RU2785342C2 - 1-(4-isoxazole-5-yl)-1h-pyrazole-1-yl)-2-methylpropane-2-ol derivatives and related compounds as il-17 and ifn-gamma inhibitors for treatment of autoimmune diseases and chronic inflammation - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes a compound of the formula (I) and its use for the manufacture of a drug for the treatment of a disease or a medical condition, in which inhibition of interleukin-17 (hereinafter – IL-17) and/or interferon-γ (hereinafter – IFN-γ) is preferable. In the formula (I), Ar is selected from a group consisting of phenyl and pyridyl, each of which is optionally substituted with one, two, or three independently selected substitutes R^Ar; R^Ar is selected from a group consisting of halogen, -OH, -CN, C_1-6-alkoxy, di-C_1-6-alkylamino-C_1-6-alkoxy, -CONHR’, benzyloxy, -CO-azetidinyl, -CO-pyrrolidinyl, -CO-morpholinyl, -CO-C_3-6-cycloalkyl, -CONH-C_3-6-cycloalkyl, and -O-C_1-6-alkyl-heterocycle, where heterocycle is selected from a group consisting of pyrrolidinyl, piperazinyl, morpholinyl, 1,1-dioxothiomorpholinyl, and (2-oxa-6-azaspiro[3.3]hept-6-yl)-C_1-4-alkoxy, and where each of the specified heterocycle groups is optionally substituted with C_1-6-alkyl, and where R’ is C_1-6-alkyl; Z is selected from a group consisting of H, -CO-R^Z, -CH₂-O-R^Z, -CO-CH₂-R^Z, -CO-CH₂-O-R^Z, -COOR^Z, -CO-NHR^Z, -C_1-6-alkyl-O-C_1-6-alkyl-O-R^Z, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, 5- or 6-element heteroaryl including one or two heteroatoms independently selected from N, S, and O, and tetrahydrofuranyl, where each of the specified alkyl and heteroaryl groups is optionally substituted with C_1-6-alkyl, OH, or C_3-6-cycloalkyl; R^Z is selected from a group consisting of H, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-6-cycloalkyl, and oxetanyl; Y is C_1-4-halogenalkyl or C_1-6-alkyl; R1 is such as specified in the claims.

EFFECT: compound of the formula (I), having inhibitory activity relatively to interleukin-17 (IL-17) and/or interferon-γ (IFN-γ).

11 cl, 1 tbl, 167 ex

Description

Introduction

The IL-17 family of cytokines is associated with the pathogenesis of autoimmune diseases and is generally associated with pathogenic symptoms of autoimmune and chronic inflammation. Overexpression of IL-17 is a hallmark of autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, multiple sclerosis, vasculitis and atherosclerosis, systemic lupus erythematosus, as well as lung disease, asthma and chronic obstructive disease lungs. (reviewed in Miossec and Kolls, Nature Reviews Drug Discovery, 2012 ¹ ).

The IL-17 family of cytokines includes six members, of which IL-17A and IL-17F are the best characterized. IL-17A and IL-17F exist both as homo- and heterodimers (IL-17AA, IL-17AF, IL-17FF). IL-17A and IL-17F are clearly associated with inflammation, while the role of other members of the IL-17 family is less understood (described in Reynold et al., Cytokine Growth Factor Rev., 2010 ² ).

The secretion of IL-17 is mainly caused by a specific subtype of T helper cells called Th17 cells. The differentiation of naive CD4+ T cells into Th17 cells is induced in the presence of the cytokines IL-1β, TGFβ, and IL-6, while IL-23 maintains the survival of TH17 cells. Important transcription factors for transcription and secretion of IL-17 from Th17 cells are RORγt and STAT3. IL-17 itself induces the production of effector molecules in IL-17R expressing cells such as endothelial cells, epithelial cells or fibroblasts, macrophages and dendritic cells, chondrocytes and osteoblasts. Such effector molecules are pro-inflammatory cytokines (IL-6, TNF-α, and IL-1b), chemokines (such as CXCL1, CXCL2, CXCL5, CCL2, CCL7, and CCL20), growth factors (G-CSF, GM-CSF), and oxide nitrogen, prostaglandin E2 and matrix metalloproteinases. Initiated by these effector molecules, neutrophil infiltration, tissue damage and chronic inflammation occur (described in Miossec and Kolls, Nature Reviews Drug Discovery, 2012 ¹ ).

Prior to the recognition of the importance of IL-17 in autoimmune inflammation, Th1-derived IFN-gamma was considered an important cytokine that causes autoimmune disorders. Transcription and secretion of IFN-gamma from Th1 effector cells is regulated by the transcription factors T-bet and STAT4. As an effector cytokine of Th1 immunity, IFN-gamma is a key regulator of macrophage activation. In parallel, IFN-gamma signaling generates other cytokines and inflammatory factors to maintain inflammation, maintain Th1 responses, and inhibit differentiation of regulatory T cells, Th2 cells, and Th17 cells (described in Pollard et al., Discov. Med., 2014 ³ and Green et al., J. Biol. Chem., 2017 ⁴ ).

The existence of hybrid Th1/Th17 cells has recently been described. These cells can be induced in vitro by IL-23 and IL-6 together with IL-1 and secrete IL-17 and IFN-gamma. These double producing cells have been shown to have pronounced pro-inflammatory properties and are involved in the pathogenesis of IBD, EAE, and type 1 diabetes (Buonocore et al., Nature, 2010 ⁵ ; Ghoreschi et al., Nature, 2010 ⁶ ; Marwaha et al., Clin Immunol, 2014 ⁷ ; Ramesh et al., J. Exp. Med. 2014 ⁸ ).

Therefore, compounds that target and inhibit both IL-17 and IFN-gamma are intended for the treatment of autoimmune disorders.

The effectiveness of blocking only IL-17 signaling as a therapeutic treatment for autoimmune diseases has already been proven in clinical trials, for example, with monoclonal antibodies against IL-17A (secukinumab, ixekizumab, ABT-122, CNTO 6785, CJM112, COVA322, ALX-0761 , bimekizumab, SCH-900117) and/or IL-17 receptor IL-17RA (AMG827, brodalumab). Other antibodies in clinical development that target the IL-17-Th17 pathway by addressing the p19 subunit of IL-23 are tildrakizumab, guselcumab, AMG139, BI655066, and LY3074828 (described in Bartlett and Million, Nature Reviews Drug Discovery 2015). ⁹ Positive results have been reported for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, uveitis, ankylosing spondylitis, and spondyloarthritis. Other autoimmune diseases being investigated are Crohn's disease, asthma and multiple sclerosis.

On the other hand, blocking only IFN-gamma signaling in autoimmune diseases with the IFN-gamma-specific monoclonal antibody AMG811 has been investigated in clinical trials for systemic and discoid lupus erythematosus with no significant clinical outcome to date (Werth et al., Arthritis 2017 ¹⁰ ).

1. Miossec, P. & Kolls, JK Targeting IL-17 and TH17 cells in chronic inflammation. Nat. Rev. Drug Discov . 11 , 763-776 (2012).

2. Reynolds, JM, Angkasekwinai, P. & Dong, C. IL-17 family member cytokines: regulation, and function in innate immunity. Cytokine Growth Factor Rev. 21 , 413-423 (2010).

3. Pollard, KM, Cauvi, DM, Toomey, C., Morris, KV & Kono, DH Interferon-γ and Systemic Autoimmunity. Discov. Med . 16 , 123-131 (2013).

4. Green, DS, Young, HA & Valencia, JC Current prospects of type II interferon gamma signaling and autoimmunity. J Biol. Chem . jbc.R116.774745 (2017). doi:10.1074/jbc.R116.774745

5. Buonocore, S. et al . Innate lymphoid cells drive IL-23 dependent innate intestinal pathology. Nature 464 , 1371-1375 (2010).

6. Ghoreschi, K. et al . Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling. Nature 467 , 967-971 (2010).

7. Marwaha, AK, Tan, S. & Dutz, JP Targeting the IL-17/IFN-γ axis as a potential new clinical therapy for type 1 diabetes. Clin. Immunol. Orlando Fla 154 , 84-89 (2014).

8. Ramesh, R. et al . Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J. Exp. Med . 211 , 89-104 (2014).

9. Bartlett, HS & Million, RP Targeting the IL-17-TH17 pathway. Nat. Rev. Drug Discov . 14 , 11-12 (2015).

10. Werth, VP et al . Brief Report: Pharmacodynamics, Safety, and Clinical Efficacy of AMG 811, a Human Anti-Interferon-γ Antibody, in Patients With Discoid Lupus Erythematosus. Arthritis Rheumatol. Hoboken NJ 69 , 1028-1034 (2017).

WO 2012/101261 A1 and WO 2012/101263 A1 describe compounds having the core structure of the compounds of the present invention, but different substitution schemes, in particular with respect to the R1 group.

Detailed description of the invention

In certain embodiments, the present invention relates to a compound of formula (I) as described in the following paragraphs:

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,

формула (I)

formula (I)

wherein

Ar is selected from the group consisting of phenyl and heteroaryl, each of which is optionally substituted with one or more independently selected R ^Ar substituents;

R ^Ar is selected from the group consisting of halo, -OH, -CN, alkoxy, haloalkoxy, alkyl, haloalkyl, mono- or dialkylamino-alkyl, mono- or dialkylamino-alkoxy, -COOR', -CONHR', -CO-R ', -SO ₂ NHR', -NH-CO-R', -NO ₂ , -NH-SO ₂ -R', -SO ₂ -R', benzyloxy, -CO-heterocyclyl, -CO-cycloalkyl, -CONH -cycloalkyl, -CONH-heterocyclyl, -O-alkyl-heterocyclyl, -O-alkyl-cycloalkyl, (2-oxa-6-azaspiro[3.3]hept-6-yl)-C _1-4 -alkoxy, amino, aralkyl , cycloalkyl, heterocyclyl, phenyl, and heteroaryl, wherein each of said alkoxy, aralkyl, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, halogen, and OH, and wherein R ' is independently selected from the group consisting of independently represented H, OH, alkyl and haloalkyl;

Z is selected from the group consisting of H, halogen, -CO-R ^Z , -CH ₂ -OR ^Z , -CO-CH ₂ -R ^Z , -CO-CH ₂ -OR ^Z , -COOR ^Z , -NHCO-R ^Z , -CO-NHR ^Z , -N(R ^Z ) ₂ , -CN, -NHCOOR ^Z , -SO ₂ -R ^Z , -SO ₂ NHR ^Z , -alkyl-OR ^Z , -alkyl-O-alkyl-OR ^Z , amino, alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl, wherein each of said alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl , -COO-alkyl, OH and cycloalkyl;

R ^Z is selected from the group consisting of H, halogen, -OH, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocyclyl, phenyl and heteroaryl,

Y is H, halogen, haloalkyl, alkyl or alkyl ether;

R1 is a structure group

wherein

n is 0 or 1;

R2 is H, deuterium or methyl;

R3 is methyl, trifluoromethyl, ethyl, or, taken together with R2, forms a cyclopropyl group, or R3 forms a methylene bridge with the carbon atom marked ⃰.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein

Ar is selected from the group consisting of phenyl, cycloalkyl, heterocyclyl and heteroaryl, each of which is optionally substituted with one or more independently selected substituents R ^Ar ;

R ^Ar is selected from the group consisting of halo, -OH, -CN, alkoxy, haloalkoxy, alkyl, haloalkyl, mono- or dialkylamino-alkyl, mono- or dialkylamino-alkoxy, -COOR', -CONHR', -CO-R ', -SO ₂ NHR', -NH-CO-R', -NO ₂ , -NH-SO ₂ -R', -SO ₂ -R', benzyloxy, -CO-heterocyclyl, -CO-cycloalkyl, -CONH -cycloalkyl, -CONH-heterocyclyl, -O-alkyl-heterocyclyl, -O-alkyl-cycloalkyl, (2-oxa-6-azaspiro[3.3]hept-6-yl)-C _1-4 -alkoxy, amino, aralkyl , cycloalkyl, heterocyclyl, phenyl, and heteroaryl, wherein each of said alkoxy, aralkyl, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, halogen, and OH, and wherein R ' is independently selected from the group consisting of independently represented H, OH, alkyl and haloalkyl;

Z is selected from the group consisting of H, halogen, -CO-R ^Z , -CH ₂ -OR ^Z , -CO-CH ₂ -R ^Z , -CO-CH ₂ -OR ^Z , -COOR ^Z , -NHCO-R ^Z , -CO-NHR ^Z , -N(R ^Z ) ₂ , -CN, -NHCO ₂ R ^Z , -SO ₂ -R ^Z , -SO ₂ NHR ^Z , -alkyl-OR ^Z , -alkyl-O-alkyl -OR ^Z , amino, alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl, wherein each of said alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkoxy , haloalkyl, -COO-alkyl, OH and cycloalkyl;

R ^Z is selected from the group consisting of H, halogen, -OH, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocyclyl, phenyl and heteroaryl,

Y is H, halogen, haloalkyl, alkyl or alkyl ether;

R1 is a structure group

wherein

n is 0 or 1;

R2 is H, deuterium or methyl;

R3 is methyl, trifluoromethyl, ethyl or, taken together with R2, forms a cyclopropyl group;

or

n is 1, R2 is H, deuterium or methyl, and R3 forms a methylene bridge with the carbon atom marked ⃰.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in which

Ar is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more R ^Ar substituents;

R ^Ar is selected from the group consisting of halo, OH, CN, C _1-4 alkyl, C _1-4 haloalkyl, -NH ₂ , acetamido, -COO-C _1-4 alkyl, C _1-4 alkoxy and (mono- or di-C _1-4 -alkylamino)-C _1-4 -alkoxy, more specifically halo, C _1-4 -alkoxy and (mono- or di-C _1-4 -alkylamino)-C _{1 -4} -alkoxy, benzyloxy, -CO-N(R ^N ) ₂ in which one ^RN is H and the other is C _1-3 -alkyl, C _3-4 cycloalkyl or both ^RN taken together with N , to which they are attached, form an azetane, pyrrolidine, or morpholine ring, -CONR ^N , in which one ^RN is H and the other is isopropyl or cyclobutyl, or both ^RN taken together with the N to which they are attached form a pyrrolidine , morpholine, 1,1-dioxothiomorpholine, 4-methylpiperazine, or 2-oxa-6-azaspiro[3.3]heptane ring;

Z is selected from the group consisting of H, halogen, -CO-C _1-4 -alkyl, -CO-CH ₂ -C _1-4 -alkoxy, -CO-CH ₂ -OC _3-5 -cycloalkyl, -CO- heterocyclyl, -CH ₂ -OH, -CH ₂ -OC _1-4 -alkyl, -CH ₂ -OC _3-5 -cycloalkyl, -NH ₂ , -NH-COO-C _1-4 alkyl, -CN, -COO -C _1-4 alkyl, -CONH-C _1-4 alkyl, -CONH-arylalkyl, -CONH-cycloalkyl, -CON(C _1-4 alkyl) ₂ , -CON(C _1-4 alkyl)-OC _{1- 4} alkyl, -CO-CH ₂ -cycloalkyl, COO-heterocyclyl, -COO-cycloalkyl, cycloalkylmethyl, alken-1-one, alkyloxyalkyl, -C _1-2 -alkyl-OC _1-2 -alkyl-OC _1-4 - alkyl, cycloalkylmethyl-alken-1-ol, heteroaryl, phenyl or heterocyclyl, wherein said phenyl and heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, -COO-alkyl, OH and cycloalkyl;

Y is selected from the group consisting of H, alkyl, haloalkyl and alkyl ether;

R1 is a structure group

wherein

n is 0;

R2 is H, deuterium or methyl;

R3 is methyl, trifluoromethyl, ethyl or, taken together with R2, forms a cyclopropyl group;

or

n is 1;

R2 is H, deuterium or methyl;

R3 is methyl or trifluoromethyl or forms a methylene bridge with the carbon atom marked ⃰.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein

Ar is selected from the group consisting of phenyl and pyridyl, each of which is optionally substituted with one or more R ^Ar substituents;

R ^Ar is selected from the group consisting of halogen, OH, -OC _1-3 alkyl, -OC _1-3 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, (mono- or dimethylamino)-C _1-3 -alkyl and (mono - or dimethylamino)-C _1-2 -alkoxy;

Z is selected from the group consisting of H, -COO-C _1-3 -alkyl, -CO-C _1-2 -alkyl, -CO-CH ₂ -C _1-3 -alkoxy, -CO-CH ₂ -OC _{3 -4} -cycloalkyl, 5- or 6-membered heteroaryl, phenyl, -COO-C _3-6 -cycloalkyl, -COO-C _3-6 -heterocyclyl, -CON-C _3-6 -cycloalkyl, -CON-C _{3 -6} -heterocyclyl, -CO-CH ₂ -C _3-6 -cycloalkyl, -CH ₂ -OC _3-6 -cycloalkyl, -CO-C _1-4 -alkyl, -C _1-2 -alkyl-OC _{1- 2} -alkyl, -CH ₂ -OH, -CH ₂ -OC _1-3 -alkyl, -CH ₂ -O-cyclobutyl, -C _1-2 -alkyl-OC _1-2 -alkyl-OC _1-2 -alkyl and -C(OH)(C _1-4 -alkyl)(CH ₂ -C _3-6 -cycloalkyl), in which the specified heteroaryl, phenyl, heterocyclyl, cycloalkyl and alkyl is optionally substituted with one or more substituents independently selected from the group, consisting of methyl, halogen, CF ₃ , OMe and OH;

Y is selected from the group consisting of CF ₃ and Me;

R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2-hydroxy-3,3 ,3-trifluoropropyl, 2-hydroxy-2-deuteropropyl and 1-hydroxycyclopropylmethyl.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein

Ar is selected from the group consisting of phenyl optionally substituted with one or more substituents R ^Ar ;

R ^Ar is selected from the group consisting of halogen, -OC _1-3 -alkyl, -OC _1-3 -haloalkyl, C _1-4 -alkyl, C _1-4 -haloalkyl and (dimethylamino) -C _1-2 -alkoxy ;

Z is selected from the group consisting of H, COO-C _1-3 -alkyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiophenyl, furan, tetrahydrofuran, cyclopropoxymethyl, cyclohexoxymethyl, cyclopentoxymethyl, -COO -cyclopropyl, -COO-cyclobutyl, -COO-cyclopentyl, -COO-cyclohexyl, pent-4-en-1-one, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclobutoxymethyl, methoxyethyl, acetyl, methoxyacetyl, -CO-CH ₂ - cyclobutyl, -CO-CH ₂ -cyclopropyl, -CO-CH ₂ -cyclopentyl, -CO-CH ₂ -cyclohexyl, -COO-oxetane, 1-cyclopropylmethylpent-4-en-1-ol, methoxyethoxymethyl, -CONH-cyclopropyl, -CONH-cyclobutyl, -CONH-cyclopentyl and -CONH-cyclohexyl, wherein said pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl imidazolyl, oxadiazolyl, thiadiazolyl, thiophenyl, tetrahydrofuran and furan are optionally substituted with one or more substituents independently selected from group consisting of methyl, halogen, CF ₃ , OMe and OH;

Y is selected from the group consisting of CF ₃ and Me;

R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2-hydroxy-3,3 ,3-trifluoropropyl, 2-hydroxy-2-deuteropropyl and 1-hydroxycyclopropylmethyl.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein

Ar is phenyl which is optionally substituted with one or more R ^Ar substituents;

R ^Ar is selected from the group consisting of Cl, -OMe, F and 2-(dimethylamino)ethoxy;

Z is selected from the group consisting of H, -acetyl, -COOMe, -COOEt, -CO-CH ₂ -OMe, pyrimidin-2-yl, pyrazin-2-yl, thiazol-2-yl, cyclopropoxymethyl, -COO-cyclopropyl , -COO-cyclobutyl, pent-4-en-1-one, pyrimidin-4-yl, 2-tetrahydrofuryl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclobutoxymethyl, 3-oxetanyloxymethyl, hydroxymethyl, pyrazin-2-yl, CO-CH ₂ -cyclobutyl, -COO-oxetane, 5-methylisoxazol-2-yl, 1-cyclopropylmethylpent-4-en-1-ol, 2-methoxyethoxymethyl, -CONH-cyclopropyl, -CONH-cyclobutyl and -CONH-cyclopentyl;

Y is selected from the group consisting of CF ₃ and Me;

R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2-hydroxy-3,3,3-trifluoropropyl, 2-hydroxy -2-deuteropropyl and 1-hydroxycyclopropylmethyl.

7. A compound according to any one of claims 1-6, wherein the compound is selected from the group consisting of the examples listed herein in the examples section.

8. A compound according to any one of claims 1 to 7 for use as a medicine.

9. A compound according to any one of claims 1 to 7 for use in the treatment of a disease or medical condition selected from the group consisting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, Graves' disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory disease bowel disease, ankylosing spondylitis, type I diabetes mellitus, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behçet's disease, atopic dermatitis, lichen planus, Sjögren's syndrome, herniated disc, acne, graft-versus-host disease, host-versus-graft disease, AIH (autoimmune hepatitis), PBC (primary biliary cholangitis), PSC (primary sclerosing cholangitis), obesity, lupus nephritis, autoimmune thyroid diseases including Graves' disease and Hashimoto's disease, autoimmune uveitis, colitis, IMQ psoriasis, juvenile idiopathic arthritis, myasthenia gravis , systemic sclerosis, diabetes mellitus and osteoarthritis.

10. The use of a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a disease or medical condition in which inhibition of interleukin-17 (IL-17) and /or interferon-γ (IFN-γ) is preferred.

11. Use according to claim 10 wherein the disease or medical condition is selected from the group consisting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, Graves' disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, diabetes type I diabetes, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behçet's disease, atopic dermatitis, lichen planus, Sjögren's syndrome, herniated discs, acne, graft versus host disease, host versus graft disease, AIH (autoimmune hepatitis), PBC (primary biliary cholangitis), PSC (primary sclerosing cholangitis), obesity, lupus nephritis, autoimmune thyroid diseases including Graves' disease and Hashimoto's disease, autoimmune uveitis, colitis, IMQ psoriasis, juvenile idiopathic arthritis, myasthenia gravis, systemic sclerosis, diabetes mellitus and osteoarthritis.

In certain embodiments, as used herein, a heteroaryl group refers to a 5- or 6-membered heterocyclic group containing at least one heteroatom independently selected from O, N, or S. This heterocyclic group is optionally fused to another aromatic or heteroaromatic 5- or a 6-membered ring containing at least one heteroatom independently selected from O, N, or S. For example, this group may be selected from the group of thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5 -yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl , isooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, benzoxazol-2-yl, benzoxazole -4-yl, benzoxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, 1,2,5-oxadiazol-4-yl, 1,3,4-oxadiazol-2 -yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1 ,3,4-thiadiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2 ,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl , 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, pyrid-6-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3 -pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazole -5-yl, 1 H -tetrazol-2-yl, 1 H -tetrazol-3-yl, tetrazolyl, acridyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl , 6-indolyl, 7-indolyl, 1-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]furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl or tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazindene, isothiazolopyrazine, 6-imidinyl, 4-dimethoxy-6-pyrimidinyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, tetrazole, tetrahydrothieno[3,4- d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine or triazolopyridazine. Certain heteroaryl groups are pyrimidin-4-yl, pyrimidin-2-yl, thiazol-2-yl, pyrazin-2-yl and isoxazol-2-yl.

In certain embodiments, as used herein, a heterocyclyl group means a 3-8 membered, more specifically 3-6 membered, heterocyclic non-aromatic group containing at least one heteroatom independently selected from the group consisting of O, N, and S, in which the heterocyclyl group is optionally fused to another non-aromatic cycloalkyl or heterocyclyl ring; the heterocyclyl residue is specifically selected from the group consisting of oxetanyl, morpholin-4-yl, piperazinyl, isoxazolidin-2-yl, 1-alkylpiperazin-4-yl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl and pyranyl. Certain heterocyclyl groups are tetrahydropyran and oxetane.

To keep definitions as short as possible, as used herein, the terms "alkyl" and "alk" (as in alkoxy, for example) should be understood to encompass linear and branched alkanyl, alkenyl and alkynyl, more specifically alkyl and alkenyl, even more specifically alkanyl. Unless otherwise indicated, they are in particular embodiments of C ₁ -C ₆ alkanyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, more specifically C ₁ -C ₅ alkanyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl, even more specifically C ₁ -C ₄ alkanyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl. The alkyl group, for example, may be selected from the group consisting of -CH ₃ , -C ₂ H ₅ , -CH=CH ₂ , -C≡CH, -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ -CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH=CH-CH ₃ , -C≡C-CH ₃ , -CH ₂ -C≡CH, -C ₄ H ₉ , -CH ₂ -CH(CH ₃ ) ₂ , -CH(CH ₃ )-C ₂ H ₅ , -C(CH ₃ ) ₃ , -C ₅ H ₁₁ , -C ₆ H ₁₃ , -C ₂ H ₄ -CH=CH ₂ , -CH=CH-C ₂ H ₅ , -CH=C(CH ₃ ) ₂ , -CH ₂ -CH=CH-CH ₃ , -CH=CH-CH=CH ₂ , -C ₂ H ₄ -C≡ CH, -C≡CC ₂ H ₅ , -CH ₂ -C≡C-CH ₃ , -C≡C-CH=CH ₂ , -CH=CH-C≡CH, -C≡CC≡CH, -C ₂ H ₄ -CH(CH ₃ ) ₂ , -CH(CH ₃ )-C ₃ H ₇ , -CH ₂ -CH(CH ₃ )-C ₂ H ₅ , -CH(CH ₃ )-CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ -C ₂ H ₅ , -CH ₂ -C(CH ₃ ) ₃ , -C ₃ H ₆ -CH=CH ₂ , -CH=CH-C ₃ H ₇ , -C ₂ H ₄ -CH=CH-CH ₃ , -CH ₂ -CH=CH-C ₂ H ₅ , -CH ₂ -CH=CH-CH=CH ₂ , -CH=CH-CH=CH-CH ₃ , -CH= CH-CH ₂ -CH=CH ₂ , -C(CH ₃ )=CH-CH=CH ₂ , -CH=C(CH ₃ )-CH=CH ₂ , -CH=CH-C(CH ₃ )=CH ₂ , -CH ₂ -CH=C(CH ₃ ) ₂ , C(CH ₃ )=C(CH ₃ ) ₂ , -C ₃ H ₆ -C≡CH,-C≡CC ₃ H ₇ , -C ₂ H ₄ -C≡C-CH ₃ , -CH ₂ -C≡CC ₂ H ₅ , -CH ₂ -C≡C-CH=CH ₂ , -CH ₂ -CH=CH-C≡CH, -CH ₂ -C ≡CC≡ CH, -C≡C-CH=CH-CH ₃ , -CH=CH-C≡C-CH ₃ , -C≡CC≡C-CH ₃ , -C≡C-CH ₂ -CH=CH ₂ , - CH=CH-CH ₂ -C≡CH, -C≡C-CH ₂ -C≡CH, -C(CH ₃ )=CH-CH=CH ₂ , -CH=C(CH ₃ )-CH=CH ₂ , -CH=CH-C(CH ₃ )=CH ₂ , -C(CH ₃ )=CH-C≡CH, -CH=C(CH ₃ )-C≡CH, -C≡CC(CH ₃ )= CH ₂ , -C ₃ H ₆ -CH(CH ₃ ) ₂ , -C ₂ H ₄ -CH(CH ₃ )-C ₂ H ₅ , -CH(CH ₃ )-C ₄ H ₉ , -CH ₂ -CH (CH ₃ )-C ₃ H ₇ , -CH(CH ₃ )-CH ₂ -CH(CH ₃ ) ₂ , -CH(CH ₃ )-CH(CH ₃ )-C ₂ H ₅ , -CH ₂ -CH (CH ₃ )-CH(CH ₃ ) ₂ , -CH ₂ -C(CH ₃ ) ₂ -C ₂ H ₅ , -C(CH ₃ ) ₂ -C ₃ H ₇ , -C(CH ₃ ) ₂ -CH (CH ₃ ) ₂ , -C ₂ H ₄ -C(CH ₃ ) ₃ , -CH(CH ₃ )-C(CH ₃ ) ₃ , -C ₄ H ₈ -CH=CH ₂ , -CH=CH-C ₄ H ₉ , -C ₃ H ₆ -CH=CH-CH ₃ , -CH ₂ -CH=CH-C ₃ H ₇ , -C ₂ H ₄ -CH=CH-C ₂ H ₅ , -CH ₂ -C (CH ₃ )=C(CH ₃ ) ₂ , -C ₂ H ₄ -CH=C(CH ₃ ) ₂ , -C ₄ H ₈ -C≡CH, -C≡CC ₄ H ₉ , -C ₃ H ₆ -C≡C-CH ₃ , -CH ₂ -C≡CC ₃ H ₇ and -C ₂ H ₄ -C≡CC ₂ H ₅ . Certain alkyl groups are methyl, ethyl, propyl, butyl, pentyl, butenyl and pentenyl.

In certain embodiments, an arylalkyl group as used herein is a linear or branched C ₁ -C ₆ alkyl substituted with at least one aryl group as defined herein. Representative arylalkyl groups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and the like.

In certain embodiments, a cycloalkyl group as used herein refers to a non-aromatic ring system containing three to eight carbon atoms, in particular four to eight carbon atoms, more specifically three to six carbon atoms, even more specifically three to five carbon atoms. .

In certain embodiments, the alkoxy group used herein is an O-alkyl group, where the alkyl group is as defined above. More specifically, the alkoxy group is methoxy, ethoxy, isopropoxy, t -butoxy or pentoxy, more specifically methoxy.

In certain embodiments, a haloalkyl group as used herein refers to an alkyl group in which one or more, in particular more than half, more specifically all of the hydrogen atoms have been replaced by halogen atoms. The haloalkyl group is, for example, -C(R ¹⁰ ) ₃ , -CR ¹⁰ (R ^10' ) ₂ , -CR ¹⁰ (R ^10' )R ^10'' , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ -C(R ¹⁰ ) ₃ , -C(R ^10' ) ₂ -CH(R ^10' ) ₂ , -CH ₂ -CR ¹⁰ (R ^10' ) ₂ , -CH ₂ -CR ¹⁰ (R ^10' )R ^10'' , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ -C(R ¹⁰ ) ₃ in which R ¹⁰ , R ^10' , R ^10'' in particular independently represent F, Cl, Br or I, more specifically F. More specifically, haloalkyl is CF ₃ .

In certain embodiments, the haloalkoxy group used herein is a -O-haloalkyl group.

In certain embodiments, the halogen or halogen group used herein is fluorine, chlorine, bromine, or iodine; in particular chlorine or fluorine.

Unless otherwise indicated, the terms "included", "including", "include" and the like should be understood as meaning including, but not limiting.

Components that are optionally substituted as described herein may be substituted, unless otherwise indicated, at any chemically feasible position.

In certain embodiments of the present invention, Ar is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, more specifically pyridyl, which is optionally substituted with one or more substituents R ^Ar independently selected from the group consisting of halogen, C _1-4 -alkyl, C _1-4 -haloalkyl, -NH ₂ , acetamido, -COO-C _1-4 -alkyl, C _1-4 -alkoxy and (mono- or di-C _1-4 -alkylamino)-C _{1- 4} -alkoxy, more specifically halo, C _1-4 alkoxy, benzyloxy, hydroxyl, 4-6 membered heterocyclylcarbonyl, C _1-4 alkylaminocarbonyl, C _3-4 cycloalkylaminocarbonyl, 5-6 membered heterocyclyl-C _{1 -4} -alkoxy, (2-oxa-6-azaspiro[3.3]hept-6-yl)-C _1-4 -alkoxy and (mono- or di-C _1-4 -alkylamino) -C _1-4 -alkoxy ;

in certain other embodiments, Ar is selected from the group consisting of phenyl and pyridyl, which are optionally substituted with one or more R ^Ar substituents independently selected from the group consisting of halogen, C _1-4 -alkoxy and (mono- or di-C _{1 -4} -alkylamino)-C _1-4 -alkoxy;

in certain other embodiments, Ar is phenyl which is optionally substituted with one or more R ^Ar substituents independently selected from the group consisting of halo, C _1-4 -alkoxy, and (mono- or di-C _1-4 -alkylamino)- C _1-4 alkoxy;

in certain other embodiments, Ar is selected from the group consisting of phenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-chloro-6-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 4- chlorophenyl, 4-methoxyphenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-fluoropyridin-4-yl, 3,5-dichloropyridin-4-yl, 3-chloro-5-fluoropyridin- 4-yl, 2-methoxyphenyl, 2-methoxypyridin-3-yl, 2-chloro-3-(N-morpholinocarbonyl)phenyl, 2-chloro-3-(N-azetanylcarbonyl)phenyl, 2-chloro-3-(N -azetanylcarbonyl)phenyl, 2-chloro-3-(N-pyrrolidinylcarbonyl)phenyl, 2-chloro-3-(ethylamino)carbonylphenyl, 2-chloro-3-(isopropylamino)carbonylphenyl, 2-chloro-3-(cyclopropylamino)carbonylphenyl , 2-chloro-3-(cyclobutylamino)carbonylphenyl, 2-methoxy-3-(ethylamino)carbonylphenyl, 2-methoxy-3-(isopropylamino)carbonylphenyl, 2-methoxy-3-(cyclopropylamino)carbonylphenyl, 2-methoxy-3 -(N-azetanylcarbonyl)phenyl, 3-(cyclobutylamino)carbonylphenyl, 3-(isopropylamino)carbonylphenyl, 2-chloro-3-methoxyphenyl, 2-chloro-3-hydroxyphenyl, 2-chloro p-3-benzyloxyphenyl, 2-chloro-3-(2-(N-morpholinyl)ethoxy)phenyl, 2-chloro-3-(2-(N-1,1-dioxothiomorpholinyl)ethoxy)phenyl, 2-chloro- 3-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy)phenyl, 2-chloro-3-(2-(N-pyrrolidinyl)ethoxy)phenyl, 2-chloro-3- (2-(N-4-methylpiperazinyl)ethoxy)phenyl, 2-chloro-3-(2-(diethylamino)ethoxy)phenyl and 2-chloro-3-(2-(dimethylamino)ethoxy)phenyl;

in certain other embodiments, Ar is selected from the group consisting of 2-chloro-6-fluorophenyl, 2-chlorophenyl, 2-chloro-3-methoxyphenyl, and 2-chloro-3-(2-(dimethylamino)ethoxy)phenyl;

in certain other embodiments, Ar is selected from the group consisting of phenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-chloro-6-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-fluoropyridin-4-yl, 3,5-dichloropyridin-4-yl, 3-chloro-5-fluoropyridin-4-yl and 2-chloro-3-(2-(dimethylamino)ethoxy) phenyl;

in certain other embodiments, Ar is selected from the group consisting of phenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-chloro-6-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-fluoropyridin-4-yl, 3,5-dichloropyridin-4-yl, 3-chloro-5-fluoropyridin-4-yl and 2-chloro-3-methoxyphenyl;

in certain other embodiments, Ar is selected from the group consisting of phenyl, 2-chloro-6-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-fluoropyridin-4-yl, 3,5-dichloropyridin-4-yl, 3-chloro-5-fluoropyridin-4-yl and 2-chloro-3-methoxyphenyl;

in certain other embodiments, Ar is selected from the group consisting of 2-chloro-6-fluorophenyl, 2-chlorophenyl, and 2-chloro-3-methoxyphenyl.

In certain embodiments of the present invention, Z is selected from the group consisting of H, halogen, -CO-heterocyclyl, -CO-alkyl, -CO-alkoxyalkyl, -NH ₂ , -NH-COO-C _1-4 -alkyl, -CN , -COO-C _1-4 alkyl, -CONH-C _1-4 alkyl, -CONH-arylalkyl, -CONH-cycloalkyl, -CON(C _1-4 alkyl) ₂ , -CON(C _1-4 alkyl)- OC _1-4 alkyl, -CO-CH ₂ -cycloalkyl, COO-heterocyclyl, -COO-cycloalkyl, cycloalkylmethyl, hydroxymethyl, -alkyl-O-alkoxyalkyl, alken-1-one, alkyloxyalkyl, cycloalkylmethylalken-1-ol, heteroaryl, phenyl or heterocyclyl, wherein said phenyl and heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, -COO-alkyl, OH, and cycloalkyl;

in certain other embodiments of the present invention, Z is selected from the group consisting of hydrogen, bromine, -COMe, -CO-CH ₂ -OMe, ethoxymethyl, isopropoxymethyl, cyclobutoxymethyl, 2-methoxyethoxymethyl, hydroxymethyl, tetrahydrofuryl, -CONH-cyclopropyl, -CONH -cyclobutyl, -CO-morpholin-4-yl, -CO-piperidin-4-yl, -COOH, -CONH ₂ , -CONHNH ₂ , -CONHNH-CO-methyl, -CONH-(2,4,6-trimethoxyphenyl )methyl, -CONHN=isopropyl, -NH-CO-methyl, -NH-CO-trifluoromethyl, -NH-COH, -CO-(N-methylpiperazin-4-yl), -CO-(4-[chlorobenzyl]- piperazin-1-yl), -CO-pyrrolidinyl, -CO-isoxazolidinyl, -NH ₂ , -NH-COO-methyl, -CN, -COO-C _1-3 alkyl, -CONH-methyl, -CONH-(trifluoromethyl-substituted benzyl), -CONH-cyclohexyl, -CON(methyl) ₂ , -CON(methyl)-O-methyl, -COOMe, -COOEt, cyclopropoxymethyl, -COO-cyclopropyl, -COO-cyclobutyl, pent-4-en-1 -one, methoxymethyl, -CO-CH ₂ -cyclobutyl, COO-oxetane, 5-methylisoxazol-2-yl, 1-cyclopropylmethyl-pent-4-en-1-ol, -CONH-cyclopentyl, phenyl, tetrazolyl, thiazo lyl, pyrimidyl, oxadiazolyl, oxazolyl, thiadiazolyl, pyrazinyl, furanyl and thiophenyl, wherein said phenyl, tetrazolyl, thiazolyl, pyrimidyl, oxadiazolyl, oxazolyl, thiadiazolyl, pyrazinyl, furanyl or thiophenyl is optionally substituted with one or more substituents independently selected from the group, containing halogen, methyl, OMe, CF ₃ , -COOMe and -COOEt;

in certain other embodiments of the present invention, Z is selected from the group consisting of H, -COO-C _1-3 -alkyl, -CO-C _1-2 -alkyl, -CO-C _1-2 -alkoxy-C _1-2 -alkyl 5 - or 6-membered heteroaryl containing one or two heteroatoms independently selected from N, S and O, -CH ₂ -OV, in which V is selected from the group consisting of H, C _1-4 -alkyl, C _3-5 -cycloalkyl and C _1-2 -alkoxy-C _1-2 -alkyl, -COO-C _3-6 -cycloalkyl, C _3-6 -alken-1-one, pyrazinyl, -CO-CH ₂ -C _3-5 -cycloalkyl, COO-(3-5-membered heterocyclyl), methylisoxazolyl, 1-cyclopropylmethyl-C _3-6 -alken-1-ol, -CONH-C _5-6 -heterocyclyl and -CONH-C _{3- 6} -cycloalkyl;

in certain other embodiments of the present invention, Z is selected from the group consisting of H, -COOMe, -COOEt, -COMe, -CO-CH ₂ -OMe, pyrimidin-2-yl, thiazol-2-yl, cyclopropoxymethyl, -COO- cyclopropyl, -COO-cyclobutyl, pent-4-en-1-one, pyrimidin-4-yl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclobutoxymethyl, 2-methoxyethoxymethyl, hydroxymethyl, pyrazin-2-yl, -CO-CH ₂ -cyclobutyl , -COO-oxetane, 5-methylisoxazol-2-yl, tetrahydrofuryl, 1-cyclopropylmethyl-pent-4-en-1-ol, -CONH-cyclopropyl, -CONH-cyclobutyl and -CONH-cyclopentyl;

in certain other embodiments of the present invention, Z is selected from the group consisting of -COOMe, -COOEt, pyrimidin-2-yl, thiazol-2-yl, pyrimidin-4-yl, methoxymethyl, and 5-methylisoxazol-2-yl.

In certain embodiments of the present invention, Y is selected from the group consisting of H, alkyl, haloalkyl, and alkyl ether;

in certain other embodiments, Y is selected from the group consisting of H, pentafluoroethyl, trifluoromethyl, methyl, and methoxycarbonyl;

in certain other embodiments, Y is selected from the group consisting of H, trifluoromethyl, methyl, and methoxycarbonyl;

in certain other embodiments, Y is selected from the group consisting of trifluoromethyl and methyl.

In certain embodiments of the present invention, R' is independently selected from the group consisting of H, OH, Me, Et, iPr, iBu and CF ₃ , more specifically H, OH, Me, Et and CF ₃ .

In certain embodiments of the present invention, R1 is a group of the structure

wherein

n is 0 or 1;

R2 is H, deuterium or methyl;

R3 is methyl, trifluoromethyl, ethyl or, taken together with R2, forms a cyclopropyl group;

or

n is 1, R2 is H, deuterium or methyl, and R3 forms a methylene bridge with the carbon atom marked ⃰;

in certain other embodiments of the present invention, R1 is a group of the structure

wherein

n is 0;

R2 is H, deuterium or methyl;

R3 is methyl, trifluoromethyl, ethyl or, taken together with R2, forms a cyclopropyl group;

or

n is 1;

R2 is H, deuterium or methyl;

R3 is methyl or trifluoromethyl or forms a methylene bridge with the carbon atom marked ⃰;

in certain other embodiments of the present invention, R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2 -hydroxy-3,3,3-trifluoropropyl, 2-hydroxy-2-deuteropropyl and 1-hydroxycyclopropylmethyl;

in certain other embodiments of the present invention, R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 2-hydroxypropyl, 3-hydroxy-3-methylcyclobutyl, 3-hydroxycyclobutyl, and 1-hydroxycyclopropylmethyl;

in certain other embodiments of the present invention, R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 2-hydroxypropyl, and 1-hydroxycyclopropylmethyl;

in certain other embodiments of the present invention, R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, and 2-hydroxypropyl;

in certain other embodiments of the present invention, R1 is 3-hydroxy-3-methylcyclobutyl or 3-hydroxycyclobutyl;

in certain other embodiments of the present invention, R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, and 3-hydroxy-3-methylcyclobutyl;

in other more specific embodiments of the present invention, R1 is 3-hydroxy-3-methylcyclobutyl.

in other more specific embodiments of the present invention, R1 is 3-hydroxy-3-methylbutyl.

Specific compounds of the present invention are the compounds of the following examples of the present invention, more specifically the compounds of the following examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166 and 167, more specifically compounds of the examples below 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 22, 23, 24, 25, 27, 29, 30, 31, 32, 33, 35, 36, 37, 44, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 66, 67, 68, 69, 72, 74, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 115, 117, 118, 119, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 154, 155, 157, 158, 159, 160 and 162, more specifically the compounds of examples 1, 2, 3, 4, 5, 6, 7 below , 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 22, 23, 25, 27, 31, 32, 33, 49, 50, 51, 53, 55, 56 , 58, 59, 61, 62, 66, 67, 69, 72, 76, 77, 78, 79, 82, 83, 85, 86, 87, 89, 90, 91, 92, 97, 98, 99, 100 , 102, 103, 104, 106, 107, 111, 112, 118, 121, 122, 123, 124, 125, 127, 128, 130, 131, 132, 133, 134, 135, 138, 139, 141, 143 , 148, 150 and 160, even more specifically the compounds of examples 3 below, 4, 6, 7, 10, 11, 12, 14, 15, 16, 27, 32, 49, 61, 82, 89, 92, 97, 98, 102, 103, 112, 121, 123, 128, 130 and 132.

Obviously, the respective options for implementation regarding the residues Ar, R ^Ar , Z, R ^Z , Y, R1 and R' described in this application can be combined with each other to obtain additional more specific options for implementation. Some examples of such combinations, without limiting the invention to certain combinations, are described in this application.

As far as the person skilled in the art knows, the compounds of the invention, as well as their salts, may contain, for example, when isolated in crystalline form, varying amounts of solvents. 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 salts of the compounds of formula (I) are within the scope of the invention.

The present invention additionally relates to methods of treating diseases or medical conditions that are described in this application, in particular a disease or medical condition in which inhibition of interleukin-17 (IL-17A), interleukin-17F (IL-17F), interleukin-22 ( IL-22) and/or interferon-γ (IFN-γ) is preferred, more specifically a disease or medical condition selected from the group consisting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, Graves' disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, type I diabetes mellitus, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behçet's disease, atopic dermatitis, lichen planus, Sjögren's syndrome, herniated disc, acne, graft versus host reactions, reactions host versus graft, AIH (autoimmune hepatitis), PBC (primary biliary cholangitis) ), PSC (primary sclerosing cholangitis), obesity, lupus nephritis, diabetes mellitus and osteoarthritis, said method comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) as described herein. Similarly, the present invention further relates to methods similar to those described above, which cover additional embodiments described in this application, in particular medical applications and compounds for use in methods of treatment, as described in this application.

The present invention further relates to pharmaceutical compositions, kits and kits of parts, comprising compounds in accordance with the present invention.

The present invention further relates to the use of the compounds according to the present invention for the manufacture of pharmaceutical compositions that are used for the treatment and/or prevention of diseases, disorders, diseases and/or conditions, as described in this application.

The present invention further relates to the methods and medicinal uses described in this application, including pharmaceutical compositions as described in this application.

Pharmaceutical compositions, as described in this application, contain one or more compounds in accordance with this invention and a pharmaceutically acceptable carrier or diluent.

In addition, the invention relates to a product that contains a packaging material and a pharmaceutical agent contained in said packaging material, in which the pharmaceutical agent is therapeutically effective against medical conditions, as described in this application, and in which the packaging material contains a label or instructions for use a preparation which indicates that the pharmaceutical agent is suitable for the prevention or treatment of said diseases, and in which said pharmaceutical agent contains one or more compounds of formula (I) in accordance with the invention. The packaging material, label and instructions for use of the drug are otherwise similar or resemble what is usually considered standard packaging material, labels and instructions for use for pharmaceutical products with appropriate suitability.

Pharmaceutical compositions in accordance with this invention receive using methods that are themselves known and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (=active compounds) are either used as such or in particular in combination with suitable pharmaceutical excipients and/or excipients, for example in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. , TTS), emulsions, suspensions, gels or solutions, wherein the content of the active compound is preferably from 0.1 to 95% and in which, with an appropriate choice of excipients and/or excipients, a form for pharmaceutical administration can be achieved (for example, a form with delayed release or enteric form) precisely matched to the active compound and/or to the desired onset of action.

The person skilled in the art is familiar with excipients, excipients, excipients, diluents, carriers or adjuvants that are suitable for the desired pharmaceutical formulations, preparations or compositions, based on his/her expert knowledge. In addition to solvents, gelling agents, ointment bases and other excipients of the active compound may be used, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or penetration promoters.

Depending on the specific disease being treated or prevented, additional therapeutically active agents that are typically administered to treat or prevent that disease may optionally be co-administered with the compounds of the present invention. As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease are known to be suitable for the disease being treated.

In a further aspect of the present invention, the compounds of the present invention, or salts or solvates of said compounds of formula (I), may be combined with standard therapeutic agents commonly used to treat medical conditions as described herein.

The person skilled in the art is aware, based on his/her expert knowledge, of the total daily dosage(s) and administration form(s) of the co-administered co-administered therapeutic agent(s). Said total daily dosage(s) may vary within wide limits. In carrying out the present invention, and depending on the details, characteristics or purposes of their use mentioned above, the compounds in accordance with the present invention may be administered in combination therapy separately, sequentially, simultaneously or in chronological order (for example, in the form of combined unit dosage forms, in as separate unit dosage forms or adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as a set of parts or as mixtures) with one or more standard therapeutic agents, in particular chemotherapeutic or targeted specific anticancer agents known in the art , such as 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 the invention or a pharmaceutically acceptable salt or solvate thereof, a second active ingredient which is a standard therapeutic agent known in the art. for the treatment of medical conditions, as described in this application, and optionally a pharmacologically acceptable carrier, diluent and/or excipient for sequential, separate, simultaneous or chronological use in therapy in any order, for example, for the treatment, prevention or improvement of the medical conditions of a patient as described in this application.

In this context, the present invention further relates to a combination comprising a first active ingredient which is at least one compound according to the present invention and a second active ingredient which is at least one known in the art. standard therapeutic agent for the treatment of medical conditions, as described in this application, for separate, sequential, simultaneous or chronological use in therapy, such as, for example, in the treatment of diseases mentioned in the present description.

The term "combination" in accordance with this invention may be present as a fixed combination, a non-fixed combination, or a set of parts. A "fixed combination" is defined as a combination in which said first active ingredient and said second active ingredient are present together in the same unit dose or formulation. One example of a "fixed combination" is a pharmaceutical composition in which said first active ingredient and said second active ingredient are present in a mixture for simultaneous administration, eg in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which said first active ingredient and said second active ingredient are present in the same unit without being in admixture.

A "set of parts" is defined as a combination in which said first active ingredient and said second active ingredient are present in more than one unit. One example of a "kit of parts" is a combination in which said first active ingredient and said second active ingredient are present separately. The components of a set of parts can be entered separately, sequentially, simultaneously, or in chronological order.

The first and second active ingredient of the combination or set of parts according to the invention may be provided as separate formulations (i.e., independently) which are further combined for simultaneous, sequential, separate or chronological use in a combined therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronological use in combination therapy.

The type of pharmaceutical composition of the first and second active ingredient of the combination or set of parts in accordance with this invention may be similar, i.e. both ingredients are formulated in separate tablets or capsules, or may be different, i. suitable for various forms of administration, such as, for example, one active ingredient is formulated as a tablet or capsule and the other is formulated, for example, for intravenous administration.

The amounts of the first and second active ingredients of the combinations, compositions or kits in accordance with this invention may together include a therapeutically effective amount for the treatment, prevention or improvement of a medical condition, as described in this application.

A further aspect of the present invention is a method of therapeutically treating medical conditions as described herein in a patient in need of such treatment, comprising administering separately, sequentially, simultaneously, a fixed or non-fixed therapeutically effective and tolerable amount of one or more compounds according to with the present invention and a therapeutically effective and tolerable amount of one or more therapeutic agents known in the art for the treatment of medical conditions, as described in this application, to the specified patient.

The references and claims for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or medical condition in their general and specific forms also refer to respective methods of treating said disease or medical condition, said method comprising administering a therapeutically effective and tolerable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need of such treatment, compositions containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for the treatment of said disease or medical condition, the compound formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of said disease or medical condition, and vice versa.

In order to obtain pharmaceutical compositions, the compounds of the invention (= active compounds) are in particular mixed with suitable pharmaceutical excipients and further processed to obtain suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, aerosols, oils, ointments, fatty ointments, creams, pastes, gels or solutions. Pharmaceutical compositions according to the invention are prepared by methods known per se.

The dosage of active compounds is carried out in a standard manner. Thus, topical formulations (such as ointments) contain active compounds at a concentration of, for example, 0.1-99%. The standard dose in case of systemic therapy (po) is usually 0.3 to 30 mg/kg per day (iv), usually 0.3 to 30 mg/kg/h. The choice of the optimal dosage regimen and duration of administration of the drug, in particular the optimal dose and route of administration of the active compounds needed in each case, can be determined by a person skilled in the art based on his/her expert knowledge.

The class of compounds of the present invention is useful in the development of drugs suitable for the treatment of autoimmune diseases and chronic inflammation, or more generally for the treatment of diseases in which inhibition of interleukin-17 (IL-17) and/or interferon-γ (IFN-γ) is preferred.

The compounds of the present invention are also useful in the treatment of diseases that are associated with or mediated by inflammatory cytokines, such as psoriasis, psoriatic arthritis, autoimmune thyroiditis, Graves' disease, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, diabetes mellitus. Type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behçet's disease, atopic dermatitis, lichen planus, Sjögren's syndrome, herniated disc, acne, graft versus host disease, host versus graft disease, AIH (autoimmune hepatitis), PBC ( primary biliary cholangitis), PSC (primary sclerosing cholangitis), obesity, lupus nephritis, diabetes mellitus and osteoarthritis.

Surprisingly, it has been found that compounds having R1 groups, as detailed herein, exhibit high cytokine induction while having favorable aqueous solubility and/or microsomal stability. The following section of examples shows additional details.

Examples

a) Synthesis

As used herein, the term "room temperature" or "RT" usually refers to about 25°C; "aqueous" refers to water; "prep." refers to the preparative; "TLC" refers to thin layer chromatography; "quant." refers to quantitative. Compounds with stereocenters, in which the stereochemistry is not specifically indicated, were obtained as mixtures of stereoisomers. For completeness, the "R" residues indicated in the following synthetic schemes, in each case, refer to a common substituent group, including, in particular, certain groups, as can be seen in the specific examples following each scheme and its analogues, and the value of "R" may vary in different synthesis schemes and positions in each scheme.

Used analytical devices

Analytical LC/ESI-MS: Waters 2700 autosampler. Waters 1525 multi-solvent delivery system. 5 µl sampling loop. Phenomenex Onyx Monolythic C18 50×2 mm column with 2 µm stainless steel prefilter. Eluent A, H ₂ O+0.1% HCOOH; eluent B, MeCN. Gradient from 5% B to 100% B over 3.80 min, then isocratic over 0.20 min, then back to 5% B over 0.07 min, then isocratic over 0.23 min; flow 0.6 ml/min or 1.2 ml/min.

Waters Micromass ZQ 4000 single quadrupole mass spectrometer with electrospray source. MS method, MS4_15minPM-80-800-35V; scanning mode of positive/negative ions, m/z 80-800 for 0.5 s; capillary voltage 3.50 kV; voltage on the cone 50 V; additional voltage 650 V; temperature of the initial block and desolvation gas 120°C and 300°C, respectively. Waters 2487 Dual λ absorption detector tuned to 254 nm. Waters Masslynx V 4.0 software.

Waters Micromass LCZ Platform 4000 single quadrupole mass spectrometer with electrospray source. MS method, MS4_15minPM-80-800-35V; scanning mode of positive/negative ions, m/z 80-800 for 1 s; capillary voltage 4.0 kV; voltage on the cone 30 V; additional voltage 900 V; temperature of the initial block and desolvation gas 120°C and 300°C, respectively. Waters 996 photodiode array detector set from 200 to 400 nm. Waters Masslynx V4.0 software.

The values for [M+H] ⁺ given in the examples are the m/z values found on the respective LC/MS chromatogram for the respective compound. All of these values were found to be within +/- 0.3 units of the calculated exact mass when the compound was protonated.

Preparative thin layer chromatography (preparative TLC): Merck PLC plates, silica gel 60 F ₂₅₄ , 0.5 mm, 1.0 mm or 2.0 mm.

Column chromatography: silica gel Acros 60A, 0.035-0.070 mm.

Preparative HPLC-MS: I) Autosampler 2767, Waters 600 multi-solvent delivery system with analytical pump heads (100 µl); Waters 600 controller; binary gradient module with preparative pump heads (500 µl) Waters 2525. Column dilution: solvent1, MeCN:H ₂ O 70:30 (v/v), solvent2, MeCN:MeOH:DMF 80:15:5 (v/v) ./rev/rev); flow rate 5 ml/min. Autosampler 2767 with 10 ml syringe and 10 ml sampling loop. Flom 401 6-way valve column with Waters X-Terra RP18, 5 µm, 19×150 mm with X-Terra RP18 5 µm, 19×10 mm guard cartridge, used at a flow rate of 20 ml/min; Waters SunFire Prep OBD 5µm 30x50mm with SunFire RP18 5µm 19x10mm Protective Cartridge used at 25ml/min flow rate; Waters Atlantis Prep T3 OBD 5µm, 30x50mm with Atlantis Protective Cartridge, used at 50ml/min flow rate; Waters X-Bridge Prep OBD 5µm, 19x150mm with X-Bridge RP18 5µm, 19x10mm Protective Cartridge, used at 20ml/min flow rate; Waters Atlantis Prep T3 OBD 5µm 19x50mm with Atlantis Guard Cartridge used at 25ml/min flow rate and YMC-Actus Hydrosphere C18 5µm 20x50mm with Actus Guard Cartridge used at 20ml flow rate /min Eluent A, H ₂ O containing 0.1% (v/v) HCO ₂ H or H ₂ O containing 0.1% (v/v) NEt ₃ ; eluent B, MeCN. Various linear gradients individually adapted to the sample. The volume of the injected sample is 9 ml, depending on the sample. Co-solvent MeOH-MeCN-H ₂ O-HCO ₂ H 80:15:4.95:0.05 (v/v/v/v). Auxiliary pump Waters Reagent Manager, flow rate 0.5 ml/min. Single quadrupole mass spectrometer with Waters ZQ electrospray source. Scanning mode of positive or negative ions m/z 105-950 for 1 s; capillary 3.6 kV; cone voltage 45 V; additional voltage 700 V; probe and desolvation gas temperatures 120°C and 250°C, respectively. 2767 Water Fraction Collector with Mass or UV Triggered Fraction Collection. Waters 2487 Dual λ absorption detector tuned to 254 nm. Waters Masslynx V 4.0 SP4 software.

¹ H NMR spectra were recorded at room temperature on a Bruker Supraleitendes NMR Fourier spectrometer (superconducting Fourier NMR spectrometer), Avance ^™ 300 MHz. Chemical shifts δ are given in ppm. The multiplicity of a certain signal (singlet, doublet, triplet, quartet, multiplet) is indicated by the corresponding abbreviation (s, d, t, k, m, respectively). "b.s" denotes a broadened singlet, " _mc " denotes a centered multiplet. Residual solvent signals were used as internal standards: δ (CDCl ₃ ) = 7.26, δ (d6-DMSO) = 2.50, δ (CD ₃ OD) = 3.31, δ (d6-acetone) = 2, 05.

General procedure for the preparation of alkyl-5-methylisoxazole-4-carboxylates

To a stirred mixture of aldehyde (volume: 60 mmol) A in ethanol (0.5 ml/mmol) and water (0.5 ml/mmol) was added hydroxylamine (1.3 eq., 50 wt.% in water) at 0° C. The mixture was stirred at room temperature for 24 h, after which all volatiles were removed under reduced pressure. The resulting crude oxime was dissolved in DMF (1 ml/mmol) and treated with NCS (1.0 eq.) at room temperature for 24 hours.

If desired, the initiation of the reaction can be better controlled by adding only 0.15 eq. NCS followed by the addition of dry hydrogen chloride, bubbling into the DMF solution until the reaction temperature rises to 35°C; then NCS (0.85 eq.) can be added in portions.

The reaction mixture was partitioned between DCM and water. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give crude hydroxamoyl chloride B .

The following hydroxamoyl chlorides B were also synthesized during the cycloaddition reactions as part of the synthesis of Examples 97 to 129 and the corresponding Building Blocks:

- 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; LC/MS result [M+H] ⁺ : 208.1;

- 2-chloro- N -hydroxybenzimidoyl chloride; LC/MS result [M+H] ⁺ : 190.1;

- 2,6-dichloro-3-methoxy- N -hydroxybenzimidoyl chloride: this type of aromatic substitution was obtained from N -[(2-chloro-3-methoxyphenyl)methylidene]hydroxylamine with 2.0 NCS treatment instead of 1.0 eq., as used to prepare 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride); LC/MS result [M+H] ⁺ : 253.9;

¹ H NMR (CDCl ₃ ): δ 3.92 (3H, s, CH ₃ ), 6.97 (1H, d, CH), 7.32 (1H, d, CH), 8.39 (1H, s , HE).

- 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; LC/MS result [M+H] ⁺ : 220.0;

- 2-methoxy- N -hydroxybenzimidoyl chloride;

- 3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride; LC/MS result [M+H] ⁺ : 295.9;

- methyl-2-chloro-3-(chloro(hydroxyimino)methyl)benzoate

- methyl-3-(chloro(hydroxyimino)methyl)-2-methoxybenzoate

- methyl-3-(chloro(hydroxyimino)methyl)benzoate

According to this methodology, the following C building blocks were synthesized with an additional synthesis step as described below:

(Z)-ethyl-3-(pyrrolidin-1-yl)but-2-enoate: Ethyl 3-oxobutanoate (1.0 eq) was slowly added to pyrrolidine (6 mmol) (WARNING: highly exothermic!) to give a yellow suspensions. Toluene (5 ml/mmol) was added to remove the H ₂ O resulting from the condensation reaction using a Dean-Stark trap. The mixture was heated at reflux for 5 h, resulting in a solution, which was further fractionated by distillation (8 mbar, 150°C) to obtain the product as a yellow oil (4.2 mmol, 70%).

¹ H NMR (CDCl ₃ ): δ 1.24 (3H, t, CH3), 1.92 (4H, m, CH ₂ ), 2.45 (3H, s, CH ₃ ), 3.28 (4H, m, CH ₂ ), 4.08 (2H, q, CH ₂ ), 4.46 (1H, s, CH).

Ethyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylate

To a solution of ( Z )-2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride (65 mmol) in DMF (2 ml/mmol) at 0°C was added a solution of ( Z )-ethyl-3-(pyrrolidine-1- yl)but-2-enoate (1.05 eq. in EtOH, 0.3 ml/mmol). After stirring at room temperature for 1 h, triethylamine (1.1 eq. in EtOH, 0.1 ml/mmol) was added dropwise over 2 h. The mixture was stirred at room temperature for 24 h. The resulting mixture was filtered and the filtrate was partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The crude product was distilled at 10 mbar and 160°C. The product was obtained as an orange oil (80%).

¹ H NMR (CDCl ₃ ): δ 1.07 (3H, t, CH ₃ ), 2.79 (3H, s, CH ₃ ), 4.14 (2H, q, CH ₂ ), 7.09 (1H , td, CH-arom), 7.29 (1H, d, CH-arom), 7.39 (1H, m, CH-arom).

Ethyl 3-(3-benzyloxy-2-chlorophenyl)-5-methylisoxazole-4-carboxylate

To a solution of ( Z )-3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride (60 mmol) in DMF (1 ml/mmol) at 0°C was added a solution of ( Z )-ethyl-3-(pyrrolidine- 1-yl)but-2-enoate (1.05 eq. in EtOH, 0.3 ml/mmol). After stirring at room temperature for 1 h, triethylamine (1.1 eq. in EtOH, 0.1 ml/mmol) was added dropwise over 2 h. The mixture was stirred at room temperature for 24 h. All volatiles were removed under reduced pressure . The crude product was distilled at 2 mbar and 175-185°C. The product was obtained as an oily yellow solid (94%).

LC/MS result [M+H] ⁺ : 372.0;

¹ H NMR (CDCl ₃ ): δ 0.98 (3H, t, CH ₃ ), 4.06 (2H, q, CH ₂ ), 4.57 (3H, s, CH ₃ ), 5.07 (2H , s, CH ₂ ), 6.80 (1H, d, CH-arom), 7.30 (7H, m, CH-arom).

Methyl 3-(2-chloro-3-methoxyphenyl)-5-methylisoxazole-4-carboxylate

( Z )-2-Chloro-N-hydroxy-3-methoxybenzene-1-carbonimidoyl chloride (17 mmol) was dissolved in DMF (2 ml/mmol) and methyl acetoacetate (2.0 eq.) was added followed by triethylamine (5.0 equiv.). The mixture was stirred at room temperature for 24 h and then partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether to petroleum ether/ethyl acetate 80:20) to give a pale brownish solid (75%).

LC/MS result [M+H] ⁺ : 282.00;

¹ H NMR (CDCl ₃ ): δ 2.75 (3H, s, CH ₃ ), 3.69 (3H, s, OCH ₃ ), 3.94 (3H, s, OCH ₃ ), 7.01 (1H , dd, CH-arom), 7.05 (1H, dd, CH-arom), 7.31 (1H, dd, CH-arom).

Methyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylate was purchased from Apollo Scientific (PC9397). Methyl 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylate and ethyl 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylate were purchased from ABCR (AB158164 and AB334755, respectively).

Preparation of 3-(2-chloro-6-fluorophenyl)-5-methyl-4-(thiazol-2-yl)isoxazole

A solution of 28.4 g (100 mmol) of ethyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylate was dissolved in 40 ml of ethanol and 40 ml of aq. NaOH (4.0 M). The mixture was heated to 60° C. for 24 hours. Ethanol was partially evaporated under reduced pressure and the remaining solution was acidified by adding aq. HCl (4.0 M). The resulting precipitate was filtered off, washed with H ₂ O and dried under vacuum to give 25.2 g (99%) of crude 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid as white to yellowish or greyish tint of solid.

LC/MS result [M+H] ⁺ : 255.9;

¹ H NMR (CDCl ₃ ): δ 2.79 (3H, s, CH ₃ ), 7.09 (1H, dt, CH-arom), 7.30 (1H, dd, CH-arom), 7 .47-7.34 (1H, m, CH-arom).

To a light beige suspension of 25.2 g (99 mmol) of crude 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid in CH ₂ Cl ₂ (300 ml) was added a catalytic amount of DMF (ca. 0.1 ml) followed by dropwise addition of oxalyl chloride (5.0 eq.) resulting in an orange-red solution. The reaction mixture was heated at reflux for 1 h, after which all volatiles were removed under reduced pressure. The crude material 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride was directly dissolved in Et ₂ O (250 ml) and cooled to 0°C. Added 10% aq. Na ₂ CO ₃ (250 ml) and the resulting biphasic mixture was vigorously stirred while aq. ammonia solution (50 ml; 35 wt.% solution of NH ₃ in water). The reaction mixture was stirred at 0° C. for 10 min and then at rt for 3 h. The two phases were separated, the organic phase was washed with H ₂ O and 5% aq. HCl, dried over MgSO ₄ and concentrated under reduced pressure to give crude 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxamide as a beige solid (22.7 g, 90%).

LC/MS result [M+H] ⁺ : 254.9;

¹ H NMR (CDCl ₃ ): δ 2.79 (3H, s, CH ₃ ), 5.40 (2H, br., NH ₂ ), 7.18 (1H, t, CH-arom), 7, 38 (1H, d, CH-arom), 7.55-7.42 (1H, m, CH-arom).

1.0 eq. Lawesson's reagent. The mixture was stirred for 4 h at reflux. After cooling to rt. the precipitate was filtered off and the filtrate was concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel; eluent: 100% CH ₂ Cl ₂ ) to give 11.0 g (81%) of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbothioamide as yellow solid.

LC/MS result [M+H] ⁺ : 270.9;

¹ H NMR (CDCl ₃ ): δ 2.84 (3H, s, CH ₃ ), 6.50 (1H, br., NH), 7.17 (1H, td, CH-arom), 7.30 (1H, br., NH), 7.36 (1H, dt, CH-arom), 7.51-7.40 (1H, m, CH-arom).

To a yellow suspension of 10.8 g (40 mmol) of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbothioamide in ethanol was added a solution of chloroacetaldehyde (10 eq.; 50 wt.% in H ₂ O) and the reaction mixture was stirred at reflux for 24 hours. All volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and washed 3 times with water. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: 100% CH ₂ Cl ₂ ). The title compound 3-(2-chloro-6-fluorophenyl)-5-methyl-4-(thiazol-2-yl)isoxazole was obtained as a yellow oil (8.37 g, 71%).

LC/MS result [M+H] ⁺ : 294.9;

¹ H NMR (CDCl ₃ ): δ 2.89 (3H, s, CH ₃ ), 7.15 (1H, td, CH-arom), 7.19 (1H, d, CH-arom), 7 .35 (1H, dt, CH-arom) 7.52-7.42 (1H, m, CH-arom), 7.80 (1H, d CH-arom).

General procedure for the preparation of 5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazoles and 5-(1-(dimethylamino)-3-oxobut-1-ene -2-yl)isoxazoles

Step 1 : To a solution of 3-aryl-5-methylisoxazole (10 mmol) in dry toluene (Sure/Seal; 2 ml/mmol) was added tert -butoxy-bis(dimethylamino)methane (Bredereck's reagent; 2.5 eq.). The reaction mixture was heated under reflux for 5 h, then cooled to room temperature, concentrated under reduced pressure and partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ and the volatiles removed under reduced pressure to give the crude enamine intermediate.

Step 2a, Y=CF ₃ : The crude enamine intermediate from step 1 (10 mmol) was dissolved in CH ₂ Cl ₂ (3 ml/mmol) and cooled to 0°C. At this temperature, trifluoroacetic anhydride (2.0 eq.) was added dropwise, followed by triethylamine (1.0 eq.). The reaction mixture was allowed to warm to room temperature over 3 h and then partitioned between CH ₂ Cl ₂ and water. The combined organic layers were washed with saturated aq. NaHCO ₃ and dried over MgSO ₄ . The crude product was purified by silica gel flash chromatography (eluent: CH ₂ Cl ₂ to CH ₂ Cl ₂ /MeOH 95:5).

Step 2b, Y=Me : The crude enamine intermediate from step 1 (10 mmol) was dissolved in THF (Sure/Seal; 3 ml/mmol) and acetyl chloride (2.5 eq.) and diisopropylethylamine (3.0 eq.) were added. The reaction mixture was heated at reflux for 18 hours. The conversion was monitored by TLC, additional acetyl chloride may be required to bring the conversion to completion. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and water. The combined organic layers were washed with saturated aq. NaHCO ₃ and dried over MgSO ₄ . The crude product was purified by silica gel flash chromatography (eluent: CH ₂ Cl ₂ to CH ₂ Cl ₂ /MeOH 95:5).

ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazol-4 -carboxylate (stage 1+2a)

White with a yellowish or grayish tint powder, 48% yield in two steps.

LC/MS result [M+H] ⁺ : 434.8;

¹ H NMR (DMSO): δ 0.84 (3H, t, CH ₃ ), 2.52 (3H, s, CH ₃ ), 3.29 (H, s, CH ₃ ), 3.92 (2H, q, CH ₂ ), 7.32 (1H, t, CH-arom), 7.42 (1H, d, CH-arom), 7.54 (7H, m, CH-arom), 8, 00 (1H, s, CH).

methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazol-4 -carboxylate (stage 1+2a)

Pale yellow powder, 53% yield over two steps.

LC/MS result [M+H] ⁺ : 420.8;

¹ H NMR (DMSO): δ 3.63 (3H, s, CH ₃ ), 3.40 (3H, s, CH ₃ ), 3.57 (3H, s, CH ₃ ), 7.44 (1H, t, CH-arom), 7.53 (1H, d, CH-arom), 7.65 (7H, m, CH-arom), 8.12 (1H, s, CH).

ethyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate (step 1+2a)

Yellow solid, 46% yield over two steps.

LC/MS result [M+H] ⁺ : 416.7;

¹ H NMR (CDCl ₃ ): δ 0.38 (3H, t, CH ₃ ), 2.75 (6H, s, 2x CH ₃ ), 4.12 (2H, q, CH ₂ ), 7.45 ( 5H, t, CH-arom).

methyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate (step 1+2a)

Pale yellow powder, 42% yield over two steps.

LC/MS result [M+H] ⁺ : 403.1;

¹ H NMR (CDCl ₃ ): δ 3.72 (3H, s, CH ₃ ), 3.34 (3H, s, CH ₃ ), 3.63 (3H, s, CH ₃ ), 7.44 (4H , m, CH-arom), 7.95 (1H, s, CH).

methyl-( Z )-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)-3-(2-methoxypyridin-3-yl)isoxazol-4 -carboxylate

Starting from the building block 2-methoxypyridine-3-carboxaldehyde (30 mmol), the general reaction procedures described above followed by step 1+2a gave the title compound as a pale yellow powder in 16% yield over 5 steps.

LC/MS result [M+H] ⁺ : 399.9;

¹ H NMR (DMSO): δ 3.64 (3H, s, CH ₃ ), 3.41 (3H, s, CH ₃ ), 3.59 (3H, s, CH ₃ ), 3.82 (3H, s, CH ₃ ), 7.15 (1H, dd, CH-arom), 7.92 (1H, dd, CH-arom), 8.09 (1H, s, CH), 8.34 (1H , dd, CH-arom.).

ethyl-( Z )-3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole -4-carboxylate (stage 1+2a)

Brownish oil, 38% yield over two steps.

LC/MS result [M+H] ⁺ : 523.1;

¹ H NMR (DMSO): δ 1.02 (3H, t, CH ₃ ), 2.73 (3H, d, N-CH ₃ ), 3.34 (3H, d, N-CH ₃ ), 4, 09 (2H, q, CH ₂ ), 5.21 (2H, s, CH ₂ ), 7.12 (2H, m, CH-arom) 7.39 (6H, m, CH-arom), 7 .97 (1H, s, CH).

methyl-( Z )-3-(3-( tert -butoxycarbonyl)-2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl )isoxazole-4-carboxylate

2-Chloro-3-formylbenzoic acid (25 mmol) was dissolved in THF (75 ml) and di-tert-butyl dicarbonate (2.0 eq) and N,N-dimethylaminopyridine (0.2 eq) were added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with saturated aq. NaHCO ₃ and brine, dried over MgSO ₄ and concentrated under reduced pressure. Flash chromatography on silica gel (eluent: petroleum ether to petroleum ether/ethyl acetate 80:20) provided tert -butyl 2-chloro-3-formyl benzoate (87%). From this building block, the general reaction procedures described above followed by step 1+2a gave the title compound as a white to yellowish or greyish powder in 27% yield over 5 steps.

LC/MS result [M+H] ⁺ : 523.1;

¹ H NMR (CDCl ₃ ): δ 1.61 (9H, s, t-Bu), 3.73 (3H, s, CH ₃ ), 3.35 (3H, s, CH ₃ ), 3.63 ( 3H, s, _CH3 ), 7.43 (1H, t, CH-arom), 7.59 (1H, dd, CH-arom), 7.81 (1H, dd, CH-arom), 7.96 (1H, s, CH).

methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate (step 1+2b)

Orange solid, 52% yield over two steps.

LC/MS result [M+H] ⁺ : 367.1;

¹ H NMR (CDCl ₃ ): δ 2.04 (3H, s, CH ₃ ), 2.63 (3H, d, N-CH ₃ ), 3.21 (3H, d, N-CH ₃ ), 3 .64 (3H, s, CH ₃ ), 7.13 (1H, t, CH-arom), 7.31 (1H, d, CH-arom), 7.41 (1H, m, CH-arom .), 7.87 (1H, s, CH).

methyl-( Z )-3-(2-chloro-3-methoxyphenyl)-5-(1-(dimethylamino)-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate (step 1+2b)

Brownish oil, 63% yield over two steps.

LC/MS result [M+H] ⁺ : 379.0;

¹ H NMR (CDCl ₃ ): δ 2.45 (3H, s, CH ₃ ), 2.67 (3H, d, N-CH ₃ ), 3.17 (3H, d, N-CH ₃ ), 3 .63 (3H, s, CH ₃ ), 3.94 (3H, s, CH ₃ ), 7.09 (2H, m, CH-arom), 7.35 (1H, t, CH-arom) , 7.41 (1H, m, CH-arom), 7.85 (1H, s, CH).

methyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-3-oxobut-1-en-2-yl)isoxazol-4-carboxylate (step 1+2b)

Beige-brown solid, 40% yield over two steps.

LC/MS result [M+H] ⁺ : 349.3;

¹ H NMR (CDCl ₃ ): δ 2.05 (3H, s, CH ₃ ), 2.70 (3H, d, N-CH ₃ ), 3.17 (3H, d, N-CH ₃ ), 3 .63 (3H, s, _CH3 ), 7.44 (4H, m, CH-arom), 7.87 (1H, s, CH).

( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino) -1,1,1-trifluorobut-3-en-2-one

A solution of methyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylate (50 mmol) was dissolved in 20 ml of ethanol and 20 ml of aq. NaOH (4.0 M). The mixture was heated to 60° C. for 24 hours. Ethanol was partially evaporated under reduced pressure and the remaining solution was acidified by adding aq. HCl (4.0 M). The precipitate formed was filtered off, washed with H ₂ O and dried under vacuum to give crude 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid quantitatively as a white with a yellowish or grayish tinge of a solid.

A solution of carboxylic acid (10 mmol) in 30 ml of SOCl ₂ was heated under reflux for 3 hours. The volatiles were carefully evaporated under vacuum. The residue was dissolved in dioxane (Sure/Seal; 100 ml) and added dropwise to a stirred mixture of N ₂ H ₄ ⃰H ₂ O (20 eq.) in 50 ml dioxane. The mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and water. The combined organic layers were washed with water and brine, dried over MgSO ₄ . Evaporation to dryness provided the crude hydrazide, which was then heated in the samples to approx. 1.85 mmol (approx. 500 mg) in the presence of 10 ml of acetic anhydride under microwave irradiation at 140°C for 6 hours. The combined mixtures of several microwave reactions were diluted with dichloromethane and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure . Silica gel column chromatography (eluent: CH ₂ Cl ₂ to CH ₂ Cl ₂ /MeOH 98:2) provided 2-[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4 -yl]-5-methyl-1,3,4-oxadiazole as a yellowish oil in 38% yield over three steps.

Starting from this building block (3 mmol), the general 1+2a reaction procedures described above gave the title compound as a yellow powder in 44% yield over 2 steps.

LC/MS result [M+H] ⁺ : 349.3;

¹ H NMR (CDCl ₃ ): δ 2.39 (3H, s, CH3), 2.73 (3H, d, N-CH ₃ ), 3.36 (3H, d, N-CH ₃ ), 7, 14 (1H, t, CH-arom), 7.33 (1H, d, CH-arom), 7.45 (1H, m, CH-arom), 8.04 (1H, s, CH) .

( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1,1-trifluorobut-3 -en-2-one (stage 1+2a)

Orange powder, 25% yield over two steps.

LC/MS result [M+H] ⁺ : 445.7;

¹ H NMR (CDCl ₃ ): δ 2.65 (3H, d, N-CH ₃ ), 3.25 (3H, d, N-CH ₃ ), 7.06 (1H, t, CH-arom) , 7.15 (1H, d, CH-arom), 7.25 (1H, d, CH-arom), 7.38 (1H, m, CH-arom), 7.60 (1H, d , CH-arom), 8.01 (1H, s, CH).

Synthesis of 3-hydrazinylcyclobutanols

3-hydrazinyl-1-methylcyclobutan-1-ol

- 2,2-dichloro-3-oxocyclobutyl pivalate

A solution _of 2,2,2-trichloroacetyl chloride (73.2 g, 0.407 mol) in Et ₂ O (150 ml). The reaction mixture was stirred at room temperature for an additional 4 hours and then filtered through a pad of celite. The filtrate was washed with water (400 ml) and brine (400 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 30:1) to obtain the desired compound (59.2 g, yield: 79%) as a colorless solid.

- 3-oxocyclobutyl pivalate

To a stirred suspension of Zn powder (80.8 g, 1.24 mol) in AcOH (300 ml) cooled to 15°C, a solution of 2,2-dichloro-3-oxocyclobutyl pivalate was added dropwise slowly (over 0.5 h). (59.0 g, 0.248 mol) in AcOH (100 ml). The reaction mixture was stirred at room temperature for another 1 hour and then filtered through a pad of celite. The filtrate was diluted with methyl t -butyl ether (1.5 L), washed with brine (400 mL x 4) and saturated aq. NaHCO ₃ (400 ml × 4) in turn, until the pH reaches approximately 8, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 25:1) to obtain the desired compound (29.0 g, yield: 59%) as an oil.

- 3-hydroxy-3-methylcyclobutyl pivalate

_A solution of 3-oxocyclobutyl pivalate (40, 0 g, 0.235 mol) in THF (100 ml). The reaction mixture was stirred at room temperature for an additional 1.5 hours. The reaction mixture was poured into cold saturated aq. NH ₄ Cl (300 ml). The organic phase was washed with brine (200 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 2:1) to obtain the desired compound (26.0 g, yield: 60%) as a sticky oil.

- 1-methylcyclobutane-1,3-diol

To a stirred solution of 3-hydroxy-3-methylcyclobutyl pivalate (3.30 g, 0.0177 mol) in MeOH (30 ml) at room temperature was added a solution of NaOH (3.18 g, 0.0775 mol) in water (30 ml) . The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove most of the MeOH. The pH of the residue was adjusted to 4 with 1M aq. HCl and washed with CH ₂ Cl ₂ (30 ml × 2). The aqueous phase was concentrated under reduced pressure at 55°C. The residue was azeotropically distilled with EtOH (20 ml x 2). Added a solution of CH ₂ Cl ₂ /EtOH 10:1 (30 ml) and solid NaHCO ₃ (2 g). The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain the desired compound (1.40 g, yield: 77%) as a light yellow oil.

- 3-hydroxy-3-methylcyclobutanone

Dess _- Martin periodinan ( _53.0 g, 0.125 mol). The reaction mixture was stirred at room temperature for 18 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude desired compound (11.4 g) as a pale yellow oil. This crude product was used in the next step without further purification.

- tert -butyl-2-(3-hydroxy-3-methylcyclobutyl)hydrazinecarboxylate

To a stirred solution of 3-hydroxy-3-methylcyclobutanone (11.4 g crude, 0.114 mol) in MeOH (200 ml) at room temperature was added BocNHNH ₂ (18.1 g, 0.137 mol) and AcOH (0.5 ml). The reaction mixture was stirred at room temperature for 3 h and then NaBH ₃ CN (14.4 g, 0.228 mol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (200 ml), washed with water (200 ml) and brine (200 ml) in turn, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH 100:1 to 40:1) to give the desired compound (12.0 g, yield: 40%) as a sticky oil.

- 3-hydrazinyl-1-methylcyclobutanol hydrochloride

A solution of tert -butyl 2-(3-hydroxy-3-methylcyclobutyl)hydrazinecarboxylate (350 mg, 1.62 mmol) in HCl/MeOH (3 M; 4 ml) was stirred at room temperature for 1 h. The reaction mixture was concentrated at reduced pressure to give the desired compound (275 mg, yield: 100%) as a sticky oil.

LC/MS result [M+H] ⁺ : 116.9;

¹ H NMR (CDCl ₃ ): δ 1.23 (3H, d, CH ₃ ), 2.09 (4H, m, CH ₂ ), 3.68 (1H, m, CH), 3.91 (2H, s, NH ₂ ).

3-hydrazineyl-1-(methoxymethyl)cyclobutan-1-ol

This hydrazinylcyclobutanol was synthesized by analogy with 3-hydrazinyl-1-methylcyclobutan-1-ol, only the reaction step using MeMgBr was replaced with a step using methoxymethylmagnesium chloride in THF (30°C, 18 h).

General procedure for the preparation of 3-aryl-5-(1,5-disubstituted-1H-pyrazol-4-yl)isoxazoles

To a solution of 2-acyl-1-(dimethylamino)ethylene in dried ethanol (4 ml/mmol) was added the corresponding hydrazine derivative (1.3 eq.) and N,N -diisopropylethylamine (1.3 eq., if hydrazine was used as free base, 3.0 eq. if hydrazine was used as the hydrochloride salt). The reaction mixture was heated at 60° C. for 2 to 18 hours, depending on the conversion monitored by LCMS. In some cases, heating to 78°C was necessary to proceed to completion. The mixture was partitioned between CH ₂ Cl ₂ and saturated aq. NH ₄ Cl, the organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The products were isolated by preparative TLC (pTLC) on silica gel.

Example 1 : 1-(4-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl )-2-methylpropan-2-ol

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (2.2 mmol) and 1-hydrazinyl-2-methylpropan-2-ol as a yellowish solid (53%; ptlc, eluent: petroleum ether/ethyl acetate 1:1 ).

LC/MS result [M+H] ⁺ : 486.8;

¹ H NMR (CDCl ₃ ): δ 1.26 (6H, s, 2xCH ₃ ), 4.26 (1H, s, OH), 4.32 (2H, s, CH ₂ ), 7.17 (1H, td, CH-arom), 7.21 (1H, d, CH-arom), 7.36 (1H, dt, CH-arom), 7.54-7.44 (1H, m, CH- arom.), 7.69 (1H, d, CH-arom.), 8.11 (1H, s, CH-arom.).

Example 2 : 1-((4-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole-1- yl)methyl)cyclopropanol

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (0.22 mmol) and 1-(hydrazinylmethyl)cyclopropanol as an orange oil (27%; ptlc, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 484.6;

¹ H NMR (CDCl ₃ ): δ 0.81-0.74 (2H, m, CH ₂ ), 1.05-0.97 (2H, m, CH2), 4.21-4.00 (1H, m, OH), 4.42 (2H, s, CH ₂ ), 7.16 (1H, td, CH-arom), 7.22 (1H, d, CH-arom), 7.35 (1H , dt, CH-arom), 7.53-7.43 (1H, m, CH-arom), 7.71 (1H, dCH-arom), 8.12 (1H, s, CH- arom.).

Example 3 : 4-(4-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl )-2-methylbutan-2-ol

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (0.57 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as a yellowish oil (2%; ptLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: CH ₂ Cl ₂ /MeOH 98:2).

LC/MS result [M+H] ⁺ : 501.2;

¹ H NMR (CDCl ₃ ): δ 1.33 (6H, s, 2xCH ₃ ), 2.14 (2H, dt, CH ₂ ), 4.54 (2H, dt, CH ₂ ), 7.16 (1H , td, CH-arom), 7.21 (1H, d, CH-arom), 7.35 (1H, dt, CH-arom), 7.52-7.43 (1H, m, CH -arom), 7.71 (1H, d, CH-arom), 8.03 (1H, s, CH-arom).

Example 4 : (2 R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)propan-2-ol

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (0.14 mmol) and ( R )-1-hydrazinylpropan-2-ol as a yellowish oil (23%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95: 5 and ptlc, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 472.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.37 (1H, d, OH), 4.25 (1H, dd, CH), 4.48-4.32 (2H, m, 2xCH), 7.16 (1H, td, CH-arom), 7.22 (1H, d, CH-arom), 7.36 (1H, d, CH-arom), 7.54-7.44 (1H, m, CH-arom), 7.71 (1H, d, CH-arom), 8.09 (1H, s, CH-arom).

Example 5 : ( 2S )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)propan-2-ol

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (0.14 mmol) and ( S )-1-hydrazinylpropan-2-ol as a yellowish oil (33%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95: 5 and ptlc, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 472.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.37 (1H, d, OH), 4.25 (1H, dd, CH), 4.47-4.32 (2H, m, 2xCH), 7.17 (1H, td, CH-arom), 7.22 (1H, d, CH-arom), 7.36 (1H, d, CH-arom), 7.54-7.44 (1H, m, CH-arom), 7.71 (1H, d CH-arom), 8.09 (1H, s, CH-arom).

Example 6 : 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl )-1H-pyrazol-1-yl}butan-2-ol (racemic)

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (0.60 mmol) and 1-hydrazino-2-butanol as a yellow solid (7%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5 and ptlc , eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 486.8;

¹ H NMR (CDCl ₃ ): δ 1.06 (3H, t, CH ₃ ), 1.69-1.55 (2H, m, CH ₂ ), 3.32 (1H, br, OH), 4 .18-4.07 (1H, m, CH), 4.25 (1H, dd, CH), 4.41 (1H, dd, CH), 7.16 (1H, td, CH-arom), 7.22 (1H, d, CH-arom), 7.35 (1H, dt, CH-arom) 7.54-7.42 (1H, m, CH-arom), 7.71 (1H , d, CH-arom), 8.09 (1H, s, CH-arom).

Example 7 : 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl )-1H-pyrazol-1-yl}-1,1,1-trifluoropropan-2-ol (racemic)

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1 ,1-trifluorobut-3-en-2-one (0.50 mmol) and 1,1,1-trifluoro-3-hydrazinylpropan-2-ol (racemic) as a yellow solid (38%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5, mixture of structural isomers with pyrazole 60:40, cf. Scheme above).

LC/MS result [M+H] ⁺ : 527.20;

¹ H NMR (CDCl ₃ ): δ 4.15 (1H, br, OH), 4.39 (1H, dd, CH), 4.71-4.49 (2H, m, CH ₂ ), 7, 17 (1H, t, CH-arom), 7.23 (1H, d, CH-arom), 7.36 (1H, d, CH-arom), 7.55-7.45 (1H, m, CH-arom), 7.71 (1H, d, CH-arom), 8.14 (1H, s, CH-arom).

Example 8 : ethyl-3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4- carboxylate

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazole-4-carboxylate (1.1 mmol) and 1-hydrazinyl-2-methylpropan-2-ol as a colorless powder (21%; ptLC, eluent: petroleum ether/ethyl acetate 1:1 and ptLC, eluent: petroleum ether/CH ₂ Cl ₂ /MeOH 9:4:1).

LC/MS result [M+H] ⁺ : 475.70;

¹ H NMR (CDCl ₃ ): δ 1.00 (3H, t, CH ₃ ), 1.26 (6H, s, 2x CH ₃ ), 4.10 (2H, q, CH ₂ ), 4.31 ( 2H, s, CH ₂ ), 7.11 (1H, td, CH-arom), 7.33 (1H, d, CH-arom), 7.43 (1H, m, CH-arom), 8.04 (1H, s, CH-arom).

Example 9 : ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2 -oxazole-4-carboxylate

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazol-4-carboxylate (2.3 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as a yellow oil (45%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 490.30;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.33 (3H, s, CH ₃ ), 1.64 (1H, br., OH), 2.15 (2H , m, CH ₂ ), 4.09 (2H, q, CH ₂ ), 4.53 (2H, m, CH ₂ ), 7.13 (1H, td, CH-arom.), 7.32 (1H , d, CH-arom), 7.41 (1H, m, CH-arom), 7.97 (1H, s, CH-arom).

и

and

Examples 10 and 11 : ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1 ,2-oxazole-4-carboxylate, syn- and anti -configuration)

The title compounds were synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazol-4-carboxylate (0.17 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -mix) (pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5 and pTLC, eluent: CH ₂ Cl ₂ /MeOH 98:2);

Example 10 : syn -diastereomer (3%)

LC/MS result [M+H] ⁺ : 488.20;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.49 (3H, s, CH ₃ ), 2.80 (4H, m, CH ₂ ), 4.09 (2H , q, CH ₂ ), 4.72 (1H, m, CH), 7.13 (1H, td, CH-arom), 7.33 (1H, d, CH-arom), 7.42 ( 1H, m, CH-arom), 8.00 (1H, s, CH-arom).

Example 11 : Anti -diastereomer (5%)

LC/MS result [M+H] ⁺ : 488.20;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.49 (3H, s, CH ₃ ), 2.65 (2H, m, CH ₂ ), 2.83 (2H , m, CH ₂ ), 4.09 (2H, q, CH ₂ ), 5.26 (1H, m, CH), 7.13 (1H, td, CH-arom.), 7.32 (1H, d, CH-arom), 7.42 (1H, m, CH-arom), 7.96 (1H, s, CH-arom).

Example 12 : ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1, 2-oxazole-4-carboxylate

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazol-4-carboxylate (0.5 mmol) and ( R )-1-hydrazinylpropan-2-ol as a yellow oil (39%; ptlc, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 461.70;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.31 (3H, d, CH ₃ ), 3.33 (1H, br., OH), 4.09 (2H , q, CH ₂ ), 4.24 (1H, dd, CH), 4.36 (2H, dd, CH ₂ ), 7.13 (1H, td, CH-arom.), 7.32 (1H, d, CH-arom), 7.42 (1H, m, CH-arom), 8.01 (1H, s, CH-arom).

Example 13 : ethyl 3-(2-chloro-6-fluorophenyl)-5-(1-(( 2S )-2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1, 2-oxazole-4-carboxylate

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazol-4-carboxylate (0.5 mmol) and ( S )-1-hydrazinylpropan-2-ol as a yellow oil (31%; ptlc, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 461.70;

¹ H NMR (CDCl ₃ ): δ 1.00 (3H, t, CH ₃ ), 1.32 (3H, d, CH ₃ ), 3.30 (1H, s, OH), 4.10 (2H, k, CH ₂ ), 4.25 (1H, dd, CH), 4.37 (2H, dd, CH ₂ ), 7.14 (1H, td, CH-arom.), 7.33 (1H, d , CH-arom), 7.43 (1H, m, CH-arom), 8.02 (1H, s, CH-arom).

Example 14 : Ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxybutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol-4 -carboxylate (racemic)

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazole-4-carboxylate (0.23 mmol) and 1-hydrazino-2-butanol as a yellow oil (26%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5 and again ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 475.8;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.06 (3H, t, CH ₃ ), 1.61 (2H, quint, CH ₂ ), 3.15 ( 1H, d, OH), 4.09 (2H, q, CH ₂ ), 4.25 (1H, dd, CH ₂ ), 4.40 (1H, dd, CH ₂ ), 7.13 (1H, td , CH-arom), 7.32 (1H, d, CH-arom), 7.42 (1H, m, CH-arom), 8.01 (1H, s, CH-arom).

Example 15 : ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3,3,3-trifluoro-2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl] -1,2-oxazole-4-carboxylate (racemic)

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazol-4-carboxylate (0.52 mmol) and 1,1,1-trifluoro-3-hydrazinylpropan-2-ol (racemic) as a colorless oil (35%; ptlc, eluent: CH ₂ Cl ₂ / MeOH 95:5 and ptLC, eluent petroleum ether/ethyl acetate 3:2, mixture of structural isomers with pyrazole 95:5 (cf. Scheme above).

LC/MS result [M+H] ⁺ : 515.8;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 4.08 (3H, m, CH ₂ , CH), 4.62 (2H, m, CH ₂ ), 7.13 (1H, td, CH-arom), 7.33 (1H, d, CH-arom), 7.43 (1H, m, CH-arom), 8.05 (1H, s, CH-arom .).

Example 16 : Ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2R )-3,3,3-trifluoro-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazole -4-yl}-1,2-oxazole-4-carboxylate

The title compound was synthesized from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazol-4-carboxylate (0.14 mmol) and ( R )-1,1,1-trifluoro-3-hydrazinylpropan-2-ol as a colorless oil (15%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 516.2;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 3.96 (1H, d, OH), 4.09 (2H, q, CH ₂ ), 4.62 (3H, m, CH ₂ , CH), 7.13 (1H, td, CH-arom), 7.33 (1H, d, CH-arom), 7.43 (1H, m, CH-arom), 8.06 (1H, s, CH-arom).

и

and

Example 17 and 18 : methyl 3-(2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-methyl-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( anti- and syn -configuration)

The title compounds were synthesized from methyl-( Z )-3-(2-chlorophenyl)-5-[1-(dimethylamino)-3-oxobut-1-en-2-yl]-1,2-oxazol-4- carboxylate (0.60 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -mix) as orange oils (pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5);

Example 17 : anti -configuration in cyclobutanol system, 21% yield;

LC/MS result [M+H] ⁺ : 402.30;

¹ H NMR (CDCl ₃ ): δ 1.55 (3H, s, CH ₃ ), 2.57 (3H, s, CH ₃ ), 2.59 (2H, m, CH ₂ ), 2.81 (2H , m, CH ₂ ), 3.66 (3H, s, O-CH ₃ ), 5.04 (1H, m, CH), 7.35 (4H, m, CH-arom.), 8.31 ( 1H, s, CH-arom.).

Example 18 : syn configuration in cyclobutanol system, 11% yield;

LC/MS result [M+H] ⁺ : 402.3;

¹ H NMR (CDCl ₃ ): δ 1.47 (3H, s, CH ₃ ), 2.57 (3H, s, CH ₃ ), 2.82-2.70 (4H, m, 2xCH ₂ ), 2 .87 (1H, br., OH), 3.65 (3H, s, _CH3 ), 4.54 (1H, quint, CH), 7.53-7.33 (4H, m, 4xCH-arom. ), 8.37 (1H, s, CH-arom).

Example 19 : Methyl-3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chlorophenyl)-5-[1-(dimethylamino)-3-oxobut-1-en-2-yl]-1,2-oxazol-4- carboxylate (0.86 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as a yellow oil (31%; pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5 and again pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 404.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (6H, s, 2xCH ₃ ), 2.05 (2H, s, CH ₂ ), 2.62 (3H, s, CH ₃ ), 3.65 (3H , s, CH ₃ ), 4.32 (2H, m, CH ₂ ), 7.34 (4H, m, CH-arom), 8.30 (1H, s, CH-arom).

Example 20 : Methyl-3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazole -4-carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-3-oxobut-1-en-2-yl)isoxazol-4-carboxylate (0.79 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as a yellow oil (29%; pTLC, eluent: CH ₂ Cl ₂ /MeOH 98:2 and pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 422.00;

¹ H NMR (CDCl ₃ ): δ 1.31 (6H, s, 2xCH ₃ ), 2.05 (2H, t, CH ₂ ), 2.64 (3H, s, CH ₃ ), 3.65 (3H , s, CH ₃ ), 4.32 (2H, m, CH ₂ ), 7.12 (1H, td, CH-arom.), 7.32 (1H, d, CH-arom.), 7.41 (1H, m, CH-arom), 8.33 (1H, s, CH-arom).

Example 21 : Methyl-( R )-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-methoxypyridin-3-yl)isoxazol-4- carboxylate

The title compound was synthesized from methyl-( Z )-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)-3-(2-methoxypyridin-3 -yl)isoxazol-4-carboxylate (0.55 mmol) and ( R )-1-hydrazinylpropan-2-ol (30%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 426.8;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 3.66 (3H, s, CH ₃ ), 3.93 (3H, s, CH ₃ ), 4.31 (3H , m, CH, CH ₂ ), 7.01 (1H, dd, CH-arom), 7.83 (1H, dd, CH-arom), 8.01 (1H, s, CH-arom) , 8.30 (1H, dd, CH-arom).

Example 22 : Methyl-( S )-3-(2-chlorophenyl)-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole -4-carboxylate (1.0 mmol) and ( S )-1-hydrazinylpropan-2-ol (49%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 429.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.64 (3H, s, OCH ₃ ), 4.24 (1H, dd, CH), 4.48-4, 31 (2H, m, CH ₂ ), 7.56-7.34 (4H, m, 4xCH-arom), 8.00 (1H, s, CH-arom).

Example 23 : methyl-( S )-3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4- carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl)isoxazole-4-carboxylate (0.83 mmol) and ( S )-1-hydrazinylpropan-2-ol (27%; ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5 and ptLC, eluent: petroleum ether /ethyl acetate 3:2).

LC/MS result [M+H] ⁺ : 448.2;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.64 (3H, s, OCH ₃ ), 4.25 (1H, dd, OCH ₂ ), 4.48-4 .32 (2H, m, CH ₂ ), 7.14 (1H, td, CH-arom), 7.33 (1H, dt, CH-arom), 7.48-7.38 (1H, m , CH-arom), 7.99 (1H, s, CH-arom).

Example 24 : Methyl-( S )-3-(2-chlorophenyl)-5-(1-(2-hydroxypropyl)-5-methyl-1H-pyrazol-4-yl)isoxazole-4-carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chlorophenyl)-5-[1-(dimethylamino)-3-oxobut-1-en-2-yl]-1,2-oxazol-4- carboxylate (1.0 mmol) and ( S )-1-hydrazinylpropan-2-ol (32%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 376.3;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 2.61 (3H, s, CH ₃ ), 3.65 (3H, s, OCH ₃ ), 4.58-3 .82 (3H, m, CH and CH ₂ ), 7.55-7.33 (4H, m, 4xCH-arom), 8.38 (1H, s, CH-arom).

Example 25 : Methyl-3-(2-chloro-3-methoxyphenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazole -4-carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chloro-3-methoxyphenyl)-5-[1-(dimethylamino)-3-oxobut-1-en-2-yl]-1,2- oxazole-4-carboxylate (1.1 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as an orange oil (33%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5 and again ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 434.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (6H, s, 2xCH ₃ ), 2.04 (2H, m, CH ₂ ), 2.62 (3H, s, CH ₃ ), 3.65 (3H , s, CH ₃ ), 3.95 (4H, s, OH, CH ₃ ), 4.31 (2H, m, CH ₂ ), 7.07 (2H, m, CH-arom.), 7.33 (1H, t, CH-arom), 8.28 (1H, s, CH-arom).

и

and

Examples 26 and 27 : methyl-3-(2-chloro-6-fluorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol- 4-carboxylate ( anti- and syn -configuration)

The title compounds were synthesized from methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-[1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl]-1,2-oxazole-4-carboxylate (0.24 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -mix) (pTLC, eluent: CH ₂ Cl ₂ /MeOH 95 :5).

Example 26 : anti -configuration in cyclobutanol system, 18% yield;

LC/MS result [M+H] ⁺ : 473.80;

¹ H NMR (CDCl ₃ ): δ 1.56 (3H, s, CH ₃ ), 2.75-2.49 (2H, m, CH ₂ ), 2.95-2.75 (2H, m, CH ₂ ), 3.63 (3H, s, OCH ₃ ), 5.26 (1H, quint, CH), 7.13 (1H, td, CH-arom.), 7.33 (1H, d, CH- arom.), 7.47-7.37 (1H, m, CH-arom.), 7.94 (1H, s, CH-CH arom.).

Example 27 : syn -configuration in the cyclobutanol system; yield 18%;

LC/MS result [M+H] ⁺ : 473.8;

¹ H NMR (CDCl ₃ ): δ 1.50 (3H, s, CH ₃ ), 2.95-2.71 (4H, m, 2xCH ₂ ), 3.63 (3H, s, OCH ₃ ), 4 .71 (1H, quint, CH), 7.14 (1H, td, CH-arom), 7.33 (1H, d, CH-arom), 7.48-7.38 (1H, m, CH-arom), 7.99 (1H, s, CH-arom).

Example 28 : Methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(3-hydroxycyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate

The title compound was synthesized from methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-[1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2 -yl]-1,2-oxazole-4-carboxylate (0.24 mmol) and 3-hydrazinylcyclobutan-1-ol ( syn/anti -mix) (46% as a mixture of syn- and anti -configuration in cyclobutanol system; pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 459.8;

¹ H NMR (CDCl ₃ ): δ 2.86-2.69 (2H, m, CH ₂ ), 3.10-2.93 (2H, m, CH ₂ ), 3.63 (3H, s, CH ₃ ), 4.26 (1H, quint, CH), 4.62 (1H, quint, CH), 7.13 (1H, td, CH-arom), 7.33 (1H, d, CH-arom .), 7.47-7.37 (1H, m, CH-arom), 7.99 (1H, s, CH-arom).

Example 29 : Methyl 3-(2-chlorophenyl)-5-(1-(3-hydroxy-3-(methoxymethyl)cyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( syn -configuration)

The title compound was synthesized from methyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole -4-carboxylate (0.30 mmol) and 3-hydrazinyl-1-(methoxymethyl)cyclobutan-1-ol ( syn/anti -mixture) in 34% yield. The syn- and anti -configurations in the resulting product were not separated at this stage, so the hydroxyl group was silylated using tert -butyldimethylsilyl triflate, N,N -diisopropylethylamine in CH ₂ Cl ₂ (cf. the general silylation procedures described below), after which separation of the isomers followed by ptlc, eluent: petroleum ether/ethyl acetate 4:1 and ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5. Desilylation was achieved using HCl in MeOH (room temperature, 2 h) to give the title compound in syn -configuration in 50% yield from a mixture of isomers along with 16% anti -isomer (pH adjusted to approx. 8 by addition of aq. NaOH (1M) and the mixture was extracted with EtOAc.The organic layers were washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure.The residue was purified by preparative TLC (eluent: petroleum ether/ethyl acetate 1:5).

LC/MS result [M+H] ⁺ : 486.20;

¹ H NMR (CDCl ₃ ): δ 2.09 (1H, br., OH), 2.86 (4H, m, CH ₂ ), 3.49 (5H, s, CH ₂ /CH ₃ ), 3, 63 (3H, s, O-CH ₃ ), 4.67 (1H, m, CH), 7.44 (4H, m, CH-arom), 8.00 (1H, s, CH-arom) .

Example 30 : 1-(4-(3-(2-chloro-6-fluorophenyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)isoxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

The title compound was synthesized from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)isoxazol-5-yl) -4-(dimethylamino)-1,1,1-trifluorobut-3-en-2-one (0.18 mmol) and 1-hydrazinyl-2-methylpropan-2-ol as a pale yellow oil (4%; pTLC, eluent: petroleum ether/ethyl acetate 4:1 and ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 485.70;

¹ H NMR (CDCl ₃ ): δ 1.27 (6H, s, 2x CH ₃ ), 2.39 (3H, s, CH ₃ ), 4.34 (2H, s, CH ₂ ), 7.16 ( 1H, td, CH-arom), 7.35 (1H, dt, CH-arom), 7.47 (1H, m, CH-arom), 8.15 (1H, s, CH-arom). ).

ethyl 3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate

The title compound was synthesized ( syn/anti -mixture) from ethyl-( Z )-3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro- 3-oxobut-1-en-2-yl)isoxazol-4-carboxylate (3.3 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -blend) as a yellow oil (34%; ptLC, eluent: petroleum ether/ethyl acetate 4:1 and ptLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 576.3;

¹ H NMR (CDCl ₃ ): δ 1.27 (3H, t, CH ₃ ), 2.04 (3H, s, CH ₃ ), 2.77 (4H, m, 2xCH ₂ ), 4.08 (1H , m, CH), 4.13 (2H, q, CH ₂ ), 5.23 (2H, s, CH ₂ ), 7.10 (2H, d, CH-arom.), 7.35 (4H, m, CH-arom), 7.47 (2H, d, CH-arom), 7.98 (1H, s, CH-arom).

ethyl 3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate

The title compound was synthesized from ethyl-( Z )-3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene -2-yl)isoxazol-4-carboxylate (6.6 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as a yellow oil (84%; silica gel column chromatography, eluent: CH ₂ Cl ₂ /MeOH 98 :2).

LC/MS result [M+H] ⁺ : 578.3;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.33 (6H, s, 2xCH ₃ ), 2.14 (2H, m, CH ₂ ), 3.38 (2H , s, CH ₂ ), 3.56 (1H, m, CH), 3.65 (1H, m, CH), 4.07 (2H, k, CH ₂ ), 7.07 (2H, dd, CH -arom.), 7.40 (6H, m, CH-arom.), 7.98 (1H, s, CH-arom.).

Synthesis of deuterated alcohols

The corresponding acetic acid derivatives were synthesized according to the general procedure described above for pyrazole formation using 2-hydrazine acetic acid. The reaction mixtures were distributed only between CH ₂ Cl ₂ and saturated aq. NH ₄ Cl, the organic layer was dried over MgSO ₄ and concentrated under reduced pressure, and the products were used as crude material for the next steps.

- 2-(4-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid from ( Z )-3-(3-(2-chloro-6-fluorophenyl)-4-(thiazol-2-yl)isoxazol-5-yl)-4-(dimethylamino)-1,1,1-trifluorobut -3-en-2-she;

LC/MS result [M+H] ⁺ : 472.7;

¹ H NMR (CDCl ₃ ): δ 3.15 (1H, s, COOH), 5.15 (2H, s, CH ₂ ), 7.16 (1H, t, CH-arom), 7.24 ( 1H, d, CH-arom), 7.35 (1H, d, CH-arom), 7.48 (1H, m, CH-arom), 7.75-7.48 (1H, d, CH-arom), 8.13 (1H, s, CH-arom).

- 2-{4-[3-(2-chloro-6-fluorophenyl)-4-(ethoxycarbonyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} acetic acid from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl) isoxazole-4-carboxylate;

LC/MS result [M+H] ⁺ : 461.7;

¹ H NMR (CDCl ₃ ): δ 0.98 (3H, t, CH ₃ ), 4.06 (2H, q, CH ₂ ), 4.97 (2H, s, CH ₂ ), 7.09 (1H , t, CH-arom), 7.29 (1H, d, CH-arom), 7.39 (1H, m, CH-arom), 8.03 (1H, s, CH-arom) .

- 2-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxycarbonyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} acetic acid from methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl) isoxazole-4-carboxylate;

Crude acetic acid derivative (1.0 mmol), N,O -dimethylhydroxylamine hydrochloride (1.0 eq.), 1-hydroxybenzotriazole (1.0 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI ; 1.2 eq.) was dissolved in dry DMF (Sure/Seal, 4 ml/mmol). N -methylmorpholine (10 eq.) was added and the reaction mixture was stirred at room temperature for 18 h.

DMF was removed under reduced pressure and aq. 5% citric acid solution. The mixture was extracted with CH ₂ Cl ₂ , the combined organic phases were washed with water and dried over MgSO ₄ and concentrated under reduced pressure:

- 2-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl} -N -methoxy- N -methylacetamide; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 7:3), orange oil, 14% yield over two steps;

LC/MS result [M+H] ⁺ : 515.8;

¹ H NMR (CDCl ₃ ): δ 3.26 (3H, s, CH ₃ ), 3.81 (3H, s, CH ₃ ), 5.34 (2H, s, CH ₂ ), 7.14 (1H , m, CH-arom), 7.23 (1H, dd, CH-arom), 7.34 (1H, m, CH-arom), 7.47 (1H, m, CH-arom) , 7.73 (1H, d, CH-arom), 8.20 (1H, s, CH-arom).

- ethyl-3-(2-chloro-6-fluorophenyl)-5-(1-{[methoxy(methyl)carbamoyl]methyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2- oxazole-4-carboxylate; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 7:3), orange oil, 38% yield over two steps;

LC/MS result [M+H] ⁺ : 504.7;

¹ H NMR (CDCl ₃ ): δ 1.04 (3H, t, CH ₃ ), 3.24 (3H, s, CH ₃ ), 3.79 (3H, s, CH ₃ ), 4.10 (2H , q, CH ₂ ), 5.33 (2H, s, CH ₂ ), 7.12 (1H, t, CH-arom.), 7.31 (1H, d, CH-arom.), 7.41 (1H, m, CH-arom), 8.13 (1H, s, CH-arom).

- methyl-3-(2-chloro-6-fluorophenyl)-5-(1-{[methoxy(methyl)carbamoyl]methyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2- oxazole-4-carboxylate; the crude material was used as such for the next step

The corresponding Weinreb amide was dissolved in THF (Sure/Seal; 4 ml/mmol) at 0°C. Methylmagnesium bromide (5.0 eq.; 3.2 M in 2-methyl-THF) was added slowly and the mixture was stirred at 0°C for 1 h and then at room temperature for an additional 5 h. The mixture was quenched with water and partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude methyl ketone:

- 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-one, 70% yield (crude);

LC/MS result [M+H] ⁺ : 470.8.

- ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(2-oxopropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate ; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:2 and pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5), 12% yield;

LC/MS result [M+H] ⁺ : 459.70;

¹ H NMR (CDCl ₃ ): δ 1.03 (3H, t, CH ₃ ), 3.23 (3H, s, CH ₃ ), 4.12 (2H, q, CH ₂ ), 5.18 (2H , s, CH ₂ ), 7.13 (1H, t, CH-arom), 7.33 (1H, d, CH-arom), 7.43 (1H, m, CH-arom), 8 .12 (1H, s, CH-arom).

- methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(2-oxopropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2-oxazole-4-carboxylate; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:2), 8% yield over three steps;

LC/MS result [M+H] ⁺ : 445.7;

¹ H NMR (CDCl ₃ ): δ 1.23 (3H, s, CH ₃ ), 3.65 (3H, s, CH ₃ ), 5.18 (2H, s, CH ₂ ), 7.14 (1H , td, CH-arom), 7.33 (1H, d, CH-arom), 7.43 (1H, m, CH-arom), 8.07 (1H, s, CH-arom) .

The corresponding methyl ketone was dissolved in THF (10 ml/mmol) and cooled to 0°C. NaBD ₄ (1.1 eq) was added and the mixture was stirred at 0°C for 1 h.

The mixture was quenched with water and partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. Alpha-deuterated alcohols were purified by preparative TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5):

Example 31 : 1-{4-[3-(2-Chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl )-1H-pyrazol-1-yl}( ^2-2H )propan-2-ol (racemic) was isolated in 28% yield.

LC/MS result [M+H] ⁺ : 473.8;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, s, CH ₃ ), 4.25 (1H, s, CH), 4.38 (1H, d, CH), 7.17 (1H, t , CH-arom), 7.22 (1H, d, CH-arom), 7.36 (1H, d, CH-arom), 7.54-7.44 (1H, m, CH-arom .), 7.71 (1H, d, CH-arom), 8.09 (1H, s, CH-arom).

Example 32 : ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[2-hydroxy( ^2-2H )propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate (racemic) was isolated as a pale yellow oil in 10% yield.

LC/MS result [M+H] ⁺ : 462.7;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.31 (3H, s, CH ₃ ), 3.25 (1H, s, OH), 4.09 (2H, q, CH ₂ ), 4.30 (2H, dd, CH ₂ ), 7.13 (1H, td, CH-arom), 7.33 (1H, d, CH-arom), 7.43 ( 1H, m, CH-arom), 8.01 (1H, s, CH-arom).

Example 33 : methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[2-hydroxy( ^2-2H )propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate (racemic) was isolated in 24% yield

LC/MS result [M+H] ⁺ : 448.80;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, s, CH ₃ ), 3.64 (3H, s, OCH ₃ ), 4.31 (2H, q, CH ₂ ), 7.14 (1H , td, CH-arom), 7.33 (1H, dt, CH-arom), 7.48-7.38 (1H, m, CH-arom), 7.99 (1H, s, CH -arom.).

Synthesis of 4-acylisoxazoles

The esters of Example 8 or Example 12 (0.25 mmol) were dissolved in 2 ml of ethanol and 2 ml of aq. NaOH (2.0 M). The mixture was heated to 60°C for 1 h and then acidified by adding aq. HCl (1.0 M). The resulting suspension was partitioned between CH ₂ Cl ₂ and water, the combined organic layers were dried over MgSO ₄ and the solvent was removed under reduced pressure to give the crude carboxylic acids:

- 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2-oxazol-4 α-carboxylic acid as a white with a yellowish or grayish tinge of a solid, 94% yield;

LC/MS result [M+H] ⁺ : 447.8;

¹ H NMR (CDCl ₃ ): δ 1.22 (6H, s, 2xCH ₃ ), 4.30 (2H, s, CH ₂ ), 7.12 (1H, td, CH-arom), 7.32 (1H, dt, CH-arom), 7.47-7.37 (1H, m, CH-arom), 8.00 (1H, s, CH-arom).

- 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol- 4-carboxylic acid as a white to yellowish or greyish solid, 75% yield;

LC/MS result [M+H] ⁺ : 433.9;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 4.24 (1H, dd, CH), 4.47-4.28 (2H, m, CH ₂ ), 7, 12 (1H, td, CH-arom), 7.32 (1H, dt, CH-arom), 7.47-7.36 (1H, m, CH-arom), 7.98 (1H, s, CH-arom.).

Crude acetic acid derivative (1.0 mmol), N,O -dimethylhydroxylamine hydrochloride (1.2 eq.), 1-hydroxybenzotriazole (1.1 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI ; 1.2 eq.) was dissolved in dry DMF (Sure/Seal, 4 ml/mmol). N -methylmorpholine (5 eq.) was added and the reaction mixture was stirred at room temperature for 18 h.

The mixture was poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic phases were washed with water and dried over MgSO ₄ and concentrated under reduced pressure:

- 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-N-methoxy- N - methyl -1,2-oxazole-4-carboxamide; pTLC (eluent: CH ₂ Cl ₂ /MeOH 95:5) as pale yellow solid, 68% yield;

LC/MS result [M+H] ⁺ : 491.3;

¹ H NMR (CDCl ₃ ): δ 1.23 (6H, s, 2xCH ₃ ), 3.11 (3H, s, NCH ₃ ), 3.38 (3H, s, OCH ₃ ), 4.13 (1H , s, OH), 4.29 (2H, s, CH ₂ ), 7.12 (1H, td, CH-arom.), 7.32 (1H, dt, CH-arom.), 7.45- 7.35 (1H, m, CH-arom), 7.99 (1H, s, CH-arom).

- 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- N -methoxy- N - methyl 1,2-oxazole-4-carboxamide, crude material as orange oil, 95% yield;

LC/MS result [M+H] ⁺ : 476.8;

The corresponding Weinreb amide was dissolved in THF (Sure/Seal; 5 ml/mmol) at 0°C. Methyl magnesium bromide (5.0 eq.; 3.2 M in 2-methyl-THF) was added slowly and the mixture was stirred at 0°C for 1.5 hours. If LCMS showed incomplete conversion, the mixture was stirred at room temperature for an additional 5 h. If necessary, additional MeMgBr (3 equiv.) was again added at 0°C and the mixture was kept at room temperature for another 18 hours.

The mixture was quenched with water and partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure.

Example 34 : 1-(3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1, 2-oxazol-4-yl)ethanone

The title compound was isolated using prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5) as dark yellow oil in 8% yield.

LC/MS result [M+H] ⁺ : 490.7;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, CH ₃ ), 2.06 (3H, s, CH ₃ ), 4.12 (1H, s, OH), 4.32 (2H, s, CH ₂ ), 7.18 (1H, td, CH-arom), 7.37 (1H, d, CH-arom), 7.47 (1H, m, CH-arom), 7, 99 (1H, s, CH-arom).

Example 35 : 1-[3-(2-Chloro-6-fluorophenyl)-5-{1-[( 2R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazol-4-yl]ethan-1-one

The title compound was isolated using prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) as a yellow oil in 10% yield.

LC/MS result [M+H] ⁺ : 431.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 2.06 (3H, s, CH ₃ ), 3.22 (1H, s, CH), 4.26 (1H, dd, CH ₂ ), 4.37 (3H, dd, OH, CH ₂ ), 7.18 (1H, td, CH-arom), 7.37 (1H, d, CH-arom), 7, 47 (1H, m, CH-arom), 7.98 (1H, s, CH-arom).

Examples 36, 37 and 38 :

Preparation of the Grignard reagent. To a suspension of magnesium (1.25 eq.) in Et ₂ O (5 ml) was added (bromomethyl)cyclobutane or cyclopropylmethyl bromide (10 mmol). After completion of the Grignard reaction, the solution was separated from the rest of the magnesium and then used as such (4 ml of the appropriate Grignard reagent in Et ₂ O).

3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)- N -methoxy- N -methylisoxazol- 4-carboxamide (0.25 mmol) was dissolved in THF and the reaction mixture was cooled to 0°C. Grignard's solution (4 ml as described above) was added dropwise at 0°C over 5 h. temperature (in the case of cyclopropylmethyl Grignard). The reaction was quenched by adding water and aqueous 1 M HCl solution and was extracted with CH ₂ Cl ₂ . The organic layers were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 98:2).

Example 36 : 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazol-4-yl]-2-cyclobutylethan-1-one

The title compound was obtained as a colorless oil (33% yield).

LC/MS result [M+H] ⁺ : 500.3;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, 2xCH ₃ ), 1.42 (2H, m, CH ₂ ), 1.80 (2H, m, CH ₂ ), 1.98 (2H , m, CH ₂ ), 2.39 (2H, d, CH ₂ ), 2.58 (1H, m, CH), 4.13 (1H, s, OH), 4.32 (2H, s, CH ₂ ), 7.17 (1H, td, CH-arom), 7.36 (1H, dt, CH-arom), 7.47 (1H, m, CH-arom), 7.97 (1H , s, CH-arom.).

Example 37 : 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazol-4-yl]pent-4-en-1-one

A rearrangement of the cyclopropylmethyl fragment with the formation of a butenyl substituent was observed. The resulting crude product was further purified by preparative HPLC/MS to give the title compound as a colorless oil (9% yield).

LC/MS result [MH ₂ O+H] ⁺ : 468.3;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, 2xCH ₃ ), 2.89-2.17 (2H, m, CH ₂ ), 2.42-2.33 (2H, m, CH ₂ ), 4.11 (1H, s, OH), 4.32 (2H, s, CH ₂ ), 4.91-4.77 (2H, m, CH ₂ ), 5.70-5.52 ( 1H, m, CH), 7.18 (1H, td, CH-arom), 7.37 (1H, d, CH-arom), 7.54-7.42 (1H, m, CH-arom .), 7.99 (1H, s, CH-arom).

Example 38 : 2-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazol-4-yl]-1-cyclopropylhex-5-en-2-ol (racemic)

If the cyclopropylmethyl Grignard addition is carried out at room temperature and stirring of the mixture is continued at this temperature for 3 hours, a second addition of the Grignard reagent to the Weinreb amide was observed, which did not rearrange in the same manner as the first cyclopropylmethyl group (cf. Example 37). The compound was purified using preparative HPLC/MS to give the title compound as a light yellow oil (14% yield).

LC/MS result [M+H] ⁺ : 542.2;

¹ H NMR (CDCl ₃ ): δ 1.09-0.91 (1H, m, CH-diastereotopic), 1.24-1.09 (1H, m, CH-diastereotopic), 1.26 (6H, s , 2xCH ₃ ), 1.45-1.30 (1H, m, CH-diastereotopic), 1.71-1.58 (1H, m, CH-diastereotopic), 1.93-1.80 (2H, m , CH ₂ ), 3.11-2.99 (1H, m, CH), 4.11 (1H, s, CH), 4.31 (2H, s, CH ₂ ), 4.68 (1H, d , CH), 4.90-4.86 (1H, m, CH), 4.96-4.90 (1H, m, CH), 5.01 (1H, dd, CH), 5.76-5 .44 (2H, m, 2xCH), 7.18 (1H, td, CH-arom), 7.37 (1H, dt, CH-arom), 7.54-7.42 (1H, m, CH-arom), 7.97 (1H, s, CH-arom).

Examples 39 and 40 :

To a solution of either 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazol-4-yl]ethan-1-one, or 1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl )-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]ethan-1-one (0.3 mmol) in acetonitrile (1 ml) was added NBS (1.02 eq.) and p- toluenesulfonic acid (1.0 eq.) and the mixture was stirred at 50°C for 18 hours. If the conversion was not complete, additional NBS (1.02 eq.) and p-toluenesulfonic acid (1.0 eq.) and stirring was continued at 50° C. for 5 hours. The solvent was evaporated under reduced pressure and saturated aq. _NaHC03 . The mixture was extracted with CH ₂ Cl ₂ , the combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude bromoacetyl derivatives were obtained as a brownish oil in approximately 95% yield.

- 2-bromo-1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]- 1,2-oxazol-4-yl]ethan-1-one

LC/MS result [M+H] ⁺ : 523.6.

- 2-bromo-1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl} -1,2-oxazol-4-yl] ethane-1-one

LC/MS result [M+H] ⁺ : 509.6.

The crude bromoacetyl derivatives were dissolved in methanol (2 ml) and BF ₃ ⃰Et ₂ O (1.1 eq.) and Ag ₂ CO ₃ (1.1 eq.) were added. The mixture was stirred at 50°C for 18 h, after which it was distributed between CH ₂ Cl ₂ and saturated aq. _NH4Cl . The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified with prep. TLC (eluent: petroleum ether/ethyl acetate 2:1).

Example 39 : 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazol-4-yl]-2-methoxyethan-1-one

The title compound was obtained as a yellowish oil (10%).

LC/MS result [M+H] ⁺ : 475.8;

¹ H NMR (CDCl ₃ ): δ 1.52 (6H, s, 2xCH ₃ ), 3.15 (3H, s, CH ₃ ), 3.89 (2H, s, CH ₂ ), 4.10 (1H , s, OH), 4.32 (2H, s, CH ₂ ), 7.19 (1H, td, CH-arom.), 7.38 (1H, dt, CH-arom.), 7.48 ( 1H, m, CH-arom), 8.02 (1H, s, CH-arom).

Example 40 : 1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazol-4-yl]-2-methoxyethan-1-one

The title compound was obtained as a brownish oil (12%).

LC/MS result [M+H] ⁺ : 461.7;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.15 (3H, s, CH ₃ ), 1.80 (2H, m, CH ₂ ), 4.25 (1H , dd, CH ₂ ), 4.37 (2H, dd, OH, CH ₂ ), 7.18 (1H, td, CH-arom), 7.37 (1H, dt, CH-arom), 7 .47 (1H, m, CH-arom), 7.99 (1H, s, CH-arom).

Synthesis of isoxazole-4-carboxamides

Or 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid, or 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4 -carboxylic acid (0.15 mmol), the corresponding amine (1.8 eq.), 1-hydroxybenzotriazole (1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 1.7 eq. .) was dissolved in 1 ml of dry DMF. N -methylmorpholine (10 eq.) was added and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between saturated aq. NH ₄ Cl and CH ₂ Cl ₂ solution, the combined organic layers were washed with water and brine and dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification of the product was achieved using prep. TLC on silica gel.

Example 41 : 3-(2-chloro-6-fluorophenyl) -N -cyclopentyl-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol- 4-carboxamide

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4 α-carboxylic acid and cyclopentylamine as a yellowish solid in 42% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 514.8;

¹ H NMR (CDCl ₃ ): δ 1.13 (2H, m, CH ₂ ), 1.25 (6H, s, 2xCH ₃ ), 1.37 (2H, m, CH ₂ ), 1.50 (2H , m, CH ₂ ), 1.82 (2H, m, CH ₂ ), 4.18 (2H, m, CH ₂ ), 4.30 (2H, s, CH ₂ ), 5.24 (1H, s , OH), 7.21 (1H, td, CH-arom), 7.40 (1H, dt, CH-arom), 7.51 (1H, m, CH-arom), 8.11 ( 1H, s, CH-arom.).

Example 42 : 3-(2-chloro-6-fluorophenyl) -N -cyclopropyl-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol- 4-carboxamide

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4 α-carboxylic acid and cyclopropylamine as a greenish oil in 23% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:2).

LC/MS result [M+H] ⁺ : 486.9;

¹ H NMR (CDCl ₃ ): δ 0.22 (2H, m, CH ₂ ), 0.69 (2H, m, CH ₂ ), 1.24 (6H, s, 2xCH ₃ ), 2.64 (1H , m, CH), 4.13 (1H, s, CH), 4.30 (2H, s, CH ₂ ), 5.42 (1H, s, OH), 7.19 (1H, td, CH- arom.), 7.38 (1H, d, CH-arom.), 7.49 (1H, m, CH-arom.), 8.10 (1H, s, CH-arom.).

Example 43 : 3-(2-chloro-6-fluorophenyl) -N -cyclobutyl-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol- 4-carboxamide

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4 α-carboxylic acid and cyclobutylamine as a greyish solid in 13% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:2).

LC/MS result [M+H] ⁺ : 500.9;

¹ H NMR (CDCl ₃ ): δ 1.24 (6H, s, 2xCH ₃ ), 1.58 (4H, m, 2xCH ₂ ), 2.23 (2H, m, CH ₂ ), 4.30 (2H , s, CH ₂ ), 4.32 (1H, m, CH), 5.41 (1H, s, OH), 7.21 (1H, td, CH-arom), 7.41 (1H, d , CH-arom), 7.51 (1H, m, CH-arom), 8.08 (1H, s, CH-arom).

Example 44 : 3-(2-Chloro-6-fluorophenyl) -N -cyclopentyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxamide

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylic acid and cyclopentylamine as an orange oil in 12% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 500.8;

¹ H NMR (CDCl ₃ ): δ 1.20-1.05 (3H, s, 3x CH-diastereotopic), 1.32 (3H, d, CH ₃ ), 1.42-1.34 (2H, m , 2x CH-diastereotopic), 1.91-1.74 (3H, m, 3x CH-diastereotopic), 4.21-4.13 (1H, m, CH), 4.29-4.22 (1H, m, CH), 4.44-4.30 (2H, m, CH ₂ ), 5.25 (1H, br. OH), 7.21 (1H, td, CH-arom.), 7.40 ( 1H, dt, CH-arom), 7.56-7.46 (1H, m, CH-arom), 8.08 (1H, s, CH-arom).

Example 45 : 3-(2-Chloro-6-fluorophenyl) -N -cyclopropyl-5-(1-(( 2R )-2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole -4-carboxamide

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylic acid and cyclopropylamine as a greenish solid in 27% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:2).

LC/MS result [M+H] ⁺ : 472.8;

¹ H NMR (CDCl ₃ ): δ 0.24 (2H, m, CH ₂ ), 0.68 (2H, m, CH ₂ ), 1.31 (3H, d, CH ₃ ), 2.63 (1H , m, CH), 3.34 (1H, s, CH), 4.23 (1H, dd, CH), 4.35 (2H, m, CH, OH), 5.46 (1H, s, NH ), 7.18 (1H, t, CH-arom), 7.37 (1H, d, CH-arom), 7.48 (1H, m, CH-arom), 8.05 (1H, s, CH-arom.).

Example 46 : 3-(2-Chloro-6-fluorophenyl) -N -cyclobutyl-5-(1-(( 2R )-2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole -4-carboxamide

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylic acid and cyclobutylamine as a yellowish solid in 41% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:2).

LC/MS result [M+H] ⁺ : 486.9;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 1.56 (4H, m, CH ₂ ), 2.22 (2H, m, CH ₂ ), 3.35 (1H , s, CH), 4.28 (4H, m, CH ₂ , OH), 5.45 (1H, s, NH), 7.20 (1H, t, CH-arom), 7.39 (1H , d, CH-arom), 7.50 (1H, m, CH-arom), 8.04 (1H, s, CH-arom).

Synthesis of isoxazole esters of 4-carboxylic acids

Starting from the corresponding methyl or ethyl esters (0.3 mmol), the corresponding carboxylic acids were prepared by saponification according to the general procedure described above for the synthesis of 4-acylisoxazoles (described from Example 8 or Example 12 ):

- 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid, cf . above.

- 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol- 4-carboxylic acid, cf. above.

- 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol- 4-carboxylic acid from Example 13 as a white to yellowish or greyish solid, 81% yield;

LC/MS result [M+H] ⁺ : 434.2;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 4.24 (1H, dd, CH), 4.46-4.31 (2H, m, CH ₂ ), 7, 12 (1H, td, CH-arom), 7.32 (1H, dt, CH-arom), 7.48-7.36 (1H, m, CH-arom), 7.97 (1H, s, CH-arom.).

- 3-(2-chlorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylic acid from Examples 17 /18 ( syn/anti -mixture, not separated at this stage) as a brownish oil, 52% yield;

LC/MS result [M+H] ⁺ : 388.2;

- 3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylic acid from Example 24 as brownish oil, 64% yield;

- 3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylic acid acid acid ( syn/anti -mixture) as a white to yellowish or grayish solid, 83% yield;

LC/MS result [M+H] ⁺ : 406.2;

The required ester methyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol- 4-carboxylate was synthesized as described above from methyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-3-oxobut-1-en-2-yl)isoxazole -4-carboxylate (0.80 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -mixture) as a white to yellowish or greyish solid (54% crude) as a syn/anti mixture -configurations in the cyclobutanol fragment.

LC/MS result [M+H] ⁺ : 420.2;

- 3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylic acid ( syn/anti -mixture) as a yellowish solid, 96% yield;

LC/MS result [M+H] ⁺ : 442.2;

The required ester ethyl-3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol-4- carboxylate was synthesized as described above from ethyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl )isoxazole-4-carboxylate (1.0 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -mix) as a yellowish oil (11%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95 :5 and ptLC, eluent: petroleum ether/ethyl acetate 1:1) as a mixture of syn/anti configurations in the cyclobutanol moiety.

LC/MS result [M+H] ⁺ : 470.2;

- 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol-4 -carboxylic acid ( syn/anti -mixture) as an orange solid, 78% yield;

LC/MS result [M+H] ⁺ : 460.1;

Necessary ester ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxylate was synthesized as described above from ethyl-( Z )-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut -1-en-2-yl)isoxazol-4-carboxylate (0.35 mmol) and 3-hydrazinyl-1-methylcyclobutan-1-ol ( syn/anti -blend) as a brownish oil (65% crude) as mixtures of syn/anti configurations in the cyclobutanol moiety.

LC/MS result [M+H] ⁺ : 488.2;

To a mixture of the appropriate carboxylic acid (0.05 mmol) and the appropriate alcohol (3.0 eq.) in CH ₂ Cl ₂ (4 ml) was added EDCI (1.5 eq.) and DMAP (0.2 eq.) at room temperature. temperature. The reaction mixture was stirred at room temperature for 18 hours. All volatiles were removed under reduced pressure. The residue was purified by preparative TLC on silica gel (eluent: PE/EtOAc 1:1).

Example 47 : oxetan-3-yl-3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazol-4 α-carboxylic acid and oxetan-3-ol as a white to yellowish or greyish solid in 24% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 418.2;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 2.63 (3H, s, CH ₃ ), 3.37 (1H, d, CH ₂ ), 4.01 (1H , dd, CH), 4.15 (1H, dd, CH ₂ ) 4.28-4.19 (2H, m, CH ₂ ), 4.33 (1H, br., OH), 4.74 (2H , t, CH ₂ ), 5.51-5.40 (m, 1H, CH), 7.56-7.35 (4H, m, 4xCH-arom), 8.41 (1H, s, CH- arom.).

Examples 48 and 49 : cyclopropyl-3-(2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( anti- and syn -configuration)

The title compounds were synthesized from 3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylic acid ( syn/anti -mixture) and cyclopropanol as pale yellow oils; ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5 and ptLC, eluent: petroleum ether/ethyl acetate 7:3.

Example 48 : cyclopropyl-3-(2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( anti- configuration), yield 39%;

LC/MS result [M+H] ⁺ : 482.2;

¹ H NMR (CDCl ₃ ): δ 0.34 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.56 (3H, s, CH ₃ ), 2.64 (2H , m, CH ₂ ), 2.84 (2H, m, CH ₂ ), 4.11 (1H, m, CH), 5.26 (1H, quint., CH), 7.38 (1H, m, CH-arom), 7.46 (3H, m, CH-arom), 7.97 (1H, s, CH-arom).

Example 49 : cyclopropyl-3-(2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( syn - configuration), 25% yield.

LC/MS result [M+H] ⁺ : 482.2;

¹ H NMR (CDCl ₃ ): δ 0.34 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.49 (3H, s, CH ₃ ), 2.80 (4H , m, 2xCH ₂ ), 4.12 (1H, m, CH), 4.72 (1H, quint., CH), 5.42 (1H, s, OH), 7.99 (1H, m, CH -arom), 7.46 (3H, m, CH-arom), 8.01 (1H, s, CH-arom).

Examples 50 and 51 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol- 4-carboxylate ( anti- and syn -configuration)

The title compounds were synthesized from 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazole-4-carboxylic acid ( syn/anti -mixture) and cyclopropanol as yellowish oils; ptLC, eluent: petroleum ether/ethyl acetate 7:3 and again ptLC, eluent: petroleum ether/ethyl acetate 7:3.

Example 50 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4- carboxylate ( anti -configuration), 1% yield;

LC/MS result [M+H] ⁺ : 500.2;

¹ H NMR (CDCl ₃ ): δ 0.32 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.58 (3H, s, CH ₃ ), 2.65 (2H , m, CH ₂ ), 2.83 (2H, m, CH ₂ ), 4.12 (1H, m, CH), 5.26 (1H, quint., CH), 7.12 (1H, t, CH-arom), 7.31 (1H, d, CH-arom), 7.42 (1H, m CH-arom), 7.96 (1H, s, CH-arom).

Example 51 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( syn -configuration), yield 1%.

LC/MS result [M+H] ⁺ : 500.2;

¹ H NMR (CDCl ₃ ): δ 0.32 (2H, m, CH ₂ ), 0.59 (2H, m, CH ₂ ), 1.56 (3H, s, CH ₃ ), 2.82 (4H , m, 2xCH ₂ ), 4.13 (1H, m, CH), 4.71 (1H, quint., CH), 7.13 (1H, t, CH-arom.), 7.32 (1H, d, CH-arom), 7.43 (1H, m, CH-arom), 8.00 (1H, s, CH-arom).

Example 52 : oxetan-3-yl-3-(2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-methyl-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( syn -config)

The title compound was synthesized from 3-(2-chlorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4- carboxylic acid ( syn -configuration obtained by saponification in Example 18 ) and oxetan-3-ol as a pale yellow oil in 7% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 444.3;

¹ H NMR (CDCl ₃ ): δ 1.47 (3H, s, CH ₃ ), 2.59 (3H, s, CH ₃ ), 2.79-2.69 (4H, m, CH ₂ ), 3 .64 (1H, br., OH), 4.24 (2H, t, CH ₂ ), 4.55 (1H, quint, CH), 4.74 (2H, t, CH ₂ ), 5.45 (1H, quint, CH), 7.55-7.36 (4H, m, 4xCH-arom), 8.42 (1H, s, CH-arom).

Examples 53 and 54 : cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4 -carboxylate ( syn- and anti -configuration)

The title compounds were synthesized from 3-(2-chlorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4- carboxylic acid ( syn/anti -mixture) and cyclopropanol as colorless oils; ptLC, eluent: petroleum ether/ethyl acetate 7:3 and again ptLC, eluent: petroleum ether/ethyl acetate 7:3.

Example 53 : cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate ( syn -configuration), 2% yield;

LC/MS result [M+H] ⁺ : 428.3;

¹ H NMR (CDCl ₃ ): δ 0.33 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.47 (3H, s, CH ₃ ), 2.58 (3H , s, CH ₃ ), 2.74 (4H, m, 2xCH ₂ ), 4.15 (1H, m, CH), 4.55 (1H, quint., CH), 7.41 (4H, m, CH-arom), 8.43 (1H, s, CH-arom).

Example 54 : cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate ( anti -configuration), 3% yield.

LC/MS result [M+H] ⁺ : 428.3;

¹ H NMR (CDCl ₃ ): δ 0.33 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.55 (3H, s, CH ₃ ), 2.58 (5H , m, CH ₃ , CH ₂ ), 2.80 (2H, m, CH ₂ ), 4.15 (1H, m, CH), 5.04 (1H, quint., CH), 7.41 (4H , m, CH-arom), 8.38 (1H, s, CH-arom).

Example 55 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2 -oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4 α-carboxylic acid and cyclopropanol as a pale yellow solid in 33% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 487.8;

¹ H NMR (CDCl ₃ ): δ 0.33 (2H, m, CH ₂ ), 0.60 (2H, m, CH ₂ ), 1.25 (6H, s, 2xCH ₃ ), 4.13 (1H , m, CH), 4.18 (1H, s, OH), 4.31 (2H, s, CH ₂ ), 7.13 (1H, t, CH-arom.), 7.33 (1H, d , CH-arom), 7.47 (1H, m, CH-arom), 8.05 (1H, s, CH-arom).

Example 56 : cyclobutyl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2 -oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4 α-carboxylic acid and cyclobutanol as a pale yellow oil in 47% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 501.8;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, 2xCH ₃ ), 1.55 (2H, m, CH ₂ ), 1.69 (2H, m, CH ₂ ), 2.19 (2H , m, CH ₂ ), 4.21 (1H, s, OH), 4.31 (2H, s, CH ₂ ), 4.97 (1H, m, CH), 7.15 (1H, t, CH -arom), 7.35 (1H, d, CH-arom), 7.45 (1H, m, CH-arom), 8.06 (1H, s, CH-arom).

Example 57 : oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl] -1,2-oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4 α-carboxylic acid and oxetan-3-ol as a colorless solid in 38% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 504.0;

¹ H NMR (CDCl ₃ ): δ 1.26 (6H, s, 2xCH ₃ ), 4.11 (1H, br., OH), 4.29-4.21 (2H, m, CH ₂ ), 4 .31 (2H, s, CH ₂ ), 4.80-4.70 (2H, m, CH ₂ ), 5.49-5.38 (1H, m, CH), 7.17 (1H, td, CH-arom), 7.37 (1H, dt, CH-arom), 7.52-7.42 (1H, m, CH-arom), 8.05 (1H, s, CH-arom). ).

Example 58 : oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-{1-[( 2R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylic acid and oxetan-3-ol as a colorless solid in 21% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 490.2;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.20 (1H, br., OH), 4.32-4.19 (3H, m, CH and CH ₂ ) , 4.47-4.32 (2H, m, CH ₂ ), 4.75 (2H, t, CH ₂ ), 5.49-5.39 (1H, m, CH), 7.17 (1H, td, CH-arom), 7.37 (1H, td, CH-arom), 7.52-7.42 (1H, m CH-arom), 8.03 (1H, s, CH-arom .).

Example 59 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1, 2-oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylic acid and cyclopropanol as a pale yellow oil in 30% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 474.2;

¹ H NMR (CDCl ₃ ): δ 0.32 (2H, m, CH ₂ ), 0.59 (2H, m, CH ₂ ), 1.32 (3H, d, CH ₃ ), 3.26 (1H , s, OH), 4.13 (1H, quint, CH), 4.25 (1H, dd, CH), 4.37 (2H, m, 2xCH), 7.13 (1H, t, CH- arom.), 7.32 (1H, d, CH-arom.), 7.44 (1H, m, CH-arom.), 8.03 (1H, s, CH-arom.).

Example 60 : oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate

The title compound was synthesized from 3-(2-chloro-6-fluorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylic acid and oxetan-3-ol as a pale yellow solid in 29% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 490.2;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.21 (1H, br., OH), 4.31-4.20 (3H, m, CH and CH ₂ ) , 4.47-4.31 (2H, m, CH ₂ ), 4.75 (2H, t, CH ₂ ), 5.50-5.38 (1H, m, CH), 7.17 (1H, td, CH-arom), 7.37 (1H, dt, CH-arom), 7.52-7.42 (1H, m.CH-arom), 8.03 (1H, s, CH- arom.).

Examples 61 and 62 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( syn- and anti -configuration)

The title compounds were synthesized from 3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylic acid ( syn/anti -mixture) and cyclopropanol as yellowish oils; ptLC, eluent: petroleum ether/ethyl acetate 7:3 and again ptLC, eluent: petroleum ether/ethyl acetate 7:3.

Example 61 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate ( syn -configuration), 7% yield;

LC/MS result [M+H] ⁺ : 446.3;

¹ H NMR (CDCl ₃ ): δ 0.29 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.53 (3H, s, CH ₃ ), 2.58 (4H , m, CH, CH ₃ ), 2.77 (3H, m, CH, CH ₂ ), 4.16 (1H, m, CH), 5.03 (1H, quint., CH), 7.10 ( 1H, t, CH-arom), 7.30 (1H, d, CH-arom), 7.40 (1H, m, CH-arom), 8.41 (1H, s, CH-arom). ).

Example 62 : cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate ( anti -configuration), 14% yield.

LC/MS result [M+H] ⁺ : 446.3;

¹ H NMR (CDCl ₃ ): δ 0.30 (2H, m, CH ₂ ), 0.58 (2H, m, CH ₂ ), 1.47 (3H, s, CH ₃ ), 2.59 (3H , s, CH ₃ ), 2.74 (4H, m, 2xCH ₂ ), 3.63 (1H, s, OH), 4.16 (1H, m, CH), 4.55 (1H, quint., CH), 7.12 (1H, t, CH-arom), 7.31 (1H, d, CH-arom), 7.39 (1H, m, CH-arom), 8.48 (1H , s, CH-arom.).

Synthesis of 4-alkoxymethylisoxazoles

Recovery step with LiAlH _four

The corresponding methyl or ethyl esters of isoxazole-4-carboxylic acid were dissolved in dry THF (Sure/Seal; 4 ml/mmol) and the solution was cooled to 0°C. LiAlH ₄ (1 M in THF; 1.5 eq.) was added slowly and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with Rochelle's salt and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give crude material which was used directly for the next steps.

- (2 S )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl) propan-2-ol from Example 13 (0.4 mmol) as an orange solid (80%).

LC/MS result [M+H] ⁺ : 419.7;

-4-{4-[3-(2-Chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} -2-methylbutan-2-ol from Example 9 (1.0 mmol) as a pale yellow oil (87%).

LC/MS result [M+H] ⁺ : 448.2;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.18-2.08 (2H, m, CH ₂ ), 3.79-3.71 (1H, m, OH ), 4.08 (1H, dc, OH), 4.40 (2H, s, CH ₂ ), 4.58-4.48 (2H, m, CH ₂ ), 7.15 (1H, td, CH -arom.), 7.35 (1H, dt, CH-arom.), 7.48-7.39 (1H, m, CH-arom.), 7.92 (1H, s, CH-arom.) .

- 3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} -1-methylcyclobutan-1-ol ( syn/anti -mixture) from Examples 10/11 (0.6 mmol) as syn/anti -mixture ( syn- and anti -isomers were not separated at the ester level for this synthesis) (quant.).

Пример 63: 1-(4-(3-(2-хлор-6-фторфенил)-4-(гидроксиметил)изоксазол-5-ил)-5-(трифторметил)-1Н-пиразол-1-ил)-2-метилпропан-2-ол из Примера 8 (0,3 ммоль) в виде желтоватого твердого вещества (пТСХ, элюент: петролейный эфир/этилацетат 1:1; 24%).

Example 63 : 1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol from Example 8 (0.3 mmol) as a yellowish solid (pTLC, eluent: petroleum ether/ethyl acetate 1:1; 24%).

LC/MS result [M+H] ⁺ : 433.8;

¹ H NMR (CDCl ₃ ): δ 1.24 (6H, s, 2xCH ₃ ), 1.67 (1H, s, OH), 4.16 (1H, s, OH), 4.31 (2H, s , CH ₂ ), 4.41 (2H, d, CH ₂ ), 7.16 (1H, td, CH-arom), 7.36 (1H, td, CH-arom), 7.44 (1H , m, CH-arom), 8.01 (1H, s, CH-arom).

- (2 R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl) propan-2-ol from Example 12 (0.55 mmol) as an orange solid (75%).

LC/MS result [M+H] ⁺ : 419.7;

- methyl ester-3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol-4 -carboxylate was synthesized as described above from methyl-( Z )-3-(2-chlorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-ene-2- yl)isoxazole-4-carboxylate (1.2 mmol) and 4-hydrazinyl-2-methylbutan-2-ol as a yellow oil (33%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 440.3;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.20-2.10 (2H, m, CH ₂ ), 3.63 (3H, s, OCH ₃ ), 4 .58-4.48 (2H, m, CH ₂ ), 7.59-7.33 (4H, m, 4xCH-arom), 7.95 (1H, s, CH-arom).

From this ester (0.4 mmol) 4-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole -1-yl}-2-methylbutan-2-ol was synthesized quantitatively according to the standard procedure.

LC/MS result [M+H] ⁺ : 430.3;

- (2 S )-1-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl }propan-2-ol from Example 22 (1.5 mmol) (90%).

- 3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutane -1-ol ( syn/anti -mixture) from ethyl-3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl ]-1,2-oxazole-4-carboxylate (0.8 mmol) ( syn/anti -mixture; synthesis described above) (63%).

Example 64 : 3-(4-(3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1 -methylcyclobutan-1-ol ( syn -configuration)

From a mixture of syn - and anti -isomers, syn - syn -isomer was separated using prep. TLC (eluent petroleum ether/ethyl acetate 1:1).

LC/MS result [M+H] ⁺ : 427.9;

¹ H NMR (CDCl ₃ ): δ 1.49 (3H, s, CH ₃ ), 2.94-2.68 (4H, m, 2xCH ₂ ), 3.49 (1H, s, OH), 4, 45 (2H, s, CH ₂ ), 4.73 (1H, quint, CH), 7.63-7.34 (4H, m, 4xCH-arom), 7.99 (1H, s, CH- arom.).

-4-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-methylbutan-2 -ol from Example 19 (0.4 mmol) as a yellow solid (84%).

LC/MS result [M+H] ⁺ : 376.0;

- 3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1-methylcyclobutan-1 -ol ( syn/anti -mixture) from Examples 17/18 (1.1 mmol) as syn/anti -mixture (for this synthesis, syn- and anti -isomers were not separated at the level of esters) (quant.).

LC/MS result [M+H] ⁺ : 374.3;

-4-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2 -methylbutan-2-ol from Example 20 (2.0 mmol) as a yellowish solid (94%).

LC/MS result [M+H] ⁺ : 394.1;

¹ H NMR (CDCl ₃ ): δ 1.30 (6H, s, 2xCH ₃ ), 2.08-2.00 (2H, m, CH ₂ ), 2.65 (3H, s, CH ₃ ), 4 .36-4.28 (2H, m, CH ₂ ), 4.45 (2H, d, CH ₂ ), 7.16 (1H, td, CH-arom.), 7.36 (1H, dt, CH -arom.), 7.49-7.39 (1H, m, CH-arom.), 7.97 (1H, s, CH-arom.).

- 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1 -methylcyclobutan-1-ol ( syn/anti -mixture) from methyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazole -4-yl}-1,2-oxazole-4-carboxylate (1.1 mmol) ( syn/anti -mixture; synthesis described above) as a yellowish solid (89%).

LC/MS result [M+H] ⁺ : 392.2;

- 3-(4-{3-[3-(benzyloxy)-2-chlorophenyl]-4-(hydroxymethyl)-1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazol-1- yl)-1-methylcyclobutan-1-ol ( syn/anti -mixture) from ethyl-3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5 -(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate (0.9 mmol) ( syn/anti -mix) as an orange-brown solid (quant.).

LC/MS result [M+H] ⁺ : 534.3;

¹ H NMR (CDCl ₃ ): δ 1.55 (3H, s, CH ₃ ), 2.94-2.55 (4H, m, 2xCH ₂ ), 3.83-3.68 (1H, m, CH ), 4.44 (2H, s, OCH ₂ ), 5.22 (2H, s, OCH ₂ ), 7.19-7.09 (2H, m, 2xCH-arom), 7.54-7, 30 (6H, m, 6xCH-arom), 7.97 (1H, s, CH-arom).

-4-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2- methylbutan-2-ol from ethyl 3-(3-(benzyloxy)-2-chlorophenyl)-5-(1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl )isoxazole-4-carboxylate as a brown oil (91%).

LC/MS result [M+H] ⁺ : 536.1;

¹ H NMR (CDCl ₃ ): δ 1.33 (6H, s, 2xCH ₃ ), 1.86 (4H, m, 2x CH ₂ ), 3.75 (2H, s, CH ₂ ), 5.23 ( 2H, d, CH ₂ ), 7.12 (1H, m, CH-arom), 7.41 (6H, m, CH-arom), 7.95 (1H, s, CH-arom).

The conversion of hydroxymethylisoxazole to bromomethylisoxazole was achieved using two methods:

A) The corresponding hydroxymethylisoxazole was dissolved in diethyl ether, THF or CH ₂ Cl ₂ (3 ml/mmol) at 0° C. and phosphorus tribromide (0.5 eq.) dissolved in diethyl ether (3 ml/mmol) was slowly added. The mixture was stirred at 0°C for 10-30 minutes. The mixture was treated with NaHCO ₃ (5%) and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ and the solvent was removed in vacuo to give crude material which was used as such in further steps.

B) The corresponding hydroxymethylisoxazole and PPh ₃ (1.5 eq.) were dissolved in dry THF (Sure/Seal; 4 ml/mmol) and cooled to 0°C. CBr ₄ (1.5 eq.) was added and the mixture was stirred at 0°C for 15 min and then at room temperature for 2 h. The mixture was quenched with water and the resulting mixture was extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ and the solvent removed in vacuo to give crude material. To remove the OPPh ₃ particulate material, the solid material was treated with Et ₂ O, sonicated, centrifuged and decanted; alternatively, the material was purified using prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5).

-4-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} -2-methylbutan-2-ol from 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}-2-methylbutan-2-ol (0.25 mmol) according to method A (Et ₂ O, 10 min) as a yellow solid (93%).

LC/MS result [M+H] ⁺ : 510.1;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.12 (2H, m, CH ₂ ), 4.15 (2H, s, CH ₂ ), 4.53 (2H , m, CH ₂ ), 7.17 (1H, t, CH-arom), 7.37 (1H, d, CH-arom), 7.44 (1H, m, CH-arom), 7 .92 (1H, s, CH-arom).

-4-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-2-methylbutane -2-ol from 4-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} -2-methylbutan-2-ol (0.40 mmol) according to method A (CH ₂ Cl ₂ , 30 min) as orange oil (60%; ptlc, eluent: CH ₂ Cl ₂ /MeOH 95:5) .

LC/MS result [M+H] ⁺ : 492.2;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.13 (2H, m, CH ₂ ), 4.23 (2H, s, CH ₂ ), 4.55 (2H , m, CH ₂ ), 7.45 (1H, m, CH-arom), 7.54 (2H, m, CH-arom), 7.65 (1H, m, CH-arom), 7 .92 (1H, s, CH-arom).

-4-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-methylbutan-2 -ol from 4-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-methylbutane -2-ol (0.25 mmol) according to method A (THF, 20 min) as a yellow solid (84%); observed a partial additional hydroxy-bromo exchange in the methylbutanol fragment (5-[1-(3-bromo-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-4-(bromomethyl)-3-(2- chlorophenyl)-1,2-oxazole).

LC/MS result [MH ₂ O+H] ⁺ : 419.9 (title compound);

LC/MS result [M+H] ⁺ : 499.8 (M+ (additional OH-Br exchange);

-4-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2 -methylbutan-2-ol from 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole- 1-yl}-2-methylbutan-2-ol (2.0 mmol) according to method B as a yellowish oil (95%).

LC/MS result [MH ₂ O+H] ⁺ : 437.9;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.05 (2H, m, CH ₂ ), 2.63 (3H, s, CH ₃ ), 4.29 (2H , s, CH ₂ ), 4.33 (2H, m, CH ₂ ), 7.17 (1H, t, CH-arom), 7.36 (1H, d, CH-arom), 7.45 (1H, m, CH-arom), 7.95 (1H, s, CH-arom).

- 3-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1 -methylcyclobutan-1-ol ( syn/anti -mixture) from 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5 -methyl-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol (0.4 mmol; syn/anti -mixture) according to method B as a yellowish solid (89%).

LC/MS result [M+H] ⁺ : 454.1;

- 3-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1-methylcyclobutan-1 -ol ( syn/anti -mixture) from 3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol (0.15 mmol; syn/anti -mixture) according to method B (quant.)

LC/MS result [M+H] ⁺ : 436.2;

- (2 R )-1-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole -1-yl}propan-2-ol from ( 2R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl )-1H-pyrazol-1-yl)propan-2-ol (0.3 mmol) according to method B (87%).

- (2 S )-1-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl }propan-2-ol from (2 S )-1-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}propan-2-ol (0.35 mmol) according to method B (55%).

- 3-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutane -1-ol ( syn/anti -mixture) from 3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol (0.3 mmol; syn/anti -mixture) according to method B (92%).

- 3-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl} -1-methylcyclobutan-1-ol ( syn/anti -mixture) from 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl] -5-(trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol (0.35 mmol; syn/anti -mixture) according to method B (77%).

- 3-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(bromomethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1- methylcyclobutan-1-ol ( syn/anti -mixture) from 3-(4-{3-[3-(benzyloxy)-2-chlorophenyl]-4-(hydroxymethyl)-1,2-oxazol-5-yl}- 5-(trifluoromethyl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol ( syn/anti -mix) (1.0 mmol) according to method A (Et ₂ O, 10 min) as yellow oil (quant.).

LC/MS result [M+H] ⁺ : 596.2;

¹ H NMR (CDCl ₃ ): δ 1.51 (3H, s, CH ₃ ), 2.78 (4H, m, 2xCH ₂ ), 4.24 (2H, s, CH ₂ ), 4.73 (1H , m, CH), 5.23 (2H, s, CH ₂ ), 7.15 (2H, d, CH-arom), 7.39 (6H, d, CH-arom), 7.97 ( 1H, s, CH-arom).

-4-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(bromomethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2- methylbutan-2-ol from 4-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1- yl)-2-methylbutan-2-ol (2.5 mmol) according to method A (CH ₂ Cl ₂ , 15 min) as a yellow solid (94%).

LC/MS result [M+H] ⁺ -H ₂ O: 580.0;

¹ H NMR (CDCl ₃ ): δ 1.34 (6H, s, 2xCH ₃ ), 1.94 (4H, m, 2xCH ₂ ), 3.45 (2H, s, CH ₂ ), 5.23 (2H , s, CH ₂ ), 7.15 (2H, m, CH-arom), 7.39 (6H, m, CH-arom), 7.99 (1H, s, CH-arom).

Final formation of 4-alkoxymethylisoxazoles; alternative ways:

A) Potassium hydroxide (powder, 4.0 eq.) was added to a stirred solution of the appropriate 4-hydroxymethylisoxazole in 2-methyltetrahydrofuran (5 ml/mmol) and the resulting suspension was stirred for 10 minutes at room temperature. Iodomethane (4.0 eq) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification was achieved by preparative TLC on silica gel.

B) Sodium hydride (1.1 eq.) was suspended in THF (Sure/Seal; 2 ml/mmol) and cooled to 0°C. The corresponding 4-hydroxymethylisoxazole was dissolved in THF (Sure/Seal; 2 ml/mmol), cooled to 0° C. and added to the NaH suspension. The mixture was stirred for 10 min at 0°C and for 0.5 h at room temperature. Alkyl bromide (2.0 eq.) was added and stirring continued at RT for 18 hours. The reaction was quenched by adding water, the mixture was partitioned between water and CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification was achieved by preparative TLC on silica gel.

C) At 0°C, NaH (1.5 eq.) was dissolved in THF (2 ml/mmol) and cyclopropanol was added. The mixture was stirred at 0°C for 20 min. The corresponding 4-bromomethylisoxazole was dissolved in DMF (2 ml/mmol) and added to the NaH suspension. The mixture was stirred at 0° C. for 1 h, warmed to room temperature and stirred at this temperature for 18 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The product was purified by preparative TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5).

D) To a stirred solution of the appropriate 4-bromomethylisoxazole in THF (4 ml/mmol) was added the appropriate alcohol (3.0 eq.), KO t Bu (3.0 eq.) and 18-crown-6 ether (1.0 eq. .). The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification was achieved by preparative TLC on silica gel.

-

Example 65 : 1-(4-(3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol

method A , from 1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2 -methylpropan-2-ol (0.1 mmol) as a yellowish oil (30%; ptlc, eluent: petroleum ether/ethyl acetate 1:1 and ptlc, eluent: petroleum ether/ethyl acetate 2:1).

LC/MS result [M+H] ⁺ : 447.8;

¹ H NMR (CDCl ₃ ): δ 1.23 (6H, s, 2xCH ₃ ), 3.14 (3H, s, CH ₃ ), 4.18 (1H, s, OH), 4.19 (2H, s, CH ₂ ), 4.31 (2H, s, CH ₂ ), 7.15 (1H, td, CH-arom), 7.35 (1H, td, CH-arom), 7.43 ( 1H, m, CH-arom), 7.94 (1H, s, CH-arom).

-

Example 66 : (2 R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole-1- yl) propan-2-ol

method A , from ( 2R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole-1 -yl)propan-2-ol (0.4 mmol) as a yellowish oil (5%; ptlc, eluent: petroleum ether/ethyl acetate 1:1 and ptlc, eluent: petroleum ether/ethyl acetate 4:1).

LC/MS result [M+H] ⁺ : 433.8;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 3.15 (3H, s, CH ₃ ), 3.27 (1H, m, CH), 4.19 (2H, s, CH ₂ ), 4.27 (1H, m, CH), 4.37 (2H, m, OH, CH), 7.15 (1H, td, CH-arom.), 7.35 (1H, td, CH-arom), 7.43 (1H, m, CH-arom), 7.91 (1H, s, CH-arom).

-

Example 67 : 4-{4-[3-(2-Chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1- yl}-2-methylbutan-2-ol

method A , from 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-2-methylbutan-2-ol (1.5 mmol) as a pale yellow oil (29%; ptLC, eluent: petroleum ether/ethyl acetate 3:2 and ptLC, eluent: CH ₂ Cl ₂ /MeOH 95 :5).

LC/MS result [M+H] ⁺ : 462.3;

¹ H NMR (CDCl ₃ ): δ 1.33 (6H, s, 2xCH ₃ ), 2.13 (2H, m, CH ₂ ), 3.13 (3H, s, CH ₃ ), 4.19 (2H , s, CH ₂ ), 4.53 (2H, m, CH ₂ ), 7.14 (1H, td, CH-arom), 7.35 (1H, d, CH-arom), 7.42 (1H, m, CH-arom), 7.85 (1H, s, CH-arom).

-

Example 68 : ( 2S )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole-1- yl) propan-2-ol

method A , from ( 2S )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole-1 -yl)propan-2-ol (0.3 mmol) as a yellowish oil (6%; ptLC, eluent: petroleum ether/ethyl acetate 1:1 and ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 433.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.15 (3H, s, CH ₃ ), 3.27 (1H, m, CH), 4.20 (2H, s, CH ₂ ), 4.26 (1H, m, CH), 4.37 (2H, m, OH, CH), 7.15 (1H, td, CH-arom.), 7.35 (1H, td, CH-arom), 7.43 (1H, m, CH-arom), 7.92 (1H, s, CH-arom).

-

Example 69 : 3-(4-(3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1- methylcyclobutan-1-ol ( syn -configuration)

method A , from 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn/anti -mix) (0.5 mmol) (17%; ptLC, eluent: petroleum ether/ethyl acetate 1:1 and ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5; only syn diastereomer isolated).

¹ H NMR (CDCl ₃ ): δ 1.50 (3H, s, CH ₃ ), 2.95-2.71 (4H, m, 2xCH ₂ ), 3.14 (3H, s, OCH ₃ ), 4 .19 (2H, s, _CH2 ), 4.72 (1H, quint, CH), 7.15 (1H, td, CH-arom), 7.35 (1H, d, CH-arom) , 7.49-7.38 (1H, m, CH-arom), 7.91 (1H, s, CH-arom).

- Examples 70 and 71 : 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn -configuration) and 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl ]-5-methyl-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( anti -configuration)

method A , from 3-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn/anti -mix) (0.3 mmol) (pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5 and again pTLC, eluent: CH ₂ Cl ₂ /MeOH 95: 5);

Example 70 : ( syn -configuration), 10% yield;

LC/MS result [M+H] ⁺ : 406.3;

¹ H NMR (CDCl ₃ ): δ 1.52 (3H, s, CH ₃ ), 2.59 (3H, s, CH ₃ ), 2.64 (4H, m, 2xCH ₂ ), 3.17 (3H , s, CH ₃ ), 4.20 (2H, s, CH ₂ ), 4.95 (1H, m, CH), 7.14 (1H, td, CH-arom), 7.35 (1H, d, CH-arom), 7.43 (1H, m, CH-arom) 7.88 (1H, s, CH-arom).

Example 71 : ( anti -configuration), 18% yield;

LC/MS result [M+H] ⁺ : 406.3;

¹ H NMR (CDCl ₃ ): δ 1.54 (3H, s, CH ₃ ), 2.59 (5H, m, CH ₂ , CH ₃ ), 2.76 (2H, m, CH ₂ ), 3, 20 (3H, s, CH ₃ ), 4.24 (2H, s, CH ₂ ), 5.03 (1H, m, CH), 7.14 (1H, td, CH-arom), 7.34 (1H, d, CH-arom), 7.42 (1H, m, CH-arom), 7.90 (1H, s, CH-arom).

Examples 72 and 73 : 3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1 -methylcyclobutan-1-ol ( syn configuration) and 3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( anti -configuration)

method A , from 3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1- methylcyclobutan-1-ol ( syn/anti -mix) (0.3 mmol) (pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5 and again pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5);

Example 72 : ( syn -configuration), 4% yield;

LC/MS result [M+H] ⁺ : 388.3;

¹ H NMR (CDCl ₃ ): δ 1.48 (3H, s, CH ₃ ), 2.59 (3H, s, CH ₃ ), 2.72 (4H, m, 2xCH ₂ ), 3.25 (3H , s, CH ₃ ), 4.24 (2H, s, CH ₂ ), 4.53 (1H, quint, CH), 7.45 (4H, m, CH-arom), 7.92 (1H , s, CH-arom.).

Example 73 : ( anti -configuration), 4% yield;

LC/MS result [M+H] ⁺ : 388.3;

¹ H NMR (CDCl ₃ ): δ 1.53 (3H, s, CH ₃ ), 2.58 (5H, m, CH ₂ , CH ₃ ), 2.77 (2H, m, CH ₂ ), 3, 25 (3H, s, CH ₃ ), 4.24 (2H, s, CH ₂ ), 5.03 (1H, quint, CH), 7.45 (4H, m, CH-arom), 7, 89 (1H, s, CH-arom).

.

.

Example 74 : 3-(4-(3-(2-chlorophenyl)-4-(methoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1- ol ( syn -configuration)

method A , from 3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 1-methylcyclobutan-1-ol ( syn/anti -mixture (0.5 mmol) (14%; ptLC, eluent: petroleum ether/ethyl acetate 1:1 and ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5; isolated only syn diastereomer).

LC/MS result [M+H] ⁺ : 441.9;

¹ H NMR (CDCl ₃ ): δ 1.49 (3H, s, CH ₃ ), 2.90-2.72 (4H, m, 2xCH ₂ ), 3.17 (3H, s, OCH ₃ ), 4 .20 (2H, s, OCH ₂ ), 4.81 (1H, m, CH), 5.04 (1H, br., OH), 7.57-7.35 (4H, m, 4xCH-arom. ), 7.90 (1H, s, CH-arom).

Example 75 : ( 2S )-1-{4-[3-(2-chlorophenyl)-4-[(2-methoxyethoxy)methyl]-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol

method B , from (2 S )-1-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol (0.2 mmol) and 2-bromoethyl methyl ether (57%; ptLC, eluent: petroleum ether/ethyl acetate 1:1 and ptLC, eluent: CH ₂ Cl ₂ /MeOH 95:5) .

LC/MS result [M+H] ⁺ : 459.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.26 (3H, s, OCH ₃ ), 3.48-3.32 (5H, m, 2xCH ₂ and CH) , 4.24 (1H, dd, CH), 4.47-4.30 (4H, m, 2xCH ₂ ), 7.48-7.34 (2H, m, 2xCH-arom), 7.57- 7.49 (2H, m, 2xCH-arom), 7.98 (1H, s, CH-arom).

Example 76 : (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(ethoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}propan-2-ol

method B , from (2 R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole-1 -yl)propan-2-ol (0.5 mmol) and ethyl bromide (46%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: CH ₂ Cl ₂ /MeOH 95:5).

LC/MS result [M+H] ⁺ : 447.8;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.32 (3H, d, CH ₃ ), 3.28 (2H, q, CH ₂ ), 4.31-4 .18 (3H, m, CH and CH ₂ ), 4.45-4.31 (2H, m, CH ₂ ), 7.14 (1H, td, CH-arom), 7.35 (1H, d , CH-arom), 7.48-7.38 (1H, m, CH-arom), 7.93 (1H, s, CH-arom).

Example 77 : 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1- yl}-2-methylbutan-2-ol

method C , from 4-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-2-methylbutan-2-ol (0.25 mmol) and cyclopropanol as a pale yellow oil (11%).

LC/MS result [M+H] ⁺ : 488.30;

¹ H NMR (CDCl ₃ ): δ 0.28 (3H, s, CH ₃ ), 1.33 (6H, s, 2xCH ₃ ), 2.14 (2H, m, CH ₂ ), 3.12 (1H , m, CH), 4.27 (2H, s, CH ₂ ), 4.53 (2H, m, CH ₂ ), 7.14 (1H, td, CH-arom.), 7.34 (1H, t, CH-arom), 7.43 (1H, m, CH-arom), 7.85 (1H, s, CH-arom).

Example 78 : 4-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-2 -methylbutan-2-ol

method C , from 4-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol (0.25 mmol) and cyclopropanol as a colorless oil (28%).

LC/MS result [M+H] ⁺ : 470.30;

¹ H NMR (CDCl ₃ ): δ 0.30 (4H, m, 2xCH ₂ ), 1.33 (6H, s, 2xCH ₃ ), 2.13 (2H, m, CH ₂ ), 3.12 (1H , m, CH), 4.29 (2H, s, CH ₂ ), 4.53 (2H, m, CH ₂ ), 7.44 (5H, m, CH-arom), 7.84 (1H, s, CH-arom.).

Example 79 : 4-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-methylbutane -2-ol

method C , from 4-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- methylbutan-2-ol (0.25 mmol) and cyclopropanol (6%).

LC/MS result [M+H] ⁺ : 416.0;

¹ H NMR (CDCl ₃ ): δ 0.34 (2H, m, CH ₂ ), 0.41 (2H, m, CH ₂ ), 1.27 (6H, s, 2xCH ₃ ), 2.03 (2H , m, CH ₂ ), 2.61 (3H, s, CH ₃ ), 3.18 (1H, m, CH), 4.32 (2H, m, CH ₂ ), 4.34 (2H, s, CH ₂ ), 7.43 (3H, m, CH-arom) 7.53 (1H, d, CH-arom), 7.87 (1H, s, CH-arom).

- Example 80 and 81 : 3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}- 1-methylcyclobutan-1-ol, syn- and anti -configuration

method C , from 3-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1- methylcyclobutan-1-ol ( syn/anti -mixture) (0.2 mmol) and cyclopropanol;

Example 80 : ( syn -configuration), 2% yield;

LC/MS result [M+H] ⁺ : 414.3;

¹ H NMR (CDCl ₃ ): δ 0.33 (2H, m, CH ₂ ), 0.40 (2H, m, CH ₂ ), 1.47 (3H, s, CH ₃ ), 2.57 (3H , s, CH ₃ ), 2.63 (2H, m, CH ₂ ), 2.75 (2H, m, CH ₂ ), 3.16 (1H, m, CH), 3.76 (1H, m, CH), 4.31 (2H, s, CH ₂ ), 7.44 (4H, m, CH-arom), 7.85 (1H, s, CH-arom).

Example 81 : ( anti -configuration), 4% yield.

LC/MS result [M+H] ⁺ : 414.3;

¹ H NMR (CDCl ₃ ): δ 0.34 (2H, m, CH ₂ ), 0.42 (2H, m, CH ₂ ), 1.57 (3H, s, CH ₃ ), 2.58 (5H , m, CH ₂ , CH ₃ ), 2.77 (2H, m, CH ₂ ), 3.18 (1H, m, CH), 4.33 (2H, s, CH ₂ ), 5.03 (1H , m, CH), 7.45 (4H, m, CH-arom), 7.89 (1H, s, CH-arom).

-

Example 82 4-{4-[3-(2-Chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl} -2-methylbutan-2-ol

method C , from 4-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol (0.3 mmol) and cyclopropanol as a yellowish oil (19%).

LC/MS result [M+H] ⁺ : 434.1;

¹ H NMR (CDCl ₃ ): δ 0.41-0.26 (4H, m, 2xCH ₂ ), 1.30 (6H, s, 2xCH ₃ ), 2.04 (2H, t, CH ₂ ), 2 .63 (3H, s, CH ₃ ), 3.23-3.14 (1H, m, CH), 4.35-4.27 (4H, m, 2xCH ₂ ), 7.14 (1H, td, CH-arom), 7.34 (1H, d, CH-arom), 7.48-7.38 (1H, m, CH-arom), 7.89 (1H, s, CH-arom). ).

- Example 83 and 84 : 3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol, syn- and anti -configuration

method C , from 3-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn/anti -mix) (0.4 mmol) and cyclopropanol as a colorless oil (additional ptlc, eluent: petroleum ether/ethyl acetate 1:1);

Example 83 : ( syn -configuration), 15% yield;

LC/MS result [M+H] ⁺ : 432.3;

¹ H NMR (CDCl ₃ ): δ 0.30 (2H, m, CH ₂ ), 0.36 (2H, m, CH ₂ ), 1.47 (3H, s, CH ₃ ), 1.76 (1H , s, OH), 2.58 (3H, s, CH ₃ ), 2.72 (2H, m, CH ₂ ), 2.74 (2H, m, CH ₂ ), 3.18 (1H, m, CH), 4.33 (2H, s, CH ₂ ), 4.53 (1H, quint, CH), 7.14 (1H, td, CH-arom), 7.34 (1H, d, CH -arom), 7.42 (1H, m, CH-arom), 7.95 (1H, s, CH-arom).

Example 84 : ( anti -configuration), 16% yield;

LC/MS result [M+H]+: 432.3;

¹ H NMR (CDCl ₃ ): δ 0.31 (2H, m, CH ₂ ), 0.36 (2H, m, CH ₂ ), 1.53 (3H, s, CH ₃ ), 1.68 (1H , s, OH), 2.57 (5H, m, CH ₃ , CH ₂ ), 2.75 (2H, m, CH ₂ ), 3.18 (1H, m, CH), 4.32 (2H, s, CH ₂ ), 5.03 (1H, quint, CH), 7.13 (1H, td, CH-arom), 7.34 (1H, d, CH-arom), 7.42 ( 1H, m, CH-arom), 7.91 (1H, s, CH-arom).

-

Example 85 : (2 R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1- yl) propan-2-ol

method C , from ( 2R )-1-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol (0.3 mmol) and cyclopropanol (9%).

LC/MS result [M+H] ⁺ : 459.8;

¹ H NMR (CDCl ₃ ): δ 0.94-0.80 (4H, m, 2xCH ₂ ), 1.32 (3H, d, CH ₃ ), 3.19-3.07 (1H, m, CH ), 4.25 (1H, dd, CH), 4.27 (2H, s, OCH ₂ ), 4.45-4.32 (2H, m, CH ₂ ), 7.15 (1H, td, CH -arom.), 7.35 (1H, dt, CH-arom.), 7.49-7.39 (1H, m, CH-arom.), 7.92 (1H, s, CH-arom.) .

-

Example 86 : 3-(4-(3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1- methylcyclobutan-1-ol ( syn -configuration)

method C , from 3-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn/anti -mixture) (0.2 mmol) and cyclopropanol (52%; only syn -diastereomer isolated).

LC/MS result [M+H] ⁺ : 486.0;

¹ H NMR (CDCl ₃ ): δ 0.27 (4H, d, 2xCH ₂ ), 1.50 (3H, s, CH ₃ ), 2.91-2.71 (4H, m, 2xCH ₂ ), 3 .16-3.08 (1H, m, CH), 4.26 (2H, s, OCH ₂ ), 4.81-4.65 (1H, m, CH), 7.14 (1H, td, CH -arom.), 7.34 (1H, dt, CH-arom.), 7.48-7.38 (1H, m, CH-arom.), 7.91 (1H, s, CH-arom.) .

-

Example 87 : 3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-1 -methylcyclobutan-1-ol ( syn -configuration)

method C , from 3-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 1-methylcyclobutan-1-ol ( syn/anti -mixture) (0.25 mmol) and cyclopropanol (26%; only syn -diastereomer isolated).

LC/MS result [M+H] ⁺ : 467.9;

¹ H NMR (CDCl ₃ ): δ 0.35-0.25 (4H, m, 2xCH ₂ ), 1.50 (3H, s, CH ₃ ), 2.91 (4H, br., 2xCH ₂ ), 3.17-3.07 (1H, m, CH), 4.29 (2H, s, OCH ₂ ), 4.72 (1H, quint, CH), 7.56-7.34 (4H, m , 4xCH-arom), 7.89 (1H, s, CH-arom).

-

Example 88 : ( S )-1-(4-(3-(2-chlorophenyl)-4-((oxetan-3-yloxy)methyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol- 1-yl)propan-2-ol

method C , from ( 2S )-1-{4-[4-(bromomethyl)-3-(2-chlorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol (0.25 mmol) and oxetan-3-ol (11%).

LC/MS result [M+H] ⁺ : 458.3;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 4.21 (2H, s, OCH ₂ ), 4.46-4.23 (6H, m, 2xCH ₂ and 2xCH) , 4.59-4.51 (2H, m, CH ₂ ), 7.58-7.37 (4H, m, 4xCH-arom), 7.91 (1H, s, CH-arom).

-

Example 89 : (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-[(propan-2-yloxy)methyl]-1,2-oxazol-5-yl]- 5-(trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol

method D , from ( 2R )-1-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol (0.25 mmol) and isopropanol (21%).

LC/MS result [M+H] ⁺ : 462.1;

¹ H NMR (CDCl ₃ ): δ 0.92 (6H, d, 2xCH ₃ ), 1.32 (3H, d, CH ₃ ), 3.28 (1H, br., OH), 3.40 (1H , sept, CH), 4.29-4.19 (3H, m, CH and CH ₂ ), 4.45-4.31 (2H, m, CH ₂ ), 7.14 (1H, td, CH- arom.), 7.34 (1H, d, CH-arom.), 7.47-7.38 (1H, m, CH-arom.), 7.93 (1H, s, CH-arom.).

-

Example 90 : (2 R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(cyclobutoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1- yl) propan-2-ol

method C , from ( 2R )-1-{4-[4-(bromomethyl)-3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol (0.25 mmol) and cyclobutanol (17%).

LC/MS result [M+H] ⁺ : 474.1;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 1.74-1.55 (4H, m, 2xCH ₂ ), 2.02-1.88 (2H, m, CH ₂ ), 3.27 (1H, br, OH), 3.75 (1H, quint, CH), 4.14 (2H, s, CH), 4.25 (1H, d, CH), 4, 45-4.31 (2H, m, CH ₂ ), 7.15 (1H, td, CH-arom), 7.35 (1H, d, CH-arom), 7.49-7.39 ( 1H, m, CH-arom), 7.94 (1H, s, CH-arom).

-

Example 91 : 4-{4-[3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1- yl}-2-methylbutan-2-ol

1.) 4-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)- 2-methylbutan-2-ol

method C , from 4-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(bromomethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl) -2-methylbutan-2-ol (1.0 mmol) and cyclopropanol as a colorless oil (20%).

LC/MS result [M+H] ⁺ : 576.5;

¹ H NMR (CDCl ₃ ): δ 0.38-0.20 (4H, m, 2xCH ₂ ), 1.32 (6H, s, 2xCH ₃ ), 2.19 (2H, m, CH ₂ ), 3 .14-3.06 (1H, m, OH), 4.58-4.47 (2H, m, CH ₂ ), 5.22 (2H, s, OCH ₂ ), 5.23 (2H, s, OCH ₂ ), 7.10 (1H, td, CH-arom), 7.52-7.28 (6H, m, 6xCH-arom), 7.84 (1H, s, CH-arom).

2.) 2-chloro-3-[4-(cyclopropoxymethyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazol-3-yl]phenol

4-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylbutane -2-ol (0.2 mmol) was dissolved in iPrOH/ethyl acetate (1:1; 1 ml) and Pd/C (10%; 0.3 eq.) was added. The atmosphere was changed to hydrogen and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give a crude material (yellow oil; 90%), which was used as such for the next step.

LC/MS result [M+H] ⁺ : 486.3;

¹ H NMR (CDCl ₃ ): δ 0.38-0.24 (4H, m, 2xCH ₂ ), 1.32 (6H, s, 2xCH ₃ ), 2.18-2.08 (2H, m, CH ₂ ), 3.18-3.06 (1H, m, CH), 4.26 (2H, s, OCH ₂ ), 4.58-4.45 (2H, m, CH ₂ ), 7.20- 6.97 (2H, m, 2xCH-arom), 7.84 (1H, s, CH-arom).

3.) NaH (1.4 eq.) was suspended in THF (Sure/Seal; 2 ml/mmol) and the solution was cooled to 0°C. A solution of 2-chloro-3-[4-(cyclopropoxymethyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 3-yl]phenol (0.6 mmol) in THF (Sure/Seal: 4 ml/mmol) was added dropwise to the mixture. The mixture was stirred at 0° C. for 15 min, then MeI (3.3 eq.) was added. The mixture was allowed to warm to room temperature and stirred at this temperature for 18 hours. Water was added and the mixture was extracted with CH ₂ Cl ₂ and ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The title compound was obtained by preparative TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 98:2 and petroleum ether/ethyl acetate 3:2) as a yellow oil (16% yield).

LC/MS result [M+H] ⁺ : 500.40

¹ H NMR (CDCl ₃ ): δ 0.30 (4H, m, 2xCH ₂ ), 1.32 (6H, s, 2xCH ₃ ), 2.13 (2H, m, CH ₂ ), 3.11 (1H , m, CH), 3.96 (3H, s, CH ₃ ), 4.29 (2H, s, CH ₂ ), 4.53 (2H, m, CH ₂ ), 7.07 (2H, m, CH-arom), 7.34 (1H, t, CH-arom), 7.84 (1H, s, CH-arom).

-

Example 92 : 3-(4-(3-(2-chloro-3-(2-morpholinoethoxy)phenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1- yl)-1-methylcyclobutan-1-ol ( syn -configuration)

1.) 3-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)- 1-methylcyclobutan-1-ol ( syn/anti -blend)

method C , from 3-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(bromomethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl) -1-methylcyclobutan-1-ol ( syn/anti -mixture) (0.30 mmol) and cyclopropanol as a colorless oil (28%).

LC/MS result [M+H] ⁺ : 574.3;

¹ H NMR (CDCl ₃ ): δ 0.58-0.24 (4H, m, 2xCH ₂ ), 1.49 (3H, s, CH ₃ ), 2.92-2.68 (4H, m, 2xCH ₂ ), 3.17-3.05 (1H, m, CH), 4.29 (2H, s, OCH ₂ ), 4.80-4.64 (1H, m, CH), 5.24 (2H , s, OCH ₂ ), 7.13-7.07 (1H, m, CH-arom), 7.44-7.28 (5H, m, 5xCH-arom), 7.52-7.46 (1H, m, CH-arom), 7.90 (1H, s, CH-arom).

2.) 2-chloro-3-(4-(cyclopropoxymethyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-3-yl )phenol ( syn/anti -blend)

O -debenzylation was achieved according to the procedure described for Example 91, step 2; starting from 3-(4-(3-(3-(benzyloxy)-2-chlorophenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1 -methylcyclobutan-1-ol ( syn/anti -mixture) (0.09 mmol) (reaction time 1 h). The crude material was obtained as a colorless oil in 52% yield.

LC/MS result [M+H] ⁺ : 484.3;

3.) 2-chloro-3-(4-(cyclopropoxymethyl)-5-(1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-3-yl )phenol ( syn/anti -mixture) (0.045 mmol) and K ₂ CO ₃ (3.0 eq.) were suspended in dry DMF (Sure/Seal; 1 ml). N- (2-chloroethyl)morpholine hydrochloride (1.2 eq) was added and the mixture was stirred at 50° C. for 2.5 h. The mixture was partitioned between water and CH ₂ Cl ₂ , the combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The title compound was isolated from prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) (14% yield).

LC/MS result [M+H] ⁺ : 597.3;

¹ H NMR (CDCl ₃ ): δ 0.30 (4H, m, 2xCH ₂ ), 2.64 (4H, m, 2xCH ₂ ), 2.80 (4H, m, 2xCH ₂ ), 2.89 (2H , t, CH ₂ ), 3.10 (1H, m, CH), 3.73 (4H, m, 2xCH ₂ ), 4.24 (2H, t, CH ₂ ), 4.27 (2H, s, CH ₂ ), 4.72 (1H, m, CH), 7.08 (2H, m, CH-arom), 7.31 (1H, t, CH-arom), 7.89 (1H, s , CH-arom.).

-

Example 93 : Methyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-3-(2-hydroxypyridin-3-yl)-1,2 -oxazole-4-carboxylate

Methyl 5-(1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-methoxypyridin-3-yl)isoxazole-4-carboxylate (synthesized analogously to Example 21 , using 1-hydrazinyl-2-methylpropan-2-ol instead of ( R )-1-hydrazinylpropan-2-ol; 0.025 mmol) and sodium iodide (3.0 eq.) were stirred together in acetonitrile (0.150 ml) . Chlorotrimethylsilane (3.0 eq.) was added dropwise to this solution. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate. The organic phase was washed with water and saturated aq. NaHCO ₃ and dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a pale yellow oil (82%).

LC/MS result [M+H] ⁺ : 433.8;

¹ H NMR (CDCl ₃ ): δ 1.24 (6H, s, 2xCH ₃ ), 3.67 (3H, s, CH ₃ ), 4.30 (2H, s, CH ₂ ), 6.43 (1H , td, CH-arom), 7.48 (1H, dd, CH-arom), 7.85 (1H, dd, CH-arom), 8.06 (1H, s, CH-arom) .

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Example 94 : ( 2R )-1-(4-(3-(2-chloro-6-fluorophenyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2- ol

1. The hydroxyl group of the alcohol fragment ethyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl} -1,2-oxazole-4-carboxylate ( Example 12 ) was protected with TBS according to method A, "Total O-silylation" described below;

2. The ethyloxazole-4-carboxylate group was saponified according to the procedure described as the first step in "Synthesis of 4-acylisoxazoles" above;

3. Decarboxylation of the obtained oxazole-4-carboxylic acid was carried out in accordance with Adv. Synth. cat . 2013 , 355 , 790 (Table 3, position 15) using catalytic Cu(I) oxide and TMEDA in NMP at 140°C while removing the silyl protecting group to give the title compound upon purification with prep. TLC (eluent: petroleum ether/ethyl acetate 1:1) in 15% yield.

LC/MS result [M+H] ⁺ : 389.8;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 4.24 (1H, dd, CH), 4.44-4.31 (2H, m, CH ₂ ), 6, 62 (1H, s, CH-arom), 7.14 (1H, td, CH-arom), 7.46-7.31 (2H, m, 2xCH-arom), 8.04 (1H, s, CH-arom.).

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Example 95 : 1-{4-[3-(2-Chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1- yl}( ^2-2H )propan-2-ol (racemic)

To a stirred solution of Example 66 (0.25 mmol) in CH ₂ Cl ₂ (1.5 ml) was added Dess-Martin periodinan (3.5 eq.). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding aq. Na ₂ S ₂ O ₃ and was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl] -5-(trifluoromethyl)-1H-pyrazol-1-yl}propan-2-one (41%).

This propanone was dissolved in THF (10 ml/mmol) and cooled to 0°C. NaBD ₄ (1.1 eq) was added and the mixture was stirred at 0° C. for 1 h. The mixture was quenched with water and partitioned between CH ₂ Cl ₂ and water. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The title compound was purified by preparative TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5) and isolated in 65% yield.

LC/MS result [M+H] ⁺ : 435.1;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, s, CH ₃ ), 3.14 (3H, s, OCH ₃ ), 3.24 (1H, s, OH), 4.19 (2H, s, CH ₂ ), 4.31 (2H, q, CH ₂ ), 7.15 (1H, td, CH-arom.), 7.35 (1H, d, CH-arom.), 7.49- 7.38 (1H, m, CH-arom), 7.91 (1H, s, CH-arom).

-

Example 96 : ( 2S )-1-{4-[3-(2-chlorophenyl)-4-(oxolan-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}propan-2-ol (as a mixture of diastereomers)

Starting from methyl-( 2S )-3-(2-chlorophenyl)-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate ( Example 22 ), the alcohol group was protected with tert -butyldimethylsilyl (cf. "General Procedures for O -silylation" below, method A), methylisoxazole-4-carboxylate was reduced using LiAlH ₄ (cf. the general procedure as the first step described above in "Synthesis 4-alkoxymethylisoxazoles") and oxidized with Dess-Martin periodinane to give the corresponding isoxazol-4-aldehyde (64%; cf. the first step described above for Example 95 ). The Grignard reagent was prepared from 3-chloropropan-1-ol and MeMgBr (1.0 eq., 1 M in THF) in THF at 0°C followed by the addition of Mg (2.0 eq.) and 1,2-dibromoethane (0 1 eq.) and stirring at reflux for 20 minutes. After cooling to room temperature, the solution was separated from the rest of the magnesium and added directly to ( 2S )-5-(1-(2-(( tert -butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazole-4- yl)-3-(2-chlorophenyl)isoxazole-4-carbaldehyde in THF to give 1-(5-(1-(( 2S )-2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl )-1H-pyrazol-4-yl)-3-(2-chlorophenyl)isoxazol-4-yl)butan-1,4-diol in 60% yield. Cyclization of the butane-1,4-diol moiety into the corresponding tetrahydrofuran ring was achieved with mesyl chloride in THF and triethylamine at reflux in 31% yield. Final deprotection with HCl/MeOH (3.0 M) (described below as step 2 in "Cycloaddition Reaction") provided the title compound as a mixture of diastereomers in 31% yield.

LC/MS result [M+H] ⁺ : 442.3;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 1.69-1.39 (4H, m, 2xCH ₂ ), 3.66-3.47 (2H, m, CH ₂ ), 4.22 (1H, dd, OCH ₂ ), 4.44-4.29 (2H, m, CH ₂ ), 4.65 (1H, t, CH), 7.55-7.32 ( 4H, m, 4xCH-arom), 7.83 (1H, s, CH-arom).

Alternative route to pyrazolylisoxazoles

Synthesis of 2-(dimethylamino)methylene)-oxobutanoates

A) ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate

To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (18.5 g, 77.3 mmol) in toluene (30.0 ml) at 0°C was added (dimethoxymethyl)dimethylamine (9.21 g, 77 .3 mmol). The reaction mixture was stirred at room temperature for approx. 3 hours until complete consumption of ethyl 4,4,4-trifluoro-3-oxobutanoate. Toluene was removed under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (15 g, yield: 81%).

LC/MS result [M+H] ⁺ : 240.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, t, CH ₃ ), 2.90 (3H, br., NCH ₃ ), 3.32 (3H, br., NCH ₃ ), 4.22 (2H, q, OCH ₂ ), 7.68 (1H, s, CH).

B) methyl 2-((dimethylamino)methylene)-3-oxobutanoate or ethyl 2-((dimethylamino)methylene)-3-oxobutanoate

Methyl or ethyl acetoacetate (20 mmol) was dissolved in N,N -dimethylformamide, dimethyl acetal (3.0 eq.) and the mixture was heated by microwave to 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the crude material (brown oil) was dissolved in a small volume of ethyl acetate and crystallized with petroleum ether to give the product as a brown solid (53-62%).

Methyl ether :

LC/MS result [M+H] ⁺ : 172.0;

¹ H NMR (CDCl ₃ ): δ 2.32 (3H, s, CH ₃ ), 3.04 (6H, br., 2xNCH ₃ ), 3.75 (3H, s, CH ₃ ), 7.70 ( 1H, s, CH).

Ethyl ether :

LC/MS result [M+H] ⁺ : 186.0;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, t, CH ₃ ), 2.32 (3H, s, CH ₃ ), 3.03 (6H, br., 2xNCH ₃ ), 4.23 ( 2H, q, OCH ₂ ), 7.66 (1H, s, CH).

Formation of pyrazole building blocks from 2-(dimethylamino)methylene)oxobutanoates

To a solution of either ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate, or methyl or ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (10.0 mmol) in EtOH (5 ml/mmol) was added N,N -diisopropylethylamine (3.0 eq.) and the appropriate hydrazinyl alcohol (usually as hydrochloride; 1.1 eq.). The reaction mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and ethyl acetate, the combined organic layers were washed with brine and dried over MgSO ₄ , filtered and concentrated under reduced pressure.

-

Using ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate and ( R )-1-hydrazinylpropan-2-ol hydrochloride: The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3:1) to give ethyl ( R )-1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (82% yield);

LC/MS result [M+H] ⁺ : 267.0;

¹ H NMR (CDCl ₃ ): δ 1.27 (3H, d, CH ₃ ), 1.36 (3H, t, CH ₃ ), 3.00 (1H, d, OH), 4.31-4, 17 (2H, m, CH ₂ ), 4.34 (2H, q, CH ₂ ), 7.98 (1H, s, CH-arom).

-

Using ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate and 4-hydrazinyl-2-methylbutan-2-ol: crude ethyl 1-(3-hydroxy-3-methylbutyl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate was obtained as an orange oil (79%);

LC/MS result [M+H] ⁺ : 295.3;

¹ H NMR (CDCl ₃ ): δ 1.29 (6H, s, 2xCH ₃ ), 1.35 (3H, t, CH ₃ ), 2.09-1.97 (2H, m, CH ₂ ), 4 .32 (2H, q, OCH ₂ ), 4.55-4.46 (2H, m, CH ₂ ), 7.93 (1H, s, CH-arom).

-

Using ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate and 3-hydrazinyl-1-methylcyclobutanol ( syn/anti -mixture): The residue was purified by silica gel column chromatography (eluent : petroleum ether/ethyl acetate 5:1) to give ethyl 1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn/anti -mixture) as a yellow oil ( yield 9%);

LC/MS result [M+H] ⁺ : 293.3;

¹ H NMR (CDCl ₃ , mixture of diastereomers=isomers 1 and 2): δ 1.34 (6H, t, CH _{3 Isomer1+2} ), 1.46 (3H, s, CH _{3 Isomer2} ), 1.50 (3H , s, CH _{3 Isomer1} ), 2.88-2.55 (8H, m, CH _{2 Isomer1 + 2} ), 4.31 (2H, t, CH _{2 Isomer2} ), 4.32 (2H, t, CH _{2 Isomer1} ), 4.75-4.65 (1H, m, CH _Isomer2 ), 5.28-5.17 (1H, m, CH _Isomer1 ), 7.93 (1H, s, pyrazole-H _Isomer2 ), 7 .97 (1H, s, pyrazole-H _Isomer1 ).

-

Using ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate and ( S )-1-hydrazinylpropan-2-ol: crude ethyl-( S )-1-(2-hydroxypropyl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate was obtained in 35% yield;

LC/MS result [M+H] ⁺ : 267.0;

-

Using methyl 2-((dimethylamino)methylene)-3-oxobutanoate and 3-hydrazinyl-1-methylcyclobutanol ( syn/anti -mixture): The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1:1 ) to give methyl 1-(3-hydroxy-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn -configuration) (39%; the second fraction provided the same amount of anti -diastereomer).

LC/MS result [M+H] ⁺ : 225.1;

¹ H NMR (CDCl ₃ ): δ 1.52 (3H, s, CH ₃ ), 2.53 (3H, s, CH ₃ ), 2.56 (4H, m, 2xCH ₂ ), 2.82 (3H , s, CH ₃ ), 4.46 (1H, m, CH), 7.91 (1H, s, CH-arom).

-

Using ethyl 2-((dimethylamino)methylene)-3-oxobutanoate and 4-hydrazinyl-2-methylbutan-2-ol: The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1:1) to give ethyl 1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazole-4-carboxylate as a reddish oil (92%).

LC/MS result [M+H] ⁺ : 241.1;

¹ H NMR (CDCl ₃ ): δ 1.27 (6H, s, 2xCH ₃ ), 3.90 (3H, t, CH ₃ ), 2.02-1.93 (2H, m, CH ₂ ), 2 .55 (3H, s, CH ₃ ), 4.34-4.17 (4H, m, 2xCH ₂ ), 7.84 (1H, s, CH-arom).

General Methods O -silylation :

A) To a solution of ethyl 1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate 4 (2.67 g, 10.0 mmol) ( R - or S -configuration) in CH ₂ Cl ₂ (20.0 ml) was added imidazole (1.02 g, 15.0 mmol), DMAP (122 mg, 1.0 mmol) and then tert -butyldimethylsilyl chloride (1.95 g, 13.0 mmol in CH ₂ Cl ₂ , 5.0 ml) at 0°C. The resulting solution was stirred at room temperature for 18 hours. The reaction was quenched with saturated aq. NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined organic phases were washed with 0.1 M aq. HCl and dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

one.

Starting from ( R )-alcohol, ethyl-( R )-1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (84%) is obtained.

LC/MS result [M+H] ⁺ : 381.1;

¹ H NMR (CDCl ₃ ): δ -0.21 (3H, s, CH ₃ ), -0.03 (3H, s, CH ₃ ), 0.80 (9H, s, 3xCH ₃ ), 1.19 (3H, d, CH ₃ ), 1.35 (3H, t, CH ₃ ), 4.40-4.25 (4H, m, CH ₂ and OCH ₂ ), 7.94 (1H, s, CH- arom.).

2.

Starting from ( S )-alcohol, ethyl-( S )-1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (55%) is obtained.

B) To a stirred mixture of either ethyl 1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn/anti -mixture) or methyl 1-(3-hydroxy -3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn -configuration) (3.0 mmol) and N, N -diisopropylethylamine (3.0 eq.) in CH ₂ Cl ₂ (5 ml / mmol) was added tert -butyldimethylsilyl triflate (1.5 eq.) slowly at 0°C. The reaction mixture was stirred at room temperature for 3 h and then diluted with water and extracted with CH ₂ Cl ₂ . The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated.

-

Using ethyl 1-(3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn -configuration): The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 50:1 to 20:1) to give ethyl 1-(3-(( tert -butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a brown oil; separation of syn- and anti -diastereomers can be achieved at this level; combined yield 84%.

¹ H NMR (CDCl ₃ , diastereomer 1): δ -0.01 (6H, s, 2xCH ₃ ), 0.77 (9H, s, tBu), 1.13 (3H, t, CH ₃ ), 1, 34 (3H, s, CH ₃ ), 2.53 (4H, m, CH ₂ ), 4.19 (2H, q, CH ₂ ), 5.03 (1H, m, CH), 7.82 (1H , s, CH-arom.)

¹ H NMR (CDCl ₃ , diastereomer 2): δ -0.02 (6H, s, 2xCH ₃ ), 0.79 (9H, s, tBu), 1.13 (3H, t, CH ₃ ), 1, 34 (3H, s, CH ₃ ), 2.53 (4H, m, CH ₂ ), 4.19 (2H, q, CH ₂ ), 5.03 (1H, m, CH), 7.80 (1H , s, CH-arom.)

-

Using methyl 1-(3-hydroxy-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn -configuration): The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 8: 1) to obtain methyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn -configuration) (38%).

LC/MS result [M+H]+: 339.1;

¹ H NMR (CDCl ₃ ): δ 0.11 (6H, 2, 2xCH ₃ ), 0.89 (9H, s, 3xCH ₃ ), 1.46 (3H, s, CH ₃ ), 2.50 (3H , s, CH ₃ ), 2.59-2.51 (2H, m, CH ₂ ), 2.90-2.76 (2H, m, CH ₂ ), 3.81 (3H, s, OCH ₃ ) , 4.33-4.17 (1H, m, CH), 7.86 (1H, s, CH-arom).

C) ethyl 1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate or ethyl 1-(3-hydroxy-3-methylbutyl)-5-methyl-1H- pyrazole-4-carboxylate (4 mmol) was dissolved in bis(trimethylsilyl)amine (10 ml) and chlorotrimethylsilane (1.0 eq.) was added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with CH ₂ Cl ₂ and washed with water and saturated aq. _NH4Cl . The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure.

-

Using ethyl 1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate: The crude product was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5) and again ptlc (eluent: petroleum ether/ethyl acetate 4:1) to give ethyl 1-(3-methyl-3-((trimethylsilyl)oxy)butyl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as an orange oil (75%).

LC/MS result [M+H] ⁺ : 367.3;

¹ H NMR (CDCl ₃ ): δ 0.13 (9H, s, 3xCH ₃ ), 1.29 (6H, s, 2xCH ₃ ), 1.35 (3H, t, CH ₃ ), 2.02-1 .92 (2H, m, CH ₂ ), 4.32 (2H, q, OCH ₂ ), 4.50-4.40 (2H, m, CH ₂ ), 7.92 (1H, s, CH-aro .).

-

Using ethyl 1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazole-4-carboxylate: If the reaction is not complete, another eq. chlorotrimethylsilane may be added and stirring continued at reflux. The crude material ethyl 5-methyl-1-(3-methyl-3-((trimethylsilyl)oxy)butyl)-1H-pyrazole-4-carboxylate was obtained as a reddish oil (88%) and used as such in the next reaction step .

LC/MS result [M+H] ⁺ : 313.1;

-

Using 1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.1 mmol; which was prepared from ethyl-1-(3-hydroxy-3-methylbutyl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxylate by saponification with 4 N aq NaOH in THF (room temperature, 18 h) was isolated in 48% yield as a brown oil upon acidification with 6 N aq HCl and extraction CH ₂ Cl ₂ ) the mixture was stirred at 60°C in a sealed tube for 18 h, after which more chlorotrimethylsilane was added, stirring was continued for another day until the conversion was completed; the crude product of 1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (84%) was used as such in the next step.

LC/MS result [M+H] ⁺ : 339.0;

Condensation of alkylpyrazole-4-carboxylates with heteroarylmethyl anions

To a solution of 2-methylpyrimidine/2-methylpyrazine/4-methylpyrimidine (1.2 eq.) in THF (1 ml/mmol) was added LiHMDS (1.0 M in THF; 2.2 eq.) at -10°C in N ₂ atmosphere. The mixture was stirred at this temperature for 30 minutes and the appropriate alkylpyrazole-4-carboxylate (1.0 eq. in THF, 1 ml/mmol) was added and the mixture was stirred at room temperature for 2-18 hours (based on progress control). reactions). The reaction was quenched with ice water and the resulting mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo.

-

Using ethyl-( R )-1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (10 mmol) and 2-methylpyrimidine: The residue was purified with chromatography on silica gel to give ( R )-1-(1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-2- yl)ethan-1-one (yield: 77%);

LC/MS result [M+H] ⁺ : 429.0.

-

Using ethyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn -configuration) (0.3 mmol) and 2- methylpyrimidine: The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) gave 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4- yl)-2-(pyrimidin-2-yl)ethanone ( syn -configuration) as a yellow oil (46%).

LC/MS result [M+H] ⁺ : 455.1;

¹ H NMR (CDCl ₃ ): δ -0.01 (6H, s, 2xCH ₃ ), 0.80 (9H, s, tBu), 1.35 (3H, s, CH ₃ ), 2.53 (4H , m, CH ₂ ), 4.38 (2H, s, CH ₂ ), 5.02 (1H, m, CH), 6.89 (1H, t, CH-arom.), 7.65 (1H, d, CH-arom), 7.82 (1H, s, CH-arom), 8.60 (1H, d, CH-arom).

-

Using methyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn configuration) (1.6 mmol) and 2-methylpyrimidine: The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:2) gives 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazol-4-yl) -2-(pyrimidin-2-yl)ethan-1-one ( syn -configuration) as a colorless solid (17%).

LC/MS result [M+H] ⁺ : 401.1.

-

Using ethyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn -configuration) (0.3 mmol) and 2- methylpyrazine: The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazole-4- yl)-2-(pyrazin-2-yl)ethan-1-one ( syn -configuration) (48%).

-

Using ethyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn -configuration) (0.3 mmol) and 4- methylpyrimidine: The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazole-4- yl)-2-(pyrimidin-4-yl)ethan-1-one ( syn -configuration) (63%).

The corresponding anti -diastereomer was appropriately prepared from the corresponding anti -structural element.

-

Using methyl 1-(3-(( tert -butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn -configuration) (0.3 mmol) and 4-methylpyrimidine: The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) gives 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-methyl-1H-pyrazol-4-yl) -2-(pyrimidin-4-yl)ethan-1-one ( syn -configuration) (76%).

-

Using methyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4-carboxylate ( syn -configuration) (0.3 mmol) and 2-methylpyrazine: the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) gives 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-methyl-1H-pyrazol-4-yl) -2-(pyrazin-2-yl)ethan-1-one ( syn -configuration) (79%).

-

Using ethyl-( R )-1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.3 mmol) and 4-methylpyrimidine: The residue was purified with the help of prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1-{1-[(2 R )-2-[( tert -butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazole- 4-yl}-2-(pyrimidin-4-yl)ethan-1-one (74%).

-

Using ethyl 5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazole-4-carboxylate (0.9 mmol) and 2-methylpyrimidine: The residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) gives 1-(5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol-4-yl)- 2-(pyrimidin-2-yl)ethan-1-one as a yellowish oil (31%).

LC/MS result [M+H] ⁺ : 361.1;

¹ H NMR (CDCl ₃ ): δ 0.11 (9H, s, 3xCH ₃ ), 1.26 (6H, 2, 2xCH ₃ ), 1.95-1.80 (2H, m, CH ₂ ), 2 .55 (3H, s, CH ₃ ), 4.24-4.09 (2H, m, CH ₂ ), 4.43 (2H, s, CH ₂ ), 7.16 (1H, t, CH-arom .), 7.90 (1H, s, CH-arom), 8.70 (2H, d, 2xCH-arom).

-

Using ethyl 1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.33 mmol) and 2-methylpyrimidine: The residue was purified with Rev. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) to give crude 1-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazole-4- yl)-2-(pyrimidin-2-yl)ethan-1-one as an orange oil (quant).

LC/MS result [M+H] ⁺ : 415.4;

¹ H NMR (CDCl ₃ ): δ 0.14 (9H, s, 3xCH ₃ ), 1.31 (6H, s, 2xCH ₃ ), 2.09-1.93 (2H, m, CH ₂ ), 4 .47-4.39 (2H, m, CH ₂ ), 4.49 (2H, s, CH ₂ ), 7.00 (1H, t, CH-arom), 7.76 (1H, s, CH -arom.), 8.71 (2H, d, 2xCH-arom.).

Synthesis of 3-(pyrazol-4-yl)-3-oxopropanoates

и

and

ethyl 3-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropanoate , syn- and anti -configuration, synthesized from ethyl 1-(3-(( tert -butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn/anti -mixture)

1.) To a solution of ethyl 1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate ( syn/anti -mixture) (1.84 mmol) in THF (3 ml) was added aq. NaOH (1 M, 4 ml) and the mixture was stirred at room temperature for 72 h. The mixture was poured into 5% aq. citric acid, which was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ and concentrated to dryness. Separation of the diastereomers was not possible at this stage, so a crude brown oil of 1-{3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (94%) was used for further transformations.

LC/MS result [M+H] ⁺ : 379.1;

2.) Solution of crude 1-{3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.73 mmol) and 1,1'- carbonyldiimidazole (1.5 eq.; CDI) in THF (Sure/Seal, 7 ml) was stirred at room temperature for 18 h to form the activated carboxylic acid derivative. 1-[(3-Ethoxy-3-oxopropanoyl)oxy]magnesio-3-ethylpropanedioate (1.2 eq., synthesis described below) was added and the solution was stirred at 55° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO ₄ and concentrated to dryness. Purification and separation of the diastereomers was carried out using silica gel column chromatography (eluent: petroleum ether/CH ₂ Cl ₂ /ethyl acetate 8:2:1). Syn - and anti -isomers (relative configuration in the cyclobutanol fragment) )-3-oxopropanoate was obtained as yellow oils (each 29-36%).

Syn -configuration:

LC/MS result [M+H] ⁺ : 449.4;

¹ H-NMR ( syn -keto isomer) (CDCl ₃ , J [Hz]): δ = 7.92 (s, 1H pyrazole-H), 4.62-4.48 (m, 1H, CH), 4.20 (q, 2H, 3J=7.1, OCH ₂ CH ₃ ), 3.80 (s, 2H, CH ₂ ), 2.92-2.86 (m, 2H, CH ₂ ), 2, 61-2.54 (m, 2H, CH ₂ ), 1.45 (s, 3H, CH ₃ ), 1.26 (t, 3H, 3J=7.1, OCH ₂ CH ₃ ), 0.89 ( s, 9H, C(CH ₃ ) ₃ ), 0.11 (s, 6H, CH ₃ ).

Anti -configuration:

LC/MS result [M+H] ⁺ : 449.3;

¹ H-NMR ( anti -keto isomer) (CDCl ₃ , J [Hz]): δ = 7.90 (s, 1H pyrazole-H), 5.21-5.08 (m, 1H, CH), 4.20 (q, 2H, 3J= 7.1, OCH ₂ CH ₃ ), 3.80 (s, 2H, CH ₂ ), 2.75-2.56 (m, 4H, CH ₂ ), 1, 46 (s, 3H, CH ₃ ), 1.26 (t, 3H, 3J= 7.1, OCH ₂ CH ₃ ), 0.91 (s, 9H, C(CH ₃ ) ₃ ), 0.12 ( s, 6H, CH ₃ ).

ethyl 3-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropanoate

Crude 1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.96 mmol; synthesis described above under General Procedures for O -silylation "") was treated with CDI and 1-[(3-ethoxy-3-oxopropanoyl)oxy]magnesio-3-ethylpropanedioate according to the procedure described above to give the title compound as an orange oil (crude, quant; partial O -desilylation).

LC/MS result [M+H] ⁺ : 409.1.

methyl-3-{1-[(2 S )-2-[( tert -butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-3-oxopropanoate

Ethyl ( S )-1-(2-(( tert -butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.8 mmol) was first saponified to give an acid which was then treated CDI and 1-[(3-methoxy-3-oxopropanoyl)oxy]magnesio-3-methylpropanedioate according to the procedures described above to give the crude title compound (quant.).

Synthesis of 1-[(3-ethoxy-3-oxopropanoyl)oxy]magnesio-3-ethylpropanedioate according to J. Am. soc. Chem . 2011 , 133 , 326: To a solution of 2.00 g (11.8 mmol) of potassium salt of ethyl malonate in 10 ml of water was added 1.19 mg (5.88 mmol) of MgCl ₂ × 6H ₂ O and the solution was stirred at room temperature for 30 minutes. 60 ml iPrOH was added to precipitate potassium chloride. The suspension was stirred for 1 h at room temperature, then filtered and washed with iPrOH (2×5 ml). The filtrate was evaporated to dryness to give 1-[(3-ethoxy-3-oxopropanoyl)oxy]magnesio-3-ethylpropanedioate as a white solid (2.00 g). 1-[(3-Methoxy-3-oxopropanoyl)oxy]magnesio-3-methylpropanedioate was synthesized, respectively.

Cycloaddition reaction

Step 1 : To a stirred solution of the appropriate pyrazol-4-yl-2-(heteroaryl)ethan-1-one or alkyl-3-(pyrazol-4-yl)-3-oxopropanoate (1.0 eq) and triethylamine (TEA) ; 4.0 eq.) in DMF (Sure/Seal; 5 ml/mmol) was added an appropriately substituted N -hydroxybenzimidoyl chloride (3.0 eq.). The mixture was stirred at the same temperature for 18 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. After purification, as specifically described below for each product, O -desilylation was performed.

Step 2 : A solution of the purified silyl-protected product (1.0 eq.) in HCl/MeOH (3.0 M; 15 ml/mmol) was stirred at room temperature for 3 hours. The pH was adjusted to approximately 8 with the addition of aq. NaOH (1.0 M) and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure.

Example 97 : ( R )-1-(4-(3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazole -1-yl)propan-2-ol

Step 1 : ( R )-1-(1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-2-yl) ethan-1-one (4.0 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at room temperature; the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 6:1) to give ( R )-5-(1-(2-(( tert -butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)- 1H-pyrazol-4-yl)-3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)isoxazole as a yellow oil (24%);

LC/MS result [M+H] ⁺ : 582.0;

Step 2, General Cycloaddition Procedure : The mixture after Step 2 was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 2:1) to give the title compound (54%).

LC/MS result [M+H] ⁺ : 467.7;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 4.24 (1H, dd, CH), 4.52-4.32 (2H, m, CH ₂ ), 7, 05 (1H, t, CH-arom), 7.10 (1H, td, CH-arom), 7.29 (1H, t, CH-arom), 7.44-7.34 (1H, m, CH-arom), 8.03 (1H, s, CH-arom), 8.48 (2H, d, 2xCH-arom).

Example 98 : 3-(4-(3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl )-1-methylcyclobutanol ( syn -configuration)

Step 1 : 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-2-yl)ethanone ( syn configuration) (0.11 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 5-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazole-4- yl)-3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)isoxazole ( syn -configuration) as a yellow oil (75%);

LC/MS result [M+H] ⁺ : 608;

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) gave the title compound as a colorless solid (12%).

LC/MS result [M+H] ⁺ : 494.2;

¹ H NMR (CDCl ₃ ): δ 1.58 (3H, s, CH ₃ ), 2.94-2.68 (4H, m, 2xCH ₂ ), 4.78-4.65 (1H, m, CH ), 7.04 (1H, t, CH-arom), 7.10 (1H, td, CH-arom), 7.31-7.28 (1H, m, CH-arom), 7, 44-7.32 (1H, m, CH-arom), 7.61 (1H, s, CH-arom), 8.47 (1H, s, CH-arom), 8.49 (1H, s, CH-arom.).

Example 99 : 3-(4-(3-(2-chlorophenyl)-4-(pyrimidin-2-yl)isoxazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-1-methylcyclobutan- 1-ol ( syn -configuration)

Alternative stage 1 :

To a solution of 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yl)ethan-1- she ( syn -configuration) (0.09 mmol) in DMF (3 ml) was added NaH (5.0 eq.) at 0°C. The ice bath was removed and the mixture was stirred at room temperature for 20 minutes. Then 2-chloro- N -hydroxybenzimidoyl chloride (3.0 eq.) was added and the mixture was stirred at 60° C. for 3 hours. The reaction was quenched with saturated aq. NH ₄ Cl and extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (eluent: petroleum ether/ethyl acetate 2:1) to give 5-(1-(3-(( tert -butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazole-4 -yl)-3-(2-chlorophenyl)-4-(pyrimidin-2-yl)isoxazole ( syn configuration) (41%);

LC/MS result [M+H] ⁺ : 536.5;

¹ H NMR (CDCl ₃ ): δ -0.08 (6H, s, 2xCH ₃ ), 0.88 (9H, s, tBu), 1.45 (3H, s, CH ₃ ), 2.52 (2H , m, CH ₂ ), 2.56 (3H, s, CH ₃ ), 2.78 (2H, m, CH ₂ ), 4.25 (1H, m, CH), 7.37 (4H, m, CH-arom), 7.86 (1H, s, CH-arom), 8.60 (1H, d, CH-arom), 8.78 (1H, d, CH-arom), 8, 82 (1H, d, CH-arom).

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) gave the title compound as a colorless solid (32%).

LC/MS result [M+H] ⁺ : 422.3;

¹ H NMR (CDCl ₃ ): δ 1.47 (3H, s, CH ₃ ), 2.55 (3H, s, CH ₃ ), 2.79-2.66 (4H, m, 2xCH ₂ ), 4 .55 (1H, quint, CH), 7.11 (1H, t, CH-arom), 7.43-7.32 (3H, m, 3xCH-arom), 7.64-7.57 ( 1H, m, CH-arom), 8.18 (1H, s, CH-arom), 8.62 (2H, d, 2xCH).

Example 100 : 3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H- pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert- Butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrazin-2-yl)ethane -1-one ( syn -configuration) (0.11 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chloro-6-fluorophenyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3- methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrazine ( syn configuration) (75%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (49%).

LC/MS result [M+H] ⁺ : 494.3;

¹ H NMR (CDCl ₃ ): δ 1.48 (3H, s, CH ₃ ), 2.94-2.67 (4H, m, 2xCH ₂ ), 4.68 (1H, quint, CH), 7, 12 (1H, td, CH-arom), 7.30 (1H, d, CH-arom), 7.49-7.36 (1H, m, CH-arom), 7.94 (1H, s, CH-arom), 8.26 (1H, br., CH-arom), 8.49-8.34 (2H, m, 2xCH-arom).

Example 101 :

3-{4-[3-(2-chlorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert- Butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrazin-2-yl)ethane -1-one ( syn -configuration) (0.22 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chlorophenyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5 -(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrazine ( syn configuration) (20%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (15%).

LC/MS result [M+H] ⁺ : 476.2;

¹ H NMR (CDCl ₃ ): δ 1.44 (3H, s, CH ₃ ), 2.81-2.64 (4H, m, 2xCH ₂ ), 4.63 (1H, quint, CH), 7, 54-7.45 (1H, m, CH-arom), 7.66-7.54 (2H, m, 2xCH-arom), 7.70 (1H, s, CH-arom), 7, 98 (1H, d, CH-arom), 8.50 (1H, s, CH-arom), 9.10 (1H, s, CH-arom).

Example 102 :

3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-2-yl)ethanone ( syn -configuration) (0.33 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chlorophenyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5 -(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrimidine ( syn -configuration) (27%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (8%).

LC/MS result [M+H] ⁺ : 476.2;

¹ H NMR (CDCl ₃ ): δ 1.48 (3H, s, CH ₃ ), 2.92-2.70 (4H, m, CH ₂ ), 4.70 (1H, quint, CH), 7, 08 (1H, t, CH-arom), 7.45-7.34 (3H, m, 3xCH-arom), 7.67-7.58 (1H, m, CH-arom), 8, 08 (1H, s, CH-arom), 8.54 (2H, d, 2xCH-arom).

Example 103 : 3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H- pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-2-yl)ethanone ( syn configuration) (0.38 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; the reaction was carried out at 65°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 7:3 and again 4:1) to give 2-[3-(2-chloro-3-methoxyphenyl)-5-{1-[3-[( tert -butyldimethylsilyl) hydroxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrimidine ( syn -configuration) as an orange oil (14%);

LC/MS result [M+H] ⁺ : 620.1;

¹ H NMR (CDCl ₃ ): δ 0.13 (6H, s, 2xCH ₃ ), 0.91 (9H, s, 3xCH ₃ ), 1.27 (3H, s, CH ₃ ), 2.69-2 .51 (2H, m, CH ₂ ), 2.84-2.70 (2H, m, CH ₂ ), 3.89 (3H, s, OCH ₃ ), 7.42-7.01 (4H, m , 4xCH-arom), 8.03 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Alternative Step 2 : A solution of the purified silyl-protected product (1.0 eq, 0.06 mmol) in THF (Sure/Seal, 0.5 ml) was treated with tetrabutylammonium fluoride (1 M in THF; 1.1 eq) at room temperature for 2 hours. The solvent was removed under reduced pressure and the title product was obtained from preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:2 and again 3:2) as a pale yellow oil (16%).

LC/MS result [M+H] ⁺ : 506.0;

¹ H NMR (CDCl ₃ ): δ 1.48 (3H, s, CH ₃ ), 2.91-2.70 (4H, m, 2xCH ₂ ), 3.91 (3H, s, OCH ₃ ), 4 .70 (1H, quint, CH), 7.10-7.03 (2H, m, 2xCH-arom), 7.26-7.22 (1H, m, CH-arom), 7.37 ( 1H, t, CH-arom), 8.08 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 104 and 105 :

3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-1-methylcyclobutan-1-ol, syn -configuration and anti -configuration

Step 1 : 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-4-yl)ethane -1-one ( syn- and anti -configuration, respectively) (0.17 mmol each) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 60°C; crude 4-[3-(2-chloro-6-fluorophenyl)-5-{1-[3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazole-4- yl}-1,2-oxazol-4-yl]pyrimidine ( syn- and anti -configuration, respectively) (quant) was directly used in step 2;

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compounds:

Example 104 , blue -configuration (9%)

LC/MS result [M+H] ⁺ : 493.9;

¹ H NMR (CDCl ₃ ): δ 1.50 (3H, s, CH ₃ ), 2.97-2.71 (4H, m, 2xCH ₂ ), 4.70 (1H, quint, CH), 6, 92 (1H, d, CH-arom), 7.15 (1H, td, CH-arom), 7.34 (1H, d, CH-arom), 7.52-7.41 (1H, m, CH-arom), 7.98 (1H, s, CH-arom), 8.56 (1H, br., CH-arom), 9.04 (1H, s, CH-arom) .

Example 105 , anti -configuration (11%)

LC/MS result [M+H] ⁺ : 494.0;

¹ H NMR (CDCl ₃ ): δ 1.56 (3H, s, CH ₃ ), 2.74-2.60 (2H, m, CH ₂ ), 2.91-2.80 (2H, m, CH ₂ ), 5.25 (1H, quint, CH), 6.98 (1H, d, CH-arom), 7.16 (1H, t, CH-arom), 7.34 (1H, d, CH-arom.), 7.53-7.42 (1H, m, CH-arom.), 7.94 (1H, s, CH-arom.), 8.56 (1H, d, CH-arom. ), 9.04 (1H, s, CH-arom).

Example 106 :

3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-4-yl)ethane -1-one ( syn -configuration) (0.18 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 4-[3-(2-chlorophenyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5 -(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrimidine ( syn -configuration) (48%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (20%).

LC/MS result [M+H] ⁺ : 476.2;

¹ H NMR (CDCl ₃ ): δ 1.50 (3H, s, CH ₃ ), 2.97-2.72 (4H, m, 2xCH ₂ ), 4.70 (1H, quint, CH), 6, 97-6.81 (1H, m, CH-arom), 7.56-7.40 (3H, m, 3xCH-arom), 7.60 (1H, d, CH-arom), 8, 00 (1H, s, CH-arom), 8.54 (1H, br., CH-arom), 9.07 (1H, s, CH-arom).

Example 107 :

3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1- methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert -Butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-4-yl)ethan-1 -one ( syn -configuration) (0.13 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 4-[3-(2-chlorophenyl)-5-{5-methyl-1-[3-[( tert -butyldimethylsilyl)oxy]-3- methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrimidine ( syn -configuration) (60%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (25%).

LC/MS result [M+H] ⁺ : 422.3;

¹ H NMR (CDCl ₃ ): δ 1.47 (3H, s, CH ₃ ), 2.49 (3H, s, CH ₃ ), 2.80-2.65 (4H, m, CH ₂ ), 3 .51 (1H, br., OH), 4.51 (1H, quint, CH), 6.95 (1H, dd, CH-arom), 7.49-7.36 (3H, m, 3xCH- arom.), 7.60-7.49 (1H, m, CH-arom.), 7.97 (1H, s, CH-arom.), 8.54 (1H, d, CH-arom.), 9.16 (1H, d, CH-arom).

Example 108 :

3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert -Butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-4-yl)ethan-1 -one ( syn -configuration) (0.12 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 4-[3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-[( tert -butyldimethylsilyl)oxy ]-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrimidine ( syn -configuration) (72%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (13%).

LC/MS result [M+H] ⁺ : 440.3;

¹ H NMR (CDCl ₃ ): δ 1.47 (3H, s, CH ₃ ), 2.49 (3H, s, CH ₃ ), 2.81-2.66 (4H, m, CH ₂ ), 3 .46 (1H, br, OH), 4.52 (1H, quint, CH), 7.05 (1H, dd, CH-arom), 7.11 (1H, td, CH-arom), 7.30 (1H, dt, CH-arom), 7.47-7.37 (1H, m, CH) 7.93 (1H, s, CH-arom), 8.57 (1H, d, CH-arom), 9.12 (1H, d, CH-arom).

Example 109 :

3-{4-[3-(2-chlorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-1- methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-methyl-1H-pyrazol-4-yl)-2-(pyrazin-2-yl)ethan-1 -one ( syn -configuration) (0.47 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chlorophenyl)-5-{5-methyl-1-[3-[( tert -butyldimethylsilyl)oxy]-3- methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrazine ( syn configuration) (25%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (32%).

LC/MS result [M+H] ⁺ : 422.3;

¹ H NMR (CDCl ₃ ): δ 1.46 (3H, s, CH ₃ ), 2.49 (3H, s, CH ₃ ), 2.81-2.61 (4H, m, CH ₂ ), 3 .51 (1H, br, OH), 4.50 (1H, quint, CH), 7.45-7.33 (3H, m, 3xCH-arom), 7.62-7.51 (1H, m, CH-arom), 7.81 (1H, d, CH-arom), 8.28 (1H, s, CH-arom), 8.43 (1H, d, CH-arom), 8.55 (1H, t, CH-arom).

Example 110 :

3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-methyl-1H-pyrazol-4-yl)-2-(pyrazin-2-yl)ethan-1 -one ( syn -configuration) (0.15 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-[( tert -butyldimethylsilyl)oxy ]-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrazine ( syn configuration) (19%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (13%).

LC/MS result [M+H] ⁺ : 440.3;

¹ H NMR (CDCl ₃ ): δ 1.46 (3H, s, CH ₃ ), 2.51 (3H, s, CH ₃ ), 2.82-2.68 (4H, m, CH ₂ ), 4 .52 (1H, quint, CH), 7.10 (1H, td, CH-arom), 7.30-7.27 (1H, m, CH-arom), 7.45-7.34 ( 1H, m, CH-arom), 7.88 (1H, s, CH-arom), 8.36 (1H, s, CH-arom), 8.44 (1H, s, CH-arom). ), 8.55 (1H, s, CH-arom).

Example 111 :

3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn -configuration)

Step 1 : 1-(1-(3-(( tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yl)ethan-1 -one ( syn -configuration) (0.15 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 50°C; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[3-[( tert -butyldimethylsilyl)oxy ]-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2-oxazol-4-yl]pyrimidine ( syn -configuration) (36%);

LC/MS result [M+H] ⁺ : 554.2;

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (21%).

LC/MS result [M+H] ⁺ : 440.3;

¹ H NMR (CDCl ₃ ): δ 1.47 (3H, s, CH ₃ ), 2.62 (3H, s, CH ₃ ), 3.01-2.70 (4H, m, CH ₂ ), 4 .58 (1H, quint, CH), 7.16-7.04 (2H, m, 2xCH-arom), 7.32-7.20 (1H, m, CH-arom), 7.43- 7.32 (1H, m, CH-arom), 8.47 (1H, br, CH-arom), 8.59 (2H, d, 2xCH-arom).

Example 112 :

3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn -configuration)

Alternative Step 1 as described for Example 99 (reaction with NaH) 2-(pyrimidin-2-yl)ethan-1-one ( syn -configuration) (0.25 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; 2-[3-(2-chloro-3-methoxyphenyl)-5-{5-methyl-1-[3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl]-1H-pyrazol-4-yl}- 1,2-oxazol-4-yl]pyrimidine ( syn -configuration) (36%) was used in the next step as crude material without purification by silica gel chromatography;

LC/MS result [M+H] ⁺ : 566.5.

Alternative Step 2 as described for Example 103 ( O -desilylation with TBAF) : The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /MeOH/NH ₃ 100:10:1 and again eluent: petroleum ether/ ethyl acetate 4:1) to give the title compound (17%).

LC/MS result [M+H] ⁺ : 452.4;

¹ H NMR (CDCl ₃ ): δ 1.45 (3H, s, CH ₃ ), 2.52 (3H, s, CH ₃ ), 2.72 (4H, d, 2xCH ₂ ), 3.89 (3H , s, OCH ₃ ), 4.50 (1H, quint, CH), 7.03 (1H, dd, CH-arom), 7.08 (1H, t, CH-arom), 7.22 ( 1H, dd, CH-arom), 7.34 (1H, t, CH-arom), 8.11 (1H, s, CH-arom), 8.59 (2H, d, CH-arom). ).

Example 113 :

(2 R )-1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH ) : yl)-2-(pyrimidin-2-yl)ethan-1-one (1.0 mmol) and 2-methoxy- N -hydroxybenzimidoyl chloride; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-(5-{1-[( 2R )-2-[( t- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H -pyrazol-4-yl}-3-(2-methoxyphenyl)-1,2-oxazol-4-yl)pyrimidine (34%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (86%).

LC/MS result [M+H] ⁺ : 445.9;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 3.29 (3H, s, OCH ₃ ), 4.19 (1H, dd, CH), 4.46-4, 26 (2H, m, _CH2 ), 6.81 (1H, d, CH-arom), 7.15-7.05 (2H, m, 2xCH-arom), 7.43 (1H, td, CH-arom), 7.69 (1H, dd, CH-arom), 8.05 (1H, s, CH-arom), 8.60 (2H, d, 2xCH-arom).

Example 114 :

1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol

To a stirred solution of Example 113 (0.25 mmol) in CH ₂ Cl ₂ (1.5 ml) was added Dess-Martin periodinan (3.5 eq.). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding aq. Na ₂ S ₂ O ₃ and was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated aq. NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3:1) to give 1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazole -5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}propan-2-one as a colorless solid (61%).

LC/MS result [M+H] ⁺ : 443.8;

¹ H NMR (CDCl ₃ ): δ 2.18 (3H, s, CH ₃ ), 3.29 (3H, s, OCH ₃ ), 5.11 (2H, s, CH ₂ ), 6.81 (1H , d, CH-arom), 7.14-7.09 (2H, m, 2xCH-arom), 7.48-7.39 (1H, m, CH-arom), 7.69 (1H , dd, CH-arom), 8.12 (1H, s, CH-arom), 8.61 (2H, d, 2xCH-arom).

To a solution of this propanone derivative (0.15 mmol) in THF (3 ml) was added dropwise MeMgBr (1 M in THF; 10 eq.) at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding saturated aq. NH ₄ Cl and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 5:1) to give the title compound as a colorless solid. (ten%).

LC/MS result [M+H] ⁺ : 459.8;

¹ H NMR (CDCl ₃ ): δ 1.23 (6H, d, 2xCH ₃ ), 3.30 (3H, s, OCH ₃ ), 4.26 (2H, s, CH ₂ ), 6.82 (1H , d, CH-arom), 7.15-7.05 (2H, m, 2xCH-arom), 7.44 (1H, td, CH-arom), 7.68 (1H, dd, CH -arom), 8.06 (1H, s, CH-arom), 8.58 (2H, d, 2xCH-arom).

Example 115 :

(2 R )-1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH ) : yl)-2-(pyrimidin-4-yl)ethan-1-one (1.6 mmol) and 2-methoxy- N -hydroxybenzimidoyl chloride; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 4-(5-{1-[( 2R )-2-[( t- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H -pyrazol-4-yl}-3-(2-methoxyphenyl)-1,2-oxazol-4-yl)pyrimidine (55%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (88%).

LC/MS result [M+H] ⁺ : 446.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 3.38 (3H, s, OCH ₃ ), 4.21 (1H, dd, CH), 4.45-4, 27 (2H, m, _CH2 ), 6.89 (1H, d, CH-arom), 6.95 (1H, d, CH-arom), 7.13 (1H, td, CH-arom). ), 7.50 (1H, td, CH-arom), 7.62 (1H, dd, CH-arom), 7.99 (1H, s, CH-arom), 8.53 (1H, br, CH-arom), 9.10 (1H, s, CH-arom).

Example 116 :

1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol

The 2-propanol derivative Example 115 (0.25 mmol) was converted to the corresponding propanone and then to the corresponding 2-methyl-2-propanol according to the procedures described for Example 114 . Oxidation to 1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl }propane-2-it was achieved with a yield of 83%;

LC/MS result [M+H] ⁺ : 443.8;

¹ H NMR (CDCl ₃ ): δ 1.26 (6H, s, 2⃰CH ₃ ), 2.24 (3H, s, CH ₃ ), 2.95 (1H, s, OH), 3.42 (3H, s, CH ₃ ), 5.17 (2H, s, CH ₂ ), 6.92 (1H, d, CH-arom), 7.08 (1H, d, CH-arom), 7.15 ( 1H, t, CH-arom), 7.53 (1H, t, CH-arom), 7.63 (1H, d, CH-arom), 8.03 (1H, s, CH-arom). ), 8.55 (1H, d, CH-arom), 9.14 (1H, s, CH-arom);

Grignard treatment provided the title compound in 10% yield.

LC/MS result [M+H] ⁺ : 459.9;

¹ H NMR (CDCl ₃ ): δ 1.24 (6H, s, 2xCH ₃ ), 3.42 (3H, s, OCH ₃ ), 4.28 (2H, s, CH ₂ ), 6.92 (1H , d, CH-arom), 7.01 (1H, d, CH-arom), 7.15 (1H, td, CH-arom), 7.53 (1H, td, CH-arom) , 7.62 (1H, dd, CH-arom), 8.01 (1H, s, CH-arom), 8.55 (1H, d, CH-arom), 9.08 (1H, s , CH-arom.).

Example 117 :

(2 R )-1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH ) : yl)-2-(pyrimidin-2-yl)ethan-1-one (3.0 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-(5-{1-[( 2R )-2-[( t- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H -pyrazol-4-yl}-3-(2-chloro-3-methoxyphenyl)-1,2-oxazol-4-yl)pyrimidine (83%);

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (77%).

LC/MS result [M+H] ⁺ : 479.8;

¹ H NMR (CDCl ₃ ): δ 1.30 (3H, d, CH ₃ ), 3.85 (3H, s, OCH ₃ ), 4.21 (1H, dd, CH), 4.44-4, 27 (2H, m, CH ₂ ), 6.97-6.89 (2H, m, 2xCH-arom), 7.09 (1H, t, CH-arom), 7.57-7.52 ( 1H, m, CH-arom), 8.04 (1H, s, CH-arom), 8.55 (1H, s, CH-arom).

Example 118 :

1-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylpropan-2-ol

The 2-propanol derivative Example 97 (1.6 mmol) was converted to the corresponding propanone and then to the corresponding 2-methyl-2-propanol according to the procedures described for Example 114 . Oxidation to 1-(4-(3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl) propane-2-it was achieved with a yield of 67%;

LC/MS result [M+H] ⁺ : 465.7;

¹ H NMR (CDCl ₃ ): δ 2.20 (3H, s, CH ₃ ), 5.14 (2H, s, CH ₂ ), 7.15-7.02 (2H, m, CH-arom) , 7.31-7.27 (1H, m, CH-arom), 7.45-7.33 (1H, m, CH-arom), 8.12 (1H, s, CH-arom) , 8.49 (2H, d, 2xCH-arom).

Grignard treatment provided the title compound in 50% yield.

LC/MS result [M+H] ⁺ : 481.8;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, 2xCH ₃ ), 4.30 (2H, s, CH ₂ ), 7.09-7.00 (1H, m, CH-arom) , 7.15-7.09 (1H, m, CH-arom), 7.31-7.24 (1H, m, CH-arom), 7.44-7.34 (1H, m, CH -arom.), 8.04 (1H, br., CH-arom.), 8.48-8.42 (2H, m, 2xCH-arom.).

Example 119 :

(2 R )-1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol

Step 1 : ( R )-1-(1-(2-(( tert- butyldimethylsilyl)oxy)propyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(pyrimidin-4-yl) ethan-1-one (2.0 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; THF was used instead of DMF; the reaction was carried out at 50°C; crude 4-(5-{1-[( 2R )-2-[( tert -butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-3-(2-chloro- 3-Methoxyphenyl)-1,2-oxazol-4-yl)pyrimidine (quant) was directly used for O -desilylation;

Step 2, General Cycloaddition Procedure : The mixture after step 2 was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (83%).

LC/MS result [M+H] ⁺ : 479.8;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.88 (3H, s, OCH ₃ ), 4.23 (1H, dd, CH), 4.49-4, 29 (2H, m, CH ₂ ), 6.86 (1H, d, CH-arom), 7.04-6.93 (2H, m, CH-arom), 7.49 (1H, d, CH-arom), 8.00 (1H, s, CH-arom), 8.52 (1H, br., CH-arom), 9.06 (1H, s, CH-arom).

Example 120 :

1-{4-[3-(2-Chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylpropan-2-ol

The 2-propanol derivative Example 119 (0.25 mmol) was converted to the corresponding propanone and then to the corresponding 2-methyl-2-propanol according to the procedures described for Example 114 . Oxidation to 1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole -1-yl}propan-2-one was achieved in 76% yield, Grignard workup provided the title compound in 16% yield.

LC/MS result [M+H] ⁺ : 494.2;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, 2xCH ₃ ), 3.88 (3H, s, OCH ₃ ), 4.29 (2H, s, CH ₂ ), 6.85 (1H , d, CH-arom), 7.03-6.95 (2H, m, 2xCH-arom), 7.49 (1H, d, CH-arom), 8.01 (1H, s, CH -arom), 8.52 (1H, d, CH-arom), 9.02 (1H, s, CH-arom).

Example 121 :

4-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl) -2-(pyrimidin-2-yl)ethan-1-one (0.6 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; reaction time: 20 h, reaction conditions led to simultaneous O -desilylation; the residue was purified with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give the title compound as a yellow oil (11%).

LC/MS result [M+H] ⁺ : 508.3;

¹ H NMR (CDCl ₃ ): δ 1.31 (6H, s, 2xCH ₃ ), 2.19-2.10 (2H, m, CH ₂ ), 3.91 (3H, s, OCH ₃ ), 4 .56-4.44 (2H, m, _CH2 ), 7.09-7.02 (2H, m, 2xCH-arom), 7.37 (1H, t, CH-arom), 8.02 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 122 :

4-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl) -2-(pyrimidin-2-yl)ethan-1-one (0.41 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; reaction time: 20 h, reaction conditions led to simultaneous O -desilylation; the residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5 and again eluent: petroleum ether/ethyl acetate 1:1) to give the title compound as a pale yellow oil (9%).

LC/MS result [M+H] ⁺ : 478.4;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.18-2.09 (2H, m, CH ₂ ), 4.55-4.46 (2H, m, CH ₂ ), 7.07 (1H, t, CH-arom), 7.43-7.36 (3H, m, 3xCH-arom), 7.66-7.59 (1H, m, CH-arom .), 8.01 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 123 :

4-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl) -2-(pyrimidin-2-yl)ethan-1-one (0.41 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; reaction time: 18 h, reaction conditions led to simultaneous O -desilylation; the residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5 and again eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound as a colorless oil (27%).

LC/MS result [M+H] ⁺ : 496.0;

¹ H NMR (CDCl ₃ ): δ 1.33 (6H, s, 2xCH ₃ ), 2.21-2.11 (2H, m, CH ₂ ), 4.57-4.47 (2H, m, CH ₂ ), 7.04 (1H, t, CH-arom), 7.10 (1H, td, CH-arom), 7.30-7.26 (1H, m, CH-arom), 7 .44-7.33 (1H, m, CH-arom), 8.00 (1H, s, CH-arom), 8.48 (2H, d, 2xCH-arom).

Example 124 :

4-{4-[3-(2-Chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol-4-yl)-2 -(pyrimidin-2-yl)ethan-1-one (0.16 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; reaction time: 3 h, reaction conditions led to simultaneous O -desilylation; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound as a yellowish solid (24%).

LC/MS result [M+H] ⁺ : 454.0;

¹ H NMR (CDCl ₃ ): δ 1.28 (6H, s, 2xCH ₃ ), 2.07-1.98 (2H, m, CH ₂ ), 2.56 (3H, s, CH ₃ ), 3 .89 (3H, s, OCH ₃ ), 4.34-4.22 (2H, m, CH ₂ ), 7.03 (1H, dd, CH-arom), 7.08 (1H, t, CH -arom), 7.22 (1H, dd, CH-arom), 7.34 (1H, t, CH-arom), 8.08 (1H, s, CH-arom), 8.59 (2H, d, 2xCH-arom).

Example 125 :

4-{4-[3-(2,6-dichloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole-1 -yl}-2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol-4-yl)-2 -(pyrimidin-2-yl)ethan-1-one (0.04 mmol) and 2,6-dichloro-3-methoxy- N -hydroxybenzimidoyl chloride; reaction time: 3 h, reaction conditions led to simultaneous O -desilylation; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound as a reddish oil (15%).

LC/MS result [M+H] ⁺ : 488.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (6H, s, 2xCH ₃ ), 2.08-2.00 (2H, m, CH ₂ ), 2.62 (3H, s, CH ₃ ), 3 .93 (3H, s, OCH ₃ ), 4.37-4.24 (2H, m, CH ₂ ), 6.96 (1H, d, CH-arom), 7.04 (1H, t, CH -arom), 7.33 (1H, d, CH-arom), 8.25 (1H, s, CH-arom), 8.55 (2H, d, 2xCH-arom).

Example 126 :

4-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol-4-yl)-2 -(pyrimidin-2-yl)ethan-1-one (0.1 mmol) and 2-chloro- N -hydroxybenzimidoyl chloride; reaction time: 1.5 h, reaction conditions led to simultaneous O -desilylation; the residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5 and again eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound (12%).

LC/MS result [M+H] ⁺ : 424.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (6H, s, 2xCH ₃ ), 2.08-2.00 (2H, m, CH ₂ ), 2.58 (3H, s, CH ₃ ), 4 .33-4.26 (2H, m, _CH2 ), 7.10 (1H, t, 2xCH-arom), 7.42-7.31 (3H, m, 3xCH-arom), 7.65 -7.56 (1H, m, CH-arom), 8.11 (1H, s, CH-arom), 8.60 (2H, d, 2xCH-arom).

Example 127 :

4-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol-4-yl)-2 -(pyrimidin-2-yl)ethan-1-one (0.1 mmol) and 2-chloro-6-fluoro- N -hydroxybenzimidoyl chloride; reaction time: 1.5 h, reaction conditions led to simultaneous O -desilylation; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound as an orange oil (30%).

LC/MS result [M+H] ⁺ : 442.0;

¹ H NMR (CDCl ₃ ): δ 1.30 (6H, s, 2xCH ₃ ), 2.04 (2H, t, CH ₂ ), 2.60 (3H, s, CH ₃ ), 4.30 (2H , t, CH ₂ ), 7.14-7.02 (2H, m, 2xCH-arom), 7.25-7.19 (1H, m, CH-arom), 7.41-7.30 (1H, m, CH-arom), 8.22 (1H, s, CH-arom), 8.56 (2H, d, 2xCH-arom).

Example 128 :

4-(4-{3-[3-(benzyloxy)-2-chlorophenyl]-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazole -1-yl)-2-methylbutan-2-ol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl) -2-(pyrimidin-2-yl)ethan-1-one (2.5 mmol) and 3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride; reaction time: 3 h, reaction conditions led to simultaneous O -desilylation; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound as an orange oil (12%).

LC/MS result [M+H] ⁺ : 584.1;

¹ H NMR (CDCl ₃ ): δ 1.25 (6H, s, 2xCH ₃ ), 2.15-2.02 (2H, m, CH ₂ ), 4.51-4.38 (2H, m, CH ₂ ), 5.11 (2H, s, OCH ₂ ), 7.07-6.97 (2H, m, 2xCH-arom), 7.42-7.16 (7H, m, 7xCH-arom) , 7.96 (1H, s, CH-arom), 8.45 (2H, d, 2xCH-arom).

Example 129 :

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol

The benzyloxy derivative Example 128 (0.9 mmol) was dissolved in isopropanol/ethyl acetate (1:1; 6 ml) and Pd/C (10%; 0.3 eq.) was added. The atmosphere inside the flask was replaced with hydrogen and the mixture was stirred at room temperature for 18 hours. Pd/C was filtered through Celite, the filtrate was concentrated to dryness under reduced pressure and then under vacuum to give the title compound as a pale brownish solid (83%) .

LC/MS result [M+H] ⁺ : 494.0;

¹ H NMR (CDCl ₃ ): δ 1.66 (6H, s, 2xCH ₃ ), 2.54-2.44 (2H, m, CH ₂ ), 4.90-4.81 (2H, m, CH ₂ ), 7.41 (1H, t, CH-arom), 7.55-7.45 (2H, m, 2xCH-arom), 7.64 (1H, q, CH-arom), 8 .40-8.32 (2H, m, CH-arom and OH), 8.87 (2H, d, 2xCH-arom).

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2-oxazole -3-yl}phenol

Alternative Step 1 as described for Example 99 (reaction with NaH) : 1-(5-methyl-1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol-4-yl)-2 -(pyrimidin-2-yl)ethan-1-one (0.75 mmol) and 3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride; reaction time: 1.5 h, reaction conditions led to simultaneous O -desilylation; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give 4-(4-{3-[3-(benzyloxy)-2-chlorophenyl]-4-(pyrimidine- 2-yl)-1,2-oxazol-5-yl}-5-methyl-1H-pyrazol-1-yl)-2-methylbutan-2-ol in 22% yield;

LC/MS result [M+H] ⁺ : 530.1;

¹ H NMR (CDCl ₃ ): δ 1.46 (6H, s, 2xCH ₃ ), 2.21 (2H, m, CH ₂ ), 2.74 (3H, s, CH ₃ ), 4.46 (2H , m, CH ₂ ), 5.33 (2H, s, CH ₂ ), 7.23 (1H, d, CH-arom.), 7.38-7.62 (8H, m, CH-arom.) , 8.27 (1H, s, CH-arom), 8.76 (2H, d, CH-arom).

The benzyloxy derivative was O -debenzylated according to the protocol described for Example 129 to give the title compound as a pale yellowish solid (96% crude).

LC/MS result [M+H] ⁺ : 440.0;

¹ H NMR (CDCl ₃ ): δ 1.29 (6H, s, 2xCH ₃ ), 2.35 (2H, m, CH ₂ ), 2.58 (3H, s, CH ₃ ), 4.28 (2H , m, CH ₂ ), 5.33 (2H, s, CH ₂ ), 7.06-7.17 (4H, m, CH-arom.), 8.09 (1H, s, CH-arom.) , 8.62 (2H, d, CH-arom).

methyl-( S )-3-(2-chloro-3-hydroxyphenyl)-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate. Alternative Step 1 as described for Example 99 (reaction with NaH ) -4-yl}-3-oxopropanoate (1.5 mmol) and 3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride; reaction time: 1.5 h; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give methyl 3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[( 2S )-2-[( tert -butyldimethylsilyl)oxy]propyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazol-4-carboxylate in 27% yield.

The benzyloxy derivative was O -debenzylated according to the protocol described for Example 129 to give the title compound as a pale yellowish solid (96% crude).

The title compound was synthesized by final O -desilylation according to the alternative step 2 described above in Example 103 (using TBAF) (15%): The residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5).

Example 130 :

3-(4-(3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1 -ol ( syn -configuration)

Stage 1 : ethyl 3-(1-{3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropanoate ( syn -configuration) (0.25 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; the reaction was carried out at 65°C; the residue was purified by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate 9:1) to give ethyl 3-(2-chloro-3-methoxyphenyl)-5-{1-[3-[( tert -butyldimethylsilyl )oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate ( syn -configuration) (72%);

LC/MS result [M+H] ⁺ : 614.2;

¹ H NMR (CDCl ₃ ): δ 0.13 (6H, s, 2xCH ₃ ), 0.91 (9H, s, 3xCH ₃ ), 0.99 (3H, t, CH ₃ ), 1.26 (3H , s, CH ₃ ), 2.68-2.54 (2H, m, CH ₂ ), 3.03-2.91 (2H, m, CH ₂ ), 3.95 (3H, s, OCH ₃ ) , 4.08 (2H, q, OCH ₂ ), 4.56 (1H, quint, CH), 7.14-7.05 (2H, m, 2xCH-arom), 7.34 (1H, t, CH-arom), 7.96 (1H, s, CH-arom).

Step 2 : The conversion of the ethyl ester group to the cyclopropoxymethyl moiety was achieved according to the general procedures for the synthesis of 4-alkoxymethylisoxazoles described above:

- LiAlH ₄ reduction of ethyl 3-(2-chloro-3-methoxyphenyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazole- 4-yl}-1,2-oxazole-4-carboxylate ( syn -configuration) (0.18 mmol) to give [5-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}- 5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-chloro-3-methoxyphenyl)-1,2-oxazol-4-yl]methanol ( syn -configuration) as a pale yellow oil ( quantity).

LC/MS result [M+H] ⁺ : 572.1;

¹ H NMR (CDCl ₃ ): δ 0.13 (6H, s, 2xCH ₃ ), 0.92 (9H, s, tBu), 1.48 (3H, s, CH ₃ ), 1.72 (1H, s, OH), 1.85 (2H, m, CH ₂ ), 3.88 (2H, s, CH ₂ ), 3.96 (3H, s, CH ₃ ), 4.42 (2H, s, CH ₂ ), 4.56 (1H, s, CH), 7.09 (2H, m, CH-arom.) 7.36 (1H, t, CH-arom.), 8.94 (1H, s, CH -arom.).

- Synthesis of bromomethylisoxazole according to method A (Et ₂ O, 20 min) to give 4-(bromomethyl)-5-(1-{3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl )-1H-pyrazol-4-yl)-3-(2-chloro-3-methoxyphenyl)-1,2-oxazole ( syn -configuration) as yellow oil (quant.)

LC/MS result [M+H] ⁺ : 634.0;

- Synthesis of 4-cyclopropoxymethylisoxazole according to method C (using cyclopropanol) to give 5-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazole-4 -yl)-3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)-1,2-oxazole ( syn -configuration) as a pale yellow oil (35%).

LC/MS result [M+H] ⁺ : 612.2;

¹ H NMR (CDCl ₃ ): δ 0.13 (6H, s, 2xCH ₃ ), 0.35-0.24 (4H, m, 2xCH ₂ ), 0.91 (9H, s, 3xCH ₃ ), 1 .48 (3H, s, CH ₃ ), 2.68-2.56 (2H, m, CH ₂ ), 3.03-2.88 (2H, m, CH ₂ ), 3.16-3.05 (1H, m, CH), 3.97 (3H, s, OCH ₃ ), 4.28 (2H, s, OCH ₂ ), 4.57 (1H, quint, CH), 7.39-6.82 (3H, m, 3xCH-arom), 7.86 (1H, s, CH-arom).

Step 3 : The title compound was synthesized by final O -desilylation according to the alternative step 2 described above in Example 103 (using TBAF): The residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5 and again eluent: petroleum ether/ethyl acetate 4:1) to give the title compound as an orange oil (12%).

LC/MS result [M+H] ⁺ : 498.0;

¹ H NMR (CDCl ₃ ): δ 0.30 (4H, m, 2xCH ₂ ), 1.50 (3H, s, CH ₃ ), 2.80 (4H, m, 2xCH ₂ ), 3.11 (1H , m, CH), 3.97 (3H, s, CH ₃ ), 4.27 (2H, s, CH ₂ ), 4.72 (1H, quint, CH), 7.08 (2H, d, CH -arom), 7.34 (1H, t, CH-arom), 7.89 (1H, s, CH-arom).

Example 131 : ethyl 3-(2-chloro-3-methoxyphenyl)-5-{1-[3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( syn -configuration)

Intermediate after Step 1, Example 130 1H-pyrazol-4-yl}-1,2-oxazol-4-carboxylate ( syn -configuration) O -desilylated according to alternative step 2 described above in Example 103 (using TBAF): The residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5) gave the title compound as an orange oil (72%).

LC/MS result [M+H] ⁺ : 500.0;

¹ H NMR (CDCl ₃ ): δ 0.99 (3H, t, CH ₃ ), 1.49 (3H, s, CH ₃ ), 2.81 (4H, m, 2xCH ₂ ), 2.95 (3H , s, CH ₃ ), 4.08 (2H, q, CH ₂ ), 4.72 (1H, m, CH), 7.09 (2H, m, CH-arom.), 7.35 (1H, t, CH-arom), 8.00 (1H, s, CH-arom).

Example 132 : ethyl 3-(2-chloro-3-methoxyphenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2 -oxazole-4-carboxylate

Stage 1 : ethyl 3-(1-{3-methyl-3-[(trimethylsilyl)oxy]butyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropanoate (0.80 mmol) and 2-chloro-3-methoxy- N -hydroxybenzimidoyl chloride; the reaction was carried out at 65°C; reaction conditions led to simultaneous O -desilylation; the residue was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5) to give the title compound as an orange oil (19%);

LC/MS result [M+H] ⁺ : 502.0;

¹ H NMR (CDCl ₃ ): δ 1.00 (3H, t, CH ₃ ), 1.32 (6H, s, 2xCH ₃ ), 2.14 (2H, m, CH ₂ ), 3.95 (3H , s, CH ₃ ), 4.08 (2H, q, CH ₂ ), 4.52 (2H, m, CH ₂ ), 7.09 (2H, m, CH-arom.), 7.34 (1H , t, CH-arom), 7.97 (1H, s, CH-arom).

Building block for the synthesis of Examples 150 and 151 :

2-chloro-3-[4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazol-3-yl]phenol ( syn -configuration)

Stage 1 : ethyl 3-(1-{3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropanoate ( syn -configuration) (0.18 mmol) and 3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 65°C; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 100:1) to give ethyl 3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[3-[ ( tert -Butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-carboxylate ( syn -configuration) as a colorless oil (64%) ;

LC/MS result [M+H] ⁺ : 690.4;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.97 (s, 1H, pyrazole-H), 7.49-7.29 (m, 6H, benzyl-H), 7.11 (d , 2H, ³ J= 7.9, benzyl-H), 5.22 (s, 2H, CH ₂ ), 4.62-4.51 (m, 1H, CH), 4.08 (q, 2H, ³ J= 7.1, OCH ₂ CH ₃ ), 3.01-2.94 (m, 2H, CH ₂ ), 2.64-2.58 (m, 2H, CH ₂ ), 1.48 (s , 3H, CH ₃ ), 0.98 (t, 3H, ³ J= 7.1, OCH ₂ CH ₃ ), 0.92 (s, 9H, C(CH ₃ ) ₃ ), 0.13 (s, 6H, CH ₃ ).

Step 2 : The conversion of the ethyl ester group to the methoxymethyl moiety was achieved according to the general procedures for the synthesis of 4-alkoxymethylisoxazoles described above:

- LiAlH ₄ reduction of ethyl 3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H- pyrazol-4-yl}-1,2-oxazole-4-carboxylate ( syn configuration) (0.12 mmol) to give {3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[ 3-[( tert -Butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl}methanol ( syn -configuration) as colorless oils (83%).

LC/MS result [M+H]+: 648.4;

- Synthesis of methoxymethylisoxazole according to method A (MeI) to give 3-[3-(benzyloxy)-2-chlorophenyl]-4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]- 3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole ( syn -configuration) as a colorless oil (32%)

LC/MS result [M+H] ⁺ : 662.5;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.88 (s, 1H, pyrazole-H), 7.50-7.32 (m, 6H, benzyl-H), 7.11 (d , 2H, ³ J=8.0, benzyl-H), 5.22 (s, 2H, CH ₂ ), 4.63-4.52 (m, 1H, CH), 4.21 (s, 2H, CH ₂ ), 3.15 (s, 3H, OCH ₃ ), 3.00-2.93 (m, 2H, CH ₂ ), 2.65-2.59 (m, 2H, CH ₂ ), 1, 49 (s, 3H, CH ₃ ), 0.92 (s, 9H, C(CH ₃ ) ₃ ), 0.14 (s, 6H, CH ₃ ).

Step 3 : The title compound was synthesized by final O -debenzylation according to the protocol described for Example 129 to give the title compound as a colorless oil after purification by silica gel flash column chromatography (eluent: petroleum ether/ethyl acetate 7:3) (51%);

LC/MS result [M+H] ⁺ : 572.1.

Building block for the synthesis of Examples 152 and 153 :

2-chloro-3-[4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazol-3-yl]phenol ( anti -configuration)

Stage 1 : ethyl 3-(1-{3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl}-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropanoate ( anti -configuration) (0.28 mmol) and 3-(benzyloxy)-2-chloro- N -hydroxybenzimidoyl chloride; the reaction was carried out at 60°C; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 100:1) to give ethyl 3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[3-[ ( tert -Butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-carboxylate ( anti -configuration) as a colorless oil (83%) ;

LC/MS result [M+H] ⁺ : 690.4;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.96 (s, 1H, pyrazole-H), 7.49-7.29 (m, 6H, benzyl-H), 7.11 (d , 2H, ³ J= 8.2, benzyl-H), 5.22-5.17 (m, 3H, CH, CH ₂ ), 4.08 (q, 2H, ³ J= 7.1, OCH ₂ CH ₃ ), 2.81-2.74 (m, 2H, CH ₂ ), 2.68-2.61 (m, 2H, CH ₂ ), 1.52 (s, 3H, CH ₃ ), 0, 99 (t, 3H, ³ J= 7.1, OCH ₂ CH ₃ ), 0.93 (s, 9H, C(CH ₃ ) ₃ ), 0.14 (s, 6H, CH ₃ ).

Step 2 : The conversion of the ethyl ester group to the methoxymethyl moiety was achieved according to the general procedures for the synthesis of 4-alkoxymethylisoxazoles described above:

- LiAlH ₄ reduction of ethyl 3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[3-[( tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H- pyrazol-4-yl}-1,2-oxazole-4-carboxylate ( syn configuration) (0.23 mmol) to give {3-[3-(benzyloxy)-2-chlorophenyl]-5-{1-[ 3-[( tert -Butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazol-4-yl}methanol ( anti -configuration) as greyish oils (73%).

LC/MS result [M+H] ⁺ : 648.4;

- Synthesis of methoxymethylisoxazole according to method A (MeI) to give 3-[3-(benzyloxy)-2-chlorophenyl]-4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]- 3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole ( anti -configuration) as a colorless oil (37%)

LC/MS result [M+H] ⁺ : 662.3;

¹ H NMR (CDCl ₃ ): δ 0.14 (6H, s, 2xCH ₃ ), 0.93 (9H, s, 3xCH ₃ ), 1.51 (3H, s, CH ₃ ), 2.84-2 .53 (4H, m, 2xCH ₂ ), 3.15 (3H, s, OCH ₃ ), 4.20 (2H, s, OCH ₂ ), 5.22 (2H, s, OCH ₂ ), 7.18 -7.07 (2H, d, 2xCH-arom), 7.55-7.28 (6H, 6xCH-arom), 7.87 (1H, s, CH-arom).

Step 3 : The title compound was synthesized by final O -debenzylation according to the protocol described for Example 129 to give the title compound as a colorless oil after purification with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 7:3) (56%).

LC/MS result [M+H] ⁺ : 572.4.

Building block for the synthesis of Examples 154-160 :

3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)-2-chlorobenzoic acid

Step 1 : 1-{1-[( 2R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-2-(pyrimidin-4-yl )ethan-1-one (1.0 mmol) and methyl 2-chloro-3-(chloro(hydroxyimino)methyl)benzoate; the reaction was carried out at 60°C; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 100:1) to give methyl 3-(5-{1-[(2 R )-2-[( tert -butyldimethylsilyl)oxy ]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol-3-yl)-2-chlorobenzoate (43%);

Step 2 : The ester group was saponified in ethanol (8 ml/mmol) and aq. NaOH (2.0 M; 8 ml/mmol), and heated to 60°C for 1 h, and then acidified by adding aq. HCl (1.0 M). The resulting suspension was partitioned between CH ₂ Cl ₂ and water, the combined organic layers were dried over MgSO ₄ , the solvent was removed under reduced pressure to give the crude carboxylic acid, which was used as such for further transformations.

Building block for the synthesis of Examples 161-165 :

3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)-2-methoxybenzoic acid

Step 1 : 1-{1-[( 2R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-2-(pyrimidin-4-yl )ethan-1-one (1.0 mmol) and methyl-3-(chloro(hydroxyimino)methyl)-2-methoxybenzoate; the reaction was carried out at 60°C; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 100:1) to give methyl 3-(5-{1-[(2 R )-2-[( tert -butyldimethylsilyl)oxy ]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol-3-yl)-2-methoxybenzoate (37%);

Step 2 : The ester group was saponified in ethanol (8 ml/mmol) and aq. NaOH (2.0 M; 8 ml/mmol), and heated to 60°C for 1 h, and then acidified by adding aq. HCl (1.0 M). The resulting suspension was partitioned between CH ₂ Cl ₂ and water, the combined organic layers were dried over MgSO ₄ , the solvent was removed under reduced pressure to give the crude carboxylic acid, which was used as such for further transformations.

Building block for the synthesis of Examples 166 and 167 :

3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzoic acid

Step 1 : 1-{1-[( 2R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-2-(pyrimidin-4-yl )ethan-1-one (1.0 mmol) and methyl-3-(chloro(hydroxyimino)methyl)benzoate; the reaction was carried out at 60°C; the residue was purified by silica gel flash column chromatography (eluent: CH ₂ Cl ₂ /MeOH 100:1) to give methyl 3-(5-{1-[(2 R )-2-[( tert -butyldimethylsilyl)oxy ]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol-3-yl)benzoate (41%);

Step 2 : The ester group was saponified in ethanol (8 ml/mmol) and aq. NaOH (2.0 M; 8 ml/mmol), and heated to 60°C for 1 h, and then acidified by adding aq. HCl (1.0 M). The resulting suspension was partitioned between CH ₂ Cl ₂ and water, the combined organic layers were dried over MgSO ₄ , the solvent was removed under reduced pressure to give the crude carboxylic acid, which was used as such for further transformations.

General procedure for aminoalkylation of phenolic groups

A) The appropriate phenol derivative (1.0 eq) was dissolved in DMF (15 ml/mmol) and K ₂ CO ₃ (3.5 eq) was added followed by the appropriate aminoalkyl halide (2.0 eq). The mixture was stirred at the same temperature for 18 hours and then diluted with CH ₂ Cl ₂ and extracted with water and brine. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5).

B) Mitsunobu reaction: The appropriate phenol derivative (1.0 eq.), PPh ₃ (1.5 eq.) and the appropriate alcohol (1.5 eq.) were dissolved in THF (15 ml/mmol) and the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (DIAD; 1.5 eq.) was added and the mixture was stirred at 0° C. for 30 minutes at room temperature for the indicated time, and then diluted with CH ₂ Cl ₂ and extracted with water and brine. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified with prep. TLC on silica gel (eluent: CH ₂ Cl ₂ /MeOH 95:5).

Example 133 : 4-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5 -yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.09 mmol) and N- (2-chloroethyl)morpholine hydrochloride were used in Method A , reaction temperature 50°C to give the title compound as an orange oil (14 %).

LC/MS result [M+H] ⁺ : 607.5;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.19-2.09 (2H, m, CH ₂ ), 2.68-2.57 (4H, m, 2xCH ₂ ), 2.90-2.79 (2H, m, CH ₂ ), 3.78-3.65 (4H, m, 2xCH ₂ ), 4.24-4.16 (2H, m, CH ₂ ) , 4.56-4.44 (2H, m, CH ₂ ), 7.09-7.03 (2H, m, 2xCH-arom), 7.25-7.21 (1H, m, CH-arom .), 7.34 (1H, t, CH-arom), 8.01 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 134 : 4-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.09 mmol) and 2-chloro- N,N -dimethylethylamine were used in Method A , reaction temperature 50°C to give the title compound as a brownish oil (8 %).

LC/MS result [M+H] ⁺ : 565.5;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.19-2.09 (2H, m, CH ₂ ), 2.37 (6H, s, 2xCH ₃ ), 2 .82 (2H, t, CH ₂ ), 4.18 (2H, t, CH ₂ ), 4.56-4.45 (2H, m, CH ₂ ), 7.09-7.03 (2H, m , 2xCH-arom), 7.25-7.21 (1H, m, CH-arom), 7.34 (1H, t, CH-arom), 8.01 (1H, s, CH-arom .), 8.52 (2H, d, 2xCH-arom).

Example 135 : 4-[4-(3-{2-chloro-3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5 -yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.09 mmol) and 1-(2-chloroethyl)pyrrolidine were used in Method A , reaction temperature 50° C. to give the title compound as a brownish oil (5% ).

LC/MS result [M+H] ⁺ : 591.5;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 1.96-1.88 (6H, m, 3xCH ₂ ), 2.18-2.10 (2H, m, CH ₂ ), 3.01-2.89 (2H, m, CH ₂ ), 3.22-3.12 (2H, m, CH ₂ ), 4.39-4.29 (2H, m, CH ₂ ) , 4.54-4.46 (2H, m, CH ₂ ), 7.09-7.03 (2H, m, 2xCH-arom), 7.25-7.21 (1H, m, CH-arom .), 7.35 (1H, t, CH-arom), 8.00 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 136 4-[4-(3-{2-chloro-3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazole -5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.09 mmol) and 1-(2-chloroethyl)-4-methylpiperazine were used in Method A , reaction temperature 100° C. to give the title compound as a brownish oil (6%).

LC/MS result [M+H] ⁺ : 620.5;

¹ H NMR (CDCl ₃ ): δ 1.31 (6H, s, 2xCH ₃ ), 2.19-2.08 (2H, m, CH ₂ ), 2.31 (3H, s, CH ₃ ), 2 .55-2.45 (4H, m, 2xCH ₂ ), 2.70-2.64 (4H, m, 2xCH ₂ ), 2.85 (2H, t, CH ₂ ), 4.18 (2H, t , CH ₂ ), 4.55-4.46 (2H, m, CH ₂ ), 7.09-7.03 (2H, m, 2xCH-arom.) 7.25-7.21 (1H, m, CH-arom), 7.33 (1H, t, CH-arom), 8.01 (1H, s, CH-arom), 8.51 (2H, d, 2xCH-arom).

Example 137 : 4-[4-(3-{2-Chloro-3-[2-(diethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.09 mmol) and 2-chloro- N,N -diethylethylamine were used in Method A , reaction temperature 50°C to give the title compound as an orange oil (13 %).

LC/MS result [M+H] ⁺ : 593.5;

¹ H NMR (CDCl ₃ ): δ 1.38-1.29 (12H, m, 4xCH ₃ ), 2.19-2.08 (2H, m, CH ₂ ), 3.20-3.07 (4H , m, 2xCH ₂ ), 3.41-3.33 (2H, m, CH ₂ ), 4.59-4.46 (4H, m, 2xCH ₂ ), 7.11-7.04 (2H, m , 2xCH-arom), 7.26-7.21 (1H, m, CH-arom), 7.36 (1H, t, CH-arom), 8.00 (1H, s, CH-arom .), 8.53 (2H, d, 2xCH-arom).

Example 138 : 4-[2-(2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidine )-2-yl)-1,2-oxazol-3-yl}phenoxy)ethyl]thiomorpholine-1,1-dione

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.06 mmol) and 4-(2-hydroxyethyl)thiomorpholin-1,1-dione were used in method B (18 hours); additional cleaning with the second prep. TLC (eluent: petroleum ether/ethyl acetate 3:7) provided the title compound as a grayish oil (6%).

LC/MS result [M+H] ⁺ : 655.4;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.19-2.10 (2H, m, CH ₂ ), 3.11-2.99 (6H, m, 3xCH ₂ ), 3.27-3.15 (4H, m, 2xCH ₂ ), 4.23-4.14 (2H, m, CH ₂ ), 4.56-4.45 (2H, m, CH ₂ ) , 7.11-7.00 (2H, m, 2xCH-arom), 7.29-7.26 (1H, m, CH-arom), 7.36 (1H, t, CH-arom) , 8.01 (1H, s, CH-arom), 8.53 (2H, d, 2xCH-arom).

Example 139 : 4-(4-{3-[2-chloro-3-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}ethoxy)phenyl]-4-(pyrimidine-2- yl)-1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.08 mmol) and 6-(2-chloroethyl)-2-oxa-6-azaspiro[3,3]heptane were used in method A , reaction temperature 70°C to give the title compound as a brownish oil (15%).

LC/MS result [M+H] ⁺ : 619.5;

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.18-2.11 (2H, m, CH ₂ ), 2.83 (2H, t, CH ₂ ), 3 .52 (4H, s, 2xCH ₂ ), 4.06 (2H, t, CH ₂ ), 4.55-4.47 (2H, m, CH ₂ ), 4.71 (4H, s, 2xCH ₂ ) , 7.00 (1H, dd, CH-arom), 7.07 (1H, t, CH-arom), 7.23 (1H, dd, CH-arom), 7.33 (1H, t , CH-arom), 8.01 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 140 : 4-[4-(3-{2-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.2 mmol) and 3-dimethylamino-1-propyl chloride were used in method A , reaction temperature 60° C. to give the title compound as a yellow oil (49%) .

LC/MS result [M+H] ⁺ : 578.9;

¹ H NMR (CDCl ₃ ): δ 1.31 (6H, s, 2xCH ₃ ), 2.07-1.95 (2H, m, CH ₂ ), 2.18-2.08 (2H, m, CH ₂ ), 2.27 (6H, s, 2xCH ₃ ), 2.51 (2H, t, CH ₂ ), 4.11 (2H, t, CH ₂ ), 4.56-4.44 (2H, m , CH ₂ ), 7.10-7.02 (2H, m, 2xCH-arom.), 7.22 (1H, dd, CH-arom.), 7.33 (1H, t, CH-arom.) , 8.01 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 141 : 4-[3-(2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidine )-2-yl)-1,2-oxazol-3-yl}phenoxy)propyl]thiomorpholine-1,1-dione

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.06 mmol) and 4-(3-hydroxypropyl)thiomorpholin-1,1-dione were used in method B (2 h); the title compound was obtained as a yellow solid (6%).

LC/MS result [M+H] ⁺ : 669.2

¹ H NMR (CDCl ₃ ): δ 1.32 (6H, s, 2xCH ₃ ), 2.02-1.94 (2H, m, CH ₂ ), 2.18-2.10 (2H, m, CH ₂ ), 2.72 (2H, t, CH ₂ ), 3.05-2.98 (8H, m, 4xCH ₂ ), 4.12 (2H, t, CH ₂ ), 4.54-4.47 (2H, m, CH ₂ ), 7.10-7.02 (2H, m, 2xCH-arom), 7.26-7.21 (1H, m, CH-arom), 7.35 (1H , t, CH-arom), 8.01 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 142 : 4-[4-(3-{2-chloro-3-[3-(pyrrolidin-1-yl)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5 -yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.2 mmol) and 1-(3-chloropropyl)pyrrolidine were used in method A , reaction temperature 60°C, second prep. TLC (eluent: CHCl ₃ /MeOH/aq NH ₃ 80:9:1) gave the title compound as a yellow oil (9%).

LC/MS result [M+H] ⁺ : 605.1;

¹ H NMR (CDCl ₃ ): δ 1.33 (6H, s, 2xCH ₃ ), 2.12-2.05 (4H, m, 2xCH ₂ ), 2.21-2.12 (2H, m, CH ₂ ), 2.47-2.33 (2H, m, CH ₂ ), 3.30-3.09 (6H, m, 3xCH ₂ ), 4.30-4.11 (2H, m, CH ₂ ) , 4.58-4.46(2H, m, _CH2 ), 7.10-6.96(3H, m, 3xCH-arom), 7.34(1H, d, CH-arom), 8 .00 (1H, s, CH-arom), 8.47 (2H, d, 2xCH-arom).

Example 143 : 4-[4-(3-{2-chloro-3-[3-(diethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ( Example 129 ) (0.2 mmol) and 3-diethylamino-1-propanol were used in method B (1.5 h); the title compound was obtained as a yellow solid (22%).

LC/MS result [M+H] ⁺ : 607.2;

¹ H NMR (CDCl ₃ ): δ 1.09 (6H, t, 2xCH ₃ ), 1.31 (6H, s, 2xCH ₃ ), 2.09-2.00 (2H, m, CH ₂ ), 2 .19-2.09 (2H, m, CH ₂ ), 2.72-2.60 (2H, m, CH ₂ ), 2.84-2.72 (2H, m, CH ₂ ), 4.12 (2H, t, CH ₂ ), 4.56-4.45 (2H, m, CH ₂ ), 7.09-7.02 (2H, m, 2xCH-arom), 7.23 (1H, dd , CH-arom), 7.33 (1H, t, CH-arom), 8.00 (1H, s, CH-arom), 8.52 (2H, d, 2xCH-arom).

Example 144 : 4-[4-(3-{2-Chloro-3-[2-(diethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-methyl-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2-oxazole -3-yl}phenol (0.08 mmol) and 2-chloro- N,N -diethylethylamine were used in Method A , reaction temperature 50° C. to give the title compound in 21% yield.

LC/MS result [M+H] ⁺ : 539.1;

¹ H NMR (CDCl ₃ ): δ 1.08 (6H, t, 2xCH ₃ ), 1.28 (6H, s, 2xCH ₃ ), 2.08-1.97 (2H, m, CH ₂ ), 2 .56 (3H, s, CH ₃ ), 2.70 (4H, q, 2xCH ₂ ), 2.96 (2H, t, CH ₂ ), 4.17 (2H, t, CH ₂ ), 4.34 -4.24 (2H, m, _CH2 ), 7.03 (1H, dd, CH-arom), 7.08 (1H, t, CH-arom), 7.20 (1H, dd, CH -arom), 7.31 (1H, t, CH-arom), 8.08 (1H, s, CH-arom), 8.60 (2H, d, 2xCH-arom).

Example 145 : 4-[4-(3-{2-Chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-methyl-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2-oxazole -3-yl}phenol (0.16 mmol) and 2-chloro- N,N -dimethylethylamine were used in Method A , reaction temperature 50° C. to give the title compound as a pale yellow oil (11%).

LC/MS result [M+H] ⁺ : 511.1;

¹ H NMR (CDCl ₃ ): δ 1.29 (6H, s, 2xCH ₃ ), 2.08-1.98 (2H, m, CH ₂ ), 2.37 (6H, s, 2xCH ₃ ), 2 .57 (3H, s, CH ₃ ), 2.81 (2H, t, CH ₂ ), 4.16 (2H, t, CH ₂ ), 4.33-4.24 (2H, m, CH ₂ ) , 7.12-7.00 (2H, m, 2xCH-arom), 7.22 (1H, dd, CH-arom), 7.32 (1H, t, CH-arom), 8.07 (1H, s, CH-arom), 8.60 (2H, d, 2xCH-arom).

Example 146 :

4-[4-(3-{2-chloro-3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-methyl-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2-oxazole -3-yl}phenol (0.16 mmol) and 1-(2-chloroethyl)pyrrolidine were used in method A , reaction temperature 50° C. to give the title compound after the second prep. TLC (eluent: CH ₂ Cl ₂ /MeOH 9:1) as a pale yellow oil (8%).

LC/MS result [M+H] ⁺ : 537.1;

¹ H NMR (CDCl ₃ ): δ 1.29 (6H, s, 2xCH ₃ ), 1.86-1.76 (4H, m, 2xCH ₂ ), 2.07-1.99 (2H, m, CH ₂ ), 2.57 (3H, s, CH ₃ ), 2.75-2.66 (4H, m, 2xCH ₂ ), 2.98 (2H, t, CH ₂ ), 4.21 (2H, t , CH ₂ ), 4.33-4.25 (2H, m, CH ₂ ), 7.04 (1H, dd, CH-arom), 7.08 (1H, t, CH-arom), 7 .21 (1H, dd, CH-arom), 7.32 (1H, t, CH-arom), 8.08 (1H, s, CH-arom), 8.60 (2H, d, 2xCH -arom.).

Example 147 : 4-[4-(3-{2-chloro-3-[3-(diethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)- 5-methyl-1H-pyrazol-1-yl]-2-methylbutan-2-ol

2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2-oxazole -3-yl}phenol (0.08 mmol) and 3-diethylamino-1-propanol were used in method B (1.5 h); the title compound was obtained as a pale yellow oil (22%).

LC/MS result [M+H] ⁺ : 553.2;

¹ H NMR (CDCl ₃ ): δ 1.13 (6H, t, 2xCH ₃ ), 1.29 (6H, s, 2xCH ₃ ), 2.07-1.98 (2H, m, CH ₂ ), 2 .16-2.07 (2H, m, CH ₂ ), 2.57 (3H, s, CH ₃ ), 2.73 (4H, k, 2xCH ₂ ), 2.82 (2H, t, CH ₂ ) , 4.11 (2H, t, CH ₂ ), 4.32-4.23 (2H, m, CH ₂ ), 7.02 (1H, dd, 2xCH-arom), 7.09 (1H, t , CH-arom), 7.20 (1H, dd, CH-arom), 7.31 (1H, t, CH-arom), 8.08 (1H, s, CH-arom), 8 .60 (2H, d, 2xCH-arom).

Example 148 : methyl-3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl) -1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate

methyl-( S )-3-(2-chloro-3-hydroxyphenyl)-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate (0 06 mmol) and N- (2-chloroethyl)morpholine hydrochloride was used in method A , reaction temperature 50° C. to give the title compound (24%).

LC/MS result [M+H] ⁺ : 559.3;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 2.69 (4H, br., 2xCH ₂ ), 2.93 (2H, t, CH ₂ ), 3.63 ( 3H, s, OCH ₃ ), 3.76 (4H, t, 2xCH ₂ ), 4.30-4.19 (3H, m, CH and CH ₂ ), 4.46-4.30 (2H, m, CH ₂ ), 7.14-7.06 (2H, m, 2xCH-arom), 7.33 (1H, t, CH-arom), 7.99 (1H, s, CH-arom).

Example 149 : methyl-3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazole -4-yl}-1,2-oxazole-4-carboxylate

methyl-( S )-3-(2-chloro-3-hydroxyphenyl)-5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate (0 .06 mmol) and 2-chloro- N,N -dimethylethylamine were used in Method A , reaction temperature 50° C. to give the title compound (19%).

LC/MS result [M+H] ⁺ : 517.3;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 2.92 (6H, s, 2xCH ₃ ), 3.48 (2H, t, CH ₂ ), 3.63 (3H , s, OCH ₃ ), 4.24 (1H, dd, CH), 4.47-4.31 (2H, m, CH ₂ ), 4.60 (2H, t, CH ₂ ), 7.19- 7.11 (2H, m, 2xCH-arom), 7.38 (1H, t, CH-arom), 7.99 (1H, s, CH-arom).

Example 150 : 3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn -configuration)

2-chloro-3-[4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazol-3-yl]phenol ( syn -configuration) (0.03 mmol) and N- (2-chloroethyl)morpholine hydrochloride were used in method A , reaction temperature 50°C; after standard workup, the crude material was dissolved in THF (0.5 mL) and treated with TBAF (1 M in THF; 1.1 eq.) at room temperature for 2 h. The solvent was removed under reduced pressure and the title compound was isolated from the prep. . TLC (eluent: CH ₂ Cl ₂ /MeOH/aq. NH ₃ 100:10:1) as a pale yellow oil (56%).

LC/MS result [M+H] ⁺ : 571.4;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.90 (s, 1H, pyrazole-H), 7.35-7.29 (m, 1H, benzyl-H), 7.11-7 .06 (m, 2H, benzyl-H), 4.77-4.67 (m, 1H, CH), 4.25-4.19 (m, 4H, CH ₂ , RCH ₂ OCH ₃ ), 3, 75-3.72 (m, 4H, morpholino-H), 3.15 (s, 3H, RCH ₂ OCH ₃ ), 2.91-2.72 (m, 6H, 3xCH ₂ ), 2.66-2 .63 (m, 4H, morpholino-H), 1.49 (s, 3H, CH ₃ ).

Example 151 :

3-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl)-5-(trifluoromethyl)-1H -pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn -configuration)

2-chloro-3-[4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazol-3-yl]phenol ( syn -configuration) (0.03 mmol) and 2-chloro- N,N -dimethylethylamine were used in method A , reaction temperature 45°C; after standard workup, the crude material was dissolved in THF (0.5 ml) and treated with TBAF (1 M in THF; 1.1 eq.) at room temperature for 3.5 h. The solvent was removed under reduced pressure and the title compound was isolated from prep. TLC (eluent: CH ₂ Cl ₂ /MeOH/aq. NH ₃ 100:10:1) as a colorless oil (48%).

LC/MS result [M+H] ⁺ : 529.50;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.91 (s, 1H, pyrazole-H), 7.35-7.29 (m, 1H, benzyl-H), 7.11-7 .06 (m, 2H, benzyl-H), 4.77-4.67 (m, 1H, CH), 4.22-4.18 (m, 4H, CH ₂ , RCH ₂ OCH ₃ ), 3, 15 (s, 3H, RCH ₂ OCH ₃ ), 2.88-2.72 (m, 6H, 3xCH ₂ ), 2.39 (s, 6H, N(CH ₃ ) ₂ ), 1.49 (s, _3HCH3 ).

Example 152 : 3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( anti -configuration)

2-chloro-3-[4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazol-3-yl]phenol ( anti -configuration) (0.02 mmol) and N- (2-chloroethyl)morpholine hydrochloride were used in method A , reaction temperature 50°C; after standard workup, the crude material was dissolved in THF (0.5 ml) and treated with TBAF (1 M in THF; 1.1 eq.) at room temperature for 4.5 h. The solvent was removed under reduced pressure and the title compound was isolated from prep. TLC (eluent: CH ₂ Cl ₂ /MeOH/aq. NH ₃ 100:10:1) as a pale yellow oil (60%).

LC/MS result [M+H]+: 571.3;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.87 (s, 1H, pyrazole-H), 7.35-7.29 (m, 1H, benzyl-H), 7.12-7 .06 (m, 2H, benzyl-H), 5.32-5.21 (m, 1H, CH), 4.25-4.19 (m, 4H, CH ₂ , RCH ₂ OCH ₃ ), 3, 75-3.72 (m, 4H, morpholino-H), 3.15 (s, 3H, RCH ₂ OCH ₃ ), 2.91-2.80 (m, 4H, 2xCH ₂ ), 2.68-2 .61 (m, 6H, CH ₂ , morpholino-H), 1.55 (s, 3H CH ₃ ).

Example 153 : 3-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl)-5-(trifluoromethyl )-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( anti -configuration)

2-chloro-3-[4-(methoxymethyl)-5-{1-[3-[( tert -butyldimethylsilyl)oxy]-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}- 1,2-oxazol-3-yl]phenol ( anti -configuration) (0.03 mmol) and 2-chloro- N,N -dimethylethylamine were used in method A , reaction temperature 50°C; after standard workup, the crude material was dissolved in THF (0.5 ml) and treated with TBAF (1 M in THF; 1.1 eq.) at room temperature for 3.5 h. The solvent was removed under reduced pressure and the title compound was isolated from prep. TLC (eluent: CH ₂ Cl ₂ /MeOH/aq. NH ₃ 100:10:1) as a pale yellow oil (87%).

LC/MS result [M+H] ⁺ : 529.30;

¹ H NMR (CDCl ₃ , J [Hz]): δ = 7.87 (s, 1H, pyrazole-H), 7.35-7.29 (m, 1H, benzyl-H), 7.11-7 .06 (m, 2H, benzyl-H), 5.31-5.21 (m, 1H, CH), 4.23-4.19 (m, 4H, CH ₂ , RCH ₂ OCH ₃ ), 3, 15 (s, 3H, RCH ₂ OCH ₃ ), 2.87-2.80 (m, 2H, CH ₂ ), 2.68-2.60 (m, 2H, CH ₂ ), 2.40 (s, 6H, N(CH ₃ ) ₂ ), 1.55 (s, 3H, CH ₃ ).

General procedure for the synthesis of isoxazol-3-ylbenzamides

Or 3-(5-{1-[( 2R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2 - oxazol-3-yl ) -2- chlorobenzoic acid ]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol-3-yl)-2-methoxybenzoic acid ( Examples 161-165 ), or 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzoic acid ( Examples 166 and 167 ) (0.15 mmol), the corresponding amine (1.8 eq.), 1-hydroxybenzotriazole (1.5 eq.) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 1.7 eq) was dissolved in 1 ml dry DMF. N -methylmorpholine (10 eq.) was added and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between saturated aq. NH ₄ Cl and CH ₂ Cl ₂ solution, the combined organic layers were washed with water and brine and dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification of the product was achieved with prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1; second prep. TLC if necessary, diluent: CH ₂ Cl ₂ /MeOH 98:2).

The final O -desilylation of the benzamides was achieved in THF (0.5 ml) with TBAF (1 M in THF; 1.1 eq.) at room temperature over 3.5 h. The solvent was removed under reduced pressure and the title compound was isolated from teacher TLC (eluent: CH ₂ Cl ₂ /MeOH 95:5).

Example 154 : ( R )-(2-chloro-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl) isoxazol-3-yl)phenyl)(morpholino)methanone

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and morpholine with a yield of 23% in two stages.

LC/MS result [M+H] ⁺ : 562.9;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 3.19 (2H, t, CH ₂ ), 3.58 (2H, t, CH ₂ ), 3.91-3 .66 (4H, m, 2xCH ₂ ), 4.23 (1H, dd, CH), 4.47-4.30 (2H, m, CH ₂ ), 6.90 (1H, br., CH-arom .), 7.57-7.45 (2H, m, 2xCH-arom.), 7.64 (1H, dd, CH-arom.), 7.97 (1H, s, CH-arom.), 8 .55 (1H, br., CH-arom), 9.06 (1H, br., CH-arom).

Example 155 : ( R )-2-chloro- N -cyclobutyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4 -yl)isoxazol-3-yl)benzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and cyclobutylamine with a yield of 14% in two stages.

LC/MS result [M+H] ⁺ : 546.9;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 2.60-1.70 (6H, m, 3xCH ₂ ), 4.24 (1H, dd, CH), 4, 50-4.31 (2H, m, _CH2 ), 4.58 (1H, quint, CH), 6.19 (1H, br., NH), 6.94 (1H, s, CH-arom) , 7.50 (1H, t, CH-arom.), 7.61 (1H, d, CH-arom.) 7.78 (1H, d, CH-arom.), 7.98 (1H, s, CH-arom), 8.61 (1H, br., CH-arom), 9.07 (1H, s, CH-arom).

Example 156 : ( R )-2-chloro- N -ethyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4 -yl)isoxazol-3-yl)benzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and ethylamine (2 M in THF) in 8% yield in two steps.

LC/MS result [M+H] ⁺ : 520.9;

¹ H NMR (CDCl ₃ ): δ 1.25 (3H, q, CH ₃ ), 1.32 (3H, d, CH ₃ ), 3.56-3.42 (2H, m, CH ₂ ), 4 .24 (1H, dd, CH), 4.48-4.31 (2H, m, _CH2 ), 6.00 (1H, br. NH), 6.91 (1H, br., CH-arom. ), 7.51 (1H, t, CH-arom), 7.61 (1H, d, CH-arom) 7.78 (1H, d, CH-arom), 7.98 (1H, s , CH-arom), 8.60 (1H, br., CH-arom), 9.06 (1H, s, CH-arom).

Example 157 : ( R )-2-chloro-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazole -3-yl) -N -isopropylbenzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and isopropylamine with a yield of 12% in two stages.

LC/MS result [M+H] ⁺ : 534.9;

¹ H NMR (CDCl ₃ ): δ 1.26 (6H, d, 2xCH ₃ ), 1.32 (3H, d, CH ₃ ), 4.48-4.18 (4H, m, 2xCH and CH ₂ ) , 5.84 (1H, d, NH), 6.96 (1H, s, CH-arom), 7.50 (1H, t, CH-arom), 7.60 (1H, d, CH- arom.), 7.76 (1H, d, CH-arom.), 7.98 (1H, s, CH-arom.), 8.62 (1H, br. CH-arom.), 9.07 ( 1H, s, CH-arom).

Example 158 : ( R )-(azetidin-1-yl)(2-chloro-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4- (pyrimidin-4-yl)isoxazol-3-yl)phenyl)methanone

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and azetidine with a yield of 19% in two stages.

LC/MS result [M+H] ⁺ : 532.9;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 2.43-2.24 (2H, m, CH ₂ ), 4.00-3.83 (2H, m, CH ₂ ), 4.49-4.14 (5H, m, CH and 2xCH ₂ ) 7.03 (1H, d, CH-arom), 7.59-7.47 (2H, m, 2xCH-arom. ), 7.63 (1H, dd, CH-arom), 7.97 (1H, s, CH-arom) 8.63 (1H, br. CH-arom), 9.08 (1H, s , CH-arom.).

Example 159 : ( R )-2-chloro -N -cyclopropyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4 -yl)isoxazol-3-yl)benzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and cyclopropylamine with a yield of 6% in two stages.

LC/MS result [M+H] ⁺ : 532.9;

¹ H NMR (CDCl ₃ ): δ 0.68 (2H, m, CH ₂ ), 0.91-0.85 (2H, m, CH ₂ ), 1.32 (3H, d, CH ₃ ), 2 .98-2.84 (1H, m, CH), 4.46-4.18 (3H, m, CH and CH ₂ ), 6.17 (1H, br., NH), 6.91 (1H, br., CH-arom), 7.56-7.46 (1H, m, CH-arom), 7.64-7.57 (1H, m, CH-arom), 7.77 (1H , dd, CH-arom), 7.97 (1H, s, CH-arom), 8.60 (1H, br., CH-arom), 9.06 (1H, s, CH-arom. ).

Example 160 : ( R )-(2-chloro-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl) isoxazol-3-yl)phenyl)(pyrrolidin-1-yl)methanone

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-chlorobenzoic acid and pyrrolidine with a yield of 23% in two stages.

LC/MS result [M+H] ⁺ : 547.0;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 2.02-1.81 (4H, m, 2xCH ₂ ), 3.13 (2H, t, CH ₂ ), 3 .62 (2H, t, CH ₂ ), 4.23 (1H, dd, CH), 4.46-4.29 (2H, m, CH ₂ ), 6.90 (1H, d, CH-arom. ), 7.55-7.44 (2H, m, 2xCH-arom), 7.65-7.55 (1H, m, CH-arom), 7.96 (1H, s, CH-arom). ), 8.56 (1H, br., CH-arom), 9.03 (1H, s, CH-arom).

Example 161 : ( R ) -N -cyclopropyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazole -3-yl)-2-methoxybenzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-methoxybenzoic acid and cyclopropylamine with a yield of 9% in two stages.

LC/MS result [M+H] ⁺ : 529.0;

¹ H NMR (CDCl ₃ ): δ 0.61-0.49 (2H, m, CH ₂ ), 0.94-0.80 (2H, m, CH ₂ ), 1.33 (3H, d, CH ₃ ), 3.06-2.78 (1H, m, CH), 3.53 (3H, s, OCH ₃ ), 4.25 (1H, dd, CH), 4.48-4.32 (2H , m, CH ₂ ), 7.08 (1H, d, CH-arom), 7.50-7.36 (2H, m, 2xCH-arom), 7.67 (1H, dd, CH-arom .), 7.94 (1H, s, CH-arom), 8.29 (1H, dd, CH-arom), 8.66 (1H, d, CH-arom), 9.14 (1H , s, CH-arom.).

Example 162 : ( R )-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazol-3-yl ) -N -isopropyl-2-methoxybenzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-methoxybenzoic acid and isopropylamine in 18% yield in two steps.

LC/MS result [M+H] ⁺ : 531.0;

¹ H NMR (CDCl ₃ ): δ 1.22 (6H, d, 2xCH ₃ ), 1.33 (3H, d, CH ₃ ), 3.57 (3H, s, OCH ₃ ), 4.48-4 .17 (4H, m, 2xCH and CH ₂ ), 7.08 (1H, br. NH), 7.21-7.11 (1H, m, CH-arom), 7.42 (1H, t, CH-arom), 7.64 (1H, dd, CH-arom), 7.95 (1H, s, CH-arom), 8.27 (1H, dd, CH-arom), 8, 64 (1H, s, CH-arom), 9.14 (1H, s, CH-arom).

Example 163 : ( R )-(azetidin-1-yl)(3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4 -yl)isoxazol-3-yl)-2-methoxyphenyl)methanone

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-methoxybenzoic acid and azetidine with a yield of 15% in two stages.

LC/MS result [M+H] ⁺ : 529.0;

¹ H NMR (CDCl ₃ ): δ 1.33 (3H, d, CH ₃ ), 2.40-2.19 (2H, m, CH ₂ ), 3.51 (3H, s, OCH ₃ ), 4 .18-3.70 (4H, m, 2xCH ₂ ), 4.48-4.18 (3H, m, CH and CH ₂ ), 7.14 (1H, d, CH-arom), 7.33 (1H, t, CH-arom), 7.58 (1H, dd, CH-arom), 7.66 (1H, dd, CH-arom), 7.95 (1H, s, CH-arom .), 8.63 (1H, br., CH-arom), 9.13 (1H, s, CH-arom).

Example 164 : ( R ) -N -cyclobutyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazole -3-yl)-2-methoxybenzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-methoxybenzoic acid and cyclobutylamine in 11% yield in two steps.

LC/MS result [M+H] ⁺ : 543.0;

¹ H NMR (CDCl ₃ ): δ 1.32 (3H, d, CH ₃ ), 1.92-1.68 (4H, m, 2xCH ₂ ), 2.47-2.26 (2H, m, CH ₂ ), 3.58 (3H, s, OCH ₃ ), 4.24 (1H, dd, CH), 4.46-4.30 (2H, m, CH ₂ ), 4.64-4.49 ( 1H, m, CH ₂ ), 6.93 (1H, br., NH), 7.38 (1H, t, CH-arom), 7.51 (1H, d, CH-arom), 7, 62 (1H, dd, CH-arom), 7.95 (1H, s, CH-arom), 8.24 (1H, dd, CH-arom), 8.58 (1H, br. CH- arom.), 9.10 (1H, s, CH-arom.).

Example 165 : ( R ) -N -ethyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazole -3-yl)-2-methoxybenzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)-2-methoxybenzoic acid and ethylamine (2 M in THF) in 4% yield over two steps.

LC/MS result [M+H] ⁺ : 517.0;

¹ H NMR (CDCl ₃ ): δ 1.18 (3H, t, CH ₃ ), 1.32 (3H, d, CH ₃ ), 3.52-3.38 (2H, m, CH ₂ ), 3 .55 (3H, s, OCH ₃ ), 4.24 (1H, dd, CH), 4.47-4.30 (2H, m, CH ₂ ), 6.90 (1H, br., NH), 7.47-7.30 (2H, m, 2xCH-arom), 7.64 (1H, dd, CH-arom), 7.94 (1H, s, CH-arom), 8.26 ( 1H, dd, CH-arom), 8.56 (1H, br, CH-arom), 9.08 (1H, s, CH-arom).

Example 166 : ( R ) -N -cyclobutyl-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazole -3-yl)benzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)benzoic acid and cyclobutylamine with a yield of 16% in two stages.

LC/MS result [M+H] ⁺ : 513.0;

¹ H NMR (CDCl ₃ ): δ 1.31 (3H, d, CH ₃ ), 1.88-1.71 (2H, m, CH ₂ ), 2.07-1.88 (2H, m, CH ₂ ), 2.54-2.36 (2H, m, CH ₂ ), 3.22 (1H, d, CH), 4.22 (1H, dd, CH), 4.47-4.29 (2H , m, CH ₂ ), 4.68-4.49 (1H, m, CH), 6.23 (1H, d, NH), 6.97 (1H, dd, CH-arom), 7.60 -7.43 (2H, m, 2xCH-arom), 8.02-7.88 (3H, m, 3xCH-arom), 8.59 (1H, d, CH-arom), 9.18 (1H, d, CH-arom).

Example 167 : ( R )-3-(5-(1-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(pyrimidin-4-yl)isoxazol-3-yl ) -N -isopropylbenzamide

From 3-(5-{1-[(2 R )-2-[( tert- butyldimethylsilyl)oxy]propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4- yl)-1,2-oxazol-3-yl)benzoic acid and isopropylamine with a yield of 8% in two stages.

LC/MS result [M+H] ⁺ : 501.0;

¹ H NMR (CDCl ₃ ): δ 1.27 (6H, d, 2xCH ₃ ), 1.31 (3H, d, CH ₃ ), 3.22 (1H, br., OH), 4.58-4 .07 (4H, m, 2xCH and CH ₂ ), 5.91 (1H, d, NH), 6.97 (1H, dd, CH-arom), 7.57-7.45 (2H, m, 2xCH-arom), 7.99-7.88 (3H, m, 3xCH-arom), 8.59 (1H, d, CH-arom), 9.18 (1H, d, CH-arom). ).

b) Biological tests

Cytokine Assay: Assay of proliferation and cytokine production by PHA-stimulated human PBMCs

Peripheral blood mononuclear cells (PBMCs) from healthy human donors were purified using the Accuspin™ System-Histopaque-1077 (Sigma) according to the protocol recommended by the manufacturer. The purified PBMCs were then washed twice with phosphate-buffered saline (PBS) and resuspended in RPMI1640 culture medium supplemented with 10% dialyzed heat-inactivated fetal bovine serum, 1.5 mM L-glutamine, 100 units of fetal calf serum. penicillin/ml and 100 mg streptomycin/ml (all from PAN Biotech, Eidenbach, Germany). For stimulation, PBMCs were seeded at 1×10 ⁵ cells/well, activated with 2 μg/ml phytohemagglutinin (PHA, Sigma) and incubated with test compounds for 48 hours. IL-17A, IL-17F and IFN-γ were then determined in the culture supernatant using the Luminex BioPlex system following the manufacturer's instructions (BioRad, Munich, Germany). Compounds were used for screening at concentrations of 10, 1, 0.1, and 0.01 µM. To determine the IC ₅₀ compounds were titrated semi-logarithmically.

Cell proliferation was analyzed using a BrdU cell proliferation ELISA from Roche (Mannheim, Germany) according to the manufacturer's instructions.

Cytokines were determined in the above culture supernatant using the following methods: IL-17A was measured using human IL-17A homodimer, ELISA Ready Set Go kit from eBioscience (Frankfurt, Germany); IL-17F using human IL-17F ELI-Pair from Hölzel DiagnosticaGmBH (Cologne, Germany); and IFN-γ using the human OptEIA IFN-g ELISA from BD Bioscience (Heidelberg, Germany), all according to the manufacturer's instructions.

c) Solubility in water

Water solubility was tested in 50 mM phosphate buffer (pH 4.0, 6.0, 7.4 and 9.0 tested, the following values were obtained at pH 7.4) and determined by HPLC/DMD system using the gradient program ( see below) and reverse phase systems. To achieve this, samples (final volume 500 µl, compound concentration 200 µM) were incubated for 24 hours at 23°C with continuous shaking at 1400 rpm (Thermomixer, Eppendorf) in aqueous phosphate buffers (pH 4.0, 6.0 , 7.4 and 9.0) with a final DMSO concentration of 1%. To separate the insoluble compound from the solution, the samples were centrifuged (30 min, 18000g at 23°C). The supernatants were measured by HPLC equipped with a UV detector and the concentrations were calculated according to the standard curve signals. A standard curve was generated by diluting a stock solution of each compound (c=0.1 mg/mL; obtained by adding 10 µl of a 20 mM compound in DMSO to 914 µl MeCN) in a specified amount of MeCN to cover the range from 0.1 to 200 µg/mL. ml. Dilution examples are shown in the table below.

Concentration [µg/ml] Stock solution [µl] solvent MeCN [µl] 0.1 one 999 0.5 5 995 one ten 990 2 twenty 980 5 fifty 950 ten 100 900

Used the following equipment:

HPLC/PDM: Dionex UltiMate 3000 Rapid Separation LC

HPLC pump: HPG-3400 #8007268

Autosampler: WPS-3000SL #8007769

Column thermostat: TCC-3200 #8006790

Detector: FDM-3000 No. 08011269

Column: depends on the test compound

Software: Chromeleon 6.80 SP3 Build 2345 (128616) no 36452

Excel 2000/2007

Glassware: Pasteur pipettes

Vials: glass vial (2 ml) with seal (Dionex)

Analytical balance: Sartorius LE225D-0CE (accuracy: 0.01 mg)

Miscellaneous: Rainin GPS tips, Rainin pipet lite, mini shaker

HPLC parameters :

Mobile phase A: depends on the test compound, e.g. water with 0.1% formic acid

Mobile phase B: depends on the test compound, e.g. acetonitrile

Injection volume: 5 µl

Column temperature: depends on the test compound, e.g. 30°C

Autosampler Temperature: Ambient Temperature

Sample loop: 25 µl

Wavelength of the FDM detector: depends on the investigated compound, Acquisition rate 5 Hz

Stop time chrome: depends on the test compound, e.g. 3.4 min

HPLC program: depends on the test compound

As an example, the following gradient was used to measure a specific compound:

Time [min] A [%] B [%] Flow [ml/min] 0.0 80 twenty 1.7 0.4 80 twenty 1.7 2.2 5 95 1.7 2.7 5 95 1.7 2.8 80 twenty 1.7 3.4 80 twenty 1.7

d) Microsomal stability

The metabolic stability of the compounds of the present invention was determined by incubation with human liver microsomes and subsequent determination of the residual amount of the corresponding compound ("parent compound") using HPLC-MS/MS.

To achieve this, in a final reaction volume of 1000 μl, each compound was incubated at a final concentration of 1 μM with 0.5 mg/ml human liver microsomes (HLM Pool 50 Donors, 20 mg/ml, BD Gentest, #452156, LotNr 88114) at 0 .1 M potassium phosphate buffer at pH 7.4, with a cofactor in the form of NADPH regenerating system (Promega, #V9510) according to manufacturers' specifications. The final concentration of DMSO in each sample was 0.4%. Incubation was carried out at 37°C under shaking conditions (thermomixer, 1400 rpm) for various time intervals up to 60 min. To stop the reaction, 200 μl of the reaction was withdrawn for each time point and 200 μl of ice-cold acetonitrile was added. Then the samples were centrifuged (4°C, 14000g for 15 min). The supernatant was analyzed for the concentration of residual parent compound and scanned for metabolites using HPLC-MS/MS. Using optimized MS methods for each compound, the peak area under the curve for a particular compound signal is determined. The change in peak areas during the analysis of 60 min resembles the remaining parent compound in % T0. At these points, a balancing line was established. The half-life as well as the clearance can be calculated based on the slope.

Equipment: Waters XevoTM TQ MS, Agilent 1200 HPLC, CTC-PAL autosampler (temperature 8°C)

Table 1 Exemplary compounds of formula (I) of the present invention include the following:

Etc. Name IL-17A Inhibition. IL-17F Inhibition. IFN-gamma Ingib. aq. sol. t _1/2
hlm one 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-2-methylpropan-2-ol ++ ++ +++ +++ +++ 2 1-({4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}methyl)cyclopropan-1-ol +++ ++ +++ ++ + 3 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-2-methylbutan-2-ol +++ +++ +++ n.a. +++ four (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5- (trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol +++ +++ +++ n.a. + 5 (2 S )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5- (trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol +++ ++ +++ n.a. ++ 6 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}butan-2-ol ( rac ) +++ +++ +++ n.a. + 7 3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1,1,1-trifluoropropan-2-ol ( rac ) +++ +++ +++ n.a. + eight ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate +++ ++ +++ ++ +++ 9 ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate +++ +++ +++ ++ ++ ten ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) +++ +++ +++ ++ +++ eleven ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( anti ) +++ +++ +++ n.a. n.a. 12 ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate +++ +++ +++ +++ + 13 ethyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate +++ +++ +++ +++ ++ fourteen ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxybutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate ( rac ) +++ +++ +++ ++ + fifteen ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3,3,3-trifluoro-2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazole-4-carboxylate ( rac ) +++ +++ +++ ++ 0 16 ethyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-3,3,3-trifluoro-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazole-4- yl}-1,2-oxazole-4-carboxylate +++ +++ +++ n.a. 0 17 methyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( anti ) + + + n.a. n.a. eighteen methyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( syn ) ++ +++ +++ n.a. +++ 19 methyl 3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate +++ ++ +++ n.a. +++ twenty methyl-3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazol-4- carboxylate +++ +++ +++ +++ +++ 21 methyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-3-(2-methoxypyridin-3-yl)-1,2-oxazole -4-carboxylate + + + n.a. n.a. 22 methyl 3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate ++ ++ +++ n.a. n.a. 23 methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate ++ ++ +++ n.a. + 24 methyl 3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate + ++ ++ n.a. n.a. 25 methyl-3-(2-chloro-3-methoxyphenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazol-4- carboxylate +++ +++ +++ n.a. +++ 26 methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( anti ) + + + + ++ 27 methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) +++ +++ +++ ++ ++ 28 methyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxycyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate + + + n.a. n.a. 29 methyl-3-(2-chlorophenyl)-5-{1-[(1 S ,3 S )-3-hydroxy-3-(methoxymethyl)cyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl} -1,2-oxazole-4-carboxylate ( syn ) + + ++ n.a. n.a. thirty 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2-oxazol-5-yl]-5 -(trifluoromethyl)-1H-pyrazol-1-yl}-2-methylpropan-2-ol ++ + + n.a. n.a. 31 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}( ^2-2H )propan-2-ol ( rac ) +++ +++ +++ 0 ++ 32 ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[2-hydroxy( ^2-2H )propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( rac ) +++ +++ +++ +++ ++ 33 methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[2-hydroxy( ^2-2H )propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( rac ) +++ +++ +++ +++ +++ 34 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]ethan-1-one + + + n.a. n.a. 35 1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2- oxazol-4-yl]ethan-1-one ++ ++ ++ +++ ++ 36 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]-2-cyclobutylethane-1-one + ++ ++ n.a. n.a. 37 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]pent-4-en-1-one ++ ++ ++ n.a. n.a. 38 2-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]-1-cyclopropylhex-5-en-2-ol ( rac ) + 0 0 n.a. n.a. 39 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]-2-methoxyethane-1-one + 0 + n.a. n.a. 40 1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2- oxazol-4-yl]-2-methoxyethane-1-one + + + n.a. n.a. 41 3-(2-chloro-6-fluorophenyl)- N -cyclopentyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxamide 0 0 0 n.a. n.a. 42 3-(2-chloro-6-fluorophenyl)- N -cyclopropyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxamide 0 0 0 n.a. n.a. 43 3-(2-chloro-6-fluorophenyl)- N -cyclobutyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxamide + + + n.a. n.a. 44 3-(2-chloro-6-fluorophenyl)- N -cyclopentyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxamide ++ + ++ +++ 0 45 3-(2-chloro-6-fluorophenyl)- N -cyclopropyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxamide + + + n.a. n.a. 46 3-(2-chloro-6-fluorophenyl)- N -cyclobutyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxamide + ++ ++ n.a. n.a. 47 oxetan-3-yl-3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazol-4 -carboxylate ++ ++ ++ n.a. n.a. 48 cyclopropyl-3-(2-chlorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1, 2-oxazole-4-carboxylate ( anti ) + + + n.a. n.a. 49 cyclopropyl-3-(2-chlorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1, 2-oxazole-4-carboxylate ( syn ) +++ +++ +++ + +++ fifty cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( anti ) ++ +++ +++ n.a. n.a. 51 cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) ++ +++ +++ ++ ++ 52 oxetan-3-yl-3-(2-chlorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-methyl-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate ( syn ) ++ ++ ++ n.a. n.a. 53 cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( syn ) +++ +++ +++ n.a. +++ 54 cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( anti ) + + ++ n.a. n.a. 55 cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate +++ +++ +++ n.a. ++ 56 cyclobutyl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate +++ +++ +++ + 0 57 oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazole-4-carboxylate + ++ ++ n.a. n.a. 58 oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylate ++ +++ +++ n.a. ++ 59 cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate +++ +++ +++ +++ + 60 oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylate ++ ++ ++ +++ + 61 cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate ( syn ) +++ +++ +++ n.a. ++ 62 cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate ( anti ) +++ +++ +++ n.a. n.a. 63 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol 0 0 0 n.a. n.a. 64 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn ) 0 0 + n.a. n.a. 65 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol + + + +++ n.a. 66 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol ++ ++ +++ +++ n.a. 67 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol ++ ++ +++ +++ +++ 68 (2 S )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol + + ++ n.a. n.a. 69 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) ++ ++ +++ n.a. +++ 70 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) + + n.a. n.a. 71 (1 S ,3 R )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( anti ) + + n.a. n.a. 72 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn ) ++ ++ +++ n.a. n.a. 73 (1 S ,3 R )-3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( anti ) + + + n.a. n.a. 74 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn ) ++ ++ ++ n.a. n.a. 75 (2 S )-1-{4-[3-(2-chlorophenyl)-4-[(2-methoxyethoxy)methyl]-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole -1-yl}propan-2-ol + + + n.a. n.a. 76 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(ethoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol ++ ++ +++ +++ + 77 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol +++ +++ +++ ++ +++ 78 4-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-2-methylbutan- 2-ol ++ +++ +++ +++ ++ 79 4-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-methylbutan-2- ol ++ ++ +++ n.a. n.a. 80 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn ) n.a. n.a. 81 (1 S ,3 R )-3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( anti ) + + ++ n.a. n.a. 82 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- methylbutan-2-ol +++ +++ +++ +++ +++ 83 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ + ++ 84 (1 S ,3 R )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( anti ) ++ ++ ++ n.a. n.a. 85 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol +++ +++ +++ n.a. + 86 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ n.a. +++ 87 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn ) ++ +++ +++ +++ +++ 88 (2 S )-1-{4-[3-(2-chlorophenyl)-4-[(oxetan-3-yloxy)methyl]-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}propan-2-ol 0 + + n.a. n.a. 89 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-[(propan-2-yloxy)methyl]-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol +++ +++ +++ +++ 0 90 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclobutoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol +++ +++ +++ +++ 0 91 4-{4-[3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol +++ +++ +++ n.a. n.a. 92 (1 R ,3 S )-3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(cyclopropoxymethyl)-1,2-oxazol- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ n.a. 0 93 methyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-3-(2-hydroxypyridin-3-yl)-1,2-oxazol- 4-carboxylate + ++ ++ n.a. n.a. 94 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}propan- 2-ol 0 0 + n.a. n.a. 95 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}( 2-2H) propan-2-ol ( rac ) ++ ++ ++ +++ +++ 96 (2 S )-1-{4-[3-(2-chlorophenyl)-4-(oxolan-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol + + ++ n.a. n.a. 97 (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol +++ +++ +++ n.a. ++ 98 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ n.a. +++ 99 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) ++ +++ +++ +++ +++ 100 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) ++ +++ +++ n.a. +++ 101 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) + 0 0 + +++ 102 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ +++ +++ 103 (1 R ,3 S )-3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ n.a. +++ 104 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ + +++ 105 (1 S ,3 R )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( anti ) + ++ ++ n.a. n.a. 106 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ +++ +++ 107 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) ++ ++ +++ n.a. n.a. 108 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) ++ ++ ++ n.a. n.a. 109 (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) + + ++ n.a. n.a. 110 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) ++ ++ ++ +++ +++ 111 (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ +++ +++ 112 (1 R ,3 S )-3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ +++ +++ 113 (2 R )-1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol + ++ + n.a. n.a. 114 1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol 0 0 + n.a. n.a. 115 (2 R )-1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol + + ++ n.a. n.a. 116 1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol 0 0 + n.a. n.a. 117 (2 R )-1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol + + ++ n.a. n.a. 118 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylpropan-2-ol +++ +++ +++ n.a. +++ 119 (2 R )-1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol + + ++ n.a. n.a. 120 1-{4-[3-(2-Chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylpropan-2-ol + 0 + n.a. n.a. 121 4-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylbutan-2-ol +++ ++ +++ n.a. +++ 122 4-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol +++ +++ +++ n.a. n.a. 123 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylbutan-2-ol +++ +++ +++ +++ +++ 124 4-{4-[3-(2-Chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol +++ +++ +++ n.a. +++ 125 4-{4-[3-(2,6-dichloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole-1 -yl}-2-methylbutan-2-ol ++ +++ +++ n.a. +++ 126 4-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- methylbutan-2-ol ++ ++ ++ +++ +++ 127 4-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol ++ ++ +++ n.a. +++ 128 4-(4-{3-[3-(benzyloxy)-2-chlorophenyl]-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazole -1-yl)-2-methylbutan-2-ol +++ +++ 0 0 0 129 2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol ++ ++ + n.a. n.a. 130 (1 R ,3 S )-3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ ++ ++ 131 ethyl 3-(2-chloro-3-methoxyphenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) +++ +++ +++ +++ +++ 132 ethyl-3-(2-chloro-3-methoxyphenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate +++ +++ +++ ++ ++ 133 4-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol +++ +++ +++ n.a. 0 134 4-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol +++ ++ ++ n.a. +++ 135 4-[4-(3-{2-chloro-3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol ++ ++ +++ n.a. ++ 136 4-[4-(3-{2-chloro-3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5- yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol ++ ++ ++ n.a. n.a. 137 4-[4-(3-{2-chloro-3-[2-(diethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol ++ ++ ++ n.a. + 138 4-[2-(2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2- yl)-1,2-oxazol-3-yl}phenoxy)ethyl]-1labmda6-thiomorpholine-1,1-dione +++ +++ ++ n.a. 0 139 4-(4-{3-[2-chloro-3-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}ethoxy)phenyl]-4-(pyrimidin-2-yl)- 1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol +++ +++ ++ n.a. + 140 4-[4-(3-{2-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol ++ ++ ++ n.a. n.a. 141 4-[3-(2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2- yl)-1,2-oxazol-3-yl}phenoxy)propyl]-1lambda6-thiomorpholine-1,1-dione +++ +++ +++ n.a. 0 142 4-[4-(3-{2-chloro-3-[3-(pyrrolidin-1-yl)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol ++ ++ ++ n.a. n.a. 143 4-[4-(3-{2-chloro-3-[3-(diethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol +++ +++ +++ n.a. n.a. 144 4-[4-(3-{2-chloro-3-[2-(diethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-methyl -1H-pyrazol-1-yl]-2-methylbutan-2-ol + + ++ +++ n.a. 145 4-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-methyl -1H-pyrazol-1-yl]-2-methylbutan-2-ol + + ++ n.a. +++ 146 4-[4-(3-{2-chloro-3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-methyl-1H-pyrazol-1-yl]-2-methylbutan-2-ol ++ + ++ n.a. +++ 147 4-[4-(3-{2-chloro-3-[3-(diethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-methyl -1H-pyrazol-1-yl]-2-methylbutan-2-ol + + ++ +++ +++ 148 methyl-3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H- pyrazol-4-yl}-1,2-oxazole-4-carboxylate +++ +++ +++ n.a. 0 149 methyl-3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazole-4- yl}-1,2-oxazole-4-carboxylate ++ + ++ n.a. n.a. 150 (1 R ,3 S )-3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn ) +++ +++ +++ n.a. 0 151 (1 R ,3 S )-3-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn ) ++ ++ ++ n.a. +++ 152 (1 S ,3 R )-3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( anti ) ++ ++ ++ n.a. 0 153 (1 S ,3 R )-3-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( anti ) 0 + + n.a. +++ 154 (2 R )-1-(4-{3-[2-chloro-3-(morpholine-4-carbonyl)phenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl} -5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol + 0 ++ n.a. n.a. 155 2-chloro -N -cyclobutyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzamide ++ ++ ++ n.a. n.a. 156 2-chloro- N -ethyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzamide 0 0 + n.a. n.a. 157 2-chloro-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl) - N - (propan-2-yl) benzamide + + ++ n.a. n.a. 158 (2 R )-1-(4-{3-[3-(azetidine-1-carbonyl)-2-chlorophenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl}- 5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol ++ ++ ++ n.a. n.a. 159 2-chloro -N -cyclopropyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzamide + + ++ n.a. n.a. 160 (2 R )-1-(4-{3-[2-chloro-3-(pyrrolidin-1-carbonyl)phenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl} -5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol +++ +++ +++ +++ + 161 N -cyclopropyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)-2-methoxybenzamide 0 0 + n.a. n.a. 162 3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol- 3-yl)-2-methoxy- N- (propan-2-yl)benzamide + 0 ++ n.a. n.a. 163 (2 R )-1-(4-{3-[3-(azetidine-1-carbonyl)-2-methoxyphenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl}- 5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol 0 0 + n.a. n.a. 164 N -cyclobutyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)-2-methoxybenzamide + + + n.a. n.a. 165 N -ethyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)-2-methoxybenzamide + 0 + n.a. n.a. 166 N -cyclobutyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)benzamide + 0 + n.a. n.a. 167 3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol- 3-yl) - N - (propan-2-yl) benzamide 0 0 + n.a. n.a.

IC ₅₀ values for cytokines are determined by cytokine assay as described herein:

+++: ˂50 nM; ++: 50 nM to ˂500 nM; +: from 500 nM to ˂5 µM; 0: ≥5 µM.

Water solubility values are determined using the method described in this application:

0: ˂1 µM; +: 1-2.99 µM, ++: 3-9.99 µM, +++: ˃10 µM, n.d.: no data

t _1/2 values for microsomal stability are determined using the method described in this application:

0: 2-9.99 min; +: 10-39.99 min, ++: 40-100 min, +++: ˃100 min, n.d.: not available.

Claims (69)

1. Compound of formula (I)

wherein Ar is selected from the group consisting of phenyl and pyridyl, each of which is optionally substituted with one, two or three independently selected substituents R ^Ar ; R ^Ar is selected from the group consisting of halogen, -OH, -CN, C _1-6 -alkoxy, di-C _1-6 -alkylamino-C _1-6 -alkoxy, -CONHR', benzyloxy, -CO-azetidinyl, -CO-pyrrolidinyl, -CO-morpholinyl, -CO-C _3-6 -cycloalkyl, -CONH-C _3-6 -cycloalkyl and -OC _1-6 -alkyl-heterocyclyl, where heterocyclyl is selected from the group consisting of pyrrolidinyl, piperazinyl, morpholinyl, 1,1-dioxothiomorpholinyl and (2-oxa-6-azaspiro[3.3]hept-6-yl)-C _1-4 -alkoxy, and where each of these heterocyclyl groups is optionally substituted with C _1-6 -alkyl, and where R' represents C _1-6 -alkyl; Z is selected from the group consisting of H, -CO-R ^Z , -CH ₂ -OR ^Z , -CO-CH ₂ -R ^Z , -CO-CH ₂ -OR ^Z , -COOR ^Z , -CO-NHR ^Z , -C _1-6 -alkyl-OC _1-6 -alkyl-OR ^Z , C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, 5 - or 6-membered heteroaryl, including one or two heteroatoms independently selected from N, S and O and tetrahydrofuranyl, wherein each of said alkyl and heteroaryl groups is optionally substituted with C _1-6 alkyl, OH or C _3-6 cycloalkyl; R ^Z is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and oxetanyl; Y is C _1-4 haloalkyl or C _1-6 alkyl; R1 is a structure group

wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, trifluoromethyl, ethyl, or together with R2 forms a cyclopropyl group, or R3 forms a methylene bridge with the carbon atom marked *. 2. The compound of formula (I) according to claim 1, in which Ar is selected from the group consisting of phenyl and pyridyl, each of which is optionally substituted with one, two or three independently selected substituents R ^Ar ; R ^Ar is selected from the group consisting of halogen, -OH, -CN, C _1-6 -alkoxy, di-C _1-6 -alkylamino-C _1-6 -alkoxy, -CONHR', benzyloxy, -CO-azetinidyl, -CO-pyrrolidinyl, -CO-morpholinyl, -CO-C _3-6 -cycloalkyl, -CONH-C _3-6 -cycloalkyl and -OC _1-6 -alkyl-heterocyclyl, where heterocyclyl is selected from the group consisting of pyrrolidinyl, piperazinyl, morpholinyl, 1,1-dioxothiomorpholinyl and (2-oxa-6-azaspiro[3.3]hept-6-yl)-C _1-4 -alkoxy, where each of these heterocyclyl groups is optionally substituted with C _1-6 -alkyl and where R' represents C _1-6 -alkyl; Z is selected from the group consisting of H, -CO-R ^Z , -CH ₂ -OR ^Z , -CO-CH ₂ -R ^Z , -CO-CH ₂ -OR ^Z , -COOR ^Z , -CO-NHR ^Z , C _1-6 -alkyl-OC _1-6 -alkyl-OR ^Z , C _1-6 -alkyl, 5- or 6-membered heteroaryl containing one or two heteroatoms independently selected from N, S and O, and tetrahydrofuranyl, where each of these alkyl and heteroaryl groups is optionally substituted with C _1-6 -alkyl, OH or C _3-6 -cycloalkyl; R ^Z is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and oxetanyl; Y is C _1-4 haloalkyl or C _1-6 alkyl; R1 is a structure group

wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, trifluoromethyl, ethyl or, taken together with R2, forms a cyclopropyl group; or n is 1, R2 is H, deuterium or methyl, and R3 forms a methylene bridge with the carbon atom marked *. 3. The compound of formula (I) according to claim 1 or 2, in which Ar is selected from the group consisting of phenyl and pyridyl, each of which is optionally substituted with one, two or three R ^Ar substituents; R ^Ar is selected from the group consisting of halogen, -OH, -CN, C _1-4 -alkoxy, di-C _1-4 -alkylamino-C _1-4 -alkoxy, benzyloxy, -CO-N(R ^N ) ₂ , in which one ^RN is H and the other is C _1-3 alkyl, C _3-4 cycloalkyl, or both ^RN taken together with the N to which they are attached form an azetane, pyrrolidine or morpholine ring; Z is selected from the group consisting of H, -CO-C _1-4 -alkyl, -CO-CH ₂ -C _1-4 -alkoxy, -CO-CH ₂ -OC _3-5 -cycloalkyl, -CH ₂ -OH , -CH ₂ -OC _1-4 -alkyl, -CH ₂ -OC _3-5 -cycloalkyl, -COO-C _1-4 alkyl, -CONH-C _1-4 alkyl, -CONH-C _3-5 -cycloalkyl , -CO-CH ₂ -C _3-5 -cycloalkyl, -COO-C _3-5 -cycloalkyl, cycloalkylmethyl, alken-1-one, -C _1-2 -alkyl-OC _1-2 -alkyl-OC _{1- 4} -alkyl, 5- or 6-membered heteroaryl containing one or two heteroatoms independently selected from N, S and O, or tetrahydrofuranyl; Y is C _1-6 alkyl or C _1-4 haloalkyl; R1 is a structure group

wherein n is 0; R2 is H, deuterium or methyl; R3 is methyl, trifluoromethyl, ethyl or, taken together with R2, forms a cyclopropyl group; or n is 1; R2 is H, deuterium or methyl; R3 is methyl or trifluoromethyl or forms a methylene bridge with the carbon atom marked *. 4. A compound according to any one of claims 1 to 3, wherein Ar is selected from the group consisting of phenyl and pyridyl, each of which is optionally substituted with one, two or three R ^Ar substituents; R ^Ar is selected from the group consisting of halogen, OH, -OC _1-3 -alkyl and dimethylamino-C _1-2 -alkoxy; Z is selected from the group consisting of -COO-C _1-3 -alkyl, -CO-CH ₂ -OC _1-2 -cycloalkyl, 5- or 6-membered heteroaryl containing one or two heteroatoms independently selected from N, S and O, -COO-C _3-5 -cycloalkyl, -CONH-C _3-5 -cycloalkyl, -CO-CH ₂ -C _3-5 -cycloalkyl, -CH ₂ -OC _3-5 -cycloalkyl, -CO- C _1-4 -alkyl and -C _1-2 -alkyl-OC _1-2 -alkyl-OC _1-2 -alkyl; Y is selected from the group consisting of CF ₃ and Me; R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2-hydroxy-3,3 ,3-trifluoropropyl, 2-hydroxy-2-deuteropropyl and 1-hydroxycyclopropylmethyl. 5. Connection according to claim 1 or 2, in which Ar is phenyl optionally substituted with one, two or three R ^Ar substituents; R ^Ar is selected from the group consisting of halogen, -OC _1-3 -alkyl and (dimethylamino)-C _1-2 -alkoxy; Z is selected from the group consisting of H, COO-C _1-3 -alkyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiophenyl, furan, tetrahydrofuran, cyclopropoxymethyl, cyclohexoxymethyl, cyclopentoxymethyl, -COO-cyclopropyl, - COO-cyclobutyl, -COO-cyclopentyl, -COO-cyclohexyl, pent-4-en-1-one, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclobutoxymethyl, acetyl, methoxyacetyl, -CO-CH ₂ -cyclobutyl, -CO-CH ₂ -cyclopropyl, -CO-CH ₂ -cyclopentyl, -CO-CH ₂ -cyclohexyl, -COO-oxetane, methoxyethoxymethyl, -CONH-cyclopropyl, -CONH-cyclobutyl, -CONH-cyclopentyl and -CONH-cyclohexyl, in which the specified pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl imidazolyl, thiophenyl, tetrahydrofuran and furan are optionally substituted with methyl or OH; Y is selected from the group consisting of CF ₃ and Me; R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2-hydroxy-3,3 ,3-trifluoropropyl, 2-hydroxy-2-deuteropropyl and 1-hydroxycyclopropylmethyl. 6. A compound according to any one of claims 1 to 5, wherein Ar is phenyl which is optionally substituted with one, two or three R ^Ar substituents; R ^Ar is selected from the group consisting of Cl, -OMe, F and 2-(dimethylamino)ethoxy; Z is selected from the group consisting of -COOMe, -COOEt, pyrimidin-2-yl, thiazol-2-yl, cyclopropoxymethyl, -COO-cyclopropyl, -COO-cyclobutyl, pent-4-en-1-one, pyrimidin-4 -yl, methoxymethyl, pyrazin-2-yl, CO-CH ₂ -cyclobutyl, -COO-oxetane, 5-methylisoxazol-2-yl, -CONH-cyclopentyl; Y is selected from the group consisting of CF ₃ and Me; R1 is selected from the group consisting of 3-hydroxy-3-methylbutyl, 3-hydroxy-3-methylcyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxycyclobutyl, 2-hydroxy-3,3,3-trifluoropropyl, 2-hydroxy -2-deuteropropyl and 1-hydroxycyclopropylmethyl. 7. The compound of claim 1, wherein the compound is selected from the group consisting of 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-2-methylpropan-2-ol 1-({4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}methyl)cyclopropan-1-ol 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-2-methylbutan-2-ol (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5- (trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol (2 S )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5- (trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}butan-2-ol ( rac ) 3-{4-[3-(2-Chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1,1,1-trifluoropropan-2-ol ( rac ) ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( anti ) ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate ethyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxybutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate ( rac ) ethyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3,3,3-trifluoro-2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazole-4-carboxylate ( rac ) ethyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-3,3,3-trifluoro-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazole-4- yl}-1,2-oxazole-4-carboxylate methyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( anti ) methyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( syn ) methyl-3-(2-chlorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate methyl-3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazol-4- carboxylate methyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-3-(2-methoxypyridin-3-yl)-1,2-oxazole -4-carboxylate methyl 3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate methyl 3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazole-4-carboxylate methyl-3-(2-chloro-3-methoxyphenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-methyl-1H-pyrazol-4-yl]-1,2-oxazol-4- carboxylate methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( anti ) methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) methyl 3-(2-chloro-6-fluorophenyl)-5-[1-(3-hydroxycyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole-4-carboxylate 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}( ^2-2H )propan-2-ol ( rac ) ethyl 3-(2-chloro-6-fluorophenyl)-5-{1-[2-hydroxy( ^2-2H )propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( rac ) methyl-3-(2-chloro-6-fluorophenyl)-5-{1-[2-hydroxy( ^2-2H )propyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxylate ( rac ) 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]ethan-1-one 1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2- oxazol-4-yl]ethan-1-one 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]-2-cyclobutylethane-1-one 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]pent-4-en-1-one 2-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]-1-cyclopropylhex-5-en-2-ol ( rac ) 1-[3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazole -4-yl]-2-methoxyethan-1-one 1-[3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2- oxazol-4-yl]-2-methoxyethan-1-one 3-(2-chloro-6-fluorophenyl)- N -cyclopentyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxamide 3-(2-chloro-6-fluorophenyl)- N -cyclopropyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxamide 3-(2-chloro-6-fluorophenyl)- N -cyclobutyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2- oxazole-4-carboxamide 3-(2-chloro-6-fluorophenyl)- N -cyclopentyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxamide 3-(2-chloro-6-fluorophenyl)- N -cyclopropyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxamide 3-(2-chloro-6-fluorophenyl)- N -cyclobutyl-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2 -oxazole-4-carboxamide oxetan-3-yl-3-(2-chlorophenyl)-5-{1-[( 2S )-2-hydroxypropyl]-5-methyl-1H-pyrazol-4-yl}-1,2-oxazol-4 -carboxylate cyclopropyl-3-(2-chlorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1, 2-oxazole-4-carboxylate ( anti ) cyclopropyl-3-(2-chlorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1, 2-oxazole-4-carboxylate ( syn ) cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( anti ) cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) oxetan-3-yl-3-(2-chlorophenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-methyl-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate ( syn ) cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( syn ) cyclopropyl-3-(2-chlorophenyl)-5-{5-methyl-1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}-1,2- oxazole-4-carboxylate ( anti ) cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate cyclobutyl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1, 2-oxazole-4-carboxylate oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylate cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1,2-oxazole -4-carboxylate oxetan-3-yl-3-(2-chloro-6-fluorophenyl)-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-1 ,2-oxazole-4-carboxylate cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate ( syn ) cyclopropyl-3-(2-chloro-6-fluorophenyl)-5-{5-methyl-1-[(1 S ,3 R )-3-hydroxy-3-methylcyclobutyl]-1H-pyrazol-4-yl}- 1,2-oxazole-4-carboxylate ( anti ) 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(hydroxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn ) 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol (2 S )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 S ,3 R )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( anti ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn ) (1 S ,3 R )-3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( anti ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn ) (2 S )-1-{4-[3-(2-chlorophenyl)-4-[(2-methoxyethoxy)methyl]-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole -1-yl}propan-2-ol (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(ethoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol 4-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}-2-methylbutan- 2-ola 4-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-methylbutan-2- ola (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( syn ) (1 S ,3 R )-3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-1-methylcyclobutan-1-ol ( anti ) 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- methylbutan-2-ol (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 S ,3 R )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( anti ) (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-1 -yl}-1-methylcyclobutan-1-ol ( syn ) (2 S )-1-{4-[3-(2-chlorophenyl)-4-[(oxetan-3-yloxy)methyl]-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}propan-2-ol (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-[(propan-2-yloxy)methyl]-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}propan-2-ol (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(cyclobutoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol 4-{4-[3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol (1 R ,3 S )-3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(cyclopropoxymethyl)-1,2-oxazol- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn ) methyl-5-[1-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-3-(2-hydroxypyridin-3-yl)-1,2-oxazol- 4-carboxylate (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}propan- 2-ola 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(methoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}( 2-2H) propan-2-ol ( rac ) (2 S )-1-{4-[3-(2-chlorophenyl)-4-(oxolan-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole- 1-yl}propan-2-ol (2 R )-1-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 S ,3 R )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-( trifluoromethyl)-1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( anti ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chlorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole -1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrazin-2-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl -1H-pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) (2 R )-1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol 1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol (2 R )-1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol- 1-yl}propan-2-ol 1-{4-[3-(2-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylpropan-2-ol (2 R )-1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol 1-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylpropan-2-ol (2 R )-1-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)- 1H-pyrazol-1-yl}propan-2-ol 1-{4-[3-(2-Chloro-3-methoxyphenyl)-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylpropan-2-ol 4-{4-[3-(2-chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylbutan-2-ol 4-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1-yl}- 2-methylbutan-2-ol 4-{4-[3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H-pyrazol-1 -yl}-2-methylbutan-2-ol 4-{4-[3-(2-Chloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol 4-{4-[3-(2,6-dichloro-3-methoxyphenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazole-1 -yl}-2-methylbutan-2-ol 4-{4-[3-(2-chlorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- methylbutan-2-ol 4-{4-[3-(2-Chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2-methylbutan-2-ol 4-(4-{3-[3-(benzyloxy)-2-chlorophenyl]-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazole -1-yl)-2-methylbutan-2-ol 2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2-yl)-1,2 -oxazol-3-yl}phenol (1 R ,3 S )-3-{4-[3-(2-chloro-3-methoxyphenyl)-4-(cyclopropoxymethyl)-1,2-oxazol-5-yl]-5-(trifluoromethyl)-1H -pyrazol-1-yl}-1-methylcyclobutan-1-ol ( syn ) ethyl 3-(2-chloro-3-methoxyphenyl)-5-{1-[(1 R ,3 S )-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl }-1,2-oxazole-4-carboxylate ( syn ) ethyl-3-(2-chloro-3-methoxyphenyl)-5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-1,2-oxazol- 4-carboxylate 4-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5- yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(diethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[2-(2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2- yl)-1,2-oxazol-3-yl}phenoxy)ethyl]-1labmda6-thiomorpholine-1,1-dione 4-(4-{3-[2-chloro-3-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}ethoxy)phenyl]-4-(pyrimidin-2-yl)- 1,2-oxazol-5-yl}-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[3-(2-chloro-3-{5-[1-(3-hydroxy-3-methylbutyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-4-(pyrimidin-2- yl)-1,2-oxazol-3-yl}phenoxy)propyl]-1lambda6-thiomorpholine-1,1-dione 4-[4-(3-{2-chloro-3-[3-(pyrrolidin-1-yl)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[3-(diethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-( trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(diethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-methyl -1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-methyl -1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl) -5-methyl-1H-pyrazol-1-yl]-2-methylbutan-2-ol 4-[4-(3-{2-chloro-3-[3-(diethylamino)propoxy]phenyl}-4-(pyrimidin-2-yl)-1,2-oxazol-5-yl)-5-methyl -1H-pyrazol-1-yl]-2-methylbutan-2-ol methyl-3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-5-{1-[( 2S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H- pyrazol-4-yl}-1,2-oxazole-4-carboxylate methyl-3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-{1-[(2 S )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazole-4- yl}-1,2-oxazole-4-carboxylate (1 R ,3 S )-3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn ) (1 R ,3 S )-3-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( syn ) (1 S ,3 R )-3-[4-(3-{2-chloro-3-[2-(morpholin-4-yl)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol- 5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( anti ) (1 S ,3 R )-3-[4-(3-{2-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-4-(methoxymethyl)-1,2-oxazol-5-yl) -5-(trifluoromethyl)-1H-pyrazol-1-yl]-1-methylcyclobutan-1-ol ( anti ) (2 R )-1-(4-{3-[2-chloro-3-(morpholine-4-carbonyl)phenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl} -5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol 2-chloro -N -cyclobutyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzamide 2-chloro- N -ethyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzamide 2-chloro-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl) - N - (propan-2-yl) benzamide (2 R )-1-(4-{3-[3-(azetidine-1-carbonyl)-2-chlorophenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl}- 5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol 2-chloro -N -cyclopropyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl )-1,2-oxazol-3-yl)benzamide (2 R )-1-(4-{3-[2-chloro-3-(pyrrolidin-1-carbonyl)phenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl} -5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol N -cyclopropyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)-2-methoxybenzamide 3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol- 3-yl)-2-methoxy- N- (propan-2-yl)benzamide (2 R )-1-(4-{3-[3-(azetidine-1-carbonyl)-2-methoxyphenyl]-4-(pyrimidin-4-yl)-1,2-oxazol-5-yl}- 5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol N -cyclobutyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)-2-methoxybenzamide N -ethyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)-2-methoxybenzamide N -cyclobutyl-3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1, 2-oxazol-3-yl)benzamide 3-(5-{1-[(2 R )-2-hydroxypropyl]-5-(trifluoromethyl)-1H-pyrazol-4-yl}-4-(pyrimidin-4-yl)-1,2-oxazol- 3-yl) -N- (propan-2-yl)benzamide. 8. A compound according to any one of claims 1 to 7 for use as a drug for the treatment of a disease or medical condition in which inhibition of interleukin-17 (IL-17) and/or interferon-γ (IFN-γ) is preferred. 9. The compound for use according to claim 8, wherein the disease or medical condition is selected from the group consisting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, diabetes mellitus I type, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behçet's disease, atopic dermatitis, lichen planus, Sjögren's syndrome, herniated discs, acne, graft versus host disease, host versus graft disease, AIH (autoimmune hepatitis), PBC (primary biliary cholangitis), PSC (primary sclerosing cholangitis), obesity, lupus nephritis, autoimmune thyroid diseases including Graves' disease and Hashimoto's disease, autoimmune uveitis, colitis, IMQ psoriasis, juvenile idiopathic arthritis, myasthenia gravis, systemic sclerosis, diabetes mellitus, and osteoarthritis . 10. The use of a compound of formula (I) as defined in any one of claims 1 to 7 for the manufacture of a medicament for the treatment of a disease or medical condition in which inhibition of interleukin-17 (IL-17) and/or interferon-γ (IFN) -γ) is preferred. 11. Use according to claim 10 wherein the disease or medical condition is selected from the group consisting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, type I diabetes mellitus , multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behçet's disease, atopic dermatitis, lichen planus, Sjögren's syndrome, herniated discs, acne, graft versus host disease, host versus graft disease, AIH (autoimmune hepatitis), PBC (primary biliary cholangitis), PSC (primary sclerosing cholangitis), obesity, lupus nephritis, autoimmune thyroid diseases including Graves' disease and Hashimoto's disease, autoimmune uveitis, colitis, IMQ psoriasis, juvenile idiopathic arthritis, myasthenia gravis, systemic sclerosis, diabetes mellitus, and osteoarthritis.