 3.40 ^{min, ([M + H] +} = 355).
¹ H-NMR (400 MHz, CDCl ₃ and HMBC): δ 8.79 (d, J = 2 Hz, 1H), 8.66 (dd, J = 5 Hz, 2 Hz, 1H), 7.91 (dt, J = 8Hz, 2Hz, 1H), 7.66 (s, 1H), 7.44-7.40 (m, 1H), 5.17 (s, 2H), 3.56-3.50 (m, 2H) , 0.94-0.87 (m, 2H), 0.0 (s, 9H).

3- (5-pentylsulfanyl-3H-imidazol-4-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 76A, Scheme 14)
To a degassed solution of xylene (100 ml) containing 73 (1.82 g, 5.16 mmol) was added 1.25 equivalents (0.80 ml) pentane-1-thiol and 1.25 equivalents K ₂ CO _{2. 3} (0.8 g) was added. The resulting mixture was stirred for further 2 hours under N _2. 10 mol% of _{Pd 2 (dba) 3 (470mg} ) and 20 mol% of Xantphos a (600 mg) were successively added. After the addition, the resulting solution was stirred at 130 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) and 3- [5-pentylsulfanyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl]. -Provided pyridine (74A) as an oil (530 mg, 30%) and starting material (73,380 mg, 21%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.38 (d, J = 2 Hz, 1H), 8.53 (dd, J = 5 Hz, 2 Hz, 1H), 8.42 (dt, J = 8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.35-7.30 (m, 1H), 5.43 (s, 2H), 3.59-3.54 (m, 2H), 2 .66 (t, J = 7 Hz, 2H), 1.47-1.38 (m, 2H), 1.28-1.10 (m, 4H), 0.96-0.89 (m, 2H) , 0.80 (t, J = 7 Hz, 3H), 0.0 (s, 9H).
3- [5-pentylsulfanyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl] using the method described for the conversion of 21A to 22A (see Scheme 3) -Pyridine (74A) was converted to 3- [5-pentylsulfanyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl] -1,2,5,6-tetrahydro-1-methylpyridine Converted to (75A). Yield 75% (amorphous).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.68 (s, 1H), 6.75-6.71 (m, 1H), 5.37 (s, 2H), 3.54-3.46 (M, 4H), 2.67 (t, J = 7 Hz, 2H), 2.57 (t, J = 6 Hz, 2H), 2.46 (s, 3H), 2.44-2.38 (m , 2H), 1.55-1.46 (m, 2H), 1.37-1.24 (m, 4H), 0.94-0.85 (m, 5H), 0.0 (s, 9H) ).
75A (0.42 g, 1.06 mmol) in anhydrous THF containing (20 ml), 3.18 ml of TBAF (3 eq) (1.0 M in THF) was added under _{N 2.} After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH) followed by further purification on (25 g) SCX-2 (MeOH followed by 1N NH ₃ / MeOH) to give the title compound 76A. (Oil, 0.2 g, 73%). LCMS (Method _A): R t: 1.0 ^{min, ([M + H] +} = 266).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.54 (s, 1H), 6.36-6.31 (m, 1H), 3.49-3.46 (m, 2H), 2.75 (T, J = 7 Hz, 2H), 2.64 (t, J = 6 Hz, 2H), 2.47 (s, 3H), 2.43-2.38
(M, 2H), 1.55-1.49 (m, 2H), 1.35-1.23 (m, 4H), 0.85 (t, J = 7 Hz, 3H).

3- (5-Hexylsulfanyl-3H-imidazol-4-yl) -1,2,5,6-tetrahydro-1-methylpyridine (Compound 76B, Scheme 14)
73 (0.6 g, 1.70 mmol) in degassed solution of xylene (30ml) containing 1.25 eq (0.30 ml) hexane-1-thiol and 1.25 equivalents of _K 2 CO ₃ (0.29 g) was added. The resulting mixture was stirred for further 2 hours under N _2. 10 mol% of _{Pd 2 (dba) 3 (160mg} ) and 20 mol% of Xantphos a (200 mg) were successively added. After the addition, the resulting solution was stirred at 130 ° C. under N _{2 for} 18 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to give 3- [5-hexylsulfanyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazol-4-yl] -pyridine (74B). As an oil (120 mg, 18%) and starting material (73,380 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.38 (d, J = 2 Hz, 1H), 8.53 (dd, J = 5 Hz, 2 Hz, 1H), 8.42 (dt, J = 8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.35-7.30 (m, 1H), 5.43 (s, 2H), 3.59-3.54 (m, 2H), 2 .66 (t, J = 7 Hz, 2H), 1.46-1.37 (m, 2H), 1.28-1.06 (m, 8H), 0.96-0.89 (m, 2H) , 0.80 (t, J = 7 Hz, 3H), 0.0 (s, 9H).
74B (0.29 g, 0.74 mmol) in anhydrous THF (30 ml) containing, 2.2 ml of TBAF (3 eq) (1.0 M in THF) was added under _{N 2.} After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with concentrated NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give 3- (5-hexylsulfanyl-3H-imidazol-4-yl) -pyridine (77) as an oil (0.14 g, 71%). .
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.25 (bs, 1H), 8.53 (dd, J = 5 Hz, 2 Hz, 1H), 8.42-8.35 (m, 1H), 7 .78 (s, 1H), 7.38-7.34 (m, 1H), 2.79-2.69 (m, 2H), 1.53-1.44 (m, 2H), 1.33 -1.09 (m, 6H), 0.80 (t, J = 7Hz, 3H).
Convert 3- (5-hexylsulfanyl-3H-imidazol-4-yl) -pyridine (77) to the title compound (76B) using the method described for the conversion of 21A to 22A (see Scheme 3). (But quaternization was performed at room temperature with a slight excess of CH ₃ I). Yield: 70% (oil). LCMS (Method A); R _t : 1.21 min, ([M + H] ⁺ = 280).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.53 (s, 1H), 6.40-6.29 (m, 1H), 3.45-3.41 (m, 2H), 2.79 -2.72 (m, 2H), 2.59 (t, J = 6 Hz, 2H), 2.45 (s, 3H), 2.41-2.37 (m, 2H), 1.55-1 .49 (m, 2H), 1.38-1.31 (m, 2H), 1.30-1.19 (m, 4H), 0.85 (t, J = 7 Hz, 3H).

§5. Pharmacological tests (I) Assays for screening muscarinic receptor ligands (in vitro; functional assay)
Test substances Compounds were dissolved in DMSO (10 mM) and diluted to test concentrations in assay buffer. Prime testing was performed at 1 μM; actives in antagonist mode (percent inhibition over PI, reference agonist and blank> 30%) and active substance in agonist mode (PS, reference agonist and percent stimulation over blank) > 30%), testing continued at lower concentrations at 10-fold dilution: 0.1 μM, 0.01 μM, etc.

Assay methods and calculations
Assay method
Isolated organ assay, agonist mode:
To confirm reactivity and obtain a standard response, tissues were exposed to the maximum concentration of each reference agonist. Following extensive washing and recovery to the initial state, the tissue was exposed to the test compound or the same agonist. In the M1 and M2 receptor assays, compounds were left in contact with tissue until a stable response was obtained or for up to 15 minutes. When several concentrations were examined, they were added cumulatively. In the M3 receptor assay, the compound was left in contact with the tissue for a time sufficient to obtain a peak response or up to 10 minutes and then washed out. When testing several concentrations, they were added continuously at 40 minute intervals. Where an agonist-like response was obtained, each reference antagonist was tested against the highest concentration of compound to confirm that the tested receptor was included in the response.

Isolated organ assay, antagonist mode:
To obtain a standard response, the tissues were exposed to submaximal concentrations of each reference agonist. In the M1 and M2 receptor assays, the test compound or reference antagonist was added after stabilization of the agonist-induced response and then left in contact with the tissue for a stable effect or up to 15 minutes. When several concentrations were examined, they were added cumulatively. In the M3 receptor assay, test compounds or reference antagonists were added 30 minutes prior to re-exposure to agonists added at 40-minute intervals. If inhibition by the compound of the resulting agonist-induced response occurs, it indicates antagonist activity at the receptor examined. Each compound was tested in three assays for agonist and antagonist activity at one or several concentrations in three separate tissues. In each assay, reference agonists and antagonists were tested at several concentrations in three separate tissues to obtain concentration-response curves.

Cell-based assays:
Cells were incubated with compounds and the response indicated was measured.

Reaction and calculation of results
Isolated organ assay:
The parameter measured was the maximum change in the amplitude of electrically drawn contractions induced by each compound concentration (M1 and M2 receptor assay) or in tension (M3 receptor assay). Results are expressed as a percentage of the standard agonist-induced response. The EC50 value of the reference agonist (concentration producing a half-maximal response) and the IC50 value of the reference antagonist (concentration producing a half-maximal inhibition of the agonist-induced response) were calculated by linear regression analysis of their concentration-response curves.

Cell-based assays:
Results are expressed as percent of the reference agonist value and blank in the presence of test compound, percent stimulation in the case of agonist mode; percent inhibition in the case of antagonist mode (test compound in the presence of reference agonist). EC50 values (concentrations that cause half-maximal stimulation of standard values), IC50 values (concentrations that cause half-maximal inhibition of standard values), and Hill equation curve fitting (Hill equation curve fitting), Determined by non-linear regression analysis.

Reference Catalog CLAGUE, R.C. U. , EGLEN, R.M. M.M. , STRACHAN, A .; C. and WHITING, R.A. L. (1985) Action of agonists and
antagonists at Muscular Receptors present on ileum and atria in vitro. Brit. J. et al. Pharmacol. 86 : 163-170.
EGLEN, R.M. M.M. , MONTGOMERY, W. W. , DAINTY, I. A. , DUBUQUE, L. K. and WHITING, R.A. L. (1988) The interaction of method and himbacine at atrial, smooth muscle and endocrine muscarinic receptors in vitro. Brit. J. et al. Pharmacol. 95 : 1031-1038.
ELTZE, M.M. (1988) Muscarinic M1- and M2-receptors mediating opposite effects on neuro-muscular transmission in rabbit bases. Eur. J. et al. Pharmacol. 151: 205-221.
STABLES, J.A. , GREEN, A. , MARSHALL, F.M. Fraser, N .; , KNIGHT, E .; , SAUTEL, M .; , MILLIGAN, G. , LEE, M.M. , And REES, S. (1997) A bioluminescent assay
for agonist activity at potentially any
G-Protein-Coupled Receptor. Anal. Biochem. 252 : 115-126.
SUR, C.I. , MALLOGA, P.M. J. et al. , WITTMANN, M .; JACOBSON, M .; A. , PASCARELLA, D.C. , WILLIAMS, J. et al. B. , BRANDISH, P.M. E. , PETTIBONE, D.M. J. et al. SCOLNICK, E .; M.M. and
CONN, P.M. J. et al. (2003) N-desmethylclozapine, an allalagonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. PNAS, 100 : 1374-13679.

(II) Assay for muscarinic receptor ligand screening (in vitro; receptor binding assay)
Test substances Compounds were dissolved in DMSO (10 mM) and diluted to test concentrations in assay buffer. Initial testing was performed at 10 μM; testing continued at lower concentrations at 10-fold dilution: 1 μM, 0.1 μM, etc. for active agent (PI, percent inhibition of total and non-specific binding> 40%).

Assay methods and calculations
After incubation of the compounds in the time and temperature indicated assay receptor preparation (from "tissue") and with the ligand, was rapidly filtered receptor preparations through the glass fiber filter under vacuum; harvester The filter was washed extensively with ice-cold buffer. Bound radioactivity was measured by scintillation counting using a liquid scintillation cocktail.

Results of the reaction and results were expressed as a percentage of total ligand binding and non-specific binding per concentration of the (dual) compound examined; from the concentration-displacement curve, using Hill's equation curve fitting IC50 values were determined by non-linear regression analysis. The inhibition constant (Ki) is calculated from the Cheng-Prusoff equation, Ki = IC50 / (1 + L / Kd), where L is the concentration of radioligand in the assay and Kd is the radioligand affinity for the receptor. is there. Results were expressed as pKi's, the mean ± SD of at least 2 separate experiments; ie, outliers (outside +/− 1 std of mean) and discrepancy values (discrepancy) Was eliminated. Compounds that did not have significant affinity at 10 μM and higher concentrations were concluded as “inactive” and indicated by a pKi of “<5.0”.

Bibliography DOERJE, F. , WESS, J. et al. , LAMBRECHT, G. , TACKE, R. , MUTSCHLER, E .; and BRANN, M .; R. (1991) Antagonist binding profiles of five cloned humans
Muscarinic receptor subtypes. J. et al. Pharmacol. Exp. Ther. 256 : 727-733.
RICHARDS, M.M. H. (1990) Rat hippocampal muscarinic autoreceptors are similar to the M 2 (cardiac) subtype: comparison with hippocampal M 1, atrial M 2 and ileal M 3 receptors. Brit. J. et al. Pharmacol. 99 : 753-761.
PERALTA, E.I. G. ASSHKENAZI, A. , WINSLOW, J.A. W. , SMITH, D.M. H. , RAMACHANDRAN, J. et al. and CAPON, D.C. J. et al. (1987) Distinct primary structures, ligand-binding properties and tissue-specific expression of four human carboxylic acid receptors. EMBO. J. et al. , 6 : 3923-3929.

Determination of metabolic stability (in vitro)
DI. L. et al. Author, Journal of Biomolecular Screening, Vol. 8, no. 4, 2003, 453-462.

§6. Pharmacological data

Claims (20)

Formula (I)

[Where:
The heterocycle comprises two double bonds, which can be present in several positions indicated by dashed lines (---);
The heterocycle contains 2 heteroatoms;
-W is N or NH;
-Y is CH, O or NH, where when Y is O, X ₁ is CH and X ₂ is the residue C-Z-R2 or C-R3, where Z is NH And when Y is CH or NH, one of X ₁ and X ₂ is CH or N and the other is the residue C—Z—R 2 or C—R 3, where Z is NH or S;
-R1 is selected from structures (a), (b) and (c):

-R2 is independently halogen, optionally, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy, (C} 1 -C ₆ ) Alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle (optionally substituted with halogen) ), (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl and (C ₂ -C), which may be substituted with one or more substituents selected from phenyl, phenyloxy and phenylthio ₁₀ ) selected from alkynyl, wherein the phenyl group may be optionally substituted with halogen;
Alternatively, -R2 is the formula (Ia)

Unbranched (C ₂ -C ₈ ) alkyl substituted at the Za- symbol of the group having
Here, when X ₁ is CH or N, X ₁ a is CH or N, and X ₂ a is C-Za.
When X ₁ is C—Z—R 2, X ₁ a is C—Za— and X ₂ a is CH or N; and the symbols Wa, Ya and Za and substituents R1a has the same meaning as previously defined with respect to the symbols W, Y and Z and the substituent R1 and is not independently selected, each of the symbols Wa, Ya and Za and the substituent R1a having the structure of formula (I) The symbols W, Y, and Z and the substituent R1 in the other parts of the group represent the same symbols and substituents, respectively;
-R3 is independently halogen, optionally, hydroxy, _{cyano, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy, (C} 1 -C ₆₎ alkenyl Thio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, From (C ₄ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) alkenyl and (C ₂ -C ₁₀ ) alkynyl which can be substituted with one or more substituents selected from phenyloxy and phenylthio Wherein the phenyl group can optionally be substituted with a halogen]
Or a pharmaceutically acceptable salt, solvate or hydrate thereof. R2 independently optionally halogen, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy,} (C 1 _-C 6) Alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl can be substituted with one or more substituents selected from phenyloxy and phenylthio _(C 1 _{-C 10) alkyl,} (C 2 _{-C 10)} alkenyl and _(C 2 _{-C 10)} alkynyl The compound of claim 1, wherein the phenyl group can be optionally substituted with a halogen. R2 independently optionally halogen, hydroxy, _{cyano, (C} 1 -C _{6) alkoxy, (C} 1 -C ₄₎ alkoxy _(C 1 -C _{4) alkoxy, (C} 5 -C ₇₎ cycloalkyl, tetrahydrofuranyl Selected from (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl, which may be substituted with one or more substituents selected from nyl and phenyl Wherein the phenyl group can optionally be substituted with a halogen. R2 can be substituted with one or more halogen or _(C 1 -C ₆₎ alkoxy optionally _(C 1 -C _{8) alkyl,} the claims are selected from _(C 2 -C ₈₎ alkenyl 3 compounds. Optionally R3 is _(C 5 -C ₇₎ can be substituted with one substituent selected from cycloalkyl or phenyl _(C 4 _{-C 10) alkyl,} (C 2 _{-C 10)} alkenyl and ( C 2 _{-C 10)} is selected from alkynyl, the compound of claim 1, wherein the phenyl may be substituted with halogens.   The compound according to any one of claims 1 to 5, wherein R1 has the structure (a).   The compound according to any one of claims 1 to 6, wherein W is N and Y is NH. 8. The compound of claim 7, wherein X ₁ is CH, X ₂ is the residue C—Z—R 2 or C—R 3, and Z is O or S. The compound of claim 8, wherein X ₂ is the residue C-Z-R2.   The compound of claim 9, wherein Z is S.   The compound according to any one of claims 1 to 6, wherein Y is O and Z is O or S.   The compound of claim 9, wherein Z is S. 3- (4-pentyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-butyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-butylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (furan-2-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- (5-butylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-butylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- (4-benzylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (4,4,4-trifluoro-butylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
N- [3- (1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1H-pyrazol-4-yl] -butyramide,
3- (4-methylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-propylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
Butyl- [3- (1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1H-pyrazol-4-yl] -amine,
3- (4-pentylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-ethylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-butyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-allylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- [3- (1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl) -1H-pyrazol-4-ylsulfanyl] -propionitrile,
3- [4- (3-methyl-butylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (3-phenyl-propoxy) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hexylsulfanyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-bute-3-enyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hexylsulfanyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-butylsulfanyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-oct-1-enyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hept-1-ynyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hex-1-enyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hex-1-enyl-isoxazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hept-1-ynyl-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-ethylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
Endo-6- (4-butylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane,
3- (4-propylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- (4-non-1-ynyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hex-1-ynyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- {4- [2- (3-Fluoro-phenyl) -vinyl] -1H-pyrazol-3-yl} -1,2,5,6-tetrahydro-1-methylpyridine 3- [4- (5- (Cyclohexyl-pent-1-ynyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridinebis- [3- (1-methyl-1,2,5,6-) Tetrahydro-pyridin-3-yl) -1H-pyrazol-4-yl] -2-sulfanylethyl] -methane,
3- [4- (5-phenyl-pent-1-ynyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-oct-1-enyl-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (3-phenyl-propylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (4,4-difluoro-but-3-enylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (3-phenyl-allylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-hexylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- (4-pentylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- [4- (3-methyl-butylsulfanyl) -1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane,
3- (4-hexyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-pentyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-Methylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2
. 2.2] Octane,
3- [4-pent-4-enylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- [4- (2-ethoxy-ethylsulfanyl) -1H-pyrazol-3-yl] -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-heptyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-heptyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (4-pent-4-enyloxy-1H-pyrazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
Endo-6- (4-iodo-1H-pyrazol-3-yl) -1-azabicyclo [3.2.1] octane,
3- (4-phenethylsulfanyl-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- (4-pentyloxy-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- (4-butoxy-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- (4-propoxy-1H-pyrazol-3-yl) -1-azabicyclo [2.2.2] octane,
3- [4- (4,4-difluoro-but-3-enylsulfanyl) -1H-pyrazol-3-yl] -1-azabicyclo [2.2.2] octane,
3- [4- [2- (2-methoxy-ethoxy) -ethylsulfanyl] -1H-pyrazol-3-yl} -1,2,5,6-tetrahydro-1-methylpyridine,
3- (5-hexylsulfanyl-3H-imidazol-4-yl) -1,2,5,6-tetrahydro-1-methylpyridine,
3- (5-pentylsulfanyl-3H-imidazol-4-yl) -1,2,5,6-tetrahydro-1-methylpyridine and endo-6- (4-pentylsulfanyl-1H-pyrazol-3-yl) The compound of claim 1 selected from -1-azabicyclo [3.2.1] octane or a pharmaceutically acceptable salt, solvate or hydrate thereof.   14. A compound according to any one of claims 1 to 13 for use in therapy.   A pharmaceutical composition comprising the compound of any one of claims 1 to 13 and a pharmaceutically acceptable adjuvant.   Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment, alleviation or prevention of diseases and conditions mediated by muscarinic receptors.   Use according to claim 16, wherein the muscarinic receptor is M1 and / or M4.   Use according to claim 16 or 17, wherein the diseases and conditions are cognitive and psychotic disorders. Formula (II)

[Where:
The heterocycle comprises two double bonds, which can be present in several positions indicated by dashed lines (---);
The heterocycle comprises two heteroatoms;
-W ^* is N, NH or N-2- (trimethylsilyl) ethoxymethyl;
-Y ^* is CH, O, N or NR4, wherein R4 is H, 2-(trimethylsilyl) - _{ethoxymethyl,} -SO 2 N _{(CH 3)} is selected from ₂ and -SO ₂ phenyl; wherein Y ^{When *} is O, X ₁ ^* is CH and X ₂ ^* is the residue C—Z ^* —R 2 ^* or C—R 3 ^* , where Z ^* is NH, O or S; And when Y ^* is CH or NH, one of X ₁ ^* and X ₂ ^* is CH or N and the other is the residue C—Z ^* —R 2 ^* or C—R 3 ^* , where Z ^* Is NH or S;
-R2 ^* is one or more than independently optionally halogen, hydroxy, cyano, _{oxo, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C ₆₎ alkenyl Oxy, (C ₁ -C ₆ ) alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle (optionally halogen) (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl which can be substituted with phenyl, phenyloxy or phenylthio Wherein the phenyl group can be optionally substituted with a halogen;
Or -R2 ^* is the formula (IIa)

The unbranched substituted in ^Z * a- symbol groups having _(C 2 -C ₈₎ alkyl,
Here, when X ₁ ^* is CH or N, X ₁ ^* a is CH or N and X ₂ ^* a is C—Z ^* a—, or X ₁ ^* is C—Z ^* −. When R2 ^* , X ₁ ^* a is C—Z ^* a— and X ₂ ^* a is CH or N; and the symbols W ^* a, Y ^* a and Z ^* a are the symbols W ^* , Y ^* and Z ^* and and independently have the same meaning as defined not chosen previously with respect to, each of the symbols W ^{* a,} Y * ^a and Z ^{* a} in the other parts of the structure of formula (II) The symbols W ^* , Y ^* and Z ^* are the same
-R3 ^* is independently halogen, optionally, hydroxy, _{cyano, (C} 1 -C _{6) alkoxy, (C} 1 -C _{6) alkylthio, (C} 1 -C _{6) alkenyloxy,} (C 1 _-C 6) Alkenylthio, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkoxy, (C ₅ -C ₇ ) cycloalkyl, 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl can be substituted with one or more substituents selected from phenyloxy and phenylthio _(C 4 _{-C 10) alkyl,} (C 2 _{-C 10)} alkenyl and _(C 2 _{-C 10)} alkynyl Wherein the phenyl group can optionally be substituted with a halogen]
Heterocyclic compounds of Formula (III)

[Where:
R5 is H and R6 is Br or R5 is —Si (CH ₃ ) ₃ and R6 is Br or —Si (CH ₃ ) ₃ ]
Heterocyclic compounds of