NZ613592B2 - Il17 and ifn-gamma inhibition for the treatment of autoimmune inflammation - Google Patents

Abstract

The present disclosure relates to pyrazolyl isoxazole compounds of the general formula (I), and the pharmaceutically acceptable salt or solvate thereof, as anti-inflammatory and immunomodulatory agents. These compounds act as inhibitors of IL17 and IFN-gamma. The conditions that may be treated by the present compounds include: psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave's disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjogren's syndrome, spinal disc herniation, acne, Graft-versus-Host-Reaction, Host-versus-Graft-Reaction and osteoarthritis. Compounds of the disclosure include: methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate, (3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl )-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-yl)(piperidin-1-yl)methanone, (3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-( trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-yl)(isoxazolidin-2-yl)methanone, S-methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbothioate, and (Z)-methyl N-(3-(2-chloro-6-fluorophenyl)-5-(1-(3 -fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-yl)-2,2,2-trifluoroacetimidate. e present compounds include: psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave's disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjogren's syndrome, spinal disc herniation, acne, Graft-versus-Host-Reaction, Host-versus-Graft-Reaction and osteoarthritis. Compounds of the disclosure include: methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate, (3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl )-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-yl)(piperidin-1-yl)methanone, (3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-( trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-yl)(isoxazolidin-2-yl)methanone, S-methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbothioate, and (Z)-methyl N-(3-(2-chloro-6-fluorophenyl)-5-(1-(3 -fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-yl)-2,2,2-trifluoroacetimidate.

Description

IL17 and mma inhibition for the ent of autoimmune inflammation The IL—17 family of cytokines has been associated with the pathogenesis of autoimmune diseases and is generally blamed for the pathogenic ms of autoimmune inflammation.

Overexpression of IL-17 is a hallmark for autoimmune diseases like rheumatoid arthritis, systemic lupus erythematomatosus, inflammatory bowel e, multiple sclerosis, and psoriasis (Yao Z et. 52]., J. Immunol, 155(12), 1995, 5483—6. Chang S H, aerial, Cytokine, 46, 2009, 7~11; Hisakata Yamada et.al., Journal of Inflamm. Res., 3, 2010, 33-44)).

The IL—l'f cytokine family comprises six members, out of which IL—17A and ILu17F are the best characterized. lL—17A and IL—l7F exist as homo— as well as as heterodirners (IL—17M, ILn17AF, IL-17FF). IL-17A and IL-17F are y ated with inflammation (Gaffen S H, Cytokine, 43, 2008, 7; Torchinsky M B et al., Cell. Mol. Life Sci, 67, 2010, 1407- 1421).

The secretion of 1L—17 is predominantly caused by a specific subtype of T helper cells termed Til-17 cells. IL—23, TGFB and lL—6 were shown to be important factors leading to conversiOn of naive CD4+ T—cells to TH17 cells. It was also reported that TGFB and IL—6 potently induce in synergy TH17 differentiation. Important ription factors for the secretion of IL~17 from Tl-Ii7 cells are RORyt and STAT3 (Ivanov,l emf. Cell 126, 2006, 11214133). IL—17 induces pro-inflammatory cytokines (IL-6, TNF~0L and IL—lb) and Chemokines (CXCL1,GCP-2,CXCL8 or IL—8,CINC,MCP—1). It increases the production of nitric oxide glandin E2 and manixnmetalloproteinases. As a consequence of these events neutrophil infiltration, tissue damage and chronic ation occurs (PECK A etal, Clin Immunol., 132(3), 2009, 295-304).

Before the recognition of the ance of IL-17 in autoimmune inflammation, mma derived from TH] cells was believed to be an important cytokine that drives autoimmune disorders (Takayanagi H at. al. Nature, 408, 2000, 600—605. Huang W. et. a1. Arthritis Res.

Ther., 5, 2.002, R49—R59) The secretion of IFN—gamma is a key feature of the TH} effector cell lineage and the secretion is regulated by the transcription factors T-bet and STAT4 (Bluestone JA et. al. Nat Rev Immunol, 11, 2009, 811—6). Infiltration of activated T—cells and elevation of M—CSF, IL—10 and TNF support this notion (Yamanda H eta]. Ann. Rheu. Dis, 67,2008, 1299—1304; Kotake S etal. Eur. J. Immunol, 35, 2005, 3353—3363).

Recently, a more complex situation was proposed, where hybrid TH17/TH1 cells d by IL—23 and lL-6 in t with IL—1 secrete IL—17 and lFN—gamma. These cells are under the l of the transcription factors RORyt and T—bet, confirming the notion, that these are true hybrids of TH1 and TH17 cells. It was also demonstrated that these double producing cells are the pathogenic species in IBD and EAE (Buonocore S emf. , 464, 2010, 1371—5; Ghoreshi K. et. al. Nature, 467, 2010, 967-971).

Compounds which target and suppress both IL—17 and IFN-gamma are predisposed for the treatment of autoimmune disorders.

The effectiveness of blocking 1L-17 signaling as therapeutic treatment in autoimmune diseases has already been proven in clinical trials with e. g. monoclonal antibodies against IL— 17A (AIN457, secukinumab; Ly2439821, ixekizumab; RG4934) and/or the ILm17 receptor IL— 17RA (AMG-827, brodalumab). Positive results have been reported for the treatment of rheumatoid arthritis, psoriasis and uveitis (Hueber W at at, Sci. Transl. Med, 2, 2010, , D01: 10.1126/scitranslrned300l107; van den Berg W B et (1]., Nat. Rev. Rheumatoi, 5, 2009, 549-553), sing spondylitis and spondyloarthritides (Song lull er (1]., Curr.

Opin. Rheumatol., 23, 2011, 346651). numab is currently under investigation in clinical trials for psoriatic arthritis, Behcet disease, uveitits, inflammatory bowel disease, Crohn’s disease, multiple sclerosis (1(0pr et (IL, Nat. Rev. Drug Disc, 9, 2010, 703-718; Song I—H e: at, Curr. Opin. Rheumatol., 23, 2011, 346—351). Brodalumab, urnab and RG4934 are currently in clinical trials for the treatment of toid arthritis, psoriasis and/or psoriatic arthritis (Kopf M et (11., Nat. Rev. Drug Disc, 9, 2010, 703—718; clinicaltrialsgov, nes in development for skin diseases, 2011, published by PhRMA, wwwphrmaccm).

With regard to blocking of IFN—gamma signaling as therapeutic treatment in mune es, the IFN—gammamspecific monoclonal antibody AMGSll is tly under clinical investigations for the treatment of systemic lupus erythematosus (Kopf M et al., Nat. Rev.

Drug Disc, 9, 2010, 703—718).

The present invention relates to a compound of formula (I) Ne'O // / Ar N’Ri formulafl) and the pharmaceutically acceptable salt or solvate thereof, wherein R1 is aryl, heteroaryl, cyctoalkyl, heterocyclyl 01‘ alkyl, which can be tuted by one or more substituents R’ AI is aryl, cycloalkyl, heterocyolyl or aryl, which can be substituted by one or more substituents R’; Z is H, halogen, —CR”O, -N(R”)2, —CN, -C(S)R”, ~N=C(R’)2, , —NR’COZR”, —CONHR”, —CON(R”)2, ~COSR”, -CSNHR”, —CSN(R")2, MSOg—alkyl, —SOg—haloalkyl, — SOgNHR”, -SOZ(N ”)2, amino or —SOgR”; Y is H, halogen, haloalkyl, alkyl or an alkylester, which can be substituted by one or more substituents R’; R’ independently represents H, , ~CONHR”, —CR”O, ~SO;N( ”)2, "SOQNI'IR", ~NR”—CO—haloalkyl, ~N02, -NR”—SOz-haloalkyl, —NR”-SOg—alkyl, -SOg—alkyl, "N ”-CO— alkyl, ~CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, n, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; R” independently ents H, kyl, hydroxyalkyl, amino, alkoxy, ’)2, —NR’—CO—R’, ~CR’O, —CO;R’, alkyl, oycloalkyl, aryl, haloaryl, haloarylalkyl, heteroaryi, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more substituents R”.

The t invention further relates to a nd of formula (I) // / Ar N’R1 “'"N Z fonnulafl) and the phannaceutieally acceptable salt or solvate thereof, wherein R1 is aryl, aryl, cycloalkyl, heterocyclyl or alkyl, which can be substituted by one or more substituents R’ Ar is aryl, cycloalkyl, heterocyclyl or heteroaryl, which can be substituted by one or more substituents R”; Z is H, halogen, —CR”O, ~N(R”)2, «CN, —C(S)R”, -N“—*C(R’)2, -C02R”, m NR’C02R°’, ~CONHR”, —CON( ”)2, -COSR”, —CSNHR”, ”)2, -SOg~alkyl, "SOg-haloalkyl, ~802NHR”, -SOg(NR”)2, amino or sozn”, which can be substituted by one or more substituents R”; Y is H, halogen, kyl, alkyl, which can be substituted by one or more substituents R’; RD independently represents H, -C02R”, ”, -CR"O, —SOZN(R”)2, - SOZNHR”, -NR”—C0~haloalkyl, -N02, —NR”—SOz-11aloalkyl, ~NR”—SO;— alkyl, —SOg—alkyl, -NR”~CO—alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, mino, alkoxy, «OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, kyl or heteroaryl; R5 9 independently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, —N:C(R’)2, —NR’-CO~R’, ~CR’O, -C02R’, alkyl, cycloalkyl, aryl, haloaryl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more tuents R’.

In a preferred ment, the present invention relates to a nd of a (I) and the pharmaceutically acceptable salt or solvate thereof, wherein R1 is aryl, which can be substituted by one or more substituents R’ In a more preferred embodiment, the present invention relates to a compound of a (I) and the pharmaceutically acceptable salt or solvate thereof, R1 is heteroaryl, which can be substituted by one or more substituents R’ In a more preferred embodiment, the present invention relates to a compound of formula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein Ar is aryl, which can be substituted by one or more substituents R’ In a more preferred embodiment, the t invention relates to a compound of formula (I) and the pharmaceutically acceptable salt or solvate f, wherein Ar is heteroaryl, which can be substituted by one or more substituents R’ In a more preferred embodiment, the present invention relates to a compound of formula (I) and the phannaceutically acceptable salt or solvate thereof, wherein Z is —CR”O, which can be substituted by one or more substituents R’ In a more preferred embodiment, the present invention relates to a compound of formula (I) and the pharmaceutically able salt or solvate thereof, wherein Z is ~C02R”, which can be substituted by one or more substituents R’ In a more preferred embodiment, the present invention relates to a compound of formula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein Z is —CON(R”)2, which can be substituted by one or more substituents R’ In a more preferred ment, the present invention relates to a compound of formula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein Y is halogen, which can be substituted by one or more substituents R’ In a more preferred embodiment, the present invention relates to a compound of formula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein Y is haloalkyl, which can be substituted by one or more substituents R’ In a more preferred embodiment, the t invention s to a nd of formula (I) and the ceutically acceptable salt or solvate thereof, wherein Y is alkyl, which can be substituted by one or more substituents R’ In another red embodiment, the present invention relates to a compound of formula (I) and the phannaceutically acceptable salt or solvate thereof, R] is aryl, heteroaryl, lkyl, heterocyclyl or alkyl, which can be substituted by one or more substituents R’ Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; is H, halogen, -CR”O, —N(R”)2, -CN, —C(S)R”, -N:C(R’)2, ~C02R”, - NR’COZR”, -CONHR”, -CON(R”)2, ~COSR”, -CSNHR”, ~CSN(R”)2, -SOz-alkyl, —SOzwhaloalkyl, —SOZNHR”, -SOZ(NR”)2, amino or -SOgR”, which can be tuted by one or more substituents R’; is H, halogen, haloalkyl or alkyl, which can be substituted by one or more substituents R”; R3 independently represents H, —COgR”, ”, -CR”O, ~SOZN( ”)2, _ SOZNHR”, 0~haloalkyi, —N02, —NR°’—SOg—haloalkyl, —NR”—SO;~ alkyl, —SO;-a1kyl, ~NR”-CO—alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, yalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyi or heteroaryl; R7! independently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, -N=C(R°)2, —NR’—CO—R’, —CR’O, -C02R’, alkyl, cycloalkyl, aryl, yl, haloarylalkyl, aryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more substituents R’; in another preferred embodiment, the present invention s to a compound of formula (I) and the ceutically acceptable salt or solvate thereof, wherein R1 is aryl or heteroaryl, which can be tuted by one or more substituents R” Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; is H, halogen, —CR”O, —N(R”)2, -CN, nC(S)R”, ~N=C(R’)z, ~COgR”, — NR’COZR”, ”, -CON(R”)2, —COSR”, —CSNHR”, ~CSN(R”)2, —SOz—alkyl, ~802-haloalkyl, —SO;NHR”, —SOg(NR”)2, amino or -SOgR”, which can be substituted by one or more substituents R”; is H, halogen, haloalkyl or alkyl, which can be substituted by one or more substituents R’; R) independently represents H, £02K”, -CONHR”, —CR”O, —SC)2N(R”)2, — SOgNHR”, -NR”-C0—haloalkyl, —N02, -NR”-SOg-haloalkyl, —NR”—SOZ~ alkyl, -SOz—alkyl, — R”—CO~alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, ~SH, alkyithio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, koxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; R): independently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, ~NEC(R’)2, -NR’-CO—R’, —CR’O, —C02R’, alkyl, cycloalkyl, aryl, haloaryl, ylalkyl, heteroaryi, heterocyclyl, arylalkyl or aminoalkyl, which are ally substituted by one or more substituents R’; In another preferred embodiment, the present ion relates to a compound of formula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein R1 is aryl or heteroaryl, which can be substituted by one or more substituents R’ Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; is H, halogen, ~CR”O, -N(R”)2, —CN, -C(S)R”, ~N=C(R°)2, cogs”, , NR’COZR”, -CONHR”, «comm», —COSR”, ”, -CSN(R")2 or amino, which can be substituted by one or more substituents R’; is H, halogen, haloalkyl, or alkyl, which can be tuted by one or more substituents R’; R5 independently ents H, ~COgR”, —CONHR”, —CR”O, R”)2, — SOZNHR”, —NR”—CO—haloalkyl, -N02, ~NR”—SO;—haloalkyl, Oz— alkyl, lkyl, —NR”—CO—alky1, ~CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyaikylarnino, halogen, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; R” independently represents H, haloalkyl, yalkyl, amino, alkoxy, ~N=C(R’)2, ~NR’—CO—R’, —CR’O, ~C02R’, alkyl, cycloalkyl, aryl, yl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are Optionally substituted by one or more substituents R”; In another preferred embodiment, the present invention s to a compound of formula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein R1 is aryl, which can be substituted by one or more substituents R’ Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; Z is H, halogen, —CR”O, 2, —CN, ”, -N:C(R’)2, —COgR”, — NR’COgR”, ~CONHR”, —CON(R”)2, , -CSNHR°’, "CSN(R”)2, amino, which can be substituted by one or more substituents R”; Y is H, halogen, haloalkyl, or alkyl, which can be substituted by one or more substituents R”; R” independently represents H, “COZR”, ‘CONHR’Z —CR”O, —SOgN(R”)g, — SOZNHR”, ~NR”—CO-haloalkyl, «N02, ~NR”—SOg—haloalkyl, -NR”—SOZ- alkyl, -SO;_-alkyl, —NR”—CO—alkyl, ~CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, kyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, ylalkyl, arylalkyl or heteroaryl; R” independently represents H, haloalkyl, yalkyl, amino, alkoxy, ‘)2, ~NR’—CO—R’, —CR’O, -C02R’, alkyl, cycloalkyl, aryl, haloaryl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more substituents R’; In another preferred embodiment, the present invention relates to a compound of a (I) and the pharmaceutically acceptable salt or solvate thereof, wherein R1 is heteroaryl, which can be substituted by one or more substituents R” Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; is H, halogen, ~CR”O, ~N(R”)2, —CN, -C(S)R”, ’)2, -C02R”, w NR’COgR”, -CONHR”, ~CON(R”)2, "COSR’Z -CSNHR”, -CSN(R”)2, amino, which can be substituted by one or more substituents R”; is H, halogen, kyl, or alkyl, which can be substituted by one or more substituents R’; R5 ndently represents H, —C02R”, —CONHR”, «CR”O, -SOzN(R”)2, - SOgNHR”, —NR”—CO-haloalky1, ‘NOZ, -NR”-SOg—haloalkyl, -NR”-SO;— alkyl, —SOg—a1kyl, O—alky1, -CN, alkyl, cycloalkyl, lkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; R59 independently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, ~N=C(R’)2, —NR’—CO—R°, -CR’O, , alkyl, cycloalkyl, aryi, haloaryl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more tuents R’; In another preferred embodiment, the present invention relates to a compound of a (I) and the phannaceutically acceptable salt or solvate thereof, wherein R1 is aryl or heteroaryl, which can be substituted by one or more substituents R’ Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; WO 01261 is H, halogen, -CR”O, -N(R”)2, -CN, -C(S)R”, —NwC(R°)2, ~C02R”, -NR’CO;R”, —CONHR”, —CON(R”)2, -cosne, —CSNHR”, -CSN(R”)2, amino, which can be substituted by one or more substituents R’; is H, n, haloalkyl, or alkyl, which can be substituted by one or more tuents R3 independently ents H, ~C02R”, -CONHR”, ~CR”O, —SOZN(R”)2, -SO;NHR”, «CN, alkyl, cycloalkyl, aminoalkyl, alkoxy, “OI-I, , hydroxyalkyl, halogen, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, ylalkyl, arylalkyl or heteroaryl; R5! independently ents H, haloalkyl, hydroxyalkyl, amino, alkoxy, ~N=C(R’)2, O-R’, —CR’O, —C02R’, alkyl, cycioalkyl, aryl, haloaryl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are ally substituted by one or more substituents R” In another preferred embodiment, the present invention relates to a compound of fonnula (I) and the pharmaceutically acceptable salt or solvate thereof, wherein R1 is aryl or heteroaryl, which can be substituted by one or more substituents R”; AI is aryl or heteroaryl, which can be substituted by one or more substituents R’; Z is H, halogen, FCR”O, -N(R”)2, —CN, —C(S)R”, —NEC(R’)2, , —NR’C02R”, -CONHR”, —CON(R”)2, -COSR”, —CSNHR”, -CSN(R”)2, amino, which can be substituted by one or more substituents R”; Y is H, halogen, haloalkyl, or alkyl, which can be substituted by one or more substituents R’; independently represents H, -COy_R”, «SOZN(R”)2, —SOgNHR”, ~CN, alkyl, alkoxy, - OH, hydroxyalkyl, halogen, kyl, haloalkoxy, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; R93 ndently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, R’)2, —NR’-CO-R’, ~CR’O, —C02R’, alkyl, cycloalkyl, aryl, yl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more substituents R’ In another preferred ment, the present invention s to a compound of a (I) and the phannaceutically acceptable salt or solvate thereof, wherein R1 is aryl or heteroaryl, which can be substituted by one or more substituents R’; Ar is aryl or heteroaryl, which can be substituted by one or more substituents R”; is H, halogen, —CR”0, ~C(S)R’, —C02R”, -NR’C02R”, —CONHR”, -CON(R”)2, - COSR”, —CSNHR”, —CSN(R”)2, which can be substituted by one or more substituents R”; is H, halogen, haloalkyl, or alkyl, which can be substituted by one or more substituents independently ents H, -C02R”, -SO;;N(R”)2, -SOZNHR”, -CN, alkyl, alkoxy, — OH, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; ' R73 independently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, —N«=C(R’)2, —NR’—CO—R’, —CR’O, , alkyl, cycloalkyl, aryl, haloaryl, haloarylalkyl, heteroaryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally substituted by one or more substituents R’ In another preferred ment, the present invention relates to a compound of formula (I) and the phannaceutically acceptable salt or solvate thereof, wherein R} is aryl, or heteroaryl, which can be substituted by one or more substituents R“; Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; is H, halogen, —CR”O, —C(S)R’, —C02R”, 2R”, CONHR”, —CON(R”)2, « COSR”, -CSNHR”, -CSN(R”)2, which can be substituted by one or more substituents R’; is H, halogen, haloalkyl, or alkyl, which can be substituted by one or more substituents R1 independently represents H, ~C02R”, —CONHR”, —CR”O, -SOZN(R”)2, ‘SOQNHRH, -CN, alkyl, alkoxy, -OH, halogen, haloalkyl or haloalkoxy; R95 independently represents H, kyl, or alkyl, which can be substituted by one or more substituents R”; In another preferred embodiment, the present invention relates to a nd of formula (I) and the pharmaceutically acceptable salt or solvate f, wherein R1 is aryl, which can be substituted by one or more substituents R’; Ar is aryl, which can be substituted by one or more substituents R’; Z is H, haloaikyl, aryl, heteroaryl, COZR”, ”, —CR”O, -CON(R”)2, COSR”, which can be substituted by one or more substituents R”; Y is H, halogen, haloalkyl, or alkyl, which can be substituted by one or more substituents R’ independently represents H, -CO;R”, -CONHR”, —CR”O, —CN, alkyl, alkoxy, —OH, halogen, kyl or haloalkoxy; R” independently represents H, haloalkyl, or alkyl, which can be substituted by one or more substituents R’; 2012/051357 wherein an aryl group denotes an aromatic group having five to fifteen carbon atoms, which may be substituted by one or more tuents R’, and may be fused to another ic ring; the aryl group is preferably a phenyl group, -0—C5H4—R’, —m—C6H4—R’, -p—C6H4—R‘, l-naphthyl,2~ naphthyl, l—anthraeenyl or 2—anthracenyl; a heteroaryl group denotes a 5- or ered heterocyclic group which contains at least one heteroatom like 0, N, S. This beterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol—Z—yl, thiazol—4—yl, thiazoI-S-yl, isothiazol-B’myl, isothiazol—4—yl, isothiazol-S-yl, oxazol—2~yl, oxazol-4uyl, oxazol—S-yl, isooxazol—Z’z—yl, isooxazol—4—yl, isooxazoLS—yl, 1,2,4—oxadiazol—3—yl, l,2,4~oxadiazol~5—yl, 1,2,5—0xadiazolyl, benzooxazol—Z-yl, xazolA—yl, benzooxazol-S-yl, benzoisooxazol- 3—yl, benzoisooxazol—4-yl, sooxazol—S—yl, 1,2,5~oxadiazol-4—yl, 1,3,4-oxadiazol—2—yl, 1,2,4—thiadiazol»3~yl, 1,2,4—thiadiazol—S—yl, 1,3,4—thiadiazol—2—yl, isothiazol—3—yl, isothiazol yl, isothiazol—S-yl, benzoisothiazol~3~yl, benzoisothiazol—4-yl, benzoisothiazol-S-yl, 1,2,5— thiadiazol—3—yl, l—imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol—4—yl, 4mimidazolyl, benzoimidazol—4—yl, 1-pyrrolyl, 2—pyrrolyl, 3—pyrrolyl, 2-furanyl, 3—furanyl, 2-thienyl, 3— thienyl, 2-pyridyl, 3—pyridy1, 4—pyridyl, 2—pyranyl, nyl, 4-pyranyl, 2—pyrimidinyl, 4- pyrimidinyl, midinyl, pyrid—Z—yl, pyrid—B-yl, pyrid-4—y1, pyrid—S-yl, pyrid—6—yl, 3— pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, l—pyrazolyl, 3-pyrazolyl, 4—pyrazolyl, 1,2,3utriazol—4— yl, 1,2,3—triazol—5—yl, 1,2,4—t1iazoln3-yl, 1,2,4-triazol—5—yl, 1H—tetrazol-2—yl, 1H—tetrazol~3—yl, tetrazolyl, acridyl, pheuazinyl, earbazolyl, phenoxazinyl, indolizine, 2—indolyl, ly1, 4- indolyl, S-indolyl, lyl, 7—indolyl, l—isoindolyl, 3~isoindolyl, 4—isoindolyl, 5-isoindolyl, 6-isoindolyl, 7—isoindolyl, 2-indolinyl, 3—indolinyl, 4—indolinyl, 5—indolinyl, 6—indolinyl, 7- indolinyl, benzo[b]fi.1ranyl, benzofurazane, benzothiofurazane, benzotriazoLl—yl, benzotriazolyl, benzotriazol-S—yl, benzotriazoI-é-yl, benzotriazol—7nyl, benzotriazine, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or tetrahydroisoquinolinyl, purine, phthalazine, ine, thiatetraazaindene, thiatriazaindene, azolopyrazine, 6— dinyl, methoxy—6-py1imidinyl, benzimidazol—Z—yl, zimidazolyl, benzimidazolyl, benz~imidazol—5-yl, benzimidazol—é-yl, benzimidazol~7—yl, tetrazole, tetrahydro—thienoB,4—d]imidazol—2-one, pyrazolo[5,l—c][1,2,4]triazine, isothiazolopyrimidine, WO 01261 pyrazolotriazine, pyrazolopyrirnidine, irnidazopyridazine, imidazopyfimidine, imidazopyridine, imidazolotriazine, triazoiotriazine, triazolopyridine, lopyrazine, triazolopyrimidine, or triazolopyridazine group. This heterocyclic group can be tuted by one or more substituents R’, wherein R’ is as defined above; a heterocyclyl group denotes a 3 to 8—membered heterocyclic nonnarornatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclyl group may be fiised to another nonwarornatic ring and may be substituted by one or more substituents R”, wherein R” is as defined above; the C3—Cg-heterocycly1 residue may be selected from the group consisting of morpholine—4—yl, piperazinyl, isoxazolidineQ-yl, l~ alkylpiperazine~4~y1, pyrrolidinyl, idino, dinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, rpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl; isoxazolidine To keep the definitions as short as possible, in the following paragraphs “alkyl” is to be understood to encompass alkyl, alkenyl and alkynyl.

In the context of the present ion, an alkyl group, if not stated otherwise, denotes a linear or branched C1-C6—alkyl, preferably a linear or branched chain of one to five carbon atoms; an alkenyl group, if not stated otherwise, denotes a linear or branched alkeny1; and an alkynyl group, if not stated otherwise, denotes a linear or branched C2-C5-alkynyl group, which may be tuted by one or more substituents R’.

The alkyl, alkenyl and C2~C5—alkynyl residue may be selected from the group consisting of -CH3, -C2H5, -CH:CH2, ~CECH, —C3H7, -CH(CH3)2, ~CH2-CH2CH2, —C(CH3)2CH2, —CHICH—CH3, CECE-CH3, CHE—CECE}, —C4H9, -CH2HCH(CH3)2, —CI~I(CH3)» Csz, ~C(CH3)3, ~C5H1z, ~C6H13, -C(R’)3= -C2(R’)53 -CH2-C(R3)3, -C3(R’)7, -C2H4-C(R’)3, -C2H4-CH=CH2, ~CH2CHmC2H5, —CH:C(CH3)2, -CH2-CH3CH—CH3, —CH=CH2, n02H4—CECH, -CEC~C2H5, —CH2—C«=»~C-CH3, —CEC-CH~—~CH2, —CECH, (SEC—CECIL ~C2H4~CH(CH3)2, -CH(CH3)»C3H7, —CH2—CH(CH3)—C;;H5, —CH(CH3)—CH(CH3)2, —C(CH3)2-CzH5, —CH2-C(CH3)3, —C3H6—CH=CH2, —CH2CH—C3H-,—, —C2H4—CH“—"CH—CH3, -CH2-CH:CH—C2H5, —CHg—CH=CH-CH=CH2, -CH=CH—CH=CH~CH3, -CH=CH—CH2—CH:CH2, —C(CH3):CH—CH:CH2, WO 01261 2012/051357 -CH=C(CH3)—CH=CH2, ~CH=CH—C(CH3)=CH2, -CH2—CHmC(CH3)2, C(CH3)=C(CH3)2, -C3H6-CECH, -CEC—C3H7, -C2H4—CEC—CH3, engage—ems, EC—CH=CH2, wenz— C-:~CH, EC-CECH, —CEC—CH=CH—Ci13, ~CH=CH~CEC~CH3, ~CEC—CEC—CH3, Hezc—cnz—chnz, ~CH=CH-CH2—CECH, —C§C-CI-Ig—CECH, -C(CH3)”—"CH-CHECH2, -0HmC(CH3)—CH=CH2, -CH:CH—C(CH3)=CH2, -C(CH3)=CH- CECH, -CH=C(CH3)—CECH, —CEC-C(CH3)=CH2, ~C3H6-CH(CH3)2, —C2H4-CH(CH3)—C2H5, — among—(34m, —CH2—CH(CH3)~CgH7, 3)—CHg-CH(CH3)2, -CH(CH3)—CH(CH3)—C2H5, —CH2-CH(CH3)-CH(CH3)2, —CI-I2~C(CH3)2—C2H5, )2-C3H7, -C(CH3)2—CH(CH3)2, £2114— C(CH3)3, "omens—omega -C4H8—CH=CH2, mCH=CH-C4H9, —C3H6—CH=CH—CH3, ~CH2— CH=CH—C3H7, -C2H4—CH:CH*C2H5, -CH2—C(CH3)=C(CH3)2, »C2H4—CHmC(CH3)2, -cins- CECH, peeping, ~C3H6—CEC—CH3, -CH2—CEC—C3H7, and -cgni—cEc—czas; an arylaikyl group denotes a linear or branched C1—C6—alkyl substituted with at least one aryi group as defined herein. Exemplary arylalkyl groups include benzyl, phenylethyl, 4— hydroxybenzyl, 3—fluorobenzy1, Z—fluorophenylethyl, and the like. This arylalkyl group can be substituted by one or more substituents R”, wherein R’ is as defined above; a cycloalkyl group denotes a non~aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be substituted by a group B, B being 0, S, SO, 802, N, or NR”, R” being as defined above; the cycloalkyl residue may be selected fiom the group consisting of —cyclo—C3H5, ~ cyclo-C4H7, —cyclonC5H9, -cyclo—C6H;1, -cyclo—C7H13, —cyclo—C3H15, morpholineyl, piperazinyl, and l-alkylpiperazine—4-yl. This cycloalkyl group can be substituted by one or more substituents R’, wherein R” is as defined above; Where used, the term cycloalky ” specifies a non-aromatic ring system comprising three to eight carbon atoms, preferably four to eight carbon atoms, more preferably five to seven carbon atoms, and most preferably six carbons atoms, i.e. a exyl ring. The carbocycloaikyl group comprises no heteroatoms in the ring. This carbocycloalkyl group can be substituted by one or more substituents R’, wherein R’ is as defined above; Where used, the term “heterocycloalkyl” specifies a cycloalkyl group as defined above, n one or more of the carbon atoms in the ring are substituted by O, S, 80, 802, N, or NR”, R” being as defined above. Preferred heterocyeloalkyl or heteroeyclyl are morpholine—4—yl, piperazinyl, and l—alkylpiperazine—4-yl. an alkoxy group denotes an O—alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a y, ethoxy, isopropoxy, r—butoxy or pentoxy group; an alkylthio group denotes a S—alkyl group, the alkyl group being as defined above; a haloaikyl group denotes a alkyl group as defined above substituted by one or more halogen atoms, preferably substituted by one to five halogen atoms, the kyl group is preferably a -C(R10)3, —CR1°(R1°’)2, w(:18"(R“”)R‘°”, 0)5,—CH2—C(R10)3, —C(R1°’)2—CH(R10’)2, -CH2- CR1°(R1°’)2, —CH2-CR‘0(R10’)R1°”, —C3(R‘0)7, or —C2H4-C(R10)3,Wherein R10, Rm’, R10” represent F, Cl, Br or 1, preferably F; more preferably, haloalkyl is CF3; a haloaryl group denotes a aryl group as defined above substituted by one or more halogen atoms, preferably substituted by one to five halogen atoms; a ylalkyl group denotes a linear or branched C1-C5—alky] substituted with at least one haloaryl group as defined herein; a hydroxyalkyl group denotes a HO~alkyl group, the alkyl group being as defined above; a haloalkoxy group denotes an alkoxy group as defined above substituted by one or more halogen atoms, preferably substituted by one to five halogen atoms, the haloalkoxy group is preferably a -ocatmh, —OCRIG(RIG’)2, —OCR1°(R1°’)R1°”, —OC2(R]0)5, bong—C(Rwh, - OCHZ—cnloai‘o’b, —OCH2—CR1°(R1°’)R‘0”, -OC3(R10)7 or —OC2H4~C(RIG)3, wherein R1”, R10, R10” represent F, Cl, Br or 1, preferably F; a yalkylamino group s a kylh—N— group or HO—alkyl-NH— group, the alkyl group being as defined above; an alkylalnino group s a HNnalkyl or N—dialkyl group, the alkyl group being as defined above; a halo or halogen group denotes fluorine, chlorine, bromine, or iodine; preferably chlorine or Compounds having infinite chains consisting for instance of repeating R’ and R” units and the like are not encompassed by this invention. Thus, the longest chain allowed in each side chain R1, Ar, Z and Y of the compounds according to the invention are three coupled substituents R’ and/or R”, e.g. R” substituted with R” r substituted with R’ or the like; This is to be understood such that oiigomeric or polymeric side chains sing more repeating R“ and/or R” ’ units as above outlined are not within the scope of the t ion.

Constituents which are optionally substituted as stated herein may be substituted, unless otherwise noted, at any chemically possible position.

In the embodiments of the present invention, Ar is preferably not ENMX which may be optionally substituted and wherein X is N or C and wherein q and r may independently be 0 or 1; furthermore, in the embodiments of the present invention Ar is preferably other than optionally substituted ycloalkyl, more preferably other than optionally substituted cyclobutyl. Thus, preferably, the aforementioned groups are excluded by disclaimer from the definition ofAr.

In the embodiments of the present invention, R” is ably not CONHR” and/or R” preferably not heteroaryl. Thus, ably, the aforementioned groups are excluded by disclaimer from the definition of Ar.

In preferred ments of the present invention, Z is selected from the group comprising halogen, -CR”O, —N(R”)2, -CN, ~C(S)R”, -N=C(R’)2, —COgR", —NR’C02R”, —CONHR”, -CON(R”)2, -COSR”, ~CSNHR”, ~CSN(R”)2, ~SOg—alkyl, ~SOg—haloalky1, ~802NHR”, —SOg(NR”)3, amino and —S()2R”; more preferably Z is selected from the group comprising en halogen, — C(O)heterocyclyl, —C(O)-R’—substituted arylalkyl, terocyclyi, -NH2, ~NI—ICO—C1_4alkyl, , —NHCO-C1_4haloalkyl, -NHCO—NHNH-CO—C1_4a1kyl, -NHCO-NHNEC1_4alkyl, - NH—COO-Cmalkyi, COOH, CONHz, CONHNHZ, —CN, -C(S)NI—I2, -C(S)NH-C1_4alkyl, - C(S)N(C1-4alkyl)2, ~N=C(~O-C14alkyl)—C1_4haloalkyl, mN2C(~O—C1-4alkyl)—C1,4alkyl, -C02-C1_ 4alky1, — -CONH—C1-4alkyl, -CONH—ary1alkyl, —CONH—cycloalkyl, -CON(C14alkyl)2, 14aikyl)—O—C1-4alkyl, and —COS~C1_4alkyi; more preferably Z is ed from the group sing halogen, -C(O)heterocyc1yl, terocyclyl, -NH2, ~NH—COO—C1_4alkyl, -CN, —C(S)NH2, -C(S)NH—Claalkyl, — C(S)N(C1_4alkyl)2, ~NflC(—O—C1-4alkyl)—C1«4haloalkyl, -N=C(-O-C1-4alkyl)-C1_4alkyl, —C02-C1_ 4alky1, , —CONH-C1_4alkyi, ~CONH—arylalkyl, -CONH—cycloalkyl, wCON(C1_4aikyl)2, -CON(C1.4alkyl)—O—C1-4alkyl, and —COS—C14alkyl; even more preferably Z is ed from the group comprising chlorine, bromine, - C(O)m01pholinyl, -C(O)—piperazinyl, —C(O)—(N~C1-4alkyl—piperazinyl), —C(O)—(N-arylalkyl— piperazinyl), -C(O)—pyrrolidinyi, —C(O)—isoxazolidinyl, ~NH2, wNH-COO-C;_4aiky1, ~CN, — C(S)NH2, —C(S)NH—C14alkyl, —N=C(—O—C14alkyl)-C14haloalkyl, iCOz-Cmalkyl, -CONH~C1, 4alkyl, ~CONH—(trifluoromethyl—substituted benzyl), -CONH_—C5W7cycloalkyl, —CON(C1_ 4alkyl)2, —CON(C1_4alkyl)—O—CHalkyl, and —COS—C1_4alkyl; even more preferably Z is selected from the group comprising hydrogen, chlorine, bromine, - —C(O)morpholinyl, —C(S)piperidinyl, ~C(O)—piperazinyi, —C(O)~(N-C1_4a1kyl-piperazinyl), — C(O)—(N-arylalkyi-piperazinyl), —C(O)—NH2, -C(O)—NHNH2, —COOH, ~C(O)—pyrrolidinyl, - C(O)-isoxazolidinyl, ~NH2, O—C1,4alkyl, -CN, «C(S)NH2, —C(S)NH-C14alkyl, —NEC(— O—C;,4alky1)-C1_4haloalkyl, —C02-C1.4alkyl, —CONH«C14alkyl, —CONH-R’—substituted benzyi, —CONH—(trifluoromethyl-substituted benzyl), —CONH-C5_7cycloa1kyl, ~CON(C;,4alkyl)2, 1-4alkyl)-O—C1w4alkyl, and 1_4alkyl, —NHCO~trifluoromethyl, —NHCO—methyl, — NHCOH, -NHCO—NHNH-CO—methyl, ~NHCO—NHNnisoprepyl; even more preferably Z is selected from the group comprising chlorine, bromine, — C(O)rn01pholinyl, “C(O)-piperazinyl, -C(O)—(N—C1-4alkylnpiperazinyl), —C(O)—(N—arylalkyl- zinyl), —C(O)—pyrrolidinyl, -C(O)—isoxazolidinyl, -NH2, —NH-COO-C1_4alky1, -CN, ~ C(S)NH2, —C(S)NH-C]_4alkyl, —N=C(~O—C1-4alkyl)—C1_4haloaiky1, —COg—C14alkyl, -CONH—C1_ 4alkyl, «CONH—(trifluoromethyl—substituted ), —CONH~C5-7cycloalkyl, ~CON(C1_ 4alkyl)2, -CON(C1-4alkyl)—O—C14alkyl, and —COS~C1_4all<y1; even more ably Z is selected fiom the group sing hydrogen, bromine, —C(O)- morpholin—4—yl, -C(S)—morpholin-4—yl, —C(O)—piperidin—4—y1, —COOH, —CONH2, —CONHNH2, H—CO—methyl, -CONH—(2,4,6-trimethoxypheny1)methyl, =isopropyl, ~NHCO-methyl , uNH—CO-trifluoromethyl, -NH-COH, —C(O)-(N~methyl~piperazinyl), —C(O)—(4- [chlorobenzylypiperazin-1—yl), -C(O)—pyrrolidinyl, ~C(O)-isoxazolidinyl, , -NH~COO- methyl, -CN, —C(S)NH2, —C(S)NH—methyl, —N=C(—O—methyl)—t1ifluoromethyl, -COg—C1-3alkyl, "CONH—rnethyl, ~CONH-(t1ifluorornethyl-substituted benzyl), —CONH—cyclohexyl, -CON(1nethyl)2, ethyl)—O—methyl, and -COS—methyl; even more ably Z is selected from the group comprising bromine, morpholin—4w yl, —C(O)-(N-methyl-piperazin—4—yl), -C(O)—(4-[chlorobenzyl]—piperazin—l-yl), -C(O)— pyrrolidinyl, —C(O)-isoxazolidinyl, -NH2, ~NH—COO—methy1, -CN, -C(S)NH2, ~C(S)NH- methyl, ~N=C(—O—methyl)—trifluoromethyl, ~COg—C;.3alkyl, ~CONl-l—methyl, -CONH— (trifluoromethyl-substituted benzyl), -CONH—cyclohexyl, ~CON(methyl)2, -CON(methyl)—O~ methyl, and —COS~methyl; yet even more preferably Z is selected from the group comprising bromine, —C(O)- isoxazolidinyl, ~N=C(—O—methyl)~trifluoromethyl, ~C02-methyl, Cog—ethyl, —C02—isopropyl, —CONH—methyl, —CON(methyl)2, —CON(methyl)—O—methy1, and —COS~methyl; . most preferably Z is selected from the group comprising bromine, —COz—methyl, ~COg—ethy1, COg—isopropyl, and COS—methyl.

In preferred embodiments ofthe present invention, R1 is selected from the group comprising aryl which is optionally substituted by one or more substituents R’, heteroaryl which is optionally substituted by one or more substituents R’, cycloalkyl which is optionally substituted by one or more substituents R”, and ky1 optionally tuted by a group selected from the group comprising trifluoromethyl, hydroxyl, methoxy, tetrahydropyranyl, morpholinyl, pyridyl , pyridinyl, fluorophenyl and tetrahydrofuranyl; in other preferred embodiments of the present invention, R1 is selected from the group comprising aryl which is ally substituted by one or more substituents R”, aryl which is optionally substituted by one or more substituents R’, cycloalkyl which is optionally tuted by one or more substituents R”, and Cl_4alky1 optionally substituted by a group selected fiom the group comprising trifluoromethyl, methoxy, ydropyranyl, morpholinyl, pyridyl and tetrahydrofuranyl; more preferably R1 is selected from the group comprising phenyl which is optionally substituted by one or more substituents R’, pyridyl which is optionally substituted by one or IO more substituents R’, pyrimidyl which is optionally substituted by one or more substituents R”, thienyi which is optionally substituted by one or more tuents R”, thiazolyl which is optionally tuted by one or more tuents R’, l,1—dioxo—tetrabydrothienyl, 2,2,2- trifluoroethyl, isopropyl, isobutyl, 2—piperidin—4—ylethyl, 2-hydroxyethyl, 2—methoxyethyl, tetrahydropyran—4—ylmethyl, 2~morpholinoethy1, pyridin—Z-ylmethyl, 2—fluorophenylrnethyl, 6—ethoxypy1imidin-4‘ylrn ethyl and tetrahydrofuran—2—ylmethyl; more preferably R1 is selected from the group comprising phenyl which is optionally substitirted by one or more substituents R’, pyridyl which is optionally substituted by one or more substituents R’, pyrimidyl which is optionally substituted by one or more substituents R’, l which is ally substituted by one or more substituents R”, 1,1-dioxo- tetrahydrothienyl, 2,2,2—trifluoroethyl, pyl, isobutyl, 2—metboxyethyl, tetrahydropyran- 4—ylrnethyl, 2-morpholinoethyl, pyridin—Z—ylrnethyl and ydrofuran—Z—ylmethyl; even more preferably R1 is selected from the group comprising phenyl which is optionally substituted by one or more substituents individually selected from trifluoromethyl, fluorine, chlorine, bromine, iodine, nitro, NHZ, —CN, —NHCO—C1.4—alky1, methoxy, CH—alkyl, —SO;NH2, or ~802NH—C1_4—alkyl; pyridyl which is optionally substituted by one or more of the aforementioned substituents for phenyl; pyrilnidyl which is optionally substituted by one or more of the aforementioned substituents for phenyl; l which is optionally substituted by one substituent—COO—CI-4alky1; thiazolyl which is optionally substituted by one substituent selected from 1_4alkyl or fluorophenyl; l,l~dioxo—tetrahydrothienyl, 2,2,2— trifluoroethyl, isopropyl, isobutyl, ridin—4—ylethyl, 2-hydroxyethy1, 2—methoxyethyl, tetrahydropyran—4—ylmethyl, 2—morpholinoethyl, pyridin—Z—ylrnethyl, 2~fluoropheny1rnethyl, 6-ethoxypyrimidin-4—ylmethyl and tetrahydrofuranQ—ylmethyl; even more preferably R1 is selected from the group comprising phenyl which is optionally substituted by one or more substituents individually selected from trifluoromethyl, fluorine, chlorine, e, nitro, NHg, -CN, -NHCO—C1_4-all<yl, y, C1_4—alkyl, ~802NH2, or — SOzNH—CM—alkyl; pyridyl which is optionally substituted by one or more of the aforementioned substituents for phenyl; pyrimidyl which is optionally substituted by one or more of the aforementioned substituents for phenyl; thienyl which is optionally substituted by one substituent—COO—Claalkyl; l,1—dioxo-tetrahydrothienyl, 2,2,2wtrifluoroethyl, isopropyl, isobutyl, 2—methcxyethyl, tetrahydropyran—4—ylmethyl, Zamorpholinoethyl, pyridin—Z—ylmethyl and tetrahydrofiiran—Z-ylmethyl; yet even more preferably R1 is selected from the group comprising phenyl which is ally substituted by one or more substituents individually selected from romethyi, fluorine, chlorine, bromine, iodine, nitro, NHQ, ~CN, —NHCO—C1_4—alkyl, y, C1_4—alkyl, -SO;NH2, or —SOzNH~C1_4-alkyl; pyrimidyl which is optionally substituted by one or more substituents selected from , methoxy or romethyl; thienyl substituted by one tuentm COO-methyl, thiazoiyl which is ally substituted by one substituent selected from— COO-ethyl or 4—fluorophenyl, l,1—dioxo—tetrahydrothienyl, 2,2,2—trifluoroethyl, isoprcpyl, isobutyl, 2-piperidin—4—ylethyl, 2—hydroxyethyl, 2-methoxyethyl, tetrahydropyran—4—ylmethyl, h01inoethyl, pyridin—Z—ylmethyl, 2-fluorophenylmethyl, 6—ethoxypyrirnidinnét-ylmethyl and tetrahydrofuran~2-ylmethyl; l,1-dioxo—tetrahydrothienyl, 2,2,2—trifluoroethyl, pyl, isobutyl, 2-methoxyethyl, tetrahydropyran—4—ylmethyl, 2—morpholinoethyl, pyfidin—Z—yimethyi and tetrahydrofiiran-2—y1methyl; yet even more preferably R] is selected from the group comprising phenyl which is optionally tuted by one or more substituents individually selected from fluorine, chlorine, bromine, nitro, NHZ, —CN, —NHCO~C;_4—alkyl, methoxy, tubutyl, 2, or —SOgNH—isopropyl; pyridyl; pyrimidyl which is optionally substituted by one or more substituents selected from methyl or trifluoremethyl; thienyl which is optionally substituted by one substituenthOOw methyl, l,l—dioxo—tetrahydrothienyl, 2,2,2utrifluereethy1, isopropyl, isobutyl, 2—methoxyethyl, tetrahydropyran—tlwylmethyl, 2—morpholinoethyl, pyridin—Zrylrnethyl and tetrahydrofuran-Z- ylmethyl; yet even more preferably R1 is selected from the group comprising phenyl, 2~fluoropheny1, 2— methoxyphenyl, Z-clflorophenyl, 2~bromophenyL 2—iodophenyl, 2—nitrophenyl, 2n eyamphenyl, Z—aminophenyl, 4—triflu0romethoxyphenyl, 4—methylsulfonylphenyl, 4— chlorophenyl, 4-flu0rophenyl, 4~tertbutylphenyL 4—nitrophenyl, 4—cyanophenyl, 3— trifluoromethylphenyl, 3-fluorophenyl, rophenyl, 3—cyanophenyl, 4—acetamidovphenyl, amid0—phenyl, Z—acetamido—phenyl, 3 —aminosu1fonyl-phenyl, 3- (isopropylamino)sulf0nyl—pheny1, 3-nitrophenyl, 3—aminophenyl, 2,4—difluorophenyl, 2,4- diehlorophenyl, 2,6—dichlorophenyl, 2,3-dichlor0phenyl, 3-chloro-S-trifluoromethylphenyl, fluorophenyl, 3,5—dichlorophenyl, 2,3,5,6—tetrafluorophenyl, 2—pyridyl; 3-pyridy1; 4- pyridyl; 4—trifluoromethyl—pyrimid—Z—yl, xy1-py1imid—4—yl, 2,6-dimethyl—pyrimid-4—yl, 2—methoxycarbonyl-thien—3—yl, xyearbonyl—thiazol—Z-yl, 4~(4—fluorophenyl)thiazol—2—yl, 1,]~dioxo~tetrahydrothienyl, 2,2,2—trifluoroethyl, isopropyl, isobutyl, 2—piperidin—4—ylethyl, 2- hydroxyethyl, 2—methoxyethy1, tetrahydropyranylmethyl, 2-morpholinoethyl, pyridin—Z— ylmethyl, 2—flu0ropheny1methyl, 6—ethoxypyrimidin-éluylmethyl and tetrahydrefiiran—Z— ylrnethyl; 1,l—diox0—tetrahydrothienyl, 2,2,2—trifluoroethyl, iSOpropyl, isobutyl, 2— methoxyethyl, tetrahydropyran—4—ylmethyl, 2—m0rpholinoethyl, pyridin-Z—ylmethyl and ydrofilran—Z—ylmethylg yet even more ably R1 is selected from the group comprising phenyl, Z—fluorophenyl, 2— methoxyphenyl, r0phenyl, 2-br0m0pheny1, 2—nitrophenyl, 2—aminophenyl, 4— fluorophenyl, 4-tertbutylphenyl, 3—fluorophenyl, 3—chlorophenyl, 3—cyan0phenyl, 3- acetamido—phenyl, Z-aeetamido—phenyl, 3—aminosulfonyl—phenyl, 3—(isopropylamin0)sulfonyl~ phenyl, 3-nitr0phenyl, 3—arninophenyl, 2,4—difluorophenyl, 3,5—difluorophenyl, 3,5- dichlorophenyl, 2,3,5,6—tetrafluorophenyl, 2—pyridyl; 3—pyridyl; 4—pyrldyl; 4— trifluoromethyl— pyrimid—Zuyl, 2,6—dimetbyl—pyrimid-4~yl, 0xycarbor1yl—thien—3-yl, 1 ,1 —dioxo- tetrahydrothienyl, 2,2,2—triflueroethyl, pyl, isobutyl, 2—methoxyethyl, tetrahydropyram 4-yl—methyl, 2—(morpholin—4—yl)—ethyl, and tetrahydrofuran—Z—yl—methyl; yet even more preferably R1 is selected from the group comprising phenyl, opheny1, 2- chlorophenyl, 0xyphenyl, 2—nitrophenyl, Z—aminophenyl, 4-fluorophenyl, 3- henyl, 3—ch10r0phenyl, 3—cyanophenyl, 3—acetamido-phenyl, 3-nitrophenyl, 3— aminophenyl, 3,5-difluorephenyl, 3,5—dichlorophenyl, 2-pyridyl; 3~pyridyl; 4—pyridyl; 2— methexycarbonyl—thiend —yl, 2,2,2—trifluoroethyl, isobutyl, and tetrahydrofiiran—E—yl—methyl; WO 01261 yet even more preferably R1 is selected from the group sing , 2-fluorophenyl, 2— yphenyl, 2—nitrophenyl, 2—aminophenyl, 4-fluorophenyl, 3—fluorophenyl, 3- chlorophenyl, 3mcyanophenyl, 3-acetamido—phenyl, 3—nitrophenyl, 3-arninophenyl, 3,5- difluorophenyl, 3,5-dichlorophenyl, 2~pyridyl; 3—pyn'dyl; 4—pyridyl; 2—methoxycarbonyl— thien—3—yl, 2,2,2—trifluoroethyl, isobutyl, and tetrahydrofuran—2~y1—Inethyl.

In preferred embodiments of the t invention, Ar is selected from the group comprising phenyl and pyridyl, which can be tuted by one or more substituents R’; more preferably Ar is selected from the group comprising phenyl and pyridyl, which can be substituted by one or more substituents independently selected from fluorine, y or chlorine; more preferably Ar is selected from the group comprising phenyl and pyIidyl, which can be substituted by one or more substituents independently selected from fluorine or chlorine; also more preferably AI is selected from the group comprising phenyl, 2,6—difluorophenyl, 2— ~6~fluorophenyh 2—chlorou6mmethoxypheny1, Z—fluorophenyl, 3—fluorophenyl, 2— chlorOphenyl, 4-chloropheny1, 4—1nethoxyphenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,4—dichloropheny1, 3-fluoropyridiny1, 3,5—dichloropyridin—4—yl and 3—chloro—5~ fluoropyridin-4—yl; even more preferably Ar is selected from the group comprising , 2,6-difluorophenyl, 2- —6—fluoropheny1, 2-chloro—6-methoxypheny1, 2—fluorophenyl, 2—chlorophenyl, 2,6— dichlorophenyl, 2,4-dichlorophenyl, 3—fluoropyridin—4—yl, 3,5—dichIoropyridin—4—yl and 3* chloro—S—fluoropyridin—Arnyl; even more preferably Ar is selected from the group comprising phenyl, 2—chloro—6— fluorophenyl, 2-fluorophenyl, Zuchlorophenyl, 2,6—dichlorophenyl, chlorophenyl, 3— fluoropyridin—4—yl, 3,5—dichloropyridin—4—yl and 3—chloro~5—fluoropyridin—4~yl.

In preferred embodiments of the present invention, Y is selected from the group comprising H, haloalkyl, and alkylester, which can be substituted by one or more substituents R”; more preferably Y is selected from the group sing H, and kyl which can be substituted by one or more substituents R", more preferably Y is selected from the group comprising H, pentafluoroethyl, trifluoromethyl and methoxycarbonyl; even more preferably Y is ed from the group comprising H, trifluoromethyl and methoxycarbonyi.

In red embodiments of the present invention, R’ is ndently selected from the group comprising H, methyl, ethyl, propyl, butyl, isopropyl, tert—butyl, morpholinyl, piperazinyl, cyclohexyl, pyrrolidinyl, CF3, F, Cl, Br, methoxy, tetrahydropyranyl, isoxazolidinyl, nitro, -NH2, acetamido, -SOzNH2, —SOgNHiPr and ethyl; more preferably R’ is independently selected from the group comprising H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, CF3, F, Cl, methoxy, tetrahydropyranyl, isoxazolidinyl, nitro, —NH2, and COO-methyl.

In preferred embodiments of the present invention, R” is independently ed from the group comprising H, trifluorornethyl, methoxy, NH;, and .

Particularly preferred compounds of the present invention are the compounds of the below examples of the present invention, more preferably the compounds of below examples 1, 3, 5, ,11,12, 14, 21, 28, 32, 42, 43, 48, 50, 62, 63, 65, 68, 84, 89, 90, 95,109, 110, 112, 118, 126, 128, 130, 132, 136, 137, 140, 145, B-3, 136, 139, B—11,B—12,B—13, 13—31, Bu32, B-37, B—38, B—41, B~45, B—47, B—61, B—62, B-64, B—67, B—68, 1369, 3—70, 13-71, B—75, B—76, B-77, B-78, B-82, B—84, B~89, B—90, B—92, 13-95, B—96, and B—98, most preferably the compounds ofbelow examples 1, 3, 5, 11, 42, 50, 84, 95, 109, 126, 128, 130, 132, 140, 145, B-6, B~31, 13—32, B-37, B-38, B—41, 13-45, B-61, 13-68,]3-71, 13—75, and B—84.

It is apparent that the aforementioned preferred embodiments regarding the residues X, Y, Ar, R1, R” and R” may be combined to yield further more red ments. Some examples of such combinations are, Without limiting the invention to these particular combinations: A compound according to the present invention, wherein R1 is selected from the group comprising phenyl which is ally substituted by one or more tuents individually selected from trifluoromethyl, fluorine, chlorine, bromine, nitro, NHQ, -CN, -NHCO—C1alkyl, methoxy, CM-alkyl, « SOzNHz, or -SOgNH-C14~alkyl; pyridyl which is optionally substituted by one or more of the aforementioned substituents for phenyl; pyrimidyl which is optionally substituted by One or more of the aforementioned substituents for phenyl; thienyl which is optionally substituted by one substituent—COO—Cl- 4alkyl; l,1—dioxo-tetrahydrotliienyl, 2,2,2—trifluoroethyl, isopropyl, isobutyl, 2- methoxyethyl, tetrahydropyran—4—ylmethyl, 2—morpholin0ethyl, pyridin-2~ ylmethyl and tetrahydrofiiran-2—ylmethyl; Ar is selected from the group comprising phenyl and pyridyl, which can be substituted by one or more tuents independently selected from fluorine or chlorine; z is selected from the group comprising halogen, —C(O)heterocyclyl, terocyclyl, —NH2, -NH—COO—C;,4alkyl, -CN, -C(S)NH2, -C(S)NH—C1- 4alkyl, —C(S)N(C14alkyl)2, -NmC(—O—C1-4alkyl)—C;.4haloalkyl, —N:C(-O—C1_ )—Clsalky1, «COg—Cmalkyl, — —CON'H-C1_4alkyl, —CONI-lrarylalkyl, -CONH—cycloalkyl, ~CON(C14alkyl)2, —CON(C1-4alkyl)-O—C1,4alkyl, and — COS—CMalkyl; Y is selected from the group sing H, trifluoromethyl and methoxycarbonyl.

A compound ing to the present invention, wherein R1 is selected from the group sing phenyl which is optionally substituted by one or more substituents individually selected from e, chlorine, e, nitro, NHz, ~CN, ~NHCO—C1_4—alkyl, methoxy, t-butyl, -SOZNH2, or -SOzNH-— isopropyl; pyridyl; pyrimidyl which is optionally substituted by one or more substituents selected from methyl or trifluoromethyl; thienyl which is 27 2012/051357 ally substituted by one substimenthOO—methyl, 1,1—dioxo- tetrahydrothienyl, trifluoroethy1, isopropyl, isobutyl, 2—methoxyethyl, tetrahydropyran—4-ylmethyl, 2-morpholinoethy1, pyridin—Z—ylrnethyl and tetrahydrofuran-Z-ylmethyl; Ar is selected from the group comprising , 2,6—difluorophenyl, 2—chloro fluorophenyl, 2-chloro—6—methoxyphenyl, ophenyl, 2-chlorophenyl, 2,6- dichlorophenyl, 2,4-dichlorophenyl, 3—fluoropyridin—4—yl, 3,5—dichloropyridin— 4—y1 and 3,5—difluoropyridinyl; is selected from the group comprising chlorine, bromine, norpholiny1, — iperazinyl, —C(O)~(N-C1-4alkyl—piperazinyl), ~C(O)-(N-ary1alky1- piperazinyl), -C(O)-pyrrolidiny1, -C(0)—isoxazolidinyl, ~NH2, -NH-COO—Cll 4alky1, —CN, H2, —C(S)NH—C14alkyl, —N=C(—O—C1-4alky1)—Cl_4haloalkyl, —COz—C1_4alky1, —CONH-Cg4alkyl, -CONI-I—(trifluorornethyl—substituted benzyl), —CONH-C5x,-cycloalkyl, —CON(C1-4alkyl)2, -CON(C1_4a1kyl)-O—C1_ 4alkyi, and —COS-C1_4alky1; is selected from the group comprising H, trifluoromethy} and methoxycarbonyi.

A compound according to the present invention, wherein R1 is selected from the group comprising phenyl, 2~fluoropheny1, 2— methoxyphenyl, rophenyl, 2-hromophenyl, 2—nitrophenyl, 2— aminophenyl, 4—fluorophenyl, 4-tertbutylphenyl, 3—fiuorophenyl, 3- chlorophenyl, 3-cyanophenyl, 3-acetamido—phenyl, 2—acetamido—pheny1, 3- aminosulfonyl—phenyl, 3—(isopropylamino)sulfonyl—phenyl, 3—nitrophenyl, 3- aminophenyl, 2,4-difluoropheny1, 3,5-difluorophenyl, 3,5-dichloropheny1, 2,3,5,6—tetrafluorophenyl, 2—pyridyl; 3—pyridyl; 4—pyridyl; 4— trifluoromethyl— pyrimid—Z-yl, 2,6wdimethyI—pyrimid—4—y1, 2—methoxycarbonyl—thien-3—yl, 1,}— dioxo-tetrahydrothienyl, 2,2,2-trifluoroathy1, pyl, isobutyl, 2- methoxyethyl, tetrahydropyran~4~yl~1nethy1, 2—(morpholin—4—yl)—ethyl, and tetrahydrofilran-Z—yl—rnethyl; Ar is selected from the group comprising phenyl, 2—chloro—6-fiuor0phenyl, 2- fluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4—dichlorophenyl, 3- fluoropyridin-4—yl, 3,5—dichloropyridin—4~yl and 3,5«difluoropyridin—4—yl; Z is selected from the group comprising bromine, -C(O)—morpholin-4—yl, «C(O)— (N-methyl—piperazin—4—yl), —C(O)-(4—[chlorobenzyl]~piperazin—1—yl), —C(O)— pyrrolidinyl, -C(O)—isoxazolidinyl, —NH2, —NH—COO—methyl, —CN, —C(S)NH2, — C(S)NH—methyl, -NWC(—O~methyl)—trifluoromethyl, -COg-C1_3alkyl, —CONH— methyl, —CONH—(trifluoromethyl—substituted benzyl), —CONH—cyclohexyl, ~CON(methyl)2, ~CON(methyl)-O—methyl, and —COS-methyl; Y is selected from the group comprising H, trifluoromethyl and methoxycarbonyl.

According to 's knowledge the compounds of the invention as well as their salts may contain, e. g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula (I) as well as all solvates and in particular all hydrates of the salts of the compounds of formula (I).

As used herein the terms disease, tion and medical condition are used interchangeably.

The present invention further relates to a method of treatment for a disease or a therapeutic indication in which the inhibition of interleukin-17 (IL—17) and/or Interferon—y (INF-y) is beneficial, or for a e or indication selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s e, toid arthritis, vitiligo, Crohn’s disease, ulcerative s, inflammatory bowel disease, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet e, atopic dermatitis, Lichen planus, Sj'ogren’s me, spinal disc herniatiou, acne, Graftmversus~Host-Reaction, Host —Versus—Grafl—Reaction and osteoarthritis, wherein the method ses administering to a t in need f an effective amount of a nd of formula (I). Analogously, the present invention further relates to methods as the one described above, which encompass the further embodiments described herein, in particular the preferred compounds, medical uses and compounds for use in medical treatments as described herein.

The present invention further relates to pharmaceutical compositions, kits and kits-of parts comprising the compounds according to the present invention.

The present invention r relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions which are employed for the treatment and/or prOphylaXis of the diseases, disorders, illnesses and/or conditions as mentioned herein.

The present invention further relates to the methods and medical uses bed herein, encompassing the pharmaceutical compositions as described herein.

The pharmaceutical compositions as described herein comprise one or more of the compounds according to this invention and a phannaceutically acceptable r or diluent. onally, the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging al, n the pharmaceutical agent is therapeutically effective against the medical conditions as described herein, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating said medical conditions, and wherein said ceutical agent comprises one or more compounds of formula (1) according to the invention. The packaging material, label and package insert otherwise parallel or resemble what is generally ed as standard ing material, labels and package inserts for pharmaceuticals having related utilities.

The pharmaceutical compositions according to this ion are prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, sions, gels or solutions, the active compound content advantageously being n 0.1 and 95% and where, by the riate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles, excipients, ts, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations compositions on account of his/her expert knowledge. in on to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, vatives, solubilizers, colorants, complexing agents or permeation promoters, can be used.

Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are ly stered to treat or prevent that disease, may ally be coadministered with the nds according to the present invention. As used herein, additional therapeutic agents that are normally administered to treat or t a particular disease are known as appropriate for the disease being treated.

In a further aspect of the present ion, the compounds according to this invention or the salts of said compounds of formula (I), may be combined with standard therapeutic agents which are commonly used for the treatment ofthe medical ions as described herein.

The person skilled in the art is aware on the base of his/her expert knowledge of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered.

Said total daily (s) can vary within a wide range. In practicing the present invention and ing on the details, characteristics or purposes of their uses mentioned above, the nds according to the present invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (eg. as combined unit dosage forms, as separate unit dosage forms or a adjacent discrete unit dosage forms, as fixed or nonfixed combinations, as kit~of~parts or as admixtures) with one or more standard therapeutics, in particular art—known chemotherapeutic or target specific ancer agents, such as those mentioned above.

Thus, a further aspect of the present invention is a combination or pharmaceutical composition comprising a first active ingredient, which is a compound according to this invention or a salt thereof, a second active ingredient, which is an artuknown standard therapeutic for the medical conditions as described herein, and optionally a pharmacologically acceptable carrier, diluent and/or ent for tial, separate, simultaneous or chronologically red use in therapy in any order, e.g. to treat, prevent or ameliorate in a patient the medical conditions as described herein.

In this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art—known standard therapeutic for the l conditions as described herein, for separate, sequential, simultaneous or chronologically staggered use in therapy, such as e.g. in therapy of those diseases mentioned herein.

The term “combination” according to this ion may be present as a fixed combination, a non—fixed combination or a kit—of—parts. A “fixed combination” is defined as a combination wherein the said first active ingredient and the said second active ingredient are present er in one unit dosage or in a single entity. One example of a “fixed combination” is a pharmaceutical composition wherein the said first active ient and the said second active ingredient are t in admixture for simultaneous administration, such as in a formulation.

Another example of a “fixed combination” is a pharmaceutical combination n the said first active ingredient and the said second active ingredient are present in one unit Without being in admixture.

A “‘kit—of-parts” is defined as a combination wherein the said first active ient and the said second active ingredient are present in more than one unit. One example of a f— parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the kit—of—parts may be administered separately, sequentially, simultaneously or chronologically staggered.

The first and second active ingredient of a combination or kit—oprarts according to this invention may be provided as separate formulations (i.e. independently of one r), which are uently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in ation therapy.

The type of pharmaceutical ation of the first and second active ingredient of a combination or kit—ofparts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is ated for e. g. intravenous administration.

The amounts of the first and second active ingredients of the ations, itions or kits according to this ion may together comprise a therapeutically effective amount for the ent, prophylaxis or amelioration of a medical condition as described herein A further aspect of the t ion is a method for treating apeutically the l conditions as described herein, in a patient in need of such treatment comprising administering separately, sequentialiy, simultaneously, fixed or non—fixed a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention and a pharmacologically active and therapeutically effective and tolerable amount of one or more art-known therapeutic agents for the medical conditions as described herein, to said patient.

For the production of the pharmaceutical compositions, the compounds of the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. le pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions. The pharmaceutical compositions according to the invention are ed by processes known per se.

The dosage of the active compounds is carried out in the customary order of magnitude.

Topical application forms (such as ointments) thus contain the active compounds in a concentration of, for example, (11-99%. The customary dose in the case of systemic y (p.o.) is usuatly between 0.3 and 30 rug/kg per day, (i. v.) is usually between 0.3 and 30 mg/kg/h. The choice of the optimal dosage regime and duration of medication, particularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the art on the basis of his/her expert knowledge.

A method for synthesis of the compounds of the formula (1) ses the step of reacting nitriloxyde with an acetoacetate, haloalkene or methylcrotonate to obtain a methyl—isooxazole derivative (Hanson JC etal. J Chem Soc 1965, 979, Lasri J et. al. I Heterocyclic Chem, 8, 1385-1389). Nitriloxydes are obtained from aldehydes by the reaction of hydroxylamine (II) to obtain oximes (Cheng FK er. al. Bioorg Med Chem Lett 2006, I6, 3376. Oximes are reacting with n-Chlorsuccinimide to obtain the corresponding chlorooxime (III) (Balachandran S et. a1. Bioorg Med Chen Lett. 19, 2009, 4773-4776).

Scheme (1) F c: -> F CI F c: \ \ \. o N-OH CE N—OH I II III The chlorooxime (III) is used in situ to form the nitriloxyde (IV) and a cycloaddition to the appropriate dipolarophile yields the appropriate 3~phenyl—5-methylisoxazole (VI).

Scheme (2) F Cl F m—p + <1 \ ll Cl NWOH F3 IV V VI The isooxazole product (VI) can be converted with Bredereck’s reagent (VII) in refluxing toluene to the appropriate enamine (VIII) (Bredereck H et. al. Chem Ber 101, 1968, 41-50).

This enamine nd (VIII) is treated with an acid anhydride or an appropriate activated acid (IX) to the key intermediate phenyl—dimethylaminowtrifluoro—oxobuteneyl—isoxazol (X).

This ediate is heated with a substituted hydrazine (XI) to obtain the pyrazo] as final product (here nd 3).

This method leads to the 4—phenyl~5—trifluorornethyl-lH—pyrazolyi isomer, this is as described in Scheme (3) the pyrazol with the phenyl group adjacent to the trifluoromethyl group.

WO 01261 Scheme (3) COQME F GE + L: o IV V Compound 3 The class of compounds of the t invention is useful for the deveIOpment of moduiatory and anti—inflammatory medicaments or, more generally, for the treatment of diseases where the inhibition of interleukin—17 (IL—17) and/or Interferon—y (INFny) is beneficial.

The compounds of the present invention are also useful for the ent of diseases which are related to or mediated by inflammatory cytokines, such as psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, Vitiligo, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, ankyiosing spondylitis, diabetes type 1, le sclerosis, oeliac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjogren’s syndrome, spinal disc herniation, acne,Graft~ versus~H05t~Reacti0n, Host s—Graft-Reaction and osteoarthritis Examples The following compounds were purchased: I. toxy—bis(dimethylamino)methan (Apollo Scientific Ltd, UK) 2. Methyl 3-(2—chlor0—6—fluorophenyi)—5-methy1isoxazole—4—carboxylate (Apollo ific Ltd, UK) 3. 3—(2—chloro-é—fluorophenyl)—5—methylisoxazole—4~carbonitrile (Fisher ific GmbH, UK) Methylamin hydrochloride (Sigma Aldrich Chemie GmbH, Germany) 2—chloro~6-fluorobenzaldehyde oxime (Fisher Scientific Gmbl-I, UK) N—Chlorosuccinimide, NCS (Acros Organics BVBA, Belgium) 953- Ethyl acetoacetate, Methyl acetoacetate (Sigma Aldrich Chemie Gth, Germany) Trifluoroacetic anhydride (Sigma Aldrich Chemie Gth, Germany) 2-(1H—Benzot1iazoie-l—yl)—1 ,1 ,3 ramethyluronium hexafluorophosphate, HBTU (Iris Biotech GmbH, Germany) . Hydroxybenzotriazole, HOBT (Sigma Aldrich Chemie GmbH, Germany) 1 l . Methyl 3 —(2—chloro—6nfluorophenyl)—5—[2~(dimethylamino)— 1 —(2—ethoxy—2— oxoacetyl)viny}]—4—isoxazolecarborylate (Key cs Ltd, UK) 12. 1m(3—dimethylaminopropyl)—3nethylcarbodiimide hydrochloride, EDC (Sigma Aldrich Chemie GmbH, Germany) 13. Hydrazines (ABCR GmbH & Co. KG, Germany) 14. Solvents generally (Sigma Aldrich Chemie GmbH, Germany) . N,N—Diisopropy1ethylamine, DIPEA (ACROS Organics, Belgium) 16. Ammoniumchlorid p.a. (Sigma Aldrich Chemie GmbH, Germany) 17. 2,4—bis(4-methoxyphenyl)-1,3,2,4—dithiadiphosphetane 2,4~disulfide, Lawcsson's Reagent (Sigma Aldrich Chemie GmbH, Germany) 18. 1,2wDichloroethyl ethyl ether (ABCR GmbH & Co. KG, Germany) 19. Natriumazid (ACROS Organics, Belgium) . N,O—Dimethy1hydroxylamine (ChemPur GmbH, Germany) 21. Lithium ium hydride (Sigma Aldrich Chemie GmbH, Germany) 22. Tosylmethyl isocyanide, TosMIC (ACROS Organics, Belgium) Synthesis of compounds of a} 1) The compounds of a (I) were obtained through the synthetic route described in scheme (1). Methyl 3—(2-chloro—6«fluorophenyD—5—methylisoxazole-4—carboxylate was sed from Apollo Scientific Ltd, Whitefield Rd, Bredbury, Stockport, Cheshire, SK6 2QR.

Bredereck's reagent (tert-Butoxy—bis(dimethylamino)methane) was purchased from Apollo Scientific Ltd, Whitefield Rd, ry, Stockport, Cheshire, SK6 2QR. Trifluoroacetic ide was purchased from Acros Organics BVBA, Janssen Pharmaceuticalaan 3a, 2440 Geel, Belgium. 3—Chiorophenylhydrazine hydrochloride was purchased from Alfa Aesar, 26 Parlqidge Road, Ward Hill, MA 01835, USA.

Synthesis of benzaldoxime derivatives, exemplar-fly shown for 2-.chloro-6~ fluorobenzaldehyde oxime F F To a stirred mixture of 2—chloro—6—fluorobenzaldehyde (5 g, 31.5 mmol), ethanol (10 mL), ice and water (30 mL) and hydroxylamine hydrochloride (2.8 g, 40.3 mmol), an aqueous solution of NaOH (3.6 g, 90 mmol in 5 mL of water) was added. The mixture was stirred for an hour and ted with 40 mL of ether to remove impurities. The aqueous layer was lized with HCl and extracted with ether (2x50mL). Extracts were dried over N21280:} and evaporated to give 5.19 g of the aldoxime (yield 93%).

Synthesis of ethyl 3-(Z-chloro—6—fluorophenyl)—5~methylisoxazole~4-carboxylate F H oflfo H3"; F or OVCH3 0 o Ell ......____.. “all on our, HCI c: e10” NaIEtOH, 15:20 To a solution of (E)-2~chloro—6—iluorobenzaldehyde oxime (2 g) in 10 mL Dimethylformamide (DMF) at room temperature 0.23 g N—Chlorosuccinimide (NCS) were added. Dry hydrogen de was bubbled into the DMF solution until the reaction temperature rise up to 35°C. Then 1.21 g N—chloro—suceinimide were added in portions, the temperature was kept at 35 - 45°C. The reaction e was cooled to room temperature and poured into 30 mL ice and extracted with ether. Combined extracts were dried and evaporated to give 2.5 g of 2—chloro—6-fluoro—N—hydroxybenzirnidoyl de as a yellow oil.

A solution of ethyl sodium acetoacetate [from sodium (0.33 g), dry ethanol (10 mL) and ethyl acetoacetate (1.75 g)] was added slowly to a stirred solution of the hydr'oxamoyl chloride (2.5 g) in 20 mL ether at 0 - 3°C. The e was allowed to warm to room temperature ght, and the solvent was evaporated in vacuo. The residue was shaken with water and ether, ether extract was evaporated and the product was d by column chromatography (hexane) to give 2.2 g of ethyl 3«(2~chloro—6-fluorophenyl)—5-methylisoxazole—4—carboxylate as a colorless oil. Result of LC/MS : 283.95; ;H NMR (DMSO—d6; CCl4): 0.98- .1 .03 (3H, t, CH3), 2.77 (3H, s, CH3), 4.05-4.12 (2H, q, CH2), 7.39—7.67 (3H, m, CH—arom.) Synthesis of methyl 3-(2,6-dichlorophenyI)-S-methylisoxazolecarboxylate O 0 / \OH DlPEA Cl CI To a solution 01°01 g (0.4455 mmol) alpha-Chloro—2,6—dichlorobenzaldoxime in 5 mL methyl 3—oxobutanoate, 0.11 mL (1.5 eq) diisopropylethlamine were added. The mixture was stirred for 24 h then ethylacetate was removed in the vacuo. The residue was dried under high vacuo and the crude product was triturated in water until it became solid. The solid was d off and timber purified by recrystallization from a waterurnethanol mixture. The crystals were filtered off, washed with water and dried under reduced pressure to afford 248 mg (87%) of methyl 3—(2,6—dichlorophenyl)—5—methylisoxazole—4-carboxylate. Result of LC/MS [M+H]+: 286.12; 1H NMR (Db/180416; CCl4): 2.77 (3H, s, CH3—isooxazole), 3.28 (3H, s, CH3— methoxy), 7.54—7.65 (3H, m, ic) Starting from either unsubstituted benzaldehyde, 4—chlorobenzaldehyde, 2~ fluorobenzaldehyde, 2—chlorobenzaldehyde, 2,4«dichlorobenzaldehyde, 4— methoxybenzaldehyde, 3—fluorobenzaldehyde, 2,6-dichlorobenzaldehyde, 2,4— dichlorobenzaldehyde, 3«fluoroisonicotinaldehyde or 3,5-dichloroisonicotinaldehyde and using either methyl or ethyl 3—oxobutanoate, the aforementioned synthetic routes were used to synthesize all differently substituted methyl or ethyl 5-rnethylphenylisoxazole carboxylate building blocks required for the ation of the respective examples of this invention, eg: Ethyl 3-(2,4-dichlorophenyl)uS-methylisoxazoIe-ét-carboxylate, oil, yield 82% 1H NMR (DMSO-Dfi, C(34): 1.10 (3H, t, CH3), 2.74 (3H, s, CH3), 4.10 (2H,,q, CH2), 7.42 (1H, d, CH—arom.), 7.47 (1H dd, CH—arom) 7.59 (1H, d, CH— arcm.) Methyl 3-(4-methoxyphenyl)—5-methylisoxazole-4—carboxylate yield 65% 1H NMR(DCC13): 2.7] (3H, s, CH3), 3.79 (3H, s, OCH3), 3.85 (3H, s, OCH3), 6.97 (2H, AB- syst., CH-arom.), 7.60 (2H AB—syst., CH—arom.).

Synthesis of methyl 3-(2-chlorofluorcphenyl)—5-(2-(dimethylamine) vinyl)isoxazole ylate O l \O 0+ F O O F / toluene ,0 \ a ~—> / / NW 6 h reflux \ \ CI / Cl To a solution of 0.1 g (0.3708 mmol) methyl 3—(2~chloro~6ufluorophenyl)—5~methylisoxazole- 4-carboxylate in 10 mL dry toluene, was added 0.15 mL (0.7417 mmol) utoxy— methylamino)methane. The reaction mixture was heated under reflux for 6 h.

The mixture was concentrated in vacuo and was dried in high vacuum. Petroleum ether was added to the oily residue and crystalline product developed. The product was collected by filtration and 0.070 g (yield of theory: 58%) of clean product were obtained. Result of LC/MS [M+H]+: 325.0; 1H NMR dfi; CCl4): 3.02 (6H, s, N—CH3), 3.53 (3H, s, CH3), 5.54— .58 (1H, d, CH), 7.72—7.76 (1H, d, CH), 7.32—7.38 (1H, dd, CH—arom.), 7.44—7.47 (1H, d, CH—arom.), .58 (1H, d, m.) Synthesis of methyl 3-(2—ch10ro—6—fluorophenyl)(1—(dimethylamino)~4,4,4-trifluoro oxobnt—l-enyl)isoxazolecarboxylate O F (:10 F F ill 0 + dry DCM x \ \ F ' \ O O 3 h N'0 F To a solution of 0.5 g (1.5397 mmol) methyl 3-(2~chloro—6-fluoropheny1)—5—[2— (dimethylamino) Vinyl]isoxazole—4—carboxylate in 20 mL dry dichloromethane, was added dropwise under th cooling 0.32 mL (2.309 mmol) uifluoroacetic anhydride. The reaction mixture was stirred for 3 h at room temperature. Afterwards the mixture was trated in vacuo and was dried in the high vacuum. The 0in residue crystallized with eum ether and the product was collected by filtration to obtain 0.604 g (yield of theory: 94%) of clean t. Result of LC/MS [M+H]+: 420.9; 1H NMR (DMSO— d6; C014): 2.63 (3H, s, N—CH3), 3.40 (3H, s, N—CH3), 3,59 (3H, s, CH3), 7.40—7.46 (1H, dd, (TH—atom), 7.51» 7.55 (1H, d, CH—arom.), .66 (1H, d, CH-arom.), 8.12 (1H, s, CH).

Synthesis of methyl 3-(2-chlorofluorophenyl)(1~(3—chlorophenyI) (trifluoromethyl)—1H—pyrazol—4-yl)isoxazolecarboxylate (example 11) dry ethanoi + Q + /L J\ N —-—M--|- Cl N’NH2 K 2h reflux To a solution of 0.5047 g (1.1994 mmol) methyl 3—(2~chloro—d—fluorophenyl)—5—(1- (dimethylamino)—4,4,4—trifluoro—3~oxobut—1—en—2-yl)isoxazole—4-carboxylate in dry ethanol, were added 0.1790 g (0.9995 mmol) 3~Chlorophenylhydrazine and 0.17 mL (0.9995 mmol) N,N-Diisopropylethylamine (DIPEA). The reaction mixture was heated under reflux for 2 h.

The product was isolated by using column chromatography (Petroleum ether:Diethyl ether 80:20) and 0.305 g (yield of theory: 61%) of clean product (example 11) was obtained. Result of LC/MS [M+H]+: 499.8; 1H NMR (DMSO— d6; CC14): 3.66 (3H, s, CH3), 7.45—7.50 (1H, dd, CH-arorn.), 7.55—7.58 (1H, d, CH—arom.), 7.65—7.77 (1H, d, CH—arom.), 7.65—7.77 (1H, dd, CH-arom. phenylhydrazine), 7.65-7.77 (1H, d, CH—arom. phenylhydrazine), 7.85 (1H, s, CH— arorn phenylhydrazine), 8,56 (1H, s, l-pyrazole) The synthesis of the methyl ester compounds of examples 1, 3, 4, 5, 7, 12, 14, 33, 46, 47, 48, 50, 51, 52, 53, 54, 61, 67, 68, 69, 70, 73, 74, 79, 80, 81, 82, 84, 85, 86, 87, 88, 92, 95, 96, 97, 106, 107, 109, 111, 116, 119, 13-20 and 13-30 was conducted in analogy to the above synthesis of the compound of example 11, using the appropriately substituted methyl 5—(1- (dimethylamino)-4,4,4-trifluoro~3—0xobut~ l -en—2—y1)—3 lisoxazole-4—carboxylate building blocks and the appropriately substituted arylhydrazine derivatives.

The following examples were synthesized in analogy but using a yl hydrazine: examples 28, 65, 66, 102, 103 and 104, incorporating isobutylhydrazine, (2,2,2~ trifluoroethyl)hydrazine, isopropylhydrazine, (2—methoxyethyl)hydrazine and 3— hydrazinyltetrahydrothiophene 0xide and 1—(2~hydrazinylethyl)piperidine tively.

Synthesis of methyl 3-(2-chloro—6-d'luorophenyl)—5-(1-(2-hydroxyethyl)—S~ (trifluoromethyl)—1H—pyrazolyl)isoxazole—4-carh0xylate (example 83) To a solution of methyl hloro-6—fluorophenyl)(1-(2—methoxyethyl)—5~ (trifluoromethyl)—lH—pyrazo1—4—yl)isoxazole—4—earboxylate (example 102) (27 mg, 0.06 mmol) in CH2C12 (1 mL) was added Bortribrornide (0.06 mmol).The mixture was stirred at 0°C for 1 h. The e was poured into iced water and extracted with ethyl acetate.The organic layer was dried over sodium sulfate, filtered and concentrated under d pressure.

The resulting oil was purified by pTLC (PE2EE 1:1) to yield example 83 as an oil (10 mg, 34%).

Synthesis of ethyl 3-(2-chlor0—6—-fluorophenyl)(1-(2-chlorophenyI)-5—(trifluoromethyl)— 1H-pyrazol~4-yl)isoxazolecarhoxylate ( example 13-33) 2012/051357 PM; o: The reaction was carried out analogously to the above reaction of example 11, wherein, r, the respective methyl ester was replaced by an ethyl ester building block and 3~ Chlorophenylhydrazine was replaced by 2—Chlorophenylhydrazine.

The synthesis of the ethyl ester compounds of examples 42, B—3, B-4, B—S, B~6, 13—7, 3-8, B- 9, B—IO, B-ll, B-12, B-13, 13—14, B—15, B—16, B~17, 8-32, B—37, 13-38, 13-40, 13—41, B-43, B- 44, 3-45, B46, 13—47, 13—70, 3-72, 884, B-90, B-94, B~95, B—99 and 13—103 was conducted in analogy to the above synthesis of the compound of example 13-33, using the appropriately substituted ethyl 5—(1 —(dirnethy1amino)—4,4,4—t1ifluoro—3—oxebut— 1 -en~2~y1)—3 - phenylisoxazole-4~carboxylate building blocks and the appropriately substituted arylhydrazine derivatives.

Example 13-2 and B—Sl were synthesized in y but using (2—methoxyethyl)hydrazine and ((tetrahydro-ZH—pyran—4—yl)methyl)hydrazine, respectively, instead of an aryl hydrazine.

Synthesis of ethyl 3-(2-chloro—6-fluorophenyl)—5-(1~(2—fluorobenzyl)—5—(trifluoromethyl)— 1H-pyrazol—4-—y1)isoxazolecarboxylate (example BHSO) GE F F ' F ‘INl F0 0 To a solution of tert—Butyl carbazate (Hydrazinecarboxylic acid tert—butyl ester) (0.3g 2.3 mmol) and 2—Fluor0benzy1 bromide (0.4g, 2.3 mmol) in dichloromethane (4 mL) was added ylaniine (0.3 mL, 2.3 mmol). The mixture was stirred at 70°C for 4h. The mixture was WO 01261 then diluted in ethyl acetate and washed with water (3 x), dried over sodium sulfate, filtered and trated under reduced pressure to give 380 mg as a white solid (yield 76 %). 1H NMR (CDC13)I 1,45 (s, 9H), 4,052 (5, 2H), 7,00-7,40 (m, 4H) Tert~hutyl 2—(2—fluorobenzyl)hydrazinecarboxylate (0.5g, 2.27 mmol) ved in dichloromethane (4 mL) was treated with HCl 4M in dioxane (0.8 mL, 22.7 mmol). The mixture was stirred at room ature for 1.5h. The solvent was concentrated under reduced pressure. The product was lyophillized to give the unprotected benzylhydrazine as a white solid (200 mg, yield 66%). The last step (formation of the N—substituted pyrazole unit) was performed as described for e 11 and gave 489 mg of the product as a pale yellow solid (yield 81 %). Result of LC/MS [M+H]+: 512,04; IH NMR (CDClg): 1,03 (t, 3H), 4,12 (q, 2H), 5,61 (s, 2H), 7,10 (m, 4H), 7,38—7,48 (m, 3H), 8,04 (s, 1H).

The synthesis of the compounds of examples 101, B—85, B—96, B-97 and B-104 was conducted in analogy to the above synthesis of the compound of example 13—80.

Synthesis of 3—(2~ehloro-6—fluor0phenyl)(l-(3—chlorophenyl)—5-(trifluoromethyl)—1H- pyrazol—4-yl)—N-methoxy—N—methylisoxazole-4—earboxamide (example 63) Cl / DIPEA F O N [\l + \N,o\ ——~«m«~m——-h- / p H Cl N 5 N,O—Dirnethylhydroxylamine (1.780 g, 18.243 mmol) was dissolved in dry THF (100 mL).

The solution was cooled to 0°C and DIPEA (3.0 ml, 18.2427 mmol) was added. 3—(2—Chloron 6-fluorophenyl)-5—methylisoxazole—4—carbonyl chloride was then added in portions and the mixture was stirred at room temperature overnight. The solvent was evaporated. Water was added and the flask was placed in the refrigerator for 2 days. The obtained white solid was filtered, washed with a 5% s solution of NaHCClg, and dried to give 5.2 g of the Weinreb amide as a white solid (yield 95 %).

Conversion of the b amide 3~(2—chloro-6—fluorophenyl)—N—methoxy—N,5- ylisoxazole-4—carboxamide into 3-(2—chloro-6—fluoropheny1)(1-(dimethylamino)— 4,4,4—trifluoro-3noxobut— 1 -en-2—y1)—N—methoxy—N—methylisoxazole—4—carboxamide and subsequently into the final product of example 63 was carried out analogously to the aforementioned synthesis of example 11.

The synthesis of the compound of example 135 was conducted in analogy to the above synthesis of the compound of example 63. fication, esterification and amidation procedures Synthesis of hloro-fi-fluorophenyl)—5—(1-(2-fluorophenyl)(trifluoromethyl}1H- pyrazol—4-yl)-N-methylisoxazoIe—4-carboxamide (example 19) N-0 NaOH CI _>. 'fN SO2C3|2 }/ /|>| HCI ,r/ / —>- -’N ’N F0 Eta“ F0 NH Saponification: 100 mg (0.27 mmol) of compound of example I were ved in‘a mixture of 10 mL ethanol/water 1:1 and a solution of 100 mg NaOH (2.5 mmol) in 5 mL of water was added.

The mixture was heated under reflux for 30 minutes. The ethanol was evaporated in the vacuum and water was added to adjust the volume to 10 mL. The mixture was filtered to remove unsoluble material and the solution adjusted to pH 1 with concentrated HCI. The precipitate which developed was collected by filtration, washed with water, and dried in the vacuum to yield 91 mg (93%) of 3—(2—chloro—6—fluorophenyl)—5—(1—(2—fluorophenyl)—S- (trifluoromethyl)— I H—pyrazol—4—yl)isoxazole—4—carboxylic acid.

Amidation: A solution of 91 mg 3—(2—chloro—6-fluorophenyl)—5-(1—(2~fluorophenyl)—5-(trifluor01nethyl)— lHupyrazol-4—yl)isoxazole—4—carboxylic acid (0.197 mmol) in 5 mL SOZCIZ was heated under reflux for 2 hours. The solution was concentrated in the vacuum and dried in the high . The residue 3—(2~chloro—6—fluorophenyl)—5—(1—(2~fluorophenyl)—5-(trifluoromethyl)- 1H-pyrazol—4—yl)isoxazole—4—carbonyl chloride was, without filrther purification, dissolved in 3 mL dry dioxane. To this solution 60 mg (0.88 mmol) methylarnine hydrochloride and 1.96 mL triethylamine was added. The reaction mixture was stirred at room temperature for 2 hours. The on mixture was concentrated in the vacuum and the residue ated with . The precipitate collected by filtration and 30 mg (31%) of example 19 were obtained.

Result of LC/MS [M+H]+: 482.9; 1H NMR (DMSO— d6; CC14): 2.609~2.619 (3H, s, CH3), 7.419—7,737 (7H, m, atom), 8.161 (1H, 5, NH), 8.472 (CH-pyrazole) The synthesis of the N~methyl carboxamides of examples 32, 37, 55, 56, 57, 58, 59, 60, 62, '75, 93, 96, 98, 105, 110, and 113, was ted in analogy to the above sis of the compound of example 19.

The following acid compounds were obtained using the saponification protocol described above for the production of 3~(2—chloro—6—fluorophenyl)-5m(1—(2-fluorphenyl)—5— (trifluor01nethyl)—lH-pyrazol~4—yl)isoxazoleu4—carboxylic acid: examples 91, 108, 114, 13-18, I B-19, 13-42, and B-86.

Synthesis of hloro-6—fluorophenyl)—5-(1-(3-chlorophenyl)—5-(trifluoromethyl)-1H- lm4-yl)isoxazole—4-carboxamide (example 121) FFF (3| Cl N'O m—sNaOH Cl N-O Q ’/ C3 EtOH '/ {3 F9 Ci F0 OH Saponification of the ester of example 11 was achieved following the description for example 19, first step, to give 3-(2—chloro~6—fluorophenyl)—5—(1—(3—chlorophenyl)—S-(trifluoromethyl)- 1H—pyrazol—4—y1)isoxazole—4—carboxylic acid in 89% yield. To a solution of 6.0 g (12.34 mmol) 3-(2-chloro-6—fluorophenyl)—5~(l—(3~ch10ropheuyl)—5—(trifluoromethy1)— 1H— pyrazol-4—yl)isoxazole—4—carboxylic acid and 1.98 g (37.021 mmol) ammoniumchlorid in mL dry DMA 9.36 g (24.681 mmol) HBTU and 6.45 mL (37.021 mmol) DIPEA were added. The mixture was stirred 3 hours at r.t.. Ethylacetate was added to the reaction mixture WO 01261 45 and it was washed twice with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq).

The organic layer was dried over anhydrous magnesium sulfate and the solvent was d in the vacuum. The oily residue became solid by drying in the vacuum. The solid was washed with petroleum ether, filtrated and dried in the vacuum to yield 5.37 g (90%) of example 121.

Result of LC/MS MH+: 484,83; 1H NMR (DMSO-dg; CCl4): 7.39-7.78 (7H, m, CH- arom. / 2H NH;), 8.43 (1H, s, CI-I-pyraz.) The synthesis of the carboxamide of example 124 was conducted in analogy to the above synthesis of the compound of example 121.

Furthermore, the synthesis of the following differently N—substituted carboxamides was conducted in y to the above synthesis of the compound of example 121, in each case using the appropriate amine: examples 2, 16, 17, 18, 20, 21, 22, 23, 24, 118, 127, and 132. 1‘5 Synthesis of (3-(2~chloro—6—fluorophenyl)—5~(1-(3-chlorophenyl)(triflu0romethyl)-1H- pyrazol~4~yl)isoxazol—4—yl)(morpholino)methanone (example 8-35) HN\/l HOBt, EDCI, NMM 3—(2—chloro—6-fluoropheny1)—5—(1—(3~chlor0phenyl)~5—(trifluoromethyl)~1H—pyrazol—4- yl)isoxazole-4*carboxylic acid (50 mg, 0.0001 mmol), Morpholine (9 mg, 0.0001 mmol), HOBt (14 mg, 0.0001 mmol) and EDCI (19 mg 2 mmol) were dissolved in 1 mL dry DMF. N-Methylmorpholine (100 uL, 0.001 mmol) was added and the reaction e was stirred at room temperature overnight. Morpholine, HOBt, EDCI and N—Methylmorpholine were added again in the aforementioned ratios. The mixture was stirred at room temperature for 24h. DMF was removed by evaporation. An aqueous solution of 5% citric acid was added.

The precipitate was filtered and dried. The t (example 13—35) was purified by pTLC (PE/EB 5/5) to give 26 mg of a yellow oil (yield 45 %). Result of LC/MS MH+: 554,7; 1H NMR (CDClg): 8.15 (1H, s, CH~pyraz.), 7,35—7,6 (6H, m, CH-arom), 7,15 (1H, t, CH—arom), 3,6 (4H, m, CHz—morpholine), 3,18 (4H, m, CH2-morpholine).

Further amide compounds were obtained as described above for compound B-35, in each case by using the appropriate amine: examples B-34, B—49, B-SO, B—Sl, 13-52, 13-53, B-54, B-SS, 13-56, 13-57, B—SS, 13—59, 8-62, 3—63, B-64, B-65, 3-66, B-74, B-87, B—88, 1391, B33, and Ba 100 (in the latter case, the amide formation was applied to the substituent at the aryl unit of the N~aryl-pyrazole moiety).

Synthesis of 3—(2—chloro~6«fluorophenyi)-5—(l—(3-chlorophenyl)—5-(trifluoromethyl)-1H- pyrazolyl)—N-methoxy—N—methylisoxazolecarboxamide (example 63) HBTU DlPEA To a solution of 10,8 g (22,2 mmol) 3-(2-chloro—6—fluoropheny1)(1—(3—chlorophenyl)—5— (trifluoromethyD—lH-pyrazolyl)isoxazole—4-carboxylic acid, 2,17 g (leq) N,O— Dimethylhydroxylamine and 8,42 g (leq) HBTU in dimethylhydroxylamine 3,68 mL DIPEA were added. The mixture was stirred overnight at r.t. The solvent was removed in the vacuum.

The residue was resolved in ethylacetate and extracted with sodium en carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous ium sulfate and the solvent was removed in the vacuum. TLC (6:4 petrolether:ethylacetate) showed residual educt. The product was ed by column chromatoghraphy (6:4) ether:ethylacetate). The product (example 63) was dried under vacuum to yield 2.28;; (19%). Result of LC/MS MH+: 5288; 1H NMR (DMSO'dfi; CCl4): 3.08 (3H, s, CH3), 3.36 (3H, s, CH3), 7.40~7.81 (7H, m, CH—arom.), 8.39 (1H, s, CH—pyraz.) Compound of example 94 was ed in analogy to the protocol of compound 63.

Esterification: Synthesis of Ethyl 3-(2-chlor0—6-fluorophenyl)—5—[1—(2-fluorophenyl)—5-(trifluoromethyl)— 1H-pyrazolyl]isoxazole—4-carboxylate (example 42) To a suspension of 3-(2-chlorow6-fluor0phenyl)—5-(l.-(2—fluorophenyl)-5~(trifluor0methyl)~ 1H-pyrazol—4-yl)isoxazole-4~carbonyl chloride (0.1 g) and ethanol (0.04 mL) in CH2C12 (1 mL) Hydroxybenzotriazole (HOBT) (50 mg) and l»ethyl—3—(3—dimethy1aminopropyl) carbodiimide (BBC) (45 mg) were added, the reaction e was stirred occasionally until a clear solution was formed and allowed to stay overnight. The solution was diluted with water and the separated organic layer was purified by column chromatography (CHC13) to give ester compound of example 42 (yield 75%). Result of LC/MS [M+H]+: 4978; 1H NMR (DMSO— d6, CCl4): 1.03 (3H, t, CH3), 4.10 (2H, q, CH2), 7.32 (1H, t, CPI—arena), 7.42—7.71 (6H 11], CH— arom.), 8.43 (1H, s, CH—pyraz.).

The synthesis of the compounds of examples 77, 78, 90, 99, 100, and 112 was conducted in analogy to the above synthesis of the compound of example 42.

Synthesis of inPropyl 3—(2-chloro~6~fluorophenyl)—5~{1-(2—flu0ropheuyl) (trifluoromethyl)—1H—pyrazolyl]isoxazolecarboxylate (example 43) 2—iodopropane _.._W_i_.._,_ 3—(2—chloro-6—fluorophenyl)-5—(1 ~(2—fluorophenyl)—S—(trifluoromethyl)-1H~pyrazol—4— y1)isoxazo1e-4—carboxy1ic acid (30 mg, 0,064 mmol), cesium fluoride (12 mg, 0,077 mmol) and 2—iodopropane (0,008 mL, 0,077 mmol) were ved in dried acetonitrile (1 mL) and the e was refluxed for 20h. The e was diluted with romethane and washed with water. The organic phase was dried over N51280:}, filtered and the solvent was solvent removed under reduced pressure. The product was purified by pTLC (PE/EB 9/1) to give 26mg of a yellow oil (yield 79 %). Result of LC/MS [M+H}+: 511.8; 1H NMR ): 1.02 (6H, d, 2 x CH3), 5,02 (1H, m, pyl), 7.18 (1H, t, CPI—atom), 7.28—7.61 (6H m, CH— arom.), 8.31 (1H, s, CH—pyraz.).

The synthesis of the compounds of examples B-31, B~60, Bn61, B-73, B48, B—79, and B-82 was conducted in analogy to the above synthesis of the compound of e 43.

Synthesis of 5-(1-(3—acetamidophenyl)—5-(trifluoromethyl)—lH-pyrazolyl)—3—(2-chloro~ 6-fluorophenyl)isoxazole—4~carboxylate (example B-89) CH3I, CsF The same esterification procedure as described above for example 43 was applied, replacing 2—iodopropoane by iodomethane to give methyl ester of example B—89 as a yellow oil (yield 15%).

Synthesis of methyl hloro-6—fluorophenyl)—5-(1-(pyridin-3—yl)—5-(trifluoromethyl)- azolyl)isoxazolecarboxylate (example B-67) To a e of 3—(2—chloro-6nfluorophenyl)-5—(l—(pyridin—3—yl)—5—(trifluoromethyl)-1H— pyrazol—4—yl)isoxazole—4—carboxylic acid (30 mg, 0.1 mmol) in methanol (15 mL) was added thionylchloride (5 ML, 0.1 mmol). The mixture was stirred at room temperature for 60h and for 5h at reflux. The mixture was diluted with dichloromethane and washed with water (3 x), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example B—67) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%).

Result of LC/MS MH+: 466,76; IH NMR (CDCl3)I 3,19 (s, 3 H), 7,15 (t, 1H), 7,33—7,55 (m, 6H), 8,25 (s, 1H) The synthesis of the compounds of examples 13—69, 13-71, 13—75, B-76, B-77, 13-92 was conducted in y to the above synthesis of the compound of example 8—67.

Synthesis of S-methyl 3-(2-chloro—6—fluorophenyl)—5-(1—(pyridinyl)—5- (triflnoromethyl)—1anyrazolyl)isoxazolecarbothioate (example 3—68) 3"(2~ch10ro—6—fluorophenyl)-5—(1-(pyridin-3~y1)—5—(trifluoromethy1)—1H—pyrazol-4— yl)isoxazole-4—carboxylic acid (30 mg, 0.066 mmol) was treated with thionylchloride (1.5 mL) and stirred at reflux for 2 h. The mixture was concentrated under reduced re. The intermediate was d with benzene (3x) and the benzene was evaporated to remove water.

Then, the obtained mixture was dissolved in benzene(1,5mL) and sodium ethiolate (32.5 mg, 0.46 mmol) was added. The reaction mixture was stirred at reflux for 5h. The mixture was diluted with dichloromethane and washed with water (3 x), dried over sodium sulfate, filtered and trated under reduced pressure. The product (example 13-68) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9 %). Result of LC/MS Mil-1+: 482,76; 1H NMR (CDC13)I 2,33 (t, 3 H), 7,19 (t, 1H), 7,334,515 (in, 611), 8,23 (s, 1H) Synthesis of S—methyl 3-(2-chloro—6-fluorophenyl)(1-(3-chlorophenyl)—5- (trifluoromethyl)~1H—pyrazol~4~yl)isoxazole-4—carbothioate (example 126) Cl c: e: OH N on N F0 ' C) 0 , o ‘s N \N F ~ C} e ~© socaz F H x CHasNa F \ “NF N0 FFF ——> 53.0 F _.__,..

F No or Cl F Carboxylic acid 3-(2—chloro—6—fluorophenyl)«5—(1—(3—ch10r0phenyl)—5~(trifluoromethyl)-1H~ pyrazol—4~y1)isoxazole—4—carboxylic acid (60 mg, 0.123 mmol) was refluxed in SOC12 (5 mL) for 2 hours and an excess of thionyl de was evaporated. The residue was dissolved in dry dioxane (5 mL), sodium thoxide (60 mg, 0.86 mmol) was added and the mixture was stirred for 1 day. After evaporation of the solvent, water (5 mL) was added to the residue.

The mixture was stirred for 30 min at It. and the supernatant was poured off the resulting resin. The product was ed from this resin by column chromatography (silica gel (1040- 0.100 mm, eluent m chloroform : hexane : 1: 1). Yield of example 126: 45 mg (71%) of a slightly grayish resin. Result of LC/MS MH+: 515.9; 1H NMR (DMSO—dé; CC14): 2.30 (s, 3 H) 7.37 (t, J38.66 Hz, 1 H) 7.49 (d, J=8.03 Hz, 1 H) 7.53 — 7.61 (In, 1 H) 7.61 — 7.73 (m, 4 H) 8.36 (s, 1 H) The synthesis of the compounds of examples 128 and 130 was conducted in analogy to the above synthesis of the compound of example 126.

Synthesis of 3-(2-chloro—G-fluorophenyl)—5-(1-(3—chlorophenyl)—5-(trifluoromethyl)—1H- pyrazol—4-yl)—N-methylisoxazole~4~carbothioamide (example 72) WPF Cf Lawesson N—O F FF / reagent 1’ FO :N ———-w~—> / NH N Q F5 1 CE NH ‘NNQ I‘ CI A mixture of compound of example 19 0.37 g, 0.74 mmol, Lawesson reagent (0.30 g, 0.74 mmol) and dry dioxane (10 mL) was refluxed for 1.5 hours. The solvent was evaporated in vacuum to s and the residue crystallized from ethanol (20 mL).

Yield of nd 72: 0.28 g (73%), yellowish crystals. Result of LC/MS Ml—H: 516.3; 1H NMR dg; CC14): 3.03 (d, J24.52 Hz, 3 H) 7.25 (t, J=8.53 Hz, 1 H) 7.38 (d, J=8.03 Hz, 8 - 7.57 (m, 2 H) 7.58 — 7.67 (m, 3 H) 8.05 (s, 1 H) 10.31 (d, J=4.52 Hz, 1 H) The synthesis of the compounds of es 76, 122, 123, v125, 129, 13-101 and 13-102 was conducted in analogy to the above synthesis of the compound of example 72. Result of LC/MS MH+: 502.3 Synthesis of 3-(2—chlorofluorophenyl)—5-(1-(4—flnorophenyl)—5-(triflnoromethyl)~1H- pyrazol-4—yl)isoxazole (example 25) “by 'ng/Wfi FOOD/«KFififi: fight" FQPEj/LQAFFFO “0A0“ + of + HN—Q—F\ _“"”* F l ethyl 1-(4-flnorophenyl)-—5—(trifluoromethyl)-lH-pyrazole—4-carboxylate: Ethyl 4,4,4—trifluoroacetoacetate (18.5g, 77.34 mmol) and N,N—Dimethylformamide dimethyl acetal (9.21 g ,77.34 mmol) were ved in benzene (10 mL). The mixture was heated under reflux for l h. The solvent was evaporated und distilled with a Kugelrohr apparatus to give 12 g of ethyl 2—((dimethylamino)methylene)-4,4,4—trifluoro-3—oxobutanoate (yield 65 %).

Phenylhydrazine (2.62g, 20.82 mmol) was dissolved in anhydrous THF (100 mL) and triethylamine (2.9 mL, 20.82 mmol) was added. The solution was cooled to 40°C. A solution of ethyl 2-((dimethylamino)methylene)—4,4,4-trifluoro—3—oxobutanoate (5 g, 20.82 mmol) in WO 01261 2012/051357 mL THF was added dropwise in 111. The mixture was then d 30 min at -10°C and then 16 h at room temperature. The solvent was evaporated. The obtained oil was dissolved in ethylacetate and washed with a solution of sodium hydrogenearbonate and citric acid. The organic phase was dried over ium sulfate, filtered and evaporated. The t was purified by column chromatography (80:20 PE:EE) to give 2.8 g of ethyl 1-(4—fluorophenyl)— —(trifluoromethyl)-1H—pyrazole—4-carboxylate (yield 44 0/o).

,OH F 0' “I F /\o F THFdry F + UM —---——-—> o / IN 0°C F "‘N under argon To a solution of 1.9243 g (10.2571 mmol) (E)-l—(2—chloro~6-tluoropher1yl)ethanone oxime in mL dry THF 8 mL (2 eq.) llithium were added dropwise under argon and icebath cooling. 1.55 g (0.5 eq.) of ethyl l—(4-fluorophenyl)—5—(trifluoromethy1)-1H—pyrazole carboxylate were dissolved in 5 mL dry THF and also added within 5 minutes. The solution was stirred for 15 minutes at 0°C.

To this reaction mixture 40 mL hydrochloric acid (10% solution in water) were added. The mixture was heated under reflux for 1 h. The aqueous on was extracted three times with ethyl acetate. The c layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo, TLC (4:1 hexane:ethyl acetate) showed several spots of impurities.

The product was purified by flash chromatography on silica gel with hexanezethyl acetate 4:1 and 355 mg (yield of theory 48%) of compound 25 were obtained. LC/MS MHJr : 426.0; 1H NMR (DMSO— d6; CCl4): 7.17 (1H, s, isooxazole); 7.42—7.71 (7H, m, arom.); 8.48 (1H, s, pyrazole) Synthesis of (E)—3-(2-chloro-6~fluorophenyl)—5—(2-(dimethylamino)vinyl)isoxazole~4~ carbonitrile F / dry toluene \N/ /‘<:_u 7 h reflux CE Bredereck's reagent To a solution of 1.5 g (6,3389 mmol) 3n(2—chloro—6—fluorophenyl)—5~methylisoxazole—4— carbonitrile in 100 mL dry toluene, were added 2.10 g (12.6779 mmol) tert—Butoxy- bis(dimethylamino)methane. The reaction mixture was heated under reflux for 12 h. The mixture was concentrated in vacuo and was dried in the high vacuum. Petroleum ether was added to the crystallized residue. The product was collected by filtration and 1.791 g (yield of theory: 95.9%) of clean product were obtained. Result of LC/MS MH‘L: 292.0; 3H NMR (DMSO— d6; CC14): 2.93 (3H, s, N-CI-Ig), 3.17 (3H, s, N-CH3), 5.15—5.20 (1H, d, C2H2), 7.74- 7.78 (1H, d , C2H2), 7.45—7.52 (1H, dd, Cid—atom), 7.57-7.59 (1H, d, CH—arorn.), 7.65-7.71 (1H, d, CH-arom.) Synthesis of (Z)-3—(2nchloro-fi-fluorophenyl)-5—(1-(dimethylamino)-4,4,4-trifluoro oxobut-l-en—2~yl)isoxazole—4-carhonitrile To a solution of 0.5 g (1.7140 mmol) (E)—3—(2—chloro-6—fluorophenyl)—5—(2- (dimethylamino)viny1)isoxazole-4—carbonitfile in 20 mL dry dichloromethane, were added dropwise under ice-bath cooling 0.36 mL (2.5710 mmol) roacetic anhydride. The reaction e was d for 2 h at r.t.. Afterwards the mixture was concentrated in vacuo and was dried in the high , Petroleum ether was added to the llized product and was collected by filtration to obtain 0.625 g (yield of theory: 94%) of clean product. Result of LC/MS MIT: 388.0; 1H NMR (DMSO—dég CC14): 2,75 (3H, s, , 3.46 (3H, s, N-CH3), 7.53—7.59 (1H, dd, CH—arom.), 7-64—7.67 (1H, d, CPI—atom), 7.73—7.81 (ll-l, d, CH—arom.), 8.23 (1H, s, CH) Synthesis of 3-(2-chlero—6-fluorophenyI)(1-(3-chlorophenyl)—5-(trifluoromethyl)—1H~ pyrazol—4-yl)isoxazoIecarbonitrile (example 49) dry ethanol *3- Q + AN W/l\ H K 3 h reflux To a solution of 0.1 g (0.2579 nimol) (Z)-3—(2—chloro—6—fluorophenyl)—5—(1~(dimethylamino)— 4,4,4~t1ifluoro—3-oxobut—1—eny1)isoxazolecarbonitrile in dry ethanol, were added 0.0462 g 9 mmol) 3—Chlorophenylhydrazine and 0.78 mL (0.2579 rnmol) DIPEA. The reaction mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo and was dried in the high vacuum. The upper spot was isolated by using the preparative thin—layer chromatography and 0.0037 g (yield of theory: 3.0%) of clean product compound 49 were obtained. Result of LC/MS MH+z 466.9; 1H NMR (DMSO— d6; CC14): 7.73-7.97 (6H, m, CH— arom.), 8.04 (1H, s, m.), 8.81 (1H, s, az.) The synthesis of the compound of example 120 was conducted in analogy to the above synthesis of the compound of example 49.

Synthesis of Synthesis of 3—(2-chloro-G-fluorophenyi)n5~(1-(3-chlor0phenyl) (trifluoromethyl)—1I-Inpyrazolyl)~N-methylisoxazole-4—earl)othioamide (example 64) F0 0 CI 0 x. \ N\ F31: he _F_H> To a cooled (frozen) solution of (E)—1nethyl 3—(2—chloro-6~fluorophenyl)—5—(2— (dimethylamino)vinyl)isoxazole-4—carboxylate (85 mg, 0.26 mmol) a mixture of absolute dioxane (2.3 g) and Hfinig's base (156 mg, 1.20 mmol) 3—tetrafluoropropanoy1 chloride (129 mg, 0.76 mmol) was added. Reaction mixture (solution) was left to melt and kept for 1.5 h at r.t. TLC in EtOAc/C7H16 9/1 showed no starting material and a single t.

Solution was evaporated to dryness, oily residue was treated by boiling hexane which was concentrated to give pure (E)—methyl 3—(2—ch10r0-6—fluor0pheny1)—5—(l—(dimethy1amino)— 5—tetrafluoro—3—oxopent—1~en-2—yl)isoxazole-4—carboxylate. The Residual oily (E)— methyl hlor0—6—flu0rophenyl)—5—(1-(dimethylarnino)—4,4,5,5—tetrafluor0-3—oxopent-1—en- 2~y1)isoxazolecarboxylate was used for further reactions without onal purification.

Treating raw (E)—methyl 3-(2~chloro-6—fluoropheny1)—5—(1-(dimethylamino)-4,4,5,5— tetrafluoro—3—oxopent~1~en—2—y1)isoxazole-4—carboxylate (116 mg) by 3—fluorophenyl hydrazine hydrochloride (42 mg) in ethanol by standard procedure gave 96 mg (73%) of pure compound 64. Result of LC/MS MH+2 516.8; 1H NMR (400 MHZ, DMSO-dé) 5ppm 3.55 - 3.78 (m, 13 H) 6.55 — 6.95 (m, 5 H) 7.24 - 7.53 (m, 20 H) 7.55 — 7.73 (In, 8 H) 8.33 (s, 4 H) Synthesis of methyl 3-(2-chlor0—6-fluorophenyl)—(1-(3-fluorophenyl)—5- oromethyl)—lH-pyrazol-4—yl)isethiazole—4-carboxylate (example 137) 0.32 g 3-(2—chloro-6—fluorophenyl)—5—(1-(3-fluor0phenyl)-5—(trifiuoromethyl)—lH-pyrazol-4~ yl)isoxazole—4-carboxylic acid (0.70 mmol) was dissolved in water NaOH solution (20 mL water + 0.115 g NaOH). Bromine (0.34 g, 2.1 mmol) was added slowly and dropwise to this solution at ng and cooling (0 w 5°C). Stirring continued for 2 hours at 0 w 5°C and for 2 days at r.t. The precipitate was filtered off and suspended in 5% water NaOl-l solution (10 mL). After 2 hours of stirring solids were filtered off, washed with water and dried on air to a yield of 0.15 g (0.30 mmol, 42%) of compound 13’? as white crystals. Result of LC/MS MH+z 505.7; IH NMR (DMSO—d5; CCl4): 7.35 u 7.48 (m, 4 H) 7.52 (d,J=8.28 Hz, 1 H) 7.61 7.74 (m, 2 H) 8.4 (s, 1 H) Further examples which were obtained in analogy to the protocol of example 137 are: 140, 144, 145, 8-23, 13-24, 3—25, 13-26, B—27, 3-28, and 13-83.

Synthesis of methyl hlorofluorophenyl)-5—(1-(3—fluorophenyl)—5— (trifluoromethyl)-lH—pyrazol-4~yl)isothiazole—4—carboxylate (eXample 133) on of 102 mg (0.217 mmol) of 3«(2—chloro—6—fluorophenyl)—5-(l-(3—fluoropher1yl)~5— (trifluoromethyl)-lH—pyrazol—4—yl)isoxazolecarboxylic acid in 8 mL SOC12 was refluxed for 3 h. Volatiles were evaporated in vacuum thoroughly. The residue was dissolved in 8 mL absolute dioxane and added at stirring dropwise to a mixture of 825 mg N2H4*H20 and 6 mL te dioxane. TLC of reaction mixture showed new product with Rf less that starting acid in EtOAc/heptane, 1/1 and greater —— in EtOAc/Eth. Volatiles were evaporated, water was added to residue to precipitate an oily pink solid. Water was removed, residue was washed by water, than treated by 5 mL water with 10 drops of AcOI—I and finally washed by water. t was partially ted by boiling heptane (38 mg) and partially extracted by other with further treatment of the ether on by heptane (39 mg). Total yield: 77 mg (73%) of compound 133. Result of LC/MS MH+: 484.8; 1H NMR (DMSO—dé; CCl4): 4.49 (2H, 5, NH;), 7,443.79 (7H, m, CH—arom.), 8.44 (1H, s, CH—pyraz.), 9.54 (1H, 3, NH) Example 134 was synthesized according to the protocol described for example 133.

Synthesis of h10rofluorophenyl)(I-(3-fluorophenyl)(trifluoromethyl)—1H— pyrazol—4—yl)isoxazol—4-amine (example 117) F9 J4. argue: .0 r: N Fg g; Compound 133 (0.60 g, 1.24 mmol) was ved in the mixture of dioxane (20 mL), H20 (5 mL), HCl conc. (1 mL). A solution of NaNOz (0.532 g) in water (10 mL) was added dropwise at stirring and g (06°C). After 30 min of stirring at this temperature the mixture was poured onto ice (approx. 50 g). A resinous residue of crude azide formed. After staying overnight in a refrigerator the supernatant was decanted. The residue was ved in the mixture of dioxane (20 mL) and water (6 mL) and refluxed for 30 min. The solvent evaporated to dryness in vacuum. The residue was dissolved in a l amount of chloroform and pure product was isolated by column tography (silica gel 0.040— 0.100 mm, eluent — chloroform, Rf z 0.3). Yield of compound 117: 0.324 g (0.73 mmol, 59%) of a yellowish solid. Result of LC/MS MH+: 440.94; 1H NMR (DMSO-d6; C014): 4.56 (2H, s, NHZ), .68 (7H, m, CH—arom.), 8.36 (1H, s, CH—pyraz.) Example B—36 was synthesized according to the protocol described for example 117.

Synthesis of Nu(3—(2»chloro-6—fluorophenyl)—5-(1~(3-fluorophenyl)—5—(trifluoromethyl)— 1H~pyrazolyl)isoxazol-4—yl)acetamide (example 139) A mixture of compound 117 (0.167 g, 0.38 mmol) and acetic ide (3 mL) was refluxed for 2 hours (until absence of starting amine by TLC). After cooling, water (15 mL) was added and the reaction mixture was stirred for 1 hour. The supernatant was removed from the oily precipitate of crude product. Purification by column chromatography (silica gel 0040-0100 mm, eluent ~ chloroform, Rf m 0.25) gave an oil, which solidified after treatment with .

Yield of compound 139: 0.112 g (0.23 mmol, 61%) of a yellowish solid. Result of LC/MS Nil-1+: 483.8; 1H NMR (DMSO‘dé; (304); 1.90 (s, 3 H) 7.28 (t, J28.66 Hz, 1 H) 7.33 - 7.46 (m, 4 H) 7.50 « 7.59 (m, 1 H) 7.59 - 7.68 (m, 1 H) 8.22 (s, 1 H) 9.55 (s, l H) e 13-39 was synthesized according to the protocol described for example 139.

Synthesis of N—(3-(2-chloro—6-fluoropheuyl)(l-(3-ehl0rophenyl)~5—(trifluoromethyl)- 1H-pyrazoi~4—yl)isoxazol—4—yl)formamide (example B-48) 3 -(2—chloro—6-fluorophenyl)—5—(l —(3 ophenyl)—5—(trifluoromethyl)— 1H~pyrazol—4— yl)isoxazol—4—amine (example 13—36) (40mg, 0,1 mmol) was dissolved in formic acid (3 mL).

The mixture was stirred at room temperature overnight. To the reaction mixture was added water. The resulting precipitate was collected, washed with water and dried under vacuum.

The product was purified by pTLC (EB/PE 2:1) to give 32 mg of the desired product (example B—48) (yield 75%). Result of LC/MS MH+: 484,82; 1H NMR (CDCIg): 6,63 (t, 111), 7,22 (m, 1H), .59 (m, 6H), 8,02 (s, 1H) 8.22 (s, 1H) Synthesis of 3-(2—chloro-6—fluorophenyl)[1-(3~fluorophenyl)(trifluoromethyl)—1H- pyrazoI-«4-yl]isoxazolu4-ylformamide le 141) CHE) QF cab/homers O N QF 1 )LH N _ AcOH A solution of 130 mg (0.295 mmol) 3—(2—chloro-6—flu0rophenyl)~5-[1—(3—fluorophenyl)—3— (trifluoromethyl)—1H—pyrazol—4-y1]isoxazolw4-amine (example 117) in a mixture of 1847 mg (17.4 mmol) hylorthoether and 1660 mg (27.7 mmol) acetic acid was stirred at r.t. for 1 h. The suspension was filtered, and the obtained white solid salts were washed on the filter with hexane. Filtrates were combined and evaporated to dryness. The residue was treated by hexane, and the extract was d by CC on silica gel, (eluent EtOAc/hexane 1/ 1). The obtained fraction of the pure product le 141) was evaporated to give 50 mg of a light greenish oil (yield 36%). Result of LC/MS MH+2 469,04; 1H NMR (400 MHZ, methanol-d4): .35 (m, 1 H) 7.44 (s, 3 H) 7.46—7.50 (m, 1 H) 7.57-7.67 (m, 2 H) 7.72 (s, 1 H) 8.26 (s, 1 H) N—{3—(2—chloro—6—fluorophenyI)[1-(3-flu0rephenyl)(triflu0r0methyl)—1H—pyrazol—4n -oxazoI—4-yl}-2,2,2-trifluor0acetamide (example B-22) A. mixture of 3—(2~ehlorofluoropheny1)(1-3—fluorophenyI)—5—(trifluor0methy1)—1H~ pyrazol-4—yl)isoxazol—4—amine (example 117) (70 mg, 0.159 mmol), dioxane (5 ml) and roacetic anhydride (50 mg) was stirred at r.t. overnight. The solvent was evaporated in vacuum and water (5 ml) was added to the residue. The precipitate was filtered off, washed with water and dried to give 77 mg of example B—22 (yield 90.2%). 1H NMR (DMSO-D6, CC14): 7,37 (m, 411), 7,57 (m 211), 8,26 (s, 1H), 11,29 (5, 1H).

Synthesis of (SEQ-methyl N—(3-(2-chloro—6—fluorophenyl)(1-(3-fiuor0phenyl)-5— (trifluoromethyl)-1H~pyrazol~4—yl)isoxazol—4-yl)—2,2,2—triflu0roacetimidate (example 136) A mixture of example 15-22 (30 mg, 0.056 mmol), acetone (5 ml), anhydrous K2CO3 (100 mg) and CH31 (100 mg) was stirred at r.t. overnight. Inorganic salts were filtered off and washed with acetone. The filtrate and rinse were combined and the solvent was evaporated in vacuum to give example 136 as Viscous resin (27 mg, 0.049 inmol, 87.5%) as a mixture of Z and E s ding to 1H NMR data). 1H NMR (DMSO—D6, ecu): 3.24-3.36 (m, 3H), 7.31— 7.57 (m, 6H), 7.58—7.75 (m 2H), 8.23 (s, 1H).

Synthesis of N'—acetyl(2-chloro—6-fluorophenyl)—5~(1-(2—fluorophenyl) (trifluoromethyl)—1H-pyrazol—4-yl)isoxazolecarbohydrazide (example 142) To a solution of 190 mg (0.393 mmol) 3-(2—chlorofluorophenyl)—5—(l-(2—fluor0phenyl) (trifluoromethyl)—1H—pyrazol—4—yl)isoxazole—4—carbohydrazide (which was synthesized in analogy to the procedure described for. example 133) in 5.8 ml absolute dioxane, 148 mg (1.885 mmol) acetyl chloride were added. The conversion is complete within minutes.

Volatiles were evaporated, residue was re-evaporated with ethanol. e was crystallized from EtOAc — heptane to give 175 mg (85%) of compound 142 as a pale yellow powder.

Result of LC/MS MH+1 ; EH—NMR z, methanol-d4) 6 ppm: 1.98 (3H, s, CH3), 7.25—7.32 (1H, m, CH—arom.), 7.41—7.48 (3H, m, CH—arom.), 7.54—7.61 (1H, m, CH-arom), 7.64—7.74 (1H, m, CH—arom.), 8.63 (1H, s, az.) Synthesis of 5-(1-(2-aminophenyl)~5~(trifluoromethyl)-IH-pyrazol—4-yl)—3-(2-chIoro fluorophenylfisoxazolecarboxylate (example 13—98) 3 -(2~chloro—6—fluorophenyl)-5—(1-(2—nitrophenyl)—5—(trifluoromethyl)— 1H—pyrazol xazole—4-carboxylate (example B-95) (100 mg, 0.19 mmol) was placed in a vial in the presence of acetic acid (1.5 mL) in tetrahydrofuran (2 mL). The solution was d and concentrated hydrochloric acid (0.03 mL, 0.19 mmol) and zinc (80.9 mg, 1.24 mmol) were added successively under ice-cooling. The mixture was allowed to stir at room temperature for 12h. An aqueous solution of ammonia (25%) was added to the on mixture to alkalify. The mixture was then extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure.

The product (example 8—98) was purified by pTLC g/MeOH 100/5) to give 25 mg as a yellow oil (yield 27%). Result of LC/MS MH+2 494,70; 1H NMR (CDCIg): 1.05 (t, 3 H), 3,80 (s, 2H), 4,18 (q, 2H), 6,85 (m, 2H), 7,11—7,45 (rm-SH), 8,23 (s, 1H) Synthesis of 5-(l-(2-acetamidophenyl)~5-(trifluoromethyl)—lpryrazolyl)-3—(2—chloro- 6-fluorophenyl)isoxazole—4—carboxylate (example B—l) To a solution of ethyl 5—(1—(2—aminophenyl)—5—(trifluoromethyl)—lH—pyrazol—4—yl)~3— (2—chloro—6—fluorophenyl)isoxazole—4—carboxylate (example B—98) (21 mg, 0.04 mmol) in acetic acid (1 mL) was added acetic anhydride (4 uL, 0.04 mmol). The mixture was stirred over night at room temperature. The mixture was diluted with dichloromethane and washed with water (3 x), dried over sodium e, filtered and concentrated under reduced The resulting oil was purified by TLC (DCM : MeOH 100:5) to give 3 mg of example B—l a yellowish oil (yield 13 %). Result ofLC/MS MH+: 536,10; 1H NMR (CDC13)I 1.05 (t, 3 H), 2,11 (s, 3H), 4,18 (q, 2H), 7,11—7,60 (m, 7H), 8,33 (s, 1H) Synthesis of methyl 3-(2~ehlorofluorophenyl)-5—[1-(3-fluorophenyl)~5~ (trifluoromethyl)—1H—pyrazol—4~yl}isoxazol—4-ylcarbamate (example 138) F FF NaN3 If—O W / / N ""hl F F0 21:2;2 F F CH30H 1/ / N _.___., , F HNYO 3~(2—chloro—6mfluorophenyl)—5—[1-(3~fluorophenyl)—5-(t1ifluoromethyl)—1H—pyrazol y1]isoxazole—4—carboxylie acid (103 mg, 0.219 mmol) was dissolved in thionyl chloride (6 mL) and refluxed for 3h. Volatiles were evaporated in vacuum, the e was dissolved in absolute benzene (~5 rnL), and sodium azide (281 mg, 4.322) and 10 drops of triethylamine were added to the solution (pl-I < 7). The suspension was stirred for 3h. Volatiles were evaporated in vacuum, and the residue was treated with 2 x 10 mL ether. Ethereal extracts were evaporated to give a s brown oil. Methanol (~5 mL) was added to the oil and the solution was kept at r.t. for 1 day. Volatiles were ated in vacuum, and the residue was treated with 2 x 10 mL boiling heptane followed by evaporation of the solvent, giving 55 crude product. Column chromatography on silica gel (eluent EtOAe/heptane, 1/1 v/v) gave pure methyl 3~(2-chloro-6—fluorophenyl)—5—[1-(3—fluorophenyl)-5—(trifluorornethyl)-1H— l—4-yl]isoxazol-4—ylcarbamate (example 138) (45 mg, 41%). Result of LC/MS MH+: Methyl 3—(2-chlor0fluorophenyl)—5-[1-(2—fluorophenyi)—1H-pyrazolyl]isoxazole carboxylate (example 89) A) methyl 3-(2-chloro-6—fluorophenyl)—5-(1~(dimethylamino)-3~oxoprop-l-en-Z- yl)isoxazolecarboxylate 0 ,CH3 I \ / Cl ng Methyl 3—(2—chlor0—6-fluorophenyl)~5—(1~(dimethylamino)—3 ~0xoprop— l -en—2—yl)isoxazole—4m carboxylate was sized from methyl 3—(2~chloro—6—fluorophenyl)-5—(2- (dimethylamino)vinyl)isoxazole—4—carboxylate using a Vilsmeier formulation in analogy to Tetrahedron Lett. 1988, 29, 2339.

To a solution of raw methyl 3-(2-chloro—6—fluorophenyl)—5—[2—(dimethylamino)-l- formylvinyl]isoxazole~4—carb0xylate (36 mg, 0.102 mmol) in l (460 mg), 2— fluorophenyl hydrazine hydrochloride (16 mg, 0.100 mmol) was added. The mixture was warmed to C until a TLC sample showed no ng enamine. The solution was evaporated to s in vacuum, the reside was extracted with 3 x 10 ml of boiling hexane, and the hexane extracts were combined and concentrated and cooled to room temperature.

Crystallization gave 25 mg of desired product (example 89) (yield 60%). Result of LC/MS MH+2 416,05; 1H NMR (CDClg): 3,67 (s, 3 H), 7,30 (t, 1H), 7,45 (m, 4H), 7,57 (m, 1H), 7,93 (t, 111), 8,50 (s, 1H), 9,13 (s, 1H).

Further examples which were obtained in analogy to the protocol of example 89 are: 115, and B—Zl.

Synthesis of methyl 3-(2-chloro—6~fluorophenyl)—5-{[1-(4-methoxycarbonyl—3—(4— chlorophenylfisoxazol-S-yl)—5—-trifluoromethyl—1H~pyrazolyl]}—isoxazolecarboxylate (example 131) CI CI CI 0 0 /CH3 0 /CH3 /CH3 O 0 o POCI3 __..._,., N/ _m,_ / Ete’N ‘0 O N\\/ CI N\\ 0 NH 0 \ A) Methyl 5~chloro—3—(4—chlorophenyl)isoxazole—4-carboxylate.

A suspension of methyl 3—(4-chlorophenyl)—5~oxo-4,5-dihydroisoxazolecarboxylate (518mg, 20411111101; building block is commercially available) in POC13 (3mL) was cooled to 0—50C, and upon stirring, 13th (0.3mL) was added dropwise. The resulting mixture was heated to 100—1100C and stirred at this temperature for 2-2.5 h, cooled to room temperature, poured into iced water and neutralized with aqueous NaOH (10%). The product was extracted with ether and purified by column chromatography (hexanezEtOAc 25:2) to give 320mg of yellow solid. Yield 57%. 1H NMR (DMSO~D6, CCl4): 3.79 (3H, s, OCl—I3), 7.50 (2H, AB- syst., rn.), 7.65 (2H, AB—syst-, CH—arom.).

B) Methyl 3-(4—c111orophenyl)—5-hydrazinoisoxazolecarboxylate.

To an ice cooled solution of hydrazine hydrate in MeOH (0.3mL in SmL) methyl 5—chloro (4—chlorophenyl)isoxazole—4-carboxylate (0.3g, 1.1mmol) ved in CH2C12 (ZmL) was added dropwise. The reaction mixture was stirred for 2h and half of the solvent was evaporated. The product was filtered off, washed with cold methanol and dried to give 227mg (77%) of 5—hydrazinoisoxazole. 1H NMR D6, (KIM): 3.1 (3H, bs, NH+H20), 3.64 (3H, s, OCHS), 4.65 (2H, bs, NHZ), 7.43 (2H, t., CH—arom.), 7.60 (2H, AB—syst., CH- arom.).

C) Methyl 3-(2-chlorofluorophenyl){11-(4-methoxycarbonyl(4- chlorophenyl)isoxazol—5-yl)trifluor0methyl-1H—pyrazolyl] }-isoxazole—4-carb0xylate (example 131) The mixture of methyl 3-(2~chlor0—6—fluorophenyl)—5—(1~(dimethylamino)-4,4,4—triflu0ro—3~ oxobut—1—en—2-yl)isoxazole-4—carboxylate (157 mg, 0.37 mmol) and methyl 3-(4— chlorophenyl)—5—hydrazinoisexazole~4-carboxy1ate (0.1 g, 0.37 mmol) in ethanol (1 mL) was heated at 60°C for 5 h, the solution was ated and the product was crystallized from methanol to give 86mg (37%) of example 131. EH NMR (DMSO—Dé, CC14): 3.69 (3H, OCH3), 3.71 (3H, s, OCH3), 7.35 (1H, dd, CH—arom.), 7.47 (1H, d, CH-arom.), 7.57 (2H, AB-Syst., CH—arom.), 7.63 (1H, m, CPI-atom), 7.84 (2H, AB—syst., CH~arom.), 8.74 (1H, s, CH pyrazol.).

Synthesis of methyl hloro-6—fluorophenyl)(5~(ethoxycarbonyl)—1-phenyl-1H— pyrazolyl)isoxazole—4-carboxylate derivatives: examples 6, 8, 9, 10, 13, 15, 26, 29, 34, 35, 38, 39, 40, 41 and 45 ng from methyl 3—(2—ch10ro—6-fluorophenyl)—5-(1-(dimethylamino)—4—ethoxy-3,4— dioxobut—l—en—2—yl)is0xazole-4—carboxylate, which is commercially available from Bionet Research Intermediates, the le ring was constructed using differently substituted arylhydrazines as described for example 11.

The s nthesis of com ounds of the Illustrative Exam les is described in the followin : General procedure for the preparation of S-methylisoxazolecarboxylate, exemplariiy shown for Ethyl 3-(2-chlorofiuorophenyl)methylisoxazole—4—carboxylate H N O HC Cl 3 OR1 0R1 NH20H*HCI 0 H A. V r 101 CH3 r '1 —W R N , ———-——- R R 0 O DMF 6H Na R \N’ HCI EtOH EtZO A B C D F H Wovem l _0H EMF, Hit! “NH Me ElOH, E129 To a stirred mixture of aldehyde A (5 g, 31,5 mmol), l (10 mL), ice and water (30 mL) and hydroxylarnine hydrochloride (2.8 g, 40.3 mmol), an aqueous solution of NaOH (3.6 90 mmol in 5 mL of water) was added. The e was stirred for an hour and extracted with 40 mL of ether to remove ties. The aqueous layer was neutralized with HCl and extracted with ether (2x50mL). Extracts were dried over NagSO4 and evaporated to give 5.19g of oxirne B (yield 93 %).

To a solution of aldoxime B (2 g, 11.5 mmol) in 10 mL of DMF, 0.23 g (1.72 mmol) of N— chlorosuccinimide (NCS) were added at room temperature. Dry hydrogen de was bubbled into the DMF on until the reaction temperature rose up to 35°C. Then 1.31 g (9.8 mmol) of NCS was added portionwise, the temperature was kept at 35—45°C. The reaction mixture was cooled to room temperature and poured onto 30 mL of ice and extracted with ether. Combined extracts were dried and evaporated to give 2.5 g of hydroxamoyl chloride C as a yellow oil.

A on of ethyl sodium acetoacetate [from sodium (0.3 g, 13 mmol), dry ethanol (10 mL) and ethyl acetoacetate (1.7 g, 13mmol)] was added slowly to a stirred solution of the hydroxarnoyl chloride C (2.5 g, 1211111101) in 20 mL of ether at 06°C. The mixture was d to warm to room temperature overnight, and the solvent was evaporated in vacuo.

The residue was taken up with water and ether, the ether extract was evaporated and the product was purified by column chromatography (hexane) to give 2.2 g of the isoxazole derivative D as a ess oil.

Ethyl 3-(2-chloro—6-fluorophenyl)~5—methylisoxazole—4-carb0xylate, oil, yield 67% Result of LC/MS [M+H]+: 283.95 1H NMR (DMSO-Ds, CC14): 1.06 (3H, t, CH3), 2.78 (3H, s, CH3), 4.09 (2H, q, CH2), 7.26 (1H, t, CH—arorn.), 7.39 (1H d, CH—arom.), 7.55 (1H, m, CH~ atom).

Synthesis of methyl 3-(2—chloro—6~fluorophenyl)-S-(2-(dimethylamino)vinyl)isoxazole carboxylate \O F O O F / e O \ 0+ / N— 6 h reflux / N~O cn CI To a solution of 0.1 g (0.3708 mmol) methyl 3—(2~chloro—6-fluorophenyl)-5—methylisoxazole— oxylate in 10 mL dry toluene, 0.15 mL (0.7417 mmol) tert—Butoxy— bis(dimethylarnino)methane (Bredereck’s reagent) were added. The reaction mixture was heated under reflux for 6 h.

The mixture was concentrated in vacuo and was dried in high vacuum. Petroleum ether added to the oily residue and crystalline product ped. The product was collected by filtration, and 0.070 g (yield of theory: 58%) of the vinyl ole derivative were obtained.

Result of LC/MS [M+H]+: 325.0; IH NMR (DMSO'dfi; CCl4): 3.02 (6H, s, N-CH3), 3.53 (3H, s, CH3), 5.54-5.58 (1H, d, CH), .76 (1H, d, CH), 7.32-7.38 (1H, dd, CH—arom.), 7.44- 7.47 (1H, d, CH—arom.), 7.56—7.58 (1H, d, CPI—atom.) Synthesis of methyl 3-(2-chloro-6—flucrophenyl)—5-(1—(dimethylamino)-4,4,4—trifluoro—3- oxobut—1-en-2—yl)isoxazole—4-carboxylate 0.,— To a solution of 0.5 g 7 mmol) methyl 3—(2—chloro-6—fluorophenyI)—5—[2- (dimethylamino) vinyl]isoxazole—4—carboxylate in 20 mL dry dichloromethane, 0.32 mL (2.309 mmol) trifluoroacetic anhydride were added dropwise under ice—bath cooling. The reaction mixture was stirred for 3 h at room ature.

Afterwards the mixture was concentrated in vacuo and was dried in high vacuum. The 0in residue crystallized from petroleum ether, and the product was collected by filtration to yield 0.604 g (yield of : 94%) of the 5~(l—(dimethylamino)—4,4,4-trifluoro—3-oxobut-1—en—2- yl)isoxazole derivative. Result of LC/MS {M+H]+: 420.9; 1H NMR (DMSO— d6; CC14): 2.63 (3H, s, N-CHg), 3.40 (3H, s, N-Cllg), 3,59 (3H, s, CH3), 7.40746 (1H, dd, CH—arom.), 7.51- 7.55 (1H, d, CH—arom.), 7.64-7.66 (1H, d, CH—arom) 8.12 (1H, s, CH).

Synthesis of methyl 3”(Z-chloro-é-fluorophenyl)—5-(1-(3-chlorophenyl)—5— (trifluoromethyl)—1H-pyrazol—4-yl)isoxazole—4-—carboxylate dry ethanol 4- A J\ + N CI/@ N’NH2 H K 2 h reflux To a solution of 0.5047 g (1.1994 mmol) methyl hloro—6—fluorophenyI)—5-(1— (dimethylamino)—4,4,4—trifluoro—3—oxobut—l—en-2—yl)isoxazole~4~carboxylate in dry ethanol, 0.1790 g (0.9995 mmol) rophenylhydrazine and 0.17 mL (0.9995 mmol) N,N~ Diisopropylethylamine (DIPEA) were added. The on mixture was heated under reflux for 2 h. The product was isolated by using column chromatography (Petroleum ether:Diethyl ether 80:20), and 0.305 g (yield of theory: 61%) of the pyrazolyl—isoxazole derivative were obtained. Result of LC/MS [M—FHT: 499.9; 1H NMR (DMSO~ d5; CC14): 3.66 (3H, s, CH3), 7.45—7.50 (1H, dd, CH—arom.), 7.55—7.58 (1H, d, CH—arom.), 7.65—7.77 (1H, d, CPI-mom), 7.65—7.77 (1H, dd, CH—arom. phenylhydrazine), .77 (1H, d, Cl-I—arom. phenylhydrazine), 7.85 (1H, s, CH—arom phenylhydrazine), 8,56 (11-1, 5, lupyrazole) Synthesis of (2-chloro-fi—fluorophenyl)(2-(dimethylamino)vinyl)isoxazole—4— carbonitrile F / \ dry e + N 0+ O \N/ / —<N-~ 7hreflux Cl Bredereck's reagent To a solution of 1.5 g (6,3389 mmol) 3-(2-chloro~6-fluorophenyl)-5~methy1isoxazole—4- carbonitrile in 100 mL dry toluene, 2.10 g (£26779 mmol) tert-Butoxy— bis(dimethylamino)rnethane (Bredereck’s reagent) were added. The reaction mixture was heated under reflux for 12 h. The mixture was concentrated in vacuo and was dried in high vacuum. Petroleum ether was added to the crude material to trigger crystallization of the t. The t was collected by filtration, and 1.79] g (yield of theory: 95.9%) of the vinyl isoxazol derivative were obtained. Result of LC/MS MH+: 292.0; 1H NMR (DMSO~ d6; C014): 2.93 (3H, s, N-CHg), 3.17 (3H, s, N-CHg), .20 (1H, d, C2112), 7.74—7.78 (1H, d CgHz), 7.45—7.52 (1H, dd, (EH-arena), 7.57~7.59 (1H, d, CH—arom.), 7.65-7.71 (1H, d, CHv arorn .) Synthesis of (Z)-3m(2—chlorofluorophenyi)(1-(dimethylamin0)—4,4,4—trifluor0 oxobut—l-en.yl)isoxazoIe—4—carhonitrile To a solution of 0.5 g (1.714 mmol) (E)—3—(2"chlor0-6—fluorophenyl)—5-(2- (dimethylamino)vinyl)isoxazole-4—carbonitrile in 20 mL dry dichloromethane, 0.36 mL (2.571 mmol) trifluoroacetic anhydride were added dropwise under ice-bath g. The reaction mixture was stirred for 2 h at r.t.. Afterwards the e was concentrated in vacuo and was dried in high vacuum. Petroleum ether was added to the crude material to trigger crystallization of the product, which was collected by filtration to obtain 0.625 g (yield of : 94%) of the 5—(1—(dimethylaniino)-4,4,4—trifluoro—3-oxobut-l—en—Z-yl)isoxazole derivative. Result of LC/MS MH+z 388.0; 1H NMR (DMSO‘dfi; CC14): 2,75 (3H, s, N-CH3), 3.46 (3H, s, N-CH3), 7.53-7.59 (1H, dd, CH—arom) 7~64—7.67 (1H, d, CH—arom.), 7.73781 (1H, d, Cl-Inarom) 8.23 (1H, s, CH) Synthesis of 3-(2-chloro—fi-fluorophenyI)—5~(l-(3—chlorophenyl)—5w(trifluoromethyl)-IH- pyrazolyi)isoxazolecarbonitrile dry ethanol N + Q NH + /L J\N —--————h- C! N‘ 2 H l\ 3h reflux F F F To a solution of 0.1 g (0.2579 mmol) (Z)—3«(2—chioro—6—fluoropheny1)(1—(dimethy1amino)— 4,4,4-t1ifluoro~3—oxobut—l—en—2-yl)isoxazole—4ncarbonitriie in dry ethanol, 0.0462 g (0.2579 mmol) 3-Chlorophenylhydrazine and 0.78 mL (0.2579 mmol) DIPEA were added.

The reaction mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo and was dried in high vacuum. ation was achieved by using pTLC, and 0.0037 g (yield of theory: 3.0%) of the lyl—isoxazole tivewere obtained. Result of LC/MS MH+2 466.9; 1H NMR (DMSO— d5; C014): 7.73—7.97 (6H, m, CH—arom.), 8.04 (1H, s, CH—arom.), 8.81 (1H, s, CH—pyraz.) sis of 3-(2-ehlorofluorophenyl)-S—(1-(3—ch10rophenyI)—5-(trifluoromethyk)-1H- pyrazol—4—yI)(lH-tetrazolw5-yl)isoxazole (example 1—3) N3Na NH4C1 To a solution of 0.115 g (0.246 mmol) cyano-isoxazole in 10 mL dry DMF, 0.080 g (1.231 mmol) sodium azide and 0,065 g (1.231 mmol) ammoniumchloride were added. The mixture was stirred 4 hours at 909C. The mixture was filtrated, and the filter cake was washed with aeetonitrile. The filtrate was evaporated in vacuo. The brown, oily residue was purified by pTLC (petroleum ether:ethylacetate 80:20 + 5 % acetic acid) and dried in vacuum to yield 49 mg (61%) of e I~3. Result of LC/MS MH+: 509,71; 1H NMR (DMSO—dfi; CC14): 7.42—7.48 (1H, t, CH—arom.), 7.51—7.534 (1H, d, CH—arom.), 7.63-7.55 (4H, m, CH—arom), 7.81 (1H, s, CH—arom.), 8.58 (1H, s CH-pyraz.) Examples [-1 and [-2 were synthesized in analogy. sis of 3-(2-chloroflu0rophenyl)-5—(l-(3—chlorophenyI)-5—(trifluoromethyl)-1H- pyrazolyl)(thiazol~2~yl)isoxazole (example [-5) F GE F CI F C' C! P F CI F N~o F C' NO N oH r NaOH f / / / / NH4C£ N N r/ / N© “'N EtoH “N ' HBTU “— F0 F0 N 0 OH oIPEA Fo K NHz 1: Cl F F C1 \/ Y\CI0 C1 F F Ni N50 Lawesscn'sreagent 0 CI " , / ————~————————I- / / / N -——-—-—-—I- 1N1 ““1 N FS F3 \N NH2 \_; 7.13g (13.86 mmol) of the ethyl ester were dissolved in 150 mL ethanol, and 10 mL NaOH (2.0 mmol) were added. The mixture was heated under reflux for 1 hour. The l was evaporated in vacuum and the basic solution was ed to pH 2 by adding hydrochloride acid (10% aq). The acidic solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the e was dried in vacuum to yield 6.0 g (89%) of the ponding carboxylic acid.

To a solution of 6.0 g (12.34 mmol) of the carboxylic acid and 1.98 g (37.021 mmol) ammoniumchlorid in 20 mL dry DMA, 9.36 g (24.681 mmol) HBTU and 6.45 mL (37.021 mmol) DIPEA were added. The mixture was stirred 3 hours at r.t.. Ethyl acetate was added to the reaction mixture, and it was washed twice with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The 0in residue became solid by drying in vacuum. The solid was washed with petroleum ether, filtrated and dried in vacuum to yield .37 g (90%) of the corresponding amide.

To a solution of 5.355 g (11.036 mmol) of the amide in 20 mL dry dioxane, 4.463 (11.036 mmol) Lawesson‘s Reagent were added. The mixture was stirred for 4 hours under reflux. Then the solvent was removed in vacuo. The 0in residue was purified by column chromatography (petroleum etherzethylacetate 80:20) to yield 1.716 g (31%) of the respective carbothioamide.

To a solution of 1.022 g (2.039 mmol) of the carbothioamide in 20 mL dry DMF, 0.5 ml. (4.07? mmol) 1,2—Dichloroethyl ethyl ether were added. The mixture was stirred 2 hours at 90°C and then 2 hours at 130°C. The solvent was removed in vacuo, and the oily residue was purified by column tography (petroleum ether:ethyacetate 80:20) to yield 180 mg. (17%) of example 1-5. Result of LC/MS MH+z 524,9; 1H NMR (DMSO—dé; CCh): 5 .53 (1H, t, CIT—atom), 7.58—7.60 (1H, d CH~arom.),7.65-7.66 (1H, d, CH—arom,) 7.65—7.67 (1H, WO 01261 d, m.), 7.71—773 (1H, t, m.), 7.744.75 (1H, d CH—arom.), .75 (1H, s, CH—thiaz.), 7.83 (1H, s, CH—arom), 7.84—7.85 (1H, s,CH~thiaz.), 7.59 (1H, s, CH—pyraz.) An alternative route was realized for examples 113—29 and IB-30, exemplarily shown for IB-29: NHdcf. HOBt on’s reagent m—w—p EDCI, NMM 3 -(2—chloro~6—fluorophenyl)—5 —( 1 - (2—chloropheny1)—5-(t1ifluorornethyl)— l H—pyrazol—4n yl)isoxazole-4~carboxylic acid (100 mg, 0.21 mmol), ammonium chloride (10 mg, 0.21 mmol), HOBt ( 27.8 mg, 0.21 mmol) and EDCI (38.3 mg, 0.25 mmol) were dissolved in 2 mL dry DMF. N—Methylmorpholine (104.2 uL, 2.1 mmol) was added and the reaction was stirred at room temperature for 72 h. DMF was removed by evaporation. An aqueous solution of aqeous 5% citric acid was added. The itate was filtered and dried. The mixture was purified by pTLC 2/MeOH 95/5) to give 50 mg (yield 50 %) of the respective carboxamide.

The Lawesson’s reagent step was performed as described within the synthesis of example 1-5.

To a solution of 3—(2—chloro~6—fluorophenyl)—5~(1—(2—chloropheny1)-5.~(trifluoromethyi)—lH— pyrazoly1)isoxazole—4—carbothioarnide (15 mg, 0.03 mmol) in 0.5 mL ethanol was added 2 chloroacetaldehyde (0.046 mL, 0.4 inmol). The mixture was stirred for 48 h at 85°C. The mixture was concentrated, diluted with dichloromethane and washed with water (3 X), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil purified by pTLC (DOM : MeOH 100:5) to give 10.4 mg of example 13—29 as a yellow oil (yield 66%). Result of LCMS MIT“: 524,57; 1H NMR (CD013): 5 7,11 (m, 1H), 7,28 (m, 1H), 7,33—7,42 (m, 6H), 7,52 (m , 1H), 8,37 (s, 1H) Synthesis of methyl 3~(2-chlorofluorophenyl)(1-(2,4-difluorophenyl)—5- (trifluoromethylylH-pyrazol—4-yl)isoxazolecarboxylate (example [—4) 3—(2-ch10ro-6—fiuorophenyl)—5—(l —(3-chlorophenyl)—5—(trifiuoromethyl)—1H-pyrazolyl) isoxazole—4—carb0thioamide (50.0 mg, 0.100 mmol) and Chleroacetone (0.04 mL 0.5 mmol) were dissolved in 10 mL dry l. The mixture was stirred at r.t. for 4 h. Purification of product was achieved by pTLC (petroleum ether:ethyl acetate 80:20). Drying in high vacuum yielded 20 mg (3 7%) of e [-4 as a colorless oil. Result of LC/MS MH+: 538,76 1H NMR (DMSO-dg; CC14): 2.32 (s, 1H, CH3), 6.72 (s, 1H, az.), 7.04—7.52 (m,7H, arom.), 8.33 (s, 1H, CH—pyraz.); Synthesis of o—3-(2-chloro—6—fluorophenyl)—5-(l—(3-fiu0rophenyl)—5n (trifluoromethyl)~1H—pyrazoi-4—yl)isoxazole 0.32 g (0.70 mmol) of the carboxylic acid were dissolved in aq. NaOH solution (20 mL water + 0.115 g NaOH). Bromine (0.34 g, 2.1 mmol) was added slowly and dropwise to this solution at stirring and cooling (0—50C). Stirring ued for 2 hours at 0—5°C and for 2 days at r.t. The precipitate was filtered off and suspended in 5% aq. NaOH solution (10 1nL). After 2 hours of stirring solids were filtered off, washed with water and dried in vacuum to yield 0.15 g (0.30 mmol, 42%) of the brominated isoxazole as white crystals. Result of LC/MS MH+1 505.7; II-l NMR (DMSO-dfi; CC14): 7.35 — 7.48 (m, 4 H) 7.52 (d,J=8.28 Hz, 1 H) 7.61 ~ 7.74 (m, 2 H) 8.4 (s, 1 H) Synthesis of methyl 3—(2-chloro—6-flu0rophenyl)—5-(1-(3-fluorophenyl)—5— (trifluoromethyl)-1H-pyrazolyl)isothiazolecarboxylate (example 1-7) A solution of 102 mg (0.217 mmol) of the carboxylic acid in 8 mL SOC12 was refluxed for 3 h. Volatiles were evaporated in vacuum thoroughly. The residue was dissolved in 8 mL absolute dioxane and added dropwise to a stirred mixture of 825 mg N2H4*H20 and 6 mL absolute dioxane. Volatiles were evaporated, some water was added to precipitate an oily pink solid. Water was removed, residue was washed with water, then treated with 5 mL water with drops of AcOH and finally washed with water. The product was lly extracted by boiling heptane (38 mg) and partially extracted by ether with further ng of ethereal solution by heptane (39 mg). The hydrazide was attained in a total yield of 77 mg (73%).

A solution of the hydrazide (125 mg, 0.258 mmol) in 2.0 mL methyl orthoether was heated to g temperature and immediately cooled to rt. Further additional 2 mL of methyl orthoether was added and the solution was refluxed for 1.5 days. Excess orthoether was evaporated, the residue was d with boiling heptane and evaporated. The residue was purified by column chromatography on silica gel (eluent EtOAc/heptane 1/3 to l/l), the on with pure t was combined and evaporated to give 47 mg (3 7%) of example L7.

Result of LC/MS MH+: 494.8; EH NMR (DMSO—dg; CCl4): 7.20 (td, $78.53, 0.75 Hz, 1 H) 7.24 - 7.44 (m, 5 H) 7.47 - 7.59 (m, 2 H) 8.35 (s, 1 H) 8.40 (s, 1 H).

Synthesis of hlorofluorophenyl)(1-(3—chlorophenyl)(trifluoromethyl)-1H- pyrazoiyi)—4-(oxazol-5*yl)isoxazole (example I-S) HBTU CE erm + N flu. DEPEA To a solution of 10.8 g (22.2 mmol) of the carboxylic acid, 2.17 g (leq) N,O— ylhydroxylamine and 8.42 g (leq) HBTU in DMF, 3.68 mL DIPEA were added. The mixture was stirred overnight at r.t. The solvent was removed in . The residue was dissolved in ethyl acetate and extracted with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuum. The product was isolated by column chromatoghraphy (6:4 petroleum etherzethyl acetate). The product resulting Weinreb amide was dried under vacuum to yield 2.28 g (19%).

To an ice—cooled on of 1.0 g 5 mmol) of the Weinreb amide in dry THF 0.95 mL (0.5 eq 2 2 eq H) lithiumaluminium hydride were added. After stirring for 30 min, TLC (4:1 eum ether:ethyl acetate) shows no more educt. To quench the remaining lithiumaluminium hydride, ice was added carefully to the mixture. For further purification, the on was diluted with ethyl acetate and extracted three times with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous ium sulfate and the solvent was removed in . The resulting aldehyde was dried under vacuum to yield 520 mg (58%).

To a solution of 0.5 g (1.0634 mmol) the aldehyde in dry methanol (10 mL), 5 mL sodium methanolate (from 83 mg sodium in 5 mL dry methanol) were added carefully under argon.

After stirring for 5 min at r.t., 0.25 g (1.2661) TosMIC were added stepwise. The mixture was stirred under reflux for 2 hours. The product of example 1-8 was isolated by preparative HPLC/MS to yield i28mg (24%). Result of LC/MS MH+2 508.78 1H NMR (DMSO‘dfi; CC14): 6.92 (1H, s, CH—oxazole), 7.49-7.78 (6H, m, CH—arom.), 7.87 (1H, s, CH—arom.), 8.41 (1H, s, CH—oxazole.), 8.50 (1H, s, CH—pyraz.) An alternative route was realized for es 113-28, 13-32 and 113-33, exemplarily shown for IB-ZS: 3 —(2-chloro-6—fluorophenyl)—5—(1-(2—fluoropheny1)—5-(trifluoromethy1)—1H-pyraz01—4— yl)isoxazole-4—oarboxy1ic acid (0.3 g, 0.64 mmol), N,O—Dimethylhydroxylamine (0.062 g, 0.64 mmol), HOBt (0.082g, 0.064 mmol) and EDCE g, 0.76 mmol) were dissolved in 3 mL dry DMF. N—Methylmorpholine (104 uL, 6.4 mmol) was added and the reaction was stirred at room temperature overnight. DMF was removed by evaporation. An aqueous on of 5% citric acid was added. The precipitate was filtered and dried. The product purified by pTLC (PE/BE 7/3) to give the Weinreb amideas an orange solid (149 mg, yield 45%). The subsequent steps were performed as described for the synthesis of example 1-8.

Within the final step of this synthetic route in similar conversions, byproduct formation was observed in a few cases resulting from a replacement of the aromatic fluoro substituent by olate, giving rise to examples IB—‘31 and IB-34.

Synthesis of 2—(3-(2-clllorofluorophenyl)—5—(1—(3—fluorophenyl)—S—(trifluoromethyl)- 1H—pyrazol-4~yl)isoxazol—4-yl)thiazolol (example 1-9) A e of 0.145g mol) ofthe above thioamide, 0.60g (0.42mrn01) bromoacetic acid and SmL toluene was heated under reflux for 2h. Then reaction mixture was evaporated in vacuum. Thick oil was washed with water and purified by column chromatography on silica gel, using CCl4, then CHClg/CCh (1 :1, v/v) as eluents. Yield of glassy nce of example 1-9 is 0.063g (40%). Result of LC/MS MH+: 525.01; 1H NMR (DMSO'dfi; CCla): 7.60- 7.94 (7H, m, CH-arom.), 8.62 (1H, s, CI-I-pyraz.), 8.84 (1H, s, CH-thiazole), 10.81 (1H, s, Synthesis of 3—(2-chloro—fi-fluorophenyl)—5-(1-(3~fluorophenyl)—5—(trifiuoromethyl)-1H- pyrazol-4—yl)—4-(4-methoxythiazol—Z—ylfisoxazole (example 1-10) NaOH F H20 —--—+ CH3: N N' a F OH 0‘.

To a stirred solution of 52 mg (0.1 mmol) hydroxyl thiazole le 1—9) in 5 ml e were added alternately in small portions 0.140 g (1.0 mmol) of CH31 and a solution of 40 (1.0 mmol) NaOH in 1 mL water. The pH has to be kept at 8—9 and the temperature at 40- 50°C. Then the reaction e was stirred for 1 hour at 40—500C, diluted with 15 mL water, neutralized with HCl to pH 6-7. Thick oil was extracted with CCl4, dried with MgSO4 and purified by column chromatography on silica gel, using CC14, then CHC13 / CCl4 (1:1, v/v) as eluents. Yield of glassy substance of example 1—19 is 20 mg (37%). Result of LC/MS MH+2 539.03; 1H NMR (DMSO'dfi; C014): 3.73 (3H, s, CH3), 6.59 (1H, s, CH—thiazole), 7.52» 7.78 (7H, m, CH—aro1n.), 8.62 (1H, s, CH-pyraz.) Synthesis of 2—(3-(2-chloro—é-fluorophenyl)—5—(1-(2—fluorophenyl)—5—(trifluoromethyl)— 1H—ZIyrazol-4~yl)isoxazoln4-yl)methyl~1,3,4-0xadiazole (example 1-11)Cl N‘O GL0/U\ N70 P FF F :N MNH2 MN N (Di/NH F A solution of 3-(2—chloro—6—fluoropheny1)—5—[1—(2—fluorophenyl)(trifluoromethyl)—1H— pyrazol—4-yl]isoxazole—4—carbohydrazide (66 mg, 0.137 mmol) in acetic anhydride (3.5 g) was kept in a sealed tube at 140°C for 18 hours. The solvent was removed in vacuum. Residue was 2012/051357 re—evaporated with ethanol, and treated with boiling heptane. The concentration and cooling of e extract gave a solid. Column chromatography on silica gel (eluent EtOH/heptane, 1/1) gave 40 mg (58%) of ess powder of example 1-11. Result ofLC/MS Nil-1+: 508.05 IH NMR (400 MHz, METHANOL—d4) 5 ppm 2.44 (s, 3 H) 7.28 — 7.35 (m, 1 H) 7.41 — 7.49 (111,3 H) 7.69 (s, 3 H) 8.48 (a, Jmoso Hz, 1 H) Alternatively, the reaction can be performed under microwave ation as realized for examples 113—4, IB-lO, IB-«lS, 113-19 and IB—26, exemplarily shown for IB~4.

F o .

A similar mixture as generated within the synthesis of example 1—1 1, consisting of hydrazide in acetic anhydride, was heated under microwave irradiation at 140°C for 6 h. The e was diluted with dichloromethane and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by pTLC (BE/PE 1:1).

Synthesis of N—(3-(4-(3-(2-chlcro~6—fluorophenyl)—4—(5—methyl—1,3,4-0xadiazol yl)isoxazolyl)(trifluoromethy1)—1H—pyrazol-I—yl)phenyl)acetamide le IB-l 1) j H J? HN J5o -(1—(3 -acetamidophenyl)—5—(trifluoromethyl)—1H-pyrazol—4—yl)—3—(2-chlor0-6—flu0rophenyl) isoxazole-4ucarboxy1ic acid (100 mg, 0.196 mmoi), acethydrazide (16.0 mg, 0.216 mmol) and HATU (97.1 mg, 0.255 mmcl) were dissolved in THF (2.00 mL). DIPEA (268 ML, 0.589 mmol) was added and the resulting mixture was stirred at r.t. for 3.5 11. Additional acethydrazide (160 mg) and HATU (100 mg) were added and stirring was continued at r.t. for 19 h. The reaction mixture was diluted with CH2C12 (40 mL) and washed with 1N aq. HCl (1 x 20 mL) and water (2 x 20 mL). The combined aqueous layers were racted with CH2C12 (20 mL) and the combined organic layers were dried over Na2804 and concentrated in vacuo. The e was purified by pTLC (EtOAc/MeOI—I = 9:1) to give 34 mg of the intermediate as brown oil (yield 31 %).

The intermediate N—(3-(4~(4—(2—acetylhydrazinecarbony1)—3~(2—chloro—6—fluorophenyl) isoxazolmS-yl)-5—(trifluoromethyl)—1H~pyrazol—1—y1)phenyl)aceta1nide (25.0 mg, 0.044 mmol) was dissolved in acetic acid (1.50 mL). Acetic anhydride (104 uL, 1.1 mmol) was added and the reaction mixture was heated in the microwave to 140 °C for 8 h.The reaction mixture diluted with water (40 mL) and extracted with (II-12012 (3 x 20 mL). The combined c layers were washed with water (10 mL), dried over NaZSO4 and concentrated in vacuo.

The residue was purified by pTLC (CHgClszeOH 2 9:1) to give 2.6 mg of example IB—ll as a yellow solid (yield 8%). Result of LC/MS MH+: 546,87; 1H NMR (MeOD): 5 ppm: 2,05 (s, 3H), 2,33 (s, 3H), 7,20 (m, 2H), 7,33—7,61 (m, 4H), 7,93 (s, 1H), 8,39 (s, 1H) Synthesis of 3~(2—chlor0fluorophenyl)(S-methyl-1,3,4-thiadiazol~2-yl)~5-(1—(pyridi11~ ~(trifluoromethyl)-lH-pyrazolyl)isoxazole (example ) / O ? F / N O N l N‘O / i \. /U\O/u\ \ / / Mfg!“ Lawesson's reagent FD 1211-: 0 To a solution of 3—(2~chlorc-6—fluorophenyl)-5—(l—(pyridin—4—yl)—5-(trifluoromethyl)—lH- pyrazol-4—y1)isoxazole—4—carbohydrazide (0.03 g, 0.06 mmoi) in acetic acid (0.03 mL) was added acetic anhydride (0.01 mL, 0.06 mmol). The mixture was stirred at r.t. for 2 h. The mixture was diluted with dichloremethane and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 29 mg of the ediate as a brown oil.

To a solution of N'—acety1—3—(2—chloro-6—fluor0phenyl)~5—(l—(pyridin—4—yl)—5-(trifluoromethyl) razol—4—yl)isoxazole—4—carbohydrazide (0.029 mg, 0.01 mmol) in dioxane (1.5 mL) was added Lawesson's Reagent (23.1 mg, 0.01 11111101). The mixture was d at reflux for 30 min. The mixture was then diluted with dichloromethane and washed with water (3 x), dried over sodium sulfate, fi1tered and concentrated under reduced pressure.

The product was purified by pTLC (CH2C12:MeOH 100:5) to give 7.7 mg of example IB-22 as an oil (yield 26%). Result of LC/MS MIT“: 506,69; 1H NMR (CDC13)I 5 ppm: 2,27 (s, 3H), 7,18 (m, 1H), 7,30 (d, 1H), 7,36 (m, 2H), 7,57 (m, 111), 8,00 (s, 1H), 8,41 (d, 1H), 8,58 (d, 1H) es IB—ZO, IB—Zl, 113—23, IB-27, and IB~3 were synthesized in analogy to example IB—22. sis of N—(3-(4-(3-(2—chloro—6-fluorophenyl)(5-methyl-1,3,4-thiadiazol yl)isoxazolyl)—5-(trifluoromethyl)—1H-pyrazol—l-yl)phenyl)acetamide (example IB-12) Treatment of N-(3—(4—(4—(2-acetylhydrazinecarbonyl)—3—(2—chloro-6—fiuorophenyl)isoxazol—5— yl)—5—(trifluoromethy1)-IH-pyrazol—l-yl)phenyl)acetamide with Lawesson’s reagent aCcording to the procedure described for example lB-22 resulted in the formation of the thiadiazole but simultaneously in the formation of a thioamide at the aryl substituent at the pyrazol ring. For a regeneration of the acetylamino substituent, N—(3.—(4—(3—(2-ehlorofluorophenyl)-4—(5— methyl-1,3 ,4—thiadiazol-2~y1)isoxazol—5-yl)—5—(trifluoromethyl)—1H—pyrazol—l— yl)pheny1)ethanethioamide (19.0 mg, 0.032 mmol) was ved in CHQCIZ (2.0 mL). 3- Chloroperoxybenzoic acid (70%, 16.2 mg, 0.065 mmol) was added and the resulting mixture was d at r.t. for 1 h. The on mixture was diluted with sat. Na2803 (10 mL) and stirred vigorously for 10 min. Satd NaI-IC03 (10 mL) was then added and the mixture was extracted with CHZCig (3 X 15 mL). The combined organic layers were washed with saturated NaHC03 (10 mL), dried over Na2804 and trated in vacuo.

The residue was purified by pTLC (CH2Clz/MeOH = 95:5) to give 10.2 mg of a yellow solid (yield 37 %). Result of LC/MS MH+z 562,75; IH NMR (CD013): 6 ppm: 2,10 (s, 3H), 2,62 (s, 3H), 7,11 (t, 1H), 7,33 (d, 1H), 7,35—7,48 (m, 2H), 7,65 (m, 3H), 8,21 (s, 1H) Synthesis of 3—(2-chlorofluorophenyl)-S-(1-(2—fiuorophenyl)(trifluoromethyl)—1H- pyrazolu4-yl)F—4-(5-methyl-I,3,4-thiadiazol—2~yl)isoxazole (example 1-12) NO HBTU DIFEA / FZN/QW’/ F F0 ca HQNH 3.44 g (7.3 mmol) of 3—(2~chloro~6—fluoropheny1)—5~(1-(2-fluorophenyl)—5—(trifluorometbyl)— 1H-pyrazol—4—y1)isoxazole—4—carboxylic acid were dissolved in 19 ml of DMF. 2.92 g (7.7 mmol) of HBTU and 6.06 1111 (36.65 mmol) of DIPEA were added at r.t.. After 20 min.

W0 2012/101261 stirring at r.t., 1.63 g (22 mmol) of acethydrazine were added and the mixture was stirred at r.t. overnight. The mixture was d with ethyl acetate (60 m1) and washed with 60 ml water. The aqueous layer was re—extracted with EB and the combined organic layers were dried over MgSO4, filtered, and the t was removed under reduced pressure. The residue was purified via pTLC (CH2C12/MeOH 95/5) to give 1.3 g of the intermediate as an orange solid (yield 34%). The thiadiazole formation out of the intermediate was achieved using Lawesson’s reagent according to the procedure described for example 113—22.

Synthesis of 3-(2-chloro-6—fluorophenyl)—5—(1—(3-chlorophenyI)—5-(trifluoromethyl)—1H- pyrazolyl)—4-(1,3,4-thiadiazol—2-yl)isoxazole (example IB—S) JOL N O H OH WNQ Lawesson's reagent HNVO 3n(2-chloro-6~fluorophenyl)—5—(l - (3 ~chlorophenyl)—5~(trifluoromethyl)—1H-pyrazol—4- yl)isoxazole—4—carbohydrazide (85 mg, 0.2 mmol) was treated with formic acid (6.4 uL, 0.2 mmol). The e was stirred at r.t. for 72 h. To the reaction mixture was added water, the resulting precipitate was collected, washed with water and dried in vacuum to give 61 mg of the intermediate as a colorless solid. To a solution of the intermediate 3—(2-chioro—6- henyl)-5—(1 -(3—chlorophenyl)—5-(trifluoromethyl)—1H—pyrazol-4—yl)—N'— isoxazole-4ucarbohydrazide (20 mg, 0.038 mmol) in dioxane (2 mL) was added Lawesson's Reagent (0.033 mL, 0.1 mmol). The mixture was stirred at reflux for 3 h. The mixture was diluted with romethane and washed with water (3 x), dried over sodium sulfate, d and concentrated under reduced pressure. The product was purified by pTLC (BE/PE 1:1) to give 6 mg of example 113-8 as a colorless solid (yield 31 %). Result of LC/MS MH+z 525,72; 1H NMR (MeOD): 6 7,35 (t, 1H), 7,49 (d, 1H), 7,59—7,71 (In, 5H), 8,37 (s, 1H), 9,38 (s, 1H) Synthesis of 3~(2—chlerofluorophenyl)—5-(1-(3—fluorophenyI)(trifluoromethyl)-1H— pyrazol—4-yl)~4~(furan~3-yl)isoxazole (example 1-13) The tube was charged with o—3—(2~chloro—6-fluorophenyl)—5—(1—(3~fluorophenyl)-5~ (trifluoromethyl)-lH—pyrazol—4—yl)isoxazole (30 mg, 0.06 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g), 1.5 mL 1,2-Dimethoxyethane and was purged with argon. Then furan~3—ylboronic acid (0.012 g, 0.1 mmol) and an aqueous solution of cesium carbonate (0.05 g in 0.2 mL) were added. The reaction mixture was heated under microwave irradiation to 100°C for 2 h. The solvent was evaporated and the product isolated by column chromatography (hexane : ethyl acetate 25 : 1) to obtain 5 mg (17%) of a yellowish solid of example 1—13. As a major side reaction, hydrodebromination was observed.

Result of LC/MS MH+: 492.05; 1H NMR (CDC13; CCl4): 6.18 (1H, m, CH-furyl), 7.12- 7.53 (9H, m, CH—arom.+ CH—furyl), 7.91 (ll-I, s, CH—pyraz.) Example 1-17 was prepared in analogy to example 1‘13. .

A similar procedure was applied to the synthesis of es 1-14, IB-6, IB-7, IB-9, and IB- 24, only replacing tetrakis(triphenylphosphine)palladium(0) by dichlorobis(triphenylphosphine) palladium (for example 1-14), and for examples IB-fi, IB~7, IB-9 and 18—24 by also replacing an aqueous solution of cesium carbonate by an aqueous solution of sodium carbonate. sis of 3—(2—chlorofluorophenyl)—5-(1—(3—fluorophenyl)—5-(trifluoromethyl)-1H- pyrazolyl)—4-(thiophen~3~yl)isoxazole (example 1-16) A microwave tube was charged with 4-bromoisoxazole (0.03 g, 0.06 mmol), Pd(PPh3)C12 (0.003 g), DME (1.5 mL) and purged with argon. Then 3-thienylboronic acid (0.014 g, 0.1 mmol) and an aqueous solution of C82CO3 (0.05 g in 0.2 mL) were added. The reaction e was heated under microwave ation to 100°C for 1.5 h. The solvent was evaporated and the resulting mixture was separated by column chromatography (hexane, hexane:EtOAc 50:1, :EtOAc 25:1) to give 0.010 g of the desired product. (yield 33%).; 1H NMR ): 6,85 (1H, m, CH—thienyl), 7,04 (1H, m, CH—thienyl), 7,11 (1H, m, CH—arom.), 7,24-,54 (7H, m, CH~arom.+CH-thienyl), 7,80 (1H, s, CH—pyraz). 2012/051357 Synthesis of 2-(3-(2-chlor0-6—fluorophenyl)—5-(1-(2-fluor0phenyl)(triflu0romethyl)— IH-pyraz01yl)isoxazoi—4-yl)-1,3,4~0xadiazole (example I-15) A solution of 3-(2~chloro~6—fluorophenyl)—5-(1-(2ufluorophenyl)~5~(trifluoromethyl)—1H- pyrazoly1)isoxazole—4—carbohydrazide (0.076 g, 0.157 mmol) in 4 g trimethyl orthoformate was kept in a sealed tube at 125°C for 3 days. The solution was evaporated to dryness and the e was crystallized from heptane to give 36 mg (46%) of a yellowish solid of example I- . Result of LC/MS MH+z 493.75; 1H NMR (methanol—d4; 400 MHZ) 6 ppm: 7.30—7.35 (1H, m, CH—arorn.), 7.42—7.48 (3H, m, m.), .70 (3H, m, CPI—3mm), 8.51 (1H, s, CH— oxadiazole), 8.93 (1H, s, CH-pyraz.) A variant of this procedure was used for the synthesis of examples IB-S, IB—I3, IB-14, 18—15, 13—16, 13-17, and IB-ZS, exemplarily shown for IB-S: The aforementioned mixture of hydrazide and trimethyl orthoformate (cf. synthesis of example I—15) was heated under microwave irradiation to 125°C for 8 h. The mixture was diluted with dichloromethane and washed with water (3 x), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by pTLC EE/PE 1:1 to give 6 mg of example [3-5 as white solid (yield 24 %).

Synthesis of methyl and ethyl 2-chloroflu0rophenyi)[l-(3-fluorophenyl)- -(trifluoromethyl)-1H-pyrazol—4—yl]isoxazol—4-yl}-I,3-thiazolecarboxylate (examples IB-l and IB-Z) 2012/051357 SOCIZ MeOH A mixture of the carbothioamide (0.242 g, 0.5 mmol) and ethyl bromopyruvate (0.118 g, 0.6 mmol) was heated under reflux for 3 h in 2 ml of dry dioxane. The reaction mixture was cooled to room ature and diluted with 20 m1 of water. The resulting oil was separated by decantation, dissolved in CCl4, dried with MgSO4. The compound was purified by column chromatography using silica gel and CC14, then CHC13 as eluents to give 0.17 g of example IBM] as an oil (yield 59%). 1H NMR (DMSO-dg, 400 MHZ): 5 8.76 (1H, s, chgasole), 8.50 (1H, s, Hpmsoie), 53 (7H, m, Harem), 4.28 (2H, q, 137.3 Hz, CH2), 1.27 (3H, t, J*—"7.3 Hz, Me).

Transesterification of example IB-l into example IB-2 was achieved as follows: To a boiling solution of 0.118 g (0.2 mmol) of the ethyl ester in 5 ml l was added solution of 0.08 g (2 mmol) NaOH in 0.5 ml water. The reaction mixture was heated to reflux for 10 min, then cooled to room temperature, diluted with water acidified to pH 3—4 and concentrated to a volume of 1 ml. The acid was extracted with 10 m1 CH2C12 and dried over MgSO4. To the solution were added 0.1 ml (1.4 mmol) SOClz, and the mixture was heated under reflux for 1 h. The mixture was evaporated in vacuum. The residue was taken up in 2 ml of dry methanol and was heated under reflux for 20 min. Then the mixture was concentrated in vacuum and diluted with 10 ml of water. The t was extracted with 10 ml CH2Clg and dried over MgSO4. The solution was evaporated in vacuum to give example IB-2 as a glassy solid (0.063 g, 56 %). 1H NMR (DMSO-d5, 400 MHZ): 5 8.72 (1H, s, ), 8.52 (1H, 5, prmole), 7.82—7.53 (71-1, 111, Harem): 3.82 (3H, s, OMe).

Synthesis of 2-Chloro~6-fluorophenyi)~5-[1-(3—fluorophenyl)—3—(trifluoromethyl)- 1H—pyrazol-4—yllisoxazol—4-yl}~5-(trifluoromethyl)—1,3,4-oxadiazole (example I—6) F F F G F 331'“! O F 2-.2 ._fF N F o F F F 93H 0 ,I is + g \ /< F OH 9' \ r F aN _... / mmb 1' N\ \ F o \ N‘O \ / “i /N F O /N \ F F \ N~O F N—O F r F F F F F A solution of 3-(2-chloro—6—tluorophenyl)—5-[l~(3—fluorophenyl)(trifluoromethyl)—1H— pyrazol—4—yl}isoxazole-4—carbohydrazide (158 mg, 0.327 mmol) and trifluoroacetic acid anhydride (342 mg, 1.628 mmol) in 9 g of absolute dioxane was heated under refluxe. TLC showed intermediate product which gradually ted into desired 1,3,4—oxadiazole. Afier heating for 3 days, the mixture was evaporated to dryness The oily e was extracted with boiling heptane, heptane extracts were combined and evaporated to dryness. Oily residue was purified by column chromatography on silica gel, eluent EtOAc/heptane, 1/2 to yield 18 mg of pure example L6 as a viscous oil (yield 10%). Ill NMR (CDCI3; C014): 5 7,24 (t, 1H), 7,32 (In, 2H), 7,41 (m 2H), 7,55 (m, 2H), 8,38 (s, 1H) Analytic : Abbreviations: min, 1ninute(s); h, ); r.t., room temperature; Rt, retention time; ‘l’, pseudo; s, singlet; t, triplet, quint, quintet; br., broad; J, coupling constant; pTLC, ative thin layer chromatography; DMAP, 4—dirnethylaminopyridine.

Analflical TLC: Merck aluminium sheets, silica gel 60 F254.

Preparative TLC; Merck PLC plates, silica gel 60 F254, 0.5 mm, 1.0 mm or 2.0 mm.

Flash chromatography: Acres silica gel 60A, 0.035 ~ 0.070 mm. Flash Master Personal or Flash Master H, Jones Chromatography, UK.

NMR spectra: Bruker Avance 300 MHZ. The 1H NMR spectra were recorded at 300 MHz; concentration, 1 to 5 mg/mL; ature, 305 K. The 13C NMR spectra at 75.5 MHZ; concentration, 5 to 20 mg/mL; temperature, 305 K. The residual solvent peaks were used as the internal standards dé: 5 H 2.49, 5c 39.5; CDClg: 5 H 7.24, 5 c 77.0; CD301): 5 H 3.30, 5 c 49.0). Alternatively, TMS was used as a standard ated with TMS).

Analflical LC/ESI—MS: Waters 2700 Autosarnpler. 2 x Waters 600 Multisolvent Delivery System, Waters 600 Controller. 50 nL sample loop. Column, Chromolith Speed ROD RPlSe (Merck, Darmstadt), 50 X 4.6 mm, with 2 pm er (Merck). 13111th A, H20 + 0.1% HCOgH; eluent B, MeCN. Gradient, 2 % B to 100 % B within 4 min, then isocratic for 0.90 min, then back to 2 % B within 0.15 min, then isocratic for 0.50 min; flow, 3 mL/min. Waters LCZ single quadrupol mass ometer with electrospray source. MS method, MSSminPM— 80—800-20V; positive/negative ion mode scanning, m/z 80 — 800 or 80 - 900 in 1 s; capillary, 3.5 kV', cone voltage, 20 V; multiplier voltage, 400 V; probe and desolvation gas temperature, 120° C and 350° C, respectively. Waters 2487 Dual 7t Absorbance Detector, set to 254 nm.

Software, Waters nx V 4.0. Values for [Mil-IT given in the Tables 1 and 2 are calculated exact mass values for the specific compound upon protonation, values found Within the corresponding LC/MS chromatogram were all within tolerable s of +/- 0.3.

Preparative HPLC—MS: Waters 2700 Autosampler, Waters 600 Multisolvent ry System with preparative pump heads, Waters 600 Controller, 5000 [1L Sample loop. At-column dilution: Waters 600 Multisolvent Delivery System with analytical pump heads; Waters 600 Controller; solvent, MeCN — MeOI-I 80 : 20 (V/v); flow rate, 0.20 or 1 mL/min. Column, Waters X—Terra RP18, 7 um, 19 X 150 mm with XnTerra RP18 guard cartridge 7 pm, 19 x 10 mm, used at flow rate 20 mL/min. Eluent A, H20 containing 0.1 % (v/v) HCOZH or H20 containing 0.1 % (V/v) NEt3; eluent B, MeCN. Different linear gradients, individually adapted to sample. Injection volume, 0.5 mL ~ 5 mL, depending on sample. Make—up solvent, MeOl-i — MeCN — H20 — HCOZH 80 : 15: 4.95 : 0.05 (V/v/v/v). Make—up pump, Waters t Manager, flow rate 0.5 mL/min. Waters ZQ single quadrupol mass ometer with electrospray source. Positive or ve ion mode scanning m/z 105 - 950 in 1 s; ary, 4 kV; cone voltage, 20 V; lier voltage, 600 V; probe and desolvation gas temperature, 120°C and 250°C, respectively. Waters Fraction Collector 11 with riggered fraction collection. Waters 2487 Dual 7L Absorbance Detector, set to 254 nm. Software, Waters Masslynx V 4.0.

Analysis of proliferation of and Cytokine production by human PBMC stimulated with Peripheral blood mononuclear cells (PBMC) from healthy human donors were purified using AccuspinTM System-Histopaque—1077 (Sigma) according to the protocol recommended by the manufacturer. Purified PBMC were then washed twice with ate—buffered saline (PBS) and resuspended in RPM11640 e medium supplemented with 10% dialyzed heat inactivated fetal calf serum, 1.5 mM L—glutamine, 100 U penicillin/m1, and 100 mg streptomycin/ml (all from PAN Biotech, Aiden‘oach, Germany). For stimulation, PBMC were seeded at 1 x 1()5 cells/well, ted with 2 ug/ml phytohaemagglutinin (PI-IA, Sigma) and incubated with the test compounds for 48 hours. , IL—17F and INF—y were then ined in the culture supernatant using a Luminex BioPlex system, ing the manufacturer’s instructions (BioRad, Munich, y). For screening, compounds were used at 10, 1, 0.1 and 0.01 uM. To determine the IC50, compounds were titrated semilogarithmically.

Cell proliferation was analysed using the BrdU based cell proliferation ELISA from Roche (Mannheim, Germany) according to the manufacturer’s instructions.

Cytokines were determined in the aforementioned culture supernatant using the following methods: IL—17AA/AF was measured using the Luminex BioPlex system (BioRad, Munich, Germany); IL—17AA using the human homodimer IL—l7A ELISA Ready Set Go Kit from eBioscience (Frankfurt, Germany); IL—l7FF using the human IL—17F ELI-Pair from Holzel DiagnosticaGrnBH (K6111, y); and IFN-y using the OptEIA human lFN—g ELISA from BD Bioscience lberg, Germany), all following the manufacturer’s instructions.

T cell proliferation assay Peripheral blood mononuclear cells (PBMC) from healthy human donors were isolated by centrifugation over Ficoll—Hypaque (Sigma—Aldrich, Germany) according to manufacturer’s instructions. Purified PBMC were washed twice with PBS and ended in RPMIl640 culture medium supplemented with 10% dialyzed heat inactivated fetal calf serum, 1.5 mM L—glutamine, 100 U penicillinfml, and 100 mg streptomycin/m1 (all from PAN Biotech, Aidenbach, Germany). For stimulation, PBMC were seeded at l x 105 cells/well, ted with 2 ug/ml phytohaemagglutinin (PHA, Sigma) and incubated with the test compound.

After 48 hours proliferation was measured using the BrdU based cell proliferation ELISA from Roche (Mannheim, Germany) according to the manual.

Claims (23)

What we claim is:

1. A compound of the general formula (I) formula (I) and pharmaceutically acceptable salts or solvates thereof, 10 wherein R1 is aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl, which can be substituted by one or more substituents R’ 15 Ar is aryl, cycloalkyl, cyclyl or heteroaryl, which can be substituted by one or more substituents R’; Z is H, halogen, -CR’’O, -N(R’’)2, -CN, -C(S)R’’, -N=C(R’)2, -CO2R’’, - NR’CO2R’’, -CONHR’’, -CON(R’’)2, -COSR’’, ’’, -CSN(R’’)2, -SO2-alkyl, 20 -SO2-haloalkyl, -SO2NHR’’, -SO2(NR’’)2, amino or -SO2R’’; Y is H, halogen, haloalkyl or alkyl, which can be substituted by one or more substituents R’; 25 R’ independently represents H, -CO2R’’, ’’, -CR’’O, -SO2N(R’’)2, - SO2NHR’’, -NR’’-CO-haloalkyl, -NO2, -NR’’-SO2-haloalkyl, -NR’’-SO2-alkyl, -SO2- alkyl, -NR’’-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, mino, alkoxy, -OH, - SH, alkylthio, yalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, amino, heterocyclyl, aryl, haloaryl, haloarylalkyl, kyl or heteroaryl; R’’ independently represents H, haloalkyl, hydroxyalkyl, amino, alkoxy, -N=C(R’)2, -NR’-CO-R’, -CR’O, -CO2R’, alkyl, cycloalkyl, aryl, haloaryl, haloarylalkyl, aryl, heterocyclyl, arylalkyl or aminoalkyl, which are optionally tuted by one or more substituents R’; 5 provided when Z is H, R1 is not piperidinyl and provided said nd is not 3-cyclopropyl[5-(1,5-dimethyl-1H-pyrazolyl)-1,2-oxazolyl]phenyl-1H- 1,2,4-triazole, 2-{5-[5-(1,5-dimethyl-1H-pyrazolyl)-1,2-oxazolyl](propanyl)-1H-1,2,4- triazolyl}pyridine, 10 3-ethylmethyl[5-(1-methyl-1H-pyrazolyl)-1,2-oxazolyl]pyrazolo[1,5- a]pyrimidinol, and 4-chloro-3,5-bis(1,5-dimethyl-1H-pyrazolyl)-1,2-oxazole.

2. A compound according to claim 1, wherein R1 is not piperidinyl.

3. A nd according to claim 1 or 2, wherein R1 is aryl, aryl, cycloalkyl, heterocyclyl or alkyl, which can be substituted by one or more substituents R’, provided R1 is not CH3. 20

4. A compound according to any one of claims 1-3, wherein R1 is aryl, heteroaryl, lkyl, heterocyclyl or is selected from -C2H5, -CH=CH2, -C≡CH, -C3H7, - CH(CH3)2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡C-CH3, -CH2-C≡CH, - C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -C6H13, -C(R’)3, -C2(R’)5, -CH2-C(R’)3, -C3(R’)7, -C2H4-C(R’)3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, 25 -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -C2H4-C≡CH, -C≡C-C2H5, -CH2-C≡C-CH3, - C≡C-CH=CH2, -CH=CH-C≡CH, -C≡C-C≡CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, - CH2-CH(CH3)-C2H5, 3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -C3H6- CH=CH2, -CH=CH-C3H7, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH2-CH=CHCH =CH2, -CH=CH-CH=CH-CH3, -CH2-CH=CH2, -C(CH3)=CH-CH=CH2, - 30 CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, H=C(CH3)2, C(CH3)=C(CH3)2, -C3H6-C≡CH, -C≡C-C3H7, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, - CH2-C≡C-CH=CH2, -CH2-CH=CH-C≡CH, -CH2-C≡C-C≡CH, -C≡C-CH=CH-CH3, - CH=CH-C≡C-CH3, -C≡C-C≡C-CH3, -C≡C-CH2-CH=CH2, -CH=CH-CH2-C≡CH, - 2-C≡CH, -C(CH3)=CH-CH=CH2, CH3)-CH=CH2, -CH=CH- C(CH3)=CH2, -C(CH3)=CH-C≡CH, -CH=C(CH3)-C≡CH, -C≡C-C(CH3)=CH2, -C3H6- CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)- CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2- C(CH3)2-C2H5, -C(CH3)2-C3H7, )2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)- 5 C(CH3)3, -C4H8-CH=CH2, -C4H9, -C3H6-CH=CH-CH3, -CH2-CH=CH-C3H7, -C2H4-CH=CH-C2H5, -CH2-C(CH3)=C(CH3)2, -C2H4-CH=C(CH3)2, C≡CH, - C≡C-C4H9, -C3H6-C≡C-CH3, -CH2-C≡C-C3H7, and -C2H4-C≡C-C2H5.

5. A compound according to any one of claims 1 to 4, wherein Z is F, Br, I, -CR’’O, - 10 N(R’’)2, -CN, -C(S)R’’, -N=C(R’)2, -CO2R’’, -NR’CO2R’’, -CONHR’’, ’’)2, - COSR’’, -CSNHR’’, -CSN(R’’)2, lkyl, -SO2-haloalkyl, -SO2NHR’’, -SO2(NR’’)2, amino or -SO2R’’.

6. A compound according to any one of claims 1 to 5, wherein Y is halogen, haloalkyl or 15 alkyl, which can be substituted by one or more substituents R’, ed R1 is not CH3.

7. A compound according to any one of claims 1 to 6, wherein Y is halogen, haloalkyl or is selected from -C2H5, -CH=CH2, -C≡CH, -C3H7, -CH(CH3)2, -CH2-CH=CH2, 20 -C(CH3)=CH2, -CH=CH-CH3, -C≡C-CH3, -CH2-C≡CH, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -C6H13, -C(R’)3, -C2(R’)5, (R’)3, )7, - C2H4-C(R’)3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CH2-CH=CH-CH3, - CH=CH-CH=CH2, -C2H4-C≡CH, -C≡C-C2H5, -CH2-C≡C-CH3, -C≡C-CH=CH2, - CH=CH-C≡CH, -C≡C-C≡CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, -CH2-CH(CH3)- 25 C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, CH=CH2, - CH=CH-C3H7, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH2-CH=CH-CH=CH2, - CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, - CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)2, =C(CH3)2, -C3H6-C≡CH, -C≡C-C3H7, -C2H4-C≡C-CH3, ≡C-C2H5, - 30 CH2-C≡C-CH=CH2, -CH2-CH=CH-C≡CH, -CH2-C≡C-C≡CH, -C≡C-CH=CH-CH3, - CH=CH-C≡C-CH3, -C≡C-C≡C-CH3, -C≡C-CH2-CH=CH2, -CH=CH-CH2-C≡CH, - C≡C-CH2-C≡CH, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CHC (CH3)=CH2, -C(CH3)=CH-C≡CH, -CH=C(CH3)-C≡CH, -C≡C-C(CH3)=CH2, -C3H6- CH(CH3)2, CH(CH3)-C2H5, -CH(CH3)-C4H9, H(CH3)-C3H7, -CH(CH3)- CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2- C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, 3)- C(CH3)3, -C4H8-CH=CH2, -C4H9, -C3H6-CH=CH-CH3, -CH2-CH=CH-C3H7, CH=CH-C2H5, -CH2-C(CH3)=C(CH3)2, -C2H4-CH=C(CH3)2, -C4H8-C≡CH, - 5 C≡C-C4H9, -C3H6-C≡C-CH3, -CH2-C≡C-C3H7, and C≡C-C2H5.

8. A compound according to claim 1, wherein Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; R1, Z, Y, R’ and R’’ are as defined in claim 1.

9. A compound ing to claim 1, wherein R1 is aryl or heteroaryl, which can be substituted by one or more substituents R’ Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; Z, Y, R’ and R’’ are as defined in claim 1. 20

10. A compound according to claim 1, wherein R1 is aryl, which can be substituted by one or more substituents R’ Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; 25 Z is H, halogen, -CR’’O, -N(R’’)2, -CN, -C(S)R’’, -N=C(R’)2, -CO2R’’, - NR’CO2R’’, -CONHR’’, -CON(R’’)2, -COSR’’, -CSNHR’’, -CSN(R’’)2, amino, which can be tuted by one or more substituents R’; Y, R’ and R’’ are as defined in claim 1.

11. A compound according to claim 1, wherein R1 is aryl or heteroaryl, which can be substituted by one or more substituents R’; Ar is aryl or aryl, which can be substituted by one or more substituents R’; Z is H, halogen, -CR’’O, -N(R’’)2, -CN, -C(S)R’’, -N=C(R’)2, -CO2R’’, - NR’CO2R’’, -CONHR’’, -CON(R’’)2, -COSR’’, -CSNHR’’, -CSN(R’’)2, amino, which can be substituted by one or more tuents R’; R’ independently represents H, -CO2R’’, -SO2N(R’’)2, -SO2NHR’’, -CN, alkyl, alkoxy, -OH, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, heterocyclyl, aryl, haloaryl, haloarylalkyl, arylalkyl or heteroaryl; 10 Y, and R’’ are as defined in claim 1.

12. A nd according to claim 1, wherein R1 is aryl, or heteroaryl, which can be substituted by one or more substituents R’; 15 Ar is aryl or heteroaryl, which can be substituted by one or more substituents R’; Z is H, halogen, -CR’’O, -C(S)R’, -CO2R’’, -NR’CO2R’’, -CONHR’’, -CON(R’’)2, -COSR’’, -CSNHR’’, -CSN(R’’)2, which can be tuted by one or more substituents R’; Y is H, n, haloalkyl, or alkyl, which can be substituted by one or more substituents R’; R’ independently represents H, ’, -CONHR’’, -CR’’O, -SO2N(R’’)2, - 25 SO2NHR’’, -CN, alkyl, alkoxy, -OH, halogen, haloalkyl or haloalkoxy; R’’ independently represents H, haloalkyl, or alkyl, which can be substituted by one or more substituents R’; 30

13. A compound according to claim 1, n R1 is aryl, which can be substituted by one or more substituents R’; Ar is aryl, which can be substituted by one or more substituents R’; Z is H, haloalkyl, aryl, heteroaryl, CO2R’’, -CONHR’’, -CR’’O, -CON(R’’)2, COSR’’, which can be substituted by one or more substituents R’; Y is H, n, haloalkyl, or alkyl, which can be substituted by one or more 5 substituents R’; R’ independently represents H, -CO2R’’, ’’, -CR’’O, -CN, alkyl, alkoxy, -OH, halogen, haloalkyl or haloalkoxy; 10 R’’ independently represents H, haloalkyl, or alkyl, which can be substituted by one or more substituents R’;

14. A compound according to claim 1 or 8, wherein 15 R1 is selected from the group comprising phenyl which is optionally substituted by one or more substituents individually selected from trifluoromethyl, fluorine, ne, bromine, nitro, NH2, -CN, -NHCO-C1alkyl, y, C1alkyl, - SO2NH2, or -SO2NH-C1alkyl; pyridyl which is optionally substituted by one or more of the aforementioned substituents for phenyl; pyrimidyl which is 20 optionally substituted by one or more of the aforementioned substituents for phenyl; thienyl which is optionally substituted by one substituent–COO-C1- 4alkyl; oxo-tetrahydrothienyl, 2,2,2-trifluoroethyl, isopropyl, yl, 2- methoxyethyl, tetrahydropyranylmethyl, holinoethyl, pyridin ylmethyl and tetrahydrofuranylmethyl; Ar is selected from the group sing phenyl and pyridyl, which can be substituted by one or more substituents independently selected from fluorine methoxy or chlorine; 30 Z is selected from the group comprising halogen, -C(O)heterocyclyl, C(S)heterocyclyl, -NH2, -NH-COO-C1-4alkyl, -CN, -C(S)NH2, -C(S)NH-C1- 4alkyl, -C(S)N(C1-4alkyl)2, O-C1-4alkyl)-C1-4haloalkyl, -N=C(-O-C1- 4alkyl)-C1-4alkyl, -CO2-C1-4alkyl, - -CONH-C 1-4alkyl, -CONH-arylalkyl, -CONH-cycloalkyl, -CON(C1-4alkyl)2, -CON(C1-4alkyl)-O-C1-4alkyl, and - COS-C1-4alkyl; Y is selected from the group comprising H, trifluoromethyl and 5 methoxycarbonyl.

15. A nd according to claim 1 or 8, wherein R1 is selected from the group comprising phenyl which is optionally substituted by 10 one or more tuents individually selected from fluorine, chlorine, bromine, nitro, NH2, -CN, -NHCO-C1alkyl, methoxy, t-butyl, -SO2NH2, or -SO2NH- isopropyl; pyridyl; pyrimidyl which is optionally substituted by one or more substituents selected from methyl or trifluoromethyl; thienyl which is ally substituted by one substituent–COO-methyl, 1,1-dioxo- 15 tetrahydrothienyl, 2,2,2-trifluoroethyl, isopropyl, isobutyl, 2-methoxyethyl, tetrahydropyranylmethyl, 2-morpholinoethyl, pyridinylmethyl and tetrahydrofuranylmethyl; Ar is selected from the group comprising phenyl, 2,6-difluorophenyl, 2-chloro 20 fluorophenyl, 2-chloromethoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2,6- rophenyl, 2,4-dichlorophenyl, ropyridinyl, 3,5-dichloropyridin- 4-yl and 3,5-difluoropyridinyl; Z is ed from the group comprising chlorine, bromine, orpholinyl, - 25 C(O)-piperazinyl, -C(O)-(N-C1-4alkyl-piperazinyl), -C(O)-(N-arylalkylpiperazinyl ), -C(O)-pyrrolidinyl, -C(O)-isoxazolidinyl, -NH2, -NH-COO-C1- 4alkyl, -CN, -C(S)NH2, -C(S)NH-C1-4alkyl, -N=C(-O-C1-4alkyl)-C1-4haloalkyl, -CO2-C1-4alkyl, -CONH-C1-4alkyl, -CONH-(trifluoromethyl-substituted benzyl), -CONH-C5-7cycloalkyl, -CON(C1-4alkyl)2, -CON(C1-4alkyl)-O-C1- 30 , and -COS-C1-4alkyl; Y is selected from the group comprising H, trifluoromethyl and methoxycarbonyl.

16. A compound according to claim 1 or 8, wherein R1 is selected from the group comprising phenyl, 2-fluorophenyl, 2- methoxyphenyl, 2-chlorophenyl, 2-bromophenyl, 2-nitrophenyl, 2- 5 aminophenyl, 4-fluorophenyl, 4-tertbutylphenyl, rophenyl, 3- chlorophenyl, 3-cyanophenyl, 3-acetamido-phenyl, 2-acetamido-phenyl, 3- aminosulfonyl-phenyl, 3-(isopropylamino)sulfonyl-phenyl, 3-nitrophenyl, 3- aminophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,3,5,6-tetrafluorophenyl, 2-pyridyl; 3-pyridyl; 4-pyridyl; 4- trifluoromethyl- 10 pyrimidyl, 2,6-dimethyl-pyrimidyl, 2-methoxycarbonyl-thienyl, 1,1- tetrahydrothienyl, 2,2,2-trifluoroethyl, isopropyl, isobutyl, 2- methoxyethyl, tetrahydropyranyl-methyl, 2-(morpholinyl)-ethyl, and tetrahydrofuranyl-methyl; 15 Ar is selected from the group comprising phenyl, 2-chlorofluorophenyl, 2- fluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3- fluoropyridinyl, and 3,5-difluoropyridinyl; Z is selected from the group comprising bromine, -C(O)-morpholinyl, -C(O)- 20 hyl-piperazinyl), -C(O)-(4-[chlorobenzyl]-piperazinyl), -C(O)- idinyl, -C(O)-isoxazolidinyl, -NH2, -NH-COO-methyl, -CN, H2, - C(S)NH-methyl, -N=C(-O-methyl)-trifluoromethyl, -CO2-C1-3alkyl, -CONH- , -CONH-(trifluoromethyl-substituted benzyl), -CONH-cyclohexyl, -CON(methyl)2, -CON(methyl)-O-methyl, and -COS-methyl; Y is selected from the group comprising H, trifluoromethyl and methoxycarbonyl.

17. A compound according to any one of claims 1 to 16, wherein the compound is selected 30 from the group comprising the nds of examples methyl 3-(2-chlorofluorophenyl)(1-(2-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(4-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(3-chlorophenyl)(ethoxycarbonyl)-1H- pyrazolyl)isoxazolecarboxylate, 5 methyl 3-(2-chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(3-cyanophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(2-(methoxycarbonyl)thiophenyl) 10 (trifluoromethyl)-1H-pyrazolyl)isoxazolecarboxylate, (3-(2-chlorofluorophenyl)(1-(2-fluorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolyl)(piperidinyl)methanone, methyl 3-(2-chlorofluorophenyl)(1-isobutyl(trifluoromethyl)-1H-pyrazol ylate, 15 3-(2-chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazol yl)-N-methylisoxazolecarboxamide, ethyl 3-(2-chlorofluorophenyl)(1-(2-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, isopropyl 3-(2-chlorofluorophenyl)(1-(2-fluorophenyl)(trifluoromethyl)-1H- 20 pyrazolyl)isoxazolecarboxylate, methyl hlorofluorophenyl)(1-phenyl(trifluomethyl)1H-pyrazol yl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(3,5-difluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, 25 3-(2-chlorofluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazol yl)-N-methylisoxazolecarboxamide, 3-(2-chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazol yl)-N-methoxy-N-methylisoxazolecarboxamide, methyl 3-(2-chlorofluorophenyl)(1-(2,2,2-trifluoroethyl)(trifluoromethyl)-1H- 30 pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(3,5-dichlorophenyl)(trifluoromethyl)-1H- lyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, methyl 3-(2-chlorofluorophenyl)(1-(2-fluorophenyl)-1H-pyrazolyl)isoxazole- 4-carboxylate, ethyl 3-(2-fluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolecarboxylate, 5 methyl 3-(2-chlorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolecarboxylate, methyl 3-(2,6-dichlorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazol- 4-yl)isoxazolecarboxylate, 3-(2,6-dichlorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazolyl)-N- 10 methylisoxazolecarboxamide, ethyl 3-(2,4-dichlorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolecarboxylate, (3-(2-chlorofluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolyl)(isoxazolidinyl)methanone, 15 yl 3-(2-chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarbothioate, S-methyl 3-(2-chlorofluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarbothioate, S-methyl 3-(2-chlorofluorophenyl)(1-(2-fluorophenyl)(trifluoromethyl)-1H- 20 pyrazolyl)isoxazolecarbothioate, chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolyl)(isoxazolidinyl)methanone, (Z)-methyl N-(3-(2-chlorofluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)- 1H-pyrazolyl)isoxazolyl)-2,2,2-trifluoroacetimidate, 25 4-bromo(2-chlorofluorophenyl)(1-(3-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazole, 4-bromo(2-chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazole, 4-bromo(2-chlorofluorophenyl)(1-phenyl(trifluoromethyl)-1H-pyrazol 30 yl)isoxazole, ethyl 3-(3-fluoropyridinyl)(1-(pyridinyl)(trifluoromethyl)-1H-pyrazol xazolecarboxylate, ethyl 5-(1-(3-acetamidophenyl)(trifluoromethyl)-1H-pyrazolyl)(3- fluoropyridinyl)isoxazolecarboxylate, ethyl 3-(3,5-dichloropyridinyl)(1-(2-fluorophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, ethyl 5-(1-(3-acetamidophenyl)(trifluoromethyl)-1H-pyrazolyl)(3,5- dichloropyridinyl)isoxazolecarboxylate, 5 ethyl 3-(3,5-dichloropyridinyl)(1-(pyridinyl)(trifluoromethyl)-1H-pyrazol- 4-yl)isoxazolecarboxylate, ethyl 5-(1-(2-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)(3-fluoropyridin- 4-yl)isoxazolecarboxylate, isopropyl 3-(2-chlorofluorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H- 10 pyrazolyl)isoxazolecarboxylate, ethyl 3-(2-chlorofluorophenyl)(1-(3-cyanophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, ethyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H-pyrazol- isoxazolecarboxylate, 15 ethyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H-pyrazol- 4-yl)-isoxazolecarboxylate, ethyl 3-(2-chlorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)- isoxazolecarboxylate, ethyl 5-(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)(2,6- 20 dichlorophenyl)-isoxazolecarboxylate, ethyl 5-(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)(2- fluorophenyl)isoxazolecarboxylate, pyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, 25 (3-(2-chlorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolyl)(isoxazolidinyl)methanone, 3-(2-chlorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)-N- methoxy-N-methylisoxazolecarboxamide, methyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H- 30 pyrazolyl)isoxazolecarboxylate, S-methyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H- lyl)isoxazolecarbothioate, methyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, ethyl 5-(1-(3-acetamidophenyl)(trifluoromethyl)-1H-pyrazolyl)(2-chloro fluorophenyl)isoxazolecarboxylate, methyl 3-(2-chlorophenyl)(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazol yl)isoxazolecarboxylate, 5 methyl 5-(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)(2,6- dichlorophenyl)isoxazolecarboxylate, methyl 5-(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)(2,4- dichlorophenyl)isoxazolecarboxylate, methyl 5-(1-(3-chlorophenyl)(trifluoromethyl)-1H-pyrazolyl)(2- 10 fluorophenyl)isoxazolecarboxylate, isopropyl 5-(1-(3-acetamidophenyl)(trifluoromethyl)-1H-pyrazolyl)(2-chloro- 6-fluorophenyl)isoxazolecarboxylate, isopropyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, 15 ethyl 3-(2-chlorofluorophenyl)(1-(pyridinyl)(trifluoromethyl)-1H-pyrazol- soxazolecarboxylate, methyl 5-(1-(3-acetamidophenyl)(trifluoromethyl)-1H-pyrazolyl)(2-chloro fluorophenyl)isoxazolecarboxylate, ethyl 3-(2-chlorofluorophenyl)(1-(3-nitrophenyl)(trifluoromethyl)-1H- 20 pyrazolyl)isoxazolecarboxylate, methyl 5-(1-(3-aminophenyl)(trifluoromethyl)-1H-pyrazolyl)(2-chloro fluorophenyl)isoxazolecarboxylate, ethyl 3-(2-chlorofluorophenyl)(1-(2-nitrophenyl)(trifluoromethyl)-1H- pyrazolyl)isoxazolecarboxylate, 25 ethyl 3-(2-chlorofluorophenyl)(1-((tetrahydrofuranyl)methyl) (trifluoromethyl)-1H-pyrazolyl)isoxazolecarboxylate, and ethyl 2-aminophenyl)(trifluoromethyl)-1H-pyrazolyl)(2-chloro fluorophenyl)isoxazolecarboxylate of the present invention.

18. A compound according to any of claims 1 to 17 for use as a medicament.

19. A compound according to any of claims 1 to 17 for use in the treatment of a disease or indication selected from the group ting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, vitiligo, Crohn’s disease, tive colitis, inflammatory bowel disease, ankylosing spondylitis, diabetes type I, le sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjögren’s syndrome, spinal 5 disc herniation, acne, Graft-versus-Host-Reaction, Host -versus-Graft-Reaction and osteoarthritis

20. Use of the compounds of the formula (I) as defined in any of claims 1 to 17, and of their pharmacologically tolerable salts in the manufacture of a ment for use in 10 treatment of a disease or a therapeutic indication in which the inhibition of interleukin- 17 (IL-17) and/or Interferon-γ (INF-γ) is beneficial.

21. The use of claim 20 wherein the disease or indication is selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, 15 rheumatoid tis, vitiligo, s disease, ulcerative s, inflammatory bowel disease, ankylosing spondylitis, es type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjögren’s syndrome, spinal disc herniation, acne, Graft-versus-Host-Reaction, Host -versus-Graft-Reaction and osteoarthritis.

22. A compound according to claim 1, substantially as herein bed or exemplified.

23. A use according to claim 20, substantially as herein described or exemplified.