HK1203961B - Bicyclic pyrazinone derivatives - Google Patents

Description

Bicyclic pyrazinone derivatives

Background

The object of the present invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to bicyclic pyrazinone derivatives which inhibit the activity of Tankyrase (TANK) and poly (ADP-ribose) polymerase PARP-1. The compounds of the invention are thus useful in the treatment of diseases such as cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

The ribozyme poly (ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family. This expanding enzyme family is represented by PARP, for example: PARP-1, PARP-2, PARP-3 and Vallt-PARP; and TANK polymerase (TANK) such as: TANK-1 and TANK-2. PARP is also known as poly (adenosine 5' -diphosphate-ribose) polymerase or PARS (poly (ADP-ribose) synthetase).

TANK-1 appears to be required for the polymerization of mitotic spindle-associated poly (ADP-ribose). The poly (ADP-ribosylation) activity of TANK-1 may be critical for the precise formation and maintenance of spindle bipolarity. Furthermore, it has been shown that PARP activity of TANK-1 is required for normal telomere segregation before the anaphase of division. Interference with tankyrase PARP activity leads to aberrant mitosis, which causes transient cell cycle arrest, most likely due to spindle checkpoint activation followed by cell death. Inhibition of tankyrase is thus expected to have a cytotoxic effect on proliferative tumor cells (WO 2008/107478).

PARP inhibitors are described by M.Rouleau et al in Nature Reviews, Vol.10, 293-301 in clinical cancer studies (Table 2, page 298).

According to the review by Horvath and Szabo (Drug News Perspectrum 20(3), 4.2007, 171-. More recent studies have also demonstrated that PARP inhibitors inhibit angiogenesis by inhibiting growth factor expression, or by inhibiting growth factor-induced cell proliferation responses. These results may also have implications for the pattern of anti-cancer effects of PARP inhibitors in vivo.

Studies by Tentori et al (Eur. J. Cancer, 2007, 43 (14) 2124-2133) also indicate that PARP inhibitors abrogate VEGF or placental growth factor-induced migration and prevent the formation of tubule-like networks in cell-based systems and impair angiogenesis in vivo. Studies have also demonstrated that growth factor-induced angiogenesis is deficient in PARP-1 knockout mice. The results of the study provide evidence for targeting PARP for anti-angiogenesis, which adds new therapeutic implications for the use of PARP inhibitors in cancer therapy.

It is well known that defects in conserved signaling pathways play a key role in the origin and behavior of essentially all cancers (e.a. fearon, Cancer Cell, vol. 16, Issue 5, 2009, 366-. The Wnt pathway is a target for anti-cancer therapy. A key feature of the Wnt pathway is the proteolysis (degradation) of β -catenin, which is regulated by β -catenin disrupting complexes. Proteins such as WTX, APC or Axin are involved in the degradation process. Proper degradation of β -catenin is important to avoid inappropriate activation of the Wnt pathway that has been observed in many cancers. Tankyrase inhibits Axin activity and thus inhibits degradation of β -catenin. Thus, tankyrase inhibitors increase the degradation of β -catenin. The latest papers in journal Nature not only present new and important insights into proteins that regulate Wnt signaling, but also further support methods of antagonizing β -catenin levels and localization via small molecules (Huang et al, 2009; Nature, Vol 461, 614-. The compound XAV939 inhibits the growth of DLD-1-cancer cells. They found that XAV9393 blocked the accumulation of Wnt-stimulated β -catenin by increasing the levels of AXIN1 and AXIN2 proteins. Subsequent studies by the authors demonstrated that XAV939 regulates AXIN levels through inhibition by tankyrase 1 and 2(TNKS1 and TNKS2), both of which are members of the poly (ADP-ribose) polymerase (PARP) protein family (s.j. Hsiao et al, Biochimie 90, 2008, 83-92).

It has been found that the compounds according to the invention and their salts have very valuable pharmacological properties while being well tolerated.

The invention particularly relates to compounds of formula I that inhibit tankyrase 1 and 2, to compositions comprising these compounds, and to methods of their use for treating TANK-induced diseases and disorders.

The compounds of formula I can additionally be used for the isolation of TANK and for the investigation of its activity or expression. Furthermore, they are particularly suitable for use in diagnostic methods for diseases associated with unregulated or disturbed TANK activity.

The host or patient may belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing models for the treatment of human diseases.

The susceptibility of a particular cell to treatment with a compound according to the invention may be determined by in vitro assays. Typically, the cell culture is mixed with various concentrations of a compound according to the invention for a period of time (usually between about 1 hour and 1 week) sufficient for the active agent, e.g. anti-IgM, to induce expression of a cellular response, e.g. a surface marker. In vitro tests can be performed using cultured cells from blood or from biopsy samples. The amount of surface marker expressed is assessed by flow cytometry using antibodies specific for the recognition marker.

The dosage will vary depending upon the particular compound employed, the particular disease, the patient's condition, and the like. The therapeutic dose is typically sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the patient's viability. Treatment generally continues until a significant reduction occurs, e.g., a reduction in cell burden of at least about 50%, and may continue until substantially no more unwanted cells are detected in the body.

Prior Art

Other pyrrolopyrazinones are described in WO2009/130231 a1 and WO 2009/130232 a1 as V1b receptor antagonists and as intermediates for the preparation of these compounds.

Other pyrazolopyrazinones are described in WO 2009/007029A 1 as intermediates for the preparation of GSK3 inhibitors

Other pyrazolopyrazinones are described in WO 2011/089400a1 as intermediates for the preparation of PI3 kinase inhibitors.

Summary of The Invention

The invention relates to compounds of formula I

Wherein

R¹Represents H, F, Cl, CN, CH₃、CH₂OH、CH₂Cl、CH₂Br、CF₃、CHF₂Or CH₂F，

R²Represents a group of a compound represented by the formula H or A,

R³represents H, F, Cl, CH₃、CF₃Or CHF₂，

X represents CR³Or the number of N is greater than the number of N,

y represents Ar¹、Carb、Het¹Or a group of cells of the group Cyc,

Ar¹represents phenyl or naphthyl, which are unsubstituted or mono-, di-or trisubstituted by: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet²、NO₂、CN、[C(R²)₂]_pCOOR²、[C(R²)₂]_pCON(R²)₂、NR²COA、NR²SO₂A、[C(R²)₂]_pSO₂N(R²)₂、S(O)_nA、COHet³、O[C(R²)₂]_mN(R²)₂、O[C(R²)₂]_pAr²、O[C(R²)₂]_pHet²、NHCOOA、NHCON(R²)₂Cyc, CHO and/or COA,

Ar²represents phenyl, which is unsubstituted or mono-or disubstituted by: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet³、NO₂、CN、[C(R²)₂]_pCOOR、[C(R²)₂]_pN(R²)₂、N(R²)₂COA、NR²SO₂A、[C(R²)₂]_pSO₂N(R²)₂、S(O)_nA、COHet³、O[C(R²)₂]_mN(R²)₂、O[C(R²)₂]_pHet³、NHCOOA、NHCON(R²)₂A CHO and/or a COA,

Het¹represents a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a tetrahydropyrazolyl group, a tetrahydropyranyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, or furo [3,2-b ] group]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet²、[C(R²)₂]_pAr²、NO₂、CN、[C(R²)₂]_pCOOR²、[C(R²)₂]_pCON(R²)₂、NR²COA、NR²SO₂A、[C(R²)₂]_pSO₂N(R²)₂、S(O)_nA、COHet³、O[C(R²)₂]_mN(R²)₂、O[C(R²)₂]_pAr²、O[C(R²)₂]_pHet²、NHCOOA、NHCON(R²)₂CHO, COA, = S, = NR and/or = O,

carb represents indanyl or tetrahydronaphthyl, each of which may be unsubstituted or mono-, di-, tri-or tetrasubstituted by A,

cyc represents cycloalkyl having 3,4,5, 6 or 7C atoms, which may be unsubstituted or monosubstituted by: A. OH, Hal, CN or Ar²Or Het²，

Het²Represents a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a tetrahydropyrazolyl group, a tetrahydropyranyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, or furo [3,2-b ] group]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet³、[C(R²)₂]_pOHet³、[C(R²)₂]_pAr²、NO₂、CN、[C(R²)₂]_pCOOR²、[C(R²)₂]_pCON(R²)₂、NR²COA、NR²SO₂A、[C(R²)₂]_pSO₂N(R²)₂、S(O)_nA、COHet³、O[C(R²)₂]_mN(R²)₂、O[C(R²)₂]_pAr²、O[C(R²)₂]_pHet³、NHCOOA、NHCON(R²)₂CHO, COA, = S, = NR and/or = O,

Het³represents dihydroPyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1,3 ] methyl]Dioxolanyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or mono-or disubstituted with: hal, CN, OR²、COOR²、CON(R²)₂、S(O)_nA、S(O)_nAr, COA, A and/or = O,

a represents an unbranched or branched alkyl radical having 1 to 10C atoms, wherein two adjacent CH and/or CH groups₂The radicals may form a double bond and one or two non-adjacent CH and/or CH₂The radicals may be substituted by N-, O-and/or S-atoms and where 1 to 7H-atoms may be replaced by F or Cl,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 1,2 or 3,

p represents 0, 1,2,3 or 4,

provided that if R is¹Is CH₂OH, then Ar¹In addition to the 2, 4-dichlorophenyl group,

and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

The invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

The present invention relates to compounds of formula I and tautomers thereof of formula Ia

.

Furthermore, the present invention relates to pharmaceutically acceptable derivatives of the compounds of formula I.

The term solvate of a compound is taken to mean an adduct in which molecules of an inert solvent are adducted to the compound due to the mutual attraction of the molecules of the inert solvent and the compound. Solvates are, for example, mono-or dihydrate or alkoxides.

It will be appreciated that the invention also relates to solvates of the salts.

By the term pharmaceutically acceptable derivatives is meant, for example, salts of the compounds according to the invention as well as so-called prodrug compounds.

As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound of formula I that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of formula I. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula I, which include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In certain embodiments, prodrugs of compounds having carboxyl functionality are lower alkyl esters of carboxylic acids. The carboxylic acid ester is conveniently formed by esterification of any carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well known methods, such as those described in Burger's medicinal Chemistry and Drug Discovery (Burger's medicinal Chemistry and Drug Discovery), 6 th edition (Donald J. Abraham ed., 2001, Wiley) and the Design and use of Prodrugs (Design and Application of Prodrugs) (H.Bundgarard, 1985, Harwood Academic Publishers Gmfh).

The expression "effective amount" means that amount of a drug or pharmaceutically active ingredient that elicits a biological or medical response in a tissue, system, animal or human that is, for example, being sought or desired by a researcher or clinician.

Furthermore, the expression "therapeutically effective amount" denotes an amount which has the following result compared to a corresponding subject not receiving this amount:

improving the treatment, curing, preventing, or eliminating a disease, syndrome, condition, affliction, disorder, or side effect or also slowing the progression of a disease, affliction, or disorder.

The expression "therapeutically effective amount" also encompasses an amount effective to enhance normal physiological function.

The invention also relates to the use of mixtures of compounds of formula I, for example two diastereomers, for example mixtures in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1: 1000.

There are especially preferred mixtures of stereoisomeric compounds.

"tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms will depend on the environment in which the compound is present and may vary depending, for example, on whether the compound is a solid or in an organic or aqueous solution.

The invention relates to compounds of formula (I) and salts thereof and to a method for producing compounds of formula (I) and pharmaceutically usable salts, solvates, tautomers and stereoisomers thereof, characterized in that

a) Reacting a compound of formula II

Wherein R is¹X and Y have the meanings specified in claim 1,

and A' represents an unbranched or branched alkyl radical having 1,2,3 or 4C atoms,

and NH₃、NH₄OAc or (NH)₄)₂CO₃The reaction is carried out in the presence of a catalyst,

or

b) Under alkaline conditions with H₂O₂Cyclizing the compound of formula III

Wherein R is¹X and Y have the meanings specified in claim 1,

or

c) Converting the group R by¹And/or Y into another group R¹And/or Y:

i) COOH or CHO is converted into H, and the obtained product is subjected to secondary reaction,

ii) converting the ester group into an alcohol group,

iii) converting the halogenobenzene ring into an aromatised benzene ring in a Suzuk coupling,

iv) converting the haloalkyl group to an alkyl group,

or

d) By treatment with a solvolytic or hydrogenolytic agent, which is released from one of its functional derivatives,

and/or

Converting the base or acid of formula I to one of its salts.

In this context, the radical R¹X and Y have the meanings specified for formula I, unless explicitly stated otherwise.

A represents an alkyl group which is unbranched (linear) or branched and has 1,2,3, 4,5, 6,7,8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1,2-, 1,3-, 2,2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1,2, 2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl.

A very particularly preferably represents alkyl having 1,2,3, 4,5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1, 1-trifluoroethyl.

Furthermore, A preferably represents CH₂OCH₃、CH₂CH₂OH or CH₂CH₂OCH₃。

Cyc represents cycloalkyl having 3 to 7C atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Ar¹Preferably o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, (R-), m-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulphonylamino) phenyl, o-, m-or p- (methylsulphonyl) phenyl, o-, m-or p-cyanophenyl, o-, m-or p-chloroanilino, p-isopropylamino, p-isopropyla, o-, m-or p-carboxyphenyl, o-, m-or p-methoxycarbonylphenyl, o-, m-or p-formylphenyl, o-, m-or p-acetylphenyl, o-, m-or p-aminosulfonylphenyl, o-, m-or p- [2- (morpholin-4-yl) ethoxy]Phenyl, o-, m-or p- [3- (N, N-diethylamino) propoxy]Phenyl, preferably in addition 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorobenzeneA radical, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2, 5-dibromophenyl, 2, 5-dinitrophenyl, 2, 5-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 2-amino-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2, 5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, m-tolyl, m-2-hydroxy-3, 5-iodophenyl, 3, 6-dichloro-4-, 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar¹Furthermore preferably represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet²、NO₂、Cyc、[C(R²)₂]_pCOOR²、O[C(R²)₂]_pAr²And/or O [ C (R) ]²)₂]_pHet²。

Ar²Preferably o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, (R-), m-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl-or p-chlorophenyl, o-, m-or p- (methylsulphonidenamido) phenyl, o-, m-or p- (methylsulphonyl) phenyl, o-, m-or p-cyanophenyl, o-, m-or p-carboxyphenyl, o-, m-or p-methoxycarbonylphenyl, o-, m-or p-formylphenyl, o-, m-or p-acetylphenyl, o-, m-or p-aminosulphonylphenyl, o-, m-or p- [2- (morpholin-4-yl) ethoxy-phenyl]Phenyl, o-, m-or p- [3- (N, N-diethylamino) propoxy]Phenyl, preferably in addition 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chloro-phenyl Phenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetylaminophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar²Furthermore preferably represents phenyl which is unsubstituted or substituted by [ C (R)²)₂]_pOR²Single substitution.

Het¹Preferably represents pyrrolidinyl, azetidinyl, tetrahydroimidazolyl, tetrahydrofuryl, tetrahydropyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidyl, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, pyrazolyl, and the like,Benzofuranyl, imidazopyridinyl, or furo [3,2-b ]]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet²And/or [ C (R)²)₂]_pAr²。

Het¹Particularly preferably pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, pyridinyl, pyrimidinyl or 1, 3-benzodioxolyl, each of which is unsubstituted or mono-or disubstituted by: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet²And/or [ C (R)²)₂]_pAr²。

Het²Preferably represents pyrrolidinyl, azetidinyl, tetrahydroimidazolyl, tetrahydrofuryl, tetrahydropyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidyl, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, or furo [3,2-b ] group]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet³And/or [ C (R)²)₂]_pOHet³。

Het²Particularly preferably, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, oxazolyl, isoxazolyl or oxadiazolyl, each of which is unsubstituted or mono-or disubstituted by: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet³And/or [ C (R)²)₂]_pOHet³。

Het³Preferably represents dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuryl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidyl, [1,3 ] amino]Dioxolanyl, tetrahydropyranyl or piperazinyl.

Het³Particularly preferably pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl.

Hal preferably denotes F, Cl or Br, but also denotes I, particularly preferably F or Cl.

Throughout the present invention, all groups appearing more than once may be the same or different, i.e. independent of each other.

The compounds of formula I may have one or more chiral centers and may therefore occur in a variety of stereoisomeric forms. Formula I encompasses all of these forms.

The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings specified above. Some preferred groups of the compounds can be represented by the following sub-formulae Ia to Ig, which are in accordance with formula I and in which the groups not specified in more detail have the meaning indicated for formula I, but in which

In Ia, Ar¹Represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet²、NO₂、Cyc、[C(R²)₂]_pCOOR²、O[C(R²)₂]_pAr²And/or O [ C (R) ]²)₂]_pHet²；

In Ib, Ar²Represents phenyl which is unsubstituted or substituted by [ C (R)²)₂]_pOR²Monosubstitution;

in Ic, Het¹Represents a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a tetrahydropyrazolyl group, a tetrahydropyranyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, or furo [3,2-b ] group]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet²And/or [ C (R)²)₂]_pAr²；

In Id, Het²Represents a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a tetrahydropyrazolyl group, a tetrahydropyranyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, or furo [3,2-b ] group]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet³And/or [ C (R)²)₂]_pOHet³；

In Ie, Het³Represents a dihydropyrrolyl group, a pyrrolidinyl group, an azetidinyl group, an oxetanyl group, a tetrahydroimidazoyl group, a dihydropyrazolyl group, a tetrahydropyrazolyl group, a tetrahydrofuranyl group, a dihydropyridinyl group, a tetrahydropyridinyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, tetrahydropyranyl or piperazinyl;

in If, R¹Represents H, F, Cl, CN, CH₃、CH₂OH、CH₂Cl、CH₂Br、CF₃、CHF₂Or CH₂F，

R²Represents a group of a compound represented by the formula H or A,

R³represents H, F, Cl, CH₃、CF₃Or CHF₂，

X represents CR³Or the number of N is greater than the number of N,

y represents Ar¹、Carb、Het¹Or a group of cells of the group Cyc,

Ar¹represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、[C(R²)₂]_pHet²、NO₂、Cyc、[C(R²)₂]_pCOOR²、O[C(R²)₂]_pAr²And/or O [ C (R) ]²)₂]_pHet²，

Ar²Represents phenyl which is unsubstituted or substituted by [ C (R)²)₂]_pOR²The process is a single substitution process,

Het¹represents a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a tetrahydropyrazolyl group, a tetrahydropyranyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazoleA group selected from the group consisting of phenyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolinyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, and furo [3,2-b ]]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet²And/or [ C (R)²)₂]_pAr²，

Carb represents indanyl or tetrahydronaphthyl, each of which may be unsubstituted or mono-, di-, tri-or tetrasubstituted by A,

cyc represents cycloalkyl having 3,4,5, 6 or 7C atoms, which may be unsubstituted or monosubstituted by: A. OH, Hal, CN or Ar²Or Het²，

Het²Represents a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a tetrahydropyrazolyl group, a tetrahydropyranyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1,3 ]]Dioxolanyl, piperazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl, imidazopyridinyl, or furo [3,2-b ] group]Pyridyl, each of which is unsubstituted or mono-or disubstituted with: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet³And/or [ C (R)²)₂]_pOHet³，

Het³Represents a dihydropyrrolyl group, a pyrrolidinyl group, an azetidinyl group, an oxetanyl group, a tetrahydroimidazoyl group, a substituted or unsubstituted dihydropyrrolyl group, a pyrrolidinyl group, an azetidinyl group, a tetrahydroimidazolyl group, a substituted or unsubstituted pyrrolyl,Dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuryl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1,3 ]]Dioxolanyl, tetrahydropyranyl or piperazinyl,

a represents an unbranched or branched alkyl radical having 1 to 10C atoms, wherein two adjacent CH and/or CH groups₂The radicals may form a double bond and one or two non-adjacent CH and/or CH₂The radicals may be substituted by N-, O-and/or S-atoms and where 1 to 7H-atoms may be replaced by F or Cl,

hal represents F, Cl, Br or I,

p represents 0, 1,2,3 or 4,

provided that if R is¹Is CH₂OH, then Ar¹Is other than 2, 4-dichlorophenyl;

in Ig, R¹Represents H, F, Cl, CN, CH₃、CH₂OH、CH₂Cl、CH₂Br、CF₃、CHF₂Or CH₂F，

R²Represents a group of a compound represented by the formula H or A,

R³represents H, F, Cl, CH₃、CF₃Or CHF₂，

X represents CR³Or the number of N is greater than the number of N,

y represents Ar¹、Carb、Het¹Or a group of cells of the group Cyc,

Ar¹represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: hal, A, [ C (R)²)₂]_pOR²、[C(R²)₂]_pN(R²)₂、 [C(R²)₂]_pHet²、NO₂、Cyc、[C(R²)₂]_pCOOR²、O[C(R²)₂]_pAr²And/or O [ C (R) ]²)₂]_pHet²，

Ar²Represents phenyl which is unsubstituted or substituted by [ C (R)²)₂]_pOR²The process is a single substitution process,

Het¹represents pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, pyridinyl, pyrimidinyl or 1, 3-benzodioxolyl, each of which is unsubstituted or mono-or disubstituted by: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet²And/or [ C (R)²)₂]_pAr²，

Carb represents indanyl or tetrahydronaphthyl, each of which may be unsubstituted or mono-, di-, tri-or tetrasubstituted by A,

cyc represents cycloalkyl having 3,4,5, 6 or 7C atoms, which may be unsubstituted or monosubstituted by: A. OH, Hal, CN or Ar²Or Het²，

Het²Represents pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, oxazolyl, isoxazolyl or oxadiazolyl, each of which is unsubstituted or mono-or disubstituted by: A. [ C (R)²)₂]_pOR²、[C(R²)₂]_pHet³And/or [ C (R)²)₂]_pOHet³，

Het³Represents a pyrrolidinyl group, a piperidinyl group, a morpholinyl group or a tetrahydropyranyl group,

A represents an unbranched or branched alkyl radical having 1 to 10C atoms, wherein two adjacent CH and/or CH groups₂The radicals may form a double bond and one or two non-adjacent CH and/or CH₂The radical may be replaced by an O atom and where 1 to 7H atoms may be replaced by F or Cl,

hal represents F, Cl, Br or I,

p represents 0, 1,2,3 or 4,

provided that if R is¹Is CH₂OH, then Ar¹In addition to the 2, 4-dichlorophenyl group,

and pharmaceutically usable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

Furthermore, the compounds of the formula I and also their starting materials for their preparation are prepared by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), under reaction conditions known and suitable for the reaction in question (to the precise extent). Variants known per se, which are not mentioned in more detail herein, can also be utilized.

The starting compounds of the formulae II and III are generally known. However, if they are novel, they can be prepared by methods known per se.

The compounds of the formula I can preferably be prepared by reacting a compound of the formula II with NH₃、NH₄OAc or NH₄)₂CO₃Obtained by reaction.

Depending on the conditions used, the reaction time is between a few minutes and 14 days and the reaction temperature is between about-10 ° and 140 °, generally between 30 ° and 130 °, in particular between about 60 ° and about 120 °. The reaction is carried out in an inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

Methanol or acetic acid is particularly preferred.

Furthermore, the compounds of the formula I can preferably be prepared by reacting a compound of the formula III with H under basic conditions₂O₂Obtained by reaction.

The reaction is carried out in an inert solvent in the presence of a hydroxide, carbonate or bicarbonate of an alkali or alkaline earth metal or other salt of a weak acid of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or caesium.

Depending on the conditions used, the reaction time is between a few minutes and 14 days and the reaction temperature is between about-10 ° and 140 °, generally between 30 ° and 130 °, in particular between about 60 ° and about 120 °.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

Particularly preferred is CH₂Cl₂And water or methanol and dimethyl sulfoxide.

Furthermore, the compounds of the formula I can be reacted via the following ringsA group R¹And/or Y into another group R¹And/or Y to obtain:

i) COOH or CHO is converted into H, and the obtained product is subjected to secondary reaction,

ii) converting the ester group into an alcohol group,

iii) converting the halogenobenzene ring into an aromatised benzene ring in a Suzuk coupling,

iv) converting the haloalkyl group to an alkyl group.

Step i) the conversion of the COOH groups into H is preferably carried out under basic conditions, preferably in an organic solvent, with copper powder; preferably in quinoline under standard conditions.

The conversion of the CHO group to H is preferably carried out in an inert solvent, preferably diglyme, in the presence of 3-diphenylphosphinopropyl (diphenyl) phosphane and rhodium (III) chloride trihydrate under standard conditions.

Step ii):

conversion of the ester group to an alcohol group, preferably in the presence of cerium (III) chloride, with an alkyl magnesium chloride in THF under standard conditions or

With lithium aluminum hydride in THF.

Step iii):

the conversion of the halobenzene ring to the arylated benzene ring is carried out under standard conditions for Suzuki coupling.

Step iv):

conversion of haloalkyl to alkyl is preferably carried out with LiAlH₄In THF or with zinc in acetic acid under standard conditions.

Alternatively, the compound of formula I may be obtained by treatment with a solvolytic or hydrogenolytic agent to release the compound of formula I from one of its functional derivatives.

Preferred starting materials for solvolysis or hydrogenolysis are starting materials which correspond to formula I but contain the corresponding protected amino and/or hydroxyl groups in place of one or more free amino and/or hydroxyl groups, preferably starting materials which carry an amino-protecting group in place of the H atom attached to the N atom, in particular starting materials which carry an R '-N group (where R' is an amino-protecting group) in place of the HN group, and/or starting materials which carry a hydroxyl-protecting group in place of the H atom of the hydroxyl group, for example starting materials which correspond to formula I but carry-COOR "groups (where R" is a hydroxyl-protecting group) in place of the-COOH group.

Furthermore, the preferred starting materials are oxadiazole derivatives, which can be converted into the corresponding amidino compounds.

It is also possible for a plurality of protected amino and/or hydroxyl groups, identical or different, to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can be selectively cleaved in many cases.

The term "amino-protecting group" is known in general terms and relates to a group which is suitable for protecting (blocking) an amino group against chemical reactions, but which can be easily removed after the chemical reactions required elsewhere in the molecule have been completed. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, arylalkoxymethyl or arylalkyl groups. Since the amino-protecting groups are removed after the desired reaction (or sequential reaction), their type and size is otherwise not critical; however, preference is given to those protecting groups having from 1 to 20, in particular from 1 to 8, carbon atoms. The term "acyl" is to be understood in the broadest sense in connection with the process of the invention. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxy-carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl and tolyl; aryloxy alkanoyl such as POA; alkoxycarbonyl, such as methoxy-carbonyl, ethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl radicals, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl groups such as Mtr. Preferred amino-protecting groups are BOC and Mtr, in addition to CBZ, Fmoc, benzyl and acetyl.

The term "hydroxy-protecting group" is also known in general terms and refers to a group that is suitable for protecting a hydroxy group against chemical reactions, but can be easily removed after completion of a desired chemical reaction elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, which may furthermore also be alkyl groups. The nature and size of the hydroxy-protecting groups are not critical, as they are removed again after the desired chemical reaction or sequence of reactions; preference is given to radicals having from 1 to 20, in particular from 1 to 10, carbon atoms. Examples of hydroxy-protecting groups are especially benzyl, 4-methoxybenzyl, p-nitro-benzoyl, p-toluenesulfonyl, tert-butyl and acetyl, of which benzyl, tetrahydropyranyl and tert-butyl are particularly preferred.

The compounds of formula (I) are liberated from their functional derivatives-depending on the protective group used-for example using strong acids, advantageously TFA or perchloric acid, but also other strong inorganic acids, for example hydrochloric acid or sulfuric acid, strong organic carboxylic acids, for example trichloroacetic acid, or sulfonic acids, for example benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid; ethers such as tetrahydrofuran or dioxane; amides, such as DMF; halogenated hydrocarbons such as dichloromethane; furthermore, alcohols, such as methanol, ethanol or isopropanol, and water. Furthermore, mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without addition of further solvent, while perchloric acid is preferably used as a 9:1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is advantageously between about 0 and about 50 ℃, preferably between 15 and 30 ℃ (room temperature).

The BOC, OBut and Mtr groups can be cleaved, for example, preferably with TFA in dichloromethane or with about 3-5N HCl in dioxane at 15-30 deg.C, and the FMOC group can be cleaved with dimethylamine, diethylamine or piperidine in about 5-50% solution in DMF at 15-30 deg.C.

The hydrogenolytically removable protecting groups (e.g. CBZ, benzyl or the liberation of amidino from its oxadiazole derivative) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents herein are those indicated above, in particular, for example alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature between about 0 and 100 ℃ and at a pressure between about 1 and 200 bar, preferably between 20-30 ℃ and 1-10 bar. Hydrogenolysis of the CBZ group, for example, on 5-10% Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30 ℃ is well performed.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, trifluoromethylbenzene, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

The ester can be saponified, for example, with acetic acid or with NaOH or KOH in water, water/THF or water/dioxane at a temperature between 0 and 100 °.

Furthermore, the free amino group can advantageously be in an inert solvent, such as dichloromethane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at-60And +30 ℃ in a conventional manner, with acyl chlorides or anhydrides or with unsubstituted or substituted alkyl halides, or with CH₃-C (= NH) -OEt reaction.

Pharmaceutically acceptable salts and other forms

The compounds according to the invention can be used in their final non-salt form. In another aspect, the invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which salts can be derived from a variety of organic and inorganic acids and bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are mostly prepared by conventional methods. If the compounds of formula I contain a carboxyl group, one of its suitable salts may be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, other inorganic acids and their corresponding salts, such as sulfates, nitrates or phosphates and the like, and alkyl-and monoaryl sulfonates, such as ethanesulfonates, toluenesulfonates and benzenesulfonates, and other organic acids and their corresponding salts, such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, hemi-lactobionate (galactarate) (obtained from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate (isethionate), isobutyrate, lactate, lactobionate (lactobionate), Malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmitate (palmoate), pectate (pectate), persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a limitation.

Furthermore, base salts of the compounds according to the invention include aluminium, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this is not intended to represent a limitation. Among the above salts, ammonium is preferred; alkali metal sodium and potassium salts, and alkaline earth metal calcium and magnesium salts. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (tromethamine), this is not intended to be a limitation.

Containing alkalinityThe compounds of the present invention containing nitrogen groups may be quaternized using the following agents: for example (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; two (C)₁-C₄) Alkyl sulfates such as dimethyl, diethyl, and diamyl sulfates; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-and oil-soluble compounds according to the invention can be prepared using such salts.

Preferred pharmaceutically acceptable salts mentioned above include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to represent a limitation.

Particularly preferred are the hydrochloride, dihydrochloride, hydrobromide, maleate, methanesulfonate, phosphate, sulfate and succinate salts.

Acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to cause the formation of the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs from its corresponding salt form in some way (with respect to certain physical properties, such as solubility in polar solvents); however, for the purposes of the present invention, salts additionally correspond to their respective free base forms.

As already mentioned, pharmaceutically acceptable base-addition salts of the compounds of formula I are formed with metals or amines, for example alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

Base-addition salts of acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause the formation of the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in some way (with respect to certain physical properties, such as solubility in polar solvents); however, for the purposes of the present invention, salts additionally correspond to their respective free acid forms.

If the compounds according to the invention contain more than one group capable of forming a pharmaceutically acceptable salt of this type, complex salts are also encompassed by the invention. Typical complex salt forms include, for example, bitartrate, diacetate, difumarate, meglumine, diphosphate, disodium and trihydrochloride, but this is not intended to represent a limitation.

With regard to the above, it can be seen that the expression "pharmaceutically acceptable salt" is used in this respect to mean the active ingredient, which includes the compound of formula I in one of its salt forms, in particular if this salt form confers on the active ingredient improved pharmacokinetic properties compared with the active ingredient in free form or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient may also provide the active ingredient for the first time with the desired pharmacokinetic properties which it did not have before and which may even have a positive effect on the pharmacodynamics of the active ingredient with respect to its therapeutic efficacy in vivo.

Isotope of carbon monoxide

Furthermore, the compounds of formula I are intended to include isotopically-labelled forms thereof. Isotopically-labelled forms of the compounds of formula I are identical to the compounds, except for the fact that one or more atoms of the compound have been replaced byOne or more atomic substitutions having an atomic mass or mass number different from the atomic mass or mass number of the atom normally found in nature. Examples of isotopes which are readily commercially available and which can be incorporated into the compounds of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and CI. Compounds of formula I, prodrugs thereof, or pharmaceutically acceptable salts thereof, containing one or more of the foregoing isotopes and/or other isotopes of other atoms are intended to be part of this invention. Isotopically-labelled compounds of formula I can be used in a number of advantageous ways. E.g. radioactive isotopes, e.g.³H or¹⁴Isotopically-labelled compounds of formula I into which C has been incorporated are suitable for use in drug and/or substrate tissue distribution assays (substrate tissue distribution assays). These radioactive isotopes, i.e. tritium (A)³H) And carbon-14 (¹⁴C) Particularly preferred because of its simplicity of preparation and excellent detectability. Heavier isotopes, e.g. deuterium (²H) Incorporation into the compounds of formula I is of therapeutic advantage due to the higher metabolic stability of such isotopically-labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which in most cases will represent a preferred embodiment of the invention. Isotopically-labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and the associated descriptions, and in the examples section and preparation section herein, substituting a readily available isotopically-labeled reactant for a non-isotopically-labeled reactant.

Deuterium (1)²H) It may also be incorporated into the compounds of formula I for the purpose of manipulating the oxidative metabolism of the compounds by primary kinetic isotope interactions. First order kinetic isotope action is the change in the rate of chemical reactions caused by the exchange of isotope nuclei, which in turn is caused by the change in ground state energy necessary for covalent bond formation after such isotope exchange. Cross linking of heavier isotopesThis usually results in a reduction in the ground state energy of the chemical bond and hence a reduction in the rate-limiting bond rupture (rate-limiting rupture) rate. If bond breakage occurs at or near the saddle-point region along the multi-product reaction coordinate (coordination of a multi-product reaction), the product distribution ratio can vary significantly. For purposes of explanation: if deuterium is bonded to a carbon atom in a non-exchangeable position, k_M/k_DA rate difference of = 2-7 is typical. If this difference is successfully applied to compounds of formula I which are susceptible to oxidation, the in vivo profile (profile) of such compounds may be significantly improved and lead to improved pharmacokinetic properties.

When discovering and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. The currently available in vitro liver microsomal assays provide valuable information on the course of this type of oxidative metabolism, which in turn allows rational design of deuterated compounds of formula I with improved stability by combating such oxidative metabolism. The pharmacokinetic profile of the compound of formula I is thus significantly improved and can be based on an increase in the in vivo half-life (t/2), the concentration at which the therapeutic effect is maximal (C)_max) Area under the dose response curve (AUC) and F; and quantitatively expressed in terms of reduced clearance, dosage and material costs.

The following is intended to illustrate the above: compounds of formula I having multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms bonded to the nitrogen atom) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms such that some, most, or all of these hydrogen atoms have been replaced with deuterium atoms. The half-life determination enables an advantageous and accurate determination of the degree of improvement in resistance to oxidative metabolism. It was determined in this way that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange in the compounds of formula I may also be used to obtain a favourable improvement in the metabolic profile of the starting compound to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite is produced by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that the deuterated analog will greatly reduce or eliminate the production of the undesirable metabolite, even if the particular oxidation is not the rate-limiting step. Further information on the state of the art relating to deuterium-hydrogen exchange can be found, for example, in Hanzlik et al, J. org. chem. 55, 3992-.

The invention further relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700mg, particularly preferably from 5 mg to 100mg, of a compound according to the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical preparations may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or a partial dose, as indicated above, or the corresponding fraction of its active ingredient. Furthermore, pharmaceutical formulations of this type may be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulations may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared using all methods known in the pharmaceutical art, for example by mixing the active ingredient with excipients or auxiliaries.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units, for example, capsules or tablets; powder or granules; a solution or suspension in an aqueous or non-aqueous liquid; edible foams or foamed foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component may be mixed with an oral, non-toxic and pharmaceutically acceptable inert excipient, e.g., ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine particle size and mixing it with a pharmaceutical excipient, such as an edible carbohydrate, for example starch or mannitol, which is comminuted in a similar manner. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules were produced by preparing a powder mixture as described above and filling into shaped gelatin shells. Glidants and lubricants, for example, highly dispersible silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture and then subjected to a filling operation. Disintegrating or solubilizing agents, such as agar-agar, calcium carbonate or sodium carbonate, may also be added to improve the availability of the drug after ingestion of the capsule.

Furthermore, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or dry-compressing the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture to give tablets. The powder mixture is prepared by mixing the compound, comminuted in a suitable manner, with a diluent or matrix as described above, and optionally with a binder, for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, a dissolution retarding agent, for example paraffin, an absorption promoter, for example a quaternary ammonium salt, and/or an absorbent agent, for example bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting it with a binder such as syrup, starch paste, gum arabic or a solution of cellulose or polymeric material and pressing it through a sieve. As an alternative to granulation, the powder mixture may be passed through a tablet press to give a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet mould. The lubricated mixture is then compressed to obtain tablets. The compounds according to the invention can also be mixed with inert, free-flowing excipients and then directly compressed without granulation or a dry-compression step to give tablets. There may be a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids, such as solutions, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, and the like, can likewise be added.

If desired, dosage unit formulations for oral administration may be encapsulated in microcapsules. The formulations may also be prepared in such a way, for example, by coating or embedding the particulate material in polymers, waxes, etc., for extended or delayed release.

The compounds of formula I and salts, solvates and physiologically functional derivatives thereof may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula I and salts, solvates and physiologically functional derivatives thereof may also be delivered using monoclonal antibodies as a single carrier to which the compound molecules are coupled. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartyl phenol, or polyethylene oxide polylysine (substituted with palmitoyl). The compounds may additionally be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphiphilic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be administered as a separate plaster in long-term, intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered by iontophoresis (as described in the general term of Pharmaceutical Research, 3(6), 318 (1986)) by plaster.

Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, such as the oral cavity and the skin, the formulation is preferably applied as a topical ointment or cream. In the case of formulations for administration of ointments, the active ingredient may be used with either a paraffin or water-miscible cream base. Alternatively, the active ingredient may be formulated with an oil-in-water cream base or a water-in-oil base to provide a cream.

Pharmaceutical formulations suitable for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.

Pharmaceutical formulations adapted for topical application to the oral cavity include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size of, for example, 20 to 500 microns, which is administered by nasal inhalation, i.e. by rapid inhalation through the nasal passages from a powder-containing container held close to the nose. Suitable formulations for administration as a nasal spray or nasal drops (with liquid as carrier material) comprise solutions of the active ingredient in water or oil.

Pharmaceutical formulations adapted for administration by inhalation comprise a fine particle dust or mist which may be generated by various types of pressurised dispensers, nebulisers or inhalers with an aerosol.

Pharmaceutical formulations adapted for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes by which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending media and thickening agents. The formulations may be administered in single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, so that only the addition of the sterile carrier liquid, for example water for injections, is required immediately prior to use. Injectable solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the components specifically mentioned above, the formulations may also comprise, for a particular type of formulation, other agents commonly used in the art; thus, for example, formulations suitable for oral administration may contain flavouring agents.

The therapeutically effective amount of a compound of formula I will depend on a number of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be determined by the physician or veterinarian performing the treatment. However, an effective amount of a compound according to the invention will generally be in the range of from 0.1 to 100mg/kg body weight of the recipient (mammal) per day, and particularly typically in the range of from 1 to 10mg/kg body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, where this amount may be administered as a single dose per day or may typically be administered in a series of partial doses (e.g. two, three, four, five or six) per day such that the total daily dose is the same. An effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound according to the invention per se. It is contemplated that similar dosages may be applicable to the treatment of other conditions as described above.

This type of combination therapy can be achieved by means of simultaneous, sequential or separate dispensing of the components of the therapy. This type of combination uses the compounds according to the invention.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

The invention also relates to a set (kit) consisting of the following separate packages:

(a) an effective amount of a compound of formula I and/or pharmaceutically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios,

and

(b) an effective amount of an additional pharmaceutically active ingredient.

The kit contains suitable containers, such as boxes, individual bottles, bags or ampoules. The kit may, for example, comprise separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of an additional pharmaceutically active ingredient in dissolved or lyophilized form.

"treating" as used herein means alleviating, in whole or in part, the symptoms associated with a disorder or disease, or delaying or interrupting the further development or worsening of these symptoms, or preventing a disease or disorder in a subject at risk of developing the disease or disorder.

The term "effective amount" in relation to a compound of formula (I) may mean an amount capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or delaying or interrupting the further development or worsening of such symptoms, or preventing a disease or disorder in a subject suffering from or at risk of developing a disease as disclosed herein, such as an inflammatory disease, an immunological disease, cancer or a metabolic disease.

In one embodiment, an effective amount of a compound of formula (I) is an amount that inhibits tankyrase in a cell, e.g., in vitro or in vivo. In some embodiments, the effective amount of the compound of formula (I) inhibits 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99% of the tankyrase in the cell compared to the activity of the tankyrase in untreated cells. An effective amount of a compound of formula (I), e.g., in a pharmaceutical composition, can be a level at which a desired effect will be exerted; for example, for both oral and parenteral administration, from about 0.005 mg/kg to about 10mg/kg of subject body weight in a unit dose.

Applications of

The compounds are suitable as pharmaceutical active ingredients in the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation in mammals, especially in humans.

The invention encompasses the use of a compound of formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

Examples of inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions, and the like.

Also included is the use of a compound of formula I and/or physiologically acceptable salts and solvates thereof, wherein for the method a therapeutically effective amount of a compound according to the present invention is administered to a diseased mammal in need of such treatment, in the manufacture of a medicament for the treatment or prevention of tankyrase-induced disease or tankyrase-induced condition in a mammal. The amount of treatment will vary depending on the particular disease and can be determined by one skilled in the art without undue effort.

The expression "tankyrase-induced disease or condition" refers to a pathological condition which depends on the activity of one or more tankyrase enzymes. Diseases associated with tankyrase activity include cancer, multiple sclerosis, cardiovascular disease, central nervous system injury and different forms of inflammation.

The invention relates in particular to compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the treatment of diseases in which inhibition, modulation and/or modulation of tankyrase plays a role.

The invention relates in particular to compounds of formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the inhibition of tankyrase.

The invention relates in particular to compounds of formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

The present invention relates to a method for the treatment or prophylaxis of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof.

Representative cancers for which compounds of formula I may be useful in the treatment or prevention include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors, and hematologic tumors (blood-borne tumors).

Representative cardiovascular diseases for which compounds of formula I may be useful include, but are not limited to, restenosis, atherosclerosis and its consequences such as stroke, myocardial infarction, ischemic damage to the heart, lung, intestine, kidney, liver, pancreas, spleen or brain.

The present invention relates to methods of treating proliferative, autoimmune, anti-inflammatory, or infectious disease conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.

Preferably, the present invention relates to a method wherein the disease is cancer.

Particularly preferably, the invention relates to a method wherein the disease is cancer and wherein the administration is simultaneous, sequential or alternating with the administration of at least one other active agent.

The disclosed compounds of formula I may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anti-cancer agent" relates to any agent that is administered to a patient suffering from cancer for the purpose of treating the cancer.

Anti-cancer treatments as defined herein may be applied as monotherapy or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Such chemotherapy may include one or more of the following classes of antineoplastic agents:

(i) antiproliferative/antineoplastic/DNA-damaging agents and combinations thereof, such as for medical oncology, for example alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea and gemcitabine); anti-tumor antibiotics (e.g., anthracyclines like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and plicamycin); antimitotic agents (e.g. vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, and taxanes like paclitaxel and taxotere); topoisomerase inhibitors (e.g. epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell differentiating agents (e.g. all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide);

(ii) cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and idoxifene (iodoxyfene)), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole and exemestane), and 5 a-reductase inhibitors such as finasteride;

(iii) drugs that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, e.g., such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb 2 antibody trastuzumab [ trastuzumab (Herceptin))^TM]And anti-erbbl antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)), inhibitors of, for example, the platelet-derived growth factor family; and inhibitors of, for example, the hepatocyte growth factor family;

(v) anti-angiogenic drugs, e.g., those that inhibit the action of vascular endothelial growth factor (e.g., anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]^TM]Compounds such as those disclosed in published international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354), and compounds that act by other mechanisms (e.g., linoamine, integrin α v β 3 function inhibitors and angiostatin);

(vi) vascular disrupting agents such as combretastatin a4 and the compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, e.g., against the above-listed targets, e.g., ISIS 2503, anti-Ras antisense drugs (anti-Ras antisense);

(viii) gene therapy methods, including, for example, methods of replacing an aberrant gene, such as aberrant p53 or aberrant BRCA1 or BRCA 2; GDEPT (gene-directed enzyme prodrug therapy) methods, such as those with cytosine deamidase, thymidine kinase, or bacterial nitroreductase enzymes, and methods of increasing the tolerance of a patient to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and

(ix) immunotherapy, including for example ex vivo and in vivo methods of increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor; a method of reducing T cell anergy; methods using transfected immune cells such as cytokine-transfected dendritic cells; a method using a cytokine-transfected tumor cell line, and a method using an anti-idiotype antibody.

Preferably the agents of table 1 below (but not exclusively) are combined with compounds of formula I.

The following abbreviations refer to the following definitions, respectively:

aq (aqueous), h (hr), g (g), L (L), mg (mg), MHz (megahertz), min. (min), mM (mM), mmol (mmol), mM (mmol equivalent), m.p. (melting point), eq (equivalent), mL (mL), L (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl (acetonitrile), hi (r), hi (₃(deuterated chloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d₆(deuterated dimethyl sulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH (ethanol), HATU (dimethylamino- ([1,2, 3))]Triazolo [4,5-b]Pyridin-3-yloxy) -methylene]Dimethyl-ammonium hexafluorophosphate), HPLC (high Performance liquid chromatography), i-PrOH (2-propanol), K₂CO₃(Potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO₄Magnesium sulfate, MS (Mass Spectrometry), MTBE (methyl Tert-butyl Ether), NaHCO₃(sodium bicarbonate), NaBH₄(sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), RT (retention time), SPE (solid phase extraction), TBTU (2- (1-H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UV (ultraviolet).

Description of in vitro assays

Abbreviations:

GST = glutathione-S-transferase

FRET = fluorescence resonance energy transfer

HTRF = (homogeneous phase time resolved fluorescence)

HEPES = 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid buffer

DTT = dithiothreitol

BSA = bovine serum albumin

CHAPS = detergent;

CHAPS = 3- [ (3-cholamido (cholamido) propyl) dimethylammonio (ammonio) ] -1-propanesulfonate.

streptavidin-XLent is a high grade streptavidin-XL 665 conjugate for which coupling conditions have been optimized to produce conjugates with enhanced performance for some assays, particularly assays requiring high sensitivity.

Biochemical activity testing of tankyrase 1 and 2: automated poly ADP nuclear glycation (autopropsy) assay

The autopolyadp ribosylation assay was performed in two steps: enzymatic reactions (where GST-labeled tankyrase-1, resp tankyrase-2 transfer biotinylated ADP-ribose to itself from biotinylated NAD as a common substrate) and detection reactions (where time resolved FRET between cryptate-labeled anti-GST bound to GST tags of the enzyme and Xlent @ labeled-streptavidin bound to biotin-poly ADP riboylated residues) were analyzed. Autopolyadp ribosylation activity can be detected directly via an increase in HTRF signal.

The automated poly ADP ribosylation assay was performed as a 384-well HTRF (Cisbio, Codolet, France) assay format in Grarner low (Greiner low volume) nb 384-well microtiter plates and used for high throughput screening. 250 nM GST-labeled Takara polymerase-1 (1023 + 1327 aa), approximately 250 nM GST-labeled Takara polymerase-2 (873 + 1166 aa) and 5 μ M bio-NAD (Biolog, Life science Inst., Bremen, Germany), respectively, were incubated in a total volume of 5 μ l (50 mEPMHES, 4 mM magnesium chloride, 0.05% Prorhenike F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) at 30 ℃ for 90 min in the absence or presence of test compounds (10-fold dilution). The reaction was stopped by adding 1 μ l of 50mM EDTA solution. 2 μ l of detection solution (1.6 μ M SA-Xlent ® (Cisbio, Codolet, France), 7.4 nM anti-GST-K (Eu-labeled anti-GST, Cisbio, Codolet, France) in 50mM HEPES, 800 mM KF, 0.1% BSA, 20mM EDTA, 0.1% CHAPS, pH 7.0) was added. After 1 hour incubation at room temperature, HTRF was measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH) at excitation wavelength 340 nm (laser mode) and emission wavelengths 615 nm and 665 nm. The ratio of the emitted signals is determined. The full value used is the inhibitor-free reaction. The pharmacological zero value used was XAV-939 (Tocris) in a final concentration of 5 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

Determination of the cytostatic Effect of tankyrase

Since tankyrase has been described as modulating the cellular level of Axin2 (Huang et al, 2009; Nature), an increase in Axin2 levels was used as a readout to determine the cytostatic effect of tankyrase in a Luminex-based assay.

Cells of colon cancer cell line DLD1 were plated at 1.5x10 per well⁴Individual cells were seeded in 96-well plates. The following day, cells were treated with serially diluted test compounds in triplicate at 0.3% final DMSO concentration in 7 steps. After 24 hours, cells were lysed in lysis buffer (20mM Tris/HCl pH 8.0, 150mM NaCl, 1% NP40, 10% glycerol) and the lysate was cleared by centrifugation through 96-well filter plates (0.65 μm). By binding to monoclonal anti-Axin 2 antibody (R) bound to fluorescent carboxyl beads (carboxybeads)&D Systems # MAB6078) were incubated together to isolate Axin2 protein from the cell lysate. Then, polyclonal anti-Axin 2 antibody (Cell Signaling #2151) and appropriate PE-fluorescein were usedThe light secondary antibody specifically detects bound Axin 2. In Luminex, according to the manufacturer's instructions²⁰⁰The amount of Axin2 protein isolated was determined on the machine (Luminex Corporation) by counting 100 events per well. Inhibition of tankyrase by test compounds resulted in higher levels of Axin2, which was directly correlated with an increase in detectable fluorescence. As a control, cells were treated with solvent only (neutral control) and with the tankyrase reference inhibitor IWR-2 (3E-06M), which served as a control for the maximal increase in Axin 2. For analysis, the data obtained were normalized to untreated solvent controls and fitted using Assay Explorer software (Accelrys) to determine EC₅₀The value is obtained.

Description of the PARP1 assay

Biochemical activity assay of PARP-1: automated poly ADP ribosylation assay

The autopolyadp ribosylation assay was performed in two steps: enzymatic reactions (where His-tagged Parp-1 transfers biotinylated ADP-ribose/ADP-ribose to itself from biotinylated NAD/NAD as a co-substrate) and detection reactions (where time resolved FRET between cryptate-tagged anti-His antibodies bound to the enzyme's His tag and Xlent @ tagged-streptavidin bound to biotin-poly ADP riboylated residues) were analyzed. Autopolyadp ribosylation activity can be detected directly via an increase in HTRF signal.

The autopolyADP ribosylation assay was performed as a 384-well HTRF (Cisbio, Codolet, France) assay format in Graham's low nb 384-well microtiter plates. A mixture of 35 nM His-tagged Parp-1 (human, recombinant, Enzo Life Sciences GmbH, Lnurrach, Germany) and 125 nM bio-NAD (Biolog, Life science Inst., Bremen, Germany) as co-substrate and 800 nM NAD in the absence or presence of test compounds (10-fold dilution concentration) was incubated in a total volume of 6 μ L (100 mM Tris/HCl, 4 mM magnesium chloride, 0.01% IGEPAL CA630, 1mM DTT, 0.5% DMSO, pH 8, 13 ng/. mu.l activated DNA (BPS Bioscience, San Diego, US)) at 23 ℃ for 150 min. The reaction was terminated by adding 4 μ l of stop/detection solution (70 nM SA-Xlent ® (Cisbio, Codolet, France), 2.5 nM anti-His-K ® (Eu-labeled anti-His, Cisbio, Codolet, France) in 50mM HEPES, 400 mM KF, 0.1% BSA, 20mM EDTA, pH 7.0). After 1 hour incubation at room temperature, HTRF was measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH) at an excitation wavelength of 340 nm (laser mode) and emission wavelengths of 615 nm and 665 nm. The ratio of the emitted signals is determined. The full value used is the inhibitor-free reaction. The pharmacological zero value used was Olaparib (LClabs, Woburn, US) in a final concentration of 1 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

Description of TNKS1 and TNKS2 ELISA assays

Biochemical activity test of TNKS1 and 2: activity ELISA (automatic poly ADP ribolysis assay)

To analyze the autopolyadp-ribosylation activity of TNKS1 and 2, an activity ELISA was performed: in the first step, GST-tagged TNKS was captured on glutathione-coated plates. The activity assay was then performed with biotinylated NAD in the absence/presence of the compound. During the enzymatic reaction GST-tagged TNKS transferred biotinylated ADP-ribose to itself from biotinylated NAD as co-substrate. For detection, streptavidin-HRP conjugate bound to biotinylated TNKS was added, and thus captured to the plate. The amount of biotinylated resp autopolyadp ribosylated TNKS was detected with a luminescent substrate of HRP. The level of the luminescence signal is directly related to the amount of autopolyadp ribosylated TNKS and thus also to TNKS activity.

Activity ELISA was performed on 384-well Glutathione-coated microtiter plates (Express capture Glutathione coated plates, Biocat, Heidelberg, Germany.) plates were pre-equilibrated with PBS plates, plates were then blocked with 50 μ l of 20 ng/well GST-labeled Tnks-1 (1023-plus 1327 aa, prepared in-house), GST-labeled Tnks-2 (873-plus 1166 aa, prepared in-house), respectively, in assay buffer (50 mM HEPES, 4 mM magnesium chloride, 0.05% Pluronic F-68, 2mM DTT, pH 7.7) overnight at 4 ℃. plates were washed 3 times with PBS-Tween-20. the plates were blocked with 50 μ l of blocking buffer (PBS, 0.05% Tween-20, 0.5% BSA) for 20 minutes at room temperature after which the plates were washed with PBS-Tween-20 (10 times) enzymatic assay compounds (10-fold) Released concentration) was performed in 50 μ l of reaction solution (50 mM HEPES, 4 mM magnesium chloride, 0.05% pluronic F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) with 10 μ M bio-NAD (Biolog, Life science Inst., Bremen, Germany) as co-substrate at 30 ℃ for 1 hour. The reaction was stopped by washing 3 times with PBS-Tween-20. For detection, 50 μ l of 20ng/μ l streptavidin in PBS/0.05% Tween-20/0.01% BSA, HRP conjugate (MoBiTec, G tincture, Germany) were added and the plates were incubated for 30 minutes at room temperature. After 3 washes with PBS-Tween-20, 50. mu.l SuperSignal ELISA Femto maximum sensitivity (Maximumsensirity) substrate solution (ThermoFisher scientific (Pierce), Bonn, Germany) was added. After incubation for 1 min at room temperature, the luminescence signal was measured at 700 nm using an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The full value used is the inhibitor-free reaction. The pharmacological zero value used was XAV-939 (Tocris) in a final concentration of 5 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

In this context, all temperatures are expressed in degrees Celsius. In the following examples, "conventional post-processing (work-up)" means: if desired with addition of water, if desired to adjust the pH to a value of between 2 and 10, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallization. Rf value on silica gel; eluent: ethyl acetate/methanol 9: 1.

HPLC/MS Condition A

Column: chromolith Performance ROD RP-18e, 50X 4.6 mm²

Gradient: a: B = 96:4-0:100 within 2.8 min

Flow rate: 2.40 ml/min

Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive ion mode

HPLC/MS Condition B

Column: chromolith Performance ROD RP-18e, 100 x 3 mm²

Gradient: a: B = 99:1-0:100 in 3.5 min

Flow rate: 2.0 ml/min

Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive ion mode

HPLC/MS Condition C

Column: chromolith Performance ROD RP-18e, 100 x 3 mm²

Gradient: a: B = 99:1-0:100 in 1.8 min

Flow rate: 2.0 ml/min

Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive ion mode

¹H NMR was recorded on a Bruker DPX-300, DRX-400 or AVII-400 spectrometer using the residual signal of the deuterated solvent as an internal standard. Chemical shifts () are reported in ppm relative to residual solvent signal (for in DMSO-d)₆In (1)¹HNMR， = 2.49 ppm)。¹H NMR data are reported below: chemical shifts (multiplicities, coupling constants, and number of hydrogen atoms). Multiple purposeThe abbreviations for the multiplicity are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Microwave Chemistry was carried out on a single mode microwave reactor, EmrysTMOptimier from Personal Chemistry.

Example 1

Synthesis of 3- (4-benzyloxy-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A1")

A suspension of 200 mg (1.60 mmol) of methyl 1H-pyrrole-2-carboxylate and 1.56 g (4.79 mmol) of cesium carbonate in 3ml of DMF is heated to 50 ℃ with stirring. Then a solution of 488 mg (1.60 mmol) 1- (4-benzyloxy-phenyl) -2-bromo-ethanone in1 ml DMF was added over 3 minutes. The reaction mixture was stirred at 50 ℃ for 18 hours. The reaction mixture was filtered off with suction and the filtrate was evaporated. The residue was crystallized from diethyl ether to give methyl 1- [2- (4-benzyloxy-phenyl) -2-oxo-ethyl ] -1H-pyrrole-2-carboxylate as beige crystals; HPLC/MS 2.51 min (A), [ M + H ] 350.

A suspension of 100mg (0.286 mmol) of methyl 1- [2- (4-benzyloxy-phenyl) -2-oxo-ethyl ] -1H-pyrrole-2-carboxylate in 7M ammonia in methanol was irradiated in a microwave apparatus at 90 ℃ for 18H. The reaction mixture was cooled to room temperature and evaporated. Performing silica gel column chromatography on the residue, and using petroleum ether/ethyl acetate as eluent to obtain 3- (4-benzyloxy-phenyl) -2H-pyrrolo [1,2-a ] pyrazine-1-ketone as beige crystals; HPLC/MS 2.26 min (A), [ M + H ] 317.

Similarly, the following compounds were obtained

Example 2

Synthesis of 3- (4-trifluoromethyl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A13")

A solution of 1.15 g (9.19 mmol) of 1H-pyrrole-2-carboxylic acid methyl ester and 2.70 g (10.1 mmol) of 2-bromo- (1- (4-trifluoromethyl-phenyl) -ethanone in 20 ml acetonitrile is treated with 3.30 g (10.1 mmol) cesium carbonate, the resulting suspension is stirred at 35 ℃ for 18 hours, the reaction mixture is filtered and the filtrate is evaporated, the residue is chromatographed on a silica gel column using cyclohexane/ethyl acetate as eluent to give 1- [ 2-oxo-2- (4-trifluoromethyl-phenyl) -ethyl ] -1H-pyrrole-2-carboxylic acid methyl ester as a yellow oil, HPLC/MS 2.52 (A), [ M + H ]312.

A solution of 106 mg (0.34 mmol) of methyl 1- [ 2-oxo-2- (4-trifluoromethyl-phenyl) -ethyl ] -1H-pyrrole-2-carboxylate and 789 mg (10.2 mmol) of ammonium acetate in2 ml of acetic acid is heated to 80 ℃ with stirring. The mixture was stirred at this temperature for 5 hours and then cooled to room temperature. The mixture was partitioned between THF and saturated sodium chloride solution. The organic phase was washed 2 times with 25% aqueous ammonia solution and 2 times with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. Subjecting the residue to silica gel column chromatography with cyclohexane/ethyl acetate as eluent to obtain 3- (4-trifluoromethyl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one as colorless crystals; HPLC/MS 2.11 (A), [ M + H ] 279;

¹H NMR (500 MHz, DMSO-d₆) [ppm]10.91 (s, 1H), 7.90 (m, 3H), 7.82(d,J=8.4, 2H), 7.49 (dd,J=2.4, 1.5, 1H), 6.95 (m, 1H), 6.61 (dd,J=3.8,2.6, 1H)。

similarly, the following compounds were prepared

3- (1-methyl-1H-pyrazol-4-yl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A14")

HPLC/MS 1.66 min (B), [M+H]215；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.62 (s, 1H), 8.15 (s, 1H), 7.86 (d,J=0.6, 1H), 7.66 (s, 1H), 7.37 (dd,J=2.5, 1.5, 1H), 6.87 (m, 1H), 6.53 (dd,J=3.9, 2.5, 1H), 3.86 (s, 3H)；

3- (4-tert-butyl-phenyl) -7-methyl-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A38")

HPLC/MS 2.94 min (B), [M+H]281；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.64 (s, 1H), 7.61 (s, 1H), 7.59 (d,J=8.6, 2H), 7.46 (d,J=8.6, 2H), 7.24(dd,J=1.5, 0.8, 1H), 6.72 (m, 1H), 2.18 (s, 3H), 1.30 (s, 10H)；

3- (4-tert-butyl-phenyl) -1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] pyrazine-7-carbonitrile ("A92")

HPLC/MS 2.34 min (C), [M+H]292.

Example 3

Synthesis of 6- (4-tert-butyl-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A15")

A solution of 849 mg (4.00 mmol) of diethyl pyrazole-3, 5-dicarboxylate and 1.02 g (4.00 mmol) of 2-bromo-1- (4-tert-butyl-phenyl) -ethanone in 4ml of acetone is treated with 663 mg (4.80 mmol) of potassium carbonate. The resulting suspension was stirred at room temperature overnight. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give 1- [2- (4-tert-butyl-phenyl) -2-oxo-ethyl ] -1H-pyrazole-3, 5-dicarboxylic acid diethyl ester as a pale yellow foam; HPLC/MS 2.77 (A), [ M + H ]387.

A solution of 1.04 g (2.71 mmol) of diethyl 1- [2- (4-tert-butyl-phenyl) -2-oxo-ethyl ] -1H-pyrazole-3, 5-dicarboxylate and 2.08 g (27.1 mmol) of ammonium acetate in 20 ml of acetic acid was stirred at 110 ℃ for 44 hours. The reaction mixture was cooled to room temperature and excess water was added. The resulting precipitate was removed by filtration and washed with water. The residue was chromatographed on silica gel column with dichloromethane/methanol as eluent to give ethyl 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carboxylate as colorless crystals; HPLC/MS 2.41 (A), [ M + H ]340.

A solution of 547 mg (1.61 mmol) of ethyl 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carboxylate in 10 ml of 1, 2-dimethoxyethane was treated with 5ml of aqueous 1N NaOH solution. The resulting suspension was heated to 100 ℃ and the resulting solution was stirred at this temperature for 48 hours. The reaction mixture was cooled to room temperature and evaporated. The residue was triturated with water, filtered to remove solids and washed with water. The filtrate was acidified with 2N HCl. The resulting precipitate was removed by filtration, washed with 2N HCl and water and dried under vacuum to give 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carboxylic acid as a colorless solid; HPLC/MS 2.03 (A), [ M + H ]312.

28.9 mg (0.454 mmol) of copper powder are added to a solution of 70.7 mg (0.227 mmol) of 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carboxylic acid in2 ml of quinoline. The mixture was stirred at 190 ℃ for 20 hours. Distilling off quinoline under vacuum, subjecting the residue to silica gel column chromatography with cyclohexane/ethyl acetate as eluent to give 6- (4-tert-butyl-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one as colorless crystals; HPLC/MS 1.88(C), [ M + H ] 268;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.49 (s, 1H), 8.03 (s, 1H), 7.92(d,J=2.2, 1H), 7.69 (d,J=8.5, 2H), 7.49 (d,J=8.6, 2H), 7.01 (d,J=1.6,1H), 1.32 (s, 9H).

similarly, the following compounds were obtained

Example 4

Synthesis of 6- (4-tert-butyl-phenyl) -2-hydroxymethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A18") and alternatively "A15"

43.4 mg (1.14 mmol) of lithium aluminium hydride are added under nitrogen to a solution of 194 mg (0.571 mmol) of ethyl 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carboxylate (see previous examples for preparation) in 20 ml of THF. The reaction mixture was stirred at room temperature for 2 hours. A few drops of methanol followed by 2 ml of 2N HCl in water were slowly added to the reaction mixture. Then filtered through a pad of celite. The filtrate was evaporated and the residue was subjected to silica gel column chromatography using cyclohexane/ethyl acetate as eluent to give 6- (4-tert-butyl-phenyl) -2-hydroxymethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("a18") as a white powder; HPLC/MS 1.72 (C), [ M + H ] 298;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.46 (s, 1H), 7.94 (s, 1H), 7.67(d,J=8.5, 2H), 7.49 (d,J=8.5, 2H), 6.91 (s, 1H), 5.28 (bs, 1H), 4.59 (s,2H), 1.31 (s, 9H).

similarly, the following compounds were obtained

599 mg (1.41 mmol) of Dess-Martin periodinane are added to a solution of 140 mg (0.471 mmol) of 6- (4-tert-butyl-phenyl) -2-hydroxymethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one in 5ml of dichloromethane and 1 ml of DMF. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was washed with saturated sodium thiosulfate solution and with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was triturated with tert-butyl methyl ether, filtered to remove solids and dried under vacuum to give 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carbaldehyde as pale yellow crystals; HPLC/MS: 1.93 (C), [ M + H ]296.

140 mg (0.473 mmol) 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carbaldehyde are dissolved in1 ml diglyme. 12 mg (0.028 mmol) of 3-diphenylphosphinoalkylpropyl (diphenyl) phosphane and 3.7 mg (0.014 mmol) of rhodium (III) chloride trihydrate are added. The reaction mixture was stirred at 160 ℃ for 42 hours. The mixture was cooled to room temperature and partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using cyclohexane/ethyl acetate as eluent to give 6- (4-tert-butyl-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("a15") as colorless crystals; HPLC/MS 1.88(C), [ M + H ]268.

Similarly, the following compounds were obtained

6- (4-bromo-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A40")

；

6- (6-pyrrolidin-1-yl-pyridin-3-yl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A42")

；

6- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl ] -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A43")

；

6- (1-tert-butyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A44")

；

6- (1-tert-butyl-1H-pyrazol-4-yl) -2-hydroxymethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A89")

HPLC/MS 1.78 (B), [M+H]288.

Example 5

Synthesis of 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A24")

5.53 g (40.0 mmol) of potassium carbonate are added to a solution of 1.70 ml (20.0 mmol) of pyrrole-2-carbonitrile and 8.34 g (30.0 mmol) of 2, 4' -dibromoacetophenone in 40 ml of DMF. The resulting suspension was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and filtered under suction. The residue was washed with dichloromethane. The filtrate was evaporated and the residue was chromatographed on silica gel using cyclohexane/ethyl acetate as eluent to give 1- [2- (4-bromo-phenyl) -2-oxo-ethyl ] -1H-pyrrole-2-carbonitrile as a pale orange solid; HPLC/MS2.80 (B), [ M + H ]289/291.

3.36 g (11.6 mmol) 1- [2- (4-bromo-phenyl) -2-oxo-ethyl ] -1H-pyrrole-2-carbonitrile and 3.95 g (11.6 mmol) tetrabutylammonium hydrogen sulfate were dissolved in 23 ml dichloromethane. 12.3 ml (121mmol) of aqueous hydrogen peroxide solution (30% by weight) are added with stirring, and 4.63 ml (50.0 mmol) of aqueous sodium hydroxide solution (32% by weight) are then added slowly with stirring. The reaction mixture was stirred at room temperature for 90 minutes and then partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography with cyclohexane/ethyl acetate to give two products:

3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-one; a white powder; HPLC/MS2.42 (B), [ M + H]289/291；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.80 (s, 1H), 7.78 (s, 1H),7.64 (m, 4H), 7.46 (m, 1H), 6.92 (d,J=3.3, 1H), 6.58 (dd,J=3.8, 2.6, 1H).

3- (4-bromo-phenyl) -3-hydroxy-3, 4-dihydro-2H-pyrrolo [1, 2-a)]Pyrazin-1-one; a white powder; HPLC/MS 2.17 (B), [ M + H]307/309；¹H NMR (400 MHz, DMSO-d₆) [ppm]8.30 (s,1H), 7.58 (m, 4H), 6.95 (s, 1H), 6.70(d,J=2.3, 1H), 6.67 (s, 1H), 6.16 (m,1H), 4.15 (m, 2H).

825 mg (2.69 mmol) 3- (4-bromo-phenyl) -3-hydroxy-3, 4-dihydro-2H-pyrrolo [1,2-a ] pyrazin-1-one are slurried in 6.6 ml dichloromethane. Then 207 μ l (2.69 mmol) of trifluoroacetic acid was added. After stirring at room temperature for 10 minutes, the reaction mixture was evaporated. The residue was triturated with saturated sodium carbonate solution. The solid was removed by filtration, washed with water and dried under vacuum to give 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one as a white powder; HPLC/MS2.42 (B), [ M + H ]289/291.

3- (4-bromo-phenyl) -7-methyl-2H-pyrrolo [1,2-a ] pyrazin-1-one was prepared analogously:

HPLC/MS 2.59 min (B), [M+H]303/305。

example 6

Synthesis of 3- [4- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A25")

141 mg (0.486 mmol) of 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a ] are introduced under nitrogen]Pyrazin-1-one, 111 mg (0.534 mmol) 1-methyl-4- (4,4,5, 5-tetramethyl- [1,3, 2)]A suspension of dioxaborolan-2-yl) -1H-pyrazole and 49 mg (0.58 mmol) of sodium hydrogencarbonate in1 ml of DMF and 0.5 ml of water was heated to 40 ℃. 6.8mg (0.010 mmol) of bis (triphenylphosphine) -palladium (II) chloride were then added. The reaction mixture was heated to 80 ℃ and stirred at this temperature for 20 hours. The reaction mixture was cooled to room temperature and excess water was added. The resulting precipitate was removed by filtration and washed with water. The residue was subjected to silica gel column chromatography using methanol/dichloromethane as eluent to give 3- [4- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -amide]-2H-pyrrolo [1,2-a]Pyrazin-1-one as pale yellow crystals; HPLC/MS 2.09 min (B), [ M + H]291；

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.73 (s, 1H), 8.21 (s, 1H), 7.93(s, 1H), 7.76 (s, 1H), 7.66 (m, 4H), 7.46 (dd,J=2.3, 1.6, 1H), 6.91 (d,J=3.2, 1H), 6.58 (dd,J=3.9, 2.6, 1H), 3.87 (s, 3H)。

Similarly, the following compounds were obtained

Example 7

Synthesis of 4- (1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] pyrazin-3-yl) -benzoic acid methyl ester ("A28") and 3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A29")

In an autoclave, a solution of 285 mg (0.986 mmol) 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one and 157 mg (1.55 mmol) triethylamine in 6 ml methanol and 6 ml toluene was purged with nitrogen. 24 mg (0.029 mmol) of (1,1' -bis (diphenylphosphino) -ferrocene) dichloropalladium (II) and 22mg (0.040mmol) of 1, 1-bis- (diphenylphosphino) -ferrocene are added. The autoclave was then filled with carbon monoxide and heated to 100 ℃. The autoclave was maintained at this temperature for 16 hours at a carbon monoxide pressure of 2-4 bar. The autoclave was returned to atmospheric pressure. Filtering to remove solids; the residue was washed with methanol and tert-butyl methyl ether and dried under vacuum to give 4- (1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] pyrazin-3-yl) -benzoic acid methyl ester as a light yellow-white solid; HPLC/MS 1.83 min (A), [ M + H ] 269;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.02 (s, 1H), 8.17 (d,J=8.4, 2H),8.07 (s, 1H), 7.99 (d,J=8.4, 2H), 7.64 (s, 1H), 7.10 (d,J=3.6, 1H), 6.76(m, 1H), 4.03 (s, 3H).

to a solution of 99.0 mg (0.369 mmol) 4- (1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] b]Pyrazine-3-yl) -benzoic acid methyl ester to a suspension in 1.5 ml THF 100mg (0.406 mmol) cerium (III) chloride were added and the mixture was stirred under argon at room temperature for 1 h. Then 517. mu.l (1.55 mmol) of a THF solution of 3M methyl magnesium chloride was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water and partitioned between 10% aqueous citric acid and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC. The product-containing fractions were evaporated and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to give 3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-one as a white solid; HPLC/MS 1.67 min (A), [ M + H]269；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.69 (s, 1H), 7.70 (s, 1H), 7.60(d,J=8.4, 2H), 7.53 (d,J=8.4, 2H), 7.45 (s, 1H), 6.90 (d,J=3.5, 1H), 6.57(m, 1H), 5.05 (s, 1H), 1.45 (s, 6H)。

Similarly, the following compounds were obtained

6- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -2-methyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A46")

HPLC/MS 1.69 min (C), [M+H]284；

6- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A47")

；

3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -7-methyl-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A56")

HPLC/MS 1.81 min (C), [M+H]283； 1H NMR (400 MHz, DMSO-d₆) ppm [ppm]10.62 (s, 1H), 7.63 - 7.56 (m, 3H), 7.54 - 7.50 (m, 2H), 7.25 - 7.21 (m, 1H),6.73 - 6.69 (m, 1H), 5.22 - 4.80 (m, 1H), 2.18 (s, 3H), 1.44 (s, 6H)。

Example 8

Synthesis of 6- (4-tert-butyl-phenyl) -2-methyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A30")

A solution of 463 mg (3.00 mmol) of ethyl 5-methyl-2H-pyrazole-3-carboxylate and 765 mg (3.00 mmol) of 2-bromo-1- (4-tert-butyl-phenyl) -ethanone in 4ml of acetone is treated with 498 mg (3.60 mmol) of potassium carbonate. The resulting suspension was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give a mixture of two isomers as brown resin, which was used as such in the next step:

2- [2- (4-tert-butyl-phenyl) -2-oxo-ethyl ] -5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester; HPLC/MS3.25 min (B), [ M + H ] 329;

1- [2- (4-tert-butyl-phenyl) -2-oxo-ethyl ] -5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester; HPLC/MS3.05 min (B), [ M + H ]329.

The crude product obtained in the previous step was dissolved in 5ml of glacial acetic acid, 1.99 g (25.8 mmol) of ammonium acetate were added and the resulting suspension was stirred at 110 ℃ for 6 hours. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed by preparative HPLC to give 6- (4-tert-butyl-phenyl) -2-methyl-5H-pyrazolo [1,5-a ] pyrazin-4-one as colorless crystals; HPLC/MS 2.76 min (B), [ M + H ] 282;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.40 (s, 1H), 7.91 (d,J=0.5, 1H),7.66 (d,J=8.6, 2H), 7.48 (d,J=8.6, 2H), 6.80 (s, 1H), 2.36 (s, 3H), 1.31(s, 9H).

the following compounds were prepared analogously

6- (4-tert-butyl-phenyl) -2-trifluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A55")

HPLC/MS 3.18 min (B), [M+H]336.

Example 9

Synthesis of 3- (4- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H-pyrazol-4-yl } -phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A31") and 3- {4- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl ] -phenyl } -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A32")

A suspension of 145 mg (0.50 mmol) 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one, 177 mg (0.55 mmol) 1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole and 50 mg (0.60 mmol) sodium bicarbonate in1 ml DMF and 0.5 ml water is heated to 40 ℃ under nitrogen. Then 7.0 mg (0.010 mmol) of bis (triphenylphosphine) -palladium (II) chloride were added. The reaction mixture was heated to 80 ℃ and stirred at this temperature for 20 hours. The reaction mixture was cooled to room temperature and excess water was added. The resulting precipitate was removed by filtration and washed with water. The residue was chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 3- (4- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H-pyrazol-4-yl } -phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one as a white powder; HPLC/MS 2.39 min (B), [ M + H ] 405;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.73 (s, 1H), 8.25 (s, 1H), 7.97(s, 1H), 7.77 (s, 1H), 7.66 (s, 4H), 7.46 (s, 1H), 6.91 (d,J=3.9, 1H), 6.57(m, 1H), 4.55 (t,J=3.3, 1H), 4.31 (m, 2H), 3.97 (dt,J=11.0, 5.5, 1H), 3.77(dt,J=10.7, 5.3, 1H), 3.57 (ddd,J=11.4, 8.6, 3.0, 1H), 3.38 (m, 1H), 1.53(m, 6H).

mu.l of a 4N solution of hydrochloric acid in dioxane was added to a solution of 150 mg (0.371 mmol) 3- (4- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H-pyrazol-4-yl } -phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one in 6 ml dichloromethane. The resulting suspension was left at room temperature for 1 h. Water and saturated sodium carbonate solution were then added until a pH of 9 was reached. The dichloromethane was removed under vacuum; the solid was removed by filtration, washed with water and dried under vacuum to give 3- {4- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl ] -phenyl } -2H-pyrrolo [1,2-a ] pyrazin-1-one as white crystals; HPLC/MS 1.93 min (B), [ M + H ] 321;

¹H NMR (300 MHz, DMSO-d₆) [ppm]10.73 (s, 1H), 8.23 (s, 1H), 7.96(s, 1H), 7.77 (s, 1H), 7.67 (s, 4H), 7.46 (dd,J=2.5, 1.5, 1H), 6.91 (dd,J=3.9, 0.8, 1H), 6.58 (dd,J=3.9, 2.5, 1H), 4.92 (t,J=5.2, 1H), 4.17 (t,J=5.6, 2H), 3.78 (q,J=5.4, 2H)。

example 10

Synthesis of 2-chloromethyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A33") and 2-methyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A34")

In analogy to WO2010/043676 (example G02), 82 mg (0.252mmol) of 2-hydroxymethyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1, 5-a) are treated with thionyl chloride in dichloromethane]Pyrazin-4-one to give 2-chloromethyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-one as a pale pink crystal; HPLC/MS1.91 min (C), [ M + H]344；

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.68 (s, 1H), 8.09 (s, 1H), 7.87(d,J=8.8, 2H), 7.49 (d,J=8.2, 2H), 7.10 (s, 1H), 4.88 (s, 2H).

A solution of 18.9 mg (0.055 mmol) 2-chloromethyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one in 0.5 ml THF is purged with nitrogen. 3.5 mg (0.092 mmol) of lithium aluminium hydride are added and the reaction mixture is stirred at room temperature for 5 hours. Then 1 ml THF, 3.5 μ l water, 3.5 μ l 15% NaOH aqueous solution and 10.5 μ l water were added in order. The resulting suspension was stirred at room temperature for 30 minutes. The precipitate was removed by filtration and washed with THF and ethanol. The filtrate was evaporated and purified by preparative HPLC to give 2-methyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one as colourless crystals; HPLC/MS 2.53 min (B), [ M + H ] 310;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.50 (s, 1H), 8.01 (s, 1H), 7.86(d,J=8.8, 2H), 7.47 (d,J=8.3, 2H), 6.81 (s, 1H), 2.36 (s, 3H)。

similarly, the following compounds were prepared

2-methyl-6- (4-pyrrolidin-1-yl-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A37")

HPLC/MS 2.57 min (B), [M+H]295；

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.24 (s, 1H), 7.75 (s, 1H), 7.54(d,J=8.8, 2H), 6.74 (s, 1H), 6.59 (d,J=8.9, 2H), 3.27 (t,J=6.6, 4H), 2.34(s, 3H), 1.97 (t,J=6.6, 4H)；

2-methyl-6- (6-pyrrolidin-1-yl-3-pyridyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one

("A48")

；

2-methyl-6- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl ] -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A49")

6-cyclohexyl-2-methyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A50")

；

2-methyl-6- (1-isopropyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A51")

；

2-methyl-6- (1-tert-butyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A52")

HPLC/MS 2.06 min (B), [M+H]272；

2-methyl-6- [1- (4-methoxyphenyl) -4-piperidinyl ] -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A53")

；

2-methyl-6- (2-pyrrolidin-1-ylpyrimidin-5-yl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A54")

。

Example 11

Synthesis of 3- (4-tert-butyl-phenyl) -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A35")

A suspension of 93.7 mg (0.655 mmol) of methyl 4-fluoro-1H-pyrrole-2-carboxylate (synthesized as described in J. Leroy et al Tetrahedron 58, p. 6713, 2002) and 640 mg (1.96 mmol) of cesium carbonate in 1.3ml of DMF is heated to 50 ℃ with stirring. 167 mg (0.655 mmol) 2-bromo-1- (4-tert-butyl-phenyl) -ethanone was added and the reaction mixture was stirred at 50 ℃ for 18 h. The reaction mixture was filtered with suction and the filtrate was evaporated. The residue was chromatographed on a silica gel column using cyclohexane/ethyl acetate as eluent to give 1- [2- (4-tert-butyl-phenyl) -2-oxo-ethyl ] -4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester as a brown amorphous solid; HPLC/MS 3.26 min (B), [ M + H ]318.

A solution of 52.4 mg (0.165 mmol) of methyl 1- [2- (4-tert-butyl-phenyl) -2-oxo-ethyl ] -4-fluoro-1H-pyrrole-2-carboxylate and 382 mg (4.95 mmol) of ammonium acetate in 0.5 ml of acetic acid is stirred at 110 ℃ for 18 hours. The reaction mixture was cooled to room temperature and excess water was added. The resulting precipitate was removed by filtration, washed with water and dried. Subjecting the extract to silica gel column chromatography with cyclohexane/ethyl acetate as eluent to obtain 3- (4-tert-butyl-phenyl) -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one as light brown crystals; HPLC/MS 2.88 min (B), [ M + H ] 285;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.97 (s, 1H), 7.61 (s, 1H), 7.58(d,J=8.5, 2H), 7.48 (m, 3H), 6.75 (d,J=1.6, 1H), 1.31 (s, 9H)。

similarly, the following compounds were prepared

7-fluoro-3-phenyl-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A93")

HPLC/MS 2.27 min (B), [M+H]229；

Example 12

Synthesis of 2-bromomethyl-6- (4-bromo-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A36") and 6- (4-bromo-phenyl) -2-methyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A39")

To a suspension of 142 mg (0.445 mmol) 6- (4-bromo-phenyl) -2-hydroxymethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one in 8 ml dichloromethane was added 52 μ l (0.56 mmol) phosphorus tribromide. The reaction mixture was stirred at room temperature for 20 hours. The mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Purifying by preparative HPLC (RP18 silica gel, eluent water/acetonitrile/formic acid) to obtain 2-bromomethyl-6- (4-bromo-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one as an off-white solid; HPLC/MS 2.21 min (A), [ M + H ]384.

To a solution of 64.4 mg (0.168 mmol) bromomethyl-6- (4-bromo-phenyl) -5H-pyrazolo [1,5-a ] pyrazin-4-one in 2.5 ml acetic acid was added 55 mg (0.84 mmol) of activated zinc powder. The reaction mixture was stirred at 100 ℃ for 18 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated to give 6- (4-bromo-phenyl) -2-methyl-5H-pyrazolo [1,5-a ] pyrazin-4-one as a white solid;

HPLC/MS 2.00 min (A), [M+H]304/306；

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.52 (s, 1H), 8.00 (s, 1H), 7.67(m, 4H), 6.81 (s, 1H), 2.36 (s, 3H).

example 13

Synthesis of 3- (1-tert-butyl-1H-pyrazol-4-yl) -7-methyl-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A57")

To a suspension of 5.00 g (29.7 mmol) of 1-tert-butyl-1H-pyrazole-4-carboxylic acid and 5.80 g (59.5 mmol) of N, O-dimethylhydroxylamine hydrochloride in 60 ml of dichloromethane were added 12.5 g (65.4 mmol) of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 4.42 g (32.7 mmol) of 1-hydroxybenzotriazole and 16.5 ml (119mmol) of triethylamine. The reaction mixture was stirred at room temperature for 18 hours. Quench it with saturated sodium bicarbonate solution and partition the mixture between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel column using cyclohexane/ethyl acetate as eluent to give 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxymethyl-amide as colorless crystals; HPLC/MS1.91 min (B), [ M + H ]212.

A solution of 5.87 g (27.7 mmol) of 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxymethyl-amide in 55 ml of THF is cooled to 0 ℃ under nitrogen and 18.5 ml (55.5 mmol) of a 3M solution of methylmagnesium bromide in ether are added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between brine and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel column with cyclohexane/ethyl acetate as eluent to give 1- (1-tert-butyl-1H-pyrazol-4-yl) -ethanone as a white solid; HPLC/MS 1.87 min (B), [ M + H ] 167;

¹H NMR (300 MHz, DMSO-d₆) [ppm]8.44 (d,J= 0.7 Hz, 1H), 7.92 (d,J= 0.7 Hz, 1H), 2.37 (s, 3H), 1.54 (s, 9H).

to a solution of 1.66 g (10.0 mmol) 1- (1-tert-butyl-1H-pyrazol-4-yl) -ethanone in 18 ml dichloromethane was added a solution of 5.86 μ l (0.10 mmol) 32% hydrobromic acid in acetic acid. A solution of 3.20 g (20 mmol) of bromine in 5ml of dichloromethane is then added dropwise. The reaction mixture was stirred at room temperature for 3 days. Aqueous sodium bisulfite was then added to reduce excess bromine. The volume of the reaction mixture was reduced under vacuum and then partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel column with cyclohexane/ethyl acetate as eluent to give 2-bromo-1- (1-tert-butyl-1H-pyrazol-4-yl) -ethanone as a yellow oil which crystallized on standing; HPLC/MS 2.28 min (B), [ M + H ]245/247.

To a suspension of 229 mg (1.50 mmol) of ethyl 4-methyl-1H-pyrrole-2-carboxylate in 3.7 ml of DMF under nitrogen were added 185 mg (1.65 mmol) of potassium tert-butoxide in portions. The mixture was stirred at room temperature for 30 minutes and cooled to 0 ℃. 367 mg (1.50 mmol) of 2-bromo-1- (1-tert-butyl-1H-pyrazol-4-yl) -ethanone are then added. The mixture was stirred at 0 ℃ for 1 hour and then at room temperature for 30 minutes. The reaction mixture was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel with cyclohexane/ethyl acetate to give 1- [2- (1-tert-butyl-1H-pyrazol-4-yl) -2-oxo-ethyl ] -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a yellow oil; HPLC/MS2.82 min (B), [ M + H ]318.

A solution of 375 mg (1.18 mmol) of ethyl 1- [2- (1-tert-butyl-1H-pyrazol-4-yl) -2-oxo-ethyl ] -4-methyl-1H-pyrrole-2-carboxylate and 4.89 g (63.5 mmol) of ammonium acetate in 4.15 ml of acetic acid is stirred at 110 ℃ for 28 hours. The reaction mixture was cooled to room temperature and excess water was added. The resulting precipitate was removed by filtration, washed with water and dried. Silica gel column chromatography using cyclohexane/ethyl acetate as eluent gave 3- (1-tert-butyl-1H-pyrazol-4-yl) -7-methyl-2H-pyrrolo [1,2-a ] pyrazin-1-one as a pale yellow solid; HPLC/MS 2.27 min (B), [ M + H ] 271;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.47 (s, 1H), 8.38 (d,J= 0.8 Hz,1H), 7.88 (d,J= 0.8 Hz, 1H), 7.60 (d,J= 0.8 Hz, 1H), 7.15 (dd,J= 1.7,0.9 Hz, 1H), 6.67 (dt,J= 1.6, 0.8 Hz, 1H), 2.17 (s, 3H), 1.53 (s, 9H).

example 14

Synthesis of 3- (4-bromo-phenyl) -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A58") and 7-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A59")

To a solution of 15.7 g (100 mmol) of ethyl 4-fluoro-1H-pyrrole-2-carboxylate and 27.8 g (100 mmol) of 2, 4' -dibromoacetophenone in 150 ml of acetone 16.6 g (120 mmol) of cesium carbonate were added. The resulting suspension was stirred at 35 ℃ for 3 days. The reaction mixture was added to 600 ml of water with stirring. The resulting precipitate was removed by filtration, washed with water and dried under vacuum to give 1- [2- (4-bromo-phenyl) -2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as a pale yellow solid; HPLC/MS 3.14 (B), [ M + H]354/356；¹H NMR (400 MHz, DMSO-d₆) [ppm]7.97 (d,J= 8.6 Hz, 2H), 7.82 (d,J= 8.6 Hz, 2H), 7.13 (dd,J= 3.3, 2.2 Hz, 1H),6.72 (d,J= 2.2 Hz, 1H), 5.82 (s, 2H), 4.08 (q,J= 7.1 Hz, 2H), 1.14 (t,J= 7.1 Hz, 3H).

A suspension of 27.4 g (77.3 mmol) of ethyl 1- [2- (4-bromo-phenyl) -2-oxo-ethyl ] -4-fluoro-1H-pyrrole-2-carboxylate and 140 g (1.82 mol) of ammonium acetate in 150 ml of acetic acid was heated to 110 ℃ and the resulting solution was stirred at 110 ℃ for 18H. The reaction mixture was allowed to cool to room temperature and added to 1.5 l of water with stirring. The resulting precipitate was removed by filtration, washed with water and dried under vacuum. It is dissolved in isopropyl acetate, heated to reflux and filtered hot. The residue was washed with isopropyl acetate and dried under vacuum to give 3- (4-bromo-phenyl) -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one as grey crystals; HPLC/MS 1.83 min (A), [ M + H ] 307/309;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.07 (s, 1H), 7.72-7.64 (m, 3H),7.63-7.57 (m, 2H), 7.47 (dd,J= 3.4, 1.9 Hz, 1H), 6.77 (dd,J= 1.9, 0.6 Hz,1H).

in an autoclave, a suspension of 20.4 g (66.5 mmol) 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one and 15.1 ml (110 mmol) triethylamine in 240 ml methanol and 240 ml toluene is purged with nitrogen. 1.69 g (2.07 mmol) of (1,1' -bis (diphenylphosphino) -ferrocene) dichloropalladium (II) and 1.53 g of 2.76 mmol) of 1, 1-bis (diphenylphosphino) -ferrocene are added under nitrogen. The autoclave was then filled with 4.5 bar of carbon monoxide and heated to 100 ℃. The autoclave was maintained at this temperature for 16 hours at a carbon monoxide pressure of 6.2-4.2 bar. The autoclave was returned to atmospheric pressure. Filtering to remove solids; the residue was washed with methanol and 2-propanol and dried under vacuum to give 4- (7-fluoro-1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] pyrazin-3-yl) -benzoic acid methyl ester as a pale pink powder; HPLC/MS 2.32min (B), [ M + H ] 287;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.14 (s, 1H), 8.02 (d, m, 2H),7.85-7.78 (m, 3H), 7.50 (dd,J= 3.5, 1.9 Hz, 1H), 6.80 (d,J= 1.8 Hz, 1H),3.88 (s, 3H).

to a suspension of 5.73 g (20.0 mmol) 4- (7-fluoro-1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] pyrazin-3-yl) -benzoic acid methyl ester in 85 ml THF was added 5.42 g (22.0 mmol) cerium (III) chloride and the mixture was stirred at room temperature under nitrogen for 1 h. Then 30.5 ml (84.0 mmol) of a 20% solution of methylmagnesium chloride in THF are added dropwise and the reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture was partitioned between THF and brine, the organic phase was dried over sodium sulfate and evaporated. Subjecting the residue to silica gel column chromatography with methanol/dichloromethane as eluent to obtain 7-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one as cream-colored powder; HPLC/MS 2.15 min (B), [ M + H ] 287;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.97 (s, 1H), 7.61 (s, 1H), 7.59(d,J= 8.5 Hz, 2H), 7.54 (d,J= 8.5 Hz, 2H), 7.47 (dd,J= 3.4, 1.9 Hz,1H), 6.75 (d,J= 1.7 Hz, 1H), 5.06 (s, 1H), 1.45 (s, 6H)。

the following compounds were prepared analogously:

7-chloro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A60")

HPLC/MS 1.81 (C), [M+H]303；¹H NMR (400 MHz, DMSO-d₆) [ppm]11.00(s, 1H), 7.66 (s, 1H), 7.63-7.58 (m, 3H), 7.56 (d,J= 8.6 Hz, 2H), 6.94 (dd,J= 1.8, 0.7 Hz, 1H), 5.09 (s, 1H), 1.46 (s, 6H)；

3- [4- (1-Ethyl-1-hydroxy-propyl) -phenyl ] -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A61")

HPLC/MS 2.47 (B), [M+H]315； 1H NMR (400 MHz, DMSO-d₆) [ppm]10.95(s, 1H), 7.64 (s, 1H), 7.59 (d,J= 8.2 Hz, 2H), 7.49-7.41 (m, 3H), 6.75 (d,J= 1.9 Hz, 1H), 4.60 (s, 1H), 1.73 (m, 4H), 0.66 (t,J= 7.3 Hz, 6H)；

3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] pyrazine-7-carbonitrile ("A62")

HPLC/MS 1.70 (A), [M+H]294；¹H NMR (400 MHz, DMSO-d₆) ppm [ppm]11.15(s, 1H), 8.14 (d,J= 1.7 Hz, 1H), 7.72 (s, 1H), 7.64-7.53 (m, 4H), 7.43-7.36(m, 1H), 5.10 (s, 1H), 1.45 (s, 6H)。

Example 15

Synthesis of 7-fluoro-3- [4- (1-fluoro-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A63")

A suspension of 57.3 mg (0.20 mmol) 7-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one in 0.5 ml dichloromethane was cooled to-78 ℃. Then 105 μ l (0.80mmol) of diethylaminosulfur trifluoride were added. The reaction mixture was allowed to reach room temperature over 30 minutes. The reaction mixture was evaporated and the residue was treated with water and saturated sodium bicarbonate solution. Filtering to remove solids, and performing silica gel column chromatography with cyclohexane/ethyl acetate as eluent to obtain 7-fluoro-3- [4- (1-fluoro-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one as white powder; HPLC/MS 2.60 min (B), [ M + H ] 289;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.01 (s, 1H), 7.70-7.63 (m, 3H),7.53-7.44 (m, 3H), 6.76 (d,J= 1.9 Hz, 1H), 1.67 (d,J= 22.2 Hz, 6H)。

example 16

Synthesis of 6- (4-tert-butyl-phenyl) -2-fluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A64")

A suspension of 149 mg (0.50 mmol) 6- (4-tert-butyl-phenyl) -2-hydroxymethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one in 1.25 ml dichloromethane is cooled to-78 ℃. Then 264 μ l (2.00 mmol) of diethylaminosulfur trifluoride was added. The reaction mixture was allowed to reach room temperature over 30 minutes. The reaction mixture was evaporated and the residue was treated with water and saturated sodium bicarbonate solution. Filtering to remove solid, performing silica gel column chromatography, and eluting with cyclohexane/ethyl acetate to obtain 6- (4-tert-butyl-phenyl) -2-fluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one as white powder; HPLC/MS2.80 min (B), [ M + H ] 300;

¹H NMR (400 MHz, DMSO-d6) 11.57 (s, 1H), 8.03 (s, 1H), 7.73-7.64(m, 2H), 7.55-7.46 (m, 2H), 7.15 (d,J= 2.0 Hz, 1H), 5.52 (d,J= 48.1 Hz,2H), 1.32 (s, 9H)。

example 17

Synthesis of 2-hydroxymethyl-6- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -5H-pyrazolo [1,5-a ] pyrazin-4-one ("A65")

HPLC/MS 1.38 min (C), [M+H]300。

Example 18

Synthesis of 6- (4-tert-butyl-phenyl) -2-difluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A66")

A suspension of 148 mg (0.50 mmol 6- (4-tert-butyl-phenyl) -4-oxo-4, 5-dihydro-pyrazolo [1,5-a ] pyrazine-2-carbaldehyde in 1.25 ml dichloromethane was cooled to-78 ℃ before 264 μ l (2.00 mmol) diethylaminosulfur trifluoride was added and the reaction mixture was allowed to reach room temperature over 30 minutes the reaction mixture was evaporated and the residue was treated with water and saturated sodium bicarbonate solution filtered to remove solids and triturated with tert-butyl methyl ether to give 6- (4-tert-butyl-phenyl) -2-difluoromethyl-5H-pyrazolo [1,5-a ] pyrazine-4-one as a beige powder, HPLC/MS 2.95 min (B), [ M + H ] 318;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.79 (s, 1H), 8.09 (s, 1H), 7.73-7.65 (m, 2H), 7.56-7.47 (m, 2H), 7.23 (s, 1H), 7.21 (t,J= 54.3 Hz, 1H),5.75 (s, 1H), 1.32 (s, 9H)。

example 19

Synthesis of 6- (4-bromo-phenyl) -2-trifluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A67"), methyl 4- (4-oxo-2-trifluoromethyl-4, 5-dihydro-pyrazolo [1,5-a ] pyrazin-6-yl) -benzoate ("A68"), and 6- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2-trifluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one ("A69")

To a solution of 1.93 g (9,27 mmol) of 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid ethyl ester and 2.58 g (9.27mmol) of 2-bromo-1- (4-bromo-phenyl) -ethanone in 13 ml of acetone was added 1.54 g (11.1 mmol) of potassium carbonate. The resulting suspension was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give a mixture of two isomers as a brown resin which was used as such in the next step. Isomer a: 2- [2- (4-bromo-phenyl) -2-oxo-ethyl ] -5-trifluoromethyl-2H-pyrazole-3-carboxylic acid ethyl ester; HPLC/MS 3.30 min (B), [ M + H ] 405/407;

isomer B: 1- [2- (4-bromo-phenyl) -2-oxo-ethyl ] -5-trifluoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester; HPLC/MS 3.16 min (B), [ M + H ] 405/407;

isomer ratio a: B = 89: 11.

The crude product obtained in the preceding step was dissolved in 32 ml of glacial acetic acid, 13.6 g (176 mmol) of ammonium acetate were added and the resulting suspension was stirred at 110 ℃ for 18 hours. The reaction mixture was allowed to cool to room temperature and excess water was added. The resulting precipitate was removed by filtration, washed with water and dried under vacuum to give 6- (4-bromo-phenyl) -2-trifluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one as a light brown powder; HPLC/MS 2.37 min (C), [ M + H ] 358/360;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.92 (s, 1H), 8.24 (s, 1H), 7.71(s, 4H), 7.54 (t,J= 0.8 Hz, 1H).

in an autoclave, a suspension of 358 mg (1.00 mmol) 6- (4-bromo-phenyl) -2-trifluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one and 210 μ l (1.5 mmol) triethylamine in 7 ml methanol and 7 ml toluene was purged with nitrogen. 25 mg (0.03 mmol) of (1,1' -bis (diphenylphosphino) -ferrocene) dichloropalladium (II) and 22mg (0.04 mmol) of 1, 1-bis (diphenylphosphino) -ferrocene are added under nitrogen. The autoclave was then filled with 2 bar of carbon monoxide and heated to 100 ℃. The autoclave was kept at this temperature for 18 hours at a maximum carbon monoxide pressure of 4.2 bar. The autoclave was returned to atmospheric pressure. Filtering to remove solids; the residue was washed with methanol and dried under vacuum to give 4- (4-oxo-2-trifluoromethyl-4, 5-dihydro-pyrazolo [1,5-a ] pyrazin-6-yl) -benzoic acid methyl ester as a red fine powder; HPLC/MS 2.20 min (C), [ M + H ] 338;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.99 (s, 1H), 8.33 (s, 1H), 8.08-8.01 (m, 2H), 7.96-7.89 (m, 2H), 7.55 (s, 1H), 3.89 (s, 3H).

to a suspension of 223 mg (0.66 mmol) 4- (4-oxo-2-trifluoromethyl-4, 5-dihydro-pyrazolo [1,5-a ] pyrazin-6-yl) -benzoic acid methyl ester in 2.8 ml THF is added 178 mg (0.72 mmol) cerium (III) chloride. The mixture was stirred at room temperature under nitrogen for 1 h. 1.31 ml (3.60 mmol) of a 20% solution of methylmagnesium chloride in THF are then added dropwise and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture was partitioned between THF and brine, the organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel column with cyclohexane/ethyl acetate as eluent to give 6- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2-trifluoromethyl-5H-pyrazolo [1,5-a ] pyrazin-4-one as a pale yellow powder; HPLC/MS2.46 min (B), [ M + H ] 338;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.84 (s, 1H), 8.17 (s, 1H), 7.70(d,J= 8.5 Hz, 2H), 7.58 (d,J= 8.5 Hz, 2H), 7.53 (s, 1H), 5.11 (s, 1H),1.46 (s, 6H)。

example 20

Synthesis of 7-fluoro-3- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl ] -phenyl } -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A70")

To a suspension of 28.6 mg (0.10 mmol) 7-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one in 0.45 ml ethane-1, 2-diol was added 1.7 mg (0.01 mmol) toluene-4-sulfonic acid monohydrate. The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using cyclohexane/ethyl acetate as eluent to give 7-fluoro-3- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl ] -phenyl } -2H-pyrrolo [1,2-a ] pyrazin-1-one as a white powder; HPLC/MS 2.17 min (B), [ M + H ] 331;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.99 (s, 1H), 7.68-7.61 (m, 3H),7.55-7.50 (m, 2H), 7.48 (dd,J= 3.4, 1.9 Hz, 1H), 6.77 (d,J= 1.9 Hz, 1H),4.55 (t,J= 5.6 Hz, 1H), 3.50 (q,J= 5.5 Hz, 2H), 3.19 (t,J= 5.6 Hz, 2H),1.50 (s, 6H)。

the following compounds were prepared analogously:

7-fluoro-3- {4- [1- (2-methoxyethoxy) -1-methyl-ethyl ] -phenyl } -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A71")

HPLC/MS 2.47 min (B), [M+H]345.

Example 21

Synthesis of 3- [4- (1-amino-1-methyl-ethyl) -phenyl ] -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A72")

To a suspension of 143 mg (0.5 mmol) of 7-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one and 71.5 mg (1.1 mmol) of sodium azide in1 ml of dichloromethane was added dropwise a solution of 316. mu.l (4.1 mmol) of trifluoroacetic acid in 0.6 ml of dichloromethane under external ice cooling. The reaction mixture was stirred at 0 ℃ for 3 hours. Ice and 25% aqueous ammonia solution were added to obtain a two-phase mixture with pH 11. A1: 1 mixture of cyclohexane/ethyl acetate was then added. The organic phase was separated, dried over sodium sulfate and evaporated to give 3- [4- (1-azido-1-methyl-ethyl) -phenyl ] -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one as a beige powder; HPLC/MS 2.29 min (A), [ M + H ]312.

To a slurry of 103 mg (0.33 mmol) 3- [4- (1-azido-1-methyl-ethyl) -phenyl ] -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one and 90 mg (1.38 mmol) zinc dust in2 ml THF was added 175 ml (3.1mmol) acetic acid and the mixture was stirred at room temperature for 3 hours. The suspension was quenched with THF/dichloromethane/ethyl acetate. The mixture was filtered off with suction and the residue was washed with methanol. The filtrate was evaporated and the residue was purified by preparative HPLC to give 3- [4- (1-amino-1-methyl-ethyl) -phenyl ] -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one formate as a white solid; HPLC/MS1.57 min (B), [ M + H ] 268;

¹H NMR (400 MHz, DMSO-d₆) [ppm]8.35 (s, 1H), 7.70-7.58 (m, 6H),7.48 (dd,J= 3.4, 1.9 Hz, 1H), 6.76 (d,J= 1.7 Hz, 1H), 4.57 (broad peak), 1.52(s, 6H).

Example 22

Synthesis of 7-fluoro-3- [4- (2-methyl-tetrahydro-furan-2-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A73") and 7-fluoro-3- [4- (4-hydroxy-1-methylene-butyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A74")

3- (4-bromo-phenyl) -7-fluoro-2H-pyrrolo [1,2-a ] pyrazin-1-one (154 mg, 0.50 mmol), palladium (II) acetate (5.6 mg, 0.03 mmol), 1, 3-bis- (diphenylphosphino) -propane (21.3 mg, 0.05 mmol), 4-penten-1-ol (51.7 mg, 0.60 mmol) and ammonium diisopropyltetrafluoroborate (142 mg, 0.75 mmol) were weighed into a reaction vial. 1, 4-dioxane (1 ml) was added and the reaction vial was purged with nitrogen. The resulting suspension was stirred for 1 minute and triethylamine (208 μ l, 1.50 mmol) was added, and the reaction vial was purged with nitrogen and sealed. The reaction mixture was stirred at 110 ℃ overnight. The reaction mixture was allowed to cool to room temperature. N-heptane (1.5 ml) and tetrafluoroboric acid (0.21 ml, 54% solution in ether, 1.5 mmol) were added and the resulting biphasic mixture was stirred vigorously at room temperature for 3 hours. Triethylamine (69 μ l, 0.5 mmol) was added and the reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using cyclohexane/ethyl acetate as eluent to give two products:

7-fluoro-3- [4- (2-methyl-tetrahydro-furan-2-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-one; a white solid; HPLC/MS 2.52 (B), [ M + H]313；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.97 (s,1H), 7.66-7.58 (m, 3H), 7.52-7.44 (m, 3H), 6.76 (d,J= 1.8 Hz, 1H), 3.99-3.89 (m, 1H), 3.83 (td,J= 8.0, 5.5 Hz, 1H), 2.17-1.90 (m, 3H), 1.82-1.67(m, 1H), 1.46 (s, 3H)；

7-fluoro-3- [4- (4-hydroxy-1-methylene-butyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-one (containing some isomers 7-fluoro-3- [4- ((E) -4-hydroxy-1-methyl-but-1-enyl) -phenyl)]-2H-pyrrolo [1,2-a]Pyrazin-1-one); HPLC/MS 2.32 (B), [ M + H [ ]]313；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.98 (s,1H), 7.69-7.53 (m, 3H), 7.53-7.43 (m, 3H), 6.75 (m, 1H), 6.45-6.39 (m, 2H),4.41 (t,J= 5.2 Hz, 1H), 3.45 (td,J= 6.4, 5.0 Hz, 2H), 2.29-2.19 (m, 2H),1.66-1.54 (m, 2H)。

Example 23

Synthesis of 3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A75")

4-phenyl-piperidine (4.0 g; 24.81mmol) was dissolved in dichloromethane (50 mL), triethylamine (3.44 mL; 24.8 mmol) was added and the solution was cooled to-78 ℃. Trifluoroacetic anhydride (3.45 ml; 24.81mmol) is added dropwise at this temperature over a period of 2 minutes. The reaction was stirred at-78 ℃ for 10 min and then warmed to room temperature over 30 min. The reaction mixture was diluted with dichloromethane and extracted with water (2 times). The organic layer was washed with saturated NaHCO₃Washing with the solution 1 time, washing with water (3 times), and passing through Na₂SO₄Dried, filtered off with suction and evaporated to dryness. The crude product, 2,2, 2-trifluoro-1- (4-phenyl-piperidin-1-yl) -ethanone, was used without further purification as a yellow clear oil.

For the reaction, the 3-neck round bottom flask was washed with acetone, heated in a desiccator and cooled. Aluminum chloride (6.38 g; 47.83 mmol) was weighed into the flask, anhydrous dichloromethane (30 ml) was added and bromoacetyl bromide (2.60 ml; 29.9 mmol) dissolved in anhydrous dichloromethane (20 ml) was added dropwise at 0-5 ℃ under argon. 2,2, 2-trifluoro-1- (4-phenyl-piperidin-1-yl) -ethanone (6.24 g; 23.92 mmol) was dissolved in 10 ml dichloromethane (dry) and added dropwise to the reaction mixture, maintaining the temperature between 0-5 ℃. The mixture was stirred at 0-5 ℃ for 1.5 h, warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice (200 g) and extracted with dichloromethane (3 times). The combined organic layers were washed with saturated NaHCO₃The solution, water and brine were washed with Na₂SO₄Dried, filtered off with suction and evaporated to dryness. The crude oil was purified by flash chromatography to give 1- {4- [4- (2-bromo-acetyl) -phenyl-]Piperidin-1-yl } -2,2, 2-trifluoro-ethanone as a colorless oil.

Make 1HPyrrole-2-carbonitrile (0.84 ml; 9.42 mmol) and 1- {4- [4- (2-bromo-acetyl) -phenyl]Piperidin-1-yl } -2,2, 2-trifluoro-ethanone (2.74 g; 7.25 mmol) was dissolved in acetone (25 ml). To the clear brown solution was added potassium carbonate (2 g; 14.49 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was removed by suction filtration and washed with acetone. The filtrate was evaporated to dryness. The residue was purified by flash chromatography to give 1- (2-oxo-2- {4- [1- (2,2, 2-trifluoro-acetyl) -piperidin-4-yl]-benzene-ethyl) -1H-pyrrole-2-carbonitrile as a light off-white crystal.

1- (2-oxo-2- {4- [1- (2,2, 2-trifluoro-acetyl) -piperidin-4-yl ] -phenyl } -ethyl) -1H-pyrrole-2-carbonitrile (1.40 g; 3.60 mmol) was slurried in methanol (10 ml). Potassium carbonate (2.49 g; 17.98mmol), anhydrous dimethyl sulfoxide (0.77 ml; 10.79 mmol) and hydrogen peroxide (1.10 ml; 10.79 mmol) were added (caution: a strongly exothermic reaction occurred upon addition of hydrogen peroxide). The yellow suspension was stirred overnight. The reaction mixture is diluted with water, the precipitate is removed by suction filtration, washed with water and dried under vacuum at 50 ℃. The crude product was purified by flash chromatography. The combined fractions were evaporated to dryness. The residue was triturated with ether, filtered off with suction and dried under vacuum at 50 ℃ to give 3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one as an off-white solid;

HPLC/MS 1.27 min (A), [M+H]294；

¹H NMR (500 MHz, DMSO-d₆) [ppm]10.47 (s, 2H), 7.68 (s, 1H), 7.59 (d,J= 8.0 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.30 (d,J= 8.0 Hz, 2H), 6.90 (d,J=4.0 Hz, 1H), 6.56 (t,J= 3.2 Hz, 1H), 3.07 - 2.98 (m, 2H), 2.66 - 2.46 (m,3H), 1.73 - 1.65 (m, 2H), 1.52 (qd,J= 12.2 Hz, 3.9, 2H)。

the following compounds were synthesized analogously:

3- (4-pyrrolidin-3-yl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A76")

A light yellow solid; HPLC/MS 1.25 min (A), [ M + H ] 280;

¹H NMR (400 MHz, DMSO-d₆) [ppm]7.70 (s, 1H), 7.62 - 7.57 (m, 2H),7.47 - 7.44 (m, 1H), 7.38 - 7.34 (m, 2H), 6.92 - 6.89 (m, 1H), 6.57 (dd,J=4.0 Hz, 2.5, 1H), 3.27 - 3.13 (m, 2H), 3.07 - 2.99 (m, 1H), 2.97 - 2.89 (m,1H), 2.69 (dd,J= 10.0 Hz, 7.6, 1H), 2.22 - 2.11 (m, 1H), 1.77 - 1.68 (m,1H)。

example 24

Synthesis of 7-fluoro-3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A77")

Ethyl 4-fluoro-1H-pyrrole-2-carboxylate (1.07 g; 6.83 mmol) and 1- {4- [4- (2-bromo-acetyl) -phenyl ] -piperidin-1-yl } -2,2, 2-trifluoro-ethanone (2.00 g; 5.26 mmol) were dissolved in acetone (20 ml). To the clear brown solution was added potassium carbonate (1.45 g; 10.51 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with acetone, filtered off with suction and washed with acetone. The filtrate was evaporated to dryness. The crude product was purified by flash chromatography to give 4-fluoro-1- (2-oxo-2- {4- [1- (2,2, 2-trifluoro-acetyl) -piperidin-4-yl ] -phenyl } -ethyl) -1H-pyrrole-2-carboxylic acid ethyl ester as an off-white solid; HPLC/MS 2.67 min (A), [ M + H ]455.

Reacting 4-fluoro-1- (2-oxo-2- {4- [1- (2,2, 2-trifluoro-acetyl) -piperidin-4-yl]-phenyl } -ethyl) -1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g; 3.42 mmol) was dissolved in acetic acid (10 ml) and ammonium acetate (5.80 g; 75.25 mmol). The reaction mixture was stirred at 110 ℃ overnight. The reaction mixture was cooled to room temperature, poured into cold water (250 ml) and extracted with ethyl acetate. The organic layer was discarded. The aqueous layer was basified with 2N NaOH (pH 11). A precipitate formed. The solid was filtered off with suction and washed with water and a small amount of ethyl acetate. The solid was then dissolved in 150 ml ethyl acetate over Na₂SO₄Dried, filtered off with suction and evaporated to dryness. The residue was triturated with ether, filtered and dried under vacuum at 50 ℃ (overnight). The aqueous filtrate was extracted 3 times with ethyl acetate/MeOH (5%). The combined organic layers were washed with brine, over Na₂SO₄Drying and passing throughFiltered and evaporated to dryness. The residue is triturated with ether, filtered off with suction and dried under vacuum to give 7-fluoro-3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a ]]Pyrazin-1-one, as a beige solid; HPLC/MS 1.37 min (A), [ M + H]312；

¹H NMR (400 MHz, DMSO-d₆) [ppm]7.63 - 7.53 (m, 3H), 7.48 - 7.45 (m,1H), 7.35 - 7.26 (m, 2H), 6.77 - 6.72 (m, 1H), 3.06 - 2.98 (m, 2H), 2.62 -2.59 (m, 1H), 2.59 - 2.53 (m, 2H), 1.73 - 1.64 (m, 2H), 1.51 (qd,J= 12.3,3.9 Hz, 2H)。

The following compounds were synthesized analogously

7-chloro-3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A78")

A beige solid; HPLC/MS 1.43 min (A), [ M + H ] 328;

¹H NMR (400 MHz, DMSO-d₆) [ppm]7.63 (s, 1H), 7.61 - 7.54 (m, 3H),7.35 - 7.28 (m, 2H), 6.92 (d,J= 1.6 Hz, 1H), 3.03 (dt,J= 12.0, 3.0 Hz,2H), 2.66 - 2.54(m, 3H), 1.74 - 1.65 (m, 2H), 1.52 (qd,J= 12.3 Hz, 3.9,2H)。

example 25

Synthesis of 3- [4- (1-methyl-piperidin-4-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A79")

Reacting 3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a]Pyrazine-1-one (50.0 mg; 0.17 mmol) was dissolved in acetonitrile (1.5 mL), 35% aqueous formaldehyde (67.0. mu.l; 0.84 mmol) was added and the reaction mixture was takenStirring for 5 min. Sodium cyanoborohydride (21.2 mg; 0.34 mmol) was added in small portions and the reaction was stirred for 2 h. The reaction mixture was diluted with water and saturated NaHCO₃The solution was treated and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, over Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was purified by preparative HPLC. The combined fractions were concentrated in vacuo and saturated NaHCO₃The aqueous residue was made alkaline by solution, treated with NaCl (solid) and extracted with ethyl acetate (4 times). The combined organic layers were washed with brine, over Na₂SO₄Drying, suction filtration and evaporation to dryness to give 3- [4- (1-methyl-piperidin-4-yl) -phenyl ] -4-carboxylic acid methyl ester]-2H-pyrrolo [1,2-a]Pyrazin-1-one, as a beige solid; HPLC/MS 1.28 min (A), [ M + H]308；

¹H NMR (500 MHz, DMSO-d₆) [ppm]10.69 (s, 1H), 7.68 (s, 1H), 7.61 -7.57 (m, 2H), 7.45 - 7.43 (m, 1H), 7.34 - 7.30 (m, 2H), 6.91 - 6.88 (m, 1H),6.56 (dd,J= 3.9 Hz, 2.5, 1H), 2.90 - 2.84 (m, 2H), 2.53 - 2.45 (m, 1H),2.20 (s, 3H), 1.97 (td,J= 11.6 Hz, 2.7, 2H), 1.79 - 1.62 (m, 4H)。

The following compounds were prepared analogously:

3- [4- (1-methyl-pyrrolidin-3-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A80")

An off-white solid; HPLC/MS 1.21 min (A), [ M + H ] 294;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.77 (s, 1H), 7.79-7.73 (m, 1H),7.69-7.61 (m, 2H), 7.51 (dd,J= 2.6, 1.5 Hz, 1H), 7.47-7.37 (m, 2H), 6.96(ddd,J= 3.9, 1.6, 0.7 Hz, 1H), 6.62 (dd,J= 4.0, 2.5 Hz, 1H), 3.42 (dq,J= 9.7, 7.0 Hz, 1H), 2.90 (dd,J= 9.0, 7.8 Hz, 1H), 2.77-2.62 (m, 2H), 2.50(dd,J= 9.0, 6.7 Hz, 1H), 2.40-2.26 (m, 4H), 1.82 (ddt,J= 12.9, 8.4, 6.6Hz, 1H).

7-fluoro-3- [4- (1-methyl-piperidin-4-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A81")

A white solid; HPLC/MS 1.39 min (A), [ M + H ] 326;

¹H NMR (400 MHz, DMSO-d₆) [ppm]10.96 (s, 1H), 7.62 - 7.53 (m, 3H),7.46 (dd,J= 3.4, 1.9 Hz, 1H), 7.36 - 7.29 (m, 2H), 6.74 (d,J= 1.8 Hz,1H), 2.91 - 2.82 (m, 2H), 2.55 - 2.44 (m, 1H), 2.19 (s, 3H), 2.02 - 1.91 (m,2H), 1.79 - 1.59 (m, 4H).

7-chloro-3- [4- (1-methyl-piperidin-4-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A82")

A white solid; HPLC/MS 1.46 min (A), [ M + H ] 342;

¹H NMR (500 MHz, DMSO-d₆) [ppm]10.96 (s, 1H), 7.62 (s, 1H), 7.60 -7.54 (m, 3H), 7.37 - 7.30 (m, 2H), 6.92 (d,J= 1.7 Hz, 1H), 2.87 (dt,J=11.9, 3.1 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.20 (s, 3H), 1.97 (td,J= 11.7, 2.8Hz, 2H), 1.78 - 1.61 (m, 4H)。

example 26

Synthesis of 6, 7-difluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A83")

Ethyl 4-fluoro-1H-pyrrole-2-carboxylate (1.57 g, 10.0 mmol) was dissolved in acetonitrile (10 ml), and 1-chloromethyl-4-fluoro-1, 4-diazotized (diazonia) bicyclo [2.2.2]Octane bis (tetrafluoroborate) (Selectfluor)^TM3.54 g, 10.0 mmol) and the mixture was irradiated in a Biotage initiated microwave synthesizer (Biotage initiator microwave synthesizer) at 70 ℃ for 5 minutes. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Subjecting the residue to silica gel column chromatography with cyclohexane/ethyl acetate as eluent to obtain 4, 5-difluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 1.78 (C), [ M + H [ ]]176；¹HNMR (500 MHz, DMSO-d₆) [ppm]12.93 (s, 1H), 6.67 (d,J= 4.5 Hz, 1H), 4.22(q,J= 7.1 Hz, 2H), 1.26 (t,J= 7.1 Hz, 3H).

The 5-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester is prepared in a similar way; HPLC/MS 1.68 (C), [ M + H [ ]]158；¹H NMR(400 MHz, DMSO-d₆) [ppm]12.58 (s, 1H), 6.69 (dd,J= 4.9, 4.0 Hz, 1H),5.69 (t,J= 4.0 Hz, 1H), 4.22 (q,J= 7.1 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H)。

The following procedure was carried out analogously to example 14. 6, 7-difluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2-carboxylic acid ethyl ester from 4, 5-difluoro-1H-pyrrole]-2H-pyrrolo [1,2-a]Pyrazin-1-one as a beige powder; HPLC/MS 1.70 (C), [ M + H [ ]]305；¹H NMR (400 MHz, DMSO-d6) [ppm]11.04 (s, 1H), 7.69-7.61 (m, 2H), 7.57-7.51 (m, 2H), 7.50 (s, 1H), 6.90 (d,J= 4.7 Hz, 1H), 5.09(s, 1H), 1.44 (s, 6H).

6-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A84")

From 5-fluoro-1H-pyrrole-2-carboxylic acid ethyl esterThe ester was prepared similarly as a beige powder; HPLC/MS 1.63 (C), [ M + H [ ]]287；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.78 (s, 1H), 7.69-7.61 (m, 2H),7.58-7.49 (m, 2H), 7.44 (s, 1H), 6.86 (dd,J= 5.1, 4.3 Hz, 1H), 6.25 (t,J=4.1 Hz, 1H), 5.08 (s, 1H), 1.45 (s, 6H)。

Example 27

Synthesis of 7-fluoro-3- [4- (1-hydroxy-cyclopentyl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A85")

A25 ml round-bottom flask was purged with nitrogen and charged with 6.9 ml of anhydrous THF, 134 mg (5.50 mmol) of magnesium turnings and 49 mg (0.20 mmol) of cerium (III) chloride. The suspension was cooled to 0 ℃ with stirring. Then 78 μ l (3.20 mmol) of 1, 4-dibromobutane was added and the suspension brought to room temperature, stirred at this temperature for 30 minutes and cooled again to 0 ℃.286 mg (1.00 mmol) of 4- (7-fluoro-1-oxo-1, 2-dihydro-pyrrolo [1,2-a ] are then added dropwise]Pyrazin-3-yl) -benzoic acid methyl ester in 2.3 ml THF. The reaction mixture was stirred at 0 ℃ for 30 minutes and at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. To a solution of 5.73 g (20.0 mmol) of 4- (7-fluoro-1-oxo-1, 2-dihydro-pyrrolo [1, 2-a)]Pyrazine-3-yl) -benzoic acid methyl ester to a suspension in 85 ml THF 5.42 g (22.0 mmol) were added and the mixture was stirred at room temperature under nitrogen for 1 h. Then 30.5 ml (84.0 mmol) of a 20% solution of methylmagnesium chloride in THF are added dropwise and the reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using cyclohexane/ethyl acetate as eluent to give 7-fluoro-3- [4- (1-hydroxy-cyclopentyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-one as a pale orange powder; HPLC/MS 2.37(B), [ M + H]313；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.99 (s, 1H), 7.62 (s, 1H),7.59 (d,J= 8.5 Hz, 2H), 7.54 (d,J= 8.5 Hz, 2H), 7.48 (dd,J= 3.4, 1.9Hz, 1H), 6.75 (d,J= 1.8 Hz, 1H), 4.85 (s, 1H), 1.92-1.80 (m, 6H), 1.80-1.69(m, 2H)。

Example 28

Synthesis of 3- [4- (3-hydroxy-azetidin-3-yl) -phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one hydrochloride ("A86")

HPLC/MS 1.13 (A), [M+H]282；¹H NMR (400 MHz, DMSO-d₆) [ppm]10.83(s, 1H), 9.24 (s, 2H), 7.82 (s, 1H), 7.78-7.73 (m, 2H), 7.70-7.62 (m, 2H),7.48 (dd,J= 2.5, 1.5 Hz, 1H), 6.93 (dd,J= 3.9, 1.3 Hz, 1H), 6.78 (s, 1H),6.59 (dd,J= 3.9, 2.5 Hz, 1H), 4.34 (d,J= 11.7 Hz, 2H), 4.11 (d,J= 11.7Hz, 2H)。

Example 29

Synthesis of 3- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -6-methyl-2H-pyrrolo [1,2-a ] pyrazin-1-one ("A87")

The reaction was carried out according to Y.Fujiwara et al, J. Am. chem. Soc. 2012, 134, 1494-1497.

Example 30

Synthesis of 7-chloro-3- [4- (1, 3-dihydroxy-1-methyl-propyl) phenyl ] -2H-pyrrolo [1,2-a ] pyrazin-1-one ("A88")

The following compounds were prepared analogously

Pharmacological data

TABLE 2 inhibition of tankyrase of some representative compounds of formula I

TABLE 3 inhibition of tankyrase of some representative compounds of formula I

The compounds shown in table 1 are particularly preferred compounds according to the invention.

The following examples relate to medicaments:

example A injection vial

A solution of 100 g of the active ingredient of the formula I and 5 g of disodium hydrogen phosphate in 3 l of bidistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile-filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contained 5 mg of active ingredient.

Example B suppository

A mixture of 20 g of the active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into a mould and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solutions of

Comprises 1 g of active ingredient of formula I, 9.38 g of NaH₂PO₄∙2 H₂O、28.48 g Na₂HPO₄∙12 H₂O and 0.1 g benzalkonium chloride in 940 ml double distilled water. The pH was adjusted to 6.8 and the solution was made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

Example D: ointment formulation

500 mg of the active ingredient of the formula I are mixed with 99.5 g of vaseline under sterile conditions.

Example E: tablet formulation

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner to give tablets in such a way that each tablet contains 10mg of active ingredient.

Example F: sugar-coated pill

Tablets were compressed analogously to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc and a dye.

Example G capsules

2 kg of active ingredient of the formula I are introduced into hard gelatin capsules in a conventional manner in such a way that each capsule contains 20 mg of active ingredient.

Example H: ampoule (CN)

A solution of 1 kg of the active ingredient of the formula I in 60 l of bidistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (7)

1. A compound selected from the group consisting of:

numbering Name (R) "A1" 3- (4-benzyloxy-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A2" 3-phenyl-2H-pyrrolo [1,2-a ]]Pyrazin-1-ones "A3" 3- (3-chloro-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A4" 3- (3-methoxyphenyl) -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A5" 3- (5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-2-yl) -2H-pyrrolo [1,2-a ]]Pyrazin-1-ones "A6" 3- (4-Nitro-phenyl) -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A7" 3- (4-methoxyphenyl) -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A8" 3- (3, 4-Dimethoxyphenyl) -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A9" 3-benzo [1,3 ]]dioxol-5-yl-2H-pyrrolo [1,2-a ] compounds]Pyrazin-1-ones "A10" 3- (4-fluoro-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A11" 3- (4-tert-butyl-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A12" 3-p-tolyl-2H-pyrrolo [1,2-a ]]Pyrazin-1-ones "A13" 3- (4-trifluoromethyl-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A14" 3- (1-methyl-1H-pyrazol-4-yl) -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A15" 6- (4-tert-butyl-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A16" 6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A17" 6- (4-pyrrolidin-1-yl-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A18" 6- (4-tert-butyl-phenyl) -2-hydroxymethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A19" 2-hydroxymethyl-6- (4-pyrrolidin-1-yl-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A20" 2-hydroxymethyl-6- (4-isopropoxy-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A21" 2-hydroxymethyl-6- [4- (5-methyl- [1,2,4]]Oxadiazol-3-yl) -phenyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A22" 2-hydroxymethyl-6- (1-isopropyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A23" 6-cyclohexyl-2-hydroxymethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A24" 3- (4-bromo-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A25" 3- [4- (1-methyl-1H-pyrazol-4-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A26" 3- {4- [1- (2-methoxyethyl) -1H-pyrazol-4-yl]-phenyl } -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A27" 3- {4- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl]-phenyl } -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A28" 4- (1-oxo-1, 2-dihydro-pyrrolo [1, 2-a)]Pyrazin-3-yl) -benzoic acid methyl ester "A29" 3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A30" 6- (4-tert-butyl-phenyl) -2-methyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A31" 3- (4- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-1H-pyrazol-4-yl } -phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A32" 3- {4- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl]-phenyl } -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A33" 2-chloromethyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A34" 2-methyl-6- (4-trifluoromethoxy-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A35" 3- (4-tert-butyl-phenyl) -7-fluoro-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A36" 2-bromomethyl-6- (4-bromo-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A37" 2-methyl-6- (4-pyrrolidin-1-yl-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A38" 3- (4-tert-butyl-phenyl) -7-methyl-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A39" 6- (4-bromo-phenyl) -2-methyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A40" 6- (4-bromo-phenyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A41" 2-hydroxymethyl-6- (6-pyrrolidin-1-yl-pyridin-3-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A42" 6- (6-pyrrolidin-1-yl-pyridin-3-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A43" 6- [4- (5-methyl- [1,2,4]]Oxadiazol-3-yl) -phenyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A44" 6- (1-tert-butyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A45" 2- (hydroxymethyl) -6- [1- (4-methoxyphenyl) -4-piperidinyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A46" 6- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-2-methyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A47" 6- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A48" 2-methyl-6- (6-pyrrolidin-1-yl-3-pyridyl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A49" 2-methyl-6- [4- (5-methyl- [1,2,4]]Oxadiazol-3-yl) -phenyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A50" 6-cyclohexyl-2-methyl-5H-pyrazolo [1,5-a ]]Pyrazin-4-ones "A51" 2-methyl-6- (1-isopropyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A52" 2-methyl-6- (1-tert-butyl-1H-pyrazol-4-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A53" 2-methyl-6- [1- (4-methoxyphenyl) -4-piperidinyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A54" 2-methyl-6- (2-pyrrolidin-1-ylpyrimidin-5-yl) -5H-pyrazolo [1,5-a]Pyrazin-4-ones "A55" 6- (4-tert-butyl-phenyl) -2-trifluoromethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A56" 3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-7-methyl-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A57" 3- (1-tert-butyl-1H-pyrazol-4-yl) -7-methyl-2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A58" 3- (4-bromo-phenyl) -7-fluoro-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A59" 7-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A60" 7-chloro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A61" 3- [4- (1-ethyl-1-hydroxy-propyl) -phenyl]-7-fluoro-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A62" 3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-1-oxo-1, 2-dihydro-pyrrolo [1,2-a]Pyrazine-7-carbonitriles "A63" 7-fluoro-3- [4- (1-fluoro-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A64" 6- (4-tert-butyl-phenyl) -2-fluoromethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A65" 2-hydroxymethyl-6- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A66" 6- (4-tert-butyl-phenyl) -2-difluoromethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A67" 6- (4-bromo-phenyl) -2-trifluoromethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A68" 4- (4-oxo-2-trifluoromethyl-4, 5-dihydro-pyrazolo [1, 5-a)]Pyrazin-6-yl) -benzoic acid methyl ester "A69" 6- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2-trifluoromethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A70" 7-fluoro-3- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl]-phenyl } -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A71" 7-fluoro-3- {4- [1- (2-methoxyethoxy) -1-methyl-ethyl]-phenyl } -2H-pyrrolo [1, 2-a)]Pyrazin-1-ones "A72" 3- [4- (1-amino-1-methyl-ethyl) -phenyl]-7-fluoro-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A73" 7-fluoro-3- [4- (2-methyl-tetrahydro-furan-2-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A74" 7-fluoro-3- [4- (4-hydroxy-1-methylene-butyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A75" 3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A76" 3- (4-pyrrolidin-3-yl-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A77" 7-fluoro-3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A78" 7-chloro-3- (4-piperidin-4-yl-phenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A79" 3- [4- (1-methyl-piperidin-4-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A80" 3- [4- (1-methyl-pyrrolidin-3-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A81" 7-fluoro-3- [4- (1-methyl-piperidin-4-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A82" 7-chloro-3- [4- (1-methyl-piperidin-4-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A83" 6, 7-difluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A84" 6-fluoro-3- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A85" 7-fluoro-3- [4- (1-hydroxy-cyclopentyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A86" 3- [4- (3-hydroxy-azetidin-3-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-one hydrochloride "A87" 3- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-6-methyl-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A88" 7-chloro-3- [4- (1, 3-dihydroxy-1-methyl-propyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A89" 6- (1-tert-butyl-1H-pyrazol-4-yl) -2-hydroxymethyl-5H-pyrazolo [1,5-a]Pyrazin-4-ones "A90" 7-fluoro-3- [4- (1-methyl-1H-pyrazol-4-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A91" 7-methyl-3- [4- (1-methyl-1H-pyrazol-4-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A92" 3- (4-tert-butyl-phenyl) -1-oxo-1, 2-dihydro-pyrrolo [1, 2-a)]Pyrazine-7-carbonitriles "A93" 7-fluoro-3-phenyl-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A94" 3- (4-bromophenyl) -6-methyl-2H-pyrrolo [1,2-a ]]Pyrazin-1-ones "A95" 3- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-6-methyl-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A96" 6- (difluoromethyl) -3- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A97" 6- (trifluoromethyl) -3- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A98" 3- [4- (3-hydroxypyrrolidin-3-yl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A99" 3- [4- (4-hydroxy-4-piperidinyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A100" 3- [4- (3-hydroxy-1-methyl-azetidin-3-yl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A101" 3- [4- (3-hydroxy-1-methyl-pyrrolidin-3-yl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A102" 3- [4- (4-hydroxy-1-methyl-4-piperidinyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A103" 7-fluoro-3- (4-pyrrolidin-3-ylphenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A104" 7-fluoro-3- [4- (1-methylpyrrolidin-3-yl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A105" 7-chloro-3- (4-pyrrolidin-3-ylphenyl) -2H-pyrrolo [1,2-a]Pyrazin-1-ones "A106" 7-chloro-3- [4- (1-methylpyrrolidin-3-yl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A107" 7-chloro-3- [4- (1, 3-dihydroxy-1-methyl-propyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A108" 3- [4- (1, 3-dihydroxy-1-methyl-propyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A109" 7-fluoro-3- [4- (1, 3-dihydroxy-1-methyl-propyl) phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A110" 3- [4- (3-hydroxy-oxetan-3-yl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones "A111" 3- [4- (1-hydroxy-cyclobutyl) -phenyl]-2H-pyrrolo [1,2-a]Pyrazin-1-ones

。

2. A medicament comprising at least one compound of claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient and/or vehicle.

3. Use of compounds according to claim 1 and their pharmaceutically acceptable salts, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment and/or prophylaxis of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

4. Use of compounds according to claim 1 and their pharmaceutically acceptable salts, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment and/or prophylaxis of diseases selected from the group consisting of: head, neck, eye, mouth, throat, esophagus, bronchus, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, and solid and hematological tumors.

5. Use of compounds according to claim 1 and their pharmaceutically acceptable salts, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment and/or prophylaxis of diseases selected from the group consisting of: head, neck, eye, mouth, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, and solid and hematological tumors.

6. Medicament comprising at least one compound according to claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

7. A kit or kit consisting of the following separate packages:

(a) an effective amount of a compound of claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios,

and

(b) an effective amount of an additional pharmaceutically active ingredient.