NZ761897B2 - 1-(4-(isoxazol-5-yl)-1h-pyrazol-1-yl)-2-methylpropan-2-ol derivatives and related compounds as il-17 and ifn-gamma inhibitors for treating autoimmune diseases and chronic inflammation - Google Patents

1-(4-(isoxazol-5-yl)-1h-pyrazol-1-yl)-2-methylpropan-2-ol derivatives and related compounds as il-17 and ifn-gamma inhibitors for treating autoimmune diseases and chronic inflammation Download PDF

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NZ761897B2
NZ761897B2 NZ761897A NZ76189718A NZ761897B2 NZ 761897 B2 NZ761897 B2 NZ 761897B2 NZ 761897 A NZ761897 A NZ 761897A NZ 76189718 A NZ76189718 A NZ 76189718A NZ 761897 B2 NZ761897 B2 NZ 761897B2
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pyrazolyl
trifluoromethyl
oxazolyl
methyl
arom
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NZ761897A
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NZ761897A (en
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Carine Chevrier
Jakob Felding
Manfred Groppel
Hella Kohlhof
Rolf Andreas Muhler
Stefan Tasler
Daniel Vitt
Mirko Zaja
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Immunic Ag
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Priority claimed from PCT/EP2018/073993 external-priority patent/WO2019048541A1/en
Publication of NZ761897A publication Critical patent/NZ761897A/en
Publication of NZ761897B2 publication Critical patent/NZ761897B2/en

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Abstract

The present invention relates to compounds of the general formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein Ar, Z and Y are as described herein and R1 is a group of the structure (formula (II)), wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, trilluoromethyl, ethyl, or taken with R2 together forms a cyclopropyl group, or R3 forms a methylene bridge to the carbon atom marked *, which are suitable for the treatment of autoimmune diseases and chronic inflammation.

Description

The present invention relates to compounds of the general formula (I), and the ceutically acceptable salts and solvates thereof, wherein Ar, Z and Y are as described herein and R1 is a group of the structure (formula (II)), wherein n is 0 or 1; R2 is H, ium or methyl; R3 is methyl, trilluoromethyl, ethyl, or taken with R2 together forms a cyclopropyl group, or R3 forms a methylene bridge to the carbon atom marked *, which are suitable for the treatment of autoimmune diseases and chronic inflammation.
NZ 761897 ISOXAZOLYL)-1H-PYRAZOLYL)METHYLPROPANOL DERIVATIVES AND RELATED COMPOUNDS AS IL-17 AND IFN-GAMMA INHIBITORS FOR TREATING AUTOIMMUNE ES AND CHRONIC MATION Introduction The lL-l7 family of cytokines has been associated with the enesis of autoimmune diseases and is generally blamed for the pathogenic symptoms of autoimmune and chronic in?ammation. Overexpression of IL-17 is a hallmark of autoimmune and chronic in?ammatory diseases like rheumatoid tis, psoriasis and psoriatic arthritis, ankylosing spondylitis, atory bowel disease, multiple sis, vasculitis and atherosclerosis, systemic lupus erythematosus, as well as lung disorders, asthma and chronic obstructive pulmonary diseases. (review in Miossec and Kolls, Nature Reviews Drug Discovery, 2012 1).
The IL—l7 cytokine family comprises six members, out of which IL-17A and lL—l7F are the best characterized. lL-l7A and lL-17F exist as homo- as well as heterodimers (IL-17AA, IL— l7AF, lL—l7FF). IL—17A and IL-17F are clearly associated with in?ammation, whereas the role of the other lL—l7 family members is less explored (summarized in Reynold et al., Cytokine Growth Factor Rev, 2010 2).
Secretion of lL—l 7 is mainly caused by a specific subtype ofT helper cells termed Thl7 cells.
Differentiation of naive CD4+ T cells into Thl7 cells is induced in the presence of the cytokines lL-lB, TGFB and lL-6, whereas IL—23 maintains TH17 cell survival. Important transcription factors for the ription and secretion of IL-17 from T1117 cells are RORyt and STAT3. lL-l7 itself induces production of effector molecules in 1L1 7R expressing cells like endothelial cells, epithelial cells or asts, macrophages and dendritic cells, chondrocytes and lasts. Those effector molecules are pro-in?ammatory cytokines (IL— 6, TNF-u and IL-lb), chemokines (like CXCLl, CXCLZ, CXCLS, CCLZ, CCL7 and CCLZO), growth factors (G-CSF, GM—CSF) and nitric oxide, prostaglandin E2 and matrix- metalloproteases. ted by these effector molecules, neutrophil in?ltration, tissue damage and chronic in?ammation occurs (summarized in Miossec and Kolls, Nature Reviews Drug Discovery, 2012 1).
Before the recognition of the importance of lL-l 7 in autoimmune ation, [EN-gamma derived from Th1 cells was ed to be the important cytokine that drives autoimmune disorders. mma ription and secretion from Th1 effector cells is ted by the transcription factors T—bet and STAT4. As an effector cytokine of Th1 immunity, IFN-gamma is the key regulator of macrophage activation. In parallel, INF-gamma signaling generates other cytokines and in?ammatory factors to sustain in?ammation, maintain Th1 responses and inhibit differentiation of regulatory T cells, Th2 cells and Thl7 cells (summarized in 3 and Pollard et at, Discov. Med, 2014 Green et al., J. Biol. Chem, 2017 4).
Recently, the existence of hybrid Th1/Thl7 cells was described. These cells can be induced in vitro by IL-23 and IL-6 in concert with IL—1 and secrete lL—l7 and IFN—gamma. It was trated that these double producing cells harbor pronounced pro-in?ammatory 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; a et a1., Clin Immunol, 2014 7; Ramesh et al., J.Exp. Med. 2014 8)‘ Compounds which target and suppress both IL—17 and lFN-gamma are therefore predestined for the treatment of autoimmune disorders.
The effectiveness of blocking lL—l7 signaling alone as therapeutic ent in autoimmune diseases has already been proven in clinical trials with eg. monoclonal antibodies against IL- 17A (sekukinumab, ixekizumab, ABT—122, CNTO 6785, CJM112, COVA322, ALX—0761, bimekizumab, SCH-900117) and/or the IL-17 receptor A (AMG827, brodalumab).
Further antibodies in clinical development targeting lL—l7—Thl7 pathway by addressing the p19 subunit of IL-23 are tildrakizumab, guselkumab, AMG139, BI655066 and LY3074828 (summarized in Bartlett and Million, Nature Reviews Drug Discovery 2015).9 ve s have been reported for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritic, uveitis, ankylosing spondylitis and spondyloarthritis. Other autoimmune diseases under investigation are s disease, asthma and multiple sclerosis.
On the other hand, blocking the mma signaling alone in autoimmune diseases with IFN-garnma-speci?c monoclonal antibody AMGSll was investigated in clinical trials for ic and discoid lupus erythematosus Without signi?cant clinical benefit so far (Werth et a1., Arthritis 2017 I0).
Miossec, P. & Kolls, J. K. Targeting IL-17 and TH17 cells in chronic in?ammation. Nat.
Rev. Drug Discov. 11, 763—776 (2012).
Reynolds, J. M., Angkasekwinai, P. & Dong, C. IL-l7 family member cytokines: regulation, and function in innate immunity. Cytokine Growth Factor Rev. 21, 413—423 (2010).
Pollard, K. M., Cauvi, D. M., Toomey, C. K. V. & Keno, D. H. Interferon-y ., Morris, and Systemic Autoimmunity. . Med. 16, 123—131 (2013).
Green, D. 3., Young, H. A. & Valencia, J. C. Current prospects of type 11 interferon gamma signaling and autoimmunity. J. Biol. Chem. jbc.Rll6.774745 (2017). doi:10.1074/jbc.R116.774745 Buonocore, S. et al. Innate lymphoid cells drive lL-23 dependent innate intestinal pathology. Nature 464, 1371w—l375 .
Ghoreschi, K. et a]. Generation of enic Thl7 Cells in the Absence of TGF—? Signaling. Nature 467, 967—971 (2010).
Marwaha, A. K., Tan, S. & Dutz, J. P. ing the IL-l7/lFN—y axis as a potential new clinical therapy for type 1 diabetes. Clin. Immunol. Orlando Fla 154, 84—89 (2014).
Ramesh, R. et al. Pro—in?ammatory human T1117 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J. Exp. Med. 211, 89—104 (2014). tt, H. S. & Million, R. P. Targeting the lL—l7~THl7 pathway. Nat. Rev. Drug Discov. 14, 11—12 (2015).
. Werth, V. P. et al. Brief Report: Pharmacodynamics, Safety, and al Ef?cacy of AMG 811, a Human Anti-Interferon—y Antibody, in ts With Discoid Lupus Erythematosus. Arthritis Rheumatol. Hoboken NJ 69, 1028—1034 (2017). structure of the compounds of the present invention, but different substitution patterns, in particular with regard to group R1.
Detailed description of the invention In certain ments the t invention s to a nd of formula (1) as described in the following items: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, formula (I) wherein Ar is selected from the group consisting ofphenyl and heteroaryl, each of which is optionally substituted by one or more independently selected substituents RAT; is selected from the group consisting of halogen, -OH, —CN, , haloalkoxy, alkyl, haloalkyl, mono— or dialkylamino-alkyl, mono- or di- alkylamino-alkoxy, —COOR’, -CONHR’, -CO—R’, -S02NHR’, -NH—CO—R’, -N02, -NH-SOz-R’, ~SOz-R’, benzyloxy, -CO-heterocyclyl, -CO—cycloa1ky1, — CONH—cycloalkyl, —CONH- heterocyclyl, ~O-alkyl-heterocyclyl, -O—alkyl- cycloalkyl., (2-oxaazaspiro[3.3]heptyl)-C]4-alkoxy, amino, aralkyl, cycloalkyl, cyclyl, phenyl and heteroaryl, wherein each of said alkoxy, l, alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl groups is optionally substituted be one or more substituents independently selected from alkyl, haloalkyl, n and OH, and wherein R’ is independently selected from the group consisting of independently represents H, OH, alkyl and haloalkyl; is selected from the group consisting of H, halogen, , -CH2—O—RZ, ~CO- CHz-RZ, -CO-CH2-O-RZ, £00117", -NHCO—Rz, —CO-NHRZ, -N(RZ 2, -CN, -NHCOORZ, , -SOzNHRZ, «alkyl-O—RZ, -alkyl—O—alkyl-O—RZ, amino, alkyl, phenyl, heteroaryl, heterocyclyl and cycloalkyl, n each of said alkyl, phenyl, heteroaryl, heterocyclyl and cycloalkyl groups is optionally substituted be one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, -COO—alkyl, OH and cycloalkyl; R2 is selected from the group consisting of H, halogen, -OH, alkyl, kyl, cycloalkyl, heterocyclyl, heterocyclyl, phenyl and heteroaryl, is H, halogen, haloalkyl, alkyl or an alkylester; R1 is a group of the structure wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, tri?uoromethyl, ethyl, or taken with R2 together forms a cyclopropyl group, or R3 forms a methylene bridge to the carbon atom marked *. 2. The compound of formula (1) according to item 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 by one or more independently selected substituents R"; is selected from the group consisting of halogen, -OH, -CN, alkoxy, haloalkoxy, alkyl, haloalkyl, mono— or dialkylamino-alkyl, mono- or di- alkylamino-alkoxy, , -CONHR’, —CO-R’, —SOgNHR’, —NH-CO—R’, -N09_, -NH—SOg-R’, -SOg-R’, benzyloxy, terocyclyl, -CO—cycloalkyl, -CONH*cycloalkyl, -CONH— heterocyclyl, yl—heterocyclyl, —O—alkyl- cycloalkyl, (2-oxaazaspiro[3.3]hept-6—yl)-CH-alkoxy, amino, aralkyl, cycloalkyl, cyclyl, phenyl and heteroaryl, wherein each of said alkoxy, aralkyl, alkyl, lkyl, heterocyclyl, phenyl and heteroaryl groups is optionally substituted be one or more tuents independently selected from alkyl, haloalkyl, halogen and OH, and wherein R’ is independently selected from the group consisting of independently ents H, OH, alkyl and haloalkyl; is selected from the group consisting of H, n, —CO-RZ, -CH2-O-RZ, -CO- CHz-RZ, -CO-CHZ—O-RZ, noon/Z, -NHCO-RZ, -CO-NHRZ, -N(RZ)2, -CN, - NHCOzRZ, —SOz—RZ, -SO;NHRZ, —alky1—O-RZ, —a1ky1-o—a1ky1—o—RZ, amino, alkyl, , heteroaryl,’ heterocyclyl and cycloalkyl, wherein each of said alkyl, phenyl, heteroaryl, heterocyclyl and cycloalkyl groups is optionally substituted be one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, -COO-alkyl, OH and cycloalkyl; is selected from the group consisting of H, halogen, -OH, alkyl, haloalkyl, cycloalkyl, heteroeyclyl, heterocyclyl, phenyl and heteroaryl, is H, halogen, haloalkyl, alkyl or an ster; R1 is a group of the structure wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, tri?uoromethyl, ethyl, or taken with R2 together forms a cyclopropyl group; or n is 1, R2 is H, deuterium or methyl and R3 forms a methylene bridge to the carbon atom marked *. 3. The compound of formula (1) according to item 1 or 2 or a ceutically acceptable salt or solvate thereof, wherein Ar is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, each of which is ally substituted by one or more substituents is selected from the group consisting of n, OH, CN, C1_4-alkyl, C14- haloalkyl, -NH2, acetamido, -COO-C1_4—alkyl, CM-alkoxy, and (mono- or di- kyl—amino)~C14—alkoxy, more particularly halogen, C1_4—a1koxy, and (mono- or di-C1_4—alkyl-amino)-C;a1koxy, benzyloxy, -CO-N(RN)2 wherein one RN is H and the other is C1_3—alkyl, C3—4cycloalkyl or both RN taken together with the N to which they are attached form an azetane, pyrrolidine or morpholine ring, -CONRN wherein 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, l,l-dioxothiornorpholine, 4-methyl- piperazin,or 2-ox.a—6—azaspiro[3.3]heptane ring; is selected from the group consisting of H, n, -CO-C].4-alkyl, -CO-CH2- CM—alkoxy, —CO-CH2-O-C3_5-cycloalkyl, terocyclyl, -CH2-OH, -CH2- O—CH—alkyl, -CH2—O—C3cycloalkyl, ~NH2, —NH-COO-C1_4alkyl, —CN, —COO— C1-4alkyl, C14alkyl, -CONH—arylalkyl, -CONH-cycloalkyl, -CON(C1_ 4alkyl)2, -CON(C14alkyl)—O-C1_4alkyl, -CO—CH2—cycloalkyl, COO— heterocyclyl, -COO-cycloalkyl, cycloalkylmethyl, alken-l—one, alkyloxyalkyl, —C1.2—alkyl-O—C1.2-alkyl-O-C1-4—alkyl, cycloalkylmethyl-alken-l-ol, aryl, phenyl, or heterocyclyl, wherein said phenyl, and heterocyclyl is optionally substituted by one or more substituents independently selected from the group comprising n, alkyl, alkoxy, haloalkyl, 1ky1, OH and cycloalkyl; is selected from the group consisting of H, alkyl, haloalkyl, and alkylester; R1 is a group ofthe structure wherein n is 0; R2 is H, deuterium or methyl; R3 is methyl, tri?uoromethyl, ethyl, or taken with R2 together forms a eyclopropyl group; n is 1; R2 is H, deuterium or methyl; R3 is methyl or tri?uoromethyl or forms a methylene bridge to the carbon atom marked *.
The compound according to any of items 1 to 3 or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from the group ting of phenyl and pyridyl, each of which is optionally substituted by one or more substituents RA"; is selected from the group consisting of n, OH, -O—C1_3—a1kyl, -O-C1-3— kyl, CH-alkyl, C1_4—haloalkyl, (mono- or dimethylamino)3-a1kyl and (mono- or dimethylamino)—C1.2—alkoxy; is selected from the group consisting of H, —COO—C]_3-alkyl, —CO-C1_2-alkyl, — CO-CHg-C1_3-alkoxy, 2-O-C3_4-cycloalkyl, 5- or 6-membered heteroaryl, phenyl, -COO-C3cycloalkyl, 3_6-heterocyclyl, -CON-C3_5- cycloalkyl, -CON-C3heterocyclyl, -CO-CH2-C3cycloalkyl, -CH2-O-C3 cycloalky], —CO—C1-4—aikyl, ~C1_2—alkyl—O-C1-2—alkyl, H, —CH2-O-C1_3- alkyl, -CH2-O-cyclobutyl, -C1.2—alkyl-O-C1.z-alkyl-O—C1-z-alkyl and — C(OH)(C1alkyl)(CH2—C3_6—cycloalkyl), wherein said heteroaryl, phenyl, heterocyclyl, cycloalkyl and alkyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, halogen, CF3, OMe and OH; is ed from the group consisting of CE; and Me; R1 is selected from the group consisting of 3—hydroxy—3-methylbutyl, 2-hydroxy— ylpropyl, 3-hydroxy-3~methyl-cyclohutyl, 2—hydroxypropyl, 2— hydroxybutyl, 3-hydroxy—cyclobutyl, 2-hydroxy—3,3,3—tri?uoropropyl, 2— y-Z-deutero-propyl, and l-hydroxy—cyclopropylmethyl.
The compound according to any of items 1 to 4 or a pharmaceutically acceptable salt or solvate thereof, wherein AI is selected from the group ting of phenyl optionally substituted by one or more substituents RA"; is selected from the group consisting of n, -O-C1.3-alky1, -O-C1.3- haloalkyl, CM-alkyl, Cln—haloalkyl and (dimethylamino)-C1.z—alkoxy; is selected from the group consisting of H, COO—C1_3-alky1, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, olyl, isothiazolyl imidazolyl, oxadiazolyl, thiadiazolyl, thiophenyl, furan, tetrahydrofuran, cyclopropoxymethyl, cyclohexoxymethyl, cyclopentoxymethyl, —COO—cyclopropyl, ~COO— cyclobutyl, -COO-cyclopentyl, —COO-cyclohexyl, pent—4-en-l-one, hydroxymethyl, methoxymethyl, methyl, isopropoxylnethyl, cyclobutoxymethyl, methoxyethyl, acetyl, methoxyacetyl, —CO-CH2- utyl, -CO-CH2—cyclopropyl, —CO—CH2—cyclopentyl, —CO-CH2— cyclohexyl, -COO-oxetan, l-cyclopropylmethyl-pent—4-en—l-ol, —methoxy— ethoxy—methyl, cyclopropyl, —CONH—cyclobutyl, -CONH-cyclopentyl, and cyclohexyl, wherein said pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl imidazolyl, oxadiazolyl, thiadiazolyl, thiophenyl, tetrahydrofuran and furan is optionally substituted with one or more substituents independently selected from the group consisting of methyl, halogen, CF3, OMe and OH; is selected ?om the group consisting of CF3 and Me; R1 is ed from the group consisting of 3-hydroxy—3 -methylhuty1, 2-hydroxy- 2—methylpropy1, 3-hydroxy—3—methyl-cyclobutyl, 2-hydroxypropyl, 2— hydroxybutyl, 3-hydroxy-cyclobutyl, 2-hydroxy—3,3,3-tri?uoropropyl, 2— hydroxy—Z—deutero—propyl, and 1-hydroxy-cyclopropylmethyl.
The compound according to any of items 1 to 5 or a pharmaceutically acceptable salt or solvate thereof, n Ar is phenyl which is optionally substituted by one or more substituents R"; is selected from the group consisting of Cl, —OMe, F and 2-(dimethylamino)— ethoxy; is selected from the group consisting of H, —acety1, ~COOMe, , —CO- CHz-OMe, pyrimidin-Z-yl, pyrazin-Z-yl, thiazol~2~y1= cyclopropoxymethyl, — COO-cyclopropyl, -COO-cyclobutyl, penten-l-one, pyrimidin—4-yl, 2- tetrahydrofuryl, methoxymethyl, ethcxyrnethyl, isopropoxymethyl, cyclobutoxymethyl, 3-oxetanyloxymethyl, hydroxymethyl, pyrazin-Z-yl, -CO- CHz—cyclobutyl, ~COO-oxetan, S-methyl—isoxazol—Z-yl, l-cyclopropyhnethyl— penten-l-ol, 2—methoxy—ethoxymethyl, -CONH—cyclopropy1, -CONH- cyclobutyl and -CONH—cyclopentyl; is selected from the group ting of CF3 and Me; R1 is selected from the group consisting of 3-hydroxy—3-methylbutyl, 3-hydroxy— 3-methyl—cyclobutyl, 2-hydroxypropyl, 2—hydroxybutyl, oxy—cyclobutyl, 2-hydroxy—3,3,3-tri?uoropropyl, 2-hydroxy—2—deutero-propyl, and l-hydroxy— cyclopropylmethyl.
The nd according to any of items 1 to 6, wherein the compound is selected from the group consisting of the examples as listed herein in the example section.
The nd ing to any of items 1 to 7 for use as a medicament. 9. The compound according to any of items 1 to 7 for use in the ent of a e or medical ion is selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, Vitiligo, Crohn’s disease, ulcerative colitis, atory bowel disease, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, s, Behcet disease, atopic dermatitis, Lichen planus, Sjogren’s syndrome, spinal disc herniation, acne, Gra?—versus—Host-Reaction, Host -versus— Graft-Reaction, AIH (Autoimmunhepatitis), PBC (peripheral biliary cholangitis), PSC (primary scleroting cholangitis), y, Lupus nephritis, Autoimmune Thyroid Disorders ing Graves Disease and Hashimoto's Disease, Autoimmune Uveitis, Colitis, IMQ Psoriasis, Juvenile Idiopathic Arthritis, Myasthenia Gravis, ic Sclerosis, diabetis melitus and osteoarthritis. 10. Use of a compound of the formula (I) as de?ned in any of items 1 to 7, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or medical condition in which the inhibition of interleukin-17 (IL-17) and/or Interferon-y (INF-y) is bene?cial. 11. The use of item 10 wherein the disease or medical condition is selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, Vitiligo, Crohn’s e, ulcerative colitis, in?ammatory bowel disease, ankylosing spondylitis, diabetes type 1, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen , nis syndrome, spinal disc herniation, acne, Graft-versus-Host—Reaction, Host -Versus-Graft-Reaction, AIH (Autoimmunhepatitis), PBC (peripheral biliary cholangitis), PSC ry scleroting cholangitis), obesity, Lupus nephritis, Autoimmune Thyroid Disorders including Graves Disease and Hashimoto's Disease, Autoimmune Uveitis, Colitis, IMQ sis, Juvenile Idiopathic Arthritis, Myasthenia Gravis, Systemic Sclerosis, diabetes mellitus and rthritis.
In particular embodiments, as used herein a heteroaryl group denotes a 5— or 6—membered cyclic group ning at least one heteroatom independently selected from O, N or S.
This heterocyclic group is optionally fused to r aromatic or heteroaromatic 5- or 6- membered ring containing at least one heteroatom independently selected from O, N or S. For example, this group can be selected from a thiadiazole, thiazol-2—y1, thiazolyl, thiazol-S—yl, azolyl, isothiazolyl, isothiazol-S-yl, oxazol—Z-yl, oxazol-4—yl, oxazol—S-yl, isooxazol—3~yl, isooxazolyl, isooxazol—S—yl, oxadiazol-3—yl, 1,2,4-oxadiazol—5-yl, 1,2,5—oxadiazolyl, benzooxazol-Z-yl, benzooxazolyl, benzooxazol-S-yl, benzoisooxazol— 3—yl, benzoisooxazolyl, benzoisooxazol-S-yl, 1,2,5-oxadiazolyl, 1,3,4—0xadiazolyl, 1,2,4-thiadiazolyl, 1,2,4—thiadiazolyl, 1,3,4—thiadiazol-2—yl, isothiazol-S-yl, isothiazol-4— yl, isothiazol—S-yl, benzoisothiazol—3—yl, benzoisothiazolyl, benzoisothiazol—S-yl, 1,2,5— thiadiazol-3 -yl, 1 zolyl, 2-i1nidazolyl, 1 ,2,5-thiadiazol~4—yl, 4-imidazoly1, benzoimidazolyl, l—pyrrolyl, 2—pyrrolyl, 3—pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3—pyridyl, 4-pyridyl, 2-pyranyl, 3~pyranyl, nyl, midinyl, 4- pyrimidinyl, 5—pyrimidinyl, pyrid-Z—yl, pyrid—S—yl, pyrid—4-yl, pyrid—S—yl, pyridyl, 3— pyridazinyl, 4-pyridazinyl, 2-pyraziny1, 1-pyrazolyl, 3—pyrazolyl, 4-pyrazolyl, 1,2,3-triazol yl, 1,2,3-triazol-5—yl, 1,2,4-triazolyl, 1,2,4-triazolyl, lH-tetrazol—Z—yl, lH-tetrazol-3—yl, tetrazolyl, acridyl, phenazinyl, carbazolyl, phenoxazinyl, zinc, 2—indolyl, 3-indolyl, 4- l, 5-indolyl, lyl, 7—indolyl, l-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-iso-indolyl, 2—indolinyl, 3—indolinyl, 4—indoliny1, S-indolinyl, linyl, 7— indolinyl, benzo[b]furanyl, benzofurazane, benzothio?n’azane, benzotriazol-l-yl, benzotriazol—4—yl, benzotxiazol—S—yl, benzotriazol—(S-yl, benzotriazol-T-yl, benzotriazine, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or ydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, 6- pyrimidinyl, 2,4-dimethoxy—6—pyrirnidinyl, benzimidazol-Z-yl, lH—benzimidazolyl, nidazol-4—yl, benz-imidazol-S-yl, benzimidazol-6—y1, benzimidazoly], tetrazole, tetrahydro—thieno[3,4-d]imidazol—2—one, pyrazolo[5,l—c][1,2,4]triazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, opyrimidine, opyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, or triazolopyridazine group. Particular heteroaryl groups are pyrimidin yl, pyrimidin-Z-yl, l-Z—yl, pyrazin—Z—yl and isoxazol-Z—yl.
In particular embodiments, as used herein a heterocyclyl group denotes a 3— to 8—membered, more particularly a 3 to 6-membered heterocyclic non—aromatic group ning at least one heteroatom ndently selected from the group consisting of O, N, and S, wherein the heterocyclyl group is optionally fused to another non—aromatic cylcloalkyl or heterocyclyl ring; the cyelyl residue is in ular selected from the group ting of oxetanyl, morpholine—4-yl, piperazinyl, isoxazolidine-Z—yl, l-alkylpiperaziue—4—yl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, lino, thiomorpholinyl, thiornorpholino, ydro?lranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. Particular heterocyclyl groups are tetrahydropyran and oxetan.
To keep the de?nitions as short as possible, as used herein "alkyl", and "alk" (as e.g. in alkoxy) is to be understood to encompass linear and branched l, alkenyl and alkynyl, more particularly alkyl and alkenyl, even more particularly alkanyl. If not stated otherwise, these are in particular embodiments C1—Csaalkanyl, C2—C5—alkenyl or C2-C5-alkynyl, more particularly C1-C5-alkany1, C2-C5-alkenyl or C2-C5 l, even more particularly C1-C4- alkanyl, C2-C4—alkenyl or C2—C4 alkynyl. The alkyl group may for instance be selected from the group consisting of —CH3, -C2H5, -CH=CH2, -CECH, -C3H7, -CH(CH3)2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, ~CEC—CH3, —CH2—CECH, —C4H9, -CH2-CH(CH3)2, —CH(CH3)- Csz, )3, ~C5H11, -C6H13, -C2H4—CH=CH.2, -CH=CH—C2H5, -CH=C(CH3)2, ~CH2- CH=CH—CH3, -CH=CH-CH=CH2, -C2H4- ECH, —CEC-C2H5, -CH2-CEC-CH3, CEC- CH=CH2, -CH=CH—CECH, —CEC-C-=~CH, —C2H4—CH(CH3)2, —CH(CH3)—C3H7, —CH2- CH(CH3)—C2H5, -CH(CH3)—CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -C3H6-CH=CH2, ~CH=CH-C3H7, CH=CH—CH3, -CH2—CH=CH—C2H5, —CH2—CH=CH-CH=CH2, -CH=CH—CH=CH—CH3, -CH=CH-CHg—CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)- , -CH=CH—C(CH3)=CH2, -CH2—CH=C(CH3)2, C(CH3)=C(CH3)2, —C3H6—CECH, —CEC-C3H7, -C2H4-CEC-CH3, -CH2-CEC-C2H5, EC-CH=CH2, -CH2-CH=CH-CECH, —CH2-CEC-CECH, ~CEC-CH=CH-CH3, —CH=CH-CEC—CH3, - EC—CEC-CI—h, —CEC-CH2— CH=CH2, —CH2-CECH, -CEC-CH2-CECH, )=CH-CH=CH2, -CH=C(CH3)- CH=CH2, —CH=CH-C(CH3)=CH2, —C(CH3)=CH-CECH, —CH=C(CH3)-CECH, CEC- C(CH3)=CH2, -C3H5—CH(CH3)2, —C2H4-CH(CH3)-C2H5, -CH(CH3)—C4H9, -CH2-CH(CH3)— C3H7, -CH(CH3)—CH2-CH(CH3)2, —CH(CH3)-CH(CH3)-C2H5, —CH2—CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, —C(CH3)2—C3H7, -C(CI-I3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)- C(CH3)3, -C4Hg-CH=CH2, -CH=CH—C4H9, —C3H6-CH=CH-CH3, —CH2—CH=CH-C3H7, -C2H4— CH=CH-C2H5, -CH2-C(CH3)=C(CH3)2, —C2H4-CH=C(CH3)2, —C4Hg~CECI-I, ~CEC-C4H9, CEC—CH3, -CH2—CEC-C3H7, and -CzH4-CEC—C2H5. Particular alkyl groups are methyl, ethyl, propyl, butyl, pentyl, butenyl and pentenyl.
In particular embodiments, as used herein an kyl group s a linear or branched C1- CG—alkyl substituted with at least one aryl group as de?ned herein. Exemplary arylalkyl groups include benzyl, phenylethyl, 4—hydroxybenzyl, 3—?uorobenzyl, 2-?uoropheny1ethy1, and the like.
In particular embodiments, as used herein a cycloalkyl group denotes a non—aromatic ring system containing three to eight carbon atoms, particularly four to eight carbon atoms, more particularly three to six carbon atoms, even more particularly three to ?ve carbon atoms.
In particular embodiments, as used herein an alkoxy group denotes an O-alkyl group, the alkyl group being as de?ned above. More particularly the alkoxy group is a methoxy, ethoxy, isopropoxy, t—butoxy or pentoxy group, even more particularly methoxy.
In particular embodiments, as used herein a kyl group denotes an alkyl group wherein one or more, particularly more than half, more particularly all, of the hydrogen atoms are replaced by halogen atoms. The haloalkyl group is for instance -C(R10)3, —CR10(RIO’)2, —CR1"(R1°’)R‘°", -C2(R}°)5, -CH2-C(R1°)3, ’)2-CH(R‘0’)2, —CH2—CR‘°(R‘°‘)2, ~CH2— CR10(RIO’)R10", -C3(R10)7, or C(R10)3, wherein R10, Rm}, R10" particularly independently represent F, Cl, Br or I, more particularly F. More particularly, haloalkyl is CF3.
In ular embodiments, as used herein a haloalkoxy group denotes an —O—haloalkyl group.
In particular embodiments, as used herein a halo or halogen group denotes ?uorine, ne, bromine, or iodine; particularly chlorine or ?uorine; Unless stated otherwise, the terms "included", "including", "include" and the like are to be tood as meaning including but non-limiting.
Constituents which are optionally substituted as stated herein may be substituted, unless otherwise noted, at any chemically le position.
In particular embodiments of the present invention, Ar is selected from the group consisting of phenyl and 5- or 6—membered heteroaryl, more particularly pyridyl, which are ally substituted by one or more substituents RAlr ndently selected from the group consisting of halogen, ll<:yl= C1-4—haloalkyl, ~NH2, acetamido, —COO-C1_4-alkyl, oxy, and (mono- or di-C1-4—alkyl-amino)—C14-alkoxy, more particularly halogen, C1.4—alkoxy, benzyloxy, hydroxyl, mbered heterocyclyl-earbonyl, CM-alkylaminocarbonyl, C34— cycloalkylaminocarbonyl, 5membered heterocyclyl—C1_4-alk0xy, (2-oxa azaspiro[3.3]heptyl)—CM—a1koxy and (mono- or di-C14-alkyl-amino)-C14-alkoxy; in other particular embodiments Ar is selected from the group consisting of phenyl and pyridyl, which are optionally substituted by one or more substituents RAr independently selected from the group consisting of halogen, CM-alkoxy, and (mono- or di—CM-alkyl- amino)—C1_4-alkoxy; in other particular embodiments AI is phenyl, which is optionally substituted by one or more substituents RN independently selected from the group consisting of halogen, CM-alkoxy, and (mono- or di—C14-alkyl—amino)-C1alkoxy; in other particular embodiments Ar is selected from the group ting of phenyl, 2,6- difluorophenyl, 2-chloro?uorophenyl, 2-chlor0-6—methoxyphenyl, Z-?uorophenyl, 3— ?uorophenyl, 2-chlorophenyl, 4-chlorophenyl, oxyphenyl, 2,6-dichloropheny1, 3,4- dichlorophenyl, 2,4-diehlorophenyl, 3-?uoropyn'din—4-yl, 3,5—dichloropyridinyl, 3-chlor0- 5—fluoropyridin—4—yl, 2-methoxyphenyl, 2-methoxypyridinyl, 2-chloro-3—(N- morpholinocarbonyl)phenyl, 2—chloro—3—(N—azetanylearbonyl)phenyl, ro—3-(N— azetanylcarbonyl)phenyl, 2—chloro(N-pyrrolidiny1carbonyl)phenyl, 2-chloro—3— (ethylamino)carbonyl—phenyl, 2—chloro(isopropylamino)carbonyl—phenyl, 2—chloro propylamino)carbonyl—phenyl, 2-chloro-3—(cyclbuty1amino)carbonyluphenyl, 2— methoxy—3-(ethylamino)carbonyl-phenyl, 2-methoxy—3-(isopropylamino)carbonyl-phenyl, 2— methoxy-3~(cyclopropylamino)carbonyl-phenyl, 2-methoxy-3—(N—azetanylcarbonyl)-phenyl, 3-(cyclobutylamino)earbonyl-pheny1, 3-(isopropylamino)earbonyl-phenyl, 2—chloro—3- yphenyl, 2—chloro—3—hydroxyphenyl, 2-chlorobenzyloxyphenyl, 2-chloro(2-(N- morpholinyl)ethoxy)phenyl, 2-chloro(2-(N—l,l-dioxothiomorpholinyl)ethoxy)phenyl, 2— chloro(2-(2-oxa~6-azaspiro[3 .3 ]hept-6—yl)eth0xy)phenyl, ro-3 -(2-(N- pyrrolidinyl)ethoxy)phenyl, 2—chloro—3-(2-(Nmethylpiperazinyl)ethoxy)phenyl, 2-chloro—3- (2-(diethylamino)-ethoxy)phenyl and 2-chloro(2-(dimethylamino)—ethoxy)—pheny1; in other particular embodiments Ar is ed from the group consisting of 2-chloro—6- fluorophenyl, 2—chlorophenyl, 2-chloro-3 -rnethoxyphenyl, and 2—chloro—3 —(2- (dimethylamino)—ethoxy)—pheny1; in other particular embodiments Ar is selected from the group consisting of phenyl, 2,6- di?uorophenyl, 2-chlor0—6—?uorophenyl, 2-chloro—6—methoxyphenyl, 2—?uorophenyl, 2— chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-?uoropyridin-4—yl, 3,5- ropyridinyl, 3-chloro-5—?uoropyridin—4-yl, and 2-chloro-3—(2—(dimethylamino)- ethoxy)—phenyl; in other particular embodiments Ar is ed from the group consisting of phenyl, 2,6- di?uorophenyl, 2-chloro—6-?uorophenyl, 2—chloromethoxyphenyl, 2-?uorophenyl, 2- chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3—?uoropyridinyl, 3,5— ropyridin—4-yl, 3—chloro-5~?uoropyridin-4—yl, and 2-chloro—3—methoxy—phenyl; in other particular ments Ar is selected ?fom the group consisting of phenyl, ro- rophenyl, 2—?uor0phenyl, 2-chlorophenyl, 2,6—dichlorophenyl, 2,4—dichlorophenyl, 3- ?uoropyridin—4-yl, 3,5-dichloropyridin—4-yl, 3-chloro-S-?uoropyridiny1 and 2-chloro methoxy-phenyl; in other particular embodiments Ar is selected from the group consisting of 2—Cliloro—6— ?uorophenyl, 2-chlorophenyl, and 2-chloromethoxy-phenyl.
In particular embodiments of the present invention, Z is selected from the group consisting of H, halogen, ~CO-heterocyclyl, ~CO-alky1, -CO-alkoxyalkyl, —NH2, ~NH-COO-C34alkyl, -CN, -COO-C1_4alkyl, -CONH-C1-4alkyl, —CONH—arylalkyl, -CONH-cycloalkyl, -CON(C1-4alkyl)2, -CON(C1_4alkyl)—O—(31-4alkyl, -CO-CH2—cycloalkyl, COO—heterocyclyl, —COO-cycloalkyl, cycloalkylmethyl, hydroxymethyl, -alkyl-O-alkoxyalkyl, alken-l-one, alkyloxyalkyl, cycloalkylmethyl-alken01, heteroaryl, , or heterocyclyl, wherein said phenyl, and heterocyclyl is optionally substituted by one or more substituents independently selected from the group comprising halogen, alkyl, alkoxy, haloalkyl, lkyl, OH and lkyl; in other particular embodiments of the present invention Z is selected. from the group ting of hydrogen, bromine, —COMe, -CO—CH2—0Me, ethoxymethyl, isopropoxmethyl, cyclobutoxymethyl, 2—methoxy—ethoxymethyl, hydroxymethyl, tetrahydrofuryl, -CONH- cyclopropyl, -CONH-cyclobutyl, -CO-morpholin—4-y1, —CO-pipetidinyl, -COOH, -CONH2, —CONHNH2, -CONHNH—CO-methyl, -CONH-(2,4,6-trimethoxyphenyl)methyl, -CONHN=isopropyl, ~NH—CO-methyl, -NH—CO—tri?uoromethyl, —NH—COH, -CO-(N—methyl— piperazinyl), -CO-(4-[chlorobenzyl]-piperazin-l—yl), -CO-pyrrolidinyl, -CO-isoxazolidinyl, —NH2, —NH—COO—methyl, —CN, '-COO-C1_3a1kyl, methyl, —CONH—(tri?uoromethyl— substituted benzyl), -CONH—cyclohexyl, -CON(methyl)2, —CON(methyl)—O-methyl, ~COOMe, ~COOEt, cyclopropcxymethyl, -COO-cyclopropyl, —COO—cyclobutyl, pent-4—en-l—one, methoxvymethyl, -CO-CH2-cyclobuty1, COO-oxetan, 5-methyl-isoxazolyl, 1- cyclopropylmethyl—penten—1—01, ~CONH—cyclopentyl, phenyl, tetrazolyl, thiazolyl, pyrimidyl, oxadiazolyl, oxazolyl, thiadiazolyl, pyrazinyl, furanyl, and thiophenyl, wherein said phenyl, tetrazolyl, thiazolyl, pyrimidyl, oxadiazolyl, oxazolyl, thiadiazolyl, pyrazinyl, furanyl, or thiophenyl is optionally substituted by one or more tuents independently selected from the group comprising halogen, methyl, OMe, CF3, -COOMe, and —CO0Et; in other particular embodiments of the present invention Z is selected from the group consisting of H, 1alkyl, -CO-C1-2—alkyl, —CO-C1-g-alkoxy—Cm-alkyl, 5- or 6- membered heteroaryl sing one or two heteroatoms independently selected from N, S and O, -V, wherein V is ed from the group consisting of H, CM—alkyl, €3 lkyl and C1_2alkoxy-C1_2-alkyl , ~COO-C3_6-cycloalkyl, C3_6-alkenone, nyl, -CO—CH2-C3_5—cycloalky1, COO-(3— to 5— membered heterocyclyl), methyl—isoxazolyl, 1- cyclopropylmethyl-C3_5-alkenol, -CONH-C5heterocyclyl and -CONH—C3cycloalkyl; in other particular ments of the present invention Z is selected from the group consisting of H, —COOMe, ~COOEt, —COMe, -CO-CH2—0Me, pyrimidin~2-yl, thiazol—Z-yl, cyclopropoxymethyl, -COO-cyclopropyl, yclobutyl, penten-l-one, pyrimidinyl, ymethyl, ethoxymethyl, isopropoxmethyl, cyclobutoxymethyl, 2-methoxy— ethoxymethyl, hydroxymethyl, pyrazin-Z—yl, ~CO-CH2-cyclobutyl, -COO-oxetan, 5-methyl- isoxazol-Z-yl, tetrahydrofuryl, 1~cyclopropylrnethyl—penten-l—ol, -CONH-cyclopropyl, cyclobutyl, and —CONH—cyclopentyl; in other particular embodiments of the present invention Z is selected from the group consisting of -COOMe, , pyrimidin-Z-yl, thiazol—Z-yl, pyrimidin—4-yl, methoxymethyl, and 5—methyl-isoxazol—2—yl.
In particular embodiments of the present invention, Y is selected from the group consisting of H, alkyl, haloalkyl, and alkylester; in other particular embodiments Y is selected from the group consisting of H, penta?uoroethyl, tri?uoromethyl, methyl and methoxycarbonyl; in other particular embodiments Y is selected from the group consisting ofH, tri?uoromethyl, methyl and methoxycarbonyl; in other particular embodiments Y is selected from the group consisting of tri?uoromethyl and methyl.
In particular embodiments of the present invention, R’ is independently selected from the group consisting of H, OH, Me, Et, iPr, iBu, and CF3, more ularly H, OH, Me, Et, and In particular embodiments of the present invention, R1 is a group of the ure wherein n is 0 or 1; R2 is H, deuterium or methyl; R3 is methyl, tri?uoromethyl, ethyl, or taken with R2 together forms a ropyl group; n is 1, R2 is H, deuterium or methyl and R3 forms a methylene bridge to the carbon atom marked *; in other particular embodiments of the present ion, Rl is a group of the structure wherein n is 0; R2 is H, deuterium or methyl; R3 is methyl, romethyl, ethyl, or taken with R2 together forms a cyclopropyl group; n is 1; R2 is H, deuterium or methyl; R3 is methyl or tri?uoromethyl or forms a methylene bridge to the carbon atom marked *; in other particular embodiments of the present invention, R1, is selected from the group consisting of 3-hydroxymethylbuty1, oxy—2-methylpropy1, 3—hydroxy—3-methy1— cyclobutyl, 2—hydroxypropyl, 2—hydroxybutyl, 3—hydroxy—cyclobutyl, 2—hydroxy-313,3— tri?uoropropyl, 2-hydroxy-2—deutero—propy1, and 1-hydroxy—cyclopropylmethyl; in other particular embodiments of the present invention, R1 is selected from the group consisting of 3—hydroxy—3—methylbutyl, 2—hydroxy—2—methylpropyl, 2-hydroxypropyl, 3- hydroxymethy1-cyclobuty1, 3-hydroxy-eyclobutyl, and 1-hydroxy-cyclopropylmethyl; in other particular embodiments of the present invention, R1 is selected from the group consisting of 3—hydroxy—3—methylbutyl, oxymethylpropyl, 2—hydroxypropyl and 1— hydroxy-cyelopropylmethyl; in other particular embodiments of the t invention, R1 is selected from the group consisting of 3—hydroxy—3-methylbutyl, oxy—2-methylpropyl, and 2-hydroxypropyl; in other particular embodiments of the t invention, R1 is 3-hydrcxymethyl- cyclobutyl or 3—hydroxy-cyclobutyl; in other particular ments 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 particular embodiments of the present invention, R1 is 3-hydroxy—3—Inethy1- cyclobuty]. in other more particular ments of the present invention, R1 is 3-hydroxy—3- methylbutyl .
Particular compounds of the present invention are the nds of the below examples of the present invention, more particularly the compounds of below examples 1, 2, 3, 4, 5, 6, 7, 8,9,10,11,12,13,14,15,l6,17,18,19, 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 particularly the compounds of below examples 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, even more particularly the compounds ofbelow examples 1, 2, 3, 4, 5, 6, 7, 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, 123,124,125,12’7, 128, 1,132,133, 134,135, 9,141, 143,148, 150 and 160, yet even more particularly the compounds of below examples 3, 4, 6, 7, 10, 11, 12, 14, ,16, 27,32, 49, 61, 82, 89, 92, 97, 98,102,103,112,121,123,128,130 and 132.
It is apparent that the respective embodiments regarding the residues Ar, RAY, Z, R2", Y, R1 and R,’ described herein may be combined with one another to yield r more particular embodiments. Some examples of such combinations are, without limiting the invention to the particular combinations, bed herein. ing to expert's knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying s of solvents. Included within the scope of the invention are therefore all solvates and in particular all es of the compounds of formula (I) as well as all solvates and in ular all es of the salts of the compounds of a (I).
The present invention further relates to methods of treatment of the diseases or l ions which are described herein, particularly a disease or medical condition in which the inhibition of eukin-1? (IL-17A), interleukin 17F (IL-17F), interleukin-22 (IL—22) and/or Interferon-y (INF-7) is bene?cial, more particularly a disease or medical condition selected from the group consisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, vitiligo, Crohn’s disease, ulcerative colitis, in?ammatory bowel disease, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjogren‘s syndrome, spinal disc herniation, acne, Gra?-versus-Host-Reaction, Host - versus-Graft—Reaction, AIH mmunhepatitis), PBC (peripheral biliary cholangitis), PSC (primary scleroting cholangitis), obesity, Lupus nephritis, diabetes mellitus and osteoarthritis, said method comprising administering to a subject in need thereof an effective amount of a nd of formula (I) as described herein. Analogously, the t invention further relates to methods as the one described above, which encompass the further embodiments bed herein, in particular the medical uses and compounds for use in medical treatments as described herein.
The present invention further relates to pharmaceutical compositions, kits and kits—of parts comprising the compounds according to the present invention.
The t invention further relates to the use of the compounds according to the present invention for the production of phannaceutical compositions which are employed for the ent and/or prophylaxis of the es, disorders, illnesses and/or conditions as mentioned herein.
The present invention further relates to the methods and l uses bed herein, encompassing the pharmaceutical compositions as described herein.
The pharmaceutical compositions as described herein comprise one or more of the compounds according to this invention and a ceutically able carrier or diluent.
Additionally, the invention relates to an article of cture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective against the l conditions as described herein, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is use?il for preventing or treating said medical conditions, and wherein said pharmaceutical agent comprises one or more compounds of formula (1) according to the ion. The packaging material, label and package insert otherwise parallel or resemble What is generally regarded as standard packaging material, labels and package inserts for ceuticals having related utilities.
The pharmaceutical compositions according to this invention are prepared by ses which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or particularly in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated s, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.
The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of r expert knowledge. In addition to ts, gel formers, ointment bases and other active nd ents, for example antioxidants, dispersants, emulsi?ers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used.
Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that e, may optionally be coadministered with the compounds according to the present invention. As used herein, additional therapeutic agents that are normally stered to treat or prevent a particular disease are known as riate for the disease being treated.
In a further aspect of the present invention, the compounds according to this invention or the salts or es of said compounds of formula (I) may be combined with standard therapeutic agents which are commonly used for the treatment of the medical conditions as described herein.
The person skilled in the art is aware on the base of his/her expert knowledge of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered.
Said total daily dosage(s) can vary within a wide range. In practicing the t invention and depending on the details, characteristics or purposes of their uses mentioned above, the compounds according to the present invention may be administered in ation therapy separately, sequentially, simultaneously or chronologically staggered (e.g. as combined unit dosage forms, as separate unit dosage forms or a adjacent discrete unit dosage forms, as ?xed or non?xed combinations, as kit-of—parts or as ures) with one or more standard therapeutics, in particular own chemotherapeutic or target speci?c anti—cancer agents, such as those mentioned above.
Thus, a further aspect of the present invention is a ation or pharmaceutical composition comprising a ?rst active ingredient, which is a compound according to this invention or a pharmaceutically acceptable salt or solvate thereof, a second active ingredient, which is an art-known standard therapeutic for the medical conditions as described herein, and optionally a pharmacologically acceptable carrier, diluent and/or excipient for tial, separate, simultaneous or chronologically staggered use in therapy in any order, e.g. to treat, prevent or rate in a patient the l conditions as described herein.
In this context, the present invention further relates to a combination compri sing a ?rst active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art—known standard therapeutic for the medical conditions as described herein, for te, tial, simultaneous or chronologically red use in therapy, such as e.g. in therapy of these diseases mentioned herein.
The term "combination" according to this invention may be present as a ?xed combination, a non—?xed combination or a -parts. A "?xed combination" is de?ned as a combination wherein the said ?rst active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "?xed combination" is a pharmaceutical composition n the said ?rst active ingredient and the said. second active ingredient are present in admixture for simultaneous administration, such as in a ation.
Another example of a "?xed combination" is a pharmaceutical combination wherein the said ?rst active ingredient and the said second active ingredient are present in one unit without being in admixture.
A "kit—of—parts" is de?ned as a ation wherein the said ?rst active ingredient and the said second active ingredient are present in more than one unit. One example of a "kit-of— parts" is a combination wherein the said ?rst active ingredient and the said second active ingredient are present separately. The ents of the kit-of—parts may be administered separately, sequentially, simultaneously or chronologically staggered.
The ?rst and second active ingredient of a combination or kit—of—parts according to this invention may be ed as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or ed and presented together as separate components of a combination pack for simultaneous, tial, separate or chronologically staggered use in combination therapy.
The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of—parts ing to this invention can be r, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for c.g. enous administration.
The amounts of the ?rst and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount for the treatment, prophylaxis or amelioration of a medical condition as described herein A further aspect of the present invention is a method for treating apeutically the medical conditions as described herein, in a patient in need of such ent comprising administering separately, sequentially, simultaneously, ?xed or non-?xed a therapeutically effective and tolerable amount of one or more of the compounds according to the present ion and a therapeutically effective and tolerable amount of one or more art—known therapeutic agents for the medical conditions as bed herein, to said patient.
References and claims to the use of a compound of the 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 speci?c forms likewise refer to the corresponding methods of treating said disease or medical condition, said method comprising administering a therapeutically effective and tolerable amount of a nd of the a (I) or a pharmaceutically acceptable salt or e thereof to a subject in need thereof, compositions comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for the treatment of said disease or medical condition, a compound of the a (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of said disease or medical condition, and Vice versa.
For the production of the pharmaceutical compositions, the compounds of the invention (= active compounds) are particularly mixed with suitable pharmaceutical auxiliaries and ?rrther processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, sions, sprays, oils, nts, fatty ointments, creams, pastes, gels or ons. The pharmaceutical compositions according to the invention are prepared by processes known per se.
The dosage of the active compounds is carried out in the customary order of magnitude.
Topical application forms (such as nts) thus contain the active compounds in a concentration of, for example, 01-99%. The customary dose in the case of ic therapy (p.o.) is y between 0.3 and 30 mg/kg per day, (i. v.) is usually between 0.3 and 30 mg/kg/h. The choice of the optimal dosage regime and duration of medication, particularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the art on the basis of his/her expert knowledge.
The class of compounds of the present invention is useful for the development of medicaments suitable for the treatment of autoimmune diseases and c ation or, more generally, for the treatment of diseases where the inhibition of interleukin-l7 (IL-l7) and/or Interferon—y (INF-y) is bene?cial.
The compounds of the present ion are also useful for the treatment of es which are related to or mediated by in?ammatory cytokines, such as psoriasis, psoriatric arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, vitiligo, Crohn’s disease, ulcerative colitis, in?ammatory bowel disease, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjo'gren’s syndrome, spinal disc herniation, raft- versus—Host-Reaction, Host ~versus-Graft-Reaction, AIH (Autoimmunhepatitis), PBC heral biliary cholangitis), PSC (primary scleroting cholangitis), obesity, Lupus nephritis, diabetes mellitus and osteoarthritis It has unexpectedly been found that compounds having the R1 groups as detailed herein show high cytokine induction while having favorable aqueous solubility and/or microsomal ity. The following example section shows further details.
Examples a) Synthesis As used herein, the term "room temperature" or "rt." usually refers to about 25°C; "aq" refers to aqueous; "prep." refers to preparative; "TLC" refers to thin layer chromatography; "quant." refers to quantitative. Compounds with stereo centers where stereochemistry is not speci?cally indicated were ed as mixtures of isomers. For sake of completeness, residues "R" ted in the following synthesis schemes in each case refer to a generic placeholder group, including in particular the speci?c groups as can be seen in the speci?c examples following each scheme and analogs thereof, and the meaning of "R" may vary between different synthesis schemes and positions within each scheme. ical devices used Analytical LC/ESI-MS: Waters 2700 Autosampler. Waters 1525 Multisolvent ry System. 5 0L sample loop. Column, enex Onyx thic (318 50x2 mm, with stainless steel 2 pm pre?lter. Eluent A, 1-120 + 0.1% HCOOH; eluent B, MeCN. Gradient, 5% B to 100% B within 3.80 min, then isocratic for 0.20 min, then back to 5% B within 0.07 min, then isocratic for 0.23 min; ?ow, 0.6 ml/min or 1.2 ml/min.
Waters Micromass ZQ 4000 single quadrupol mass spectrometer with electrospray source.
MS method, MS4_15minPM—80-800—35V; positive/negative ion mode g, m/z 80—800 in 0.5 s; capillary voltage, 3.50 kV; cone voltage, 50 V; multiplier voltage, 650 V; source block and desolvation gas ature, 120°C and 300°C, respectively. Waters 2487 Dual 7L Absorbance Detector, set to 254 nm. Software, Waters Masslynx V 4.0.
Waters Micromass LCZ Platform 4000 single quadrupol mass ometer with electrospray source. MS method, MS4_15minPM800-35V; positive/negative ion mode scanning, m/z 80—800 in l s; capillary voltage, 4.0 kV; cone voltage, 30 V; multiplier voltage, 900 V; source block and desolvation gas temperature, 120°C and 300°C, respectively. Waters 996 Photodiode Array Detector, set 200 to 400 nm. Software, Waters Masslynx V4.0.
Values for ]+ given in the examples are those m/z found within the corresponding LC/MS chromatogram for the respective compound. These values were all found within ble margins of +/- 0.3 units compared to calculated exact mass upon protonation of the compound.
Preparative thin layer chromatography (preparative TLC): Merck PLC plates, silica gel 60 F254, 0.5 mm, 1.0 mm or 2.0 mm.
Column chromatography: Acres silica gel 60A, 0035-0070 mm.
Preparative HPLC—MS: 1) Waters 2767 Autosampler, Waters 600 Multisolvent Delivery System with analytical pump heads (100 uL); Waters 600 ller; Waters 2525 Binary Gradient Modul with preparative pump heads (500 uL). At-Column—Dilution: solventl, go 70:30 (V/v), solvent2, MeCN:MeOH:DMF 80:15:5 (v/v/v); ?ow rate, 5 mL/min.
Autosarnpler 2767 with 10 mL sy?nge and 10 mL Sample loop. Column 6—position valve Flom 401 with Waters X-Terra RPlS, 5 mm, 19X150 mm with X—Terra RP18 guard cartridge um, 19x10 mm, used at ?ow rate 20 mL/min; Waters SunFire Prep OBD 5 pm, 30x50 mm with SunFire RP18 gmard cartridge 5 um, 19X10 mm, used at ?ow rate 25 ; Waters Atlantis Prep T3 OBD 5 um, 30x50 mm with Atlantis guard cartridge, used at ?ow rate 50 mL/min; Waters X—Bridge Prep OBD 5 um, l9x150 mm with X—Bridge RP18 guard dge um, 19x10rnrn used at ?ow rate 20 mL/min; Waters Atlantis Prep T3 OBD 5 um, 19x50 mm with Atlantis guard cartridge, used at ?ow rate 25 mL/min and YMC—Actus Hydrosphere C18 5 um, 20x50 mm with Actus guard cartridge, used at ?ow rate 20 mL/min. Eluent A, H20 ning 0.1% (v/v) HCOZH or H20 containing 0.1% (v/v) NEtg; eluent B, MeCN.
Different linear gradients, individually adapted to sample. Injection volume 9 mL, depending on sample. Make—up solvent, MeOH-MeCN—HzO-HCOZH 80:15:4.95:0.05 (v/v/v/v). Make—up pump, Waters Reagent Manager, flow rate 0.5 mL/min. Waters ZQ single quadrupole mass spectrometer with electrospray source. Positive or ve ion mode scanning m/z 105-950 in l s; capillary, 3.6 kV; cone voltage, 45 V; multiplier voltage, 700 V; probe and desolvation gas temperature, 120°C and 250°C, respectively. Waters Fraction Collector 2767 with mass or ggered fraction collection. Waters 2487 Dual 7» Absorbance Detector, set to 254 nm.
Software, Waters Masslynx V 4.0 SP4. 1H NMR spectra were recorded at room temperature on a Bruker Supraleitendes Fourier NMR Spektrometer (superconducting Fourier NMR spectrometer), AvanceTM 300 MHz.
Chemical shifts (5 are reported in ppm. Multiplicity of a certain signal (singlet, doublet, t, quartet, multiplet) is indicated by the respective abbreviation (s, d, t, q, m respectively). "br 3" indicates a broad singlet, "mg" a centered multiplet. The solvent residual signals were used as internal standards: 6(CDC13) = 7.26, 6(d6—DMSO) = 2.50, 5(CD30D) = 3.31, 5(d6-acetone) = 2.05. l re for the ‘ re .1 aration of alkvl 5-meth disoxazolecarboxvlates To a stirred e of aldehyde (scale: 60 mmol) A in ethanol (0.5 l) and water (0.5 mL/rnmol) was added hydroxylarnine (1.3 eq., 50 wt% in water) at 00C. The e was stirred at room temperature for 24 h, upon which all volatiles were removed under reduced pressure. Resulting crude oxime was taken up in DMF (1 mL/mmol) and treated with NCS (1.0 eq.) at room temperature for 24 h.
If required, reaction initiation can be better controlled by adding only 0.15 eq. NCS followed by dry hydrogen chloride being bubbled into the DMF solution until the reaction temperature rises up to 35°C; afterwards NCS (0.85 eq.) can be added portionwise.
The reaction mixture was partitioned between DCM and water. Combined organic layers were dried over MgSO4, ed and concentrated under reduced pressure to give crude hydroxamoyl chloride B.
The following hydroxamyl chlorides B were also synthesized for conversions within the "Cycloaddition reaction" section, being part of the syntheses of Examples .97 through 129 and related ng Blocks: - 2-chloro?uoro-N-hydroxybenzimidoyl chloride; Result of LC/MS [M+H]+: 208.1; - 2-ch1oro—N—hydroxybenzirnidoyl chloride; Result of LC/MS [M+H]+: 190.1; - chloro—3-methoxy~N-hydroxybenzimidoyl chloride: this aromatic substitution pattern was generated from N-[(2-chloro-3— methoxyphenyl)methy1idene]hydroxylamine when treated with 2.0 NCS instead of 1.0 eq. as used to generate 2-chlorornethoxy—N—hydroxybenzimidoyl de); Result of LC/MS [M+H]+: 253.9; 'H NMR(CDC13): 6 3.92 (3H, s, CH3), 6.97 (1H, d, CH), 7.32 (1H, (1, CH), 8.39 (1H, s, OH). - 2-chlorornethoxy-N-hydroxybenzirnidoyl chloride; Result of LC/MS [M+H]+: 220.0; — 2-methoxy-N—hydroxybenzirnidoyl chloride - 3—(benzyloxy)—2-chloro—N—hydroxybenzirnidoyl de; Result of LC/MS : 295.9; — methyl 2-chloro—3—(chloro(hydroxyimino)methyl)benzoate - methyl 3-(chloro(hydroxyirnino)rnethyl)methoxybenzoate - methyl 3~(chloro(hydroxyimino)methyl)benzoate According to this procedure, the following building blocks C were synthesized with an additional tic step as described below: (Z)—ethyl rolidin-1—y1)but~2—enoate: To pyrrolidine (6 mmol) was Slowly added ethyl 3- oxobutanoate (1.0 eq.), (ATTENTION: highly exothermic!) to give a yellow suspension.
Toluene was added (5 l) to remove H20 resulting from the condensation reaction using a Dean Stark trap. The mixture was heated under re?ux for 5 h resulting in a solution, which was fractionated afterwards by distillation (8 mbar, 150°C) to yield the product as a yellow oil (4.2 mmol, 70%). 1H NMR (CDC13): 5 1.24 (3H, t, CH3), 1.92 (4H, m, CH2), 2.45 (3H, s, CH3), 3.28 (4H, m, CH2), 4.08 (2H, q, CH2), 4.46 (1H, s, CH).
Ethyl 3-(2—chloro—6—?uorophenyl)methylisoxazole-4—carboxylate To a solution of (Z)n2-chloro?uoro-N—hydroxybenzimidoyl chloride (65 mmol) in DMF (2 mL/mrnol) at 0°C was added dropwise a on of (Z)-ethyl 3-(pyrrolidin—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/minol) was added dropwise over 2 h. The mixture was stirred at room temperature for 24 h. The resulting mixture was ?ltered and the ?ltrate was partitioned between CH2C12 and water. Combined organic layers were dried over Mgso. and concentrated under reduced pressure. The crude t was distilled at 10 mbar and 160°C.
The product was obtained as an orange oil (80%). 1H NMR (CDC13)Z 8 1.07 (3H, t, CH3), 2.79 (3H, s, CH3), 4.14 (2H, (.1, CH2), 7.09 (1H, td, CH~arom.), 7.29 (1H, d, CH—arom.), 7.39 (1H, m, (EH—atom.) metCl N’O 0 OK Ethyl 3-(3-1)enzyloxy—Z-chloro-phenyl)-5~methylisoxazole-4—carboxylate To a on of (Z)(benzyloxy)—2-chloro—N—hydroxybenzimidoyl chloride (60 mmol) in DMF (1 mL/mmol) at 0°C was added dropwise a on of (Z)-ethy1 3—(pyrrolidin—1-yl)but- 2—enoate (1.05 eq. in EtOH, 0.3 mL/mmol). After ng 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 d 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%).
Result of LC/MS [M+H]+: 372.0; H NMR (CDC13)Z 5 0.98 (3H, t, CH3), 4.06 (2H, q, CH2), 4.57 (3H, s, CH3), 5.07 (2H, s, CH2), 6.80 (1H, d, Ch-arom.), 7.30 (7H, m, CH-arom.).
Methyl hloromethoxy—phenyl)—5—methylisoxazole-4—carboxylate (Z)—2~Chloro-N—hydroxy—3—methoxybenzene—l—carbonimidoyl chloride (17 mmol) was dissolved in DMF (2 mL/mmol), and methyl acetoacetate (2.0 eq.) was added, followed by triethylamine (5.0 eq.). The mixture was stirred at room temperature for 24 h and then partitioned between CH2C12 and water. Combined organic layers were dried over MgSO4, ed and concentrated under reduced pressure. Crude product was puri?ed by column chromatography on silica gel t: petroleum ether to eum ether/ethyl acetate 80:20) to yield a pale brownish solid (75%).
Result of LC/MS [M+H]+: 282.00; 1H NMR (CDC13)I 5 2.75 (3H, s, CH3), 3.69 (3H, s. OCH3), 3.94 (3H, s, OCH3), 7.01 (1H, dd, CH-arom.), 7.05 (1H, dd, CH-arom.), 7.31 (1H, dd, CH-arom.).
Methyl 3~(2-chloro-6~?uorophenyl)-5~methylisoxazole~4-carboxylate was purchased from Apollo Scienti?c (PC9397). Methyl 3-(2—chlorophenyl)—5-methylisoxazole—4-carboxylate and ethyl 3—(2~ehlorophenyl)—5—methylisoxazole—4—carboxylate were purchased from ABCR (AB158164 and AB334755, respectively). w0 CI N’0 C‘ "’0 CN' . l/ W . O 0‘2 0? OK Pre aration of 3- 2-chloro—6-?uoro henvl methvl l—Z-vl' isoxazole 1)aq. NaOH EtOH 2) oxaly! chloride Cl N—Q 3).aq ammonia NO 1 / 4) Lawessons t F'/ A solution of 28.4 g (100 mmol) of ethyl 3-(2-chloro-é—?uorophenyl)—5-methylisoxazole-4— carboxylate was dissolved in 40 mL ethanol, and 40 mL aq. NaOl—I (4.0 M) were added. The mixture was heated to 60°C for 24 h. The ethanol was partially evaporated under reduced pressure and the ing solution was acidi?ed by addition of aq. HCl (4.0 M). A precipitate formed, which was ?ltered off, washed with H20 and dried in vacuum to yield .2 g (99%) of crude 3~(2—chloro—6-?uorophenyl)-S-methylisoxazole—4—carboxylic acid as an off-white solid.
Cl N'O Result of LC/MS [M+H]+: 255.9; 1H NMR(CDC13):3 2.79 (3H, s, CH3), 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) crude 3-(2-chloro—6—?uorophenyl)—5- methylisoxazolecarboxylic acid in CH2C12 (300 mL) a catalytic amount ofDMF was added (ca. 0.1 mL), followed by dropwise addition of oxalyl chloride (5.0 eq.), resulting in an orange-red solution. The reaction mixture was re?uxed for 1 h, upon which all volatiles were removed under d pressure. The crude material hloro—6-?uorophenyl)—5- methylisoxazolecarbonyl chloride was directly taken up in EtZO (250 mL) and cooled to 0°C. 10% aq. Na2C03 was added (250 mL), and the resulting two—phase mixture was vigorously stirred as aq. ammonia on was added slowly (50 mL; 35 wt% solution of NH3 in . The reaction mixture was stirred at 0°C for 10 min and then at r.t. for 3 h. The two phases were separated, the organic phase was washed with H20 and 5% aq. HCl, dried over MgSO4 and concentrated under reduced pressure to yield crude 3-(2-chloro-6— ?uorophenyl)—5—methy1isoxazole-4—carboxamide as a beige solid (22.7 g, 90%). o NH2 Result ofwars [M+H]+: 2549; 1H NMR (CDC13): 5 2.79 (3H, s, CH3), 5.40 (2H, br, NHZ), 7.18 (1H, t, CH—arom.), 7.38 (1H, d, CH—arorn.), 7.55-7.42 (1H, m, CH—arom.).
To a solution of 12.7 g (50 mmol) crude 3—(2-chloro—6~?uorophenyl)—5-rnethy1isoxazole-4— carboxamide in 150 mL e (Sure/Seal), 1.0 eq. Lawesson's Reagent were added. The mixture was stirred for 4 h under re?ux. Upon cooling to r.t., a precipitate was ?ltered off and the ?ltrate was concentrated under reduced pressure. The oily residue was d by column chromatography (silica gel; eluent: 100% CH2C12) to yield 11.0 g (81%) of 3-(2-chloro ?uoropheny1)—5-methy1isoxazole-4—carbothioamide as a yellow solid.
CI N‘0 Result of LC/MS [M+H]+: 270.9; ‘H NMR(CDC13): 5 2.84 (3H, s, CH3), 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) 3~(2-chloro-6—f1uorophenyl)-S-methylisoxazole- 4—carbothioamide in ethanol was added chloroacetaldehyde solution (10 eq.; 50 wt% in H20) and the on mixture was stirred at re?ux for 24 h. 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 MgSO4, d and concentrated under reduced pressure. The residue was puri?ed by ?ash column chromatography on silica gel (eluent: 100% 12).
The title compound 3—(2—chloro?uorophenyl)—5-methyl(thiazol-2—yl)isoxazole was obtained as a yellow oil (8.37 g, 71%).
Result of LC/MS [M+H]+: 294.9; 1H NMR(CDC13): 5 2.89 (3H, s, CH3), 7.15 (1H, td, CH—arom.), 7.19 (1H, d, CH—arom), 7.35 (1H, dt, CH—arom.), 7.52—7.42 (1H, m, m.), 7.80 (1H, d CH-arom.).
Bredereck's reagent Step 1: To a solution of 3-arylmethylisoxazole (10 mmol) in dry e Seal; 2 mL/mmol) was added tert—butoxy—bis(dimethylamino)methane (Bredereck’s reagent; 2.5 eq.).
The reaction mixture was heated under re?ux for 5 h, then cooled to room temperature, concentrated under reduced pressure and partitioned between CH2C12 and water. Combined organic layers were dried over MgSO4, volatiles were removed under reduced pressure to give crude enamine intermediate.
Step 23, Y = €ng Crude enamine intermediate out of step 1 (10 mmol) was dissolved in CH2C12 (3 mL/mmol) and cooled to 0°C. Tri?uoroacetic anhydride (2.0 eq.) was added dropwise at this temperature, followed by ylamine (1.0 eq.). The reaction mixture was allowed to warm to room temperature within 3 h, and was next partitioned between CH2C12 and water. Combined organic layers were washed with saturated aq. NHHC03 and dried over MgSO4. Crude product was puri?ed by ?ash chromatography on silica gel (eluent: CHZClz to /MeOH 95:5).
Step 2b, Y = Me: Crude e intermediate out of 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 on mixture was heated under re?ux for 18 h. Conversion was monitored by TLC, additional acetyl chloride might be required to drive conversion to completion. Upon cooling to room temperature, the e was partitioned between CHzClz and water. Combined organic layers were washed with saturated aq. NaHC03 and dried over MgSO4. Crude product was puri?ed by ?ash chromatography on silica gel (eluent: CH2C12 to CHZClz/MeOH 95:5). ethyl (Z)—3 -(2—chloro?uoropheny1)—5 -(1 -(dimethylamino)—4,4,4-tri?uoro—3—oxobut-l -en yl)isoxazole—4—carboxy1ate (step 1+2a) Off-white powder, 48% yield over two steps.
Result of LC/MS {M+H]+: 434.8; 1H NMR (DMSO): 8 0.84 (3H, t, CH3), 2.52 (3H, s, CH3), 3.29 (H, s, CH3),3.92 (2H, q, CH2), 7.32 (1H, t, CH»ar0m.), 7.42 (1H, d, (SH-atom), 7.54 (7H, m, CH—arom.), 8.00 (1H, s, CH).
C! hf"? o F0 9 ‘ methyl (Z)—3-(2-chloro?uorophenyl)—5-(1-(dimethylamino)-4,4,4-tri?uoro—3 —0xobut-l -en— 2-yl)isoxazolecarboxylate (step 1+2a) Pale yellow powder, 53% yield over two steps.
Result ofLC/MS : 420.8; 1H NMR (DMSO): 5 3.63 (3H, s, CH3), 3.40 (3H, s, CH3), 3.57 (3H, s, CH3),7.44 (1H, t, CH- arom.), 7.53 (1H, d, CH-arom.), 7.65 (7H, m, CH—arom.), 8.12 (ll-l, s, CH). c: 11—0 o / \ / O \ O K ethyl (Z)—3 —(2-chlorophenyl)—5—(l thylamino)—4,4,4—tri?uoro—3—oxobut— l -en yl)isoxazolecarboxylate (step 1+2a) Yellow solid, 46% yield over two steps.
Result ofLC/MS : 416.7; IH NMR(CDC13): 8 0.38 (3H, t, CH3),2.75 (6H, 5, 2x CH3),4.12 (2H, q, CH2), 7.45 (5H, t, CH—arom.).
CI bro 0 / \ / O \ 0 \ methyl (Z)—3 lorophenyl)( 1 -(dimethylamino)-4,4,4—tri?uoro-3 -oxobut-1 -en—2— yl)isoxazole-4—carboxylate (step 1+2a) Pale yellow powder, 42% yield over two steps.
Result of LC/MS [M+.H]+: 403.1; lH NMR (CDC13): 8 3.72 (3H, s, CH3),3.34 (3H, s, CH3), 3.63 (3H, s, CH3),7.44 (4H, m, CH- arom.), 7.95 (1H, s, CH). methyl (Z)(1 -(dimethylamino)-4,4,4-trifluorooxobutenyl)—3-(2-methoxypyridin yl)isoxazole-4—carboxylate Starting with building block 2-methoxypyridine—3-carboxaldehyde (30 mmol), the general reaction procedures described above ed by step 1+2a yielded the title compound as pale yellow powder in 16% yield over 5 steps.
Result of LC/MS [M+H]+: 399.9; 1H NMR : 5 3.64 (3H, s, CH3), 3.41 (3H, s, CH3),3.59 (3H, s, CH3), 3.82 (3H, s, CH3), 7.15 (1H, dd, CH—arom.), 7.92 (1H, dd, m.), 8.09 (1H, s, CH), 8.34 (1H, dd, CH-arom.). ethyl (Z)-3 —(3 -(benzyloxy)~2—chlorophenyl)—5-( 1 -(dimethylamino)—4,4,4—tri?uoro0xobut- 1 — en—2-yl)isoxazole-4—carboxylate (step 1+2a) Brownish oil, 38% yield over two steps.
Result of LC/MS [M+H]+: 523.1; 1H NMR (DMSO): 5 1.02 (3H, t, CH3), 2.73 (3H, d, N—CHg), 3.34 (3H, d, N—CH3), 4.09 (2H, q, CH2), 5.21 (2H, s, CH2), 7.12 (2H, m, CH-arom.) 7.39 (6H, m, CH-arom.), 7.97 (1H, s, CH). methyl (Z)-3—(3—(tert—butoxyoarbonyl)-2~chlorophenyl)—5-(1-(dimethylamino)—4,4,4—tri?uoro- 3-oxobut-1 -en-2—yl)isoxazolecarboxylate 2—Chloro-3—formylbenzoic acid (25 mmol) was dissolved in THF (75 mL) and di-tert— butyldicarbonate (2.0 eq.) and N,N—dimethylaminopyridine (0.2 eq.) were added. The mixture was stirred at room temperature for 18 h. The mixture was partitioned between ethyl acetate and water. Combined organic layers were washed with saturated aq. NaHCO; and brine, dried over MgSO4 and concentrated under reduced re. Flash chromatography on silica gel (eluent: petroleum ether to eum ether / ethyl acetate 80:20) yielded tert—butyl ro— 3—formylbenzoate (87%). Starting with this building block, the l reaction procedures described above followed by step 1+2a yielded the title compound as an off-white powder in 27% yield over 5 steps.
Result of LC/MS [M+H]+: 523.1; 1H NMR (CDC13)I 5 1.61 (9H, s: t-Bu), 3.73 (3H, s, CH3), 3.35 (3H, s, CH3), 3.63 (3H, s= CH3), 7.43 (1H, t, CH-arom.), 7.59 (1H, dd, CH—arom.), 7.81 (1H, dd, m.)_, 7.96 (1H, s, C! N—0 o '/ \ / F \ o ‘1 methyl (Z)-3 —(2—chloro-6—?uoropheny1)—5—(1—(dimethylarnino)—3—oxobut— 1 -enyl)isoxazole— 4-carboxylate (step 1+2b) Orange solid, 52% yield over two steps.
Result of LC/Ms [M+H]+: 367.1; 1H NMR (CDC13)Z 8 2.04 (3H, s, CH3), 2.63 (3H, d, N-CH3), 3.21 (3H, d, N-CH3), 3.64 (3H, s, CH3), 7.13 (1H, t, CH—arom.), 7.31 (1H, d, CH-arom.), 7.41 (1H, m, CH-arom.), 7.87 (1H, s, methyl (Z)-3 —(2—chloro-3—methoxyphenyl)—5-( 1 -(dimethylamino)oxobut-1 -en yl)isoxazole—4—earboxylate (step 1+2b) Brownish oil, 63% yield over two steps.
Result of LC/MS [M+H]+: 379.0; 1H NMR (CD013): 6 2.45 (3H, s, CH3), 2.67 (3H, d, , 3.17 (3H, d, N-CHg), 3.63 (3H, s, CH3), 3.94 (3H, s, CH3), 7.09 (2H, m, (EH-atom), 7.35 (1H, t, CH-arom.), 7.41 (1H, m, CH- arom.), 7.85 (1H, s, CH). methyl (Z)-3 -(2-chlor0phenyl)-5—(l —(dimethylamino)—3—oxobut— l —en—2—yl)isoxazole—4- carboxylate (step 1+2b) Beige-brown solid, 40% yield over two steps.
Result of LC/MS [M+H]+: 349.3; 1H NMR (CDCl3): 5 2.05 (3H, s, CH3),2.70 (3H, d, N—CH3), 3.17 (3H, d, N-CHg), 3.63 (3H, s, CH3), 7.44 (4H, m, CH—arom.), 7.87 (1H, s, CH). cs [3'0 o / \ / F0);'3' \ (Z)-3 -(3—(2-chloro—6-?uoropheny1)—4-(5-methyl- 1 ,3 ,4-oxadiazolyl)isoxazol-5—yl)—4— hylamino)—1,l ,l —tri?uorobuten—2-one A solution of methyl 3-(2—chloro—6—?uorophenyl)methylisoxazolecarboxylate (50 mmol) was dissolved in 20 mL ethanol, and 20 mL aq. NaOH (4.0 M) were added. The mixture was heated to 60°C for 24 h. The ethanol was lly evaporated under reduced pressure and the remaining solution was acidi?ed by addition of aq. HCl (4.0 M). A itate formed, which was ?ltered off, washed with H20 and dried in vacuum to yield crude 3-(2-ehloro—6—?uorophenyl)methylisoxazolecarhoxy1ic acid quantitatively as an off—white solid.
A solution of of the ylic acid (10 mmol) in 30 mL SOC12 was re?uxed for 3 h.
Volatiles were thoroughly ated in vacuum. The residue was dissolved in dioxane (Sure/Seal; 100 mL) and added dropwise to a stirred mixture of N2H4*H20 (20 eq.) in 50 mL dioxane. The mixture was stirred at room temperature for 2 h, and was next partitioned between ethyl acetate and water. Combined organic layers were washed with water and brine, dried over MgSO4. Evaporation to dryness yielded crude hydrazide, which was next heated in samples of ca. 1.85 mmol (ca. 500 mg) in the presence of 10 mL acetic ide under microwave irradiation at 140°C for 6 h. The combined es of multiple microwave reactions were diluted with dichloromethane and washed with water, dried over sodium sulfate, ?ltered and concentrated under reduced pressure. Column chromatography on silica gel (eluent: CH2C12 to CH2C12/MeOH 98:2) gave 2-chloro?uoropheny1)—5-methyl— 1,2-oxazoly1]methyl-1,3,4—oxadiazole as a yellowish oil in 38% yield over three steps. ng with this building block (3 mmol), the general reaction steps scribed above yielded the title compound as yellow powder in 44% yield over 2 steps.
Result of LC/MS [M+H]+: 349.3; 1H NMR (CDC13): 6 2.39 (3H, s, CH3), 2.73 (3H, d, N—CH3), 3.36 (3H, d, N—CHg), 7.14 (1H, t, CH—arom.), 7.33 (1H, d, CH—arom.), 7.45 (1H, m, CPI—atom), 8.04 (1H, s, CH). cu N’0 o "I \ / FS \N \ (3-(2-chloro—6-fluorophenyl)—4—(thiazol—Z-yl)isoxazolyl)—4-(dimethylamin0)- l ,1 , l - tri?uorobutenone (step 1+2a) Orange powder, 25% yield over two steps.
Result of LC/MS [M+H]": 445.7; 1H NMR (CDC13)I 6 2.65(3H, d, N-CH3), 3.25 (3H, d, N-CH3), 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).
S is of 3-hedrazin ’lfcvclobutanols 3-hydrazinyl—1-methylcyclobutan—1-ol )8CIeICM‘XKOKWZn HOAcO OH #0 W?oHOI MeMgBr ?— Zn Ergo CIC‘ 2. NaOH HO Dess~MartIn 0231.14 1 BocNHNHz periodinane 2 NaCNBH3 NDL. 3 HCl/MeOH - 2.2-dichloro-«3«oxocyclobutyl pivalatc To a stirred solution of Vinyl pivalate (40.0 g, 0.321 mol) and Zn powder (41.2 g, 0.634 mol) in EM) (300 mL) cooled to 15°C was added dropwise slowly (over 2 h) a solution. of 2,2,2-t1ichloroacetyl chloride (73.2 g, 0.407 mol) in 320 (150 mL). The on mixture was stirred at room temperature for additional 4 h and then ?ltered through a pad of celite.
The e was washed with water (400 mL) and brine (400 mL), dried over anhydrous NazSO4 and trated under reduced pressure. The residue was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 30: l) to afford the desired compound (59.2 g, yield: 79%) as a colorless solid. - 3-oxocyclohutgl pivalate To a stirred suspension ofZn powder (80.8 g, 1.24 mol) in ACOH (300 mL) cooled to °C was added dropwise slowly (over 0.5 h) a solution of chlorooxocyclobutyl pivalate (59.0 g, 0.248 mol) in ACOH (100 mL). The reaction e was stirred at room temperature for additional 1 h and then ?ltered through a pad of celite. The ?ltrate was diluted with methyl tart—butyl ether (1.5 L), washed with brine (400 mL x 4) and saturated aq. NaHC03 (400 mL x 4) in turn until the pH was approximately 8, dried over anhydrous Na2304 and concentrated under reduced pressure. The e was d by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 25:1) to afford the desired compound (29.0 g, yield: 59%) as an oil. ~ 3-hEdroxk3methylgyclobutxlupivalate To a stirred suspension ofMeMgBr (118 mL, 0.353 mol, 3 M in Eth) in dry THF (80 mL) cooled to 0°C was added dropwise slowly (over 0.5 h) a solution of 3-oxocyclobutyl pivalate (40.0 g, 0.235 mol) in THF (100 mL). The on mixture was stirred at room temperature for additional 1.5 h. The reaction mixture was poured into cold saturated aq.
NH4C1 (300 mL). The organic phase was washed with brine (200 mL), dried over anhydrous Na2804 and trated under reduced pressure. The residue was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 2:1) to afford the desired compound (26.0 g, yield: 60%) as a sticky oil. 1 -methylcyclobutane- 1 .3419le 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 ofNaOH (3.18 g, 0.0775 mol) in water (30 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced. pressure to remove most of MeOH. The e was adjusted to pH = 4 with 1 M aq. HCl and washed with CH2C12 (30 mL x 2). The aqueous phase was concentrated under reduced pressure at 55°C. The residue was subjectd to azeotropic lation with EtOH (20 mL X 2). A solution of CH2Clz/EtOH 10:1 (30 mL) and NaHC03 solid (2 g) were added. The resulting mixture was ?ltered through a pad of celite.
The ?ltrate was concentrated under d pressure to afford the desired nd (1.40 g, yield: 77%) as a light yellow oil. 3—hvdrgggymethvlcyclobutanone To a stirred solution of l-methylcyclobutane-l ,3—diol (11.6 g, 0.114 mol) in CHQCIZ (200 mL) and THF (30 mL) at room temperature was added Bess—Martin periodinane (53.0 g, 0.125 mol). The on mixture was stirred at room ature for 18 h and then ?ltered through a pad of celite. The ?ltrate was trated under reduced pressure to afford the crude desired compound (11.4 g) as a pale yellow oil. This crude product was used in the next step without r puri?cation.
WWW—Q—hydroxv—3-meth‘rlcyclgmbutv1)hydrazinecarboxrlate 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 BocNHNHz (18.1 g, 0.137 mol) and AcOH (0.5 mL). The reaction. mixture was stirred at room temperature for 3 h and then NaBH3CN (14.4 g, 0.228 mol) was added at room temperature The reaction mixture was stirred at room temperature for 2 h and then heated to 80°C for 18 h. 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 NaZSO4 and concentrated under reduced pressure. The e was puri?ed by column chromatography on silica gel (eluent: CH2C12/MeOH 100:1 to 40:1) to afford the desired compound (12.0 g, yield: 40%) as a sticky oi1. - 3 —hydra_;iny1— 1 -methvlcyclobutanol hirdrochloride A solution of tert—butyl 2—(3-hydroxymethylcyclobutyl)hydrazinecarboxylate (350 mg, 1.62 mmol) in HCl/MeOH (3 M; 4 mL) was stirred at room ature for 1 h. The reaction mixture was concentrated under reduced pressure to afford the desired compound (275 mg, yield: 100%) as a sticky oil.
Result of LC/MS [M+H]+: 116.9; 1H NMR (CDClg): 5 1.23 (3H, (1, CH3), 2.09 (4H, m, CH2), 3.68 (1H, m, CH), 3.91 (2H, s, NHg). 3-hydrazineyl—1-(methoxymethyl)cyclobutan01 H2N.N/DL_\O_ H This hydrazinyl-cyclobutanol was synthesized in analogy to 3-hydrazinyl methylcyclobutan-l-ol, only the reaction step using MeMgBr was substituted by using ymethyl magnesium chloride in THF (30°C, 18 h).
General roeedure for the re aration of 3-ar .1 1 5-disubstituted-1H- 7razol-4~ v1 isoxazoles Y Y o H hi],' ti/"0 .R‘l hi/‘0 / N\ HZN‘N‘R1 / N \\'I‘1 A, Wm» A.- ’N Ar N.
Y R1 Z O DIEA Z Z minor structural isomer To a on of 2-acyl-1—(dimethylamino)—ethylene in dried ethanol (4 mL/mmol), were added the respective hydrazine derivative (1.3 eq.) and isopropylethylamine ( 1.3 eq. if hydrazine was used as a free base, 3.0 eq. if hydrazine was used as hydrochloride salt). The reaction mixture was heated at 60°C for 2 to 18 11, depending on conversion as monitored by LCMS. In a few cases, heating up to 78°C was necessary to drive conversion to completion.
Mixtures were partitioned n CH2C12 and saturated. aq. NH4C1, c layer was dried over MgSO4 and concentrated under reduced pressure. Products were isolated by using preparative TLC (pTLC) on silica gel.
Example 1: 1-(4—(3-(2-chloro?uorophenyl)-4—(thiazolyl)isoxazoly1) (tri?uoromethyl)— 1H-pyrazo1—l —yl)methylpropan—2-ol Title compound was synthesized. from (Z)(3—(2~chloro—6—?uoropheny1)—4—(thiazol-2— yl)isoxazoly1)(dimethy1amino)—1,1,1-tri?uorobutenone (2.2 mmol) and 1- hydrazinyl—Z-methylpropan—2—01 as yellowish solid (53%; pTLC, eluent: petroleum ethyl acetate 1:1).
Result of LC/MS : 486.8; 1H NMR (CDC13): 6 1.26 (6H, s, 2XCH3), 4.26 (1H, s, OH), 4.32 (2H, s, CH2), 7.17 (1H, td, m.), 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?uoropheny1)(thiazol-Z-y1)isoxazoly1) (tri?uoromethyl)— 1H-pyrazol- 1 —y1)methy1)cyclopr0panol Title compound was synthesized from (Z)(3-(2-ch1oro-6—?uoropheny1)~4—(thiazol yl)isoxazol—5-y1)—4-(dimethylamino)—1,1,1—t??uor0but—3-en-2—one (0.22 mmol) and 1- (hydrazinylmethyl)cyclopropanol as orange oil (27%; pTLC, eluent: petroleum ethyl acetate 1:1).
Result of LC/MS [M+H]*: 484.6; 1H NMR (CDC13): 6 0.81-0.74 (2H, m, CH2), 1.05—0.97 (2H, m, CH2), 4.21-4.00 (1H, m, OH), 4.42 (2H, s, CH2), 7.16 (1H, td, CH-arom.), 7.22 (1H, d, CH-arom.), 7.35 (1H, dt, CH- , 7.53-7.43 (1H, m, CH-arom.), 7.71 (1H, d (SH—atom), 8.12 (1H, s, CPI-atom).
Example 3: 4-(4—(3-(2-chloro-6—?uorophenyl)—4-(thiazol—2—yl)isoxazol~5-yl)~5— (tri?uoromethyl)-1 H-pyrazoly1)methylbutan01 Title compound was synthesized from (Z)—3-(3-(2-chloro—6—?uorophenyl)—4—(thi3201—2- y1)isoxazolyl)(dimethylamino)—1,1,1-tri?uorobutenone (0.57 mmol) and 4- hydrazinylmethylbutan—2—ol as yellowish oil (2%; pTLC, eluent: eum ether/ethyl e 1:1 and pTLC, eluent: CH2C12/MeOH 98:2).
Result of LC/MS [M+H3+: 501.2; 1H NMR (CDC13)I 8 1.33 (6H, s, 2XCH3), 2.14 (2H, dt, CH2), 4.54 (2H, dt, CH2), 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: (2R)(4-(3-(Z-chloro?uoropheny1)(thiazol—2—yl)isoxazoly1)~5- (tri?uoromethyl)—1H-pyrazol-l -yl)propan—2—ol Title compound was synthesized ?'om (Z)—3-(3-(2-ch10ro?uor0pheny1)-4—(thiazol yl)isoxazolyl)—4-(dimethy1amino)-1,1,1-tri?uorobut—3-en—2-one (0.14 mmol) and (R)—l- inylpropan—Z—ol as yellowish oil (23%; pTLC, eluent: CHzClg/MeOI-I 95:5 and pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result of LC/MS : 472.8; 1H NMR (CD013): 6 1.32 (3H, (1. CH3), 3.37 (1H, d, OH), 4.25 (1H, dd, CH), .32 (2H, m, 2XCH), 7.16 (1H, td, (EH-atom), 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.).
F F’e,JIOH Example 5: l—(4-(3—(2-chloro-6—?uorophenyl)—4—(thiazol-Z—yl)isoxazol-5—yl)—5— (tri?uoromethyl)- 1 H-pyrazol- 1 —yl)propan01 Title compound was synthesized from (Z)—3-(3-(2-chloro-6—?uorophenyl)-4—(thiazol y1)isoxazolyl)—4-(dimethylamino)—1,1,1—tri?uorobut—3-en-2—one (0.14 mmol) and (S) hydrazinylpropan—Z-ol as yellowish oil (33%; pTLC, eluent: /MeOH 95:5 and pTLC, eluent: eum ether/ethyl acetate 1:1).
Result of LC/MS [M+H]+: 472.8; 1H NMR (CD013): 6 1.32 (3H, d, CH3), 3.37 (1H, (1, 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-chlorofluorophenyl)(1,3-thiazoly1)—l,2—oxazolyl] (tri?uoromethyl)— lH-pyrazol-l -yl}butan~2—ol (racemic) Title compound was synthesized from (Z)(3-(2~0hloro?uoropheny1)(thiazol yl)isoxazol—5—yl)—4-(dimethylamino)-1,1,1—tri?uorobuten-2—one (0.60 mmol) and 1- hydrazino~2~butanol as yellow solid (7%; pTLC, eluent: CH2C12/M60H 95:5 and pTLC, eluent: petroleum ether/ethyl acetate 1:1). 2O Result of LC/MS : 486.8; 1H NMR (CDC13): 5 1.06 (3H, t, CH3), 1.69-1.55 (2H, m, CH2), 3.32 (111, hr, OH), 4.18-4.07 (1H, m, CH), 4.25 (1H, dd, CH), 4.41 (1H, dd, CH), 7.16 (1H, td, (EH-atom), 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, (EH—atom.) e 7: 3- {4— [3—(2—chloro?uorophenyl)-4—(1 ,3-thiazol—2-yl)-1 ,2-oxazol—5—y1]—5- (tri?uoromethyl)- 1H-pyrazol- 1 —y1}-1 ,1, 1 ropropanol (racemic) Title compound was synthesized from (Z)—3-(3—(2—chloro—6—?uorophenyl)—4-(thiazol-2— y1)isoxazol-5—y1)—4—(dimethy1amino)-l,1,1-tri?uorobut-3—enone (0.50 mmol) and 1,1,]- tri?uorohydrazinylpropan—2—ol (racemic) as yellow solid (38%; pTLC, eluent: CHZClg/MeOH 95:5; mixture of structural isomers at pyrazol 60:40, of. Scheme .
Result of LC/MS [M+H}+: 527.20; 1H NMR (CDC13)I 5 4.15 (1H, br, OH), 4.39 (1H, dd, CH), 4.71—4.49 (2H, to, CH2), 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—G-?uorophenyl)—5-(1 —(2-hydroxy—2-methylpropyl) (tri?uoromethyl)-1H-pyrazol-4—yl)isoxazole~4—carboxylate Title compound was synthesized from ethyl (2-chloro—6-?uorophenyl)(1- (dimethylamino)—4,4,4-tri?uorooxobut-1 -en-2—y1)isoxazolccarboxylate (1.1 mmol) and 1-hydraziny1methylpropan—2-ol as colorless powder (21%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, : petroleum ether/CH2C12/MeOH 924:1).
Result of LC/MS ; 475.70; 1H NMR (CDClg): 5 1.00 (3H, t, CH3), 1.26 (6H, 5, 2x CH3), 4.10 (2H, q, CH2), 4.31 (2H, s, CH2), 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?uorophenyl)—5-[1—(3—hydroxy—3—methylbutyl)-5— (t??uoromethyl)-1H-pyrazol-4—y1]-1 ,2-0xazole—4-carboxylate Title compound was sized from ethyl (Z)-3—(2—chloro-6—?uorophenyl)-5—( 1- (dimethylamino)-4,4,4-tri?uoro—3-oxobuteny1)isoxazole—4-carboxy1ate (2.3 mmol) and 4-hydraziny1—2-methylbutan—2—01 as yellow oil (45%; pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS [M+H]+: 49030;, 1H NMR ): 5 0.99 (3H, t, CH3), 1.33 (3H, s, CH3), 1.64 (1H, hr, OH), 2.15 (2H, m, CH2), 4.09 (2H, q, CH2), 4.53 (2H, m, CH2), 7.13 (1H, td, CH—arom.), 7.32 (1H, d, CH-arom), 7.41 (1H, m, CH—arom.), 7.97 (1H, s, CH-arom).
Examples 10 and 11: ethyl 3~(2—chloro—6-?uoropheny1)—5-[1-(3—hydr0xy—3— methylcyclobutyl)(tri?u0r0methyl)-1H-pyrazoly1]—1,2-oxazole—4-carboxylate, syn- and anti—con?guration) Title compounds were sized from ethyl (Z)-3 -(2-chloro-6—?uoropheny1)—5-(1— (dimethylamino)—4,4,4-tri?u0r0—3—0x0but—1-en—2-y1)isoxazole—4—carboxylate (0.17 mmol) and 3-hydraziny1methy1cyclobutan—1-ol (syn/anti mixture) (pTLC, eluent: CH2Cl2/MeOH 95:5 and pTLC, eluent: CH2C12/MeOH 98:2); Example 10: syn-diastereomer (3%) Result of LC/MS [M+H]+: 488.20; IH NMR(CDC13): 6 0.99 (3H, t, CH3), 1.49 (3H, s, CH3), 2.80 (4H, m, CH2), 4.09 (2H, q, CH2) 4.72 (1H, m, CH), 7.13 (1H, td, CH—arom.), 7.33 (1 H, d, CH—arom.),7.42 (1H, m CH- , , , 8.00 (1H, s, CH—arom).
Example 11: anti-diastereomer (5%) Result of LC/MS [M+H]+: 488.20; 1H NMR (CD013); 5 0.99 (3H, t, CH3), 1.49 (3H, s, CH3), 2.65 (2H, m, CH2), 2.83 (2H, m, CH2), 4.09 (21-1, q, CH2) 5.26 (1H, m, CH), 7.13 (1H, td, CH—arom.), 7.32 (1H, , (1, CH— arom.),7.42 (1H, m 7.96 (1H, s, CH-arom).
, CH-arom.), Example 12: ethyl 3 loro?uor0phenyl)—5- {1—[(ZR)—2—hydroxypropyl] (tri?uoromethyl)- 1H-pyrazol-4—yl} — 1 ,2-0xazolecarboxylate Title nd was sized from ethyl (Z)-3—(2-chloro~6-?uorophenyl)(1- (dimethylamino)-4,4,4— tri?uorooxobut—1—eny1)isoxazolecarboxylate (0.5 mmol) and (R)—1-hydraziny1propan—2-ol as yellow oil (39%; pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result of LC/MS [NIH—11+: 461.70; 1H NMR (CDC13)I 5 0.99 (311,1, CH3), 1.31 (3H, d, CH3), 3.33 (1H, br, OH), 4.09 (2H, q, CH2), 4.24 (1H, dd, CH), 4.36 (2H, dd 7.13 (1H, td, m.), 7.32 (1H, d, CH— , CH2), arom), 7.42 (1H, m, CH—arom.), 8.01 (1H, s, CH-arom).
Example 13: ethyl 3-(2-ch1oro-6—?uorophenyl)—5-(1-((2S)hydr0xypropy1) (tri?uoromethyl)-1H—pyrazoly1)— 1 ,2-0Xazoleearb0xy1ate Title compound was synthesized from ethyl (Z)-3~(2-ch101'0?uor0phenyl)(l- (dimethylamino)-4,4,4— tri?uoroox0buten-2—yl)isoxazole—4—carboxylate (0.5 mmol) and (S)hydrazinylpropan-2—ol as yellow oil (31%; pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result ofLC/MS [M+H]+: 461.70; 1H NMR (CD013): 6 1.00 (3H, t, CH3), 1.32 (3H, d, CH3), 3.30 (1H, s, OH), 4.10 (2H, q, CH2), 4.25 (1H, dd, CH), 4.37 (2H, dd 7.14 (111, rd, CPI—atom), 7.33 (1H, , CH2), (1, CH- arom), 7.43 (1H, m, CH-arom.), 8.02 (1H, s, CH-arom).
Example 14: ethyl hloro?uorophenyl)[1~(2-hydroxybutyl)-S-(tri?uoromethyl)- 1H-pyrazol-4—yl]-1,2—oxazole—4-carboxylate (racemic) Title compound was synthesized from ethyl (Z)-3—(2-chloro?uorophenyl)(1— (dimethylamino)—4,4,4~tri?uorooxobutenyl)isoxazolecarboxylate (0.23 mmol) and 1-hydrazinobutanol as yellow oil (26%; pTLC, eluent: CH2C12/MeOI-1 95:5 and again pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS [M+H]+: 475.8; lH NMR(CDC13): 5 0.99 (3H, t, CH3), 1.06 (3H, t, CH3), 1.61 (2H, quint, CH2), 3.15 (1H, d, OH) 4.09 (2H, q, CH2), 4.25 (1H, dd, CH2), 4.40 (1H, dd, CH2), 7.13 (1H, td, CH-arom.), 7.32 (1H, d, CH-arom.),7.42 (1H, m 8.01 (1H, s, CH-arom).
, CH-arom.), Example 15: ethyl 3—(2-chloro—6—?uorophenyl)—5-[1-(3,3,3 —trif1uoro—2-hydroxypropy1)—5— (tri?uoromethyD-lH-pyrazol-4—yl]—1,2-oxazolecarboxylate (racemic) Title compound was sized from ethyl (2—ehloro?uorophenyl)—5-(1- (dimethylamino)-4,4,4-tri?uorooxobut-1—enyl)isoxazole—4-carboxylate (0.52 mmol) and 1,1,1—tri?uoro-3—hydrazinylpropan—2-ol (racemic) as colorless oil (35%; pTLC, eluent: /MeOH 95:5 and pTLC, eluent: petroleum ether/ethyl acetate 3:2; mixture of structural isomers at pyra2019525, of. Scheme above).
Result of LC/MS [M+H]+: 515.8; 1H NMR (CD013): 5 0.99 (3H, t, CH3), 4.08 (3H, m, CH2, CH), 4.62 (2H, m, CH2), 7.13 (1H, td, m.), 7.33 (1H, d, CH-arom), 7.43 (1H, m, CH—arom.), 8.05 (1H, s, CH—arom).
Example 16: ethyl 3-(2-chloro?uorophenyl)—5-{1-[(2R)-3,3,3—tri?uorohydroxypropyl]- -(tri?uoromethyl)— 1 H-pyrazolyl} -1 ,2—oxazolecarboxylate Title compound was synthesized from ethyl (Z)(2-ch10ro?uorophenyl)—5-(1- (dimethylamino)—4,4,4-tri?uoro0xobuten—2-y1)isoxazole-4—carboxy1ate (0.14 mmol) and (R)-1,l ,1-tri?uoro-3—hydraziny1propan—2-ol as colorless oil (15%; pTLC, eluent: CHgClngeOH 95:5).
Result of LC/MS [M+H]+: 516.2; 1H NMR (CDC13)Z 5 0.99 (3H, t, CH3), 3.96 (1H, d, 0H), 4.09 (2H, q, CH2), 4.62 (3H, m, CH2, CH), 7.13 (1H, td, CH-arom.), 7.33 (1H, d, CH—arom), 7.43 (1H, m, CH-arom.), 8.06 (1H, s, CH-amm).
O ’0 Example 17 and 18: methyl 3-(2-chloropheny1)(1-(3-hydroxy—3—methyleyclobutyl) methyl-1H—pyrazoly1)isoxazole—4—carboxylate (anti- and syn—con?guration) Title compounds were synthesized from methyl (2—chlorophenyl)—5—[l- (dimethylamino)—3-oxobut—1-enyl]-1,2-oxazolecarboxylate (0.60 mmol) and 3— inyl-l-methylcyclobutan—1-ol (syn/anti mixture) as orange oils (pTLC, eluent: eeOH 95:5); Example 17: anti-con?guration Within cyclobutanol system, 21% yield; Result of LC/MS [M+H]+: 402.30; 1H NMR(CDC13): 5 1,55 (3H, s, CH3), 2,57 (3H, s, CH3), 2.59 (2H, m, CH2), 2.81 (2H, m, CH2), 3.66 (3H, s, O-CH3) 5.04 (1H, m, CH), 7.35 (4H, m, CPI-3mm), 8.31 (1H, s, CH- atom).
Example 18: syn-con?guration within cyclobutanol system, 11% yield; Result of LC/MS [M+H]+: 402.3; 1H NMR (CDC13)I 5 1.47 (3H, s, CH3), 2.57 (3H, s, CH3), 2.82-2.70 (4H, m, 2XCH2), 2.87 (1H, hr, OH), 3.65 (3H, s, CH3), 4.54 (1H, quint, CH), 7.53-7.33 (4H, m, 4xCH-ar0m.), 8.37 (11-15 s, m) Example 19: methyl 3-(2—chloropheny1)—5—[1—(3-hydroxy—3~methylbutyl)methyl—lH- pyrazolyl] — 1 ,2-0xazole—4—carboxylate Title compound was synthesized from methyl (Z)—3—(2-chlorophenyl)—5-[l—(dimethylamino)— 3-oxobuten—2-yll-l,2-oxazole—4—carboxylate (0.86 mmol) and 4-hydraziny1—2-methylbutan— 2—01 as yellow oil (31%; pTLC, eluent: CH2Cl2/MeOH 95:5 and again pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS {M+H]+: 4040; 1H NMR ): 6 1.30 (6H, 3, 2x CH3), 2.05 (2H, s, CH2), 2.62 (3H, s, CH3) 3.65 (3H, s, CH3), 4.32 (2H, m, CH2), 7.34 (4H, m, CH-arom.), 8.30 (1H, s, CH-arom).
Example 20: methyl 3-(2-chloro?uorophenyl)[1-(3-hydroxy—3—methy1butyl)methy1- 1H—pyrazolyl]—1,2-oxazolecarboxylate Title compound was synthesized from methyl (Z)(2-chloro?uorophenyl)—5-(1- hylamino)—3-oxobut—1-eny1)isoxazole—4—carboxylate (0.79 mmol) and 4-hydrazinyl- 2-methylbutanol as yellow oil (29%; pTLC, eluent: /MeOH 98:2 and pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS [M+H]’*’: 422.00; 1H NMR (CDC13)Z 6 1.31 (6H, 5, 2x CH3), 2.05 (2H, t, CH2), 2.64 (3H, s, CH3), 3.65 (3H, s, CH3), 4.32 (2H, m, CH2), 7.12 (1H, td, CH—arom.), 7.32 (1H, d, CH-arom), 7.41 (1H, m, CH- arom.), 8.33 (1H, s, CH-arom). e 21: methyl (R)(1-(2-hydr0xypropyl)(tri?uoromethyl)-1H-pyrazolyl)(2- methoxypyridin—3-y1)isoxazole—4—carboxylate Title compound was synthesized from methyl (Z)(l-(dimethylamino)—4,4,4-tri?uor0—3— oxobut—l-en—2-yl)—3—(2-meth0xypyridin—3-yl)isoxazole-4—carboxylate (0.55 mmol) and (R)-l- hydrazinylpropan-Z-ol (30%; pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS [M+H]+: 426.8; 1H NMR (CDCl3): 6 1.31 (3H, (1, CH3), 3.66 (3H, s, CH3), 3.93 (3H, s, CH3), 4.31 (3H,. m, CH, CH2), 7.01 (1H, dd, CH-arom.), 7.83 (1H, dd, (SH—atom), 8.01 (1H, s, CH—arom.), 8.30 (1H, dd, CH- atom).
Example 22: methyl (S)(2-chlorophenyl)—5—(l-(2-hydroxypropyl)(tri?uorornethy1)—1H— pyrazol-4—y1)isoxazole—4-carboxylate Title compound was synthesized from methyl (Z)(2-cl?orophenyl)—5—(l-(dimethylamino)- 4,4,4—tri?uor00xobuten—2—y1)isoxazole-4—carboxylate (1.0 mmol) and (S)-l- hydrazinylpropan-Z-ol (49%; pTLC, eluent: CHZClz/MCOH 95:5).
Result ofLC/MS : 429.8; 1H NMR (CDC13)1 5 1.32 (3H, d, CH3), 3.64 (3H, s, OCH3), 4.24 (1H, dd, CH), 4.48—4.31 (2H, m, CH2), 7.56-7.34 (4H, m, mm.), 8.00 (1H, s, CH-arom.).
Example 23: methyl (S)(2-chlor0-6—?uorophenyl)—5-(l —(2—hydroxypropyl) (tri?uoromethyl)—l H-pyrazolyl)isoxazole-4—carboxylate Title compound was synthesized from methyl (2-chloro?uorophenyl)(1- (dimethylamino)-4,4,4—tri?uoro—3-ox0but—1—en—2-yl)isoxazolecarboxylate (0.83 mmol) and (S)—1-hydrazinylpropanol (27%; pTLC= eluent: CH2Clz/MeOH 95:5 and pTLC, eluent: petroleum ether/ethyl acetate 3 :2).
Result of LC/MS [M+H]+: 448.2; 1H NMR (CDC13)I 5 1,32 (3H, (1, CH3), 3.64 (3H, s, OCH3), 4.25 (1H, dd, OCHZ), 4.48—4.32 (2H, m, CH2), 7.14 (1H, td, m.), 7.33 (1H, dt, CH-arom.), .38 (1H, m, CH— arom.), 7.99 (1H, s, (EH—arena).
Cl hrs CS/TOH 9 Example 24: methyl (S)—3—(2-chlorophenyl)(1-(2-hydroxypropyl)methyl-1H-pyrazol—4— yl)isoxazole—4—carboxylate Title compound was synthesized from methyl (Z)(2—chlorophenyl)[l-(dimethylamino)— 3—oxobut-l-en-2—yl]—l,2—oxazole—4—carboxylate (1.0 mmol) and (S)—1—hydrazinylpropan—2—ol (32%; pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS {M+H]+: 376.3; lH NMR(CDC13): 8 1.30 (3H, d, CH3), 2.61 (3H, s, CH3), 3.65 (3H, s, OCH3), 4.58-3.82 (3H, m, CH and CH2), 7.55—7.33 (4H, m, 4xCH—arom.), 8.38 (1H, s, (EH-arena.) Example 25: methyl hloromethoxyphenyl)-5—[1—(3—hydr0xy-3—methylbutyl)—5- methyl- 1 H-pyrazol-4—yl]- 1 ,2-oxazole-4—earboxylate Title compound was sized from methyl (Z)(2-chloro-3~methoxyphenyl)[1— (dimethylamino)oxobut-l-en—Z-yl]-l,2—oxazole—4-earboxylate (1.1 mmol) and 4- hydrazinyl-2—methylbutan-2—ol as orange oil (33%; pTLC, eluent: CH2Clz/MeOH 95:5 and again pTLC, eluent: CHZClz/MeOH 95:5).
Result of LC/MS [M+H]+: 434.0; 1H NMR(CDC13): 6 1.30 (6H, s, 2x CH3), 2.04 (2H, m, CH2), 2.62 (3H, s, CH3), 3.65 (3H, s, CH3), 3.95 (4H, s, OH, CH3), 4.31 (2H, m, CH2), 7.07 (2H, m, CPI-atom), 7.33 (1H, t, CH— arom.), 8.28 (1H, s, CH—arom.). '7 O_ CF3 OH / / N,0", CD 0 Examples 26 and 27 : methyl 3-(2—chloro?uoropheny1)(1—(3-hydroxy methylcyclobutyl)(tri?uoromethyl)—1H-pyraz01—4—yl)isoxazole—4-carboxylate (anti- and syn—con?guration) Title compounds were synthesized from methyl (Z)—3-(2-chlor0—6—?uorophenyl)—5-[1- (dimethylamino)-4,4,4~tri?u0ro0xobut—1-en—2—yl.]-l,2—0xazole—4—carboxylate (0.24 mmol) and 3-hydraziny1—1—methylcyclobutan-l-ol (syn/anti mixture) (pTLC, eluent: /MeOH 95:5).
Example 26: on?guration within cyclobutanol system, 18% yield; Result of LC/MS [M+H]+: 473.80; 1H NMR (CDC13)Z 5 1.56 (3H, s, CH3), 2.75-2.49 (2H, m, CH2), 2.95-2.75 (2H, m, CH2), 3.63 (3H, s, OCH3), 5.26 (1H, quint, CH), 7.13 (1H, td, CH—arom.), 7.33 (1H, d, CH-arom.), 7.47- 7.37 (1H, m, m.), 7.94 (1H, s, CH-arom.).
Example 27: syn—con?guration within cyclobutanol system; 18% yield; Result of LC/MS [M+H]+: 473.8; 1H NMR (CDClg): 5 1.50 (3H, s, CH3), 2.95-2.71 (4H, m, 2XCH2), 3.63 (3H, s, OCH3), 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, CPI-atom.) CF3 0" F N'0 '/ / N’D/ CD \ Example 28: methyl 3 -(2-chloro-6—?uorophenyl)—5-(1 -(3 xycyclobuty1)—5- (tri?uoromethyl)-lH-pyrazolyl)isoxazole—4-carboxylate Title nd was synthesized from methyl (Z)(2—chlor0?uorophenyl)-5—[l- (dimethylamino)—4,4,4—tri?uoro—3—oxobut—1—eny1]—l,2-oxazole—4-carboxylate (0.24 mmol) and 3-hydrazinylcyclobutan—1—ol (syn/anti mixture) (46% as mixture of syn— and anti- configuration within cyclobutanol system; pTLC, eluent: CH2C12/MeOH 95:5).
Result of LC/MS [M+H]+: 459.8; 1H NMR )Z 5 2.86—2.69 (2H, m, CH2), 3.10-2.93 (2H, m, CH2), 3.63 (3H, s, CH3), 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—ehlorophenyl)—5—(l -(3-hydroxy—3-(methoxymethyl)cyclobutyl)—5— (tri?uoromethyl)-lH-pyrazol—4—yl)isoxazolecarboxylate on?guration) Title compound was synthesized from methyl (Z)—3-(2~chlorophenyl)—S—(1—(dirnethylamino)— 4,4,4-tri?uorooxobut-1 -eny1)isoxazolecarboxylate (0.30 mmol) and azinyl(methoxymethyl)cyclobutan-l—ol (mixture syn/anti) in 34% yield. Syn— and anti—con?gurations within the resulting t were not separable at this stage, ore, the hydroxyl group was silylated using tert-butyldimethylsilyl tri?ate, NJV—diisopropylethylamine in CH2C12 (cf. general silylation procedures described , upon which a separation of isomers succeeded by pTLC, eluent: petroleum ether/ethyl acetate 4:1 and pTLC, eluent: CH2C12/MeOH 95:5. Desilylation was achieved using HCl in MeOH (room temperature, 2 h) to give the title nd with syn-configuration in 50% yield from the mixture of isomers, along with 16% of the anti-isomer (the pH was adjusted to around 8 by adding aq. NaOH (1 M), and the mixture was extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: petroleum ether/ethyl acetate 1:5).
Result of LC/MS [M+H]+: 486.20; lH C13): 5 2.09 (1H, br, OH), 2.86 (4H, m, CH2), 3.49 (5H, s, CH2/ CH3), 3.63 (3H, s, O—CH3) , 4.67 (1 H, m, CH), 7.44 (4H, m, CH-arom.), 8.00 (1H, s, CH—arom).
Example 30: 1-(4—(3-(2—chloro-6—?uorophenyl)—4-(5-methy1-1,3,4—oxadiazol-2—yl)isoxazol—5- yl)(tri?uoromethy1)-1 H-pyrazoly1)—2-methylpropan—2-ol Title compound was synthesized from (Z)—3—(3—(2-chloro—6—?uorophenyl)—4-(5-methyl-1,3,4— oxadiazol-Z-yl)isoxazol-5—yl)(dimethylamino)-1 ,1 , l orobut—3-enone (0.18 mmol) and 1—hydrazinylmethylpropanol as pale yellow oil (4%; pTLC, eluent: petroleum ether/ethyl acetate 4:1 and pTLC, eluent: CHZClz/MeOH 95:5).
Result of LC/MS [M+H]+: 485.70; 1H NMR (CDC13)Z 8 1.27 (6H, 5, 2): CH3), 2.39 (3H, s, CH3), 4.34 (2H, s, CH2), 7.16 (1H, td, (EH—atom), 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— (tri?uoromethyl)-1H—pyrazol—4—yl)isoxazole—4—carboxylate Title compound was synthesized (syn/anti mixture) from ethyl (Z)—3-(3—(benzyloxy)—2- chlorophenyl)(l-(dimethylamino)—4,4,4-t1i?uoro—3-oxobut- l yl)isoxazole-4— carboxylate (3.3 mmol) and 3-hydraziny1methylcyclobutan~1-ol (syn/anti mixture) as yellow oil (34%; pTLC, eluent: eum ether/ethyl e 4:1 and pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result ofLC/MS [Ml-HT: 576.3; 1H NMR (CDC13): 8 1.27 (3H, 1', CH3), 2.04 (3H, s, CH3), 2.77 (4H, m, 2x CH2), 4.08 (1H, m, CH), 4.13 (2H, q, CH2), 5.23 (2H, s, CH2), 7.10 (2H, d, om), 7.35 (4H, m, CPI-atom), 7.47 (2H, d, CH-arom.), 7.98 (1H, s, CH—arom.). ethyl 3-(3~(benzyloxy)—2-chlorophenyl)—5-(1-(3-hydroxymethylbutyl)-5— (tri?uoromethyl)—lH—pyrazol—4—yl)isoxazole—4—carboxylate Title compound was synthesized from ethyl (Z)-3—(3—(benzyloxy)—2-chlorophenyl)—5-(1- (dimethylamino)-4,4,4—tri?uoro—3-oxobut—1-eny1)isoxazole—4-carhoxylate (6.6 mmol) and 4-hydrazinyl-2~1nethylbutanol as yellow oil (84%; column chromatography on silica gel, eluent: CH2C12/MeOH 98:2).
Result of LC/MS [M+H]+: 578.3; 1H NMR(CDC13): 6 0,99 (3H, t, CH3), 1.33 (6H, 5, 2x CH3), 2.14 (2H, m, CH2), 3.38 (2H, s, CH2), 3.56 (1H, m, CH), 3.65 (1H, m, CH), 4.07 (211, q, CH2), 7.07 (2H, dd, CH-arom.), 7.40 (6H, rn, CH-arom.), 7.98 (1H, s, CH—arom.).
S is of deuterated alcohols 1.) MeONHMe, EDCI Y Y 2.) MeMgBr -o «0 Ar ’N O WWW—an» Ar "N D Z Z Respective acetic acid derivatives were synthesized according to the general procedure decribed above for pyrazole formation using azinylacetic acid. Reaction mixtures were only partitioned between CH2C12 and saturated. aq. NH4C1, organic layer was dried over MgSO4 and concentrated under reduced pressure, and products were used as crude material for the ing steps. - 3-(2-chlorofluorophenyl)(thiazolyl)isoxazolyl)(tri?uoromethyl)—1l-I- pyrazol-l-yl)acetic acid from (3—(2~ch10ro~6—?uorophenyl)~4—(t11iazol—2-yl)isoxazol— -yl)(dimethyla1nino)-l ,1 , 1 -t1i?uorobut—3~en—2—one; Result of LC/MS [M+H]+: 472.7; 1H NMR (CDC13)I 5 3.15 (1H, 5, COOH), 5.15 (2H, s, CH2), 7.16 (1H, t, CPI-atom), 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?uorophenyl)(cthoxycarbonyl)-l ,2—oxazoly1]-5— oromethyl)-lH-pyrazol—l-yl}acetic acid from ethyl (Z)-3—(2-chloro—6-?uorophenyl)- —(1—(dirnethy1amino)—4,4,4-tri?uorooxobuteny1)isoxazole-4—carboxy1ate; Result of LC/MS [M+H]*: 461.7; 1H NMR (CDC13)I 8 0.98 (3H, t, CH3), 4,06 (2H, q, CH2), 4.97 (2H, s, CH2), 7.09 (1H, t, CH—arorn.), 7.29 (1H, d, CH-arom.), 7.39 (1H, m, CH-arom.), 8.03 (1H, s, CH-arom.). - 2- {4—[3-(2-chloro?uoropheny1)(methoxycarbonyl)—1 ,2-oxazolyl] (tri?uoromethyl)—1H-pyrazol—l-yl}acetic acid from methyl (Z)—3—(2-chloro—6— ?uoropheny1)(1 -(dimethylamino)-4,4,4-tri?uorooxobuten—2-y1)isoxazole—4— carboxylate; Crude acetic acid derivative (1.0 mmol), N,O-dimethy1hydroxy1amine hydrochloride (1.0 eq.), 1-hydroxybenzot1iazole (1.0 eq.) and 1-(3-dimethy1aminopropyl)ethylcarbodiimide hydrochloride (EDCI; 1.2 eq.) were dissolved in dry DMF (Sure/Seal, 4 mL/mmol). N- methylmorpholine (10 eq.) was added and the on was stirred at room temperature for 18 DMF was removed under reduced pressure and an aq. 5% solution of citric acid was added.
The e was extracted with CH2C12, the combined organic phases washed with water and dried over MgSO4 and concentrated under reduced pressure: - 2— {4-[3-(2-chloro—6-?uoropheny1)-4—(1 ,3 olyl)-l ,2-oxazol—5-yl] (tri?uoromethyl)-1H-pyrazol—l-yl}~N—rnethoxy-N—methy1acetamide; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 7:3), orange oil, 14% yield over two steps; Result of LC/MS [M+H]+: 515.8; 1H NMR (CDC13)I 5 3.26 (3H, s, CH3), 3.81 (3H, s, CH3), 5.34 (2H, s, CH2), 7.14 (1H, m, CH-arom.), 7.23 (1H, dd, m.), 7.34 (1H, m, CH—arorn.), 7.47 (1H, rn, CH—arorn.), 7.73 (1H, d, CH-arom.), 8.20 (1H, s, CH-arom.). - ethyl 3 -(2-chloro?uoropher1yl)-5~(1 - { [methoxy(rnethyl)carbainoyl]methyl}—5- (tri?uoromethyl)-1H-pyrazolyl)-l,2-oxazolecarboxylate; ative TLC on silica gel (eluent: petroleum ether/ethyl acetate 7:3), orange oil, 38% yield over two steps; Result of LC/MS [M+H]+: 504.7; 1H NMR (CDC13)Z 5 1.04 (3H, t, CH3), 3.24 (3H, s, CH3), 3.79 (3H, s, CH3), 4.10 (2H, q, CH2), 5.33 (2H, s, CH2), 7.12 (1H, t, m.), 7.31 (1H, d, CH—arom.), 7.41 (1H, m, CH—arom.), 8.13 (1H, s, CH-arorn.) - methyl hloro?uoropheny1)-5—(l — {[methoxy(methyl)carbamoyl]methyl} (tri?uoromethyl)—1H—pyrazol—4-yl)—l,2-cxazole—4—carboxylate; crude material was used as such for the next step The respective Weinreb amide was dissolved in THF (Sure/Seal; 4 mL/mmol) at 0°C. magnesium bromide (5.0 eq.; 3.2 M in 2-methyl-THF) was added slowly and the mixture was stirred at 0°C for l h and then at room temperature for additional 5 h. The mixture was quenched with water and partitioned between CH2C12 and water. Combined organic layers were dried over MgSO4, ?ltrated and concentrated under reduced pressure to give crude methyl ketone: - 1- {4-[3-(2—chloro?uorophenyl)(1 ,3 —thiazol—2—yl)—l zol—5~yl] (tri?uoromethyl)-1H—pyrazol—l—yl}propan-2—one, 70% yield (crude); Result of LC/MS [M+H]+: 470.8. - ethyl 3-(2—chloro?uoropheny1)[1-(2-oxopropyl)-5—(tri?uoromethyl)-1H-pyrazol yl]-1,2—0xazole—4-carboxylate; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:2 and pTLC, elucnt: CH2C12/MeOH 95:5), 12% yield; Result of LC/MS [M+H]+: 459.70; 1B NMR (CDC13)I 5 1.03 (3H, t, CH3), 3.23 (3H, s, CH3), 4.12 (2H, q, CH2), 5.18 (2H, s, CH2), 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-ch10ro?uorophenyl)—5-(1-(2-oxopr0pyl)—5-(tri?uoromethyl)-lH—pyrazol y1)-l,2—cxazole—4-carboxylate; preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:2), 8% yield over three steps; Result of LC/MS [M+H]+: 445.7; 1H NMR (CDC13): 8 1.23 (3H, s, CH3), 3.65 (3H, s, CH3), 5.18 (2H, s, CH2), 7.14 (1H, td, CPI—atom), 7.33 (1H, d, m.), 7.43 (1H, m, CH-arom.), 8.07 (1H, s, CH—arom.).
The respective methyl ketone was dissolved in THF (10 mL/mmol) and cooled to 0°C.
NaBD4 (1.1 eq.) was added and the mixture was d at 0°C for 1 h.
The mixture was quenched with water and partitioned between CH2C12 and water. Combined c layers were dried over MgSO4, ?ltrated and concentrated under reduced pressure.
Alpha—deuterated ls were puri?ed by preparative TLC on silica gel (eluent: CHgClZ/MeOH 95:5): Example 31: 1—{4—[3-(2—ch10ro—6-?uor0phenyl)—4—(l ,3—thiazol-2—yl)-1,2-oxazolyl] (tri?uoromethyl)—lH-pyrazol-l -yl}(2—2H)propanol (racemic) was isolated in 28% yield.
Result of LC/MS [M+H]+: 473.8; 1H NMR (CDC13)I 5 1.31 (3H, s, CHg), 4.25 (1H, s, CH), 4.38 (1H, (1, CH), 7.17 (1H, t, CH- arom.), 7.22 (1H, d, om), 7.36 (1H, d, CH-arom.), 7.54—7.44 (1H, m, CH-arom.), 7.71 (1H, d, CH-arom.), 8.09 (1H, s, CPI-atom).
Example 32: ethyl 3-(2~chloro-é-?uorophenyl)—5~ {l—[2-hydroxy(2—2H)pr0pyl]—5— (tri?uoromethyl)-1H—pyrazol-4—yl}-1,2-0xazole—4—carboxylate (racemic) was isolated as pale yellow oil in 10% yield Result of LC/MS [M+H]+: 462.7; 1H NMR (CDC13): 5 0.99 (3H, t, CH3), 1.31 (3H, s, CH3), 3.25 (1H, s, OH), 4.09 (2H, q, CH2), 4.30 (2H, dd, CH2), 7.13 (1H, td, (EH-arena), 7.33 (1H, d, (EH-atom), 7.43 (1H, m, CH- , 8.01 (1H, s, Cl—l—arom).
Example 33: methyl 3 -(2—chloro-6—?u0r0phenyl)~5 - { 1 -[2-hydroxy(2-2H)propyl] (tri?uoromethyl)—1H~pyrazol-4—yl}-1,2-0xazole—4—carboxylate (racemic) was isolated in 24% yield Result of LC/MS [M+H]+: 448.80; 1H NMR (CDClg): 5 1.31 (3H, s, CH3), 3.64 (3H, s, OCH3), 4.31 (2H, q, CH2), 7.14 (1H, td, CH—arom.), 7.33 (1H, dt, CH-arom.), .38 (1H, m, m.), 7.99 (1H, s, CPI-atom.) Synthesis of 4-acyl isoxazoles N‘0 Y, 1.) 2 M NaOH R1 W0 ’R1 2.) MSONHMe, EDCI 1 / / 1‘" , / / 1" Ar ,N 3.) R MgBr N (N O R2 o 0 Esters Example 8 or Example 12 (0.25 mmol) were dissolved in 2 mL ethanol, and 2 mL aq.
NaOH (2.0 M) were added. The mixture was heated to 60°C for 1 h and then acidi?ed by addition of aq. HCl (1.0 M). The resulting suspension was partitioned between CH2C12 and water, combined organic layers were dried over MgSO4, and the solvent was removed under reduced re to give crude ylic: acids: (2-chloro-6—?uorophenyl)(1 -(2-hydroxy—2-methylpropy1)—5-(tri?uoromethyD-l H- pyrazol-4—yl)—1,2—oxazole—4—carboxylic acid as off-white solid, 94% yield; Result of LC/MS [M+H]+: 447.8; 1H NMR (CDC13): 5 1.22 (6H, s, , 4.30 (2H, s, CH2), 7.12 (1H, td, CPI-atom), 7.32 (1H, dt, CH-arom.), 7.47-7.37 (1H, m, CH—arom.), 8.00 (1H, s, CH—arom.). — 3 —(2—chloro?uorophenyl)~5- {l hydroxypropyl] —5—(tri?uoromethyl)— l H—pyrazol- 4-y1}-1,2-oxazole—4-carboxylic acid as off—white solid, 75% yield; Result of LC/MS [M+H]+: 433.9; 1H NMR (CD013): 5 1.30 (3H, d, CH3), 4.24 (1H, dd, CH), 4.47-4.28 (2H, m, CH2), 7.12 (1H, td, m.), 7.32 (ll-I, dt, (EH-aroma), 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 l-(3-dimethylaminopropyl)—3—ethylearbodiimide hydrochloride (EDCI; 1.2 eq.) were ved in dry DMF (Sure/Seal, 4 mL/mmol). N- Methylmorpholine (5 eq.) was added and the reaction was stirred at room temperature for 18 The mixture was poured into ice water and extracted with CH2C12. ed organic phases were washed with water and dried over MgSO4 and concentrated under reduced pressure: — 3 -(2-chloro?uorophenyl)—5 -( l ~(2-hydroxy—2—methylpropyl)—5-(tri?uoromethyl)—1 H- pyrazolyl)-N-methoxy—N-rnethyl-1,2—oxazolecarboxamide; pTLC (eluent: CH2C12/MeOH 95:5), as pale yellow solid, 68% yield; Result of LC/MS [M+H]+: 491.3; 1H NMR (CDClg): 5 1.23 (6H, s, 2XCH3), 3.11 (3H, s, NCH3), 3.38 (3H, s, OCH3), 4.13 (1H, s, OH), 4.29 (2H, s, CH2), 7.12 (1H, td, m.), 7.32 (1H, dt, CH-arom.), 7.45- 7.35 (1H, m, m.), 7.99 (1H, s, CH-arom.). (2-chloro?uorophenyl)—5— {1—[(2R)—2—hydroxypropyl]—5-(t1i?uoromethyl)—1H—pyrazol- 4-yl}-N-methoxy—N-methyl-1,2-oxazolecarboxamide, crude material as orange oil, 95% yield; Result of LC/MS [M+H]*: 476.8; The respective b amide was dissolved in THF (Sure/Seal; 5 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 1.5 h. If LCMS indicated incomplete sion, the e was stirred at room temperature for additional 5 h. If necessary, an additional MeMgBr (3 eq.) was added at 0°C again and the mixture was kept at room temperature for another 18 h.
The mixture was quenched with water and partitioned between CH2C12 and water. Combined c layers were dried over MgSO4, ?ltrated and concentrated under reduced pressure.
Example 34: 1 -(3-(2-ch1oro—6-?uorophenyl)( 1 —(2~hydroxy—2—methylpropyl) (trifluoromethyl)— l H-pyrazolyl)— 1 ,2—oxazol-4—y1)ethanone The title compound was isolated by prep. TLC on silica gel (eluent: CHzClz/MeOH 9525) as a dark yellow oil in 8% yield.
Result of LC/MS [M+H]+: 490.7; lH NMR(CDC13): 5 1.25 (6H, s, CH3), 2.06 (3H, s, CH3), 4.12 (1H, s, OH), 4.32 (2H, s, CH2), 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-chlorofluorophenyl) { 1 —[(2R)hydroxypropyl]—5— (tri?uoromethyl)-1H-pyrazol—4-yl} -1 ,2—oxazol—4—y1]ethanone The title compound was isolated by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) as a yellow oil in 10% yield.
Result of LC/MS [M+H]+: 431.8; 1H NMR(CDC13): 6 1.32 (3H, d, CH3), 2.06 (3H, s, CH3), 3.22 (1H, s, CH), 4.26 (1H, dd, CH2), 4.37 (3H, dd, OH, CH2), 7.18 (1H, td, CH-arom.), 7.37 (1H, d, CH-arom), 7.47 (1H, m, rn.), 7.98 (1H, s, CH-arom). es 36, 37 and 38: ation of the grignard reagent: To a suspension of magnesium (1.25 eq.) in EtZO (5 mL) was added (bromomethyl)cyclobutane or cyclopropylmethyl bromide (10 mmol). After the completion of the Grignard on the solution was separated from the rest ofmagnesium and further used as such (4 ml of the respective Grignard reagent in Eth). 3 -(2-chloro?uorophenyl)—5—( 1 —(2—hydroxy—2-methylpropy1)(tri?uoromethyl)- 1 H- pyrazoly1)-N—methoxy—N—methylisoxazole-4—carb0xamide (0.25 mmol) was dissolved in THF and the reaction mixture was cooled to 0 °C. The Grignard solution (4 mL, as described above) was added se at 0 °C over a period of 5 h. After addition the mixture was stirred for 1. h. at 0°C (in the case of the cyclobutane-Grignard) or for 4 h with slow warming to room temperature (in the case of the cyclopropylmethyl—Grignard). The reaction was quenched by the addition of water and an aqueous l M HCl solution and extracted with CHzClz. Organic layers were combined, dried over MgSO4, ?ltered and concentrated under reduced pressure. The residue was puri?ed by preparative TLC on silica gel (eluent: CHZClg/MeOH 98:2).
Example 36: 2-chloro?uorophenyl)[1-(2-hydroxy—2-methylpropyl)—5- (trifluoromethyl)— l H—pyrazol-4—yl] -l ,2-oxazolyl]—2—cyc10butylethan— 1 -one The title compound was obtained as a colorless oil (33% .
Result of LC/MS [M+H]+: 500.3; IH NMR(CDC13): 5 1.25 (6H, 3, 2x CH3), 1.42 (2H, m, CH2), 1.80 (2H, m, CH2), 1.98 (2H, m, CH2), 2.39 (2H, (1, CH2), 2.58 (1H, m, CH), 4.13 )1H, s, OH), 4.32 (2H, s, CH2), 7.17 (1H, td, m.), 7.36 (1H, dt, CH-arom), 7.47 (1H, m, CH-arom.), 7.97 (1H, s, CH-arorn).
Example 37: 1-[3-(2-chloro—6-?uorophenyl)-5—[1—(2-hydroxymethy1propyl)—5— (tri?uoromethyl)-1H—pyrazol—4-yl] - l zolyl]pent-4—en-1 -one A rearrangement ofthe cyclopropylmethyl unit to give a butenyl substituent was ed.
The obtained crude product was further puri?ed by preparative HPLC/MS to give the title compound as a colorless oil (9% yield).
Result of LC/MS [M—H2O+H]+: 468.3; 1H NMR (CDC13)I 6 1.25 (6H, s, 2XCH3), 2.89—2.17 (2H, m, CH2), 2.42—2.33 (2H, m, CH2), 4.11 (1H, s, OH), 4.32 (2H, s, CH2), 4.91-4.77 (2H, m, CH2), 5.70—5.52 (1H, m, CH), 7.18 (1H, td, CH—arom.), 7.37 (1H, d, CH-arom.), .42 (1H, m, CH-arorn.), 7.99 (1H, s, CH— arom.).
Example 38: 2-[3-(2-chloro?uorophenyl)[1-(2-hydroxy—2-methylpropy1) (tri?uoromethyl)—1H-pyrazol-4—y1] — 1 ,2—oxazol—4-yl] -1 -cyclopropy1hex—5-en—2-01 ic) If the addition of the cyclopropylmethyl-Grignard is conducted at room temperature and stirring of the mixture is continued at this temperature for 3 h, a second on of the Grignard reagent to the Weinreb amide was observed, which did not rearrange in a similar fashion as the ?rst cyclopropylmethyl group (of. Example 37). Compound puri?cation was ed using preparative HPLC/MS to give the title compound as alight yellow oil (14% yield).
Result of LC/MS [M+H]+: 542.2; 1H NMR (CDCl3)Z 5 1.09-0.91 (1H, m, CH-diastereotopic), 1.24-1.09 (1H, m, CH- diastereotopic), 1.26 (6H, s, 2XCH3), 1.45-1.30 (1H, m, CH-diastereotopic), 1.71-1.58 (1H, m, CH-diastereotopic), 1.93-1.80 (2H, m, CH2), 3.11-2.99 (1H, m, CH), 4.11 (1H, s, CH), 4.31 (2H, s, CH2), 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, EXCH), 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?uorophenyl)[1-(2-hydroxymethylpropyl) (tri?uoromethyl)—1H—pyrazol—4—yl]—1,2—oxazoly1]ethan—l—one or 1—[3 -(2-chloro ?uorophenyl) { l -[(2R)-2~hydroxypropyl] (tri?uoromethy1)- 1 H—pyrazolyl} — 1 ,2-oxazol- than—1-one (0.3 mmol) in acetonitrile (1 ml) were added NBS (1.02 eq.) and p— toluenesulfonic acid (1.0 eq.) and the e was stirred at 50°C for 18 h. If conversion was not complete, additional NBS (1.02 eq.) and p-toluenesulfonic acid (1.0 sq.) were added and stirring continued at 50°C for 5 h. The solvent was ated under reduced pressure and ted aq. NaHCO3 was added. The mixture was extracted with CHZClz, combined organic layers were dried over MgSO4, ?ltrated and concentrated under reduced pressure. Crude cetyl derivatives were obtained as brownish oil in around 95% yield. - 2-bromo[3 -(2-chloro—6~?uorophenyl)—5~[1-(2-hydroxymethylpropyl) (tri?uoromethyl)— 1 H—pyrazol-4—yl]—1 ,2-oxazol—4—yl] ethanone Result of LC/MS [M+H]+: 523.6. - 2-bromo[3 -(2-chloro?uoropheny1)—5- { 1-[(2R)hydroxypropyl](tri?uoromethy1)- 1H-pyrazolyl}—l,2-oxazolyl]ethan—1—one Result of LC/MS [M+H]+; 509.6.
The crude bromoacetyl derivatives were taken up in methanol (2 mL) and BF3*Et20 (1.1 eq.) and Ag2C03 (1.1eq.) were added. The mixture was stirred at 50°C for 18 h, upon which it was partitioned between CH2€12 and saturated aq. NH4C1. Combined organic layers were dried over sodium sulfate, ?ltered and concentrated under reduced pressure. Residue was puri?ed via prep. TLC (eluent: petroleum ether/ethyl acetate 2:1).
Example 39: 2-chloro?uoropheny1)[ 1 -(2-hydroxy—2-methy1propyl) (tri?uoromethyl)-lH-pyrazoly1] -1 ,2-oxazolyl]-2—1nethoxyethan— 1 -one Title compound was obtained as yellowish oil (10%).
Result of LC/MS [M+H]+; 475.8; lH NMR(CDC13): 8 1.52 (6H, 3, 2x CH3), 3.15 (3H, s, CH3), 3.89 (2H, s, CH2), 4.10 (1H, s, OH), 4.32 (2H, s, CH2), 7.19 (1H, td, CH—arom.), 7.38 (1H, dt, CH-arom), 7.48 (1H, m, CH— arom.), 8.02 (1H, s, m).
Example 40: 1-[3—(2-chloro—6—?uorophenyl)—5—{1-[(ZR)—2-hydroxypropyl] (tri?uoromethyl)-1H-pyrazoly1}-1,2-oxazol-4—yl]methoxyethan-1 ~0ne Title compound was obtained as brownish oil (12%).
Result of LC/MS [M+H]+: 461.7; 1H NMR (CDC13): 5 1.32 (3H, d, CH3), 3.15 (3H, s, CH3), 1.80 (2H, m, CH2), 4.25 (1H, dd, CH2), 4.37 (2H, dd, OH, CH2), 7.18 (1H, td, CH-arom.), 7.37 (1H, dt, CH-arom), 7.47 (1H, m, CH—arom.), 7.99 (1H, s, CH-arom). mthesis of isoxazolescarboxamides Y Y we ,R1 N’O .R1 1 / N / z 5/ / N Ar ,K, H2NR,EDCI Ar ,? OH NH O O ,‘Qz Either hloro—6-?uorophenyl)(1 —(2—hydroxy—Z—methylpropyl)—5-(tri?uorornethyl)—1 H— pyrazolyl)isoxazole—4-carboxylic acid or 3-(2-chlor0?uorophenyl)—5—{1-[(2R) hydroxypropyl]—5—(tri?uoromethyl)—1H-pyrazol—4—y1}-1,2-0xazole—4—carboxy1ic acid (0.15 mmol), the respective amine (1.8 eq.), 1-hydroxybenzot?azole (1.5 eq.) and 1-(3- dimethylaminopropyl)—3-ethylcarbodiimide hydrochloride (EDCI; 1.7 eq.) were dissolved in 1 mL dry DMF. N—Methylmorpholine (10. eq.) was added and the e was stirred at room temperature for 18 h. The mixture was ioned between saturated aq. solution and CH2C12, combined organic layers were washed with water and brine and and dried over MgSO4, ?ltrated and concentrated under reduced pressure. Product puri?cation was achieved by prep. TLC on silica gel.
Example 41: 3-(2-chloro—6-?uorophenyl)-N—cyclopentyl—5—(1-(2-hydroxymethylpropyl)—5— (tri?uoromethyl)—l H-pyrazolyl)isoxazolecarboxamide Title compound was synthesized from 3-(2-chloro—é—?uorophenyl)(1—(2-hydroxy—2- methylpropyl)(tri?uoromethyl)—1H-pyrazol-4—y1)isoxazolecarboxylic acid and entylamine as yellowish solid in 42% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result of LC/MS [M+H]+: 514.8; IH NMR(CDC13): 5 1.13 (2H, m, CH2), 1.25 (6H, s, 2x CH3), 1.37 (2H, m, CH2), 1.50 (2H, m, CH2), 1.82 (2H, m, CH2), 4.18 (2H, m, CH2), 4.30 (2H, s, CH2), 5.24 (1H, s, OH), 7.21 (1H, td, CPI—atom), 7.40 (1H, dt, CH—arom), 7.51. (1H, m, CH-arom.), 8.11 (1H, s, CH-arom).
Example 42: 3-(2-chlor0?uorophenyl)-N—cyclopropyl(1-(2-hydroxy—2—methylpropyl) (tri?uoromethyl)—1 H-pyrazolyl)isoxazole—4—carboxamide Title nd was synthesized from 3—(2-chloro?uorophenyl)—5-(1-(2-hydroxy methylpropyl)—5—(tri?uoromethyl)—1H-pyrazol-4—y1)isoxazole—4-carboxylic acid and cycloppropylamine as greenish oil in 23% yield (pTLC, eluent: petroleum ether/ethyl e 1:2).
Result of LC/MS [M+H]+: 486.9; 1H C13): 8 0.22 (2H, m, CH2), 0.69 (2H, m, CH2), 1.24 (6H, 5, 2x CH3), 2.64 (1H, m, CH), 4.13 (1H, s, CH), 4.30 (2H, s, CH2), 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). e 43: 3-(2-chloro?uoropheny1)-N-cyclobuty1—5—(1-(2-hydroxy—2—methylpropyl) (tri?uoromethyl)-1H-pyrazol-4—yl)isoxazole—4—carboxamide Title compound was synthesized from 3-(2-ch10ro?uoropheny1)(1 -(2-hydroxy—2— methylpropyl)—S—(tri?uoromethy1)—1H-pyrazoly1)isoxazole-4—carboxylic acid and cyclobutylamine as grayish solid in 13% yield (pTLC, eluent: petroleum ether/ethyl e 1:2).
Result ofLC/MS [M+H]+: 500.9; 1H NMR (CDC13): 8 1.24 (6H, 5, 2x CH3), 1.58 (4H, m, 2x CH2), 2.23 (2H, m, CH2), 4.30 (2H, s, CH2), 4.32 (1H, m, CH), 5.41 (1H, s, OH), 7.21 (1 H, td, CH-arom.), 7.41 (1H, (1, CH— arom), 7.51 (1H, m, CH-arom.), 8.08 (1H, s, CH-arom).
Example 44: hloro?uorophenyl)—N—cyclopenty1 { 1 —[(2R)hydroxypropy1} (tri?uoromethyl)—lH—pyrazol—4-yl}-1,2—oxazole-4—carboxamide - Title compound was synthesized from hloro?uorophenyl)—5-{1-[(2R) hydroxypropyl]—5-(t1i?uoromethy1)-1H-pyrazol—4—yl}—1,2-oxazolecarb0xylic acid and cyclopentylamine as orange oil in 12% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result of LC/MS [M+H]+: 500.8; 1H NMR (CDC13)2 5 1.20-1.05 (3H, 3, 3x CH—diastereotopic), 1.32 (3H, (1, CH3), 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, CH2), 5.25 (1H, br, OH), 7.21 (1H, td, CH- arom.), 7.40 (1H, dt, m.), 7.56-7.46 (1H, m, CH—arom.), 8.08 (1H, s, CH-arom.).
Example 45: 3—(2-chloro-6—?uorophenyl)-N-cyclopropyl—5-(1-((2R)hydroxypropyl) (tri?uoromethyl)—1H-pyrazol—4—y1)isoxazole—4-carboxamide Title nd was synthesized from 3-(2-chloro?u0r0phenyl){1-[(2R)—2- hydroxypropyl](tri?uoromethyl)- lH-pyrazol—4-y1‘ -1,2-oxazole—4-carboxylic acid and propylamine as sh solid in 27% yield (pTLC, eluent: petroleum ether/ethyl acetate 122).
Result ofLC/MS : 472.8; 1H NMR(CDC13): 8 0.24 (2H, m, CH2), 0.68 (2H, m, CH2), 1.31 (3H, (1, CH3), 2.63 (1H, m, CH), 3.34 (1H, s, CH), 4.23 (1H, dd, CH), 4.35 (2H, m, CH, OH), 5.46 (1H, 3, NH), 7.18 (11-1, 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—?uoropheny1)—N—cyclobutyl—5—(1—((2R)—2-hydroxypropyl)—5- (tri?uoromethyl)-1H-pyrazoly1)isoxazolecarboxamide Title compound was synthesized from 3-(2—chloro—6—?uorophenyl){1-[(2R)-2— hydroxypropyl](tri?uoromethyl)-1H-pyrazol-4—yl}~1,2-oxazolecarboxylic acid and cyclobutylamine as yellowish solid in 41% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:2).
Result ofLC/MS [M+H]+: 486.9; IH NMR(CDC13): 6 1.30 (3H, (1, CH3), 1.56 (4H, m, CH2), 2.22 (2H, m, CH2) , 3,35 (1H, s, CH), 4.28 (4H, m, CH2, OH), 5.45 (1H, 8, 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 isoxazolecarb0xvlic acid esters 1.) 2 M NaOH 2.) RZOH, EDCI, DMAP Starting from respective methyl or ethyl esters (0.3 mmol), ponding carboxylic acids were generated by saponi?cation according to the l procedure described above within the synthesis of 4—acyl isoxazoles (described there starting with Example 8 or Example 12): (2-chloro—6—?uorophenyl)-5 -(1 ~(2—hydroxy—2—rnethy1propy1)-5—(trifluoromethyl)-1 H- pyrazol—4-yl)isoxazole—4-carboxylic acid, cf. above. — 3 —(2-chloro?uorophenyl)—5- { 1-[(2R)—2-hydroxypropy1](tri?uoromethyl)—lH-pyrazol- 4—yl}-1,2-0xazolecarboxylic acid, cf. above. - 3—(2—chloro?uorophenyl){l-[(2.S’)-2—hydroxypropyl](tri?uoromethyl)-1H-pyrazol- 4—yl}—l,2-oxazolecarb0xylic acid from Example 13 as off-white solid, 81% yield; Result of LC/MS [M+H]+: 434.2; 1H NMR )I 5 1.30 (3H, d, CH3), 4.24 (1H, dd, CH), 4.46-4.31 (2H, m, CH2), 7.12 (lH, td, CH-arom.), 7.32 (1H, dt, CH—arom.), .36 (1H, m, CH-arom.), 7.97 (1H, s, CPI—atom.) — 3 -(2—chlorophenyl)—5 — hyl-1—[3-hydroxy—3 -methylcyclobutyl] — l H—pyrazol-4—yl} -1 ,2— oxazole-4—carboxylic acid from Examples 17/18 (syn/anti mixture not separated at this stage) as brownish oil, 52% yield; Result of LC/MS : 388.2; — 3 ~(2-chlorophenyl) { l — [(2S)-2—hydroxypropyl] -5 -methyl- 1 H—pyrazolyl} - l ,2-oxazole- 4—carboxylic acid from Example 24 as brownish oil, 64% yield; (2-chloro-6—?uor0phenyl)—5— {5—methyl- l —[3~hydroxymethylcyclobutyl]~ l H—pyrazol- 1,2-oxazole—4-carboxylic acid nti—mixture) as off—white solid, 83% yield; Result of LC/MS [M+H]+: 406.2; The required ester methyl 3-(2-chloro?uorophenyl)—5-{5-methy1-1—[3-hydroxy—3- methylcyclobutyl]—lH-pyrazol~4—yl}—l,2-oxazole-4—carboxylate was synthesized as described above from methyl (Z)(2-chloro—6-?uorophenyl)—5-(1~(dimethylamino)—3- oxobut-l ~en—2-yl)isoxazole—4-carboxylate (0.80 mmol) and 3 —hyd.razinyl— 1 - methylcyelobutan-l -ol (syn/anti mixture) as an off-white solid (54% crude) as a mixture of syn/anti-eon?gurations within the cyclobutanol unit.
Result of LC/MS [M+H]+: 420.2; (2-ehlorophenyl)[ 1 -(3-hydroxy—3 -methylcyclobutyl)-5~(tri?uoromethyl)- 1 H-pyrazol- 4—yl]-1,2—oxazole—4—carboxylic acid (syn/anti—mixture) as yellowish solid, 96% yield; Result ofLC/MS [M+H]+: 442.2; The required ester ethyl 3-(2—ehloropheny1)—5—[1—(3-hydroxy—3-methylcyclobutyl)—5- (tri?uoromethy1)-1H—pyrazol-4—yl]—1 ,2—oxazolecarboxylate was synthesized as described above from ethyl (Z)-3~(2—chlor0phenyl)-5—(l-(dimethylamino)-4,4,4-tri?uoro-3— oxobut- l -en—2-yl)isoxazolecarboxylate (1 .0 mmol) and 3 -hydrazinyl— 1 - methylcyclobutan—l-ol nti mixture) as a yellowish oil (11%; pTLC, eluent: CH2C12/MeOH 95:5 and pTLC, eluent: petroleum ether/ethyl e 1:1) as a mixture of syn/anti—con?gurations within the cyclobutarlol unit.
Result of LC/MS [M+H]+: 470.2; — 3 —(2—chloro-6—?uorophenyl)—5—[ 1 —(3-hydroxy—3 —rnethylcyclobuty1)—5—(tri?uoromethyl)— 1 H- pyrazolyl]—1,2-oxazolecarboxylic acid nti—mixture) as orange solid, 78% yield; Result of LC/MS [M+H]+: 460.1; The required ester ethyl 3 -(2-chloro?uorophenyl)-5— [ 1 -(3 -hydroxy—3- methyleyclobutyl)—3—(tri?uororrlethy1)- 1 H-pyrazol—4—yl] - 1 ,2-oxazolecarboxylate was synthesized as described above from ethyl (Z)-3 -(2-chloro—6—?uorophenyl)-5—(l— hylamino)—4,4,4-tri?uorooxobut-l-enyl)isoxazole—4—carboxylate (0.35 mmol) and 3—hydrazinyl-l~methylcyclobutan—1—01 (syn/anti mixture) as a brownish oil (65% crude) as a mixture of ti-con?gurations Within the utanol unit.
Result of LC/MS [M-l—Hf': 488.2; To a mixture of the respective carboxylic acid (0.05 mmol) and the respective alcohol (3.0 eq.) in CHQClg (4 mL) were added EDCI (1.5 eq.) and DMAP (0.2 eq.) at room temperature.
The reaction mixture was stirred at room temperature for 18 h. All volatiles were removed under reduced pressure. The e was puri?ed by preparative TLC on silica gel (eluent: PE/EtOAc 1:1).
Example 47: oxetan-3 -yl 3 -(2-ehlorophenyl)—5- { 1 -[(ZS—Z-hydroxypropyl]—5—methy1— l H- pyrazoly1}—1,2-oxazolecarboxylate Title compound was synthesized from 3—(2-chloropheny1){l—[(2S)—2—hydroxypropyl] methyl—lH-pyrazol—4-yl}-1,2—oxazole—4—carboxylic acid and oxetan-3 -01 as ite solid in 24% yield (pTLC, eluent: eum ether/ethyl acetate 1:1).
Result of LC/MS [M+H]+: 418.2; 1H NMR (CDC13): 8 1.30 (3H, (1, CH3), 2.63 (3H, s, CH3), 3.37 (1H, d, CH2), 4.01 (1H, dd, CH), 4.15 (1H, dd, CH2) 4.28—4.19 (2H, m, CH2), 4.33 (1H, br, OH), 4.74 (2H, t, CH2), 5.51— .40 (m, 1H, CH), 7.56-7.35 (4H, m, 4xCH—arom.), 8.41 (1H, s, m.).
FF , '0 DO" 1/ my Examples 48 and 49: cyclopropyl 3-(2-chlorophenyl)(1—(3—hydroxy—3-methylcyclobutyl)— ?uoromethyl)-1H-pyrazoly1)isoxazole—4-carboxylate (anti— and syn-con?guration) Title compounds were synthesized from 3—(2-chlorophenyl)-5—[1—(3—hydroxy—3- methylcyclobutyl)(tri?u0r0methyl)- l H-pyrazol-4—yl]-l ,2-oxazolecarboxylic acid (syn/anti-mixture) and cyclopropanol as pale yellow oils; pTLC, eluent: CH2C12/MeOH 95:5 and pTLC, eluent: eum ether/ethyl acetate 7:3.
Example 48: cyclopropyl 3-(2—chlorophenyl)(l—(3—hydroxy—3-methylcyclobutyl)—5- (tri?uoromethyl)-lH-pyrazol—4-yl)isoxazole—4-carboxylate (anti—con?guration), 39% yield; Result ofLC/MS [M+H]+: 482.2; 1H NMR(CDC13): 6 0.34 (2H, m, CH2), 0.58 (2H, m, CH2), 1.56 (3H, s, CH3), 2.64 (2H, m, CH2), 2.84 (2H, m, CH2), 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)(1-(3-hydroxymethylcyclobuty1)-5— (trifluoromethyl)—1H-pyrazol-4—yl)isoxazole—4—carboxylate (syn-con?guration), 25% yield.
Result of LC/MS [M+H]+: 482.2; 1H NMR (CDClg): 5 0.34 (2H, m, CH2), 0.58 (2H, m, CH2), 1.49 (3H, s, CH3), 2.80 (4H, m, 2x CH2), 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—chl0r0—6-?uorophenyl)—5—(l—(3-hydroxy—3- methylcyclobutyl)(tri?uoromethyl)-1H-pyrazolyl)isoxazolecarboxylate (anti- and syn—con?guration) Title compounds were synthesized from 3—(2-chloro—6-?uorophenyl)[1-(3-hydr0xy methylcyclobutyl)—5-(trifluoromethyl)- 1 H-pyrazolyl]— 1 ,2-oxazolecarboxylic acid (syn/anti-mixmre) and ropanol as yellowish oils; pTLC, eluent: eum ether/ethyl acetate 7:3 and again pTLC, : petroleum ether/ethyl acetate 7:3.
Example 50: cyclopropyl 3-(2-chloro?uoropheny1)(1-(3-hydroxy—3—methylcyclobutyl)- 5-(tri?u0romethyl)-1H-pyrazolyl)isoxazolecarb0xylate (anti-con?guration), 1% yield; Result of LC/MS [M+H]+: 500.2; 1H NMR(CDC13): 5 0.32 (2H, m, CH2), 0.58 (2H, m, CH2), 1.58 (3H, s, CH3), 2.65 (2H, m, CH2), 2.83 (2H, m, CH2), 4.12 (1H, m, CH), 5.26 (1H, quint, CH), 7.12 (1H, t, CH-arom.), 7.31 (1H, d, m.), 7.42 (1H, m, CH—arom), 7.96 (1H, s, CH-arom).
Example 51: cyclopropyl 3-(2-chlorofluorophenyl){1—[3—hydroxy—3-methylcyclobutyl]— uor0methyl)—1H—pyrazolyl}-1 ,2-oxazole-4—carboxy1ate (syn—con?guration), 1 % yield.
Result of LC/MS [M+H]+: 500.2; 1H NMR (CDC13): 6 0.32 (2H, m, CH2), 0.59 (2H, m, CH2), 1.56 (3H, s, CH3), 2.82 (4H, m, 2x CH2), 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).
CI N" H..." Example 52: oxetan—3—yl 3-(2-chloropheny1)(1~(3-hydroxymethylcyclobutyl)—5—methyl- 1H-pyrazoly1)isoxazole—4—carboxylate (syn-con?guration) Title compound was synthesized from 3-(2—chlorophenyl){5-methyl[3-hydroxy—3- methylcyclobutyl]-1H-pyrazolyl}—1,2-oxazole—4-carboxy1ic acid (syn-con?guration, resulting from saponi?cation of Example 18) and oxetan-3—ol as pale yellow oil in 7% yield (pTLC, eluent: petroleum ether/ethyl e 1:1).
Result ofLC/MS [M+H]+: 444.3; 1H C13): 5 1.47 (3H, s, CH3), 2.59 (3H, s, CH3), 2.79—2.69 (4H, m, CH2), 3.64 (1H, br, OH), 4.24 (2H, t, CH2), 4.55 (1H, quint, CH), 4.74 (2H, t, CH2), 5.45 (1H, quint, CH), 755-736 (4H, m, 4xCH-ar0m.), 8.42 (1H, s, CH-arom.).
Examples 53 and 54: cyclopropyl hloropheny1){5—1nethy1—1-[3-hydroxy methylcyclobutyl}1H-pyrazol—4—yl}-1,2~oxazole-4—carboxylate (syn— and anti—con?guration) Title compounds were synthesized from 3-(2-chlorophenyl){5-methy1-1—[3-hydroxy—3- methylcyclobutyl]—lH—pyrazol—4—yl}-1,2—oxazole—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 e 7:3.
Example 53: cyclopropyl 3—(2-chlorophenyl)-5— {5—methyl—l -[3—hydroxy methylcyclobutyl]—1H—pyrazol-4—y1}-l,2-oxazole—4-carboxy1ate (syn—con?guration), 2% yield; Result ofLC/MS [M+H]+: 428.3; 1H NMR (CDC13)Z 6 0.33 (2H, m, CH2), 0.58 (2H, m, CH2), 1.47 (3H, s, CH3), 2.58 (3H, s, CH3), 2.74 (4H, m,2x CH2), 4.15 (1H, m, CH), 4.55 (1H, quint, CH), 7.41 (4H, m, CH- arom.), 8.43 (1H, s, CH—arom).
Example 54: ropyl 3-(2—chlorophenyl){5-methy1[3-hydroxy-3— methylcyclobutyl]—1H-pyrazol~4—yl}-l,2—oxazole—4—carboxylate (anti—con?guration), 3% yield.
Result of LC/MS {M+H]+: 428.3; 1H NMR (CDC13)Z 8 0.33 (2H, m, CH2), 0.58 (2H, m, CH2), 1.55 (3H, s, CH3), 2.58 (5H, m, CH3, CH2), 2.80 (2H, m, CH2), 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-é-?uorophenyl)-5—[1—(2-hydroxy-2—methylpropy1)—5— (tri?uoromethyl)— l H—pyrazol—4—yl]— l ,2-oxazole—4-carboxy1ate Title compound was synthesized from 3-(2-chloro-6~?uorophenyl)(1-(2-hydr0xy—2— methylpropyl)(tri?uoromethyl)—1H—pyrazol—4-yl)isoxazolecarboxylic acid and ropanol as pale yellow solid in 33% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result of LC/MS [M+H]+: 487.8; 1H NMR(CDC13): 5 0.33 (2H, m, CH2), 0.60 (2H, m, CH2), 1.25 (6H, 3, 2x CH3), 4.13 (1H, m, CH), 4.18 (1H, s, OH), 4.31 (2H, s, CH2), 7.13 (1H,, t, CH-arom.), 7.33 (1H, (1, CH- arom.), 7.47 (1H, m, CH-arom), 8.05 (1H, s, CH-arom).
Example 56: utyl 3-(SI-chloro—6-?uorophenyl)—5-[1-(2-hydroxymethylpropyl) oromethyl)—1H-pyrazol—4—yl]—1 ,2-oxazolecarboxylate Title compound was sized from 3-(2—chloro—6-?uorophenyl)(1—(2-hydroxy—2— methylpropyl)—5-(tri?uoromethyl)-1H—pyrazol—4-yl)isoxazole—4-carboxy1ic acid and cyclobutanol as pale yellow oil in 47% yield (pTLC, eluent: petroleum ether/ethyl acetate 2O 1:1).
Result ofLC/MS [M+H]+: 501.8; 1H NMR (CDC13): 8 1.25 (6H, s, 2X CH3), 1.55 (2H, m, CH2), 1.69 (2H, m, CH2), 2.19 (2H, m, CH2), 4.21 (1H, s, OH), 4.31 (2H, s, CH2), 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-S -y1 3-(2-chloro?uorophenyl)[1-(2-hydroxymethy1pr0pyl) (tri?uoromethyl)—1H-pyrazol—4—yl]-1,2-oxazole-4—carboxylate Title compound was synthesized from 3-(2-chloro?uorophenyl)—5-(1.—(2-hydroxy methylpropyl)—5-(tri?uoromethyl)—1H—pyrazol—4—yl)isoxazole—4—carboxylic acid and oxetan 01 as colorless solid in 38% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result of LC/MS [M+H]+: 504.0; 1H NMR (CDC13)I 5 1.26 (6H, s, 2xCH3), 4.11 (1H, br, OH), 4.29-4.21 (2H, m, CH2), 4.31 (2H, s, CH2), 4.80—4.70 (2H, m, CH2), .38 (1H, m, CH), 7.17 (1H, td, CH—arom.), 7.37 (1H, dt, CH-arom.), 7.52-7.42 (1H, m, m.), 8.05 (1H, s, CH-arom.) Example 58: oxetan—S—yl 3—(2—chlor0—6—?uorophenyl)—5—{1-[(2R)hydroxypropyl] (tri?uoromethyl)—1H-pyrazol-4—yl}-1 ,2-oxazolecarboxylate Title compound was synthesized from 3-(2-chloro-6—?u0r0phenyl)—5—{1—[(2R)—2— hydroxypropyl]—5-(tri?uoromethyl)—lH-pyrazol—4—yl}—1,2—oxazole—4—carboxylic acid and —S—ol as colorless solid in 21% yield (pTLC, eluent: petroleum ether/ethyl acetate 1:1).
Result S [M+H]+: 490.2; 1H NMR (CDCls): 8 1.32 (3H, d, CH3), 3.20 (1H, br, OH), 4.32-4.19 (3H, m, CH and CH2), .32 (2H, m, CH2), 4.75 (2H, t, CH2), 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.). e 59: cyclopropyl 3-(2—chloro—6—?uorophenyl)—5-{l-[(25)—2—hydroxypropyl]—5— (tri?uoromethyl)—1H-pyrazol«4—y1 }—1 ,2-oxazoleearboxylate Title compound was synthesized from hloro—6—?uoropheny1){l-[(ZS)~2- hydroxypropyl]—5-(tri?uoromethyl)—1H—pyrazol—4—y1}—1,2-oxazolecarboxylic acid and cyclopropanol as pale yellow oil in 30% yield (pTLC, eluent: petroleum etherfethyl acetate 121).
Result of LC/MS [M+.H}*": 474.2; 1H NMR (CDC13)I 8 0.32 (2H, m, CH2), 0.59 (2H, m, CH2), 1.32 (3H, (1, CH3), 3.26 (1H, s, OH), 4.13 (1H, quint, CH), 4.25 (1H, dd, CH), 4.37 (2H, 11], BX CH), 7.13 (1H, t, CH~arom.), 7.32 (ll-l, d, CH-arom.), 7.44 (1H, m, m), 8.03 (1H, s, CH-arom).
Example 60: oxetan—3-y1 3—(2~chloro-6—?uoropheny1){1—[(2S)hydroxypropyl]—5— (tri?uoromethyl)- 1H—pyrazol-4—y1} -1 ,2-oxazolecarboxylate Title compound was synthesized from 3-(2—ch10ro—6-?uorophenyl)-5—{1-—[(2S)—2- hydroxypropyl](tri?uoromethyl)-1H-pyrazoly1}—1,2-oxazole—4-carboxylic acid and oxetan-3—01 as pale yellow solid in 29% yield (pTLC, eluent: petroleum ethyl acetate 1:1).
Result of LC/MS [M+H]+; 490.2; 1H NMR (CDCl3)Z 5 1.32 (3H, d, CH3), 3.21 (1H, br, 0H), 4.31-4.20 (3H, m, CH and CH2), 4.47-4.31 (2H, m, CH2), 4.75 (2H, t, CH2), 5.50-5.38 (1H, m, CH), 7.17 (1H, td, CPI-atom), 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?uorophenyl)-5—{5—methyl[3-hydroxy—3- cyclobuty1]-1H-pyrazolyl}-1,2-oxazole—4-carboxylate (syn- and anti—con?guration) Title compounds were synthesized from 3-(2-chloro—6—?uoropheny1)—5- {5-methyl-1—[3— hydroxymethylcyclobutyl]- 1 H—pyrazol-4—yl}-1 ,2-oxazolecarboxylio acid (syn/anti mixture) and cyclopropanol as yellowish oils; pTLC, eluent: petroleum ether/ethyl acetate 7:3 and again pTLC, eluent: petroleum ethyl acetate 7:3.
Example 61: cyclopropyl hloro-6—?uorophenyl)—5-{5-methyl[3-hydroxy—3— methylcyclobutyl}1H-pyrazoly1}-1,2—oxazolecarboxy1ate (syn-con?guration), 7% yield; Result of LC/MS [M+H]+: 446.3; 1H NMR (CDC13)I 5 0.29 (2H, m, CH2), 0.58 (2H, m, CH2), 1.53 (3H, s, CH3), 2.58 (4H, ,m, CH, CH3), 2.77 (3H, m, CH, CH2), 4.16 (1H, m, CH), 5.03 (1H, quint, CH), 7.1.0 (1H, t, CH— 21mm), 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—?uoropheny1)-5—{5-methy1—1—[3-hydroxy—3— methylcyclobutyl]—1H—pyrazol-4—y1}-1,2—oxazole-4—carboxy1ate (anti-con?guration), 14% yield.
Result of LC/MS : 446.3; 1H NMR (CDC13): 6 0.30 (2H, m, CH2), 0.58 (2H, m, CH2), 1.47 (3H, s, CH3), 2.59 (3H, s, CH3), 2.74 (4H, m, 2x CH2), 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-alkoxrmeth§ll isoxazoles Y Y N’0 .R1 N'O .R1 ' / Cl" ' / LiAIH4 Ar N Ar Char]! 0 Q 0" Me/Et PBT3 RZ-Hal 0r NaH or KOH Pphg, CBT4 Y Y N13 "f /— , 0 .R1 / NR1 NaH / [)1 Ar ' "N Ar "N Br Q Reduction stem. with LiAlH? Respective isoxazole-4—carboxylic acid methyl or ethyl esters were dissolved in dry THF (Sure/Seal; 4 ol) and the solution was cooled to 0°C. LiA1H4 (1 M in THF; 1.5 eq.) was slowly added 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 CH2€12.
Combined organic layers were dried over MgSO4, ?ltrated and concentrated under reduced pressure to give crude al, which was directly used for next steps. — (283—1-(4—(3—(Z-chloro—6-?uorophenyl)—4-(hydroxymethy1)isoxazol—5-yl) (trifluoromethyl)-1H—pyrazol—1—y1)propanol from Example 13 (0.4 mmol) as an orange solid (80%).
Result of LC/MS [M+H1+: 419.7; - 4- {4-[3 -(2—chloro?uorophenyl)—4-(hydroxymethyl)—1 ,2-oxazol—5—yl]-5— (tri?uoromethyl)~1H-pyrazol~1-yl}methy1butanol from Example 9 (1.0 mmol) as pale yellow oil (87%).
Result of LC/MS [M+H]+: 448.2; 1H NMR (CDC13)I 6 1.32 (6H, s, 2XCH3), 2.18-2.08 (2H, m, CH2), 3.79-3.71 (1H, m, OH), 4.08 (1H, dq, 0H), 4.40 (2H, s, CH2), .48 (2H, m, CH2), 7.15 (1H, td, m.), 7.35 (1 H, dt, CH-arom.), 7.48-7.39 (1H, m, CH—arom.), 7.92 (1H, s, CH-arom.). {4—[3-(2—chloro-6—?uoropheny1)—4~(hydroxymethyl)—1 ,2-oxazolyl]—5— (tri?uoromethyl)—1H-pyrazol-l -yl} -1 -methylcyclobutan— 1 -ol (syn/anti-mixture) from Examples 10/11 (0.6 mmol) as syn/anti-mixture (for this synthesis, syn- and anti-isomers were not separated at the ester level) (quant).
Example 63: l-(4-(3-(2-chloro?uorophenyl)—4- xymethyl)isoxazol-5—y1)—5-(tri?uoromethyl)- lH—pyrazol-l -yl)methy1propan-2—ol from Example 8 (0.3 mmol) as yellowish solid (pTLC, eluent: petroleum ethyl acetate 1:1; 24%).
Result of LC/MS [M+H]+; 433.8; lH NMR(CDC13): 6 1.24 (6H, 3, 2x CH3), 1.67 (1H, s, OH), 4.16 (1H, s, OH), 4.31 (2H, s, CH2), 4.41 (2H, d, CH2), 7.16 (1H, td, CH—arom.), 7.36 (1H, td, CH-arom.), 7.44 (1H, m, CH-arom), 8.01 (1H, s, CH-arom). (2R)-l -(4-(3 —(2—chloro—6—?uorophenyl)(hydroxymethyl)isoxazol-5—yl)-5 - (tri?uoromethyl)—1H-pyrazol-l-yl)propan-2—ol from Example 12 (0.55 mmol) as orange solid (75%).
Result of LC/MS : 419.7; Ester methyl hlorophenyl)—5-[ l —(3 -hydroxy-3 -methy1butyl)—5—(tri?uoromethyl)— 1 H- pyrazol~4-yl]—1,2-oxazolecarboxylate was synthesized as described above from methyl (Z)—3-(2-chlorophenyl)-5—(l —(dimethy1amino)-4,4,4-tri?uorooxohut- l -en—2— yl)isoxazolecarboxylate (1.2 mmol) and 4-hydrazinylmethylbutan—2—ol as a yellow oil (33%; pTLC, eluent: CHzClz/MeOH 95:5).
Result of LC/MS [M+H]+: 440.3; 1H NMR ): 8 1.32 (6H, s, 2XCH3), 2.20—2.10 (2H, m, CH2), 3.63 (3H, s, OCHg), 2O 4.58-4.48 (2H, m, CH2), 7.59—7.33 (4H, m, 4XCH-ar0m.), 7.95 (1H, s, CH-arom.).
From this ester (0.4 mmol), 4- {4-[3—(2-chlorophenyl)(hydroxymethyl)—l,2-oxazol-5—yl]— -(tri?uor01nethyl)—lH—pyrazol—l—yl}—2-methylbutan—2-ol was synthesized quantitatively according to the rd procedure.
Result of LC/MS {M+H]+: 430.3; (ZS)- l - {4-[3-(2-ch10rophenyl)-4~(hydroxymethy1)-l ,2-oxazolyl] (t1i?u0romethyl)— 1H—pyrazol—l~yl}propanol from Example 22 (1.5 mmol) (90%). 3 - {4-[3 -(2-ohlorophenyl)(hydroxymethy1)— l ,2—oxazolyl](tri?uoromethyl)— l H- pyrazol—l-yl}methylcyclobutan—1~01 (syn/anti—mixture) from ethyl 3—(2—ohlorophenyl)— -[1-(3-hydroxy—3-methylcyclobutyl)(tri?uoromethy1)-l H-pyrazolyl] —l ,2—oxazole carboxylate (0.8 mmol) (syn/anti-mixture; synthesis described above) (63%).
Example 64: 3-(4-(3-(2~chlorophenyl)(hydroxymethy1)— 1 ,2-oxazolyl)(tri?uoromethyl)-1H—pyrazol-1 -yl)—l —methylcyclobutan— 1 —ol (syn- con?guration) From the mixture of syn- and anti-isomers, the syn syn isomer was separated by prep. TLC (eluent petroleum ether/ethyl e 1:1).
Result of LC/MS [M+H]+: 427.9; 1H NMR (CD013): 5 1.49 (3H, s, CH3), 2.94-2.68 (4H, m, 2xCHz), 3.49 (1H, s, OH), 4.45 (2H, s, CH2), 4.73 (1H, quint= CH), 763-7.34 (4H, m, 4xCH-arom), 7.99 (1H, s, CH— arom.) 4- {4-[3-(2-chlor0phenyl)(hydroxymethyl)—1,2-oxazolyl]methyl-1H-pyrazolyl}— 2—methylbutan—2—ol from e 19 (0.4 mmol) as yellow solid (84%).
Result of LC/MS ; 376.0; 3 — {4—[3 —(2—ehlorophenyl)(hydroxymethyl)—1 ,2—0xazol—5—y1]—5-methyl-1H—pyrazol—l -y1}— 1—methylcyclobutanol (syn/anti—mixture) from Examples 17I18 (1.1 mmol) as syn/anti- mixture (for this synthesis, syn— and anti-isomers were not separated at the ester level) (quant).
Result of LC/MS [M+H}+: 374.3; 4- {4-[3-(2-chloro?uorophenyl)(hydroxymethyl)-1 ,2-oxazoly1]methyl—1H— pyrazol-l-yl}—2—methylbutan—2—ol ?'om Example 20 (2.0 mmol) as yellowish solid (94%).
Result of LC/MS [M+H]+: 394.1; 1H NMR (CD013): 5 1.30 (6H, s, 2xCH3), 2.08-2.00 (2H, m, CH2), 2.65 (3H, s, CH3), 4.36- 4.28 (2H, m, CH2), 4.45 (2H, d, CH2), 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-?uorophenyl)-4—(hydroxymethyl)—1 zol—5-yl]methyl- 1H- pyrazol-l—y1}methy1cyclobutan-1—ol (syn/anti—mixture) from methyl 3-(2-chloro ?uoropherlyl)-5— {5—methyl— 1 —[3 -hydroxy—3 -methylcyclobutyl]— l H—pyrazol-4—yl } ~1 ,2 — e-4—carboxylate (1.1 mmol) (syn/anti-mixture; synthesis described above) as yellowish solid (89%).
Result of LC/MS [M+H]+: 392.2; 3 -(4— {3 -[3 -(benzyloxy)—2-chlorophenyl] —4—(hydroxymethyl)— 1 ,2—oxazol-5—yl } ~5— (tri?uoromethyl)-ll-I-pyrazol-l-yl)-l-methylcyclobutanol (syn/anti-mixture) from ethyl 3 —(3-(benzyloxy)-2—chloropheny1)—5-( 1 -(3 -hydroxy—3-methylcyclobutyl)—5— (tri?uoromethyl)—1H-pyrazol—4-yl)isoxazole—4-carboxylate (0.9 mmol) (syn/anti—mixture) as orange-brown solid (quant).
Result of LC/MS [M+H}+: 534.3; 1H NMR (CDClg): 6 1.55 (3H, s, CH3), 2.94-2.55 (4H, m, 2XCH2), 3.83-3.68 (1H, m, CH), 4.44 (2H, s, OCHg), 5.22 (2H, s, OCHg), 7.19—7.09 (2H, m, 2xCH—arom.), 7.54-7.30 (6H, m, 6xCH—arom.), 7.97 (1H, s, CH—arom) — 3-(3—(benzyloxy)-2—chlorophenyl)—4-(hydroxymethyl)isoxazol—S-yl) oromethyl)-lH—pyrazol-l—yl)methylbutan-2—ol from ethyl 3-(3-(benzyloxy) l O chlorophenyl)—5-(1 —(3—hydroxy—3 -methy1buty1)—5-(tri?uoromethyl)- l H—pyrazol-4— yl)isoxazo]e—4-carboxylate as brown oil (91%).
Result of LC/MS [M+H]+; 536.1; 1H NMR (CDC13)Z 5 1.33 (6H, s, 2X CH3), 1.86 (4H, m, 2x CH2), 3.75 (2H, s, CH2), 5.23 (2H, (1, CH2), 7.12 (1H, m, CH—arom.), 7.41 (6H, m, CH-arom.), 7.95 (1H, s, CH-arom.). sion of a hydroxymethyl—isoxazole into a hromomethyl-isoxazole was ed by two methods: A) The respective hydroxymethyl-isoxazole was dissolved in diethylether, THF or CH2C12 (3 mL/mmol) at 0°C and phosphorus tribromide (0.5 eq.) dissolved in diethylether (3 mL/mmol) was added slowly. The e was stirred at 0°C for 10-30 min. The e was treated with NaHCO3 (5%) and extracted twice with CH2C12. Combined organic layers were dried over MgSO4, and the solvent was removed in vacuo to give crude material, which was used as such in further steps.
B) The respective hydroxymethyl-isoxazole and PPh3 (1.5 eq.) were ved in dry THF (Sure/Seal; 4 mL/mmol) and cooled to 0°C. CBr4 (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 CHQClz.
Combined organic layers were dried over MgSO4, and the t was removed in vacuo to give crude material. In order to remove bulk material of OPPh3, the solid material was treated with 320, sonicated, centrifuged and decanted; alternatively, material was puri?ed by prep. TLC on silica gel (eluent: CH2C12/MeOH 95:5). - 4- {4-[4-(bromomethyl)—3-(2-ch10ro-6—fluorophenyl)-1 ,2-oxazolyl] —5-(tri?uoromethyl)— l H—pyrazol— l —yl} methylbutan—2—ol from 4- {4— [3 -(2-chloro—6—?uor0phenyl) (hydroxymethyl)— 1 ,2—oxazol—5-y1](tri?uoromethyl)-l H—pyrazoly1}methylbutan—2- 01 (0.25 mmol) according to method A (B20, 10 min) as yellow solid (93%).
Result of LC/MS [M+H]+: 510.1; 1H NMR (CDC13)I 5 1.32 (6H, s, 2x CH3), 2.12 (2H, m, CH2), 4.15 (2H, s, CH2), 4.53 (2H, m, CH2), 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-oxazolyl] (tri?uoromethyl)- 1 H- l—l—yl}—2-methylbutan—2-ol from 4— {4-[3-(2-chlorophenyl)—4—(hydroxymethyl)-1,2— oxazol-S—yl](tri?uoromethyl)—1H-pyrazol-l -yl}methylbutan—2-ol (0.40 mmol) according to method A (CH2C12, 30 min) as orange oil (60%; pTLC, eluent: CH2Cl2/MeOH 95:5).
Result of LC/MS [M+H]+: 492.2; 1H NMR (CDCl3): 5 1.32 (6H, 8, 2x CH3), 2.13 (2H, m, CH2), 4.23 (2H, s, CH2), 4.55 (2H, m, CH2), 7.45 (1H, m, CH-arom.), 7.54 (2H, m, CH-arom.), 7.65 (1H, m, (EH-atom), 7.92 (1H, s, (EH-atom). 4—{4-[4—(bron10methyl)—3-(2-chlorophenyl)—1,2-oxazol-5—yl]—5-methyl-1H—pyrazol—l—yl}—2- methylbutan-Z—ol from 4- {4-[3-(2-chlorophenyl)(hydroxymethyl)—1,2-oxazolyl]-5— methyl-1H-pyrazol-l-y1}methylbutanol (0.25 mmol) according to method A (THF, min) as yellow solid (84%); a partial additional hydroxy-bromine exchange in methylbutanol unit was observed (3-bromo—3—methylbutyl)-5—methyl-1H-pyrazol yl]-4—(bromomethy1)—3—(2-chlorophenyl)—1,2-oxazole).
Result of LC/MS [M—H2O+H]+: 419.9 (title compound); Result of LC/MS [M+H}+: 499.8 (M+ (additional exchange); 4— {4—[4-(bromomethyl)(2-chloro?uorophenyl)- 1 ,2-oxazoly1]methyl- 1H- pyrazolyl} ~2—methylbutan—2-ol from 4- {4— [3-(2—chloro-6—?uorophenyl)-4— (hydroxymethyl)—1 ,2-oxazolyl]methyl- l H-pyrazol-l -yl}methylbutan-2—ol (2 .0 mmol) according to method B as yellowish oil (95%).
Result of LC/MS [M-H2O +H]+: 437.9; 1H NMR (CDC13)I 8 1.32 (6H, s, 2x CH3), 2.05 (2H, m, CH2), 2.63 (3H, s, CH3), 4.29 (2H, s, CH2), 4.33 (2H, m, CH2), 7.17 (1H, t, CH-arom.), 7.36 (1H, d, CH—arom.), 7.45 (1H, m, CH-arom.), 7.95 (1H, s, m.) 3 - {4-[4-(bromomethyl)-3—(2-chloro?uorophenyl)—1 ,2-oxazoly1]methyl-1H— l—l-yl}—l-methylcyclobutan—l-ol (syn/anti-mixmre) from 3—{4—[3 loro-6— henyl)~4—(hydroxymethyl)- 1 ,2-oxazolyl]—5-methyl—1 H-pyrazol-l -yl } - 1 — methylcyclobutan—l -01 (0.4 mmol; syn/anti—mixturc) according to method B as yellowish solid (89%).
Result of LC/MS [M+H]+: 454.1; 3 - {4-[4—(bromomethyl)-3 ~(2-chlorophenyl)-l ,2-oxazol—5-yl}~5—methyl-1H-pyrazol-l —yl} — 1— methylcyclobutan-l ~01 (syn/anti-mixture) from 3- {4-[3 —(2—chlorophenyl) (hydroxymethyl)- 1 ,2-oxazol—5—y1]-5—methyl— 1 H-pyrazol— l —yl} —l —mcthylcyclobutan-l ~01 (0.15 mmol; syn/anti-mixture) according to method B ) Result of LC/MS [M+H]+: 436.2; (2R){4-[4-(bromomethyl)(2-chloro—6—?uorophenyl)-1 ,2-oxazoly1] (tri?uoromcthyl)—1H-pyrazol-1—y1}propan—2-ol from (2R)—1—(4-(3-(2-chloro-6— ?uorophenyl)(hydroxymethyl)isoxazolyl)(tri?uoromethyl)-1H-pyrazol-1 - yl)propan—2~ol (0.3 mmol) according to method B (87%). (28H - {4-[4-(bromomethyl)(2-chlorophenyl)- 1 ,2-oxazolyl] (tri?uoromethyl)- 1 H- pyrazol— 1 -y1}propanol from (2S)— 1 - {4—[3 —(2—ch1orophenyl)—4-(hydroxymethyl)— l ,2- —S-yl](tri?uoromethyl)~1H—pyrazol-l—y1}propan—2-ol (0.35 mmol) according to method B (55%). 3 - {4-[4-(bromomethyl)—3—(2-chlorophenyl)—1 ,2—oxazoI-5—yl] -5—(tri?uoromethyl)— l H- pyrazolyl}methy1cyclobutan-1 -ol (syn/anti—mixture) from 3- {4-[3-(2—chloropheny1)- roxymethyl)—l zol-5—yl](tri?uoromethyl)—lH-pyrazol-1 —y1}-1 — methylcyclobutan-l-ol (0.3 mmol; syn/anti—mixture) according to method B (92%). 3— {4-[4-(bromomcthyl)—3—(2-chlorofluorophenyl)-1 ,2-oxazolyl] (tri?uoromethyl)— lH—pyrazol-l-yl}methy1cyclobutan-l-ol (syn/anti—mixture) from 3- {4-[3 -(2—chloro henyl)-4'-(hydroxymcthy1)—l ,2-oxazoly1]—5-(tri?uoromethy1)—lH-pyrazol-l -yl} - hylcyclobutan—l -01 (0.35 mmol; syn/anti-mixture) according to method B (77%). 3-(4—(3—(3—(benzyloxy)—2—chlorophenyl)—4—(bromomcthyl)isoxazoly1)—5- (tri?uoromethyl)- 1 zoly1)-1 -methylcyclobutan— 1 -01 (syn/anti—mixture) from 3 -(4- {3—[3-(bcnzyloxy)—2-chlorophenyl]—4—(hydroxymethyl)— l ,2—oxazolyl}-5— (tri?uoromethyl)— 1 H-pyrazolyl)- 1 —methy1cyclobutan— 1 -01 (syn/anti—mixture) (1 .0 mmol) according to method A (Eth, 10 min) as yellow oil (quaint).
Result of LC/MS [Ms-HT: 596.2; lH NMR(CDC13): 5 1.51 (3H, s, CH3), 2.78 (4H, m, 2x CH2), 4.24 (2H, s, CH2), 4.73 (1H, m, CH), 5.23 (2H, s, CH2), 7.15 (2H, d, CH-arom.), 7.39 (6H, d, CH-arom.), 7.97 (1H, s, CH-arom.). 4—(4-(3 -(3 yloxy)chlorophenyl)—4-(bromomethyl)isoxazol-S—y1) (tri?uorornethyl)-lH-pyrazol—1-yl)-2—methylbutanol from 4—(4-(3—(3 —(benzyloxy) chlorophenyl)(hydroxymethyl)isoxazol-S-yl)—5-(tri?uoromethyl)- l H-pyrazol- l —yl)—2— methylbutan—Z-ol (2.5 mmol) according to method A z, 15 min) as yellow solid (94%).
Result of LC/MS [M+H]+~H20: 580.0; 1H NMR (CDC13)I 5 1.34 (6H, s, 2x CH3), 1.94 (4H, m, 2x CH2), 3.45 (2H, s, CH2), 5.23 (2H, s, CH2), 7.15 (2H, m, CPI-atom), 7.39 (6H, m, CH—arom.), 7.99 (1H, s, CH—arom.).
Final generation of 4—alkoxymethyl isoxazoles; alternative methods: A) To a stirred solution of the respective 4-hydroxymethy1 isoxazole in 2— methyltetrahydrofurane (5 ml/rnmol) was added potassium hydroxide (powder, 4.0 eq.) and the resulting suspension was stirred for 10 min at room temperature. Iodomethane (4.0 eq.) was then added and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between water and CH2C12. Combined organic layers were dried over MgSO4, ed and concentrated under reduced pressure. Puri?cation was achieved by preparative TLC on silica gel.
B) Sodium hydride (1.1 eq.) was supended in THF (Sure/Seal; 2 ol) and cooled to 0°C. The respective 4—hydroxymethyl isoxazole was dissolved in THF (Sure/Seal; 2 mL/rnmol), cooled to 0°C and added to the NaH suspension. The mixture was stirred for min at 0°C and for 0.5 h at room temperature. Alkylbromide (2.0 eq.) was added and stirring continued at r.t. for 18 h. The reaction was ed by on of water, the mixture was ioned between water and CH2C12. Combined organic layers were dried over MgSO4, tiltrated and concentrated under reduced pressure. Puri?cation 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.
Mixture was d at 0°C for 20 min. The respective 4-bromomethyl ole was dissolved in DMF (2 mL/mmol) and was added to the NaH suspension. The mixture was stirred at 0°C for l h, warmed to room temperature and stirred at this temperature for 18 h. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Product was puri?ed by preparative TLC on silica gel (eluent: CHzClg/MeOI-l 95:5).
D) To a d solution of the respective 4—bromomethyl isoxazole in THF (4 ml/mmol) was added the respective alcohol (3.0 eq.), KOtBu (3.0 eq.) and 18-crown—6 ether (1.0 eq.).
The mixture was stirred at room temperature for 18 h. The mixture was partitioned between water and CH2C12. Combined organic layers were dried over MgSO4, ?ltrated and concentrated under reduced re. Puri?cation was achieved by preparative TLC on silica gel.
Example 65: 1-(4-(3—(2—chloro?uorophenyl)—4—(methoxymethyl)isoxazol-5—yl)—5- (tri?uoromethyl)— 1 H-pyrazolyl)methylpropan—2—ol method A, from 1-(4-(3 —(2—chloro—6—?uorophenyl)(hydroxymethy1)isoxazol-S-y1)- —(tri?uoromethyl)-1H-pyrazol-l—yl)—2-methylpropan—2-ol (0.1 mmol) as yellowish oil (30%; pTLC, eluent: petroleum ethyl acetate 1:1 and pTLC, eluent: petroleum ether/ethyl acetate 2:1).
Result of LC/MS [M+H]+: 447.8; 1H NMR ): 5 1.23 (6H, 5, 2x CH3), 3.14 (3H, s, CH3), 4.18 (1H, s, OH), 4.19 (2H, s, CH2), 4.31 (2H, s, CH2), 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: (2R)(4—(3-(2-chloro?uorophenyl)-4~(methoxymethy1)isoxazol-S- yl)(tri?uoromethyl)- 1 H-pyrazol- I -y1)propanol method A, from (2R)(4-(3—(2-chloro—6—?u0rophenyl)-4—(hydroxymethyl)isoxazol (tri?uoromethy1)—1I-I-pyrazol-l-yl)propanol (0.4 mmol) as yellowish oil (5%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: petroleum ether/ethyl acetate 4:1).
Result of LC/MS [M+H]+: 433.8; 1H NMR (CDC13)Z 8 1.31 (3H, (1, CH3), 3.15 (3H, s, CH3), 3.27 (1H, m, CH), 4.19 (2H, s, CH2),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-?uorophenyl)(methoxymethyl)—1,2—oxazol—5—y1]— —(tri?uoromethyl)- 1 H-pyrazol—l -y1} —2-methylbutan—2-01 method A, from 4- {4-[3—(2-ch1oro—6-?uorophenyl)(hydroxymethyl)-1,2-oxazol y1]-5—(tri?u0romethy1)—lH—pyrazol-l -y1}-2—methylbutan-2—ol (1.5 mmol) as pale yellow oil (29%; pTLC, eluent: petroleum ether/ethyl acetate 3:2 and pTLC, eluent: Cchlg/MeOH 95:5).
Result ofLC/MS [M+H]+: 462.3; 1H NMR (CDC13): 5 1.33 (6H, 5, 2); CH3), 2,13 (2H, m, CH2), 3,13 (3H, s, CH3), 4.19 (2H, s, CH2), 4.53 (2H, m, CH2), 7.14 (1H, td, m.), 7.35 (1H, d, CH-arom.), 7.42 (11H, m, CH—arom), 7.85 (1H, s, om). e 68: (2S)-l-(4-(3-(2-chloro?uorophenyl)(methoxymethyl)isoxazol y1)(tri?uoromethyl)- 1 H—pyrazol— 1 -y1)propan—2—ol method A, from (2S)-1—(4—(3—(2—ch1ore—6-?uoropheny1)~4-(hydroxymethyl)isoxazol yl)-5—(tri?uoromethyl)—l H—pyrazol-l-y1)propan-2—ol (0.3 mmol) as yellowish oil (6%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: CH2012MeOH 95:5).
Result of LC/MS [M+H]+: 433.8; 1H NMR (CDC13)2 5 1.32 (3H, (1, CH3), 3.15 (3H, s, CH3), 3.27 (1H, m, CH), 4.20 (2H, s, CH2), 4.26 (1H, m, CH), 4.37 (2H, m, OH, CH), 7.15 (1H, td, CH~arom.), 7.35 (1H, td, om), 7.43 (1H, m, CH—arom), 7.92 (1H, s, CH—arom).
Example 69: 3-(4-(3—(2—chloro?uorophenyl)(methoxymethyl)isoxazoly1) (tri?uoromethyl)- IH-pyrazol—1~yl)-1 —methy1cyclobutan-1 ~01 (syn-con?guration) method A, ?rom 3- {4-[3-(2-ch10r0-6—?uor0phenyl)(hydroxymethyl)—l,2-oxazol—5- y1]-5 —(tn'?uoromethy1)-lH-pyrazol-l *y1}— 1 -methylcyclobutan—l -01 (syn/anti—mixture) (0.5 mmol) (17%; pTLC, eluent: petroleum ethyl acetate 1:1 and pTLC, eluent: CH2C12/M60H 95:5; only syn diastereomer isolated). 1H NMR (CD013): 8 1.50 (3H, s, CHg), 2.95-2.71 (4H, m, 2XCH2), 3.14 (3H, s, OCH3), 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, m.).
Examples 70 and 71: 3- {4-[3-(2-chloro—6—?u0r0phenyl)-4—(meth0xymethyl)—1,2- oxazol-S-yl]—5—methyl- 1 H-pyrazol-l -y1}- 1 lcyclobutan- l -01 (syn-con?guration) and 3 - {4-[3—(2-chloro—6—?uorophenyl)-4—(methoxymethy1)— 1 ,2-oxaz01—5—y1]—5—methyl— 1H~pyrazolyl} methy1cyclobutan-l -ol (anti-con?guration) method A, from 3—{4-[3—(2—chloro?uoropheny1)—4-(hydroxymethyl)—1,2—0xa201 y1]—5 -methyl-1H-pyrazol-1 -y1} - l —methylcyclobutanol (syn/anti-mixture) (0.3 mmol) (pTLC, eluent: CH2Clz/MeOH 95:5 and again pTLC, : /MeOH 95:5); vlllll CI -0 «D, I\1/ /'." F o 1 Example 70: (syn-con?guration), 10% yield; Result of LC/MS [M+H]+: 406.3; 1H NMR (CDC13)Z 8 1.52 (3H, s, CH3), 2,59 (3H, s, CH3), 2.64 (4H, m, 2x CH2), 3,17 (3H, s, CH3), 4.20 (2H, s, CH2), 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-con?guration), 18% yield; Result ofLC/MS [M+H]+: 406.3; 1H NMR (CD013): 8 1-54 (3H, s, CH3), 2,59 (5H, m, CH2, CH3), 2.76 (2H, m, CH2), 3,20 (3H, s, CH3), 4.24 (2H, s, CH2), 5.03 (1H, m, CH), 7.14 (1H, td, m.), 7.34 (1H, d, (EH—atom), 7.42 (1H, m, CH—arom), 7.90 (1H, s, CH-arom).
Examples 72 and 73: 3-{4-[3-(2-chloropheny1)(meth0xymethyl)—1,2-oxazoly1]- -methy1—1H-pyrazoly1}methy1cyclobutan—1-ol on?guration) and 3-{4-[3— (2-chlor0phenyl)(methoxymethy1)—1 zol—5-y1]-5—methy1— 1 H—pyrazoly1} methylcyclobutan-l—ol (anti-con?guration) method A, from 3-{4-[3-(2-ch1orophenyl)(hydroxymethyl)-1,2-oxazol-5—yl]—5- methyl—1H—pyrazoly1}methylcyclobutan—1—ol (syn/anti—mixture) (0.3 mmol) (pTLC, eluent: CH2C12/MeOI-I 95:5 and again pTLC, eluent: CHZClz/MeOH 95:5); Example 72: (syn-con?glration), 4% yield; Result of LC/MS : 388.3; 1H NMR (CDC13): 5 1.48 (3H, s, CH3), 2.59 (3H, s, CH3), 2.72 (4H, m, 2x CH2), 3.25 (3H, s, CH3), 4.24 (2H, s, CH2), 4.53 (1H, quint, CH), 7.45 (4H, m, CH—al'om.), 7.92 (1H, s, CH—arom).
IO Example 73: (anti-con?guration), 4% yield; Result of LC/MS [M+H]+: 388.3; ‘H NMR (CDC13): 5 1.53 (3H, s, CH3), 2.58 (5H, m, CH2, CH3), 2.77 (2H, m, CH2), 3.25 (3H, s, CH3), 4.24 (2H, s, CH2), 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)isoxazolyI) (tri?uoromethyl)-1H-pyrazol- 1-y1)methylcyclobutan- 1—01 (syn—con?guration) method A, from 3—{4-[3-(2-ehlorophenyl)(hydroxymethyl)—1,2—oxazolyl]—5— (tri?uoromethyly 1H-pyrazol- 1 —y1} — 1 -methylcyclobutanol (syn/anti—mixture) 0.5 mmol) (14%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: CHZCIQ/MeOH 95:5; only syn diastereomer isolated).
Result ofLC/MS [M+H]+: 441.9; 1H NMR (CD013): 6 1.49 (3H, s, CH3), 2.90-2.72 (4H, m, 2XCH2), 3.17 (3H, s, OCH3), 4.20 (2H, s, OCHg), 4.81 (1H, m, CH), 5.04 (1H, br, OH), .35 (4H, m, 4xCH-arom.), 7.90 (1H, s, CH—arom.). 0* w,-0 H /0 Example 75: -{4-[3—(2-chlorophenyl)—4—[(2— methoxyethoxy)methyl] — l ,2—oxazol-5—yl]—5—(tri?uoromethyl)— 1 zol y1}propanol method B, from (ZS)-1—{4-[3-(2—chlorophenyl)—4—(hydroxymethyl)—1,2-0xazol—5—yl]-5— (tri?uoromethyl)—1H—pyrazol-l-yl}propan—2—ol (0.2 mmol) and 2-bromoethyl methyl ether (57%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: CHzClglMeOH 95:5).
Result of LC/MS [M+H]+; 459.8; lH NMR(CDC13): 6 1.32 (3H, (1, CH3), 3.26 (3H, s, OCH3), 3.48-3.32 (5H, m, 2XCH2 and CH), 4.24 (1H, dd, CH), .30 (4H, m, 2xCH2), 7.48-7.34 (2H, m, EXCH- arom.), 757-7.49 (2H, m, 2xCH-arom.), 7.98 (1H, s, CH-arom.).
Example 76: - {4-[3-(2-chloro-6—?uoropheny1)—4-(ethoxymethyl)-1,2—oxazol y1]-5 uoromethyl)— 1 H—pyrazol-1 —yl }propanol method B, from (2R)(4-(3-(2-chloro?uorophenyl)(hydroxymethyl)isoxazol-S- yl)—5—(tri?uoromethyl)-1H—pyrazol-l-yl)propan—2—ol (0.5 mmol) and ethyl bromide (46%; pTLC, eluent: petroleum ether/ethyl acetate 1:1 and pTLC, eluent: CHzClz/MeOH 95:5).
Result of LC/MS [M+H]+: 447.8; 1H NMR (CDC13): 6 0.99 (3H, t, CH3), 1.32 (3H, d, CH3), 3.28 (2H, q, CH2), 4.31— 4.18 (3H, m, CH and CH2), 4.45-4.31 (2H, m, CH2), 7.14 (1H, td, CH—arom.), 7.35 (1H, d, CH—arom.), 7.48—7.38 (1H, m, CH-arom.), 7.93 (1H, s, m.).
Example 77: 4— {4-[3-(2-chlor0?uorophenyl)(cyclopropoxymethyl)—1,2—oxazol— -y1] (tri?uoromethyl)—1H-pyrazol—1-yl}—2-methylbutan01 method C, from 4— {4—[4—(bromomethyl)—3—(2—ch10ro?uor0phenyl)—l,2—0xazoly1]— —(t1‘i?uoromethy1)—lH-pyrazol-l -y1}methy1butan—2-ol (0.25 mmol) and cyclopropanol as pale yellow oil (11%).
Result S [M+H]+: 488.30; 1H NMR (CDClg): 6 0.28 (3H, s, CH3), 1.33 (6H, 8, 2x CH3), 2.14 (2H, m, CH2) 3.12 (1H, m, CH), 4.27 (2H, s, CH2), 4.53 (2H, m, CH2), 7.14 (1H, td, CH-arom.), 7.34 (1H, t, CH-arom.), 7.43 (1H, m, CH-arom), 7.85 (1H, s, CPI-atom). e 78: 4-{4—[3-(2—chlorophenyl)—4—(cyclopr0poxymethyl)—1,2—oxazoly1] (tri?uoromethyl)- lH-pyrazol— l -y1} -2—methylbutan-2—01 method C, from 4- {4—[4—(bromomethyl)—3-(2—chlorophenyl)—1,2-oxazol-5—yl]—5- (tri?uoromethyl)-1H-pyrazolyl}methylbutan~2-ol (0.25 mmol) and cyclopropanol as colorless oil (28%).
Result of LC/MS [M+H]+: 470.30; 1H NMR (CDC13)I 5 0.30 (4H, m, 2x CH2), 1.33 (6H, s, 2x CH3), 2.13 (2H, m, CH2), 3.12 (1H, m, CH), 4.29 (2H, s, CH2), 4.53 (2H, m, CH2), 7.44 (5H, m, CH-arom.), 7.84 (1H, s, CH-arom.).
Example 79: 4— (2—ch10r0pheny1)(cycloprop0xymethyl)-1,2-0xazoly1]—5- methyl— 1 zoly1} methylbutan—2-01 method C, from 4-{4-[4-(br0momethy1)—3-(2—chloropheny1)-1,2—0xazol-5—y1]—5- methyl-lH—pyrazol—l—y1}-2—methy1butanol (0.25 mmol) and cyclopropanol (6%).
Result ofLC/MS [M+H]+: 416.0; 1H NMR (CDC13): 5 0.34 (2H, m, CH2), 0.41 (2H, m, CH2), 1.27 (6H, 3, 2x CH3), 2.03 (2H, m, CH2), 2.61 (3H, s, CH3), 3.18 (1H, m, CH), 4.32 (2H, m, CH2), 4.34 (2H, s, CH2), 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)(cyclopr0poxymethyl)-1,2-oxazol—5- y1]—5—methy1—1 H-pyrazol—l -y1} -1 -methylcyclobutan— 1 ~01, syn— and anti—con?guration method C, from 3-{4-[4—(bromomethy1)(2-ch10rophenyl)—1,2-0xazoly1]—5— methyl-lH-pyrazol-lvyl}-1~methylcyclobutanol nti-mixture) (0.2 mmol) and cyclopropanol; CI NvO ?ll" 1 / / I)! A Example 80: (syn—con?guration), 2% yield; Result ofLC/MS [M+H]+: 414.3; 1H NMR (CDC13): 6 0.33 (2H, m, CH2), 0.40 (2H, m, CH2), 1.47 (3H, s, CH3), 2.57 (3H, s, CH3), 2.63 (2H, m, CH2), 2.75 (2H, m, CH2), 3.16 (1H, m, CH), 3.76 (1H, m, CH), 4.31 (2H, s, CH2), 7.44 (4H, m, CH-arom.), 7.85 (1H, s, CH—arom).
In H 01 N’0 «Clo A Example 81: (anti-con?guration), 4% yield.
Result of LC/MS [M+H]+: 414.3; 1H NMR (CDC13): 6 0.34 (2H, m, CH2), 0.42 (2H, m, CH2), 1.57 (3H, s, CH3), 2.58 (5H, m, CH2, CH3), 2.77 (2H, m, CH2), 3.18 (1H, m, CH), 4.33 (2H, s, CH3), 5.03 (1H, m, CH), 7.45 (4H, m, m.), 7.89 (1H, s, CH—arom). e 82: 4- {4-[3-(2—chloro?uorophenyl)-4—(cyclopropoxymethyl)-1,2-oxazol- -y1]methyl-1H-pyrazol-1—yl}—2—methylbutan—2-01 method C, from 4- {4-[4-(bromomethyl)(2-chloro?uoropheny1)—l,2-oxazoly1]- -methyl—1H—pyrazoly1}—2~methylbutan-2—ol (0.3 mmol) and cyclopropanol as yellowish oil (19%).
Result ofLC/MS [M+H]+: 434.1; 1H NMR (CDC13): 5 0.41-0.26 (4H, m, 2XCH2), 1.30 (6H, s, 2xCH3), 2.04 (2H, t, CH2), 2.63 (3H, s, CH3), 3.23-3.14 (1H, m, CH), 4.35-4.27 (4H, m, 2XCH2), 7.14 (1H, td, CH-arom.), 7.34 (1H, d, m.), 7.48—7.38 (1H, m, CH-arom.), 7.89 (1H, s, CH—arom.).
Example 83 and 84: 3-{4-[3—(2-chloro?uorophenyl)(cyclopropoxymethy1)-1,2- oxazo1—5—y1]—5—methy1— 1 H-pyrazolyl} — 1 lcyc10butan— 1 -01, syn— and anti- con?guration method C, ?om 3-{4-[4-(bromomethyl)—3~(2—ch10ro—6—?uorophenyl)-1,2-0xazol—5—y1]- —1nethyl-1H-pyrazol—1—yl}—1—methylcyclobutan—1-ol (syn/anti—mixture) (0.4 mmol) and cyclopropanol as colorless oil (additional pTLC, eluent: petroleum ether/ethyl acetate 1:1); A Example 83: (syn-con?guration), 15% yield; Result of LC/MS [M+H]+: 432.3; 1H NMR (CDC13): 8 0.30 (2H, m, CH2), 0.36 (2H, m, CH2), 1.47 (3H, s, CH3), 1.76 (1H, s, OH), 2,58 (3H, s, CH3), 2.72 (211,111, CH2), 2.74 (2H, m, CH2 ), 3.18 (1H, m, CH), 4.33 (2H, s, CH2), 4.53 (1H, quint., CH), 7.14 (1H, td, CH-arom.), 7.34 (1H, d, CH-arom.), 7.42 (1H, m, m), 7.95 (1H, s, CH-arom).
Example 84: (anti-con?guration), 16% yield; Result of LC/MS [M+H]+: 432.3; 1H NMR ): 5 0.31 (2H, m, CH2), 0.36 (2H, m, CH2), 1.53 (3H, s, CH3), 1.68 (1H, s, OH), 2,57 (5H, m, CH3, CH2), 2.75 (2H, m, CH2 ), 3.18 (1H, m, CH), 4.32 (2H, s, CH2), 5.03 (1H, quint, CH), 7.1.3 (1H, td, CPI-atom), 7.34 (1H, d, CI-I-arom.), 7.42 (1H, m, CH-arom), 7.91 (1H, s, CH-arom).
CI N’O ’N OH F 3; Example 85: (2R)(4-(3-(2—chloro?uorophen.y1) (cyclopropoxymethyl?soxazol—S—y1)(tri?u0romethy1)— 1H-pyrazoly1)pr0pan—2—01 method C, from (212){4—[4-(bromomethy1)—3-(2-chloro?uorophenyl}1,2-oxazol- —y]]—5-(tri?uoromethy1)—1H-pyrazol—1-y1}propan-2—ol (0.3 mmol) and cyclopropanol (9%).
Result of LC/MS [M+H]+: 459.8; 1H NMR (CDC13)Z 5 0.94—0.80 (4H, m, 2xCH2), 1.32 (3H, d, CH3), 3.19-3.07 (1H, m, CH), 4.25 (1H, dd, CH), 4.27 (2H, s, OCH2), 4.45—4.32 (2H, m, CH2), 7.15 (1H, td, CH-arom.), 7.35 (1H, dt, (EH-mom), 7.49—7.39 (1H, m, CH—arom.), 7.92 (1H, s, CH- atom).
Example 86: 3 -(4-(3 —(2-ch10ro?uor0pheny1)—4-(cyclopropoxymethyl)isoxazo1 y1)(tI‘i?uor0methyl)— 1 H—pyrazolyl)- 1 —methylcyclobutan01 (syn-con?guration) method C, from 3-{4-[4—(bromomethyl)(2-chlor0?uorophenyl)—1,2-oxazol—5-yl]- -(tri?uoromethyl)— 1H-pyrazol— 1 -y1} methylcyclobutan—1 -ol (syn/anti-mixture) (0.2 mmol) and cyclopropanol (52%; only syn diastereomer isolated).
Result of LC/MS [M+H]+: 486.0; 1H NMR (CDC13)Z 5 0.27 (4H, d, 2XCH2), 1.50 (3H, s, CH3), 2.91—2.71 (4H, m, , 3.16—3.08 (1H, m, CH), 4.26 (2H, s, OCHz), .65 (1H, m, CH), 7.14 (1H, td, CH-arom.), 7.34 (IE, (it, CH-arom.), 7.48-7.38 (1H, m, CH-arom.), 7.91 (1H, s, CPI—atom).
Example 87: 3-{4—[3~(2—ch10r0pheny1)-4—(cyclopropoxymethyl)—1,2-oxazolyl]-5— (tri?uoromethyl)—1H—pyrazol-l -yl } methylcyclobutan—1—ol (syn-con?guration) method C, from 4—(bromomethyl)—3-(2—chloropheny1)-1,2-oxazoly1]—5- (tri?uoromethyl)—1H-pyrazoly1}-1~methylcyclobutan—1—ol (syn/anti-mixture) (0.25 mmol) and cyclopropanol (26%; only syn diastereomer isolated).
Result ofLC/MS : 467.9; 1H NMR (CDClg): 6 .25 (4H, m, ZXCHg), 1.50 (3H, s, CH3), 2.91 (4H, br, 2XCH2), 3.17-3.07 (1H, m, CH), 4.29 (2H, s, OCHg), 4.72 (1H, quint, CH), 7.56-7.34 (4H, m, 4xCH-arom.), 7.89 (1H, s, CH—arom.).
Example 88: (S)(4w(3~(2-chlor0phenyl)—4-((oxetan-3—yloxy)methyl)isoxazol—5-y1)- -(tri?uoromethyl)-1 H-pyrazoly1)propan01 method C, from (23)—1~{4-[4—(bromomethyl)-3—(2-chloropheny1)—1,2—oxazol—5—y1]-5— (tri?uoromethyl)—1H—pyrazol-l ~y1}pr0panol (0.25 mmol) and oxetan—3 -01 (1 1%).
Result of LC/MS [M+H]+: 458.3; 1H NMR (CDC13): 5 1.32 (3H, (1, CH3), 4.21 (2H, s, OCH2), 4.46-4.23 (6H, m, 2210112 and 2XCH), 4.59—4.51 (2H, m, CH2), 7.58—7.37 (4H, m, 4xCH-arom.), 7.91 (1H, s, CH- arom.) Example 89: (2R){4-[3—(2-chloro—6—?uorophcnyl)—4—[(propan-Z—yloxy)methy1]-1,2— oxazol-S-yl](tri?uor0methy1)-1H—pyrazol-l-y1}propan-2—01 method D, from (2R)—1—{4—[4—(br0momethyl)(2~ch10r0?uorophenyl)-1,2-oxazol— -y1](tri?uoromethyl)—lH-pyrazol-l-yl}propan—2-ol (0.25 mmol) and isopropanol (21%).
Result of LC/MS [M+H]+: 462.1; 1H NMR ): 5 0.92 (6H, d, 2xCH3), 1.32 (3H, (1, CH3), 3.28 (1H, br, OH), 3.40 (1H, sept, CH), 4.29-4.19 (3H, m, CH and CH2), 4.45-4.31 (2H, m, CH2), 7.14 (1H, td, CH—arom.), 7.34 (1H, d, CH—arom.), 7.47—7.38 (1H, m, m.), 7.93 (1H, s, CH- atom).
Cl 514/3 / «Y ’N CH Example 90: (2R)-1—(4—(3—(2-ch101‘0—6—?uorophenyl)—4—(cyclobutoxymethyl?soxazol— -y1)(tri?uor0methyl)- 1 H-pyrazol— 1 —yl)propan—2—01 method C, ?'om (2R)-1—{4—[4—(bromomethy1)—3—(2-ch10ro—6—?uor0phenyl)-1,2—0xa201- -y1](tri?uoromethy1)-1H-pyrazoly1}propanol (0.25 mmol) and cyclobutanol (17%).
Result of LC/MS [M+H]+: 474.1; 1H NMR (CDC13): 5 1.31 (3H, d, CH3), 1.74-1.55 (4H, m, ZXCHz), .88 (2H, m, CH2), 3.27 (1H, br, OH), 3.75 (1H, quint, CH), 4.14 (2H, s, CH), 4.25 (1H, (1, CH), 4.45-4.31 (2H, m, CH2), 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)—l,2- oxazol—S—yl]—5~(tri?uorornethyl)— 1 H—pyrazol— 1 —yl} -2~1nethylbutan—2-ol 1.) 4-(4—(3-(3-(benzyloxy)—2-chlor0phenyl)-4—(cyclopropoxymethyl?soxazol—S—yl)—5— (tri?uoromethyl)— l H—pyrazolmethylbutan—2—ol method C, from 4-(4-(3-(3 -(benzyloxy)—2—chlorophenyl)—4— (bromomethyl)isoxazolyl)—5-(t??uorornethyl)-1 H-pyrazol- l -yl) methylbutan-Z—ol (1.0 mmol) and ropanol as colorless oil (20%).
Result of LC/MS [M+H]+: 576.5; 1H NMR (CDC13): 5 0.38—0.20 (4H, m, 2XCH2), 1.32 (6H, s, 2xCH3), 2.19 (2H, m, CH2), 3.14-3.06 (1H, m, OH), 4.58-4.47 (2H, m, CH2), 5.22 (2H, s, OCHZ), 5.23 (2H, s, OCHz), 7.10 (1H, td, CH—arorn.), 7.52-7.28 (6H, m, 6xCH-arom.), 7.84 (1H, s, CH—arom.). 2.) 2-chloro—3 ~[4—(cyclopropoxymethyl)-5 - [ l -(3-hydroxy—3—methylbutyl)—5 - oromethyD- l H-pyrazolyl]—1 ,2—oxazol-3 -yl]phenol 4—(4-(3-(3—(benzyloxy)chlorophenyl)(cyclopropoxymethyl)isoxazol-S—yl)—5- (tri?uoromethyl)-lH-pyrazol-l-y1)methylbutanol (0.2 mmol) was dissolved in iPrOH/ethyl acetate (1:1; 1 ml) and I’d/C (10%; 0.3 eq.) was added. The atmosphere was replaced with en and the mixture was stirred at room temperature for 18 h. The mixture was ?ltrated over celite, the ?lter cake was washed with ethyl acetate, and the ?ltrate was concentrated under reduced pressure to give crude material (yellow oil; 90%), which was used as such for the next step.
Result of LC/MS [M+H]+: 486.3; 1H NMR (CDC13)I 8 .24 (4H, m, 2xCH2), 1.32 (6H, s, 2XCH3), .08 (2H, m, CH2), 3.18—3.06 (1H, m, CH), 4.26 (2H, s, OCHZ), 4.58-4.45 (2H, m, CH2), 7.20—6.97 (2H, m, 2xCH—arom.), 7.84 (1H, s, CH-arom.). 3.) NaH (1.4 eq.) was ded in THF (Sure/Seal; 2 mL/mmol) and the solution was cooled to 0°C. A solution of 2—Cliloro-3—[4-(cyclopropoxymethyl)—5-[l—(3- hydroxy-3 -methylbuty1)-5'(tri?uoromethyl)-1H-pyrazolyl]-] ,2-oxazol-3 - yl]phenol (0.6 mmol) in THF Seal: 4 mL/mmol) was added se to the mixture. The mixture was stirred at 0°C for 15 min, then Mel (3.3 eq.) was added.
The mixture was allowed to warm to room ature and was stirred at this temperature for 18 h. Water was added and the mixture was extracted with CH2C12 and ethyl acetate. Combined organic layers were dried over MgSO4, ?ltered and concentrated under reduced pressure. The title compound was obtained by ative TLC on silica gel (eluent: CHZCIZ/MeOH 98:2 and petroleum/ether/ethyl acetate 3 :2) as yellow oil (16% yield).
Result of LC/MS [M+H]+: 500,40 1H NMR (CDC13)I 5 0.30 (4H, m, 2x CH2), 1.32 (6H, 5, 2x CH3), 2.13 (2H, m, CH2), 3.11 (1H, m, CH), 3.96 (3H, s, CH3), 4.29 (2H, s, CH2), 4.53 (2H, m, CH2), 7.07 (2H, m, CH—arorn.), 7.34 (1H, t, CH—arorn.), 7.84 (1H, s, CH—arom.).
Example 92: 3-(4—(3—(2—ehloro—3-(2-morpholinoethoxy)pheny1)-4— (cyclopropoxymethyl)isoxazol-S-y1)—5-(tri?uoromethyl)-1H-pyrazol-l -y1) methylcyclobutan-l-ol (syn—con?guration) 1.) 3-(4-(3-(3—(benzyloxy)chlorophenyl)(cyclopropoxymethyl)isoxazol-S-y1) (tri?uoromethyl)— l H—pyrazol— 1 —yl)—1 lcyclobutan—1 -01 (syn/anti—mixture) method C, from 3-(3-(benzyloxy)-2—chloropheny1) (bromomethyl)isoxazol—5-y1)(tri?uoromethyl)—1H—pyrazol—l -yl)—1 — methylcyclobutan—l—ol (syn/anti—mixture) (0.30 mmol) and cyclopropanol as colorless oil (28%).
Result of LC/MS [M+H]*: 574.3; 1H NMR (CDC13)Z 5 0.58-0.24 (4H, m, 2XCH2), 1.49 (3H, s, CH3), 2.92-2.68 (4H, m, 2xCH2), 3.17~3.05 (1H, m, CH), 4.29 (2H, s, OCHz), 4.80-4.64 (1H, m, CH), .24 (2H, s, OCHZ), 7.13—7.07 (1H, m, CH—arom.), 7.44-7.28 (5H, m, SxCH- arom.), 7.52—7.46 (1H, m, CH-arorn.), 7.90 (1H, s, CH—arom.). 2.) Zachloro-3 -(4-(cyclopropoxymethyl)—5~(1 droxy—3-methylcyclobutyl) (tri?uoromethyl)—1H—pyrazoly1)isoxazoly1)phenol (syn/anti-mixture) O-debenzylation was achieved ing to the procedure bed for e 91, step 2; starting from 3—(4—(3—(3-(benzyloxy)chlorophenyl) (cyclopropoxymethyl)isoxazol—5-y1)(tri?uoromethy1)— 1 H-pyrazol- l -yl)— 1 - cyclobutan—1-ol (syn/anti-mixture) (0.09 mmol) (reaction time 1 h). Crude material was obtained as colorless oil in 52% yield.
Result of LC/MS [M+H]+: 484.3; 3 .) 2-chloro(4-(cyclopropoxymethyl)—5 -(l -(3-hydroxy—3-methylcyclobutyl)—5- (tri?uorornethyl)—lH-pyrazoly1)isoxazol—3—yl)phenol (syn/anti mixture) (0.045 mmol) and K2C03 (3.0 eq.) were suspended in dry DMF (Sure/Seal; 1 mL). N—(2- Chloroethyl)morpholine hydrochloride was added (1.2 eq.) and the mixture was stirred at 50°C for 2.5 h. The mixture was partitioned between water and CHZCIZ, combined organic layers were dried over MgSO4 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).
Result of LC/MS [M+H]*: 597.3; 1H NMR (CDC13): 5 0.30 (4H, m, 2x CH2), 2.64 (4H, m, 2x CH2), 2.80 (4H, m, 2x CH2), 2.89 (2H, t, CH2), 3.10 (1H, m, CH), 3.73 (4H, m, 2x CH2), 4.24 (2H, t, CH2), 4.27 (2H, s, CH2), 4.72 (1H, m, CH), 7.08 (2H, m, m.), 7.31 (1H, t, CH-arom.), 7.89 (1H, s, CH—arom).
Example 93: methyl 5—[1-(2—hydroxymethylpropyl)—5-(t1i?uoromethyl)—1H- l-4—yl]—3—(2-hydr0xypyridin—3 —y1)-1 ,2—oxazolecarboxylate Methyl 5-(1 —(2-hydroxymethylpropyl)—5-(tri?uoromethyl)— 1 zol-4—yl)-3 -(2- methoxypyridin—3-yl)isoxazole—4-carboxylate (synthesized in analogy to Example 21 using 1—hydrazinyl—2-methylpropanol instead of(R)-l-hydrazinylpropan-Z—ol; 0.025 mmol) and sodium iodide (3.0 eq.) were stirred together in acetonitrile (0.150 mL). To this solution chlorotrimethylsilane (3.0 eq.) was added dropwise. The mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate. The organic phase was washed with water and saturated aq. NaHC03 and dried over MgSOa, ?ltered and trated under reduced pressure to give the title compound as pale yellow oil (82%).
Result of LC/MS [M+H]+: 433.8; 1H NMR(CDC13): 5 1.24 (6H, 3, 2x CH3), 3.67 (3H, s, CH3), 4.30 (2H, s, CH2), 6.43 (1H, td, CH-arom.), 7.48 (1H, dd, CH—amm.), 7.85 (1H, dd, CH—arom), 8.06 (1H, s, CH—arom).
Example 94: (2R)-l -(4-(3 -(2-chloro-6—?uorophenyl)isoxazol-S—yl) (trifluoromethyl)-1H-pyrazol-1—y1)propan—2—ol 1. The hydroxyl group of the alcoholic moiety of ethyl 3-(2-chloro-6—?uorophenyl) { 1 -[(2R)—2—hydroxypropyl]—5 —(tri?u0romethyl)-1 H—pyrazol—4-yl} -1 ,2—oxazole-4— carboxylate (Example 12) was TBS protected according to method A, al 0- silylation" described below; 2. The ethyl oxazole—4-carb0xylate group was saponi?ed according to the ure described as ?rst step in "Synthesis of 4—acyl isoxazoles" above; 3. Decarboxylation of the resulting oxazole-4—carboxylic acid was performed according to Adv. Synth. Cam]. 2013, 355, 790 (Table 3, entry 15) using catalytic Cu(I) oxide and TMEDA in NMP at 140°C, simultaneously removing the silyl protecting group to give the title compound upon ation by prep. TLC (eluent: petroleum ether/ethyl acetate 1. :1.) in 15% yield.
Result of LC/MS [M+H]+: 389.8; 1H NMR ): 6 1.31 (3H, d, CH3), 4.24 (1H, dd, CH), 4.44-4.31 (2H, m, CH2), 6.62 (1H, s, m.), 7.14 (1H, td, CH—arom.), 7.46-7.31 (2H, m, 2xCH-arom.), 8.04 (1H, s, CH-arom.).
Example 95: 1- {4-D-(Z—chloro—6-?uorophenyl)—4—(methoxymethyl)-1,2-oxazolyl]- ~(tri?uoromethyl)-1H—pyrazol~ 1 —yl } (2~2H)propanol (racemic) To a stirred solution of Example 66 (0.25 mmol) in CH2012 (1.5 mL) was added Dess- Martin periodinane (3.5 eq.). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched by adding aq. Na28203 and ted with CH2C12. Combined organic layers were washed with ted aq. NaHC03 and brine, dried over anhydrous , and concentrated under reduced pressure. The residue was puri?ed by prep. TLC on silica gel t: petroleum ether/ethyl acetate 3:1) to give 1— {4-[3-(2-chloro-6—?uorophenyl)(methoxymethyl)-1 ,2-oxazoly1] (tri?uoromethyl)— 1 H—pyrazol— 1 —y1}propanone (41%).
This propanone was dissolved in THF (10 mL/mmol) and cooled to 0°C. NaBD4 (1.1 eq.) was added and the mixture was stirred at 0°C for l h. The mixture was quenched with water and partitioned between CH2C12 and water. Combined organic layers were dried over MgSO4, ed and concentrated under reduced pressure. Title compound was puri?ed by preparative TLC on silica gel (eluent: CHZCIZ/MeOH 95:5) and isolated in 65% yield.
Result of LC/Ms [M+H]+: 435.1; 1H NMR ): 8 1.31 (3H, s, CH3), 3.14 (3H, s, OCH3), 3.24 (1H, s, OH), 4.19 (2H, s, CH2), 4.31 (2H, q, CH2), 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: (ZS)— 1 - {4- [3 -(2—chlor0phenyl)—4—(oxolan—2—yl)—1 ,2—oxazol—5-yl]-5 - (tri?uoromethy1)-lH—pyrazol-l-yl}propanol (as mixture of diastereomers) 1_ TBS—Ci 2. LiAIH4 "mm—*— 3. Bess-Martin periodinane 1. MS-CI, TEA 2. HCIIMeOH Starting from methyl (253-3 -(2-chlorophenyl)(l -(2-hydroxypropyl) (trifluoromethyl)—lH—pyrazolyl)isoxazolecarboxylate (Example 22), the alcohol group was tert-butyldimethylsilyl protected (cf. below "General O-silylation procedures", method A), the methyl isoxazol-4—carboxylate was reduced using LiAlH4 (of. general procedure as ?rst step described above in "Synthesis of 4-alkoxymethyl isoxazoles") and oxidized with Doss—Martin periodinane to give the corresponding isoxazol—4—aldehyde (64%; cf. ?rst step described above for e 95). The Grignard t was prepared from 3-chloropropanol and MeMgBr (1.0 eq., 1 M in THF) in THF at 0°C, followed by addition of Mg (2.0 eq.) and 1,2—dibromoethane (0.1 eq.) and stirring under re?ux for 20 min. Upon cooling to room temperature, the solution was separated from the rest of magnesium and directly added to (253-5—(1-(2— ((tert-butyldimethylsilyl)oxy)propyl)(tri?uoromethyl)-1 H—pyrazolyl)(2- chlorophenyl)isoxazole—4-carbaldehyde in THF to give l-(S-(l-((2S)—2-((tert- butyldimethylsilyl)oxy)propy1)(tri?uoromethyl)— l zolyl)-3 -(2— chlorophenyl)isoxazol-4—yl)butane-l,4-diol in 60% yield. Cyclization of the butane— ol unit to the respective ydrofuran ring was achieved with mesyl de in THF and triethylarnine under re?ux in 31% yield. Final 0—deprotection with HCl/MeOH (3.0 M) (described below as step2 in "Cycloaddition reaction") gave the title compound as mixture of diastereomers in 31% yield.
Result ofLC/MS [M+H]+: 442.3; 1H NMR (CDC13)I 8 1.31 (3H, (1, CH3), 1.69—1.39 (4H, m, 2xCH2), 3.66-3.47 (2H, m, CH2), 4.22 (1H, dd, OCHZ), 4.44—4.29 (2H, m, (311;), 4.65 (1H, t, CH), 7.55-7.32 (4H, m, 4XCH—arom.), 7.83 (1H, s, CH—arom.).
Alternative Route to rrazol l-isoxazoles Synthesis of 2—(dimethylamin0)methylene)-oxobutanoates A) ethyl 2-((dimethylamino)rnethy1ene)-4,4,4-tri?uoro-3~oxobutanoate To a solution of ethyl 4,4,4-tri?uorooxobutanoate (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 was stirred at room ature for ca. 3 h until ethyl 4,4,4—trifluoro oxobutanoate was completely ed. Toluene was removed under reduced pressure. The residue was puri?ed by column chromatography on silica gel to give ethyl 2—((dimethylamino)rnethylene)—4,4,4-tri?uoro-3~oxobutan0ate (15 g, yield: 81%).
Result of LC/MS : 240.0; 1H NMR (CDC13): 5 1.30 (3H, t, CH3), 2.90 (3H, br, NCH3), 3.32 (3H, br, NCH3), 4.22 (2H, q, OCHZ), 7.68 (1H, s, CH).
B) methyl 2-((dimethylamino)methylene)oxohutanoate or ethyl 2- ((dimethylamino)methylene)oxo‘outanoate O O \rr/iko/ \IPI/IIkOA‘ O 0 Methyl or ethyl acetoacetate (20 mmol) was dissolved in N,N-dimethylforrnamide dimethyl acetal (3 .0 eq.) and the mixture was heated by microwave irradiation to 80°C for 3 h. The reaction mixture was concentrated under reduced pressure and the crude material (brown oil) was taken up in a small volume of ethyl acetate and crystallized by on ofpetroleum ether to give the product as brown solid (53-62%).
Methyl ester: Result of LC/MS [M+H}+: 172.0; 1H NMR (CDC13): 6 2.32 (3H, s, CH3), 3.04 (6H, br, 2xNCH3), 3.75 (3H, s, CH3), 7.70 (1H, s, CH).
Ethyl ester: Result of LC/MS [M+H]’*: 186.0; 1H NMR (CDC13): 5 1.32 (3H, t= CH3), 2.32 (3H, s, CH3), 3.03 (6H, hr, 2XNCH3), 4.23 (2H, q, OCHZ), 7.66 (1H, s, CH).
Formation of :17 e buildin blocks from 2- dimethvlamino meth -"lene - oxobutanoates To a solution of either ethyl methylamino)methylene)—4,4,4-tri?uorooxobutanoate or methyl or ethyl 2-((dimethylamino)methylene)-3 -oxobutanoate (10.0 minol) in EtOH (5 mL/mmol) was added N,N-diisopropylethylamine (3.0 eq.) and the respective hydrazinyl— alcohol (usually as hloride; 1.1 eq.). The reaction was stirred at room temperature for 18 h. The mixture was partitioned between water and ethyl acetate, ed organic layers were washed with brine and dried over MgSO4, ?ltered and concentrated under reduced pressure.
F o JN‘ : a, N Using ethyl 2-((dimethylamino)methylene)—4,4,4—tri?uorooxobutanoate and (R) hydrazinylpropan—Z—ol hloride: The residue was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give ethyl (R)(2-hydroxypropyl)—5-(tri?uoromethy1)—lH—pyrazole—4—carboxylate (82% yield); Result of LC/MS [M+H]+: 267.0; 1H NMR (CDC13): 8 1.27 (3H, (1, CH3), 1.36 (3H, t, CH3), 3.00 (1H, d, OH), 4.31—4.17 (2H, m, CH2), 4.34 (2H, q, CH2), 7.98 (1H, s, CH-arom.).
HOV N’N Using ethyl 2-((dimethylamino)methylene)-4,4,4-tri?uorooxobutanoate and 4- inylmethylbutan—2—ol: crude ethyl 1-(3-hydroxymethy1butyl)—5- (tri?uoromethyl)-1H-pyrazole—4-carboxylate was obtained as orange oil (79%); Result of LC/MS [M+H]+: 295.3; 1H NMR (CDClg): 8 1.29 (6H, s, 2XCH3), 1.35 (3H, t, CH3), 2.09-1.97 (2H, m, CH2), 4.32 (2H, q, OCH2), 4.55—4.46 (2H, m, CH2), 7.93 (1H, s, CH—arom.).
Using ethyl 2—((dimethylamino)methylene)-4,4,4—tri?uorooxobutanoate and 3— hydrazinyl-l-methylcyclobutanol (syn/anti-mixture): The residue was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 5:1) to give ethyl 1 dr0xy-3 ~methylcyclobutyl)-5~(tri?uoromethyl)— l H—pyrazole—4- carboxylate (syn/anti—mixture) as yellow oil (9% yield); Result of LC/MS [M+H]+: 293.3; 1H NMR(CDC13, mixture of diasteromers = s l and 2): 5 1.34 (6H, t, CH3 1+2)2 1.46 (3H, s, CH3150mer2), 1.50 (3H, s, CH3 130mm), 2.88—2.55 (8H, m, CH2 Isomerel+ 2), 4.31 (2H, t, CH2 13mm), 4.32 (2H, t, CH2 150mm), 4.75-4.65 (1H, m, CH 190mer2): 5.28-5.17 (1H, m, CH 13mm), 7.93 (1H, s, pyrazole—H 13mm), 7.97 (1H, s, pyraZOlC-H 150111611).
Using ethyl 2-((dimethylamino)methylene)-4,4,4-tri?uoro-3—oxobutanoate and (5)1— hydrazinylprop‘an-2—olz crude ethyl (S)(2-hydroxypropyl)(tri?uoromethyl)- 1 H- pyrazole—4—carboxylate was obtained in 35% yield; Result of LC/MS [M+H]+: 267.0; HO N>j/KO/ "w N Using methyl 2-((dimethylamino)methylene)—3—oxobutanoate and 3-hydrazinyl methylcyclobutanol (syn/anti—mixture): The residue was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 1 :1) to give methyl 1—(3-hydroxymethylcyclobutyl)—5-methy1—1H-pyrazole—4-carb0xylate (syn— ration) (39%; a second fraction yielded the anti—diastereomer in a similar amount).
Result of LC/MS [M+H]+: 225.1; 1H NMR (CDC13): 5 1.52 (3H, s, CH3), 2.53 (3H, s, CH3), 2.56 (4H, m, 2x CH2), 2.82 (3H, s, CH3), 4.46 (1H, m, CH), 7.91 (1H, s, CH—arom.).
N175)" Using ethyl 2—((dimethylamino)methylene)—3-oxobutanoate and 4-hydrazinyl—2— methylbutan—Z—ol: The residue was d by column tography on silica gel (eluent: petroleum ether/ethyl acetate 1:1) to give ethyl 1-(3-hydroxy—3-methylbutyl)- 5—methyl-lH-py‘razolecarboxylate as a reddish oil (92%).
Result of LC/MS : 241.1; 1H NMR (CDC13)Z 8 1.27 (6H, s, 2xCH3), 3.90 (3H, t, CH3), 2.02—1.93 (2H, m, CH2), 2.55 (3H, s, CH3), .17 (4H, m, 2xCH2), 7.84 (1H, s, CH-arom.).
General 0—silylation procedures: A) To a solution of ethyl ydroxypropyl)—5-(tri?uoromethyl)—1H-pyrazole carboxylate 4 (2.67 g, 10.0 mmol) (R or S con?guration) in CH2C12 (20.0 mL) were added ole (1.02 g, 15.0 mmol), DMAP (122 mg, 1.0 mmol) and then tert- imethylsilyl chloride (1.95 g, 13.0 mmol in CH2C12, 5.0 mL) at 0°C. The resulting solution was stirred at room temperature for 18 h. The reaction was quenched with saturated aq. NaHC03 and extracted with CH2C12. Combined organic phases were washed with 0.1 M aq. HCl and dried over MgSO4, ?ltered and concentrated under reduced pressure. The residue was puri?ed by column chromatography on silica gel. ego O r}: ‘\ 1 0"\ ng from the (R)—alcohol to give ethyl (R)(2-((zert- butyldimethylsilyl)oxy)propyl)(tri?uoromethyl)— azolecarboxylate (84%).
Result ofLC/MS [M+H]+: 381.1; xH NMR(CDC13): 8 -0.21 (3H, s, CH3), -0.03 (3H, s, CH3), 0.80 (9H, s, 3xCH3), 1.19 (3H, (1, CH3), 1.35 (3H, t, CH3), 4.40-4.25 (4H, m, CH2 and OCHZ), 7.94 (1H, s, CH- atom). >510ng \ ° - N‘ 2. 0"\ Starting from the (S)-alcohol to give ethyl (S)(2—((tert— butyldimethylsi]yl)oxy)propyl)(tri?uoromethyl)- 1 H—pyrazoleca1‘hoxylate (55%).
B) To a stirred mixture of either ethyl l-(3 xy-3—methyleyclobutyl)—5- (tri?uoromethyl)-1H—pyrazolecarboxylate (syn/anti-mixture) or methyl 1-(3-hydroxy- 3-methylcyclobutyl)—5—methyl—1H-pyrazole—4-carboxylate (syn-con?guration) (3.0 mmol) and NN-diisopropylethylamine (3.0 eq.) in CH2C12 (5 mL/mmol) was added tert- butyldimethylsilyl tri?ate (1.5 eq.) slowly at 0°C. The reaction mixture was stirred at room temperature for 3 h and was then diluted with water and extracted with CH2C12.
Combined organic phases were washed with brine, dried over anhydrous MgSO4, ?ltrated, and concentrated.
Using ethyl 1-(3-hydroxy—3-methylcyc10butyl)(tri?uoromethyl)-lH-pyrazole carhoxylate (syn-con?guration): The e was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 50:1 to 20:1) to give ethyl 1-(3- ((terr—butyldimethylsilyl)oxy)methylcyclobuty1)(tri?uoromethyl)— 1 H—pyrazole—4— carboxylate as a brown 0i1; a separation of syn— and anti—diastereomers can be achieved at this level; combined yield of 84%. 1H NMR(CDC13, disatereomer 1): 8 — 0.01 (6H, 5, 2x CH3), 0.77 (9H, s, tBu), 1.13 (3H, t, CH3), 1.34 (3H, s, CH3), 2.53 (4H, m, CH2), 4.19 (2H, q, CH2), 5.03 (1H, m, CH), 7.82 (1H, s, CH-arom.) 1H NMR (CDC13, disatereomer 2): 5 — 0.02 (6H, 5, 2x CH3), 0.79 (9H, s, tBu), 1.13 (3H, t, CH3), 1.34 (3H, s, CH3), 2.53 (4H, m, CH2), 4.19 (2H, q, CH2), 5.03 (1H, m, CH), 7.80 (1H, s, m.) N50/ /S{Oe"' Using methyl 1—(3-hydroxy—3-methylcyclobutyl)—5-methy1—1H—pyrazole-4—carboxylate (syn-con?guration): The residue was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl e 8:1) to give methyl 1-(3 -((tert- butyldimethylsilyl)oxy)—3-methy1cyclobuty1)—5-methyl— 1H—pyrazole—4-carboxylate (syn-con?guration) (38%).
Result of LC/MS : 339.1; 1H NMR(CDC13): 8 0.11 (6H, 2, 2XCH3), 0.89 (9H, s, 3XCH3), 1.46 (3H, s, CH3), 2.50 (3H, s, CH3), 2.59-2.51 (2H, m, CH2), 2.90-2.76 (2H, m, CH2), 3.81 (3H, s, OCHg), 4.33—4.17 (1H, m, CH), 7.86 (1H, s, CH-arom.).
C) ethyl 1-(3-hydroxy—3-methylbutyl)(tri?uoromethyl)—1H—pyrazole—4-carboxylate or ethyl 1-(3 -hydroxy—3-methy1buty1)—5—methyl-1H-pyrazolecarboxylate (4 mmol) was taken up in bis(trimethylsilyl)amine (10 mL) and chlorotrimethylsilane (1.0 eq.) was added. The mixture was stirred at room temperature for 18 h. The mixture was d with CH2C12 and washed with water and saturated aq. NH4C1. The organic phase was dried over MgSO4, d and concentrated under reduced pressure. \ 0/\ \ MN" —Si"O Using ethyl 1 —(3 -hydroxy—3 —methylbutyl)—5-(tri?uoromethyl)— 1H—pyrazole-4— carboxylate: Crude product was puri?ed by prep. TLC on silica gel (eluent: CH2C12/MeOH 95:5) and again pTLC (eluent: eum ether/ethyl acetate 4:1) to give ethyl 1 -(3 -rnethy1-3 -((t1imethylsilyl)oxy)butyl)—5-(tri?u0rornethyl)- 1 H—pyrazole- 4—carboxylate as orange oil (75%).
Result of LC/MS [M+H]+: 367.3; 1H NMR (CDCl3)I 6 0.13 (9H, s, SXCH3), 1.29 (6H, s, 2xCl—l3),51.35 (3H, t, CH3), 2.02—1.92 (2H, m, CH2), 4.32 (2H, q, OCHZ), 4.50-4.40 (2H, m, CH2), 7.92 (1H, s, CH-arom.).
—Si-O Using ethyl 1-(3 xy-—3—methylbutyl)methy1-lH-pyrazolecarboxy1ate: if reaction is not reaching completion, r eq. chlorotrirnethylsilane can be added and stirring to be continued under re?ux. Crude material ethyl 5-methy1-1—(3—methyl— 3-((trimethy1silyl)oxy)butyl)—lH-pyrazolecarboxylate was obtained as a reddish oil (88%) and was used as such in the next reaction step.
Result ofLC/MS [M+H]+: 313.1; \ ' >4" Si. 0 N‘ OH Using 1 -(3 xy-3 -methylbuty1)-5—(tri?uoromethyl)- l H—pyrazole—4-carboxylic acid (1.1 mmol; which was obtained from ethyl l-(3 -hydroxy—3-rnethy1butyl) (trifluoromethyl)—1 H—pyrazolecarboxylate by saponi?cation using 4 N aq. NaOH in THF (room temperature, 18 h), isolated in 48% yield as brown oil upon cation with 6 N aq. HCl and tion with CH2C12)Z mixture was stirred at 60°C in a sealed tube for 18 h, upon which more chlorotrimethylsilane was added an stirring continued for another day, until conversion was completed; crude product 1— {3—methyl—3- [(trimethylsilyl)oxy]buty1} (tri?uoromethyl)-1H-pyrazolecarboxylie acid (84%) was used as such in next step.
Result ofLC/MS [M+H]+: 339.0; Condensation of alkvl wrazole—4—carbox ‘lates with heteroarvl—methvl anions To a solution of 2-methy1pyrirnidine / 2-methy1pyrazine / 4-methylpyrimidine (1.2 eq.) in THF (1 mL/mmol) was added LiHMDS (1.0 M in THF; 2.2 eq.) at —10°C under N2 atmosphere. The mixture was stirred at this temperature for 30 min and the respective alkyl pyrazole—4—carboxylate (1.0 eq. in THF, 1 mL/mmol) was added, and the mixture was stirred at room temperature for 2—18 h (based on progress l). The reaction was quenched with ice water and the ing mixture was extracted with EtOAc. Combined organic phases were washed with brine, dried over MgSO4, d and concentrated in vacuo.
Using ethyl (R)-1 -(2-((tert-butyldimethylsilyl)oxy)propyl)(tri?uoromethyl)—1H- pyrazolecarboxylate (10 mmol) and 2-methy1pyrirnidine: The residue was puri?ed by chromatography on silica gel to give (R)(1-(2-((tert— hutyldimethylsily1)oxy)propyl)(tri?uoromethyl)— 1 H-pyrazolyl)—2-(pyrimidin—2- y1)ethan- 1 —one : 77%); 2O Result of LC/MS [M+H]+: 429.0.
C! O F O"Sik _ N‘ Using ethyl (tert-butyldimethy1sily1)oxy)-3 -methylcyclobutyl) (trifluoromethyl)-1H—pyrazole—4-carboxylate (syn—con?guration) (0.3 mmol) and 2— methylpyrimidine: The residue was ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1—(1-(3-((tert—butyldimethylsilyl)oxy) methyleyclobutyl)(tri?uoromethyl)- 1 H—pyrazolyl)(pyrimidiny1)ethanone (syn—con?guration) as a yellow oil (46%).
Result ofLC/MS [M+H]+: 455.1; 1H NMR (CDClg): 8 — 0.01 (6H, 5, 2x CH3), 0.80 (9H, s, tBu), 1.35 (3H, s, CH3), 2.53 (4H, m, CH2), 4.38 (2H, s, CH2), 5.02 (1H, m, CH), 6.89 (1H, t, CPI—atom), 7.65 (1H, d, CH-arom.), 7.82 (1H, s, CH-arom.), 8.60 (1H, d, CH-arom.).
C" 0 \N'WN "I’O;SiJ< N 9 / \ Using methyl 1-(3 t—butyldimethylsilyl)oxy)methylcyclobutyl)~5—methyl-lH- pyrazole—4-carboxylate (syn-con?guration) (1.6 mmol) and 2-methylpyrimidine: The e was puri?ed by prep. TLC on silica gel t: petroleum ether/ethyl acetate 1:2) to give 1—(1-(3 -((tert—butyldimethylsilyl)oxy)Inethylcyclobutyl)methyl-lH- pyrazol—4-yl)—2—(pyrimidin—Z-yl)ethan—1-one (syn-con?guration) as colorless solid (1 7%).
Result of LC/MS [M+H]+: 401.1. ’l 09% "/x/\ Using ethyl 1-(3—((tert—buty1dimethylsilyl)oxy)methylcyclobutyl) (tri?uoromethyl)—lH-pyrazole—4—carboxylate (syn—con?guration) (0.3 mmol) and 2- methylpyrazine: The residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1—(1-{3-[(tert—hutyldimethylsilyl)oxy]—3— methylcyclobutyl } —5-(tri?uoromethyl)- 1 zolyl)(pyrazinyl)ethan— 1 -one (syn-con?guration) (48%).
N’A F ’N F Using ethyl 1-(3 -((tert—butyldimethylsilyl)oxy)-3 -rnethylcyclobutyl)-S- (tri?uoromethyD—lH—pyrazole—4—carboxylate (syn-con?guration) (0.3 mmol) and 4- methylpyrimidine: The e was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 1-(1 ~ {3-[(tert—butyldirnethylsilyl)oxy]-3~ methylcyclobutyl } (tri?uoromethyl)- l H-pyrazol—4-yl)(pyrimidin—4—yl)ethan— 1 - one (syn-con?guration) (63%).
The corresponding anti’diastereomer was obtained accordingly, ng from the respective uilding-block.
/N O‘Sik \N. '99 I \ Using methyl l—(3-((terr—butyldimethylsilyl)oxy)—3-niethylcycl0butyl)—5-methyl-1H- pyrazole—4-carboxylate (syn—con?guration) (0.3 mmol) and 4—methylpyrimidine: The e was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 3—[(tert—butyldimethylsilyl)oxy]methylcyclobutyl}—5-methyl—1H— pyrazol-4—yl)(pyn'midinyl)ethan—l-one (syn-con?guration) (76%).
(Aldo N\lWM 6’ O‘Slk N 4'! / \ Using methyl l—(3 —((tert—butyldimethylsilyl)oxy)—3—methylcyclcbutyl)~5~methyl- 1H— pyrazole-4ucarboxylate (syn-con?guration) (0.3 mmol) and 2-methylpyrazine: The residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 3: 1) to give l—(l - {3-[(tert-butyldimethylsilyl)oxy]—3-methylcyclobutyl}methyl-1H- pyrazol—4—yl)—2—(pyrazin-2uyl)ethan-l—one (sywconfiguration) (79%).
Using ethyl (R)-l-(2-((tert~butyldimethylsilyl)oxy)propyl)—5-(tri?uoromethyl)-l H- pyrazole—4—carboxylate (0.3 mmol) and 4—methylpyri1nidine: The residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3: l) to give l-{l- [(ZR)[({err—butyldimethylsilyl)oxy]propyl]-5—(tri?uoromethyl)—1H—pyrazol—4-yl} ~2- (pyrimidin-4—yl)ethan~l -one (74%).
Using ethyl 5-methyl-1 - {3 -methy1—3 -[(trimethylsilyl)oxy]butyl} ~1H—pyrazole—4— carboxylate (0.9 mmol) and y1pyrimidine: The residue was puri?ed by prep.
TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) to give 1—(5-methy1{3— methyl~3~[(uimethyls?yl)0xy]butyl} — 1H-pyrazol-4—y1)~2-(pyrimidin—2~y1)ethan— 1 ~one as yellowish oil (31%).
Result ofLC/MS [Mm]? 361.1; 1H NMR (CDCI3)I 6 0.11 (9H, s, 3XCH3), 1.26 (6H, 2, 2XCH3), 1.95—1.80 (2H, m, CH3), 2.55 (3H, s, CH3), 4.24-4.09 (2H, m, CH2), 4.43 (2H, s, CH2), 7.16 (1H, t, CH- arom.), 7.90 (1H, s, CH-arom.), 8.70 (2H, d, 2xCH-arom.).
Using ethyl 1 — {3 —methyl[(trimethylsilyl)oxy]butyl} i?uoromethyl)- 1H- pyrazole—4—earboxylate (0.33 mmol) and Zumethylpyrimidine: The residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1) to give crude 1 -(1- {3 -methy1-3 —[(trimethy1silyl)oxy]butyl}~5~(tri?uor0methyl)-1H~pyrazol~4— (py?midin-2~yl)ethan-1—one as orange oil (quant).
Result 01" LC/MS [M+H]+: 415.4; 111 NMR (CDCI3)I 8 0.14 (9H, s, 3XCH3), 1.31 (6H, s, 2XCH3), 2.09—1.93 (2H, m, CH2), 4.47—4.39 (2H, m, CH2), 4.49 (2H, s, CH2), 7.00 (1H, t, m.), 7.76 (1H, s, CH-amm.), 8.71 (2H, d, 2xCH-arom.) Synthesis of 3-(pyrazol~4—yl)—3~oxopropanoates R1 ’«01,1, gx, .4_ . D.110 a , "Wok-Rik"-R1. ._N. 5N.
F \ o o F [8‘s A0 ’ N ,, NN‘ ’ ethyl 3-(1-{3- [(tert-butyldimethylsilyl)oxy] methylcyclobutyl}(tri?uoromethyl)-1H— pyrazolyl)—3-oxopropanoate, syn- and anti-con?guration, was sized from ethyl 1- (3 t—butyldimethylsi1y1)oxy)—3 -methylcyclobutyl)—5-(tri?uoromethy1)—1H-pyrazole-4— carboxylate (syn/anti mixture) 1.) To a solution of ethyl 1-(3—((tert-butyldimethylsilyl)oxy)—3-methylcyclobutyl)—5- (tri?uoromethyl)-1H-pyrazole—4-carboxylate (syn/anti e) (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 CH2C12. Combined organic layers were dried over MgSO4 and concentrated to s. Separation of diastereomers was not le at this stage, thus the crude brown oil 1- {3-[(tert—butyldimethylsily1)oxy]—3-methylcyclobutyl}—5- (tri?uoromethyl)-1H-pyrazolecarboxylic acid (94%) was used for further conversions.
Result of LC/MS [M+H]+: 379.1; 2.) A solution of crude 1-{3-[(tert—butyldimethylsily1)oxy]—3 -methylcyclobutyl}—5- oromethyl)-1H-pyrazole—4—carboxylic acid (1.73 mmol) and 1,1"- carbonyldiimidazole (1.5 eq.; CD1) in THF (Sure/Seal, 7 mL) was stirred at room temperature for 18 h to form an activated carboxylic acid derivative. 1-[(3 -ethoxy—3— oxopropanoyl)0xy]magnesio 3-ethy1 propanedioate (1.2 eq., synthesis described below) was added and the solution was stirred at 55°C for 2 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and combined organic layers were dried over MgSO4 and concentrated to dryness. Puri?cation and diastereomer tion was accomplished via column chromatography on silica gel (eluent: eum ether/CH2C12/ethyl acetate 8:2: 1). Syn— and anti-isomers (relative con?guration within cyclobutanol unit) of ethyl 3-(1 — {3 -[(tert-butyldimethylsilyl)oxy]-3 -methylcyclobutyl} (tri?uor0methy1)— 1 H— pyrazolyl)-3~oxopropanoate were obtained as yellow oils (each 29-36%).
Syn—configuration: Result of LC/MS [M+H]+: 449.4; 1H-NMR eto-Isomer) (CDC13, J [Hz]): 5 = 7.92 (s, 1H pyrazole-H), 4.62—4.48 (m, 1H, CH), 4.20 (q, 2H, 3.1 = 7.1, 3), 3.80 (s, 2H, CH2), 2.92-2.86 (m, 2H, CH2), 2.61-2.54 (m, 2H, CH2), 1.45 (s, 3H, CH3), 1.26 (t, 3H, 3] = 7.1, OCH2CH3), 0.89 (s, 9H, C(CH3)3), 0.11 (s, 6H, CH3).
Anti-configuration: Result of LC/MS [M+H]+: 449.3; lH-NMR (anti-Keto-Isomer) (CDClg, J [112]): 5 = 7.90 (s, 1H le-H), 5.21-5.08 (m, 1H, CH), 4.20 (q, 2H, 3J = 7.1, OCH2CH3), 3.80 (s, 2H, CH2), 2.75—2.56 (m, 4H, CH2), 1.46 (s, 3H, CH3), 1.26 (t, 3H, 3.1 = 7 .1, OCH2CH3), 0.91 (s, 9H, C(CH3)3), 0.12 (s, 6H, CH3). ,\( / 0—81: ethyl 3-(1-{3-methyl[(trimethylsilyl)oxy]butyl}(trifluoromethyl)-1H-pyrazol—4-yl)— 3—oxopropanoate Crude 1- {3 ~methy1—3 —[(trimethylsilyl)oxy]buty1}-5—(tri?uoromethyl)— 1 H-pyrazol e carboxylic acid (0.96 mmol; synthesis described above Within section "General O—silylation procedures" ) was treated with CD1 and 1—[(3-ethoxy—3-oxopropanoyl)oxy]magnesio 1 propanedioate according to the procedure described above to give the tide compound as orange oil (crude, quant; partial 0-desi1y1ation occurred).
Result of LC/MS [M+H]+: 409.1. methyl 3-{1-[(ZS) [(tert-butyldimethylsilyl)oxy]propyl] (tri?uoromethyl)-1H-pyrazol- 4-yl}oxopropanoate Ethyl (S)- 1 —(2-((tert—buty1dimethy1si1y1)oxy)propyl)-5~(tri?uoromethy1)~ 1 H-pyrazole—4— carboxylate (0.8 mmol) was ?rst saponi?ed to give the acid, which was next treated with CD1 and l—[(3-methoxyoxopropanoy1)oxy]magnesio 3—methyl propanedioate according to the procedures described above to give crude title compound (quant).
Synthesis of l-[(3-ethoxyoxopropanoyl)oxy]magnesio 3—ethyl edioate according to J. Am. Soc. Chem. 2011, 133, 326: To a solution of 2.00 g (11.8 mmol) ethyl malonate potassium salt in 10 ml water were added 1.19 mg (5.88 mmol) MgC12x6H20 and the solution was stirred at room temperature for 30 min. 60 ml of iPrOH were added to precipitate potassium chloride. The sion was stirred for l h at room temperature followed by ?ltration and washing with iPrOl—I (2 x 5 ml). The ?ltrate was evaporated to dryness to yield l—[(3—ethoxye3-0xopropanoyl)oxy]magnesio 3-ethyl propanedioate as a white solid (2.00 g). l-[(3-methoxyoxopropanoyl)oxy]magnesio 3-methyl propanedioate was synthesized accordingly.
Cycloaddition reaction Y Y .OH o i 1. TEA, DMF Ml}!N-O .R1 J1 + / N‘R‘I or NaH, DMF Ar Ci Z "N war Ar 2. O-desnlylatlon 2 ,, O-silylated Step I: To a stirring solution of the respective pyrazol-4—yl(heteroaryl)ethan-l—one or alkyl 3-(pyrazoly1)oxopropanoate (1.0 eq.) and ylamine (TEA; 4.0 eq.) in DMF (Sure/Seal; 5 mL/mmol) was added the appropriately substituted N—hydroxybenzimidoyl chloride (3.0 eq.). The e was stirred at indicated temperature for 18 h. The reaction was poured into water and extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced re. Upon puri?cation as described speci?cally below for each product, 1ylation was conducted.
Step 2: A solution of puri?ed silyl~protected product (l .0 eq.) in HCl/MeOH (3.0 M; 15 mL/mmol) was d at room temperature for 3 h. The pH was adjusted to around 8 by adding aq. NaOH (1.0 M), and the mixture was extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous NaZSO4, trated under reduced pressure.
Example 97: (R)—1—(4—(3-(2—chloro-6—?uorophenyl)(pyrimidinyl)isoxazol-5—yl)—5- (tri?uoromethyl)— 1 H-pyrazol~ l -yl)propanol Step 1: (R)-1—(l tert—butyldimethylsilyl)oxy)propyl)—5-(tri?uoromethyl)— l H—pyrazol—4- yl)(pyrimidinyl)ethan—l-one (4.0 mmol) and 2-chloro?uoro—N-hydroxybenzimidoyl chloride; the on was ted at room temperature; the e was puri?ed by column chromatography on silica gel (eluent: petroleum ethyl acetate 6:1) to give (R)(l-(2- ((tert-butyldimethylsilyl)oxy)propyl)—5-(tri?uoromethyl)— 1 H—pyrazolyl)-3—(2—chloro—6— ?uoropheny1)(pyrimidiny1)isoxazole as a yellow oil (24%); Result of LC/MS [M+H]+: 582.0; Step 2, general ddition procedure: Mixture after step 2 was puri?ed by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 2: 1) to give the title compound (54%).
Result of LC/MS [M+H]+: 467.7; 1H NMR (CDC13)Z 5 1.32 (3H, (1, CH3), 4.24 (1H, dd, CH), 4.52—4.32 (2H, m, CH2), 7.05 (1H, t, CPI-atom), 7.10 (1H, td, CH~arom.), 7.29 (l H, 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?uorophenyl)—4-(pyrimidin—Z-yl)isoxazol~5-yl)—5- (tri?uoromethyl)— l H—pyrazol-l -yl)-l -methylcyclobutanol (syn-configuration) Step 1: l-(1-(3-((tert—butyldimethylsily1)oxy)methylcyclohutyl)—5-(tri?uorornethyl)—1H— pyrazoly1)(pyrimidin—2-yl)ethanone (syn-con?guration) (0.11 mmol) and 2-ehloro ?uoro-N-hydroxybenzimidoyl chloride; the reaction was conducted at 50°C; the e was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 5-(1—(3- ((z‘ert—butyldimethylsilyl)oxy)-3 —methylcyclobutyl)(tri?uoromethyl)— l H-pyrazol-4—yl)—3 — (2-chloro-6—?uorophenyl)-4—(pyrimidin—2—yl)isoxazole (syn—con?gWation) as yellow oil (75%); Result of LC/MS [M+H]J": 608; Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ethyl acetate 1:1) to give the title compound as a ess solid (12%).
Result of LC/MS [M+H]+: 494.2; 1H NMR (CDCl3): 6 1.58 (3H, s, CH3), 2.94—2.68 (4H, m, ZXCHz), 4.78—4.65 (1H, m, CH), 7.04 (1H, t, CPI—atom), 7.10 (1H, td, om), 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—Z-yl)isoxazol—5~yl)~5-methyl~ l H— pyrazol- l -yl)- l -rnethylcyclobutan- 1 —ol (syn-con?guration) Alternative Step 1: To a solution of l-(l-(3 -((tert-butyldimethylsilyl)oxy)-3 -methy1cyclobutyl)~S-methyl—lH- pyrazol-4—yl)~2—(pyrimidin—2—yl)ethan-l—one (syn—configuration) (0.09 mmol) in DMF (3 mL) was added NaH (5.0 eq.) at 0°C. Ice bath was removed and the mixture was stirred at room temperature for 20 min. Then 2-ehloro—N—hydroxybenzimidoyl chloride (3.0 eq.) was added, and the mixture was d at 600C for 3 h. The reaction was quenched with saturated aq.
NH4Cl, and extracted with EtOAe. The organic layers were washed with brine, dried over ous NaZSO4 and concentrated. The e was puri?ed by preparative TLC t: petroleum ether/ethyl acetate 2:1) to give 5—(1-(3 -((tert—butyldimethylsilyl)oxy) methyleyclobutyl)v5-1nethyl~l H—pyrazol—4-yl)-3~(2—chlorophenyl)~4-(pyrimidin—Z— yl)isoxazole (syn-con?guration) (41%); Result of LC/MS [M+H]+: 536.5; ]H NMR (CDC13)I 5 -0.08 (6H, 5, 2x CH3), 0.88 (9H, s, tBu), 1.45 (3H, s, CH3), 2.52 (2H, m, CH2), 2.56 (3H, s, CH3), 2.78 (2H, m, CH2), 4.25 (1H, m, CH), 7.37 (4H, m, CH-arom.), 7.86 (1H, s, CPI—atom), 8.60 (1H, d, CH-arom.), 8.78 (1H, d} CH—arom.), 8.82 (1H, d, CH- atom), Step 2, general ddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound as a colorless solid (32%).
Result of LC/MS [M+H]+; 422.3; 1H NMR (CDCI3)Z 5 1.47 (3H, s, CH3), 2.55 (3H, s, CH3), 2.79-2.66 (4H, m, 2xCH2), 4.55 (1H, quint, CH), 7.11 (1H, t, CPI—atom), 7.43—7.32 (3H, m, 3xCH-arom.), .57 (1H, m, CH—arom.), 8.18 (1H, s, CH—arom.), 8.62 (2H, d, 2XCH).
Example 100: 3- {4-[3-(2-chloro?uorophenyl)(pyrazin-Z-yl)—1,2-oxazol-5—yl]—5- oromethyl) 1 H-pyrazoly1} — 1 -methylcyelobutan-1 -01 (syn—con?guration) Step 1: 1-(1 - {3-[(tert-butyldimethylsilyl)oxy]-3 —methylcyclobutyl}(tri?uoromethyl)— l H- pyrazolyl)(pyrazinyl)ethan0ne (syn-con?guration) (0.11 mmol) and 2—chloro ?uoro~N-hydr0xybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was d by prep. TLC on silica gel t: petroleum ether/ethyl e 3: 1) to give 2-[3-(2- ch10ro—6-?u0rophenyl)-5 - { 1 -[3 —[(tert-butyldimethylsilyl)0xy] -3 -methylcyclobuty1] ~5- (tri?uoromethyl)—1H—pyrazol—4-yl}-1,2—oxazolyl]pyrazine (syn-con?guration) (75%); Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (49%).
Result ofLC/MS [M+H]+: 494,3; 1H NMR (CDC13): 5 1.48 (3H, s, CH3), 2.94—2.67 (4H, m, 2XCH2), 4.68 (1H, quint, CH), 7.12 (1H, td, CH-arom.), 7.30 (1H, d, CH-arom.), 7.49—7.36 (1H, m, om), 7.94 (1H, s, CH- arom.), 8.26 (1H, br, CPI-atom), 8.49-8.34 (2H, m, 2XCH-arom.).
Example 101: 3 - {4- [3 —(2-chloropheny1)(pyrazin—2-y1)-1,2-oxazoly1](tri?uoromethyl)-.lH-pyrazol-l- yl} —1 -methy1cyclobutanol (syn-con?guration) Step 1: 1—(1 — {3 — [(tert-butyldimethylsilyl)oxy]—3-methylcyclobutyl} —5 -(tri?uoromethyl)- 1 H— pyrazoly1)-2—(pyraziny1)ethanone (syn-con?guration) (0.22 mmol) and 2-chloro-N- hydroxybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2—[3-(2- chlorophenyl)-5 - {1 — [3 - [(tert—butyldimethylsi1y1)oxy] —3-methy1cyclohutyl] (tri?uorornethyl)-1H—pyrazolyl}~1,2—oxazol—4-y1]pyrazine (syn—con?guration) (20%); Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (15%).
Result of LC/MS [M+H]+: 476.2; 1H NMR )Z 6 1.44 (3H, s, CH3), .64 (4H, m, 2xCH2), 4.63 (1H, quint, CH), 7.54-7.45 (1H, m, CH—arom.), .54 (2H, m, 2XCH-arorn.), 7.70 (1H, s, CH—arom.), 7.98 (1H, d, m.), 8.50 (1H, s, CH—arom.), 9.10 (1H, s, CH-arom.).
Example 102: 3 - {4- [3-(2-ch10ropheny1)~4-(pyrimidiny1)— 1 ,2-oxazol-5—yl]—5—(t1i?uoromethyl)- 1H- pyrazol-l -y1} - 1 —methylcyclobutan01 (syn-con?guration) Step 1: l—(1-(3 -((tert-butyldimethy1silyl)oxy)—3-methylcyclo'butyl)(tri?uoromethy1)—1H— pyrazolyl)-2—(pyrimidin—2-yl)ethanone (syn-con?guration) (0.33 mmol) and 2-chloro-N- hydroxybenzimidoyl de; the reaction was conducted at 50°C; the residue was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 3:1) to give 2-[3-(2- ch10rophenyl)-5 - { 1 - [3 -[(tert-butyldimethylsilyl)0xy] —3 -methylcyclohutyl] -5 — (t??uoromethyD-lH~pyrazol-4—y1}-1,2-oxazoly1]pyrimidine (syn—con?guration) (27%); Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 1:5) to give the title compound (8%).
Result of LC/MS [Mi—HT: 476,2; 1H NMR (CDCIg): 5 1.48 (3H, s, CH3), 2.92-2.70 (4H, m, CH2), 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, (EH-arena), 8.08 (1H, s, CH-arom.), 8.54 (2H, d, 2xCH-arom.).
CF3 ?n" C! N‘O / . p N /0 / ,g.
Example 103: 3-{4—[3-(2-chloromethoxyphenyl)—4—(pyrimidin—Z-yl)—1,2-oxazolyl]—5- (tri?uoromethyl)-1H-pyrazolyl} -1 -methylcyclobutan-1 -ol (syn-con?guration) Step 1: 1-(1-(3 -((tert—butyldirnethylsilyl)oxy)-3 -methy1cyclobutyl)(tri?uoromethyl)-1H— pyrazolyl)-2—(pyrimidiny1)ethanone (syn-con?guration) (0.38 mmol) and 2-chloro methoxy—N—hydroxybenzimidoyl de; reaction was conducted at 65°C; the e was puri?ed by 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)oxy] -3 - methylcyclobutyl](tri?uoromethyl)-1H—pyrazolyl}—l,2—oxazol-4—yl]pyrimidine (syn— con?guration) as an orange oil (14%); Result ofLC/MS [M+H]+: 620.1; 1H NMR ): 8 0.13 (6H, s, 2xCH3), 0.91 (9H, s, 3xCH3), 1.27 (3H, s, CH3), .51 (2H, m, CH2), 2.84-2.70 (2H, m, CH2), 3.89 (3H, s, OCH3), 7.42—7.01 (4H, m, 4xCH-arom.), 8.03 (1H, s, CPI—atom), 8.52 (2H, d, 2xCH-arom.). ative Step 2: A solution of puri?ed protected product (1.0 eq., 0.06 mmol) in THF (Sure/Seal, 0.5 mL) was treated with tetrabutylammonium ?uoride (1 M in THF; 1.1 eq.) at room temperature for 2 h. Solvent was removed under reduced pressure and title product was obtained from preparative TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:2 and again 3 :2) as pale yellow oil (16%).
Result of LC/MS : 506.0; 1H NMR (CDC13): 5 1.48 (3H, s, CH3), 2.91-2.70 (4H, m, 2XCH2), 3.91 (3H, s, OCH3), 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, ZXCH-arom.) Example 104 and 105: 3 - {4-[3-(2-chloro?uorophenyl)—4—(pyrimidinyl)-1,2-oxazolyl]—5-(tri?uoromethy1)— 1H-pyrazol—1-y1}—1-methylcyclobutanol, syn—con?guration and anti-con?guration Step 1: 1-(1—{3—[(tert—butyldimethylsily1)oxy]methylcyclobutyl}(tri?uoromethyl)-1H- pyrazol-4—yl)(pyrimidiny1)ethan—1-one (syn and anti—con?guration, respectively) (0.17 mmol each) and 2-chloro?uoro—N—hydroxybenzimidoyl chloride; the reaction was conducted at 60°C; crude 4-[3-(2-ehloro?uorophenyl)—5-{1—[3-[(tert- butyldimethylsilyl)oxy] -3 -methylcyclobuty1](tri?uoromethyl)—1H—pyrazolyl} -1 ,2- oxazol-4—y1]pyrimidine (syn and anti—con?guration, respectively) (quant) were ly used in step 2; Step 2, general cycloaddition procedure: Mixture after step 2 was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 1:5) to give the title compounds: Example 104, syn-con?guration (9%) Result ofLC/MS [M+H]+: 493.9; lH NMR(CDC13): 6 1.50 (3H, s, CH3), 2.97-2.71 (4H, m, , 4.70 (1H, quint, CH), 6.92 (1H, d, CH-arom.), 7.15 (1H, td, CH-arom.), 7.34 (1H, d, CH—arorn.), 7.52-7.41 (1H, m, CH— arom.), 7.98 (1H, s, (SH-atom), 8.56 (1H, br, m.), 9.04 (1H, s, CH—arom.) Example 105, anti—con?guration (11%) Result of LC/MS [M+H]+: 494.0; 1H NMR (CDC13): 5 1.56 (3H, s, CH3), 2.74-2.60 (2H, m, CH2), 2.91-2.80 (2H, m, CH2), 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, (EH—mom), 8.56 (1H, d, CH—arorn.), 9.04 (1H, s, CH-arom.).
Example 106: 3 ~ {4—[3 ~(2—chloropheny1)~4—(pyrimidiny1)-1,2-oxazol—5-y1]-5 -(tri?uoromethyl)-1H- pyrazol-l -y1} — l -methylcyclobutan— 1 -ol (syn—con?guration) Step 1: 1-(1-{3-[(tert—butyldimethy]silyl)oxy]'3-methylcyclobutyl}(tri?uoromethyl)—1H— pyrazoly1)(pyrimidinyl)ethan-l -one on?guration) (0.18 mmol) and 2-chloro-N- ybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 4-[3-(2- chlorophenyl)-5 - { 1 - [3 — [(tert—butyldimethylsily1)oxy] —3 —methylcyclobutyl ]~5- (tri?uoromethyD-lH—pyrazoly1}-1,2-oxazoly1]pyrimidine (syn-con?guration) (48%); Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (20%).
Result of LC/MS : 476.2; 1H NMR (CDCl3)I 5 1.50 (3H, s, CH3), .72 (4H, m, 2xCH2), 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-y1)-1,2-oxazol-5 -y1] -5 -methy1—1H—pyrazol—1 -yl} - l - methylcyclobutan- 1 ~01 (syn—con?guration) Step 1: 1 -(1-{3 - [(tert-butyldimethylsilyl)oxy]-3 -m.ethylcyclobuty1} -5 -methy1-1H-pyrazol-4— yl)(pyrimidiny1)ethan—1-one (syn-con?guration) (0.13 mmol) and 2-chloro-N- ybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 4-[3-(2- chlorophenyl) -5 — {5 —methyl- 1 — [3 - [(tert—butyldimethylsi1y1)oxy] rnethylcyclobutyl] -1 H— pyrazoly1}- 1 ,2-oxazolyl]pyrimidine on?guration) (60%); Step 2, general ddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (25%).
Result ofLC/MS [M+H]+: 422,3; 1H NMR (CDClg): 5 1.47 (3H, s, CH3), 2.49 (3H, s, CH3), 2.80-2.65 (4H, m, CH2), 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 loro?uorophenyl)~4—(pyrimidinyl)-1,2-oxazolyl]—5—methyl—lH—pyrazol- l —y1}- 1 —methylcyclobutan-l -01 (syn—con?guration) Step 1: 1—(1—{3—[(tert—butyldimethylsilyl)oxy]methylcyclobutyl}methyl-1H-pyrazol—4- yl)(pyrimidinyl)ethan—1-one (syn-con?guration) (0.12 mmol) and 2-chloro-6—?uoro-N— hydroxybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 3:1) to give 4-[3-(2-ehloro ?uorophenyl) {5-methy1— l -[3 - [(tert-butyldimethylsilyl)oxy] —3 -methylcyclobutyl]-1H- pyrazol-4—yl}-1,2-oxazolyl]pyrimidine (syn—con?guration) (72%); Step 2, general ddition procedure: Mixture after step Zwas puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (13%).
Result ofLC/MS [M+H]+: 440,3; 1H NMR (CDC13)Z 8 1.47 (3H, s, CH3), 2.49 (3H, s, CH3), 2.81—2.66 (4H, m, CH2), 3.46 (1H, br, OH), 4.52 (1H, quint, CH), 7.05 (1H, dd, CH-arom.), 7.11 (1H, td, m.), 7.30 (1H, dt, CH-arom.), 7.47—7.37 (1H, m, CH), 7.93 (1H, s, Gil—atom), 8.57 (1H, d, (SH—atom), 9.12 (1 H, d, CH-arom.).
Example 109: 3- {4—[3—(2-chlorophenyl)(pyrazin-2—yl)-l ,2—oxazol-5—y1]methyl- 1 H—pyrazol-l -y1} -1 — methylcyclobutanol (syn-con?guration) Step 1: l—(l - {3 - [(tert—butyldimethylsilyl)oxy]-3 -rnethylcyclobutyl}~5 -methy1- 1H-pyrazol—4- y1)(pyrazin—2-y1)ethan—l—one (syn-configuration) (0.47 mmol) and 2-ch10ro-N— hydroxybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was puri?ed by 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 —methy1cyclobutyl] - l H- pyrazoly1}-l,2—oxazolyl]pyrazine (syn-con?guration) (25%); Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ethyl acetate 1:5) to give the title nd (32%).
Result of LC/MS : 422,3; 1H NMR (CDCI3)Z 6 1.46 (3H, s, CH3), 2.49 (3H, s, CH3), 2.81-2.61 (4H, m, CH2), 3.51 (1H, br, OH), 4.50 (ll-I, quint, CH), 7.45—7.33 (3H, m, 3xCH-arom.), .51 (1H, m, CH-arom.), 7.81 (1H, d, m.), 8.28 (1H, s, CH-arom.), 8.43 (1H, d, CH-arorn.), 8.55 (1H, t, CH- arom.) Example 110: 3 - {4- [3 -(2-chlorofluorophenyl)(pyrazin—2-yl)- '1 ,2-oxazolyl]—5-methyl— 1 H-pyrazol-l - y1}-1 —methyleyclobutan— 1 -ol (syn—con?guration) Step 1: 1-(1 - {3-[(tert-butyldimethylsilyl)oxy]methylcyclobutyl}-5—methy1-1H-pyrazol yl)(pyrazin-2—yl)ethan-l—one (syn-con?guration) (0.15 mmol) and 2-chloro—6—?uoro-N— hydroxybenzimidoyl chloride; the reaction was conducted at 50°C; the residue was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2—[3-(2—chloro-6— ?uoropheny1) {5~methy1- l -[3 - [(rert-butyldimethyisilyl)oxy] -3 —methylcyclobuty1] - 1 H- pyrazolyl}-1,2-oxazol~4-yl]pyrazine (syn—con?guration) (19%); Step 2, general cycloaddition procedure: e after step Zwas d by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (13%).
Result of LC/MS [M+H]+: 440,3; 1H NMR (CDC13)Z 8 1.46 (3H, s, CH3), 2.51 (3H, s, CH3), 2.82—2.68 (4H, m, (31-12), 4.52 (1H, quint, CH), 7.10 (1H, td, (EH-atom), 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.).
(U"I!" Cl N‘0 l/ / IN FN’ a" Example 111: 3-{4-[3—(2—ehloro?uorophenyl)(pyrimidinyl)-1,2-oxazolyl]-5—methyl—1H-pyrazol— 1-y1}methylcyclobutan-1 -01 (syn-con?guration) Step 1: 1-(1-(3-((tert—butyldimethylsily1)oxy)methylcyclobutyl)~5—methyl-1H—pyrazol yl)—2-(pyrimidinyl)ethan—l-one (syn—con?guration) (0.15 mmol) and 2-chloro-6—?uoro-N— hydroxybenzimidoyl chloride; the on was conducted at 50°C; the residue was puri?ed by prep. TLC on silica gel t: petroleum ether/ethyl acetate 3:1) to give 2-[3-(2-chloro-6— ?uorophenyl)—5 - {5-methyl [3 - [(tert—butyldimethylsilyl)oxy] -3 lcyclobutyl] - l H- pyrazoly1}-1,2-oxazol—4—yl]pyrimidine (syn-con?guration) (36%); Result of LC/MS [M+H]*: 554.2; Step 2, l ddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (21%).
Result of LC/MS [M+H]+: 440,3; 1H NMR (CDCl3): 5 1.47 (3H, s, CH3), 2.62 (3H, s, CH3), 3.01—2.70 (4H, m, CH2), 4.58 (1H, quint, CH), 7.16-7.04 (2H, m, 2XCH—ar0m.), 7.32-7.20 (1H, m, CH-arorn.), 7.43—7.32 (1H, m, CH-arom.), 8.47 (1H, br, CH-arom.), 8.59 (2H, d, rom.).
CI N’0 O l/ 'i‘l / ’N N" '3 Example 112: 3 — {4— [3 -(2-chloromethoxyphenyl)—4-(pyrimidin—2—yl)—l ,2—oxazol-5 -yl]methyl-1H— pyrazol- l -yl} methylcyclobutanol (syn-con?guration) Alternative Step 1 as described for Example 99 (reaction with N3H): 1-(1—(3—((tert- butyldimethylsilyl)oxy)—3—methylcyclobutyl)—5-methy1— 1H-pyrazol-4—yl)(pyrimidin—2— yl)ethan-l-one onfiguration) (0.25 mmol) and 2-chloromethoxy-N- hydroxybenzimidoyl chloride; 2- [3 -(2~chloro-3—methoxyphenyl)—5- {5—methyl [3 — [(tert— butyldimethylsilyl)oxy] -3 -methylcyclobutyl]-1H-pyrazolyl} - l ,2-oxazolyl]pyrimidine (syn-con?guration) (36%) was used in next step as crude material without puri?cation by chromatography on silica gel; Result ofLC/MS [M+H]+: 566.5.
Alternative Step 2 as bed for Example 103 (0—desilylation using TBAF): The residue was puri?ed by column tography on silica gel (eluent: CH2C12/M60H/NH3 100: 10:1 and again with eluent: petroleum ethyl acetate 4:1) to give the title compound (1 7%).
Result of LC/MS [M+H]+: 452.4; 1H NMR (CDC13): 5 1.45 (3H, s, CH3), 2.52 (3H, s, CH3), 2.72 (4H, d, 2xCH2), 3.89 (3H, s, OCHg), 4.50 (1H, quint, CH), 7.03 (1H, dd, CH-arom.), 7.08 (1H, t, CH-arom.), 7.22 (1H, dd, (EH—atom), 7.34 (1H, t, CH-arom.), 8.11 (1H, s, CPI—atom), 8.59 (2H, d, CH-arom.).
Example 113: (2R) {4—[3 -(2-methoxyphenyl)(pyrimidin-2—yl)—1,2—oxazol—5—yl]—5-(tri?uoromethyl)-1H— pyrazol—l opan-2—ol ative Step 1 as described for Example 99 (reaction with NaH): (R)—1—(l-(2—((tert— butyldimethylsilyl)oxy)propyl)—5-(tri?uoromethyl)- l H-pyrazol~4-yl)—2-(pyrimidinyl)ethan- 1-one (1.0 mmol) and 2-methoxy—N—hydroxybenzimidoyl chloride; the residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 3:1) to give 2-(5-{1—[(2R) [(terz—butyldimethylsilyl)oxy]propyl]—5—(tri?uoromethyl)—1H—pyrazol—4-y1}(2- methoxyphenyl)-l ,2-oxazol—4-yl)pyrimidine (34%); Step 2, general cycloaddition procedure: Mixture after step 2was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (86%).
Result ofLC/MS [M+H]+: 445,9; 1H NMR (CDCIg): 6 1.30 (3H, (:1, CH3), 3.29 (3H, s, OCH3), 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)(pyrimidin—2-yl)— l ,2-oxazol—5—yl] —5—(tri?uoromethyl)— lH- pyrazol— 1 ~y1} methy1propan-2—ol To a stirred solution of Example 113 (0.25 mmol) in CH2C12 (1.5 mL) was added Dess— Martin periodinane (3.5 eq.). The reaction e was stirred at room temperature for 18 h.
The reaction mixture was quenched by adding aq. Na28203, and extracted with CHZCIZ.
Combined organic layers were washed with saturated. aq. NaHC03 and brine, dried over anhydrous N32804, and concentrated under reduced pressure. The residue was puri?ed by column chromatography on silica gel t: petroleum ether/ethyl acetate 3:1) to give 1- {4- [3 -(2-methoxyphenyl)(pyrimidin-2—yl)- l ,2-oxazol—5—yl] —5-(tri?uoromethyl)— l H—pyrazol pan~2~one as a colorless solid (61%).
Result of LC/MS [M+H]+: 443.8; 1H NMR (CDClg): 8 2.18 (3H, s, CH3), 3.29 (3H, s, OCH3), 5.11 (2H, s, CH2), 6.81 (1H, d, CH—arom.), 7.14—7.09 (2H, m, 2xCH-arom.), 7.48—7.39 (l H, m, m.), 7.69 (1H, dd, CH- arom.), 8.12 (1H, s, CH—arom.), 8.61 (2H, d, r0m.).
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 N2. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched by adding saturated aq. NH4C1 and extracted with CHzClz. Combined organic layers were washed with brine, dried over ous Na2804, and concentrated under reduced pressure.The residue was puri?ed by column tography on silica gel (eluent: petroleum ether/ethyl acetate 5:1) to give the title compound as a colorless solid (10%).
Result of LC/MS [M+H]+: 459.8; 1H NMR )Z 6 1.23 (6H, d, , 3.30 (3H, s, OCHg), 4.26 (2H, s, CH2), 6.82 (1H, d, CH—arom.), 7.15-7.05 (2H, m, rom.), 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: (2R)-1 — {4-[3 -(2-methoxypheny1)—4-(pyrimidin-4—yl)-1,2-oxazolyl]-5 -(t1i?uoromethyl)- 1 H- l- 1 opanol ative Step 1 as described for Example 99 (reaction with NaH): (R)(1-(2-((tert— butyldimethylsily1)oxy)propy1)~5—(tri?uoromethy1)— l H-pyrazol-4—yl)—2-(pyrimidin-4—yl)ethan— 1-one (1.6 mmol) and 2-methoxy—N—hydroxybenzimidoyl chloride; the residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 3:1) to give 4*(5- {1—[(2R)—2— [(tert-butyldimethylsily])oxy]propyl] i?uoromethy1)- 1 H~pyrazolyl} -3 -(2- methoxypheny1)-1,2-oxazol-4—yl)pyrimidine (55%); Step 2, general cycloaddition procedure: Mixture after step 2was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (88%).
Result of LC/MS [M+H]+: 446.0; 1H NMR (CDC13)I 8 1.30 (3H, (1, CH3), 3.38 (3H, s, OCH3), 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, CPI—atom), 7.50 (1H, td, CH—arom.), 7.62 (1H, dd, CH-ar0m.), 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—(pyrimidinyl)- 1 ,2-oxazoly1] (tri?uoromethyl)~ 1H- pyrazol-l -y1} methy1propanol 2-Propanol derivative Example 115 (0.25 mmol) was converted into the corresponding propanone and then into the corresponding ylpropanol according to the procedures described for Example 114. Oxidation to 1— {4-[3—(2-methoxyphenyl)(pyrirnidin-4—yl)—1 ,2- oxazol-S-yl](tri?uoromethyl)-lH-pyrazolyl}propan-2—one was achieved with 83% yield; Result of LC/MS [M+H]+: 443.8; 1H NMR(CDC13): 6 1.26 (6H, s, 2*CH3), 2.24 (3H, s, CH3), 2.95 (1H, s, OH), 3.42 (3H, s, CH3), 5.17 (2H, s, CH2), 6.92 (1H, d, CH-arom.), 7.08 (1H, d, (EH—atom), 7.15 (1H, t, CH- , 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 nd in 10%yield.
Result of LC/MS [M+H]+: 459.9; lH NMR(CDC13): 5 1.24 (6H, s, , 3.42 (3H, s, OCHg), 4.28 (2H, s, CH2), 6.92 (1H, d, CI-I-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 (ll-l, s, m.).
Example 117: (2R)—1-{4-[3 -(2-chloro-3 -methoxyphenyl)(pyrimidinyl)—1,2-0xazol—5-yl] (tri?uoromethyl)- 1H—pyrazol-l —yl}propau-2—ol Alternative Step 1 as described for Example 99 (reaction with NaH): (R)-1~(1-(2-((tert- butyldimethylsilyl)0xy)propyl)—5-(tri?uoromethyl)— 1 H-pyrazolyl)—2—(pyrimidin-Z-yl)ethan— 1—one (3.0 mmol) and 2—chlor0—3-methoxy-N-hydroxybenzimidoyl chloride; the residue was puri?ed by prep. TLC on silica gel (eluent: eum ether/ethyl acetate 3:1) to give 2-(5-{1— [(2R)—2—[(tert-butyldimethylsilyl)oxy]propyl] -5~(tri?u0romethyl)— 1 H-pyrazol—4-yl} -3 - oro—3 —methoxyphenyl)— 1 ,2—oxazolyl)pyrimidine (83%); Step 2, general cycloaddition procedure: Mixture after step 2 was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (77%).
Result ofLC/MS : 479.8; 1H NMR (CD013): 5 1.30 (3H, d, CH3), 3.85 (3H, s, OCH3), 4.21 (1H, dd, CH), 4.44-4.27 (2H, m, CH2), 6.97—6.89 (2H, m, 2xCH—ar0m.), 7.09 (1H, t, m.), 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-ch10r0—6—?uoropheny1)-4—(pyrimidin—2-y1)-1 ,2—oxazolyl] -5 uoromethy1)— 1 H—pyrazoly1}methy1propanol 2-Propanol derivative Example 97 (1.6 mmol) was converted into the corresponding propanone and then into the corresponding 2—methy1propanol according to the procedures described for Example 114. Oxidation to 1-(4-(3-(2-chloro?uoropheny1)(pyrimidin—2— y1)isoxazoly1)(tri?uoromethyl)-1H-pyrazol—l—y1)propanone was achieved with 67% yield; Result of LC/MS [M+H]+: 465.7; 1H NMR (CDC13): 5 2.20 (3H, s, CH3), 5.14 (2H, s, CH2), 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, CPI-atom), 8.49 (2H, d, 2xCH-arom.).
Grignard treatment provided the title compound in 50% yield.
Result ofLC/MS [M+H]+: 481.8; 1H NMR (CDC13): 8 1.25 (6H, s, 2XCH3), 4.30 (2H, s, CH2), 7.09-7.00 (1H, m, CH-arom.), 7.15-7.09 (1H, m, m.), .24 (1H, m, CH-arorn.), .34 (1H, m, CH—arom.), 8.04 (1H, br, CH-arom.), 8.48—8.42 (2H, m, 2xCH-arom.).
Example 1 19: (2R)- 1 — {4— [3 -(2—chloro—3 ~methoxypheny1)-4—(pyrimidin—4—y1)—1,2-oxazolyl]—5- (tri?uoromethyl)- 1 H-pyrazol- 1 opanol Step 1: (R)— 1 -(1 -(2-((Ierr—butyldimethylsi1y1)oxy)propy1)(t1i?uoromethyl)—1 H—pyrazol-4— y1)(py1imidin—4—y1)ethan—1-one (2.0 mmol) and 2-chloro—3—methoxy—N— hydroxybenzimidoyl chloride; THF was used instead ofDMF; the reaction was conducted at 50°C; crude 4-(5 — { 1 - [(2R)—2—[(tert—butyldimethylsi1y1)oxy]propyl]—5 —(tri?uoromethy1)-1H— pyrazolyl}(2-chloromethoxyphenyl)-l,2-oxazol—4-yl)pyrimidine (quant) was directly used for 0—desilylation; Step 2, general cycloaddition procedure: Mixture after step 2was d by prep. TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:5) to give the title compound (83%).
Result of LC/MS [M+H]+: 479.8; 1H NMR (CDCl3)C 5 1.32 (3H, d, CH3), 3.88 (3H, s, OCH3), 4.23 (1H, dd, CH), 4.49-4.29 (2H, m, CH2), 6.86 (1H, d, CH—arom.), .93 (2H, m, CH-arorn.), 7.49 (1H, d, CH—arom.), 8.00 (1H, s, CH—arom.), 8.52 (lH, br, CH-arom.), 9.06 (1H, s, CH—arom.).
C! N’0 ,0 ’/ / l"¥ "N HO N Example 120: l - {4-[3-(2—chloro—3-methoxyphenyl)-4—(pyrimidin—4-yl)-l ,2-oxazolyl](tri?uoromethyl)— lH—pyrazol- 1 —yl} -2—methylpropanol 2-Propanol tive Example 119 (0.25 mmol) was converted into the ponding propanone and then into the corresponding 2-1nethylpropanol according to the procedures bed for Example 114. Oxidation to 1- {4—[3-(2-chloro—3—methoxyphenyl)(pyrimidin- l,2-oxazol-S—yl](tri?uoromethyl)-lH-pyrazol-l-yl}pr0pan—2-one was achieved with 76% yield, Gn'gnard treatment provided the title compound in 16%yield.
Result of LC/MS [M+H]+: 494.2; 1H NMR(CDC13): 5 1.25 (6H, s, 2XCH3), 3.88 (3H, s, OCH3), 4.29 (2H, s, CH2), 6.85 (1H, d, CH—arom.), 7.03—6.95 (2H, m, 2xCH—amm.), 7.49 (ll-I, d, CH—arorn.), 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—(pyrimidinyl)-l ,2—oxazolyl] —5-(tri?uoromethyl)— lH—pyrazolyl} methylbutanol ative Step 1 as described for Example 99 (reaction with NaH): 1-(1-{3—methy1—3- [(trimethylsilyl)oxy]butyl}—5—(tri?uoromethyl)—1 H-pyrazol-4—yl)(py1imidin—2-yl)ethan—1 - one (0.6 mmol) and 2-chloromethoxy-N-hydroxybenzimidoyl chloride; reaction time: 20 h, reaction ions led to simultaneous O-desilylation; the residue was puri?ed by prep. TLC on silica gel (eluent: petroleum ether/ethyl e 3:1) to give the title compound as yellow oil (1 1%).
Result of LC/MS [M+H]+: 508.3; 1H NMR (CDCIg): 8 1.31 (6H, s, 2xCl-l3), 2.19-2.10 (2H, m, CH2), 3.91 (3H, s, OCH3), 4.56— 4.44 (2H, m, CH2), .02 (2H, m, 2xCH-arom.), 7.37 (1H, t, CPI-atom), 8.02 (1H, s, CH- , 8.52 (2H, d, 2xCH—arom.).
Example 122: 4- {4- [3 -(2—chlorophenyl)(pyrimidinyl)-1,2-oxazolyl]-5—(tri?uorornethyl)- 1H- pyrazol-l -yl } -2—methylbutanol Alternative Step 1 as described for Example 99 (reaction with NaH): 1-(1- {3—methyl-3— [(trimethylsilyl)oxy]butyl}—5—(triiluoromethyl)-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 puri?ed by prep. TLC on silica gel (eluent: CHzClg/MeOH 95:5 and again with eluent: eum ether/ethyl acetate 1:1) to give the title compound as pale yellow oil (9%).
Result of LC/MS {M+H]+: 478.4; 1H NMR (CDCl3)I 5 1.32 (6H, s, 2xCH3), 2.18—2.09 (2H, m, CH2), 4.55-4.46 (2H, m, CH2), 7.07 (1H, t, CH-arom.), 7.43-7.36 (3H, m, -arom.), 7.66-7.59 (1H, m, (SH-atom), 8.01 (1H, s, CH-arom.), 8.52 (2H, d, 2xCH—ar0m.). e 123: 4- {4- [3 -(2-chloro?uoropheny1)(pyrimidiny1)-1 ,2-oxazolyl]-5—(tri?uoromethyl)- 1H—pyrazol—1-yl}—2—methylbutan-2—ol Alternative Step 1 as described for Example 99 ion with NaH): 1—(1—{3-methyl [(trimethylsilyl)oxy]butyl}(tri?u0romethyl)~ 1 H—pyrazol—4—yl)—2—(pyrimidin—2—yl)ethan- 1 — one (0.4] mmol) and 2-chloro?uoro-N-hydroxybenzimidoyl de; reaction time: 18 h, reaction conditions led to simultaneous 0~desilylation; the e was puri?ed by prep. TLC on silica gel (eluent: CH2C12/MeOH 95:5 and again with eluent: CH2C12/MeOH 95:5) to give the title compound as colorless oil (27%).
Result of LC/MS [M+H]+: 496.0; 1H NMR (CDC13)Z 5 1.33 (6H, s, 2XCH3), 2.21-2.11 (2H, m, CH2), 4.57-4.47 (2H, m, CH2), 7.04 (1H, t, CH—arom.), 7.10 (1H, td, CH—arom.), 7.30—7.26 (1H, m, CH-arom.), .33 (1H, m, CH-arom.), 8.00 (1H, s, CH-arom.), 8.48 (2H, d, 2XCH-arorn.).
C! N’0 l / N ,0 / ,h', Example 124: 4— {4-[3—(2—chloro—3—methoxyphenyl)—4-(pyrimidinyl)-l,2—oxazol—S-yl]—5-methyl-1H- pyrazol-l -yl}methylbutan—2-ol Alternative Step 1 as described for Example 99 (reaction with NaH): 1-(5—methyl—1-{3— methyl-B—[(trimethylsilyl)oxy]butyl} - l H—pyrazolyl)(pyrimidin-2—y1)ethan—1 -one (0. l 6 mmol) and 2-chloro—3-methoxy—N—hydroxyhenzimidoyl chloride; reaction time: 3 h, reaction conditions led to simultaneous 0-desi1ylation; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: /MeOH 95:5) to give the title compound as a yellowish solid (24%).
Result of LC/MS [M+H]+: 454.0; 1H NMR(CDC13): 5 1.28 (6H, s, 2xCH3), 2.07—1.98 (2H, m, CH2), 2.56 (3H, s, CH3), 3.89 (3H, s, OCHg), 4.34—4.22 (2H, m, CH2), 7.03 (1H, dd, CH—arom.), 7.08 (1H, t, CH—arorn.), 7.22 (1H, dd, m.), 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-dichloromethoxyphenyl)(pyrirnidiny1) - 1 ,2~0xazol—5-y1] methyl-1H— pyrazol-l -yl } -2—methylbutanol Alternative Step 1 as described for e 99 (reaction with N311): l-(5-methyl-l-{3- methyl—3-[(trimethylsilyl)oxy]butyl}-1H-pyrazol—4-y1)~2—(pyrimidiny1)ethan—l —one (0.04 mmol) and 2,6-dichloromethoxy—N—hydroxybenzirnidoyl chloride; reaction time: 3 h, on conditions led to simultaneous 0—desilylation; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CH2Clg/MeOH 95:5) to give the title compound as a h oil (15%).
Result of LC/Ms [M+H]+: 488.0; 1H NMR (CDCI3)I 5 1.30 (6H, s, 2xCl-l3), 2.08-2.00 (2H, m, CH2), 2.62 (3H, s, CH3), 3.93 (3H, s, OCH3), 4.37-4.24 (2H, m, CH2), 6.96 (1H, d, CH—arom.), 7.04 (1H, t, CH—arom.), 7.33 (ll-l, d, CH—arom.), 8.25 (1H, s, CH—arom.), 8.55 (2H, d, 2xCH-arom.).
CI N—0 w" l / ll"?! Example 126: 4-{4-[3—(2-chloropheny1)-4—(pyrimidin—2—y1)—l,2—oxazol—5—y1]methyl-lH-pyrazol-l-yl}-2~ methylbutan-Z—ol Alternative Step 1 as described for Example 99 (reaction with NaH): 1-(5-rnethyl-l — {3- -3—[(trimethylsilyl)oxy]buty1 } -1 H-pyrazol-4uyl)(pyrimidiny1)ethanone (0. 1 mmol) and 2-chloro-N-hydroxybenzimidoyl chloride; reaction time: 1.5 h, reaction conditions led to aneous O-desilylation; the residue was puri?ed by prep. TLC on silica gel (eluent: CHgClg/MeOH 95:5 and again eluent: CHZCIQ/MSOH 95:5) to give the title compound (12%).
Result of LC/MS [M+H]+: 424.0; 1H NMR (CDC13): 5 1.30 (6H, s, 2xCH3), 2.08-2.00 (2H, m, CH2), 2.58 (3H, s, CH3), 4.33— 4.26 (2H, m, CH2), 7.10 (1H, t, ZXCH-arom.), 7.42-7.31 (3H, m, rom.), 7.65-7.56 (1H, m, CPI—atom), 8.11 (1H, s, CH-arom.), 8.60 (2H, d, 2xCH-arom.) Example 127: 4- {4— [3 -(2—chloro-6—?uorophenyl)(pyrimidinyl)-1,2-oxazol~5-yl]methyl-lH-pyrazol- l -yl} hylbutan—2—ol Alternative Step 1 as described for Example 99 (reaction with NaH): 1-(5-methyl—1—{3— methyl[(trimethylsilyl)oxy]butyl } -1H-pyrazolyl)-2—(pyrimidin—2—yl)ethan— 1 -one (0. 1 mmol) and 2-chloro?uoro-N-hydroxybenzimidoyl chloride; reaction time: 1.5 h, reaction conditions led to simultaneous 0—desily1ation; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CHZCIZ/MeOH 95:5) to give the title compound as an orange oil (30%).
Result of LC/MS [M+H]+: 442.0; 1H NMR (CDC13)I 6 1.30 (6H, s, 2xCH3), 2.04 (2H, t, CH2), 2.60 (3H, s, CH3), 4.30 (2H, t, CH2), .02 (2H, m, 2xCH—axom.), 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](pyrimidinyl)-1,2-oxazolyl} uoromethyl)—1H-pyrazol— l ~yl)methylbutan—2—ol Alternative Step 1 as described for Example 99 (reaction with NaH): 1-(1-{3-methyl—3— [(trimethylsilyl)oxy]buty1} —5—(tri?uoromethyl)—1 H—pyrazol—4—y1)(py1imidin—2—yl)ethan— l - one (2.5 mmol) and 3—(benzyloxy)—2-chloro-N-hydroxybenzimidoy1 chloride; reaction time: 3 h, on conditions led to simultaneous 0-desilylation; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CH2C12/MeOH 95:5) to give the title compound as an orange oil (12%).
Result of LC/MS [M+H]+: 584.1; 1H NMR )Z 8 1.25 (6H, s, ZXCHg), 2.15—2.02 (2H, m, CH2), 4.51—4.38 (2H, m, CH2), .11 (2H, s, OCHZ), 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.). e 129: 2-chloro-3 - {5-[1—(3-hydroxy—3 -rnethylbutyl)—5—(tri?uoromethyl)-1H-pyrazol—4—y1]—4— (pyrimidin—Z—yl)— 1 ,2—oxazol-3 -y1}phen01 Benzyloxy derivative Example 128 (0.9 mmol) was dissolved in isopropanol/ethyl acetate (1 :1; 6 m1) and I’d/C (10%; 0.3 eq.) was added. The atmosphere within the ?ask was replaced with hydrogen and the mixture was d at room ature for 18 h. Pd/C was d off over celite, the ?ltrate was concentrated to dryness under reduced pressure and then in vacuo to give the title compound as pale brownish solid (83%).
Result of LC/MS : 494.0; 1H NMR (CDC13)2 5 1.66 (6H, s, 2xCI-I3), 2.54-2.44 (2H, m, CH2), 4.90-4.81 (2H, m, CH2), 7.41 (1H, t, (EH—arena), 7.55-7.45 (2H, m, ZXCH—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{5-[1-(3-hydroxy-3—methylbutyl)-5—methyl-1H—pyrazol—4—yl]-4—(pyrimidin—2- yl)-1,2—0xazol—3-yl}phenol Alternative Step 1 as described for e 99 (reaction with NaH): 1-(5—methy1—1-{3- methyl[(trimethylsilyl)oxy]butyl}—1H—pyrazol—4-yl)—2—(py?midin—2-yl)ethan—1 -one (0.75 mmol) and 3-(benzyloxy)chloro-N-hydroxybenzimidoyl chloride; reaction time: 1.5 h, reaction conditions led to simultaneous 0-desilylation; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CH2Cl2/MeOH 95:5) to give 4-(4-{3—[3— (benzyloxy)—2—chlorophenyl]-4—(pyrimidin-2—yl)—1,2-0xazoly1}methyl-1H—pyrazol- 1 —yl)- ylbutanol in 22% yield; Result ofLC/MS : 530.1; 1H NMR (CDC13)I 5 1.46 (6H, 5, 2x CH3), 2.21 (2H, m, CH2), 2.74 (3H, s, CH3), 4.46 (2H, m, CH2), 5.33 (2H, s, CH2), 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.) oxy tive was 0—debenzylated following the protocol described for Example 129, providing the title compound as pale yellowish solid (crude 96%).
Result of LC/MS [M+H]+: 440.0; 1H NMR (CDC13)I 6 1.29 (6H, s, 2x CH3), 2.35 (2H, m, CH2), 2.58 (3H, s, CH3), 4.28 (2H, m, CH2), 5.33 (2H, s, CH2), 7.06—7.17 (4H, m, (EH-atom), 8.09 (1H, s, m.), 8.62 (2H, d, CH-arom.). methyl (S)—3-(2—chlorohydroxyphenyl)—5-(1-(2- hydroxypropyl)(trit1uoromethyl)-1H—pyrazolyl)isoxazolecarboxylateAlternative Step 1 as described for Example 99 (reaction with NaH): methyl 3- {1~[(ZS)-2—[(tert— butyldimethylsilyl)oxy]propyl]_(tri?uoromethy1)-1H-pyrazol-4—y1}oxopropanoate (1 .5 mmol) and 3—(henzyloxy)—2—chloro—N—hydroxybenzimidoy1 chloride; reaction time: 1.5 h; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CH2Cl2/MeOH 95:5) to give methyl 3—[3-(benzyloxy)—2—chlorophenyl]{l-[(2S)—2-[(tert— butyldimethylsilyl)oxy]propyl]methy1— l H—pyrazol—4—y1} —1 ,2—oxazole—4—carboxylate in 27% yield. oxy derivative was O-debenzylated following the protocol described for Example 129, providing the title compound as pale yellowish solid (crude 96%).
The title compound was synthesized by ?nal O-desilylation according to the alternative step 2 described above in Example 103 (using TBAF) (15%): The residue was puri?ed by prep.
TLC on silica gel (eluent: CHZClz/MeOH 95:5).
Cl N'O I / ND, /O / , Example 130: 3-(4-(3 ~(2—chloromethoxyphenyl)—4—(cyclopropoxymethy1)isoxazol-S-yl) (tri?uoromethyl)—1H-pyrazol-l -y1)methylcyclobutan—1 -ol (syn-con?guration) Step 1: ethyl 3 ~(l ~ {3 —[(tert—butyldimethylsily1)oxy] -3 -methylcyclobutyl} (tri?uoromethy1)- 1H-pyrazol-4—yl)—3—oxopropanoate (syn—con?guration) (0.25 mmol) and 2-chloro—3-methoxy— N-hydroxybenzimidoyl chloride; the reaction was conducted at 65°C; the residue was puri?ed by ?ash column tography on silica gel (eluent: petroleum ether/ethyl acetate 9:1) to give ethyl 3—(2—chloro-3 —methoxyphenyl)—5-{1—[3—[(tert—butyldimethylsilyl)oxy]—3- methylcyclobutyl](tri?uoromethyl)— l H-pyrazolyl} -1 zolecarboxylate (syn— con?guration) (72%); Result of LC/MS [M+H]+: 614.2; 1H NMR (CDC13): 6 0.13 (6H, s, 2xCH3), 0.91 (9H, s, , 0.99 (3H, 1:, CH3), 1.26 (3H, s, CH3), 2.68-2.54 (2H, m, CH2), 3.03-2.91 (2H, m, CH2), 3.95 (3H, s, OCH3), 4.08 (2H, q, OCHz), 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: Conversion of the ethyl ester group into a cyclopropoxymethyl unit was achieved according to the general procedures for the sis of 4-a1koxymethyl isoxazoles described above: - LiA1H4 reduction of ethyl hloromethoxyphenyl){1-[3-[(tert- imethylsilyl)oxy]-3—methylcyclobutyl](tri?uoromethyl)— 1 H-pyrazol-4—y1 } — 1,2-oxazolecarboxylate (syn~con?guration) (0.18 mmol) to give [5—(1-{3-[(tert- butyldimethylsilyl)oxy] —3 —methylcyclobutyl} -5 -(tri?uoromethyl)— 1 H-pyrazol—4~yl)-3 - (2-chloromethoxyphenyl)—1,2-oxazolyl]methanol (syn—con?guration) as a pale yellow oil (quant).
Result of LC/MS [M+H]+: 572.1; 1H NMR (CDCl3)Z 6 0.13 (6H, 3, 2x CH3), 0.92 (9H, s, tBu), 1.48 (3H, s, CH3), 1.72 (1H, s, OH), 1.85 (2H, m, CH2), 3.88 (2H, s, CH2), 3.96 (3H, s, CH3), 4.42 (2H, s, CH2), 4.56 (1H, s, CH), 7.09 (2H, m, CH-arom.), 7.36 (1H, t, CH—arom.), 8.94 (1H, s, CH-arom.).
- Synthesis ofbromomethyl-isoxazole according to method A (B20, 20 min) to give 4- (bromomethyl)(l-{3-[(tert-butyldimethylsilyl)oxy]-3~methyleyclobutyl}~5- (tri?uoromethyl)—1H—pyrazol-4—yl)—3 —(2—chloro—3-methoxyphenyl)- l ,2-oxazole (syn~ con?guration) as yellow oil (quant) Result of LC/MS [M+H]+: 634.0; — sis of 4-cyclopropoxymethyl—isoxazole ng to method C (using cyclopropanol) to give 5-(1-{3-[(tert?butyldimethylsilyl)oxy]~3-methylcyclobutyl} (tri?uoromethyl)- 1H-pyrazol—4-yl)(2-chloromethoxypheny1) (cyclopropoxymethyl)—1,2-oxazole (syn-con?guration) as a pale yellow oil (35%).
Result of LC/MS [M+H]+: 612.2; 1H NMR (CDCl3)Z 8 0.l3 (6H, s, 2xCH3), 0.35-0.24 (4H, m, ZXCH2), 0.91 (9H, s, 3xCH3), 1.48 (3H, s, CH3), 2.68—2.56 (2H, m, CH2), 3.03—2.88 (2H, m, CH2), 3.16- 3.05 (1H, m, CH), 3.97 (3H, s, OCH3), 4.28 (2H, s, OCH2), 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 sized by ?nal 0-desilylation ing to the alternative step 2 described above in Example 103 (using TBAF): The residue was puri?ed by prep. TLC on silica gel (eluent: CH2Cl2/MeOH 95:5 and again with eluent: eum ethyl acetate 4: 1) to give the title compound as orange oil (12%).
Result of LC/MS [M+H]+: 498.0; 1H NMR(CDC13): 5 0.30 (4H, m, 2x CH2), 1.50 (3H, s, CH3), 2.80 (4H, m, 2x CH2), 3.11 (1H, m, CH), 3.97 (3H, s, CH3), 4.27 (2H, s, CH2), 4.72 (1H, quint, CH), 7.08 (2H, (1, CH- arom.), 7.34 (1H, t, CH-arom.), 7.89 (1H, s, CH-arom.).
Example 131: ethyl 3-(2-chloromethoxyphenyl)—5- {1-[3-hydroxy—3—methylcyclobutyl] (tri?uorometh.yl)- 1 H-pyrazolyl} — l zole—4-carboxylate (syn~con?guration) ediate after step 1, Example 130, ethyl 3-(2—chloro-3~rnethoxypheny1){l-[3-[(tert- butyldimethylsilyl)oxy] -3 —methyleyclobutyl] —5-(tri?uoromethyl)— l H—pyrazolyl} —1 ,2- oxazolecarboxylate (syn-con?guration), was lylated according to the alternative step 2 bed above in Example 103 (using TBAF): The e was puri?ed by prep. TLC on silica gel (eluent: CH2Cl2/MeOH 95:5) to give the title compound as orange oil (72%).
Result of LC/MS [M+H]+: 500.0; 1H NMR (CDCl3)I 5 0.99 (3H, t, CH3), 1.49 (3H, s, CH3), 2.81 (41-1, 110, 2x CH2), 2.95 (3H, s, CH3), 4.08 (2H, q, CH2), 4.72 (1H, rn, 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) (tri?uoromethyl)— l H-pyrazol—4—yl] - 1 ,2—oxazole—4-carboxylate Step 1: ethyl 3 -( l - {3 -methyl-3 -[(trimethylsilyl)oxy]butyl} (tri?uoron1ethy1)— 1 H-pyrazol y1)—3 —oxopropanoate (0.80 mmol) and 2-chloromethoxy-N—hydroxybenzimidoyl de; the reaction was conducted at 65°C; reaction conditions led to simultaneous O-desilylation; the residue was puri?ed by prep. TLC on silica gel (eluent: CH2Cl2/MeOH 95:5) to give the title compound as an orange oil (19%); Result of LC/MS [M+H]+: 502.0; 1H NMR (CDC13)I 5 1.00 (3H, t, CH3), 1.32 (6H, s,2x CH3), 2.14 (2H, m, CH2), 3.95 (3H, s, CH3), 4.08 (2H, q, CH2), 4.52 (2H, m, CH2), 7.09 (2H, m, CH—arorn.), 7.34 (1H, t, CH-arom.), 7.97 (1H, s, CH-arom.). c; N-FO !/ /N Building Block for the synthesis of Examples 150 and 151: 2-chloro-3 - [4-(methoxymethyl)—5- { l -[3- [(tert—butyldimethylsilyl)oxy] -3 -methylcyclobutyl] - ?uoromethyl)— l H—pyrazol-4—yl } -1 ,2-oxazol-3 -y1]phenol (syn-con?guration) Step 1: ethyl 3-(1-{3—[(tert—butyldimethylsilyl)oxy]methylcyclobutyl}(tri?uoromethyl)— 1H-pyrazol-4—y1)-3—oxopropanoate (syn-con?guration) (0.18 mmol) and 3-(benzyloxy)—2— chloro—N—hydroxybenzimidoyl chloride; the reaction was conducted at 65°C; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CH2Cl2/MeOH 100:1) to give ethyl 3 -[3 —(benzyloxy)chlorophenyl] { 1 -[3-[(tert—butyldimethylsilyl)oxy] -3 - methylcyclobutyl](tri?uoromethy1)-1H—pyrazol-4—yl} —1 ,2-oxazolecarboxylate (syn- con?guration) as a colorless oil (64%); Result ofLC/MS [M+H]+: 690.4; lH-NMR (CDCl3, J [Hz]): 5 = 7.97 (s, 1H pyrazole—H), 7.49-7.29 (m, 6H, -H), 7.11 (d, 2H, 31 = 7.9, benzyl-H), 5.22 (s, 2H, CH2), 4.62—4.51 (m, 1H, CH), 4.08 (q, 21-1, 3} = 7.1, OCH2CH3), 3.01—2.94 (m, 2H, CH2), .58 (m, 2H, CH2), 1.48 (s, 3H, CH3), 0.98 (t, 3H, 3J = 7.1, 3), 0.92 (s, 9H, 3), 0.13 (s, 6H, CH3).
Step 2: Conversion of the ethyl ester group into a methoxymethyl unit was achieved according to the general procedures for the synthesis of4-a1koxymethy1 oles described above: - LiAlH4 reduction of ethyl 3—[3—(benzyloxy)—2-chlorophenyl] {1 —[3-[(tert- butyldimethylsilyl)oxy] -3 -methylcyclohutyl] —5-(tri?uoromethyl)— 1 H—pyrazolyl } - azolecarboxylate (syn—con?guration) (0.12 mmol) to give {3-[3—(benzyloxy) 2—chlorophenyl] { 1 —[3 — [(tert-butyldimethylsilyl)oxy] -3 -methylcyclobuty1]-5— (tri?uoromethyl)—lH—pyrazolyl}-1,2—oxazolyl}methanol (syn—con?guration) as a colorless oil (83%).
Result of LC/MS : 648.4; - Synthesis of methoxymethyl-isoxazole according to method A (Mel) to give 3—[3- (benzyloxy)-2—chlorophenyl]—4-(methoxymethyl)-5— { 1 - [3-[(tertbutyldimethylsilyl )oxy] -3 -methylcyclobutyl] (tri?uoromethy1)- 1 H-pyrazol-4—yl} - 1,2—oxazole (syn-con?guration) as colorless oil (32%) Result of LC/MS [M+H]+: 662.5; 1H-NMR (CDC13, J [Hz]): 5 = 7.88 (s, 1H pyrazole-H), 7.50-7.32 (m, 6H, benzyl—H), 7.11 (d, 2H, 3] = 8.0, benzyl-H), 5.22 (s, 2H, CH2), 4.63-4.52 (m, 1H, CH), 4.21 (s, 2H, CH2), 3.15 (s, 3H, OCH3), 3.00—2.93 (in, 2H, CH2), 2.65-2.59 (m, 2H, CH2), 1.49 (s, 3H, CH3), 0.92 (s, 9H, C(CH3)3), 0.14 (s, 6H, CH3).
Step 3: the title nd was synthesized by ?nal nzylation according to following the protocol described for Example 129, providing the title compound as ess oil after puri?cation by ?ash column chromatography on silica gel (eluent: petroleum ether/ethyl e 7:3) (51%); Result of LC/MS [M+H]+: 572.1.
Building Block for the synthesis of Examples 152 and 153: 2-chloro-3—[4-(methoxymethyl)—5 - { l -[3 - [(tert—butyldirnethylsilyl)oxy] —3 -methylcyclobutyl] - 5-(trifluoromethyl)— l zol—4-yl} —1 ,2—oxazol-3 ~yl]phenol (anti-con?guration) Step 1: ethyl 3 -(l - {3 - [(tert—butyldimethylsilyl)oxy] -3 lcyclobutyl} i?uoromethyl)- 1H—pyrazolyl)ox0pr0panoate (anti-con?guration) (0.28 mmol) and 3-(benzyloxy)-2— chloro-N-hydroxybenzimidoyl chloride; the reaction was conducted at 60°C; the e was puri?ed by ?ash column chromatography on silica gel (eluent: CH2C12/MeOH 100:1) to give ethyl 3{3-(benzyloxy)chlorophenyl] -5 — {1 -[3—[(tert—butyldimethylsilyl)oxy]—3 - methylcyclobutyl]—5-(tri?uoromethyl)- 1 H-pyrazolyl}-1 ,2-oxazolev4—carboxylate (anti- con?guration) as a colorless oil (83%); Result of LC/MS [M+H]+: 690.4; 1H-NMR (CDCl3, J [Hz]): 6 = 7.96 (s, 1H pyrazole-H), 7.49-7.29 (m, 6H, benzyl-H), 7.11 (d, 2H, 3] = 8.2, benzyl—H), 5.22-5.17 (m, 3H, CH, CH2), 4.08 (q, 2H, 3.1 = 7.1, OCHZCH3), 2.81- 2.74 (m, 2H, CH2), 2.68—2.61 (m, 2H, CH2), 1.52 (s, 3H, C H3), 099 (t, 3H, 3J = 7.1, OCHZCH3), 0.93 (s, 9H, C(CH3)3), 0.14 (s, 6H, CH3).
Step 2: Conversion of the ethyl ester group into a methoxymethyl unit was achieved according to the general procedures for the synthesis of 4-alkoxymethyl isoxazoles described above: - LiAlH4 reduction of ethyl 3-[3-(benzyloxy)chlorophenyl] {l-[3-[(tert— butyldimethylsilyl)oxy]methylcyclobutyl]—5 -(tri?uoromethyl)— 1H-pyrazoly1} - 1,2—oxazolecarboxylate (syn-con?guration) (0.23 mmol) to give {3—[3—(benzyloxy)- 2—chlorophenyl] -5— {1 —[3 — [(tert—butyldimethylsilyl)oxy] -3—methylcyclobutyl] (tri?uoromethyl)-lH—pyrazol-4—y1}-1,2-oxazolyl}methanol (anti-con?guration) as a grayish oil (73%).
Result ofLC/MS [M+H]+: 648.4; — Synthesis of methoxymethyl—isoxazole according to method A (Mel) to give 3-[3- (benzyloxy)chlorophenyl]-4—(meth0xymethyl)-5 - { 1 —[3 -[(tert- butyldimethylsilyl)oxy] —3 -methylcyc10butyl] —5—(tri?uoromethyl)— lH—pyrazol-4—yl} - 1,2-oxazole (anti-con?guration) as colorless oil (37%) Result of LC/MS [M+H]+: 662.3; 1H NMR (CDC13)Z 8 0.14 (6H, s, ZXCH3), 0.93 (9H, s, 3xCH3), 1.51 (3H, s, CH3), 2.84-2.53 (4H, m, 2xCH2), 3.15 (3H, s, OCH3), 4.20 (2H, s, OCHQ), 5.22 (2H, s, OCHz), 7.18-7.07 (2H, d, 2xCH—arom.), 7.55-7.28 (6H, rom.), 7.87 (1H, s, CH—arom.).
Step 3: the title compound was sized by ?nal O-debenzylation following the protocol described for e 129, providing the title compound as colorless oil after puri?cation by prep. TLC on silica gel (eluent: petroleum ethyl e 7:3) (56%).
Result of LC/MS [M+H]+: 572.4.
Building Block for the synthesis of Examples 154 to 160: 3 -(5- { l -[(2R)—2—[(tert—butyldimethylsilyl)oxy]propyl](t1i?uoromethy1)-lH—pyrazolyl} - 4-(pyrimidin—4-yl)—1,2—oxazolyl)—2—chlorobenzoic acid Step 1 : 1 - { 1 -[(2R)—2-[(tert-butyldimethylsilyl)oxy]propyl](tri?uoromethyl)—1H-pyrazol (pyrimidin-4—yl)ethan-1 none (1.0 mmol) and methyl 2-chlor0—3- (chloro(hydroxyimino)methyl)benzoate; the reaction was conducted at 60°C; the residue was puri?ed by ?ash column tography on silica gel t: CH2C12/M30H 100:1) to give methyl 3 ~(5- {1 -[(2R)—2- [(tert-butyldimethylsilyl)oxy]propy1] —5 -(tri?uoromethyl)-1 H-pyrazol- 4-yl}-4—(pyrimidinyl)—1,2-oxazoly1)chlorobenzoate (43%); Step 2: ester group was saponi?ed in ethanol (8 mL/mmol) and aq. NaOH (2.0 M; 8 mL/mmol) and heating to 60°C for 1 h. and then acidi?ed by addition of aq. HCl (1.0 M). The resulting suspension was partitioned between CH2C12 and water, combined organic layers were dried over MgSO4, the solvent was removed under reduced pressure to give the crude carboxylic acid, which was used as such in further conversions.
Building Block for the synthesis of es 161 to 165: 3 -(5 — { 1 -[(2R)—2-[(tert—butyldimethylsilyl)oxy]propy1](tri?uoromethyl)—1H—pyrazol—4—y1}- 4-(pyrimidiny1)—1,2-oxazol—3-yl)methoxybenzoic acid Step 1: 1 -{1 —[(ZR)—2-[(tert—butyldimethylsilyl)oxy]propyl] -5 -(tri?uoromethyl)-1H—pyrazol-4— yl}(pyrimidin-4—y1)ethan—1-one (1.0 mmol) and methyl 3-(chloro(hydroxyimino)1nethyl)- 2-methoxybenzoate; the reaction was ted at 60°C; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CHZClz/MeOH 100:1) to give methyl 3-(5-{1— [(2K) [(tert-butyldimethylsilyl)oxy]propyl] -5—(tri?uoromethyl)— azol—4-yl} (pyrimidiny1)-1,2-oxazoly1)methoxybenzoate (37%); Step 2: ester group was saponi?ed in ethanol (8 mL/mmol) and aq. NaOH (2.0 M; 8 mL/rnrnol) and heating to 60°C for 1 h. and then ed by on of aq. HCl (1.0 M). The resulting suspension was partitioned between CHZClz and water, combined organic layers were dried over MgSO4, the solvent was removed under reduced pressure to give the crude carboxylic acid, which was used as such in further conversions.
Building Block for the synthesis of Examples 166 and 167: 3 -(5 - { 1 -[(2R)—2- [(zert-butyldimethylsi1y1)oxyjpropyl] (tri?uoromethyl)- 1 zolyl} - 4-(pyrimidin—4-yl)-l ,2-oxazol-3—y1)-benzoic acid Step 1: 1 - {1 - [(2R) -butyldimethylsi1y1)oxy]propy1] (tri?uoromethyl)— 1 H—pyrazol yl}—2-(pyrimidin—4—yl)ethan—l -one (1.0 mmol) and methyl 3— (chloro(hydroxyimino)methyl)benzoate; the reaction was conducted at 60°C; the residue was puri?ed by ?ash column chromatography on silica gel (eluent: CHQClz/MCOH 100:1) to give methyl 3-(5- {l - [(ZR) [(tert-butyldimethylsilyl)oxy]propyl]—5 uoromethyl)- lH-pyrazol- 4—yl} —4-(pyrimidinyl)- 1 ,2-oxazolyl)-benzoate (41 %); Step 2: ester group was saponi?ed in ethanol (8 mL/rnmol) and aq. NaOH (2.0 M; 8 InL/mmol) and heating to 60°C for 1 h and then acidi?ed by addition of aq. HCl (1.0 M). The resulting suspension was partitioned between CH2C12 and water, combined organic layers were dried over MgSO4, the solvent was removed under d pressure to give the crude carboxylic acid, which was used as such in further sions.
General procedure for aminoalkvlation of phenolic groups Cl N' HO R. O R.N/\H,OH N/leI l 1,2 Mitsunobu R' A) The respective phenol derivative (1.0 eq.) was dissolved in DMF (15 l) and K2C03 (3.5 eq.) was added, ed by the tive aminoalkyl halogenid (2.0 eq.).
The mixture was stirred at indicated temperature for 18 h and then diluted with CH2C12 and extracted with water and brine. The organic phase was dried over MgSO4, ?ltered and concentrated under reduced pressure. Crude product was puri?ed via prep.
TLC on silica gel (eluent: CH2Clz/Me0H 95:5).
B) Mitsunobu on: The respective phenol derivative (1.0 eq.), PPh3 (1.5 eq.) and the tive 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 min at room temperature for the indicated time, and then diluted with CH2C12 and extracted with water and brine. The organic phase was dried over MgSO4, ?ltered and concentrated under reduced pressure. Crude product was puri?ed Via prep. TLC on silica gel (eluent: CH2C12/MeOl-l 95:5).
Example 133: 4-[4-(3 — {2-chloro-3 -[2-(morpholin—4—y1)ethoxy]pheny1}(pyrimidinyl)- 1 ,2-oxazol—5 —yl)—5—(tri?uoromethyl)—1H—pyrazol-1 -y1]methylbutanol ro {5—[1 -(3-hydroxy-3 -methy1butyl)(tri?uoromethyl)- lH-pyrazolyl] (pyrimidin-Z—yl)-1,2-oxazol-3—y1}phenol (Example 129) (0.09 mmol) and N—(Z- ethy1)morpholine hydrochloride were used in method A, reaction temperature 50°C, to give title compound as an orange oil (14%).
Result of LC/MS [M+H]*: 607.5; lH NMR(CDC13): 8 1.32 (6H, s, 2XCH3), 2.19—2.09 (2H, 1n, CH2), 2.68-2.57 (4H, m, ZXCH2), .79 (2H, m, CH2), 3.78—3.65 (4H, m, 2XCH2), 4.24-4.16 (2H, m, CH2), 4.56-4.44 (2H, m, CH2), 7.09-7.03 (2H, m, 2XCH-arom.), 7.25-7.21 (1H, m, (SH—atom), 7.34 (1H, t, CH- arom.), 8.01 (1H, s, (EH-mom), 8.52 (2H, d, 2xCH-arom.).
Example 134: 4-[4-(3 — {Z-chloro-3 imethylamino)ethoxy]pheny1} (pyrimidin—2-y1)~ 1,2-oxazol—5—y1)(t1i?uorornethyl)— 1 H-pyrazol-l -yl] methylbutanol 2-chloro—3 - {5 —[ 1-(3 -hydroxy—3 ~methy1butyl)—5-(tri?uoromethyl)—1H-pyrazolyl] (pyrimidin-Z-yl)—1,2-oxazoly1}phenol (Example 129) (0.09 mmol) and 2—Cliloro-N,N— dimethylethylamine were used in method A, reaction ature 50°C, to give title compound as a brownish oil (8%).
Result of LC/MS [M+H]+: 565.5; 1H NMR (CDC13)S 6 1.32 (6H, s, 2xCH3), 2.19-2.09 (2H, m, CH2), 2.37 (6H, s, 2XCH3), 2.82 (2H, t, CH2), 4.18 (2H, t, CH2), 4.56-4.45 (2H, m, CH2), 7.09-7.03 (2H, m, 2xCH-arom.), 7.25-7.21 (1H, m, m.), 7.34 (1H, t, m.), 8.01 (1H, s, CPI-atom), 8.52 (2H, d, ZXCH-arom.) Example 135: 4-[4—(3 — {2-ch10r0[2-(pyrrolidiny1)ethoxy]pheny1}(pyrimidiny1)— 1,2-oxazol—5-y1)(tri?u0romethy1)-1H-pyrazol—1-y1]—2—methy1butan01 2-ch10r0-3 - {5 — [ 1 -(3 xy—3 -methylbutyl)(tri?uoromethy1)-1H-pyrazol-4—y1] (pyrimidin—Z-y1)-1,2—oxazol-3—y1}phenol (Example 129) (0.09 mmol) and 1-(2- chloroethyl)pyrr01idine were used in method A, reaction temperature 50°C, to give title compound as a sh oil (5%).
Result of LC/MS [M+H]+: 591.5; 1H NMR(CDC13): 6 1.32 (6H, s, 2XCH3), 1.96—1.88 (6H, m, 3XCH2), 2.18-2.10 (2H, m, CH2), 3.01-2.89 (2H, m, CH2), 3.22-3.12 (2H, m, CH2), 4.39-4.29 (2H, m, CH2), 4.54—4.46 (2H, m, CH2), 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, (EH-atom), 8.52 (2H, d, 2XCH—arom.).
Example 136: 3 - {2—ch10r0-3 -[2-(4—methylpiperaziny1)ethoxy]phenyl} rimidin- 2-y1)-1 zoly1)—5 -(tri?uoromethyl)- 1 H-pyrazol-l -y1] methy1butanol 2-chloro-3 - {5- [ 1 —(3 —hydroxy-3 —methy1butyl)—5-(t1’i?u0romethy1)-1H-pyraz01—4-y1]n4- (pyrimidin-Z-yl)-1,2-oxazoly1}phenol (Example 129) (0.09 mmol) and 1-(2-chloroethyl)— 4~methylpiperazine were used in method A, reaction temperature 100°C, to give title compound as a brownish oil (6%).
Result ofLC/MS [M+H]+: 620.5; 1H NMR (CDCI3)I 5 1.31 (6H, s, 2XCH3), 2.19—2.08 (2H, m, CH2), 2.31 (3H, s, CH3), 2.55— 2.45 (4H, m, 2XCH2), .64 (4H, m, 2xCH2), 2.85 (2H, t, CH2), 4.18 (2H, t, CH2), 4.55- 4.46 (2H, m, CH2), 7.09—7.03 (2H, m, 2XCH—arom.), 7.25—7.21 (1H, m, CH—arom.), 7.33 (1H, t, om), 8.01 (1H, s, CH-arom.), 8.51 (2H, d, EXCH-arom.) e 137: 4-[4—(3 - {2-chloro-3 —[2-(diethylamino)ethoxy]phenyl} —4-(pyrimidinyl)— 1 ,2- oxazol-S-yl)—5—(tri?uoromethyl)— 1 H—pyrazol— 1 —y1]methylbutan—2—ol 2-ch10ro-3 - {5—[ 1 -(3 —hydroxy—3 —methy1butyl)-S-(tri?uoromethyl)-1H-pyrazol-4—yl]—4- (pyrimidin-Z-yl)-1,2-oxazol-3—y1}phenol (Example 129) (0.09 mmol) and 2-chloro-NJV- diethylethylamine were used in method A, reaction ature 50°C, to give title compound as an orange oil (13%).
Result of LC/MS [M+H]+: 593.5; 1H NMR (CDCI3): 6 1.38—1.29 (12H, m, 4XCH3), 2.19—2.08 (2H, m, CH2), 3.20-3.07 (4H, m, ZXCH2), 3.41-3.33 (2H, m, CH2), 4.59-4.46 (4H, m, 2xCH2), 7.11-7.04 (2H, m, 2xCH-arom.), 7.26-7.21 (1H, m, CH~arom.), 7.36 (1H, t, m.), 8.00 (1H, s, CH—arom.), 8.53 (2H, d, ZXCH-arom.).
Example 138: 4-[2-(2-chloro-3 — {5 — [1 —(3 -hydroxy—3 lbutyl)—5—(tri?uoromethyl)—1 H— pyrazolyl] (pyrimidin-2—yl)— 1 ,2—oxazolyl}phenoxy)ethyl]-thiomorpholine- l ,1 -dione 2—chloro {5 -[1 -(3-hydroxy—3 -methylbutyl)—5-(tri?uoromethyl)- 1H-pyrazolyl]-4— (pyrimidin-Z-yl)-1,2-oxazol—3-yl}phenol (Example 129) (0.06 mmol) and 4—(2- hydroxyethyl)thi0morpholin—1,1-dione were used in method B (18 h); additional puri?cation by a second prep. TLC (eluent: petroleum ether/ethyl acetate 3 :7) yielded the title compound as h oil (6%).
Result ofLC/MS [M+H]+: 655.4; 1H NMR (CDC13)I 5 1.32 (6H, s, ZXCH3), .10 (2H, m, CH2), 3.11—2.99 (6H, m, 3XCH2), 3.27-3.15 (4H, m, 2xCH2), 4.23-4.14 (2H, m, CH2), 4.56-4.45 (2H, m, CH2), 7.11-7.00 (2H, m, 2XCH-arom.), .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-oxaazaspiro[3 .3]heptan-6—y1}ethoxy)pheny1] (pyrimidin—Z-yl)- 1 zoly1} -5—(tn'?uoromethyl)— 1 H-p‘yrazol — 1 -y1)methylbutanol 2—chloro—3 — {5 — [ 1 —(3 -hydroxy—3 -methy1buty1)-5—(tri?uoromethy1)-1H-pyrazoly1]-4— (pyrimidinyl)—1,2-oxazoly1}phenol (Example 129) (0.08 mmol) and 6-(2-ch10roethyl)— 2-oxaazaspiro[3.3]heptane were used in method A, on temperature 70°C, to give title compound as a brownish oil (15%).
Result of LC/MS [M+H]+: 619.5; 1H NMR (CD013): 5 1.32 (6H, s, 2xCI-I3), 2.18-2.11 (2H, m, CH2), 2.83 (2H, t, CH2), 3.52 (4H, s, 2xCH2), 4.06 (2H, t, CH2), 4.55-4.47 (2H, m, CH2), 4.71 (4H, s, 2XCH2), 7.00 (1H, dd, CH-arom.), 7.07 (1H, t, CH-arom.), 7.23 (1H, dd, m.), 7.33 (1H, t, CH-arom.), 8.01 (1H, s, CH-arorn.), 8.52 (2H, d, rorn.).
Example 140: 4-[4-(3-{2—chloro—3-[3—(dimethylamino)propoxy]pheny1}—4-(pyrimidiny1)- 1,2-oxazoly1)(tri?uoromethy1)- 1 H-pyrazolmethy1butan-2—ol 2—chloro-3 - {5— [1 -(3-hydroxy—3 lbutyl)(tri?uoromethy1)—1H—pyrazolyl]—4- (pyrimidin-Z-yl)—1,2-oxazoly1}phen01 (Example 129) (0.2 mmol) and 3—dimethylamino propyl chloride were used in method A, reaction temperature 60°C, to give title compound as yellow oil (49%).
Result of LC/MS [M+H]+: 578.9; 1H NMR (CDC13): 5 1.31 (6H, s, 2XCH3), 2.07-1.95 (2H, m, CH2), 2.18-2.08 (2H, m, CH2), 2.27 (6H, s, 2XCH3), 2.51 (2H, 1;, CH2), 4.11 (2H, t, CH2), 4.56—4.44 (2H, m, CH2), 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 —methylbuty1)—5-(tri?uoromethyl)— l H- pyrazol-4—y1](pyrimidin—2-y1)— 1 ,2-oxazol-3 -yl}phenoxy)propyl]-thiomorpholine-1,1—dione 2—chloro-3— {5-[1 -(3 —hydroxy—3 —methy1butyl)-5—(tn'?uoromethyl)— azol—4—yl]—4— (pyrimidin-Z-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 11); title compound was obtained as yellow solid (6%).
Result ofLC/MS [M+H]+: 669,2 1H NMR (CDCIg): 8 1.32 (6H, s, 2xCH3), 2.02—1.94 (2H, m, CH2), 2.18-2.10 (2H, m, CH2), 2.72 (2H, t, CH2), 3.05-2.98 (8H, m, 4XCH2), 4.12 (2H, t, CH2), 4.54—4.47 (2H, m, CH2), 7.10-7.02 (2H, m, rom.), 7.26—7.21 (1H, m, (EH-atom), 7.35 (1H, t, CH-arom.), 8.01 (1H, s, CH-arom.), 8.52 (2H, d, 2xCH-ar0m.).
Example 142: 4-[4—(3— {2-chloro[3 -(pyrrolidin-1 -yl)propoxy]phenyl} rimidin-2—yl)— 1 zolyl)(tri?uoromethyl)- lH-pyrazol-l -y1] methylbutanol r0—3 - {5 -[ 1-(3-hydr0xy-3 vmethylbutyl)(tri?uoromethyl)— l H-pyrazol—4-yl] -4— (pyrimidin-Z—yl)-1,2-oxazol-3—y1}phenol (Example 129) (0.2 mmol) and 1—(3- chloropropyl)pyrrolidine were used in method A, reaction temperature 60°C, second prep.
TLC (eluent: CHClg/MeOH/aq. NH3 80:9:1 to give title compound as yellow oil (9%).
Result of LC/MS : 605.1; 1H NMR (CDC13)I 5 1.33 (6H, s, , 2.12—2.05 (4H, m, 2xCH2), 2.21-2.12 (2H, m, CH2), 2.47—2.33 (2H, m, CH2), 3.30-3.09 (6H, m, 3xCH2), 4.30-4.11 (2H, m, CH2), 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} (pyrimidin—2-yl)— 1 ,2-oxazol-5 -(tri?uorornethyl)- 1 H-pyrazoly1] methy1butan01 2-ch10ro—3- {5-[1 -(3 -hydr0xy-3 -methylbutyl)—5—(tri?uoromethy1)-1H—pyrazolyl]—4— (pyrimidin-Z-yl)-1,2-oxazol-3—y1}phenol (Example 129) (0.2 mmol) and hylamino-l- propane] were used in method B (1.5 h); title compound was obtained as yellow solid (22%).
Result of LC/MS [M+H]+: 607.2; 1H NMR (CDC13)Z 5 1.09 (6H, t, 2xCH3), 1.31 (6H, s, 2xCH3), 2.09-2.00 (2H, m, CH2), 2.19— 2.09 (2H, m, CH2), 2.72-2.60 (2H, m, CH2), 2.84-2.72 (2H, m, CH2), 4.12 (2H, t, CH2), 4.56- 4.45 (2H, m, CH2), 7.09-7.02 (2H, rn, 2xCH-arom.), 7.23 (1H, dd, rn.), 7.33 (1H, t, CH-arom.), 8.00 (1H, s, CH-arom.), 8.52 (2H, d, rorn.).
C, h: 3 / [Pl/\K /\N/\,O ’N K N Example 144: 4-[4-(3- oro[2-(diethy1amino)ethoxy]pheny1} (pyrimidin-2—yl)- 1 ,2- oxazol-S-y1)-5 -rnethyl- l H-pyrazol- 1 —y1]methy1butanol 2-chloro {5-[ 12(3'hydroxy—3 -methylbutyl)—5-methyl-1H-pyrazol—4-yl]—4—(pyrimidin-2—yl)— 1,2—oxazol—3—yl}phenol (0.08 mmol) and 2-ehloro-N,N-diethylethylamine were used in method A, reaction temperature 50°C, to give title compound in 21% yield.
Result of LC/MS [M+H]+: 539.1; 1H NMR (CDClg): 5 1.08 (6H, t, 2XCH3), 1.28 (6H, s, 2XCH3), 2.08-1.97 (2H, m, CH2), 2.56 (3H, s, CH3), 2.70 (4H, q, 2XCH2), 2.96 (2H, t, CH2), 4.17 (2H, t, CH2), 4.34-4.24 (2H, m, CH2), 7.03 (1H, dd, CH-arom.), 7.08 (1H, t, CH-arorn.), 7.20 (1H, dd, CH-arom.), 7.31 (1H, t, CH-arom.), 8.08 (1H, s, CH-arom.), 8.60 (2H, d, 2xCH-arorn.).
Example 145: 4-[4-(3 - {2-chloro[2-(dimethy1amino)ethoxy]pheny1 } (pyrimidinyl)— 1 ,2-oxazol—5 —yl)methy1—1H—pyraz01y1]—2-methy1butanol 2-ehloro {5-[1 droxy—3 ~methylbuty1)-S-methy1—1H-pyrazol—4-y1](pyrimidin—2-yl)— 1,2-oxazoly1}phen01 (0.16 mmol) and 2—ch10ro-N,N—dimethylethy1amine were used in method A, reaction temperature 50°C, to give title nd as pale yellow oil (11%).
Result ofLC/MS [M+H]+: 511.1; 1H NMR (CDC13)Z 6 1.29 (6H, s, 2xCH3), 2.08—1.98 (2H, m, CH2), 2.37 (6H, s, 2xCH3), 2.57 (3H, s, CH3), 2.81 (2H, t, CH2), 4.16 (2H, t, CH2), 4.33-4.24 (2H, m, CH2), 7.12-7.00 (2H, m, rom.), 7.22 (1H, dd, CH-arom.), 7.32 (1H, t, CH—arom.), 8.07 (1H, s, CPI—atom), 8.60 (2H, d, 2xCH-arom.).
Example 146: 4- [4-(3 — {2-chloro-3 -[2-(pyrrolidin—1-y1)ethoxy]pheny1}(pyrimidiny1)-1,2-oxazol-5 -yl)- -1nethy1-1H-pyrazol-1 -y1]—2—methy1butan01 ro {5—[1-(3—hydroxy—3-methylbutyl)methy1-1 H—pyrazolyl]—4-(pyrimidinyl)- 1,2-oxazoly1}phenol (0.16 mmol) and 1—(2-chloroethyl)pyrr01idine were used in method A, reaction temperature 50°C, to give title nd upon second prep. TLC (eluent: CHQCIZ/MCOH 9:1) as pale yellow oil (8%).
Result of LC/MS [M+H]+: 537.1; 1H NMR (CDC13): 5 1.29 (6H, s, 2XCH3), 1.86-1.76 (4H, m, 2xCH2), 2.07-1.99 (2H, m, CH2), 2.57 (3H, s, CH3), 2.75-2.66 (4H, m, 2XCH2), 2.98 (2H, t, CH2), 4.21 (2H, t, CH2), 4.33—4.25 (2H, m, CH2), 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-ar0m.). 3 Cl N’O \/N\/\/O ’ / wH Example 147: 4-[4-(3 — {2-chloro—3 - [3 -(diethy1arnino)propoxy]phenyl}(pyrimidinyl)— 1 ,2—oxazol-5—y1)methyl—1H—pyrazolyl]-2—methylbutan—2-ol 2-chloro—3 - {5—[1-(3-hydroxy—3 -methylbutyl)methy1-1H-pyrazolyl](pyrimidin—2-yl)— 1,2~0xazoly1}phenol (0.08 mmol) and 3-diethylamin0pr0panol were used in method B (1.5 h); title compound was obtained as a pale yellow oil (22%).
Result of LC/MS [M+H]+: 5532; 1H NMR (CDClg): 6 1.13 (6H, t, 2xCl-13), 1.29 (6H, s, 2xCI-I3), 2.07-1.98 (2H, m, CH2), 2.16- 2.07 (2H, m, CH2), 2.57 (3H, s, CH3), 2.73 (4H, q, 2XCH2), 2.82 (2H, t, CH2), 4.11 (2H, t, CH2), 4.32-4.23 (2H, m, CH2), 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—ehlor0-3—[2-(morpholin—4-y1)ethoxy]pheny1} {1 - [(253—2- ypropyl]-5—(trifluoromethyl)-1H-pyrazoly1}-l ,2-oxazolecarboxylate methyl (SD—3 10ro-3 -hydr0xyphenyl)-5 -( l -(2-hydr0xypropyl)—5-(t1i?uor0methyl)— l H— pyrazol-4—y1)isoxazole—4-carboxylate (0.06 mmol) and N—(2-chloroethyl)morpholine hydrochloride were used in method A, on temperature 50°C, to give title compound (24%).
Result S [M+H]+: 559.3; 1H NMR (CDC13)Z 8 1.32 (3H, d, CH3), 2.69 (4H, hr, 2xC1-I2), 2.93 (2H, t, CH2), 3.63 (3H, s, OCH3), 3.76 (4H, t, 2xCH2), 4.30-4.19 (3H, m, CH and CH2), 4.46-4.30 (2H, m, CH2), 7.14- 7.06 (211,111, 2xCH-arom.), 7.33 (1H, t, CH—arom.), 7.99 (1H, s, CH-arom.).
Example 149: methyl 3 - oro-3—[2-(dimethylamino)ethoxy]pheny1} ~5- { 1 - [(2S)—2- hydroxypropyl](tri?uoromethyl)- 1 H-pyrazoly1} — l ,2-oxazolecarboxylate methyl (S)—3 -(2-chloro—3-hydroxyphenyl)—5-( l —(2-hydroxypropyl)—5~(tri?uoromethyl)~ l H- lyl)isoxazolecarboxy1ate (0.06 mmol) and 2-chloro-N,N—dimethylethylamine were used in method A, reaction temperature 50°C, to give title compound (19%).
Result of LC/MS [M+H]+: 517.3; 1H NMR (CDC-13): 6 1.32 (3H, d, CH3), 2.92 (6H, s, 2xCH3), 3.48 (2H, t, CH2), 3.63 (3H, s, OCH3), 4.24 (1H, dd, CH), 4.47-4.31 (2H, m, CH2), 4.60 (2H, t, CH2), 7.19-7.11 (2H, m, 2xCH—arom.), 7.38 (1H, t, CH-arom.), 7.99 (1H, s, m.).
Example 150: 3-[4—(3— {2—chloro[2-(morpholin—4-y1)ethoxy]phenyl}(methoxymethyl)— l ,2—oxazol-5 -(tri?uoromethyl)— l H-pyrazol—l —y1]—1 —Inethylcyclobutan- 1 ~01 (syn— con?guration) 2-chloro-3 - [4-(methoxymethyl)—5 — {_ l {3 — [(tert—butyldimethylsilyl)oxy] -3 -rnethylcyclobutyl] - -(tn'?uoromethyl)-1H-pyrazol—4-yl}-1,2-oxazolyl]phenol (syn-con?guration) (0.03 mmol) and N-(Z-chloroethyl)morpholine hydrochloride were used in method A, reaction temperature 50°C; upon standard workup, crude material was taken up 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 d pressure and the title compound was isolated from prep. TLC (eluent: CH2C12(MeOH/aq. NH3 10021021) as pale yellow oil (56%).
Result of LC/MS [M+H]+: 571.4; lH-NMR (CDC13, J [112]): 5 = 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, CH2, RCHzOCH3), 3.75- 3.72 (m, 4H, morpholino-H), 3.15 (s, 3H, RCH20CH3), 2.91-2.72 (m, 6H, 3 x CH2), 2.66— 2.63 (m, 4H, morpholino-H), 1.49 (s, 3H CH3).
Example 151: 3 -[4-(3 - {2—chloro methylamino)ethoxy]pheny1 } (rnethoxymethyl)—1 ,2-oxazol—5—yl)— -(tri?uoromethyl)- 1 H-pyrazol- 1 —yl]-1—methylcyclobutan— 1 —ol (syn—con?guration) 2—011101'0 [4-(methoxymethyl)-5~ {1 —[3 - [(tert-butyldimethylsilyl)oxy] —3 -methylcyclobuty1] — ?uoromethyl)-1H—pyrazol—A-yl}-1 ,2-oxazolyl]phenol (syn—con?guration) (0.03 mmol) and 2-chloro-N,N-dimethylethy1amine were used in method A, reaction ature 45°C; upon standard workup, crude material was taken up 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 ?om prep. TLC t: CH2C12(MeOH/aq. NH3 100: 10:1) as colorless oil (48%).
Result ofLC/MS [M+H]+: 529.50; ‘H-NMR (CDC13, J [112]): 8 = 7.91 (s, 1H pyrazole-I-I), 7.35-7.29 (m, 1H,benzy1-H), 7.11- 7.06 (m, 2H, benzyl-H), 4.77- .67 (m, 1H, CH), 4.22—4.18 (m, 4H, CH2, H3), 3.15 (s, 3H, RCHZOCHg), 2.88-2.72 (m, 6H, 3 x CH2), 2.39 (s, 6H, N(CH3)2), 1.49 (s, 3H CH3). 0 0 e 152: 3-[4-(3-{2-chloro-3—[2-(morpholiny1)ethoxy]phenyl}(methoxymethyl)- 1 ,2—oxazol—5-y1)(t1i?uoromethy1)-lH-pyrazoly1] methylcyclobutanol (anti- con?guration) 2—chlor0-3 - [4-(rnethoxymethy1)—5— {1 -[3 —[(tert—butyldimethylsily1)oxy] -3 —methylcyclobutyl] — -(trifluoromethyl)~1H—pyrazoly1}-1,2-oxazol—3-y1]phenol (anti—con?guration) (0.02 mmol) and N-(Z-chloroethyl)morpholine hloride were used in method A, reaction temperature 50°C; upon standard workup, crude material was taken up 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 d pressure and the title compound was isolated from prep. TLC (eluent: CHzClz(MeOH/aq. NH3 100:10: l) as pale yellow oil (60%).
Result of LC/MS [M+H]+: 571.3; 1H-NMR(CDC13, J [Hz]): 8 = 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, CH2, H3), 3.75- 3.72 (m, 4H, morpholino-H), 3.15 (s, 3H, RCHzOCHg), 2.9l—2.80 (m, 4H, 2 x CH2), 2.68- 2.61 (m, 6H, CH2, morpholino-H), 1.55 (s, 3H CH3).
CF .
C' [1'0 / ND." \NNO / ’5'] e 153: 3-[4-(3- {2-chloro-3—[2—(dimethylamino)ethoxy]phenyl}(methoxymethyl)— l ,2—oxazolyl)-5—(tri?uoromethyl)-1H-pyrazol-l —yl]—1—methylcyclobutan—l -ol (anti- con?guration) 2-chloro—3 -[4-(methoxymethyl)—5 — {l -[3 - [(tert—butyldimethylsilyl)oxy] -3 -methylcyclobutyl] - -(tri?uoromethyl)-lH-pyrazoly1} ~I ,2-oxazol-3 -y1]phenol (anti-con?guration) (0.03 mmol) and 2—chloro—N,N—dimethylethylamine were used in method A, on temperature 50°C; upon standard workup, crude material was taken up in THF (0.5 mL) and treated with TBAF (l 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: CH2C12/MeOH/aq. NH3 100:10: l) as pale yellow oil (87%).
Result ofLC/MS [M+H]+: 529.30; 1H-NMR (CDC13, J [Hz]): 6 = 7.87 (s, 1H pyrazole—H), 7.35-7.29 (m, 1H, benzyl-H), 7.11— 7.06 (m, 2H, benzyl—H), 5.3l—5.21 (m, 1H, CH), .19 (m, 4H, CH2, RCHzOCH3), 3.15 (s, 3H, RCHZOCHg), 2.87—2.80 (m, 2H, CH2), 2.68-2.60 (m, 2H, CH2), 2.40 (s, 6H, N(CH3)2), 1.55 (s, 3H, CH3).
General ure for the synthesis of isoxazol-S-grl-benzamides Y R.
O RAr N'0 31* W 1/ / I}! 1. R EDC|,HOBt HO‘ "N WMWM z 2.TBAF * O-silylatecl Either 3 -(5 - { l - [(2R)[(tert—butyldimethylsilyl)oxy]propyl] (tri?uoromethyl)- 1 H-pyrazol- 4-(pyrirnidin—4-yl)-l,2-oxazoly1)chlorobenzoic acid (Examples 154 to 160), 3-(5— { l —[(2R)-2— [(tert-butyldimethylsilyl)oxy]propyl](tri?uoromethyl)— 1 H-pyrazol—4—yl } (pyrimidin—4—yl)-l,2-oxazolyl)methoxybenzoic acid (Examples 161 to 165), or 3—(5—{1— [(2R)—2-[(tert-butyldimethylsilyl)oxy}propyl] (tri?uoromethyl)- l H-pyrazolyl} (pyrimidin-4—yl)—l,2-oxazolyl)—benzoic acid (Examples 166 and 167) (0.15 mmol), the respective amine (1.8 eq.), l-hydroxybenzotriazole (1.5 eq.) and l-(3 -dimethylarninopropy1)— 3—ethylcarbodiimide hloride (EDCI; 1.7 eq.) were dissolved in 1 mL dry DMF. NMethylmorpholine (10. eq.) was added and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between saturated aq. NH4C1-solution and CH2C12, combined organic layers were washed with water and brine and and dried over MgSO4, ?ltrated and concentrated under reduced pressure. Product puri?cation was ed by prep.
TLC on silica gel (eluent: petroleum ether/ethyl acetate 1:1; if ed, second prep. TLC, diluent: CH2Clg/MeOH 9822).
Final 0-desily1ation of benzamides was achieved in THF (0.5 mL) with TBAF (1 M in THF; 1.1 eq.) at room temperature for 3.5 h. The t was removed under reduced pressure and the title compound was isolated from prep. TLC (eluent: CH2Clz/MeOI-l 95:5).
Example 154: (R)-(2-chloro(5-(1~(2-hydroxypropyl)-5—(tri?uoromethyl)—1H-pyrazol yl)—4—(pyrimidinyl)isoxazol-3—yl)phenyl)(morpholino)methanone From 3~(5— { 1 —[(2R)—2—[(tert—butyldimethylsilyl)oxy]propyl] —5—(tri?uoromethyl)— 1 H—pyrazol— 4-(pyrimidin—4-yl)—l,2—0xazoly1)chlorobenzoic acid and line in 23% yield over two steps.
Result of LC/MS [M+H]+: 562.9; 1H NMR (CD013): 5 1.32 (3H, d, CH3), 3.19 (2H, t, CH2), 3.58 (2H, t, CH2), 3.91—3.66 (4H, m, , 4.23 (1H, dd, CH), 4.47-4.30 (2H, m, CH2), 6.90 (1H, br, CH-arom.), 7.57-7.45 (2H, m, 2xCH-arorn.), 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: eh10ro—N—cyc10buty1—3 -(5-(1 —(2-hydroxypropyl)-5—(tri?uoromethy1)—1 H- pyrazol-4—y1)-4—(pyrimidin—4—yl)isoxazol-3~yl)benzamide From 3 -(5~ { 1 )[(tert-butyldimethylsi1y1)0xy]propy1]-5—(tri?uoromethy1)~1H-pyrazol— 4—y1}—4-(pyrimidinyl)-1,2-oxazolyl)—2-chlor0benzoic acid and cyclobutylamine in 14% yield over two steps.
Result of LC/MS [M+H]+: 546.9; 1H NMR (CDClg): 5 1.32 (3H, (1, CH3), 2.60-1.70 (6H, m, 3XCH2), 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, CPI-atom), 7.61 (1H, d, CH-arom.), 7.78 (1H, d, (EH-atom), 7.98 (1H, s, CH-arom.), 8.61 (1H, br, CPI-atom), 9.07 (1H, s, CH-arom.) Example 156: (R)chloro-N-ethyl—3-(5-(1-(2-hydr0xypropy1)—5-(tri?uoromethyl}1H- pyrazol-4—yl)(pyrimidin-4—y1)isoxazoly1)benzamide From 3—(5— { 1 —[(2R)-2—[(tert—butyldimethylsi1y1)0xy]propyl] —5 —(tri?uoromethy1)— 1 H-pyrazol— 4-y1}(pyrimidiny1)-1,2-oxazol-3~y1)—2-ch10robenzoic acid and ethylamine (2 M in THF) in 8% yield over two steps.
Result of LC/MS [M+H]*: 520.9; 1H NMR (CDC13): 5 1.25 (3H, q, CH3), 1.32 (3H, (1, CH3), 3.56-3.42 (2H, m, CH2), 4.24 (1H, dd, CH), 4.48-4.31 (2H, m, CH2), 6.00 (1H, br, N—H), 6.91 (1H, br, CH-arom.), 7.51 (1H, t, CH-arom.), 7.61 (1H, d, ("SH-atom), 7.78 (1H, d, m.), 7.98 (1H, s, CH-arom.), 8.60 (1H, br, CH-arom.), 9.06 (1H, s, CH-arom.) Example 157: (R)chloro(5-(1—(2—hydroxypropyl)—5-(tri?uoromethy1)-1H—pyrazol—4—yl)— 4-(pyrimidiny1)isoxazol—3-y1)—N-isopropy1benzamide From 3-(5- { 1 -[(2R)—2-[(tert—butyldimethylsi1y1)0xy]propyl]-5—(tri?uoromethy1)—lH-pyrazol— 4-y1}(pyrimidin—4-y1)~1,2~oxazolyl)chlorobenzoic acid and isopropylamine in 12% yield over two steps.
Result of LC/MS [M+H]+: 534.9; 1H NMR (CDCIg)! 8 1.26 (6H, d, 2xCH3), 1.32 (3H, (1, CH3), 4.48-4.18 (4H, m, 2XCH and CH2), 5.84 (1H, d, N—H), 6.96 (1H, s, (EH—atom), 7.50 (1H, t, CH-arom.), 7.60 (1H, (1, CH— arom.), 7.76 (1H, d, CPI-atom), 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-ch]oro—3-(5-(1—(2-hydroxypropy1)—5-(tri?uoromethy1)- 1H-pyrazo1~4-yl)(pyrimidin—4—yl)isoxazoly1)phenyl)methanone From 3-(5- {1 — [(ZR) [(zert—butyldimethylsilyl)oxy]propyl] —5-(tri?uoromethyl)- 1 zol- 4-y1}(pyrimidiny1)-1,2-0xazol-3—y1)chlorobenzoic acid and azetidine in 19% yield over two steps.
Result of LC/MS [M+H]+: 532.9; 1H NMR (CDC13)I 5 1.32 (3H, d, CH3), 2.43-2.24 (2H, m, CH2), 4.00-3.83 (2H, m, CH2), 4.49-4.14 (5H, m, CH and 2XCH2), 7.03 (1H, d, m.), 7.59-7.47 (2H, m, rom.), 7.63 (1H, dd, om), 7.97 (1H, s, CH-arom.), 8.63 (1H, br, CH-arom.), 9.08 (1H, s, CH— atom).
Example 159: (R)-2—ch10ro-N—cyclopr0pyl—3-(5-(1-(2-hydroxypropyl)—5-(tri?uor0methyl)— 1H-pyrazol-4—y1)(pyrimidiny1)isoxazol-3—y1)benzamide From 3—(5- { 1 -[(2R)—2—[(tert—butyldimethylsi1y1)0xy]propyl] (tri?u0romethyl)- 1 H—pyrazol- 4-y1}(pyrimidinyl)-1,2—oxazol-3—y1)chlorobenzoic acid and ropylamine in 6% yield over two steps.
Result of LC/MS [M+H]+: 532.9; 1H NMR (CDC13): 6 0.68 (2H, m, CH2), 0.91-0.85 (2H, m, CH2), 1.32 (3H, (1, CH3), 2984.84 (1H, m, CH), 4.46-4.18 (3H, m, CH and CH2), 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, om), 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-ch10ro-3 -(5-(1—(2—hydroxypr0pyl)—5—(tri?uoromethyl)-lH-pyrazol yl)(pyrimidinyl)isoxazoly1)pheny1)(pyrrolidin—1—y1)methan0ne From 3-(5- { 1-[(2R)—2—[(tert-butyldimethylsilyl)oxy]propyl]—5—(tri?u0romethy1)-1 H-pyrazol— 4-y1}(pyrimidiny1)-1,2-oxazoly1)—2-chlorobenzoic acid and pyrrolidine in 23% yield over two steps.
Result of LC/MS [M+H]+: 547.0; 1H NMR (CDC13): 5 1.31 (3H, (1, C113), 2.02—1.81 (4H, m, ZXCH2), 3.13 (2H, t, CH2), 3.62 (2H, t, CH2), 4.23 (1H, dd, CH), 4.46—4.29 (2H, m, CH2), 6.90 (1H, d, CH-arom.), .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.). e 161 : (R)—N—cyclopropy1—3—(5-(1 -(2-hydroxypr0pyl)—5—(tri?uoromethy1)-1H-pyrazol— 4-y1)—4—(pyrimidiny1)isoxazolyl)—2-methoxybenzamide From 3-(5- { 1 —[(212)-2—[(tert—butyldimethylsily1)0xy]propyl]—5—(tri?uoromethy1)—1H-pyrazol- 4—y1}(pyrimidin-4—y1)—1,2—oxazol—3—y1)—2—meth0xybenzoic acid and ropylamine in 9% yield over two steps.
Result of LC/MS [M+H]+: 529.0; lH NMR (CDC13)I 8 0.61-0.49 (2H, m, CH2), 0.94-0.80 (2H, m, CH2), 1.33 (3H, (1, CH3), 3.06-2.78 (1H, m, CH), 3.53 (3H, s, OCH3), 4.25 (1H, dd, CH), 4.48—4.32 (2H, m, CH2), 7.08 (1H, d, CH-arom.), 7.50-7.36 (2H, m, 2xCH-arom.), 7.67 (1H, dd, CH-arom.), 7.94 (1H, s, CPI-atom), 8.29 (1H, dd, CH—arom.), 8.66 (1H, d, CH—amm.), 9.14 (1H, s, CH—arom.) Example 162: (R)—3-(5—( 1 dr0xypropy1)—S~(tri?uoromethyl)-1H-pyrazol-4—y1)—4— (pyrimidinyl)isoxazol-3—y1)-N-isopropylmethoxybenzamide From 3—(5- { 1 —[(2R)-2—[(tert—butyldimethylsi1y1)0xy]propy1](tri?u0r0methyl)— 1 H—pyrazol— 4-y1}—4~(py1imidiny1)—1,2-0xazoly1)-2—meth0xybenzoic acid and isopropylamine in 18% yield over two steps.
Result ofLC/MS [M+H]+: 531.0; 1H NMR (CDClg): 5 1.22 (6H, d, 2XCI‘I3), 1.33 (3H, (1, CH3), 3.57 (3H, s, OCH3), 4.48-4.17 (4H, m, ZXCH and CH2), 7.08 (1H, br, NH), 7.21-7.11 (1H, m, CH-arom.), 7.42 (1H, t, CH- arom.), 7.64 (1H, dd, om), 7.95 (1H, s, CH-amm.), 8.27 (1H, dd, CH—arom.), 8.64 (1H, s, (EH-atom), 9.14 (1H, s, CH-arom.).
Example 163: (R)-(azetidin—1 -y1)(3 -(5—(1 ~(2-hydr0xypropyl)—5-(tri?uoromethyl)-1H-pyrazol- 4—y1)—4—(pyrimidin—4-y1.).isoxazol—3 -y1)-2—methoxyphenyl)methanone From 3 —(5— { 1 -[(2R)—2-[(tert-butyldimethylsi1y1)oxy]propyl]—5-(tri?uoromethyl)— 1 H-pyrazol- 4-y1}—4~(py1imidin—4-yl)—1,2-oxazol-3—yl)-2—meth0xybenzoic acid and azetidine in 15% yield over two steps.
Result of LC/MS [M+H]+: 529.0; 1H NMR (CDC13)2 8 1.33 (3H, (1, CH3), 2.40-2.19 (2H, m, CH2), 3.51 (3H, s, OCHg), 4.18- 3.70 (4H, m, 2xCH2), 4.48—4.18 (3H, m, CH and CH2), 7.14 (1H, d, CH—arom.), 7.33 (1H, t, CH-arom.), 7.58 (1H, dd, (EH-atom), 7.66 (1H, dd, CH-arom.), 7.95 (1H, s, CH-arom.), 8.63 (1H, hr, CH—arom.), 9.13 (1H, s, CH—arom.).
Example 164: (R)—N—cyclobuty1—3-(5—(1-(2-hydr0xypropyl)(tri?uoromethyl)—lH—pyrazol- 4—y1)(pyrimidinyl)isoxazoly1)methoxybenzamide From 3-(5- { 1—[(2R)—2-[(tert—butyldimethylsilyl)oxy]propyl]—5—(tri?uor0methy1)—1H—pyrazol- 4-y1}(pyrimidin—4-yl)—1,2—oxazoly1)methoxybenzoic acid and cyclobutylamine in 11% yield over two steps.
Result of LC/MS {M+H]*: 543.0; 1H NMR (CDC13): 6 1.32 (3H, d, CH3), 1.92-1.68 (4H, m, ZXCHZ), 2.47-2.26 (2H, H), CH2), 3.58 (3H, s, OCH3), 4.24 (1H, dd, CH), 4.46-4.30 (2H, m, CH2), .49 (1H, m, CH2), 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.) e 165: (R)—N—ethy1—3-(5-(1-(2—hydr0xypropyl)—5-(tri?uoromethy1)-lH—pyrazol—/—y1)- 4-(pyrimidinyl)isoxazoly1)-2—methoxybenzamide From 3—(5— { 1 —[(2R)-2— [(tert-butyldimethylsi1y1)0xy]propy1] —5—(tri?uoromethyl)-1 H-pyrazol- 4-y1}—4-(pyrimidin—4-yl)—1,2—oxazoly1)—2—methoxybenzoic acid and ethylamine (2 M in THF) in 4% yield over two steps.
Result ofLC/MS [M+H]+: 517.0; 1H NMR (CDC13)Z 8 1.18 (3H, t, CH3), 1.32 (3H, d, CH3), 3.52-3.38 (2H, m, CH2), 3.55 (3H, s, OCH3), 4.24 (1H,dd, CH), 4.47—4.30 (2H, m, CH2), 6.90 (1H, br, NH), .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.).
HN ’N Example 166: (R)-N—cyclobuty1(S-(1—(2-hydroxypropy1)-5—(tri?uoromethy1)—lH—pyrazol- 4-y1)(pyrimidiny1)isoxazolyl)benzamide From 3-(5— { 1 -[(2R)-2— —butyldimethylsi1y1)oxy]propyl] —5-(tri?uoromethy1)— 1 H-pyrazol— 4-y1}(pyrimidin-4—y1)—1,2-oxazoly1)-benzoic acid and cyclobutylamine in 16% yield over two steps.
Result of LC/MS [M+H]+: 513.0; 1H NMR (CDC13): 8 1.31 (3H, d, CH3), 1.88-1.71 (2H, m, CH2), 2.07—1.88 (2H, m, CH2), 2.54-2.36 (2H, m, CH2), 3.22 (1H, d, CH), 4.22 (1H, dd, CH), 4.47-4.29 (2H, m, CH2), 4.68- 4.49 (1H, m, CH), 6.23 (1H, d, N-H), 6.97 (1H, dd, CPI-atom), 7.60—7.43 (2H, m, 2XCH- atom), 8.02—7.88 (3H, m, rom.), 8.59 (1H, d, CH—arom.), 9.18 (1H, d, CH-arom.) e 167: (R)—3—(5—(1—(2-hydroxypropyl)—5-(tri?uoromethyl)—1H—pyrazol-4—yl)—4— (pyrimidinyl)isoxazol—3-y1)-N-isopropylhenzamide From 3—(5— { 1 —[(2R)[(tert—butyldimethylsilyl)oxy]propyl](tri?uoromethy1)-lH-pyrazol- 4—yl}-4—(pyrimidin—4—yl)-1,2-oxazol-3—yl)—benzoic acid and isopropylamine in 8% yield over two steps.
Result ofLC/MS ; 501.0; 1H NMR (CDC13)I 5 1.27 (6H, d, 2XCH3), 1.31 (3H, d,’CH3), 3.22 (1H, br, OH), 4.58—4.07 (4H, m, 2xCH and CH2), 5.91 (1H, d, N-H), 6.97 (1H, dd, CPI—atom), .45 (2H, m, ZXCH-arom.), 7.99-7.88 (3H, m, 3xCH-arom.), 8.59 (1H, d, CH-arom.), 9.18 (1H, d, CH— atom). b) Biological Tests Cytokine Assay: Analysis of proliferation of and Cytokine tion by human PBMC stimulated with FHA Peripheral blood clear cells (PBMC) from healthy human donors were puri?ed using AceuspinTM System-Histopaque-1077 (Sigma) according to the ol recommended by the manufacturer. Puri?ed PBMC were then washed twice with ate-buffered saline (PBS) and resuspended in RPM11640 culture medium supplemented with 10% dialyzed heat inactivated fetal calf serum, 1.5 mM L-glutamine, 100 U penicillin/m1, and 100 mg streptomycin/m1 (all from PAN Biotech, Aidenbach, Germany). For stimulation, PBMC were seeded at 1 x 105 cells/well, activated with 2 ug/ml phytohaemagglutinin (PHA, Sigma) and incubated with the test compounds for 48 hours. , IL—17F and INF—y were then determined in the culture supernatant using a Luminex BioPlex system, following the manufacturer’s instructions (BioRad, Munich, Germany). For screening, compounds were used at 10, 1, 0.1 and 0.01 uM. To determine the ICSD, compounds were titrated semilogarithmically.
Cell proliferation was analyzed using the BrdU based cell proliferation ELISA from Roche (Mannheim, Germany) according to the manufacturer’s instructions.
Cytokines were determined in the aforementioned culture supernatant using the following methods: IL—17A was ed using the human homodimer IL-17A ELISA Ready Set Go Kit from eBioscience (Frankfurt, Germany); IL—17F using the human lL—17F ELI—Pair from Holzel DiagnosticaGmBH (Koln, Germany); and IFN—y using the OptElA human lFN—g ELISA from BD Bioscience (Heidelberg, Germany), all following the cturer’s instructions. c) Aqueous solubility Aqueous solubility was tested in 50 mM phosphate buffer (pH 4.0, 6.0, 7.4 and 9.0 were tested, the below values were obtained with pH 7.4) and determined with. a HPLC/DAD system using a gradient m (see below) and a reversed phase system. To achieve this, the samples (?nal volume 500141, ZOOuM compound concentration) were incubated for 24 hours at 23° C under continuous shaking at 1400 rpm (Thermomixer, ort) in aqueous phosphate buffers (pH 4.0, 6.0, 7.4 and 9.0) with a ?nal DMSO tration of 1%. To separate the undissolved compound from the solution, the samples were centrifuged (30 min 18000 g at 23° C). Supematants were measured via HPLC equipped with a UV detector and concentrations were calculated according to signals of a standard curve. The standard curve was prepared by diluting a stock solution of each compound (c=0.1 mg/ml; received by adding 10pl of 20mM compound in DMSO to 914 pl MeCN) in a certain amount ofMeCN to cover a range of 0.1 to 200 ug/ml. Examples for dilution are given in the table below.
Concentration [pg/ml] ..
: Stocksolution [pl] solventheéN [pl] WMWG1WMWMWMWWW 60.5 .. ..,.....Wm§95... m MMMMMMM i "WiiiiiiiiW "ii—i i 990 w .- - "me ,2. 20 980 HMHMMMW. , we , WWW 50 950 ‘ " i ‘ ibo 900 The following equipment was used: HPLC/PDA: Dionex Rapid tion LC—System te 3000 HPLC-Pump: OO no 8007268 Autosampler: WPS-BOOOSL no 8007769 Column Oven: TOG-3200 no 8006790 Detector: FDA—3000 no 08011269 Column: dependent on the test compound Software: Chromeleon 6.80 SP3 Build 2345 (128616) no 36452 Excel 007 Glassware: pasteur—pipettes Vials: glass vial (2 ml) with gasket (Dionex) Analytical balance: Sartorius LE225D-0CE acy: 0.01 mg) Miscellaneous: Rainin GPS Tips, Rainin pipet lite, Minishaker HPLC-parameters: Mobile phase A: dependent on the test compound, e.g. water with 0.1 % formic acid Mobile phase B: dependent on the test compound, e.g. acetonitrile Injection volume: 5 pl Column temperature: dependent on the test compound, e.g. 3 0°C Autosampler temperature: ambient temperature Sample loop: 25 ul PDA detection wavelength: dependent on the test compound, Data collection rate 5H2 Chrom.-stop-timc: dependent on the test compound, 6.g. 3.4 min Program HPLC: ent on the test compound As an e, the ing gradient was used for the measurement of a speci?c compound: Time [min] A rm in [% Flowmlinl/min] WEB" W "éo W .. ‘ [36W 1.7 0.4 80 kid" 3W 5 "2.7:::::::::::: - E5 W19?. $6.5m... ,,,,,,,,,,,- W WEE" MW "EWW 80 W W:::::::::::::::: E 3 4 L80 §20 $1.7 W. WW ::::::W..... d) Microsomal stability Metabolic ity of compounds of the present invention was determined by incubation with human liver microsomes and uent determination of residual amount of the respective compound ("parent compound") by HPLC-MS/MS.
In order to achieve this, in a ?nal reaction volume of 1000 ul, each compound was incubated at a ?nal concentration of 1 uM with 0.5 111ng human liver microsomes (HLM Pool 50 Donors, 20 mg/ml, BD Gentest, #452156, LotNr 88114) in 0.1 M Potassium phosphate buffer at pH 7.4, with a or in form of a NADPH regenerating system (Promega, #V9510) according to the manufacturers" speci?cations. The ?nal DMSO concentration in each sample was 0.4%. The incubation was performed at 37°C under g conditions omixer, 1400 rpm) for different time intervals up to 60 min. To stop the on, for each time point 200 pl of the reaction were taken out and 200 pl ice—cold acetonitrile was added. Then, the samples were centrifuged (4°C, 14000*g for 15 min). The supernatant was analyzed for residual parent compound concentration and scanned for metabolites using HPLC-MS/MS.
By using optimized MS methods for each compound, the peak area under curve for the compound speci?c signal is determined. The change of the peak areas over the assay time of 60 min resemble the remaining parent compound in % of T0. By these points, a ing line was set. The half-time, as well as the clearance, can then be calculated on the basis of the slope.
Equipment: Waters XevoTM TQ MS, Agilent 1200 HPLC, CTC-PAL Autosampler (temperature 8°C) Table 1 ary compounds of formula (I) of the present invention include the following: Ex. Name IL— TL— Ihmiilm- aq. 11/2 1 7A 1 7F gamma solub. hLM Inhib. Inhib. Inhi .
WW. . mm» mm mm}.wwwwww 1 1- {4-[3 -(2-chloro?uorophenyl)—4— ++ ++ +++ +++ +++ (1 ,3—thiazol—2—yl)-l,2-0xazol—5-yl]—5- (tri?uoromethyl)- lH-pyrazol-l -y1} propan—Z-ol 2 "WT-l {4-[3-(2-chloro?uorophenyl) +++ ++ +++ ++ + (1 ,3—thiazol-2—yl)-l,2-oxazolyl]—5- oromethyl)- 1H—pyrazol— 1 — yl }methy1)cyclopropan—l —ol 3 mZlffgiéfelilmdi‘mg-6~?u3iophmyl)-d- +++ +++ +++ n.t. 1+4; (l,3—thiazol—2—yl)—l,2—oxazol-5—yl]—5- (tri?uoromethyl)~1H—pyrazol-1 -yl } -2— l methylbutan-Z-ol mm 4 (2R)—1—{4-[3—Eé—chlom +++ l1"; " +++ n.t.i '+ ...... .t . M...?uSFbp?e?E-zt—(l,3—thiazol—2—y1)—1,2— oxazol-S-yl](tri?uoromethy1)—1H— pyrazol—l-yl}propan—2-ol +++ ++ ?uorophenyl)(1,3 -thiazolyl)-1,2- oxazol—S—yl]—5-(tri?uoromethyl)—1H— pyrazol- 1 —y1}propanol 6 l - {4— [3 —(2-ch10ro?uorophenyl)—4— +++ +++ +++ (1,3 oly1)-1 ,2—0xazoly1]—5- (tri?uoromethyl)-1H-pyrazol—1 - y1}butanol (rac) 7 E3—{$612-chf3¥"6?§2[b’rophenyl) +++ E (1,3-thiazol-2—y1)-l,2—oxazol—5-y1] ’ (t??uoromethyl)—1H—pyrazol-1 -y1}— 1 ,1 1 -tri?uoropropan-2—ol (rac) ‘ , 8 ethyl 31W8¥6fgi?$d¥6phenyliy +++ ++ +++ ++‘+ [1 ~(2-hydroxymethy1propyl) (tri?uoromethyl)- 1H-pyrazol—4—y1] - 1 ,2—oxazolecarboxylate 9 ethyl 3-(2-cl§10?g¥g?i?ophenyl}5-v ++ . +++ +++ +++ ++ [ 1 -(3-hydr0xy-3 —methy]butyl)—5 — (tri?uoromethyl)—1H—pyrazol-4—y1]— 1 ,2-oxazolecarboxy1ate w WWW." w.
E ethyl hloro?uorophenyl) 1++ +++ ++ 11+ {1-[(1R,3S)—3—hydroxy—3- methylcyclobutyl]~5-(tri?uoromethyl)- 1H—pyrazol-4—y1 } —1 ,2—oxazole—4- carboxylate (syn) "MWLWMW—W WW 1 1 ""3in 3-(2—ch10r0-6—?u0r0pheny1)—5— +++ +++ 4++ n.t. {1 -[(1S,3 R)hydroxy-3 - methylcyclobutyl](tri?uoromethyl)— 1H-pyrazolyl} —1 ,2-oxazole—4- carboxylate (anti) 12 ethyl 3-(Z—c?lero—6—?uorophenyl) +++ +++ 44+" (tri?uoromethyl)— 1 H-pyrazol-4—y1} - l ,2-oxazolecarboxylate , WWWWWWE 13 ethyl 3-(2—chloro—6—?uor0phenyl)—5- "94+ ‘ +++ +++ +++ ++ {1-[(2S)hydroxypropyl] (tri?uoromethyl)— 1 H—pyrazol—4-yl} - 1 ,2—0xazole—4-carboxylate 14 11+ Th +++ ++ [l —(2—hydroxybutyl)-5— (tri?uoromethyl)—lH—pyrazolyl]- 1,2-oxazolecarboxylate (rac) LN ethyl 3-(2-chloro—6-?u0rophenyl)5:" 1++ [1 -(3 ,3,3~tri?uor0hydroxypropyl) E (tri?uoromethyl)—lH—pyrazol—4-yl]— E 1,2-oxazole-4—carboxylate (rac) 16 ethyl 3-(2—chloro?uor0pherl§l):3": "43:1" 331+" ¥++ n.t.
R)-3,3 ,3 —t??uor0 ypropyl] —5~(tri?uoromethyl)— lH—pyrazol-4—y1}—1,2-oxazole—4- carboxylate "mmmmWWWWMMW X 17 methyl 3'(2'°h1°ropheny1)-5—{53W n.t. n.t. methyl[(lS,3R)-3.hydroxy_3_ methylcyclobutyl]- l H-pyrazolyl} - E 1,2-oxazolecarboxylate (anti) i 18 methyl 3-(2-chlorophenyl)—5— {5 - ++ 11++"v.1.":14 n.t. +++ methyl[(1R,3S)hydr0xy—3 - methylcyclobutyl]—1H-pyrazol-4—yl} - 1,2-oxazolecarboxylate (syn) 19 methyl lllblophen?)—5—[1 -(3 - +++ ++ +++ n.t. 4:31; hydroxy—3~methylbutyl)methyl- 1 H- pyrazol—4-yl]—1,2-oxazole carboxylate methyl 3-(2-chl0r0?uorophenyl):§fw wi?w +++ +++ +++ [1-(3-hydroxy~3-methy1butyl) methyl— 1 H—pyrazol—4—y1] -1 ,2-0xazole- 0xylate 2] methyl 5- { l -[(2K)hydroxypr0pyl] - -(tri?uoromethyl)— l H-pyrazolyl} - 3~(2—methoxypyridin—3 —yl)- l ,2- oxazole—4—carboxylate 22 methyl hlorophenyl)—5-{1-[(25')- ++ ++ 11W}. n.t. oxypr0pyl]—5-(t1i?u0romethyl)— 1H—pyrazol-4—y1}-l,2-oxazole carboxylate 23 ' methyl 3-(2-chlor0?uorophenyl)—5- ++ ++ { l —[(25)—2-hydr0xypropyl]—5- (tri?uoromethy1)-lH-pyrazolyl}— 1,2-oxazolecarboxylate ‘24 fnethyl 3-(2-chlor0phenyl)-5—{1-[(2S)- ++ ++' n.t. 2-hydroxypropyl]—5—methyl- 1H- l l pyrazolyl}-1,2-oxazole Lb carboxylate 125 methyl 3-(2—chlor0methoxypheny1)- +++ +++ ++T —[ l —(3 —hydroxy—3 -methylbutyl)-5 — methyl—1H-pyrazol-4—yl]—l ,2-oxazole- w; 4-carboxylate 26 7++ {1- [(l S,3R)-3 —hydroxy—3 - methylcyclobutyl]-5—(tri?uoromethyl)— lH—pyrazolyl} -1,2-0xazole carboxylate (anti) 27 methyl 3-(2-chlgfo—64?ubrophenyl)—5- +++ ++ ++ {1 -[(lR,3S)—3 —hydroxy—3 — cyclobutyl](tri?uoromethyl)- lH-pyrazol-4—yl}—1,2-oxazole—4- carboxylate (syn) 28 mfnelhyl 3-(2-5hloro?horophenyl) [ l -(3 ~hydroxycyclobuty1)—5- (tri?uéfbmethyl)-1H-pyrazol-4—y1]— 3 1,2—0xazole-4—carb0xylate ‘ 2' 29 g met?yl 3 -(2-ch10rophenyl)—5- {1 - f + ++ [(1S,3S)—3-hydr0xy—3— (methoxymethyl)cyclobutyl] (tri?uoromethyl)-1H-pyrazol-4—y1}- 1,2—0xazole—4-carb0xylate (syn) WWW" WNW—H4.mm——mwm—W_ 9—. "mum 3O 1-{fig-(2-chloro?uoropheny1) ++ (5—methy1—1,3 diazolyl)-1 ,2- oxazol-S-yl] (tri?u0romethy1)- 1 H— pyrazol-l—yl}~2-methylpropanol 131 L 1-{4-[3—(2-chloro?uor0pheny1) +++ +++ +++ (1,3 -thiaz01~2-y1)-1 zolyl] (’m'?uoromethyl}1H—pyrazoly1}(2- 2H)propa1n—2-ol (rac) m 32 "Nah;3-(2-chiord—6—?uorophenyl) +++ +++ +++ +++: { 1-[2-hydroxy(2-2H)propy1]~5- (tri?uoromethyl)- 1H-pyrazol-4—y1} - 1,2-oxazole—4-carboxy1ate (me) 33 methyl 3-(2-chlofo?uorophenyl) +++ +++ +++ +++ { ydroxy(2—2H)propy1]—5— (tri?uoromethyl)- 1 H—pyrazol—4-y1} - 1,2-0xazole—4—carboxylate (rac) W??ag?éhyl?f? + n.t. (2~hydroxy—2—methylpropyl)—5- (tri?uoromethyl)— lH-pyrazoly1] - 1 ,2—0xazol—4—yl]ethan—1 -0ne 1~[3-(2-chloro-6—?uoropheny1)-5":"{17W ~ ++ ++ +++ ++ 2—hydroxypropyl]—5- (tri?uoromethyl)-1 H-pyrazolyl } - 1 ,2-0xazol-4—y1]ethanone 36 l-[3 -(2-chloro—6—?u0rophenyl)[ 1 - + ++ ++ 1i}? in. (2—hydroxy—2—methylpropyl) (tri?uoromethyl)—1H-pyrazolyl]- E 1,2—oxazol—4—y1]cyclobuty1ethén—1— E one 37 jé1-[3—(2~ch10ro?uoropheny1)—5—[1— ++ +1— ++ n.t. n.t. é (2-hydr0xy—2-methylpr0py1)—5- (tri?uoromethyl)-1H-pyrazol—4—yl]— 1 ,2-oxazol—4-y1]pent—4-en—1 —one h 1 A m‘ w Wm", mm 38 2-[3-(2-ch10r0-6—?uorophenyl)—5-[ 1 - + 0 0 n.t. n.t. (2-hydr0xy—2-methylpr0py1)—5- f (tri?uoromethyl)- 1 H-pyrazol—4-y1]— 1 ,2—oxazolyl] —1 -cyclopr0pylheX—5- § 611—2-01 (me) 3 9 1—[3-(2—chloro-G—?uoropheny1)—5—[ 1 - + (2-hydroxy1nethy1propy1) (ni?uoromethyl)- 1H—pyrazol-4—y1]— 1,2-oxazoly1]—2-methoxyethan— 1 - 40 I1-[3-(2—ch10ro-6—?uorophenyl)-5—{"1"- + + + yn.t. n.t. [(2R)hydr0xypropyl]—5- (tri?uoromethyl)— 1 zol—4—y1} — 1 ,2-oxazoly1] methoxyethan— 1 - W ML 1 3-(i:mghloro?uorophenyl)-N— . E _....... .1 41 0 0 O n.t. n.t. entyl-5—[ 1 droxy—2— methylpropyl)-S-(tri?uoromethy1)~ 1 H- pyrazol-4—yl]— 1 ,2—oxazole—4- carboxamide 42 3-(2-chloro?uorophenyl)-N- O O 0 cyclopropyl[ 1 -(2-hydroxy methylpropy1)—5~(tri?uor0methy1)— 1 H- pyrazoly1] -1 ,2-oxazole»4- carboxamide F- 7 43 ; 3—(2—chloro?uorophenyl)-N_ + +, +~ : cyclobutyl-S —[ 1 -(2-hydroxy—2_ i propyl)-5 -(tri?u0r0methyl)— 1 H- .WWM».._WEWMWW_WW ....1 44 3—(2—chloro-6—?u0ropheny1)—N— ++ ++ cyclopentyl-S- {1-[(2R) hydroxypropyl] —5—(tri?uor0methy1)- 1H—pyrazol-4—yl}—1,2-oxazole-4— carboxamide 1""qu m‘mmmm.3—(2-chloro—6:?m?3ropnilmem;yl)—N:W , L M,M_._9._.WW"WM 45 ;+ n.t. cyclopropyl-S- {1 -[(2R) hydroxypropyl]—5—(tri?uoromethyl)- ; 1H—pyrazoly1}-1,2-0xazole—4- carboxamide ‘46 ' ‘ 3-(2—ch10r0?uoropheny1)—N— ++ ++ nm cyclobutyl—S- { 1 -[(2R) hydroxypropyl]~5—(tri?uoromethy1) - 1H-pyrazol—4—y1}—1,2—0xazole—4- amide ++ ’++ ++ [(2.5)—2—hydroxypropyl] methy1— 1 H~ pyrazoly1}-1 ,2-oxazole-4— carboxylate WwWLm ‘WWWWWWWWWWWWW,,,,,,,,,,,,,,,, mum.mwm~n ‘48 cycinropyl h10rophenyl) { 1 - [(1S,3R)—3—hydroxy—3- methylcyclobutyl]-5—(tri?uor0methy1)- 1H-pyrazolyl}-1,2—oxazole-4— i carboxylate (anti) 3 MWvw,M‘WWWMWMWpN_wW,w-M4 49 cyclopropyl 5:6-chlorophenyly5- { 1- +++ wwwmwmmmwwuwr +313; T3r++ g [(1R,3S)hydroxy methylcyclobutyl](tri?uoromethyl)— 1H-pyrazol-4—y1}-1,2-oxazole ylate (syn) WMHA ' "mm..." cyclopropizlm3;(§-chlor0 ‘ ++ +++ +++ m." ?uorophenyl){1-[(1S,3R) hydroxy—B-methylcyclobutyl] WWWWWWWWWMW (tri?uoromethyl)- 1 H—pyrazolyl } - 1,2-oxazole—4-carboxylate (anti) 51 cyélwopwropyl 3-(2-chloro ++ «MWmm".wwmwmmmmp?u—«Wmmww +++ ++ ++ ?uorophenyl) {1—[(1R,3S)—3- hydroxy—3-methylcyclobuty1]—5— (tri?uoromethyl)-1H—pyrazol—4-y1}- 3 1,2-oxazolecarboxylate (syn) #32$¥§?fi§?ifilchiéféphenylys- { 1 - 1++ M ++ ++ n.t. ')-3 -hydroxy—3 - methylcyclobutyl] methyl- 1 H- pyrazol~4-yl}-1,2-oxazole-4— carboxylate (syn) i 53 éjblopropyl 3-(2-chlorophenyI) {5- +++ +++ +++" lit.w methyl—1—[(1R,3S)—3-hydr0xy—3— methylcyclobuty1]-l H-pyrazoly1} - 1,2—oxazole—4wcarboxylate (syn) 54 a cygfgpropyi 3 lorophenyl) {5 - ++ nt n.t. methyl—1-[(1S,3R)—3-hydroxy—3 — methylcyclobutyl} 1 H—pyrazoI—4—yl } — 1,2-0xazole—4-carboxy1ate (anti) WHWWMH Wm.ummmwmw—f 55 byelbpropyl h10ro—6— +++ +++ +++:— ++ ?uorophenyD-S-[1 -(2-hydr0xy—2— ; methylpropyl)—5-(tri?u0r0methyl)- 1 H- g ; pyrazol-4—y1]—1,2-oxazole carboxylate 56 i" cyclobutyl 3-é-5hloro 9 +++: W +++ +++ henyl)—5—[ 1 —(2-hyd1'oxy—2— methylpropy1)(tri?uoromethyl)- 1 H- pyrazol-4—y1]—1 ,2-oxazole carboxylate Axmuwwmvmwwwww‘uw"4»A‘—«v4 oxetan—3-y1 3 -(2-chloro ++ ++ n.t. ?uorophenyl)[1—(2-hydroxy—2- methylpropy1)—5-(tri?u0romethy1)- 1 H- pyrazol-4—y1]—1,2-oxazole _..__..y ..www.mmw.m.m ,mmwwmw m............ .................. m carboxylate 58 bxetan—3 -y1 3 -(2-chloro—6— ++ +++ +++ n.t. ++ ?uoropheny]){1-[(2R) hydroxypropyl] -5—(tn'?uoromethyl)- 1H-pyrazoly1}-1,2-oxazole-4— L carboxylate 59 ' cyélopropylwg-(2-ch10i‘o—6— +++ +++ +++ +++ ?uorophenyl)-5 -{1-[(2.S')—2- i hydroxypropyl](tri?uoromethyl)- 1H—pyrazol-4—y1}-1,2-oxazole—4— E carboxylate 65WEmoxa?wn—Eyiyl 33;"(2-0h10r0—6—I ,++ ++ 7++ ?uorophenyl)-5—{1-[(2S)—2- hydroxypropyl]—5-(ni?uoromethyl)- 1H-pyrazoly1}-1,2-oxazole carboxylate ""61 ' +++ +++ +++ heny1)-5— {5-methy1-1—[(1R,3S)- 3-hydroxymethylcyc10butyl] - 1 H- ly1}-1,2-0xazole carboxylate (syn) _.MWWWWWWIWMVWWWWWW,mum"........... 62 cyclopropyl 3 loro 4+4": ++"+ +++ n.t. n.t. ?uoropheny1)—5— {5—methyl-1—[(1S,3R)— 3-hydroxy—3—methylcyclobuty1]- 1 H— pyrazol—4—yl } — 1 ,2-oxazole ylate (anti) 63 1—{4—[3—(2—chloro—6—?€6¥opheny1)—4— 0 n.t. n.t. % (hydroxymethy1)-1,2—oxazol—5—y1]—5— E (tri?uoromethy1)- 1 H-pyrazol— 1 —y1 } —2— methylpropan-Z—ol "'62? n.t. (hydroxymethyl)-1,2—0xazol—5-y1]—5- (tri?uoromethyl)—1H-pyrazol-1 -y1} methylcyclobutan-l-ol (syn) Ho— "WWW"..wmm mm mm.
V +45?" 65 1- {4-[3 -(2-ch10ro?uor0phenyl) nf (methoxymethyl)—1 ,2—oxazol—5—y1]—5- (tri?uoromcthyl)—1H-pyrazol-1 -y1} ~2- methylpropan-Z—01 66 (2R){4—[3—(2-chlor0 _++ +++ n.t. ?uorophenyl)~4—(meth0xymethyl)- 1 ,2- oxazoI-S-yl](tri?uoromethyl)- l H- pyrazol- 1-y1}propanol mm", «V . 1 67 4-{4-[3-(2-chloro—6—?uorophenyl) ++ ++ +++ +++ #14 (methoxymethy1)-1,2-oxazolyl]-5— (tri?uoromethyl)- 1H-pyrazol-I -yl} methylbutan—Z—ol 68 (253{4-[3-(2-chloro ++ mi" ?uoropheny1)—4—(methoxymethyl)—1 ,2- oxazol-S-yl]~5-(tri?uoromethy1)—1 H- pyrazol- 1 opan—2-ol g... . WWW 69 E (1R,3S)—3- {4[3-(2-chloro qu ++ +++ n.t. 1++ ‘ ophenyl)—4(methoxymethyl)-1,2- E oxazol-5—y1]——5——(tri?u0r0methy])— 1H— l WWW pyrazol1-y1}- 1-methylcyclobutan01 (syn) WWWmmmmwmmmW.mm WWWW "' 70 (IR,35') {4-[3-(2-chloro n.t. nLt. ?uorophenyl)—4—(meth0xymethyl)-1 ,2- oxazol-S-yl]methy1-1H—pyrazol-l— yl} — 1 -methylcyclobutan— 1 -ol (syn) ‘3 (15,3R){4-E‘3"f(2-ch18¥83’6- 3 71 n.t. n.t. ?uorophenyl)—4—(methoxymethy1)—1 ,2— -S-yl]methy1-1H-pyrazol-l— y1}methylcyclobutanol (anti) 72 (1R,3S){4-[3-(2-chlorophenyl) 4+ (methoxymethy1)—1,2-oxazolyl] methyl—lH-pyrazol-l -y1} methylcyclobutan— 1 —01 (syn) yum..." 73 (1S,3R3—3{4[3(2-0h1°r°Pheny1)4' methyl—1H—pyrazol-l-y1}-1— i cyclobutan-I —01 (anti) 74 (1R,3S)—3-{4-[3-(2-ch10rophenyl) n.t. n.t. (methoxymethyl)-1 ,2-oxazoly]] (tri?uoromethyD-1H-pyrazoly1} methylcyclobutan-l-ol (syn) 75 (2S)—1—{4-[3-(2-chlorophenyl)[(2— E methoxyethoxy)methyl]-1,2-0xazol—5- g yl]—5-(tri?uoromethyl)—1H—pyrazol-l— , y1}pr0panol L 76 (2R){4-[3-(2-chloro i ++ ++ "m + ?uoropheny1)(ethoxymethyl)-1,2- é -S-yl]—5-(tri?uoromethy1)-1H- 3 pyrazol-l—yl}propanol 1 { ’ ’ 77 E4-{4-[3-(2-ch10ro?u0ropheny1)-4— +++ +++ +++ ++ ¥++ (cyclopropoxymethyD-l ,2-0xazol yl] -5—(tri?uor0methyl)-] H-pyrazol yl}methy1butan—2-01 78 4— {4—[3-(2-ch10r0pheny1)-4_ ++ +++ +++ (cyclopropoxymethyl)- 1 ,2-0xazol—5 - y1]-5 -(tri?uor0methy1)-1 H—pyrazol-l - yl } —2-methylbutan—2-ol 79' "X‘Z:{4-[31(2-chlorophenyl) , ++ ++ +++ n.t. n1." ‘ (cyclopropoxymethyl)— 1 ,2-oxazol—5- y1}methy1- 1 H-pyrazol-l -y1} methylbutanvZ—ol 80 (1R";"'§E:9-'3—{4:11éilmfz-chlo1roph«enwiifjilil° n.t. n.t. (cyclopropoxymethyl)- 1 ,2—oxazol—5 ~ . yl]methyl-1H-pyrazoly1} methylcyclobutan-l-ol (syn) 8i" ){4-[3-(2-chlorophenyl)M .4 WWW "Wmmmw...‘‘‘‘‘‘WW—————-mN—? + ++ (cyclopropoxymethyl)- 1 ,2-oxazol-5— 1 yl]—5-methy1—1H-pyrazol~1-y1}-1 — A..."‘‘‘‘‘‘‘3,,__ methylcyclobutan-l-ol (anti) 82 4- {4-[3 10r0-6—?uorophenyl)4: +3" 7+++ (cyclopropoxymethy1)-1 ,2-oxazol y1]-5 -methyl-1H-pyrazol—1-y1}—2- methylbutan—2-01 (1W3(2ch10ro-6— +++ ?uorophenyl)—4- (cyclopropoxymethyl)-1 ,2—0xazol—5— yl]methy1-1H-pyrazoly1} methylcyclobutan-l—ol (syn) 84 (IS;'3R) {4-[3 -(2—chloro ++ ++ ++ ' heny1)-4— , (cyclopropoxymethy1)-1,2-oxazol—5- yl]methy1-1H—pyrazol-1—y1}—1— methylcyclobutan— 1 -ol (anti) 85 -{4-[3-(2-EMOro-6; +++ +++ +++ n.t.
E ?uoropheny1)- E V (cyclopropoxymethy1)- 1 2-oxazol—5- iyl](tri?uoromethyl) lH-pyrazol-l-y1}propan—2—01 F "WWWWWVM 86 (11%359—3{4—[[3—(2ch10r0 +++ +++ +++ +++ ?uorophenyl)—4- (cyclopropoxymethy1)- 1 ,2—oxazol yl](tri?uoromethy1)- 1 H-pyrazol yl} — 1 —methylcyc10butan—11-01 (syn) __._.1. ,1m"WWWm L ' 87 (IR,SS) {4—[3—(2—chloropheny1)—4- E ++ +++ +++ (cyclopropoxymethyl)— 1 ,2-oxazol-5 - (tri?uoromethy1)- 1 H-pyrazol i y1}—1—methylcyc1ohutan01 (syn) 1 83 (ZS){4-[3-(2-chlorophenyl) "'6 n.t. [(oxetanyloxy)methy1]-1 ,2—oxazol- -(tri?uor0methyl)- 1 H—pyrazol- 1—yl}pr0pan—2-ol 86' (2R)1{4-[(2:--ch10ro6- ?uoropheny1)—4-[(pr0pan—2- yloxy)methyl]— 1 ,2—oxazol—5-yl] —5— (tri?uoromethyl)- 1H—pyrazol-l - y1}propan—2—01 90 (2R){4-[3-(2—ch10r0 +++ +++ +++ +++ ?uoropheny1)-4—(cyclobutoxymethyD— 1,2-0xazoly1]-5~(tri?uoromethy1)- azol-l -y1}propan—2-01 91 4— {4-[3-(2-chloro-3—meth63{yphényl)- +++ +++ +++ ILL 11.1. lopropoxymethy1)—1 ,2—oxazol—5— y1]-5—(tri?uoromethyl)—1H-pyrazol-l- yl}methy1butanol 92 (1R,3S)—3 -[4-(3 — {2-chlorol3-[2- +++ +++ +++ n.t. (morpholin—4—y1)ethoxy]phenyl} (cyclopropoxymethyl)- 1 ,2—oxazol y1)—5-(tri?uoromethyl)— 1 H—pyrazol— 1 - y1]— 1 —methylcyclobutanol (syn) 93 meth§1 5-[1-(2—hydroxy—2— m ++ ++ n.t. n.t. i methylpropyl)—S—(tri?uoromethy1)— 1 H- lyl] -3 -(2-hydroxypyridin-3 - y1)- 1 ,2—0xazole—4—carboxy1ate 94 "(5R){41[3 -(2:"3'HiE>m n.t. n.t. ?uoropheny1)- 1 ,2~oxazoly1]-5 — (tri?uoromethyl)-1H—pyrazol— 1 - yl }propan—Z-01 95 ++ ++ ++ xymethyD-l,2-oxazol-5—yl]-5— (tri?uoromethyl)-1H-pyrazolyl} (2- 2H)pmpan01 (rac) ‘96 (259 {4-[3 -(2-chloropheny1) ++ (oxolan-Z—y1)- 1 ,2-0xazol—5—yl]-5— (tri?uoromethyl)—1H-pyrazol—1 — y1}pr0pan-2—01 72—53-{4—13~(2—chléro—6:m """""" 97 134+ """""""""""T ?udESbhenylj-JT®§§?idiByi)IKE: ' "1 " MM"— oxazol-S-yl] -5 -(tri?uoromethy1)~ 1 H- : pyrazol-l-yi}propan01 w§§"""""""""'??j‘ésja:{4:‘féméféfWWW"Timirwwl?w +1111:111111111 "Hit, ‘ ?uorophcnyl)—4-(pyrimidin—2~y1)- 1 ,2- oxazol-S—yl] -5~(tri?uoromethy1)- 1 H- pyrazoly1}methylcyclobutanol i_,.____,m,.m,,,._£ (Syn) (112,353-3—{4—[33(2—ch1oropheny1y4- W 11______ ...___1_1_,__________ L 99 ++ >+++ +++ "4511+" 149+ idin—Z-yl)—1,2-oxazoly1] i methyl-1H-pyrazolyl} methylcyclobutan—l -01 (syn) 1’60 w ,,,,,,w WW mWWW,WWWWWWMWW (1R,3S) {4-[3-(2-chloro ++ +++ +++ n.t. +++ 3 ?uorophenyl)—4—(pyrazin—2-yl)— 1 ,2- ; oxazol-S—yl] (tri?uoromethyl)- 1 H- pyrazoly1} — 1 lcyclobutan01 (112,353—3-{Z-[3-(2-c1ilompheny1) 1,-" . E W ..... ,0 1 101 + 0 0 + 4:1": (pyrazin—Z—y1)-1,2—0xazol—5—yl] —5 — oromethyl)— 1H-pyrazoly1 } methylcyclobutan-l-ol (syn) 102 (1R,3S)-3—{4-[3—(2-ch1ompheny1) +++ +++ +++ +++‘ 3L4; (pyrimidin—2~y1)-1 ,2—oxazol-5—yl] (tri?uoromethyl)— 1H—pyrazoly1 } methylcyclobutan—l-ol (syn) 103' (1R,3S){4-[3-(2-chloro +++ +++ ‘+++ n.t. +++ methoxyphenyl)—4—(pyrimidin~2—yl)— 1 zoly1](tri?uoromethy1)- lH-pyrazol- 1 —y1}—1-methylcyclobutan- 1-01 (syn) 104 (111,353—3-{4—t3if2-chlom—6- +++ 5+++ +++ 4? $++ ?uorophenyl)(pyrimidinyl)-1,2- oxazol-S-yl]-5—(tri?uoromethyl)— 1 H- 3 pyrazol— 1 —y1}-1 -methylcyclobutan-1 -01 1 uuuuuuuu(syn)w,1, 1 _ ____..,1 - .
E H.
W‘T‘Tm(15,3R)3 {4—T3"(2chloro6— T ' 137%" ' f++ " + ++ 11.1. ?uoropheny1)—4-(pyrimidin-4—y1)-1,2- 5 oxazol—S—yl]-5—(t11'?uoromethy1)—1H— I pyrazoly1}-1—methylcyclobutan01 i : (anti) ,_2 3 WM, 1, .1,...... ,.......... 106 (IR,SS) {4- [3-(2-ch10ropheny1)—4— +++ +++ 3++ +++ +++ (pyrimidin—4-y1)-1,2—oxazoly1] (tn'?uoromethyl)— 1H—pyraz01—1 -y1} —1- methylcyclobutan01 (syn) 107 (IR,35')3{4[3(2chloropheny'ij2‘1 ++ ++ +++ 311.1. n.t. (pyrimidin—4-y1)-1,2-oxazol—5-y1] methyl-1H—pyrazoly1} E 108 :,(1R3S)--{4[3(2-ch10ro--"'""'6- ++ ++ ++ n.t. n.t. ?uorophenyl)4——(pyrimidin-4—y1)—1,2- oxazo1-S-y1]methy1— 1 Hapyrazol T » y1}-1 —methylcyclobutan— 1 ~01 (syn) f M ........WWWWWWMW WMWWW . , 109 (IR,35')——3 2chloropheny1)4- + + ++ 111.1. n.t. (pyrazin—Z-y1)-1 ,2-oxa201y1]-5— methyl-1H-pyrazol—l -y1} —1 - T116 methylcyclobutan-l -ol (syn) (IR,315)3— {4-[3(2--chloro ++ 3++ ++ 3++ V +++ ?uorophenyl)—4-(pyrazin—2-y1)- 1 ,2- y1]—5—methy1- 1 H-pyrazol— 1 — yl}methylcyclobutanol (syn) 111 (1R,3S)—3 {4[3(201110106- +++ +++ +++ +++ +++ ? ?uorophenyl)(pyrimidinyl)-1,2- oxazol-S-y1]—5—methyl- 1 H—pyrazol y1}--1—-methy1cyclobutan 1 -01 (syn) 112 §,(1R3S)---3 {4- [3-(2-chloro +++ +++ +++ +++ +++ g ypheny1)--(pyrimidiny-1) :11 ,2—oxazol-5—y1]—5-methy1-1H-pyrazoly1}-methylcyclobuta11-1 ~01 (syn) (2116-1 - {4-[3 —(2;meth0xypheny1)—4— +1 W 113 1 1 + n.t. (pyrimidin—Z—yl)—1,2—0xa201—5-y1]-5 - (tri?uoromethyl)- 1H—pyrazol- 1 — pan—2-01 114 3-(2-methoxypheny1) TY}uuuuuu n.t. n.t. (pyrimidin—Z—yl)—1,2-oxazolyl]—5— (tri?uoromethyl)—1H-pyrazoly1}—2- methylpropan—Z-ol (210{4—[3—(2—metho'52ypheny'13‘i4— ‘ ms: 115 ++ n.t. n.t. (pyrimidin—4-y1)-1,2-0xazoly1]—5- (tri?uorornsethyl)~ 1 H-pyrazol yl}propan—2—ol 116 n.t. nt (pyrimidin—4—y1)—1,2—oxazol-5—yl] (tn'?uoromethy1)- 1H—pyrazol»1 ~y1} -2— methylpropan-Z-ol "T "— WWWMW? 117 (2R){4—[3-(2—chloro-3— ++ n.t. methoxyphenyl)(pyrimidiny1)— : 1,2—oxazol—5-yl]—5—(tri?uoromethy1)- ] H—pyrazoly1}pr0pan—2-ol idin—Z-yl)— 1,2—0xazoly1]-5— (tn'?uoromethyl)- 1H-pyrazol- 1 —y1} ~2— methylpropan-Z-ol ___W.r___~_._.. (2R){4—[3-(2-ch10r0—3— methoxyphenyl)(pyrimidinyl)- 1 ,2-0xaz01y1] -5—(tri?uoromethy1)— 1H—pyrazoly1}pr0panol 120 1- {4—[3 -(2—chlo;omethoxyp?er1yl)— 4-(pyrimidin—4-y1)—l ,2-oxazoly1] oromethyl)—1H-pyrazol—1 -y1} ~2- methylpropan-Z—ol .44 ' +43?" K 4- {4_[3-(2—chlommethoxyp?ény?- "1+ ++3+ n.t. +++ «.mm..,,,w""""" ".4.-. wI. ...............m"Wmm...m..m............mwww i (tx‘i?uoromethyl?nim?r??ézol—l -y1} methylbutan-z-ol 122 4- f44fé-(2-é?i‘brdbh23§133hi ' +++ +++ +++ (pyrimidin—Z-yl)— 1 zoly1] —5— (ui?uoromethyl)-1H-pyrazoly1 } methylbutan—Z-ol " 123"" ?; " g 4-{4‘73i(2-cmngb—6-?uor5fi?eny1374- +++ +++ +++ (pyrimidin-Z-yl)—1 ,2-oxazoly1] (tri?uoromethyl)- 1H—pyrazoly1} methylbutan-2—o1 "133, W 4-{4—[3 -(2-c11101‘ometh0xyphenyl)- +++ +—1:+ +++ 4-(pyrimidiny1)—1,2—oxazoly1]—5- methyl- 1H-pyrazolyl} -2— methylbutan—Z—ol 125 4-{4-[3-(2,6-dichloro:§:m ++ +++ yphenyl)(pyrimidin—2-y1)- 1 ,2-oxazol-5—y1]~5-methy1—1H-pyrazol- 1-y1}methylbutan—2-01 pdr?—mm_nm_w_.m2m ..... 126 - 4—{4—[3-(2-chlorophcnyl) ++ ++ +++ +++ (py?midin—Z-y1)- 1 ,2-oxazoly1] ' methyl-1H-pyrazoly1}—2— . methylbutan-Z-ol . m; Em," 127 4- {4-[3-(2-chloroW ++ ++ +++ n.t. +++ (py?midin—Z-y1)-1,2-oxazoly1]—5- methyl-1H—pyrazolyl}—2— methylbutan—2.—ol ifil?é?gféxyyz— " +++ +++ chlorophenyl](pyrimidinyl)-1 ,2- oxazol—S—yl}(tri?uor0methy1)— 1 H— pyrazol-l—y1)—2-methy1butan—2-01 129 2—chloro {5—[1-(3-hydroxy—3- 1+;L ++ n.t. methylbutyl)-5—(tri?uoromethy1)- 1 H- pyrazol—4—yl]—4-(pyrimidinyl)-1 ,2— 130 (1R,35)—3- {4-[3 -(2-chloro;3- 11+ +++ +1 ++ methoxyphenyl)—4— (cyclopropoxymethy1)-1 ,2—oxazol—5- (tri?uoromethyl)- 1 H-pyrazol-l — yl } -1 -methylcyclobutan01 (syn) +++ +++ {1-[(1R,3S)hydroxy—3- : methylcyclobutyl]-S—(t1‘i?uoromethy1)— 1H«pyrazol-4—y1 } -1 ,2—0xazole carboxylate (syn) 132 ethyl 3-(2-chloromethoxyphenyl) ++ ++ [ 1 {3 -hydroxy-3 -methy1buty1)—5 — (tri?uoromethyl)-1H~pyrazol—4-y1]— 1 ,2—oxazole—4—carboxylate " 4-[4-(3-{2-chloro[2—(morpholin-4¥ ' +++ 133 +++ oxy]pheny1}-4—(pyrimidiny1)— 1,2-oxazoly1)~5-(tri?uoromethyl)- 1H~pyrazol-1 -y1] hylbuta11-2—01 4—[4—(3-{2—ch10r0-3—[2- +++ (dimethylamino)ethoxy]pheny1} (pyrimidin-Z—yl)~1,2—oxazoly1)—5- (tri?uoromethyl)-1H—pyrazol~1 -y1] methylbutan-Z—01 mn—éwnmramm...........4-[4-(3—{2—chlofo[2-(p§z}rolidin-1— ".qummmwmmmwm 135 ++ +++ n.t. ++ y1)ethoxy]pheny1}—4-(pyrimidiny1)— 1 ,2—oxazoly1)(t??uoromethyl)— lH-pyrazol-l —y1]-2—methy1butan01 __ ' 136 4-[4-(3- {2-chloro[2-(4- '1+ ,++ ++ n.t. n.t. methylpiperazin— 1 -yl)ethoxy]pheny1} — imidin-2—y1)-1,2-oxazoly1)~5- (tri?uoromethyl)- 1H—pyrazol-1 —yl] -2— methylbutan-Z-ol rum-.1"...~137 "WM"...MWMMM. "211111113—{2-61110m[2— ++ ++ ++ (diethylamino)ethoxy]phenyl} m...» (pyrimidin—Z-y1)—1 zol—5-yl)—5- (tri?uoromethyl)—1H—pyrazol-1 -y1] ~2— butan-Z-ol 4—[2—(2—ch10r0{5-[1-(3—hydr0xy—3:Wm WM»... 4‘le methylbuty1)(tri?uoromethyl)— 1 H- pyrazol-4—y1](pyrimidin—2—y1)-1 ,2- y1}phen0xy)ethy1]- 1 lambda6—thiomorpholine- 1 ,1 —dione 139 4—(4- {3 -[2-ch101'0(2- {2-0xa—6— +++ TH n.t. azaspiro[3 .3 ]heptan y1} ethoxy)pheny1](pyrimidin—2—yl)- 1 ,2—oxazol—5—y1}—5-(tri?u0romethyl)- 1 H-pyrazoly1)-2—methy1butan01 140 4—[4Ié1{2—ch10ro—3—[3 — ++ ++ n.t. 11.1. (dimethylamino)propoxy]phenyl} (py?midin—Z—yl)— azoly1) (tri?uoromethyl)—1H-pyrazol-1 ~y1]—2— methylbutan—Z-ol g ’ MlmmW.......M» 141 4—[3-(2-chloro-3—{5—[1-(3-hydroxy—3- +++ +++ +++ n.t. methylbutyl)—5—(tri?uoromethy1)— 1 H- pyrazol—4—y1](pyrimidin-2—y1)—1 ,2- oxazoly1}phenoxy)p:r0py1]— 1 1ambda6-thiomorpholine~ 1 ,1 -dione 521-[4-(331‘iichlom[é{py?o?din- 1 — ++ ++ ++ y1)pr0poxy]phenyl}(pyrimidin y1)-1,2-oxazolyl)-5 - (tri?uoromethyl)— 1H—pyrazol— 1 -y1] —2- methylbutan—Z—ol 143 4-[4—(3-{2-ch10ro[3— 41+ +++ +++ n.t. (diethylmnino)propoxy]pheny1} (py?midin-Z-yl)-1 ,2—0xazoly1)~5- (tri?uoromethyD- 1H-pyrazoly1] L124m 4—[4L(3—{2—chlor6—3-[2-methylbutan—E-ol M (di‘éh?émino)éi?bxyj'g?e?yl}—4— (py?midin-Z-y1)-1,2-oxazolyl) methyl- 1H—pyrazol-1 -yl]—2- methylbutan—Z—ol 145 4-[4-(3-{2-c1i10ro[2- n.t. § (dimethylamino)ethoxy]phenyl}~4— (pyri1nidin—2-y1)-1,2-0xazoly1) methyl—1H-pyrazol-1—y1]-2— 3 methylbutan-Z-ol i 146 ?l??i?j??olidififim- ++ n.t. yl)ethoxy]pheny1}—4-(pyrimidin—2-yl)- 1,2-0xazol—5-yl)methy1-1H-pyrazol- , 1 -y1] methy1butan—2-ol "147 3-{2-ch10r0—3-[3- +++ "+14" (diethylamino)propoxy]phenyl} (pyrimidin—Z-yl)—1,2-oxazolyl)—5- methyl- 1 H—pyrazol—l —y1] methylbutan—Z—ol Til—Sm ‘ methyl ?iwbr33~[Erzgoirpho?m—ZTW ¥++ n.t. ! yl)ethoxy]phenyl}{1—[(2S) i hydroxypropyl] (tri?uoromethyl) — t azol-4—y1}-1,2—0xazole—4- carboxylate 149 methyl 3- {2-chloro-3—[2— +4" n.t. (dimethylamino)ethoxy]phenyl} { 1- [(2S)hydroxypropy1] (tri?uoromethyl)- 1 H—pyrazol—4—y1 } — 1 ,2-oxazole-4—carb0xy1ate 15b (1R,3S‘3—3-[4—(3—{2-ch10ro[2- +++ +++ +++ (morpholin-4—yl)ethoxy]phenyl} (methoxymethyl)—1,2—oxazol-5—y1)—5- (tri?uoromethyl)-1H-pyrazol-l -y1]-1 - methylcyclobutan-l-ol (syn) 1 5 1 (1R,3S)_3-[4_(3 _ {2"Ch101‘O[z-lW" +++ (dir?ei?ylarfiino?thoi??iény?—4- (methoxymethy1)-1,2-oxazoly1)—5- (tri?uoromethyl)-1H-pyrazol—1 - cyclobutan01 (syn) (1S,3R)43-[4-(3-{§-chlorofi- " 152 ++ ++ ++ olin—4—yl)ethoxy]phenyl } ~4— (methoxymethyl)—1,2-oxazol—5-y1)-5— (tri?uoromethyl)- azol— 1 -y1]-1— methylcyclobutan-l -01 (anti) 153 (15,3R)—3-[4-(3J{2—ch1W"mmmwwm 0 (dimethylamino)ethoxy]pheny1 } ~4- (methoxymethy1)—1,2—0xazoly1) (tri?uoromethyl)-1H-pyrazol-1 -y1]- 1 — methylcyclobutan-l-ol (anti) #154 (2R)(4-{3-f53hlor6'3ii?r??6?m?e- + ++ n.t. 4—carbonyl)phenyl](pyrimidin—4—y1)— 1 ,2-oxazol—5-yl} —5—(tri?u0r0methy1)- lH-pyrazol-l —y1)propan—2-ol WW,«MM—.m— wvvvvvv WWW—"WW. 155 E 2-chloro—N—cyclobuty1-3—(5—{l—EEER} ++ ++ n.t. 1 2—hydmxypropy1](tri?uoromethyl)- 1H-pyrazoly1} (pyrimidin—4-y1)— 1,2—oxazolyl)benzamide 4W.WMWWWWWWW TB? 2—chloro-N-ethy1—3—(5— {_ 1—[(2R)-2— 0 0 n.t. n.t. ypropyl](tri?u0romethy1)— 1 H—pyrazol—4—y1} —4~(pyn'midin—4-yl)— 1 ,2-oxazoly1)benzamide WWW mm‘‘‘‘‘‘‘‘‘‘‘‘"MW 157 2-c31316—3-(Ei?—[(2R)—2— + ++ n.t. 11.1. hydroxypropyl](tri?uoromethyl)- 1H—pyrazol-4—y1}—4-(pyrimidinyl)- 1 ,2-oxazol-3 -yl)-N-(propan—2- yl)benzamide "158W (2R)(4-{3-[3-(azetidine ++ ++ n.t. carbonyl)chloropheny1] (pyrimidin—4—yD-1,2—oxazolyl}—5— ‘ kw... y1)propan-2—01 159W 2-ch16rb-N-c§3i‘3f§f3§§ifé-(5-{1—[(2R)— ++ nil" 2-hydr0xypr0pyl]—5—(tri?uoromethy1)— 1H-pyrazol—4—y1}(pyrimidiny1)- 1 ,2-oxazol—3 -y1)benzamide 160 (2R)(4—{3-f‘é?hlor3f'53W5ii?i?‘é- +++ +++ +++ 1-carbony1)phenyl]-4—(pyrimidin—4-yl)— 1 ,2—0xazol—5—yl} -5—(tri?uor0methyl)- i azoly1)propan—2—ol. 161 opropyl-a—Es—{1—[(2R)" n.t. hydmxypropyl](tn‘?uoromethyl)- lH—pyrazolyl}(pyrimidinyl)- 162 n.t. (pyrimidiny1)- 1 ,2-oxazola3~yl) methoxy—N—(propan—Z-yl)benzamide 163 -(4—{3—[3 -(azetidine— 1 - n.t. n.t. , carbonyl)methoxyphenyl]-4— (py?midiny1)—1,2-oxazoly1}—5- (tri?uoromethyD-l H-pyrazol-l - y1)propan-Z-ol 'é N-cyci'Sbutyl—s—(s—{l{(212)—2— 1&2". ' , 164 n.t. hydroxypropyl]-5—(tri?uoromethyl)- 1 H-pyrazoly1} (pyn'midiny1)- 1 ,2-0xazol—3-yl)-2—meth0xybenzamide 165 N-et?371i3{5-{"13[(2R) n.t. hydroxypropyl]—5—(tri?uoromethyl)- azoly1} —4—(pyrimidiny1)— 1,2—0xazol—3—y1)methoxybenzamide .Hmmm N-cyclobutyl-3 -(5- { 1 - [(2156 n}. n.t. hydroxypropyl]—5-(tri?uoromethyl)- 166 N-cyclobutyl(5-{1-[(2R) + 0 + n.t. n.t. hydroxypropyl](trifluoromethyl)- azolyl}(pyrimidinyl)- 1,2-oxazolyl)benzamide 167 1-[(2R)hydroxypropyl] 0 0 + n.t. n.t. (trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)-N- (propanyl)benzamide The IC50 values for the cytokines are determined with the Cytokine Assay as described herein: +++ : < 50 nM; ++ : 50 nM to < 500 nM; + : 500 nM to <5 µM; 0 : = 5 µM.
The values for aqueous solubility are determined with the method described herein: 0 : <1 µM; + : 1-2.99 µM, ++ : 3-9.99 µM, +++ : >10 µM, n.t. : not tested The t1/2 values for microsomal stability are determined with the method described herein: 0 : 2-9.99 min; + : 10-39.99 min, ++ : 40-100 min, +++ : >100 min, n.t. : not tested Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be tood to imply the inclusion of a stated integer or step or group of integers or steps but not the ion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this ication relates.

Claims (11)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A compound of formula (I) or a pharmaceutically able salt or solvate thereof, formula (I) wherein Ar is selected from the group consisting of phenyl and 5- or 6-membered aryl, each of which is optionally substituted by one or more independently selected substituents RAr; RAr is selected from the group consisting of halogen, -OH, -CN, C1alkoxy, C1 koxy, C1alkyl, aloalkyl, mono- or di-C1alkylamino-C1alkyl, mono- or di-C1alkylamino-C1alkoxy, -COOR’, ’, -CO-R’, - SO2NHR’, -NH-CO-R’, -NO2, -NH-SO2-R’, -SO2-R’, benzyloxy, -CO- heterocyclyl, -CO-C3cycloalkyl, -CONH-C3cycloalkyl, -CONH- heterocyclyl, -O-C1alkyl-heterocyclyl, -O-C1alkyl-C3cycloalkyl, (2-oxa- 6-azaspiro[3.3]heptyl)-C1alkoxy, amino, benzyl, phenylethyl, C3 cycloalkyl, heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein each of said alkoxy, benzyl, phenylethyl, alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl groups is optionally substituted be one or more substituents independently selected from C1alkyl, C1haloalkyl, halogen and OH, and wherein R’ is ndently selected from the group consisting of H, OH, C1alkyl and aloalkyl; Z is selected from the group consisting of H, halogen, -CO-RZ, -CH2-O-RZ, -COCH2-RZ , -CO-CH2-O-RZ, -COORZ, -NHCO-RZ, -CO-NHRZ, 2, -CN, - NHCOORZ, -SO2-RZ, -SO2NHRZ, -C1alkyl-O-RZ, alkyl-O-C1alkyl- O-RZ, amino, C1alkyl, phenyl, 5- or 6-membered heteroaryl, heterocyclyl and C3cycloalkyl, wherein each of said alkyl, phenyl, heteroaryl, heterocyclyl and cycloalkyl groups is optionally substituted be one or more substituents independently selected from the group consisting of halogen, C1alkyl, C1 alkoxy, C1haloalkyl, -COO-C1alkyl, OH and C3cycloalkyl; RZ is selected from the group consisting of H, halogen, -OH, C1alkyl, C1 haloalkyl, C3cycloalkyl, heterocyclyl, phenyl and 5- or 6-membered heteroaryl, Y is H, halogen, C1haloalkyl or C1alkyl; R1 is a group of the structure n is 0 or 1; and R2 is H, deuterium or methyl; and R3 is , trifluoromethyl, ethyl, or a cyclopropyl group when taken together with R2, or forms a methylene bridge to the carbon atom marked *, wherein heteroaryl contains at least one heteroatom independently selected from O, N or S, and wherein heterocyclyl denotes a 3- to ered heterocyclic non-aromatic group containing at least one heteroatom independently selected from O, N or S.
2. The compound of formula (I) according to claim 1 or a ceutically acceptable salt or e thereof, wherein Ar is selected from the group consisting of phenyl, and 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more independently selected substituents RAr; RAr is selected from the group ting of halogen, -OH, -CN, C1alkoxy, haloalkoxy, C1alkyl, aloalkyl, mono- or di-C1alkylamino-C1alkyl, mono- or di-C1alkylamino-C1alkoxy, -COOR’, -CONHR’, -CO-R’, - SO2NHR’, -NH-CO-R’, -NO2, -NH-SO2-R’, -SO2-R’, oxy, -CO- heterocyclyl, -CO-C3cycloalkyl, C3cycloalkyl, -CONH- heterocyclyl, -O-C1alkyl-heterocyclyl, -O-C1alkyl-C3cycloalkyl, (2-oxa- 6-azaspiro[3.3]heptyl)-C1alkoxy, amino, benzyl, phenylethyl, C3 cycloalkyl, heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein each of said alkoxy, benzyl, phenylethyl, alkyl, cycloalkyl, heterocyclyl, phenyl and aryl groups is optionally substituted be one or more substituents independently selected from C1alkyl, C1haloalkyl, halogen and OH, and wherein R’ is independently selected from the group consisting of H, OH, C1alkyl and C1haloalkyl; Z is selected from the group consisting of H, halogen, -CO-RZ, -CH2-O-RZ, -COCH2-RZ , -CO-CH2-O-RZ, -COORZ, -NHCO-RZ, -CO-NHRZ, -N(RZ)2, -CN, -NHCO2RZ, Z, -SO2NHRZ, alkyl-O-RZ, alkyl-O-C1alkyl- O-RZ, amino, C1alkyl, phenyl, 5- or 6-membered heteroaryl, heterocyclyl and C3cycloalkyl, wherein each of said alkyl, phenyl, heteroaryl, heterocyclyl and cycloalkyl groups is optionally substituted be one or more tuents independently selected from the group consisting of halogen, C1alkyl, C1 alkoxy, C1haloalkyl, -COO-C1alkyl, OH and C3cycloalkyl; RZ is ed from the group consisting of H, halogen, -OH, C1alkyl, C1 haloalkyl, C3cycloalkyl, heterocyclyl, phenyl and 5- or 6-membered heteroaryl, Y is H, halogen, C1haloalkyl or lkyl; R1 is a group of the structure wherein n is 0 or 1; R2 is H, deuterium or ; R3 is methyl, trifluoromethyl, ethyl, or taken with R2 together forms a cyclopropyl group; n is 1, R2 is H, deuterium or methyl and R3 forms a methylene bridge to the carbon atom marked *, wherein aryl contains at least one heteroatom independently selected from O, N or S, and wherein heterocyclyl denotes a 3- to ered heterocyclic non-aromatic group containing at least one heteroatom independently selected from O, N or S.
3. The compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more tuents RAr is selected from the group consisting of halogen, OH, CN, C1alkyl, C1 haloalkyl, -NH2, acetamido, -COO-C1alkyl, C1alkoxy, and (mono- or di- C1alkyl-amino)-C1alkoxy, more particularly halogen, C1alkoxy, and (mono- or di-C1alkyl-amino)-C1alkoxy, oxy, -CO-N(RN)2 wherein one RN is H and the other is C1alkyl, C3-4cycloalkyl or both RN taken together with the N to which they are attached form an azetane, pyrrolidine or morpholine ring, -CONRN wherein 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-methyl-piperazine, or 2-oxaazaspiro[3.3]heptane ring; Z is selected from the group ting of H, halogen, -CO-C1alkyl, -CO-CH2- C1alkoxy, 2-O-C3cycloalkyl, terocyclyl, -CH2-OH, -CH2- O-C1alkyl, -CH2-O-C3cycloalkyl, -NH2, O-C1-4alkyl, -CN, -COOC1-4alkyl , -CONH-C1-4alkyl, -CONH-C3cycloalkyl, -CO-CH2-C3 cycloalkyl, COO-heterocyclyl, -COO-C3cycloalkyl, C3cycloalkylmethyl, alkyloxyalkyl, -C1alkyl-O-C1alkyl-O-C1alkyl, 5- or 6-membered heteroaryl comprising one or two heteroatoms independently selected from O, N or S, phenyl, or heterocyclyl, wherein said phenyl, and heterocyclyl is optionally substituted by one or more substituents independently selected from the group comprising halogen, C1alkyl, C1alkoxy, C1haloalkyl, -COOC1alkyl , OH and C3cycloalkyl; Y is selected from the group consisting of H, C1alkyl and C1haloalkyl; R1 is a group of the structure wherein n is 0; R2 is H, ium or methyl; R3 is methyl, trifluoromethyl, ethyl, or taken with R2 together forms a ropyl group; n is 1; R2 is H, deuterium or methyl; R3 is methyl or trifluoromethyl or forms a methylene bridge to the carbon atom marked *, n heteroaryl ns at least one heteroatom independently selected from O, N or S, and wherein heterocyclyl s a 3- to 8-membered heterocyclic non-aromatic group ning at least one heteroatom independently selected from O, N or S.
4. The compound ing 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 by one or more substituents RAr; RAr is selected from the group ting of halogen, OH, -O-C1alkyl, -O-C1 haloalkyl, C1alkyl, C1haloalkyl, (mono- or ylamino)-C1alkyl and (mono- or ylamino)-C1alkoxy; Z is selected from the group consisting of COO-C1alkyl, -CO-CH2-O-C1 alkyl, 5- or 6-membered heteroaryl comprising one or two heteroatoms independently selected from O, N or S, phenyl, -COO-C3cycloalkyl, -COOC3heterocyclyl , -CON-C3cycloalkyl, -CON-C3heterocyclyl, -CO-CH2- C3cycloalkyl, -CH2-O-C3cycloalkyl, -CO-C1alkyl, -C1alkyl-O-C1 alkyl, -C1alkyl-O-C1alkyl-O-C1alkyl and -C(OH)(C1alkyl)(CH2-C3 cycloalkyl), wherein said aryl and phenyl is optionally substituted with one or more substituents independently selected from the group consisting of methyl, halogen, CF3, OMe and OH; Y is selected from the group consisting of CF3 and Me; R1 is selected from the group consisting of 3-hydroxymethylbutyl, 2-hydroxy- 2-methylpropyl, 3-hydroxymethyl-cyclobutyl, 2-hydroxypropyl, 2- hydroxybutyl, 3-hydroxy-cyclobutyl, 2-hydroxy-3,3,3-trifluoropropyl, 2- hydroxydeutero-propyl, and 1-hydroxy-cyclopropylmethyl, n heterocyclyl denotes heterocyclic non-aromatic group containing at least one heteroatom independently selected from O, N or S.
5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is ed from the group consisting of phenyl ally tuted by one or more substituents RAr; RAr is selected from the group consisting of halogen, -O-C1alkyl, -O-C1 haloalkyl, C1alkyl, C1haloalkyl and (dimethylamino)-C1alkoxy; Z is selected from the group ting of H, COO-C1alkyl, pyrimidyl, pyrazinyl, lyl, oxazolyl, isoxazolyl, isothiazolyl imidazolyl, oxadiazolyl, thiadiazolyl, enyl, furan, tetrahydrofuran, cyclopropoxymethyl, cyclohexoxymethyl, cyclopentoxymethyl, -COO-cyclopropyl, -COO- cyclobutyl, -COO-cyclopentyl, -COO-cyclohexyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclobutoxymethyl, methoxyethyl, acetyl, methoxyacetyl, -CO-CH2-cyclobutyl, -CO-CH2- cyclopropyl, -CO-CH2-cyclopentyl, -CO-CH2-cyclohexyl, -COO-oxetan, - methoxy-ethoxy-methyl, -CONH-cyclopropyl, -CONH-cyclobutyl, -CONH- cyclopentyl, and -CONH-cyclohexyl, wherein said pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, olyl, isothiazolyl imidazolyl, oxadiazolyl, thiadiazolyl, enyl, tetrahydrofuran and furan is optionally substituted with one or more substituents independently selected from the group consisting of methyl, halogen, CF3, OMe and OH; Y is ed from the group consisting of CF3 and Me; R1 is selected from the group consisting of 3-hydroxymethylbutyl, 2-hydroxy- 2-methylpropyl, 3-hydroxymethyl-cyclobutyl, 2-hydroxypropyl, 2- hydroxybutyl, 3-hydroxy-cyclobutyl, 2-hydroxy-3,3,3-trifluoropropyl, 2- hydroxydeutero-propyl, and oxy-cyclopropylmethyl.
6. The 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 tuted by one or more substituents RAr; RAr is selected from the group consisting of Cl, -OMe, F and 2-(dimethylamino)- ethoxy; Z is selected from the group consisting of , -COOEt, pyrimidinyl, thiazolyl, cyclopropoxymethyl, -COO-cyclopropyl, -COO-cyclobutyl, pyrimidinyl, ymethyl, pyrazinyl, -CO-CH2-cyclobutyl, COO- oxetan, 5-methyl-isoxazolyl and -CONH-cyclopentyl; Y is selected from the group ting of CF3 and Me; R1 is selected from the group consisting of 3-hydroxymethylbutyl, 3-hydroxy- 3-methyl-cyclobutyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxy-cyclobutyl, 2-hydroxy-3,3,3-trifluoropropyl, 2-hydroxydeutero-propyl, and 1-hydroxycyclopropylmethyl.
7. The compound according to any one of claims 1 to 6, wherein the compound is ed from the group consisting of 1-{4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylpropanol 1-({4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methyl)cyclopropanol 4-{4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylbutanol (2R){4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol (2S){4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol 1-{4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}butanol (rac) 3-{4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}-1,1,1-trifluoropropanol (rac) ethyl hlorofluorophenyl)[1-(2-hydroxymethylpropyl)(trifluoromethyl)- 1H-pyrazolyl]-1,2-oxazolecarboxylate ethyl 3-(2-chlorofluorophenyl)[1-(3-hydroxymethylbutyl)(trifluoromethyl)-1H- pyrazolyl]-1,2-oxazolecarboxylate ethyl 3-(2-chlorofluorophenyl){1-[(1R,3S)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) ethyl 3-(2-chlorofluorophenyl){1-[(1S,3R)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (anti) ethyl 3-(2-chlorofluorophenyl){1-[(2R)hydroxypropyl](trifluoromethyl)-1H- pyrazolyl}-1,2-oxazolecarboxylate ethyl 3-(2-chlorofluorophenyl){1-[(2S)hydroxypropyl](trifluoromethyl)-1H- pyrazolyl}-1,2-oxazolecarboxylate ethyl 3-(2-chlorofluorophenyl)[1-(2-hydroxybutyl)(trifluoromethyl)-1H-pyrazol yl]-1,2-oxazolecarboxylate (rac) ethyl 3-(2-chlorofluorophenyl)[1-(3,3,3-trifluorohydroxypropyl) uoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxylate (rac) ethyl 3-(2-chlorofluorophenyl){1-[(2R)-3,3,3-trifluorohydroxypropyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate methyl 3-(2-chlorophenyl){5-methyl[(1S,3R)hydroxymethylcyclobutyl]-1H- pyrazolyl}-1,2-oxazolecarboxylate (anti) methyl 3-(2-chlorophenyl){5-methyl[(1R,3S)hydroxymethylcyclobutyl]-1H- lyl}-1,2-oxazolecarboxylate (syn) methyl 3-(2-chlorophenyl)[1-(3-hydroxymethylbutyl)methyl-1H-pyrazolyl]-1,2- oxazolecarboxylate methyl 3-(2-chlorofluorophenyl)[1-(3-hydroxymethylbutyl)methyl-1H-pyrazol- 4-yl]-1,2-oxazolecarboxylate methyl 5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl}(2- ypyridinyl)-1,2-oxazolecarboxylate methyl 3-(2-chlorophenyl){1-[(2S)hydroxypropyl](trifluoromethyl)-1H-pyrazol yl}-1,2-oxazolecarboxylate methyl 3-(2-chlorofluorophenyl){1-[(2S)hydroxypropyl](trifluoromethyl)-1H- pyrazolyl}-1,2-oxazolecarboxylate methyl 3-(2-chlorophenyl){1-[(2S)hydroxypropyl]methyl-1H-pyrazolyl}-1,2- oxazolecarboxylate methyl 3-(2-chloromethoxyphenyl)[1-(3-hydroxymethylbutyl)methyl-1H- pyrazolyl]-1,2-oxazolecarboxylate methyl 3-(2-chlorofluorophenyl){1-[(1S,3R)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (anti) methyl 3-(2-chlorofluorophenyl){1-[(1R,3S)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) methyl 3-(2-chlorofluorophenyl)[1-(3-hydroxycyclobutyl)(trifluoromethyl)-1H- pyrazolyl]-1,2-oxazolecarboxylate 1-{4-[3-(2-chlorofluorophenyl)(5-methyl-1,3,4-oxadiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylpropanol 1-{4-[3-(2-chlorofluorophenyl)(1,3-thiazolyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}(2-2H)propanol (rac) ethyl 3-(2-chlorofluorophenyl){1-[2-hydroxy(2-2H)propyl](trifluoromethyl)-1H- lyl}-1,2-oxazolecarboxylate (rac) methyl 3-(2-chlorofluorophenyl){1-[2-hydroxy(2-2H)propyl](trifluoromethyl)-1H- pyrazolyl}-1,2-oxazolecarboxylate (rac) 1-[3-(2-chlorofluorophenyl)[1-(2-hydroxymethylpropyl)(trifluoromethyl)-1H- lyl]-1,2-oxazolyl]ethanone 1-[3-(2-chlorofluorophenyl){1-[(2R)hydroxypropyl](trifluoromethyl)-1H- lyl}-1,2-oxazolyl]ethanone 1-[3-(2-chlorofluorophenyl)[1-(2-hydroxymethylpropyl)(trifluoromethyl)-1H- pyrazolyl]-1,2-oxazolyl]cyclobutylethanone 1-[3-(2-chlorofluorophenyl)[1-(2-hydroxymethylpropyl)(trifluoromethyl)-1H- pyrazolyl]-1,2-oxazolyl]methoxyethanone 1-[3-(2-chlorofluorophenyl){1-[(2R)hydroxypropyl](trifluoromethyl)-1H- pyrazolyl}-1,2-oxazolyl]methoxyethanone 3-(2-chlorofluorophenyl)-N-cyclopentyl[1-(2-hydroxymethylpropyl) (trifluoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxamide 3-(2-chlorofluorophenyl)-N-cyclopropyl[1-(2-hydroxymethylpropyl) (trifluoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxamide 3-(2-chlorofluorophenyl)-N-cyclobutyl[1-(2-hydroxymethylpropyl) (trifluoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxamide 3-(2-chlorofluorophenyl)-N-cyclopentyl{1-[(2R)hydroxypropyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxamide 3-(2-chlorofluorophenyl)-N-cyclopropyl{1-[(2R)hydroxypropyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxamide 3-(2-chlorofluorophenyl)-N-cyclobutyl{1-[(2R)hydroxypropyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxamide oxetanyl 3-(2-chlorophenyl){1-[(2S)hydroxypropyl]methyl-1H-pyrazolyl}- 1,2-oxazolecarboxylate cyclopropyl 3-(2-chlorophenyl){1-[(1S,3R)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (anti) cyclopropyl 3-(2-chlorophenyl){1-[(1R,3S)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) cyclopropyl 3-(2-chlorofluorophenyl){1-[(1S,3R)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (anti) cyclopropyl 3-(2-chlorofluorophenyl){1-[(1R,3S)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) oxetanyl 3-(2-chlorophenyl){1-[(1R,3S)hydroxymethylcyclobutyl]methyl- 1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) cyclopropyl 3-(2-chlorophenyl){5-methyl[(1R,3S)hydroxymethylcyclobutyl]- 1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) cyclopropyl 3-(2-chlorophenyl){5-methyl[(1S,3R)hydroxymethylcyclobutyl]- 1H-pyrazolyl}-1,2-oxazolecarboxylate (anti) cyclopropyl 3-(2-chlorofluorophenyl)[1-(2-hydroxymethylpropyl) (trifluoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxylate utyl 3-(2-chlorofluorophenyl)[1-(2-hydroxymethylpropyl) (trifluoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxylate yl 3-(2-chlorofluorophenyl)[1-(2-hydroxymethylpropyl) (trifluoromethyl)-1H-pyrazolyl]-1,2-oxazolecarboxylate oxetanyl 3-(2-chlorofluorophenyl){1-[(2R)hydroxypropyl](trifluoromethyl)- 1H-pyrazolyl}-1,2-oxazolecarboxylate cyclopropyl 3-(2-chlorofluorophenyl){1-[(2S)hydroxypropyl](trifluoromethyl)- 1H-pyrazolyl}-1,2-oxazolecarboxylate oxetanyl 3-(2-chlorofluorophenyl){1-[(2S)hydroxypropyl](trifluoromethyl)- 1H-pyrazolyl}-1,2-oxazolecarboxylate cyclopropyl 3-(2-chlorofluorophenyl){5-methyl[(1R,3S)hydroxy cyclobutyl]-1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) cyclopropyl 3-(2-chlorofluorophenyl){5-methyl[(1S,3R)hydroxy cyclobutyl]-1H-pyrazolyl}-1,2-oxazolecarboxylate (anti) 1-{4-[3-(2-chlorofluorophenyl)(hydroxymethyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylpropanol (1R,3S){4-[3-(2-chlorophenyl)(hydroxymethyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylcyclobutanol (syn) 1-{4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylpropanol (2R){4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol 3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylbutanol (2S){4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol (1R,3S){4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl]methyl- 1H-pyrazolyl}methylcyclobutanol (syn) (1S,3R){4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl]methyl- 1H-pyrazolyl}methylcyclobutanol (anti) (1R,3S){4-[3-(2-chlorophenyl)(methoxymethyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylcyclobutanol (syn) (1S,3R){4-[3-(2-chlorophenyl)(methoxymethyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylcyclobutanol (anti) (1R,3S){4-[3-(2-chlorophenyl)(methoxymethyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylcyclobutanol (syn) (2S){4-[3-(2-chlorophenyl)[(2-methoxyethoxy)methyl]-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol (2R){4-[3-(2-chlorofluorophenyl)(ethoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol 4-{4-[3-(2-chlorofluorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylbutanol 4-{4-[3-(2-chlorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl](trifluoromethyl)-1H- pyrazolyl}methylbutanol 4-{4-[3-(2-chlorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl]methyl-1H-pyrazol- 1-yl}methylbutanol (1R,3S){4-[3-(2-chlorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylcyclobutanol (syn) (1S,3R){4-[3-(2-chlorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl]methyl-1H- lyl}methylcyclobutanol (anti) 4-{4-[3-(2-chlorofluorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylbutanol (1R,3S){4-[3-(2-chlorofluorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl] -1H-pyrazolyl}methylcyclobutanol (syn) (1S,3R){4-[3-(2-chlorofluorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl] methyl-1H-pyrazolyl}methylcyclobutanol (anti) (2R){4-[3-(2-chlorofluorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol (1R,3S){4-[3-(2-chlorofluorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorophenyl)(cyclopropoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (2S){4-[3-(2-chlorophenyl)[(oxetanyloxy)methyl]-1,2-oxazolyl] uoromethyl)-1H-pyrazolyl}propanol (2R){4-[3-(2-chlorofluorophenyl)[(propanyloxy)methyl]-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol (2R){4-[3-(2-chlorofluorophenyl)(cyclobutoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol 4-{4-[3-(2-chloromethoxyphenyl)(cyclopropoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylbutanol (1R,3S)[4-(3-{2-chloro[2-(morpholinyl)ethoxy]phenyl}(cyclopropoxymethyl)- 1,2-oxazolyl)(trifluoromethyl)-1H-pyrazolyl]methylcyclobutanol (syn) methyl 5-[1-(2-hydroxymethylpropyl)(trifluoromethyl)-1H-pyrazolyl](2- hydroxypyridinyl)-1,2-oxazolecarboxylate (2R){4-[3-(2-chlorofluorophenyl)-1,2-oxazolyl](trifluoromethyl)-1H-pyrazol yl}propanol 1-{4-[3-(2-chlorofluorophenyl)(methoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}(2-2H)propanol (rac) (2S){4-[3-(2-chlorophenyl)(oxolanyl)-1,2-oxazolyl](trifluoromethyl)-1H- pyrazolyl}propanol (2R){4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol (1R,3S){4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorophenyl)(pyrimidinyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylcyclobutanol (syn) ){4-[3-(2-chlorofluorophenyl)(pyrazinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorophenyl)(pyrazinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorophenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) (1S,3R){4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (anti) (1R,3S){4-[3-(2-chlorophenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorophenyl)(pyrimidinyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl]methyl- 1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorophenyl)(pyrazinyl)-1,2-oxazolyl]methyl-1H-pyrazol- 1-methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorofluorophenyl)(pyrazinyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl]methyl- 1H-pyrazolyl}methylcyclobutanol (syn) (1R,3S){4-[3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl] methyl-1H-pyrazolyl}methylcyclobutanol (syn) (2R){4-[3-(2-methoxyphenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}propanol 1-{4-[3-(2-methoxyphenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)-1H- pyrazolyl}methylpropanol (2R){4-[3-(2-methoxyphenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}propanol 1-{4-[3-(2-methoxyphenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)-1H- pyrazolyl}methylpropanol -{4-[3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol 1-{4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylpropanol (2R){4-[3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}propanol 1-{4-[3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylpropanol 3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylbutanol 4-{4-[3-(2-chlorophenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)-1H- pyrazolyl}methylbutanol 4-{4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl](trifluoromethyl)- 1H-pyrazolyl}methylbutanol 4-{4-[3-(2-chloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylbutanol 4-{4-[3-(2,6-dichloromethoxyphenyl)(pyrimidinyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylbutanol 4-{4-[3-(2-chlorophenyl)(pyrimidinyl)-1,2-oxazolyl]methyl-1H-pyrazolyl}- 2-methylbutanol 4-{4-[3-(2-chlorofluorophenyl)(pyrimidinyl)-1,2-oxazolyl]methyl-1H- pyrazolyl}methylbutanol 3-[3-(benzyloxy)chlorophenyl](pyrimidinyl)-1,2-oxazolyl} (trifluoromethyl)-1H-pyrazolyl)methylbutanol 2-chloro{5-[1-(3-hydroxymethylbutyl)(trifluoromethyl)-1H-pyrazolyl] (pyrimidinyl)-1,2-oxazolyl}phenol (1R,3S){4-[3-(2-chloromethoxyphenyl)(cyclopropoxymethyl)-1,2-oxazolyl] (trifluoromethyl)-1H-pyrazolyl}methylcyclobutanol (syn) ethyl 3-(2-chloromethoxyphenyl){1-[(1R,3S)hydroxymethylcyclobutyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (syn) ethyl 3-(2-chloromethoxyphenyl)[1-(3-hydroxymethylbutyl)(trifluoromethyl)- 1H-pyrazolyl]-1,2-oxazolecarboxylate 4-[4-(3-{2-chloro[2-(morpholinyl)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(dimethylamino)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(pyrrolidinyl)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(4-methylpiperazinyl)ethoxy]phenyl}(pyrimidinyl)-1,2- oxazolyl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(diethylamino)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazolyl)- 5-(trifluoromethyl)-1H-pyrazolyl]methylbutanol 2-chloro{5-[1-(3-hydroxymethylbutyl)(trifluoromethyl)-1H-pyrazolyl] (pyrimidinyl)-1,2-oxazolyl}phenoxy)ethyl]-1lambda6-thiomorpholine-1,1-dione 4-(4-{3-[2-chloro(2-{2-oxaazaspiro[3.3]heptanyl}ethoxy)phenyl](pyrimidin yl)-1,2-oxazolyl}(trifluoromethyl)-1H-pyrazolyl)methylbutanol 4-[4-(3-{2-chloro[3-(dimethylamino)propoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[3-(2-chloro{5-[1-(3-hydroxymethylbutyl)(trifluoromethyl)-1H-pyrazolyl] (pyrimidinyl)-1,2-oxazolyl}phenoxy)propyl]-1lambda6-thiomorpholine-1,1-dione 4-[4-(3-{2-chloro[3-(pyrrolidinyl)propoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[3-(diethylamino)propoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)(trifluoromethyl)-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(diethylamino)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazolyl)- 5-methyl-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(dimethylamino)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)methyl-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[2-(pyrrolidinyl)ethoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)methyl-1H-pyrazolyl]methylbutanol 4-[4-(3-{2-chloro[3-(diethylamino)propoxy]phenyl}(pyrimidinyl)-1,2-oxazol yl)methyl-1H-pyrazolyl]methylbutanol methyl 3-{2-chloro[2-(morpholinyl)ethoxy]phenyl}{1-[(2S)hydroxypropyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate methyl hloro[2-(dimethylamino)ethoxy]phenyl}{1-[(2S)hydroxypropyl] (trifluoromethyl)-1H-pyrazolyl}-1,2-oxazolecarboxylate (1R,3S)[4-(3-{2-chloro[2-(morpholinyl)ethoxy]phenyl}(methoxymethyl)-1,2- oxazolyl)(trifluoromethyl)-1H-pyrazolyl]methylcyclobutanol (syn) (1R,3S)[4-(3-{2-chloro[2-(dimethylamino)ethoxy]phenyl}(methoxymethyl)-1,2- oxazolyl)(trifluoromethyl)-1H-pyrazolyl]methylcyclobutanol (syn) (1S,3R)[4-(3-{2-chloro[2-(morpholinyl)ethoxy]phenyl}(methoxymethyl)-1,2- oxazolyl)(trifluoromethyl)-1H-pyrazolyl]methylcyclobutanol (anti) (1S,3R)[4-(3-{2-chloro[2-(dimethylamino)ethoxy]phenyl}(methoxymethyl)-1,2- yl)(trifluoromethyl)-1H-pyrazolyl]methylcyclobutanol (anti) (2R)(4-{3-[2-chloro(morpholinecarbonyl)phenyl](pyrimidinyl)-1,2-oxazol yl}(trifluoromethyl)-1H-pyrazolyl)propanol 2-chloro-N-cyclobutyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazol yl}(pyrimidinyl)-1,2-oxazolyl)benzamide ro-N-ethyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)benzamide 2-chloro(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)-N-(propanyl)benzamide (2R)(4-{3-[3-(azetidinecarbonyl)chlorophenyl](pyrimidinyl)-1,2-oxazol yl}(trifluoromethyl)-1H-pyrazolyl)propanol 2-chloro-N-cyclopropyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazol yl}(pyrimidinyl)-1,2-oxazolyl)benzamide (2R)(4-{3-[2-chloro(pyrrolidinecarbonyl)phenyl](pyrimidinyl)-1,2-oxazol yl}(trifluoromethyl)-1H-pyrazolyl)propanol N-cyclopropyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)methoxybenzamide 1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl}(pyrimidinyl)- 1,2-oxazolyl)methoxy-N-(propanyl)benzamide (2R)(4-{3-[3-(azetidinecarbonyl)methoxyphenyl](pyrimidinyl)-1,2-oxazol yl}(trifluoromethyl)-1H-pyrazolyl)propanol N-cyclobutyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)methoxybenzamide N-ethyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)methoxybenzamide N-cyclobutyl(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl} (pyrimidinyl)-1,2-oxazolyl)benzamide and 3-(5-{1-[(2R)hydroxypropyl](trifluoromethyl)-1H-pyrazolyl}(pyrimidinyl)- 1,2-oxazolyl)-N-(propanyl)benzamide.
8. The compound according to any one of claims 1 to 7 for use as a medicament.
9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or medical ion selected from the group consisting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, vitiligo, Crohn’s e, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, es type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen planus, Sjögren’s syndrome, spinal disc herniation, acne, Graft-versus-Host-Reaction, Host-versus- Graft-Reaction, AIH (Autoimmunhepatitis), PBC ry biliary cholangitis), PSC (primary scleroting cholangitis), obesity, Lupus nephritis, Autoimmune d Disorders including Graves Disease and Hashimoto's Disease, Autoimmune Uveitis, Colitis, IMQ Psoriasis, Juvenile Idiopathic Arthritis, Myasthenia Gravis, Systemic Sclerosis, is melitus and osteoarthritis.
10. Use of a compound of the formula (I) as defined in any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or medical condition in which the inhibition of interleukin-17 (IL-17) and/or Interferon-? (IFN-?) is beneficial.
11. The use of claim 10, wherein the e or medical condition is selected from the group ting of psoriasis, psoriatic arthritis, autoimmune thyroiditis, Grave’s disease, rheumatoid arthritis, vitiligo, Crohn’s disease, ulcerative colitis, inflammatory bowel e, ankylosing spondylitis, diabetes type I, multiple sclerosis, celiac disease, systemic lupus erythematosus, uveitis, Behcet disease, atopic dermatitis, Lichen , Sjögren’s syndrome, spinal disc herniation, acne, versus-Host- Reaction, Host-versus-Graft-Reaction, AIH (Autoimmunhepatitis), PBC (primary biliary cholangitis), PSC (primary scleroting cholangitis), obesity, Lupus nephritis, Autoimmune Thyroid Disorders including Graves Disease and Hashimoto's e, Autoimmune s, Colitis, IMQ Psoriasis, Juvenile thic Arthritis, Myasthenia Gravis, Systemic Sclerosis, diabetes mellitus and osteoarthritis.
NZ761897A 2018-09-06 1-(4-(isoxazol-5-yl)-1h-pyrazol-1-yl)-2-methylpropan-2-ol derivatives and related compounds as il-17 and ifn-gamma inhibitors for treating autoimmune diseases and chronic inflammation NZ761897B2 (en)

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EP17189652 2017-09-06
PCT/EP2018/073993 WO2019048541A1 (en) 2017-09-06 2018-09-06 1-(4-(isoxazol-5-yl)-1h-pyrazol-1-yl)-2-methylpropan-2-ol derivatives and related compounds as il-17 and ifn-gamma inhibitors for treating autoimmune diseases and chronic inflammation

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NZ761897B2 true NZ761897B2 (en) 2024-01-30

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