TW201028152A - Soluble guanylate cyclase activators - Google Patents

Abstract

A compound having the structure useful for treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or cirrhosis of the liver in a human or animal patient.

Description

201028152 VI. INSTRUCTIONS: [Prior Art] Circulating GMP is an important intracellular messenger that elicits a large number of different effects by modulating cGMP-dependent protein kinases, phosphodiesterases, and ion channels. Examples are relaxation of smooth muscle, inhibition of platelet activation, inhibition of smooth muscle cell proliferation, and leukocyte adhesion. The cGMP system is produced by the action of particulate and soluble tobraric acid cyclase as a response to a variety of extracellular and intracellular stimuli. In the case of granular uridine cyclase, stimulation is substantially performed by a peptide messenger such as atrial lilinide or brain lilinide. In contrast, the soluble uridine cyclase ("sGC"), which is an intracellular heteromeric hemoglobin protein, is substantially regulated by a family of low molecular weight factors that are enzymatically formed. The most important irritant is nitric oxide ("NO") or closely related substances. The function of other factors, such as carbon monoxide or hydroxyl groups, remains largely unclear. It is proposed that the combination of N〇 and hemochromin forms a pentacoordinated hemoglobin_nitrostidine-based complex which is a mechanism activated by N〇. The release of histidine, which is associated with iron in a basal state, converts the enzyme into an active configuration. The active soluble amylin cyclases each comprise an alpha subunit and a p subunit. Several subunit subtypes have been described which differ from one another in terms of sequence, tissue specific distribution and performance at different stages of development. Subtypes ^ and ^ are mainly expressed in the brain and lungs, while Pa is especially found in the liver and kidneys. Subunits called 々 and β3 are isolated from the human brain and are homologous to ... and .... More current studies have shown an a2i subunit that has an insert inserted in the catalytic domain with a right insert into your ^^ 〒3. All subunits exhibit greater homology in the region of the catalytic domain. Therefore, these enzymes may contain a hemoglobin in each heterodimer containing 137610.doc 201028152, which is combined via p1_CyS_78&/or PrHis-lOS and is part of the regulatory center. In the pathological state, the formation of guanylate cyclase activating factor may be reduced due to an increase in the production of free radicals, or degradation thereof may be promoted. The reduced activation of the resulting sGC results in, for example, increased blood pressure, platelet activation or increased cell proliferation and increased cell adhesion by attenuating individual cgmP mediated cellular responses. This results in the formation of endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina, thrombosis, myocardial infarction, stroke or erectile dysfunction. Pharmacological stimulation of sGC makes it possible to normalize CGMP production and thus make it possible to treat and/or prevent such conditions. To achieve pharmacological stimulation of sGC, compounds that have been utilized based on intermediate no release, such as organic nitrates. The drawback of this treatment is the development of resistance and reduced activity, and therefore the higher doses required.

Vesely describes a number of sGC stimulators that do not act via no release in a series of publications. However, most of these compounds, most of which are hormones, phytohormones, vitamins or natural compounds such as lizard toxin, have only a weak effect on cGMP formation in cell lysates. L. Vesely,

Eur·J. Clin. Invest., Vol. 15, 1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm. ’, vol. 88, 1979, p. 1244. Ignarro et al., Adv. Pharmacol., Vol. 26, 1994, p. 35, shows the stimulation of the non-hemoglobin guanylate cyclase by the original 卟 IX. Pettibone et al., 'Eur. J. Pharmacol., Vol. 116, 1985, page 307, describes the antihypertensive effect of hexafluoro acid diphenyl-lock and attribute this to stimulation of sGC. According to YU et al., Brit. j. Pharmaco 137610.doc 201028152, Vol. 114, 1995, p. 1587, isoliquiritin which has a relaxing effect on isolated rat aorta also activates SGC. Ko et al., Blood, Vol. 84, 1994 'p. 4226; Yu et al., Biochem. J., Vol. 306, 1995, p. 787; and Wu et al., Brit. J. Pharmacol., Vol. 116 '1995 'p. 1973 shows 1-phenylhydrazino-3-(5-hydroxymethyl_2-c-cylyl) ° stimulating σ GC stimulating activity and not inhibiting proliferation and platelet inhibition. European Patent Application No. 908,456 and German Patent Application No. 19,744,027, the disclosure of which is incorporated herein by reference. Stearylaminobenzoic acid N-aryl decylamine. The N.aryl group usually has a group which is susceptible to oxidation as other substituents (such as two via groups which are in para position relative to each other) and in this case can be regarded as a hydroquinone derivative for the preparation of a photosensitive material. Auxiliaries (see, for example, Chemical Abstracts 119, 105757; 120 4185 8; 123, 70224; or 126, 257007). British Patent Publication No. 876,526 (Chemical Abstract 56, 15432e) discloses 3,5_diox-2-methylsulfonylaminobenzoic acid]^_ (5_gas_2_(4_) Phenylphenyl)-phenyl)-guanamine The compounds of the present invention have now been found to achieve potent guanylate cyclase activation and are therefore suitable for the treatment and prevention of conditions associated with low CGMP levels. SUMMARY OF THE INVENTION The present invention relates to a compound which activates a soluble uridine cyclase, which is for the treatment and prevention of diseases (for example, cardiovascular diseases such as hypertension, angina pectoris, diabetes, cardiac insufficiency, thrombosis or atherosclerosis) ) 137610.doc 201028152 Effective pharmaceutically active compounds. The guanidine compound is capable of modulating the production of cyclic guanosine monophosphate ("cGMP") in vivo and is generally suitable for the treatment and prevention of diseases associated with cgMP imbalance disorders. The present invention further relates to the use of the formula [Method for the preparation of a compound] for the treatment and prevention of the above-mentioned diseases and for the preparation of a medicament for the purpose' and for a pharmaceutical preparation comprising a compound of the formula I. [Embodiment] The present invention relates to a compound which activates a soluble uridine cyclase:

And a pharmaceutically acceptable salt thereof, wherein Z1 is selected from the group consisting of CH and N;

A is a ring selected from the group consisting of the following rings:

137610.doc 201028152

D1 is CH, CR4 or N; R7 is selected from the group consisting of: 1) hydrogen; 2) C!-6 alkyl group, wherein the alkyl group may be unsubstituted or substituted with 1⁄3 fluorine atoms and Substituted or monosubstituted by OC^alkyl; 3) C3_6 cycloalkyl' wherein the cycloalkyl group may be unsubstituted or substituted with 1 to 3 fluorine atoms and unsubstituted or monosubstituted with 〇C!-3 alkyl, and 4) phenyl' wherein the phenyl group is unsubstituted or substituted with a 4 alkyl group, a 〇Ci 4 group, a γ group, a CN, a NOjSiO^Cw alkyl group, wherein the Cl-4 group and the -oq·4 alkyl group Unsubstituted or substituted by 1_3 fluorine atoms; L1 is selected from the group consisting of 〇, S, C(R丨2)2; and CF2; 2 L is selected from the group consisting of: Ch2) 2_4, -c(r12)2, -cf2-0 and 8' are limited such that when L1 is 〇 or s, L2 is not 〇 or S; R12 is independently selected from the group consisting of: Hydrogen and a C13 alkyl group, wherein the $C]-3 alkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; E is a ring selected from the group consisting of: υ 6-1 芳 aryl ring, 2) Having independently selected from 0, 1, 2, and 3 ruthenium atoms, ruthenium or 1 ruthenium atom 137610.doc -8 - 201028152 5-10 membered heteroaryl ring, 3) C3_8 cycloalkyl ring; wherein aryl, heteroaryl, 1 or 2 or 3 heteroatoms And the C3.8 cycloalkyl group is unsubstituted or monosubstituted by R5' and is unsubstituted, monosubstituted by R8 or independently disubstituted by R8; R4 is, at each occurrence, independently selected from the group consisting of: Halogen, C!-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with 13 fluorine atoms, -OC!.6 alkyl, wherein the alkyl group may be unsubstituted or substituted with 13 fluorine atoms, C3 · 8-cycloalkyl, unsubstituted or substituted by 1-3 fluorine atoms, -〇-C3_8 cycloalkyl, unsubstituted or substituted by 13 fluorine atoms, CN, and N〇2; R5 in each The second occurrence is independently selected from the group consisting of: 1) R6, 2) -OR6, 3) C!·6 alkyl, which may be unsubstituted or substituted with 丨3 fluorine atoms, and not Monosubstituted by a group substituted or independently selected from the group consisting of c3.6 cycloalkyl, _〇_Ci 4 alkyl, 〇H, =〇, s(〇)〇4 alkyl, -OR6 and R6, 4) C!·6 alkenyl, which may be unsubstituted or 3 groups of fluorine atoms substituted, unsubstituted or independently selected from the following groups 137610.doc 201028152 generation · -O-Cu alkyl, 0H ' = 〇, s (〇) 〇 , 〇 6 r6 and R6, 5) 〇C丨_6 alkyl 'wherein the alkyl group may be unsubstituted or substituted by 3 fluorine atoms' and unsubstituted or independently selected from the group consisting of ~ ring and R6 a group monosubstituted, 6) -S-Cw alkyl, 7) C3.8 cycloalkyl ring which is unsubstituted or independently selected from fluoro and

The group of the Cyalkyl group is monosubstituted, disubstituted or trisubstituted and unsubstituted or monosubstituted by a group independently selected from the group consisting of Cm alkyl which may be unsubstituted or substituted with 1 to 3 fluorine atoms, 〇_

Cw alkyl, 〇H, =〇, s(〇). 2(: 丨4 alkyl, _〇r6, 尺6, and NR9R10, 8) C5·8 cycloalkenyl ring, which is unsubstituted or monosubstituted with a group independently selected from a fluoro group and a Cw alkyl group, Substituted or trisubstituted, and unsubstituted or monosubstituted by a group independently selected from the group consisting of: unsubstituted or substituted with 1-3 fluorine atoms (: __4 alkyl, -0-Cl· 4 alkyl, OH, =〇, S(0)G.2C, _4 alkyl and R6, 9) 5 to 6 membered heterocyclyl ring having 1 or 2 selected from the group consisting of N, 〇 and S a hetero atom, and unsubstituted or monosubstituted with a group independently selected from the group consisting of Cm alkyl, _0Cl 4 alkyl and 〇, which may be unsubstituted or substituted with 1-3 fluorine atoms, and 10) Halogen; R is selected from the group consisting of: 1) a stupid ring which is unsubstituted, monosubstituted by a group independently selected from the group consisting of 137610.doc -10- 201028152 or Disubstituted: halogen, OH, CN, Cl 4 alkyl which may be unsubstituted or substituted by a fluorine atom, 烷基Ci 4 alkyl which may be unsubstituted or substituted by 1 to 3 fluorine atoms, N02, 8 (0 ) 0.2 (^-4 alkyl, c2.4 alkenyl, 〇-C2-4 Alkenyl, NR9R10 and COOH, and 2) 5-6 members contain 1-2 heteroaryl rings independently selected from the group consisting of a hetero atom of the formula, wherein the heteroaryl ring is unsubstituted, independently Mono- or di-substituted groups selected from the group consisting of _, 〇H, CN, possibly unsubstituted or substituted ici4 alkyl via i_3 fluorine atoms, alkyl may be unsubstituted or via 丨3 a fluorine atom-substituted OCI-4 succinyl group, N〇2, SCOVzCu alkyl group, s(〇)0-2 aryl group, C2-6 dilute group, dilute group, NR9R10 and C; Q〇H; R8 is selected from the following a group consisting of: c. 4 alkyl, wherein the alkyl group may be unsubstituted or substituted with 13 fluorine atoms, C2.4 dilute 'halogen, C3.6 cycloalkyl' where the cycloalkyl group may Unsubstituted or substituted with 3 fluorine atoms, OC!.4 alkyl, wherein the alkyl group may be unsubstituted or substituted with 3 fluorine atoms, 0-C2.4, NO2, alkyl, and 137610.doc 201028152 CN ; 10 R: and R1. They are independently selected from the group consisting of hydrogen and a Ci 6 alkyl group. The Rn system is selected from the group consisting of hydrazine and Cw alkyl. And in another embodiment, A is a ring selected from the group consisting of the following rings

and

(^0-1 and all other variables are as previously defined. In another embodiment, Rn is gas and all other variables are as previously defined. In another embodiment

E J is selected from the group consisting of J (RV consisting of the following groups)

Where E1 is CH or N, and all other variables are as previously defined. In another embodiment, the E J is selected from the group consisting of:

137610.doc and

R5 •12- 201028152 and all other variables are as previously defined. In another embodiment, Z1 is CH and all other variables are as previously defined. In another embodiment, R7 is selected from the group consisting of CH;, CF3 and CF2H' and all other variables are as previously defined. In another embodiment, the L1 is selected from the group consisting of 〇 and 8, and all other variables are as previously defined. In another embodiment, 'L2 is selected from the group consisting of: ch2, ch(ch3), 〇, ch2ch2, cf2, and ch2ch2ch2', with the constraint that when L2 is O, L is not ο, and all Other variables are as previously defined. In another embodiment, the L2 is selected from the group consisting of CH2 and Cf2, and all other variables are as previously defined. In another embodiment, R4 is selected from the group consisting of C, F, Br, CH3, cyclopropyl, N?2, and CF3, and all other variables are as previously defined. In another embodiment, R4 is selected from the group consisting of and, and all other variables are as previously defined. In another embodiment, R6 is a phenyl ring which is unsubstituted or monosubstituted, disubstituted or trisubstituted, independently selected from the group consisting of:

Cl ' F ' -CH3 ' -C(CH3)3 \ CF3 - -〇CF3 ' -0CH3 ' -OCH(CH3)2 and COOH' and all other variables are as previously defined. And R. The group of the following groups is mono-, di- or tri-substituted: phenyl, F, CF3, CH3, OH and = 〇, 3) ° pyridine ring, wherein the point of attachment to the ton pyridine ring is a carbon atom And wherein the pyridyl ring is unsubstituted or monosubstituted by CF3, 4) -CH2-L3-R6, wherein L3 is _CH2- or -〇_, 5) -OR6, 6) -OCH2R6,

8) -CF3, 9) CM, F or Br, 10) -CH3, 11) OCH3, 12) OCF3, 13) _CH=CHR6, and 14) -SCH2CH3, and all other variables are as previously defined. In another embodiment, R5 is selected from the group consisting of Cl, F, Br, -CH3, -C(CH3)3, OCH3, 〇CF3, -SCH2CH3,

137610.doc -14- 201028152

Cf3

OCH3

0CH3

o \—CH2CH2—^ ^

毫—ch20 — cf3 卜 〇 &~<0>ch2. ^3~ci 卜 -ch2ch2

Cf3 Φ ^-CH2CH2

F 毫—CH=CH “ })—CF; • CF3 CH 0— —CF3 \-^ /)—F -CH

〇CF3

Bu 0

Bu 0

Cl ch3, 丨 'Bu. Bu. -^ Bu

Cf3

Och3

so2CH3 OCH3

Cl

P

Ch3

CH2CH3

Cl

Och(ch3)2

Cl

Cl

Cf3 .cf3

Cl

CF. Cl cf3

COOH CF,

and

Cf3 137610.doc •15- 201028152 and all other variables are as previously defined. In another embodiment, R5 is selected from the group consisting of:

丨~0^. Naa-丨' and all other variables are as previously defined. In another embodiment, R8 is selected from the group consisting of CH3, CBu F, cyclopropyl, and cf3. In another embodiment, the compound of the invention is selected from the group consisting of: 1·[6-(2-{[4·(2-phenylethyl)benzyl)oxy}phenyl Acridine · 2 yl] 5- 5-(trifluoromethyl hydrazine-4-carboxylic acid, 5-(difluoromethyl)_1_[6_(2-{[4'-(trifluoromethyl)biphenyl _ 4-yl]methoxy) benzyl) ρ than 1-2 base] 峻 -4--4-carboxylic acid, 5-(difluoromethyl)_1_(6-{2-[(4-{2-[4 -(Trifluoromethyl)phenyl]ethyl}benzyl)-oxy]phenyl}» than bit-2-yl)-1Η_〇 嗤-4-carboxylic acid, 1-{6-[2 -({4-[(18,28)-2-phenylcyclopropyl]phenylhydrazino}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1Η-pyrazole -4-decanoic acid, l-{6-[2-({4-[(lR,2R)-2-phenylcyclopropyl]benzyl}oxy)phenyl]pyridin-2-yl}- 5-(Trifluoromethyl)-1Η-pyrazole-4-furic acid, 137610.doc •16- 201028152 1-[6-(2·{[4-(4_气苯氧)Benzyl] Oxy}phenyl)n-pyridyl-2-yl]-5-(trifluoromethyl)-1Η-" ratio -4-carboxylic acid, 5-(trifluoromethyl)-1-{6-[ 2-({4-[4-(trifluoromethyl)phenoxy]benzyl}oxy)phenyl]» is more than -2-4}-ΐΗ-η than 〇4_ decanoic acid, 5-(trifluoromethyl)-1 -(6-{2-[(4-{[4-(trifluoromethyl)phenoxy]methyl))methyl)-oxy]yl}}0-bit-2-yl)_ΐΗ-° More than tons of 4-carboxylic acid, 1-{6-[5-methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine- 2-yl}-5-(trifluoropyridazole_4_decanoic acid, 1-{6-[5-methyl-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]] Benzyl}oxy)phenyl]pyridin-2-yl}-5·(trifluoromethyl)_1Η_pyrazole_4_carboxylic acid, 1-{6-[5-gas-2-({4- [trans-4-(trifluoromethyl)cyclohexyl]benzyl)oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)_1Η•pyrazole_4_carboxylic acid, 1- {6-[5-gas-2_({4-[cis-4-(tris-decyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl) Pyrazole_4_decanoic acid, 1-[6-(2·{[4-(4-oxocyclohexyl)phenylhydrazinyl]oxyindole phenyl)β-pyridyl-2-yl]-5-( Tris-methyl)-1Η-» than β-sodium 4-acid, 1-[6-(2-{[4-(4,4-difluorocyclohexyl)benzyl]oxy}phenyl)比β啶_2_基]-5-(tri-lactylmethyl)-1Η-π ratio η sit _4_carboxylic acid, 1-[6-(2-{[4-(trans-4-methoxycyclohexyl) Benzyl]oxyindole phenyl) „Bite-2-yl]-5-(difluoromethyl )-]^-0 is more than -4-carboxylic acid, 1-[6-(2-{[4-(cis-4-methoxycyclohexyl)phenyl)]oxy}phenyl) bite- 2-Based]-5-(difluoroanthracene ratio. Sitting _4-decanoic acid, 1_[6-(2-{[4-(trans)-4.methoxycyclohexyl)·2_mercaptobenzyl]oxy}phenyl)pyridin-2-yl ]-5-(trifluoromethyl)_ΐΗ_pyrazole_4_carboxylic acid, 137610.doc •17· 201028152 5-(difluoromethyl)-l-{6-[2-({4_[6-( Trifluoromethyl)pyridine-3-yl]benzyl}-oxy)phenyl]« than biti-2-yl b Η Η 比 吐 · 4_ formic acid, 1-(6-{2-[(2' 4-Dimethylbenzyl)oxy]_3_methylphenyl}|1pyridin-2-yl)-5-(trifluoromethyl)-1Η-. Than salivary_4_carboxylic acid, 1-{6·[5_gas-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyloxy)phenyl]pyrazine- 2-yl}-5-(trifluoromethyl)-indole-pyrazole-4-furoate ethyl ester, i-{6-[5-gas-2-({4-[cis-4-(trifluoro) Mercapto)cyclohexyl]phenylmethyloxy)phenyl]pyrazin-2-yl}-5·(trifluoromethyl)·1Η_"biazole_4_carboxylic acid ethyl acetate, 5-(trifluoroanthracene) -1[4-(2-{[4.-(Trifluoromethyl) phenyl-4-yl]methoxy}phenyl)-1,3-thiazol-2-yl]-1Η- Pyrazole-4-carboxylic acid, 1-[2-(2-{[4-(2-propenylethyl)-fluorenyl]oxy}phenyl)-doped 4-yl]- 5-(trifluoro Methyl)-lH-pyrazole-4-carboxylic acid ' 1-{4-methyl-6-[5-methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzene) Mercapto}-oxy)phenyl] than bite_2_yl)-5-(trifluoromethyl)-1Η-η-pyrazole-4-carboxylic acid, 5-(trifluoromethyl)-b[6_(2 -{2-[4'-(Trifluoromethyl)biphenyl-4-yl]ethyl}phenyl)pyridine-2·yl]-1Η-pyrazole-4-furic acid, 5-(trifluoromethyl) Base)-b (2'_{[4 _(difluoromethyl)biphenyl-4-yl]methoxy}_ 2,3'-bipyridin-6-yl)_1Η-吼嗤-4-carboxylic acid , 1-(5,-fluorenyl-2·-{[3-methyl_4'-(trifluoromethyl)-linked Phen-4-yl]methoxy}_ 2,3'-bipyridin-6-yl)_5-(trifluoromethyl)_1Η-pyrazole-4-furoic acid' 1-(5,-gas^- {Ρ-Methyl-4·-(trifluoromethyl)biphenyl-4_yl]decyloxy 2,3,-bipyridyl-6-yl)_5-(trifluoromethyl)_1Η-pyrazole -4-decanoic acid, 1-[2'-{[3 -methyl-4*-(difluoromethyl)biphenyl-4-yl]methoxy b 5,-(trifluoro 137610.doc - 18 - 201028152 Methyl)-2,3'-bipyridin-6-yl]_5_(trifluoromethyl)-1 -pyrazole-4-carboxylic acid, 5-(trifluoromethyl(trifluoromethyl) Biphenyl-4-yl]oxy}methyl)phenyl]0 is more than -2-yldi 1 Η-° ratio _4_carboxylic acid, 5-(trifluoromethyl)-1_(6_{2-[ ({5·[4·(Trifluoromethyl)phenyl p-pyridin-2-yl}oxy)methyl]phenyl is more than 0 _2_yl)-1Η_Βbazole _4-carboxylic acid, . 1 -{6-[5-methyl-2-({[4'-(difluoromethyl)biphenyl-4-yl]methyl)thio)phenyl]pyridin-2-yl}_5-(three Fluoromethyl)_1Η-pyrazole-4-carboxylic acid, 1-[6-(2-{difluoro[4'-(trifluoromethyl)biphenyl-4-yl]foxy}phenyl)吼# Pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole·4-decanoic acid, 1-{6-[2-(difluoro{4-[trans-4_(trifluoromethyl)) Cyclohexyl]phenyl}decyloxy)phenyl]pyridine_2- }}_5-(trifluoromethyl)-1Η-"biazole-4-carboxylic acid' 1-{6-[2-(difluoro{4-[cis_4_(trifluoromethyl)cyclohexyl]benzene Phenyl}methoxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid, 1_(6_{2-[{2-ethyl_4- [4-(Trifluoromethyl)cyclohexyl]phenyl}(difluoro)nonyloxy]phenyl}anthracene-2-yl)-5-(trifluoromethyl)-1H-.峻君-4-carboxylic acid, ^642-(difluoro{[4'-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)phenyl]]]pyridin-2-yl}- 5-(trifluoromethylbisazole-4_carboxylic acid, and 5-(trifluoromethyl)-1-[6·(2_{[4·-(trifluoromethyl)biphenyl-4-yl]-) Oxyl}. Phenyl)pyridin-2-yl]-indole-1,2,3-triazole-4-carboxylic acid and pharmaceutically acceptable salts thereof. In another embodiment, wherein R1 is deuterium, Ζ1 is CH, R7 is CF3 or CF2H, D1 is CH' L1 is 〇' L2 is CH2 or CF2, and ring A is 137610.doc -19· 201028152 N:

Is ^^(R5)o-i -(0

And R5 is

In another embodiment, the compound of the invention is selected from the group consisting of: methyl-2-((4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy) Phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1Η-pyrazole_4_carboxylic acid, 1-{6-[5-methyl-2-({4-[cis-4 -(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]0 is indole-2-yl}-5-(trifluoromethyl)-1Η-β than 嗤-4-carboxylic acid, 1- {6-[5-Gas-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoro Mercapto)-1Η-pyrazole-4-furic acid, and 1-{6-[5-gas-2-({4.[cis-4.(trifluoromethyl)cyclohexyl]benzyl}oxy) Phenyl]pyridin-2-yl b-5-(trifluoromethyl)-1-indole-pyrazole-4-furic acid, and a pharmaceutically acceptable salt thereof, unless otherwise specified, π-burning as used herein The base " is intended to include a branching bond with a specified number of shunting atoms and a straight-bonded saturated aliphatic group. The term "cycloalkyl" means a carbon ring containing no heteroatoms. Examples of cycloalkyl groups include cyclopropyl 137610. Doc -20- 201028152 yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl and Like a group. Common abbreviations for alkyl groups are used throughout the specification, for example, methyl "T is a well-known abbreviation from a symbol including Me or CH3 or an extended bond without a defined end group (eg, V__'). It is indicated that the ethyl group may be represented by "Et" or CH2CH3, the propyl group may be represented by "Pr" or CHfHAH3, and the butyl group may be represented by "Bu" or CHzCI^CHaCH3, etc. For example, "Ci·6 alkyl group" (or alkyl ") means a straight or branched alkyl group having the specified number of carbon atoms,

Includes all isomers. C!·6 alkyl includes all hexylalkyl and pentyl alkyl isomers as well as n-butyl, isobutyl, t-butyl and t-butyl, n-propyl and isopropyl, ethyl and methyl The base e "Cl4 alkyl" means n-butyl, isobutyl, t-butyl and tert-butyl, n-propyl and isopropylethyl and methyl right not referred to (four) mesh, shell for straight The bond or branch bond is expected to be (7) carbon atoms. The phrase "alkyl which may be unsubstituted or substituted with a W(tetra) atom" means an alkyl group having fluorene, 1, 2 or 3 fluorine atoms bonded to - or a plurality of carbon atoms. For example, hydrazine, see the group " is a methyl group having three fluorine atoms bonded to the same carbon atom. Unless otherwise specified, "dilute group" means a carbon bond containing at least one carbon double bond, and it may be a straight chain or a branch Chain or a combination thereof. Examples of the dilute group include a vinyl group, an allyl 'isopropenyl group, a pentenyl group, a hexenyl heptenyl group, a 1-propenyl group, a 2 · a butyl group, a 2 - methyl 2 - butyl group and Similar group. The term "环县" means a carbon having at least one carbon-carbon double bond and no hetero atom. 137610.doc •21- 201028152 Similar groups. "Aryl" also includes a monocyclic ring fused to an aryl group. Examples include tetrahydronaphthyl, indanyl and the like. Unless otherwise specified, "heteroaryl" means at least a monocyclic or bicyclic aromatic ring or ring system selected from the group consisting of a hetero atom of ruthenium, S and osmium, wherein each ring contains 5 to 10 atoms. Examples include pyrrolyl, isoxazolyl, isosuccinyl, pyrazole Base, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxime, mito, tris, tetrazolyl, indolyl, tridecyl, fluorenyl, pyrimidinyl , pyridazinyl, pyrazinyl and the like. The heteroaryl group also includes an aromatic heterocyclic group fused to a non-aromatic or partially aromatic heterocyclic ring and an aromatic heteropoly group fused to a cycloalkyl ring. Heteroaryl. Heteroaryl also includes such groups in a charged form, for example, "thank bite" unless otherwise specified, "heterocyclyl" means at least one selected from the group consisting of N, S and oxime A 5- or 6-membered monocyclic saturated ring of an atom in which the point of attachment may be carbon or nitrogen. Examples of "heterocyclic group" include "•pyrrolidyl, piperidine, hexahydro Piperazinyl, morpholinyl, imidazolidinyl, 2,3-dihydro-furo (2,3-b) pyridyl, benzoxazinyl and the like groups. The term also includes partially unsaturated non-aromatic monocyclic rings such as 2-pyridone or 4-pyridone linked via nitrogen, or N-substituted-(1H,3H)-pyrimidine-2,4-dione (N Substituted uracil; heterocyclyl additionally includes such moieties in a charged form, such as a bite iron. Unless otherwise specified 'other', "halogen" includes fluorine, gas, bromine and iodine. Unless otherwise stated, allow Substitution with a specified substituent at any atom in the ring (e.g., aryl, heteroaryl ring or saturated heterocyclic ring) is limited in that the ring substitution is chemically acceptable and results in a stable compound. "Stability" a compound which can be prepared and isolated and maintained in structure and properties of 137610.doc •22· 201028152, or which can be kept substantially unchanged over a period of time sufficient for the compound to be used in the class, +, , Said purpose (for example, therapeutic or prophylactic administration to an individual).

In the following ring representative of variable A:

The 1,3 substitution of each ring is oriented to give the carbon atom and group of the soil A

Connecting, and making the carbon atom of the ring A and the group

(R4) 〇-2 connection. 137610.doc '23. 201028152 In A - the example order, follow the same〗, 3 substitution mode:

Invention includes! All stereoisomeric forms of the compound <. The asymmetry of the formula compound allows the core to have a configuration or a ruler independently of each other. The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, such as enantiomers and /' diastereomers in all ratios. . Because &, the enantiomers are the subject of the invention 'which is the enantiomerically pure form (both left-handed enantiomer and right-handed enantiomer)' form of the racemate, and two pairs of pairs The isomers are in the form of a mixture of all ratios. In the case of cis/trans isomerism, the invention includes both cis and trans and mixtures of such ratios in all ratios. If desired, the preparation of individual stereoisomers can be carried out by conventional methods (for example by chromatography or knot sa), by synthesis using stereochemically homogeneous materials or by stereoselective synthesis. . Derivatization can be carried out prior to separation of the stereoisomers, as appropriate. The separation of the mixture of stereoisomers can be carried out at the stage of the compound of formula I or at the intermediate stage during the synthesis. The invention also includes all tautomeric forms of the compounds of formula I. If the compound of formula I contains - or more acidic or a testable groups, the invention also includes corresponding physiologically or toxicologically acceptable salts, especially pharmaceutically acceptable salts. Thus, a compound of formula J containing an acidic group may be present and may be used in accordance with the present invention, for example, as an alkali metal salt, an alkaline earth metal salt 137610.doc -24 - 201028152 ==?! Unload salt, salt or salt. Containing two or more test groups (also known as protonated groups) such as broad amine, ethanolamine, triethanolamine or amino acid

And the organic acid may be used according to the invention, and the compounds are in the form of an acid addition salt formed by an organic acid or an organic acid, for example, in the form of a salt formed with each of the following acids: hydrogen acid, Hydrogen indole, sulphuric acid, sulfuric acid, nitric acid, methyl anhydride, p-toluene acid, naphthalene acid oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, Diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminophosphinic acid, phenylpropionic acid, gluconic acid, anti-malase Niacin, citric acid, adipic acid, and the like. If the hydrazine compound contains both acidity and (d) (d) in the molecule, the present invention includes, in addition to the extracted salt form, an internal salt or a betaine (zwitterion). Salts can be self-contained by conventional methods known to those skilled in the art, for example by combining with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. And get. The present invention also encompasses all salts of the compounds of the formula which are not directly compatible with the drug due to their low physiological phase, but which can be used, for example, as a chemical reaction or as an intermediate for the preparation of a physiologically acceptable salt. The invention is also directed to a process for the preparation of a compound of formula I as described hereinafter and which provides a compound of the invention. The compound of the formula I of the present invention achieves an increase in cGMP concentration via activation of a soluble uridine cyclase (sGC), and thus it is associated with or resulting in a decrease in treatment and prevention associated with low cGMP s or cGMP inclusion, or Treatment or prevention 137610.doc -25- 201028152 A useful agent for a condition with an increased cGMP content. Activation of the sGC by a compound of formula j can be examined, for example, in the activity assay described below. Conditions and pathological conditions associated with low cGMP levels or requiring increased CGMP levels and which can be treated and prevented using a compound of formula j are, for example, cardiovascular diseases such as endothelial dysfunction, diastolic dysfunction, atherosclerosis, Hypertension, stable and unstable angina, thrombotic restenosis, myocardial infarction, stroke, cardiac insufficiency or excessive pulmonary pressure, or (for example) erectile dysfunction, bronchial asthma, chronic renal insufficiency, and diabetes. The compounds of formula I may additionally be used in the treatment of cirrhosis and in the improvement of restricted _ recall ability or learning ability. The compound of the formula I and its physiologically acceptable salt can be administered to the animal as a drug, in a mixture with another compound or in the form of a pharmaceutical preparation, preferably administered to a mammal and especially to humans. . Accordingly, the subject matter of the present invention is also a use of a compound of the formula j and a physiologically acceptable salt thereof for use in activating a soluble guanylate cyclase, normalizing a disordered cGMP balance, and particularly The use of the above-mentioned syndromes for the treatment and prevention of the above-mentioned syndromes, and their use for the preparation of medicaments for such purposes. Furthermore, the subject matter of the present invention is to comprise an effective amount of at least one compound of the formula I and/or a physiologically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier (ie one or more pharmaceuticals) A pharmaceutical preparation (or pharmaceutical composition) of an acceptable carrier substance and/or additive). The subject matter of the present invention is also known per se as an activator of soluble guanylate cyclase and is excluded by the disclainer as defined above, which is the subject of the invention of 137610.doc -26 - 201028152 A compound of formula i other than a compound of formula j and a physiologically acceptable salt thereof. Accordingly, the subject matter of the present invention is, for example, a compound suitable for use as a medicament and a physiologically acceptable salt thereof, an effective amount of the compound and/or a physiologically acceptable salt thereof, as an active ingredient and a conventional one. Pharmaceutical preparations of pharmaceutically acceptable carriers, and the use of the compounds and/or physiologically acceptable salts thereof for the treatment or prevention of the above-mentioned syndromes, and their use for the preparation of medicaments for such purposes . The medicament of the present invention can be, for example, in the form of a pill, a lozenge, a coated lozenge, a sugar coating, a granule, a hard gelatin capsule and a soft gelatin capsule, an aqueous, alcoholic or oily solution, a syrup, an emulsion or a suspension. Oral administration or, for example, rectal administration in the form of a suppository. Parenteral administration can also be carried out, for example, subcutaneously, intramuscularly or intravenously in the form of a solution for injection or infusion. Other suitable modes of administration are, for example, transdermal or topical administration, for example, in the form of an ointment, elixirs, spray or transdermal therapeutic system, or by inhalation or in the form of a nasal spray or aerosol mixture, or Microcapsules, implants or rods. The preferred form of administration will depend, for example, on the condition to be treated and its severity. The amount of the active compound of the formula I and/or its physiologically acceptable salt in the pharmaceutical preparation is usually from 0.2 to 200 mg, preferably from 1 to 2 mg, per dose, depending on the type of pharmaceutical preparation. . The pharmaceutical preparations usually comprise from 5 to 9% by weight of a compound of the formula I and/or a physiologically acceptable salt thereof. The preparation of the pharmaceutical preparation can be carried out in a manner known per se. For this purpose H or a plurality of compounds of formula I and/or physiologically acceptable salts thereof together with - or a plurality of 137610.doc -27- 201028152 solid or liquid pharmaceutical carrier materials and / or additives (or auxiliary substances), And, if desired, in combination with other pharmaceutically active compounds having a therapeutic or prophylactic effect, in a suitable pharmaceutical form or dosage form, which may be subsequently employed as a medicament in human or veterinary medicine. For the production of pills, lozenges, dragees and hard gelatin capsules, for example, lactose, starch (for example corn starch) or starch derivatives, talc, stearic acid or its salts, etc., can be used for soft gelatin capsules and suppositories. The agents are, for example, fats, waxes, semi-solid and liquid polyols, natural or hard oils, and the like. Suitable carriers for preparing solutions (for example, preparing injectable solutions or emulsions or syrups) are, for example, water, physiological sodium carbonate solution, alcohols (such as ethanol, glycerol, polyols), sucrose, invert sugar, glucose, mannitol , vegetable oil, etc. The compound of the formula I and its physiologically acceptable salt can also be lyophilized and the resulting lyophilizate can be used, for example, to prepare an injection or infusion preparation. Suitable carriers for the microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. In addition to the active compound and the carrier, the pharmaceutical preparation may also contain conventional additives such as fillers, disintegrating agents, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersing agents, preservatives, sweeteners, A coloring agent, a flavoring agent, a fragrance, a thickener, a diluent, a buffering substance, a solvent, a solubilizing agent, a reagent for achieving a storage effect, a salt for changing the osmotic pressure, a coating agent or an antioxidant. The dosage of the active compound of the formula I to be administered and/or its physiologically acceptable salt depends on the individual case and is adjusted according to the usual circumstances to achieve an optimum effect. Therefore, it depends on the nature and severity of the condition to be treated and on the sex, age, weight of the human or animal to be treated and 137610.doc -28- 201028152 Individual reactions' depending on the efficacy of the compound used and the duration of action Whether the therapy is a short-term therapy or a long-term therapy or a prophylactic therapy depends on whether other active compounds are administered in addition to the compound of formula I. In general, a dose of about 0.01 to 100 mg/kg, preferably 0.01 to 1 mg/kg, especially 0.3 to 5 mg/kg (in each case, milligrams per kilogram of body weight) is suitable for body weight For approximately 75 kg adults, the desired result is obtained. The sputum dose can be administered in a single dose or, in particular, administered in divided doses (e.g., two, three or four individual doses) when administered in larger amounts. In some cases, depending on individual reactions, it may be necessary to increase or decrease on a given daily dose basis. The compound of formula I activates soluble uridine cyclase. Based on this property, in addition to being used as a pharmaceutically active compound in human drugs and veterinary drugs, it can also be used as a scientific tool or adjuvant for biochemical studies requiring this effect on guanylate cyclase. For diagnostic purposes, for example, in vitro diagnostics for samples or tissue samples. The compounds of formula I and salts thereof may additionally be used as intermediates for the preparation of other pharmaceutically active compounds as mentioned above. The above compounds are also suitable for use in combination with other pharmacologically active compounds comprising angiotensin converting enzyme inhibitors (e.g., aracepril, benazeprU, capt〇prii). , ceronapril, Ciiazapril, deLapril, enalapril, enaiapriiat, fosinopril, Imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, sulpriril (spirapril), 137610.doc -29- 201028152 temocapril or trandolapril, angiotensin receptor receptor antagonists (eg losartan (i〇sratan), green sand Vaisartan, candesartan, olmesartan, telmesartan, neutral endopeptidase inhibitors (eg thiorphan and phosphatidyl) Peptide (phosphoramidon), reinforced net antagonist, renin inhibitor Urea derivatives such as dipeptides and tripeptides (see U.S. Patent No. 5,1,835), amino acids and derivatives (U.S. Patent 5, 〇95,119 and 5,104,869), linked by non-peptide bonds Amino acid chains (U.S. Patent 5,114,937), dipeptides and tripeptide derivatives (U.S. Patent 5,1,6,83 5), peptidylamino diols (U.S. Patents 5,063, 2, 8 and 4,845,079) and Peptidyl β-aminomercaptoaminoglycol urethane (U.S. Patent No. 5,089,471); and various other peptides similar to those disclosed in U.S. Patent Nos. 5,071,837; 5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437 ' and small molecule renin inhibitors (including diol sulfonamides and sulfinamides (U.S. Patent 5,098,924)), Ν-morpholinyl derivatives (U.S. Patent 5,05 5,466) 'Ν-heterocyclic alcohols (U.S. Patent 4,885,292) and pyrazolidazolone (U.S. Patent 5,075,451); and pepstatin derivatives (U.S. Patent 4,980,283) and fluorine derivatives and gas derivatives containing statone peptides (U.S. Patent 5,066,643), Enalkrein, RO 42-5892, A 65317, CP 80794 ES 1005, ES 8891, SQ 34017, aliskiren (auskiren, 2(8), 4(8), 5(8), 7(8)_1^-(2-aminomercapto-2-methylpropane )5·amino- 4-hydroxy-2,7-diisopropyl-8·[4-methoxy-3-(3-decyloxypropoxy)-phenyl]octylamine Butenoic acid salt) SPP600, SPP63 0 and SPP63 5), endothelin receptor antagonist, blood vessel 137610.doc •30- 201028152

Dilators, about channel blockers (eg, amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine) ), nimodipin, nicardipine, slant channel activator (eg, nicord (uniorand U), 0 pinacidil, cromakalim, miner Minoxidil, aprilkalim, loprazolam, diuretics (eg, dihydrochloropyrazine), sympathetic inhibitors, beta-adrenergic blockers (eg, propranolol) Propranolol, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol (11161(^]'〇1〇1 ) tartrate), 01 adrenergic blocker (eg, dox "doxazocin", 0 prazocin or alpha methyldopa), central alpha adrenergic agonist, peripheral vasodilation Agents (such as hydralazine), lipid lowering agents (such as simvastatin (simva) Statin), lovastatin, ezetamibe, atorvastatin, pravastatin, pratastatin, metabolic modifiers (including tamsen sensitizers and related compounds) (eg, muglidazar, glibizide, metformin, rosiglitazone), or other drugs that are beneficial in preventing or treating these diseases. (Including a combination of nitroprusside and diazepine) The compounds of formula I can be synthesized according to the general procedure provided below, taking into account the specific examples provided, where Z1, A, D1, L1, L2, E, R4 , R5, R6, R7, R8 and R" are as defined above. Unless otherwise specified, the following abbreviations are used: 137610.doc 31 201028152 aq, aqf aqueous BuLi, n-BuLi= n-Binyl Short Ar=Aryl DME=1,2-Dimethoxyethane Ac=Acrylic Acid Bn=Benzyl Bu=Butyl't-Bu^Ter Butyl CBZ, Cbz=Benzyl Oxygen Carbocarbonyl cPr=cyclopropyl cone, cone ·=rolling BOC, Boc=third butyloxycarbonyl DAS T = trifluorinated (diethylamino) sulfur DCM = dioxane methane dba = dibenzylideneacetone; pd2dba3 = ginseng (diphenylmethylene propyl hydrazine) di-saturated DIEA = diisopropylethylamine DIAD = diisopropyl azodicarboxylate DMAC, DMA = dimethyl acetamide DMAP = 4-dimethylaminopyridine DMSO diterpenoid DMF = N, N-dimethylformamide Et31 hexyl dppf DPPF=1,1·-bis(diphenylphosphino)ferrocene EtOAc=ethyl acetate DffiAL, DroAL-H=diisobutylaluminum hydride.=equivalent ESI=electrospray ionization HO Ac=acetic acid EtOH=ethanol iPr=isopropyl HPLC=high pressure liquid chromatography h, hr=hour LAH=hydrogenation chain IPA, i-Pr〇H=isopropanol LCMS=liquid chromatography-mass spectrometry MeOH=methanol LHMDS= Bis(trimethyldecyl) guanamine lithium Me=methyl min, min_=min OMs, mesyl=pitpit performance brewing base Py=n ratio bite base NMP=N-methylpyramine bite Pd/c=i&amp ; / activated carbon NMR = nuclear magnetic resonance RT, rt = room temperature Ph = phenyl sat. = saturated Pr = propyl Tosyl = toluene dish THF = tetrahydrofuran OTf, triflate = triflate; triflic = trifluoro Methanesulfonic acid TBAI = tetrabutyl iodide TLC = thin layer chromatography; prepTLC = preparative thin layer ~~ TFA = trifluoroacetic acid Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimercaptodibenzopyran. If Z^CH, the pyrazole acids and corresponding esters are commercially available. It is known in the literature or can be readily prepared by those skilled in the art. One such -32-137610.doc 201028152 procedure is shown in Scheme 1 comprising aryl hydrazine or heteroaryl hydrazine 1 and acetophenone in the presence of a base such as Et3N and a solvent such as acetonitrile at ambient or elevated temperature. The ester derivative 2 is reacted to provide pyrazole 3 (J. Comb. Chem. 2003, 5, 465; Heterocycles 1992, 34, 791).

Process 1

Such aryl hydrazines and heteroaryl hydrazines 1 are commercially available and are known in the literature and can be prepared by a variety of methods by those skilled in the art. A synthetic method for forming 2-mercaptopyridine lb is shown in Scheme 2, which comprises reacting 2-p-pyridine derivative 4 with hydrazine hydrate in refluxing ethanol. Another method, also shown in Scheme 2, involves the addition of 4 and di-t-butyl groups in a solvent crucible such as toluene in the presence of a metal catalyst such as Pdadba3, a ligand such as dppf, and a base such as CkCO3 at elevated temperature.肼-1,2-didecanoate is reacted to provide bis-tert-butyloxycarbonyl-hydrazinopyridine 5, which is then deprotected in an acidic solution (such as Ermingyuan/Agricultural Hydrochloride) to provide 2-cultivated η Than ib (Org. Lett. 2001, 3 (9), 1351-1354). 137610.doc -33 - 201028152 Process 2

As outlined in Scheme 3, thiazolyl pyrazole 8 can be readily prepared by reacting an aminothiourea with a beta-ketoester 2 in a solvent such as EtOH to form the intermediate thiosylamine pyrazole The porphyrin 6, which is then reacted with an alpha-bromo ketone (such as 7) in a solvent such as EtOH at elevated temperature to provide the thiazolyl pyrazole 8 (J. Comb. Chem. 2002, 4, 23). Process 3

H2N hn-nh2 2

EtOH -150C to rt, 16h

If Z^N, the triazoles 11 can be prepared as described in Scheme 4, including aryl azide or in the presence of a base such as sodium ethoxide or Et3N at elevated temperature in a suitable solvent such as MeCN. Heteroaryl azide 9 is reacted with β-ketoester 10 (J. Med. Chem. 1990, 3 3 (9), 2646; U.S. Patent 4,474,599). Such azide 9 is commercially available and is known in the literature and can be obtained by a variety of methods by those skilled in the art. One such method is also shown in Scheme 4, which involves reacting hydrazine 1 with NaN02 in a suitable acidic solvent such as a mixture of diethyl ether and concentrated hydrochloric acid (137610.doc • 34-201028152 solvent) (U.S. Patent 4,474,599). Flow 4 ^A^)-N3 9

NaN02 1 -

Et20, HC1 (aq) 0 °C, 2 h • If desired, a suitable stupid base or a pyridyl ring can be attached to ring A by a person skilled in the art to provide compound 14 ^. The method 'comprising an appropriately substituted intermediate 1 2 in a suitable solvent such as acetonitrile, usually at elevated temperature using a catalyst such as dioxobis(triphenylphosphine)palladium(II) and a base such as an aqueous solution of sodium carbonate. (Y=C1, Br, I, OTf) and suzuki cross-coupling reaction between succinyl acid or succinic acid (HeteroCyCles, 2003, 60, 1891). Conversely, a catalyst such as Pd(dppf)Cl2 can be used at high temperatures, in the presence of an appropriate solvent such as an acetic acid clock and such as DMSO (J 〇rg chem. 1995, 60, • 7508), or using such as a double (Tricyclohexylphosphine) palladium (ruthenium) catalyst and such as sodium chlorate, in a solvent such as acetonitrile (Tetrahedr〇n, 2〇〇1, 57, 9813) makes 12 (丫 = (: 1, 31) :, 1) is converted to the _ester 15 by reaction with bis(pinacolyl)diboron. The resulting s-acid coupling conditions can then be used to react the resulting s-acid oxime with an appropriately substituted aryl or heteroaryl ring. 16, work, OTf) cross-coupling to provide compound 14. 137610.doc -35- 201028152 Process 5

OR" PdCl2(Ph3P)2>Na2C〇3 CsF, MeCN, 90 °C, 2h These compounds may additionally be purified by methods known to those skilled in the art. Such operations may include, but are not limited to, substitution, reduction , oxidation, alkylation, deuteration, and hydrolysis reactions. An example of such a compound for the preparation of L1 = hydrazine is shown in Scheme 6, and the examples include at ambient or slightly elevated temperatures, such as K2C〇3 Or in the presence of a Cs2C〇3 base, the phenol or hydroxypyridine 17 is usually present in a polar solvent such as DMF (as is well known to those skilled in the art), the hydroxypyridine may also exist as a tautomeric pyridone, but is simple For the first time, it is shown that the hydroxypyridine is alkylated with an alkyl group or a benzyl dentate Υ-ΙΛε (Y=C1, Br) to provide an ether 18. These ethers 18 can also be used in Mitsunobu conditions. Forming, including 17 with an alkyl alcohol or benzene, usually in an aprotic solvent such as DCM or THF, in the presence of a phosphine such as triphenylphosphine and an azodicarbonyl reagent such as diisopropyl azodicarboxylate , methyl alcohol E-L2-OH reaction (Synthesis 1981, page 1). 1376 10.doc -36- 201028152 Process 6

Y-l2-e

Cs2C03, DMF HO-Lz-E ----) DIAD, Ph3P, DCM

As shown in Scheme 7, i is right D = N, then compound 18b can also be subjected to a suitable reactive Pg (such as fluorine K) in a polar solvent such as a surface by the presence of a τ such as Na〇tBu. 19) formed by reacting with a mercapto alcohol or a benzohydrin alcohol H〇_L2-E. Process 7

OR11 If the phenyl ring or the pyridyl ring is suitably substituted, the compounds can be changed using the cross-coupling conditions. An example of this is shown in Scheme 8, where acetonitrile is present at ambient temperature in the presence of copper (I) iodide, bis(triphenylphosphine)palladium (II), tetrabutylammonium iodide, and Et3N. The aryl trifluorosulfonate 20 is reacted with the corresponding alkyne ECCH to provide an alkyne 21 (Tetrahedr〇n Lett. 2001, p. 5275). The pendant bond is provided to provide an extended ethyl derivative 22 by hydrogenation using a metal catalyst such as pt 2 in a solvent such as EtOAc under hydrogen atmosphere. 137610.doc -37· 201028152 Process 8

The compound of l/ = S can also be obtained from trifluorosulfonate 20 as shown in Scheme 9. Providing a high temperature at a high temperature in the presence of a metal catalyst such as Pd2dba3, a ligand such as Xantphos, and a test such as DIEA, in a suitable solvent such as a dioxin, with a 4-methoxy alpha-toluenethiol for 15 h. Oxyphenyl sulfonyl sulphur [23] (Organic Letters 2004, 6 (24), 4587). Removal of the benzyl group in the presence of a collector such as anisole in an acidic solvent such as TFA provides the thiol 24, which is sometimes accompanied by the corresponding disulfide dimer. The thioether 25 is provided by alkylation of the desired alkyl halide or phenylhydrazine halide Y-L2-E (Y=C1, Br) in the presence of a base such as K2C03 or Cs2C03, usually in a polar solvent such as DMF. . In the presence of a disulfide, the addition of a reducing agent such as NaBH4 to the reactant can aid in improving the product yield by converting the disulfide to the mercaptan in the field. Process 9

TFA, anisole 0R11 60 °C, 15 h

24 y-l2-e

137610.doc -38 - 201028152 A method for obtaining a compound of LLCH2 and l2=o is shown in Scheme 10, which comprises appropriately substituting a compound 12 (Y=I, Br, Cl, 〇Tf) with an appropriate gp such as 26 The acid ester is subjected to Suzuki cross and coupled to provide a hydroxymethyl analog 27. If desired, the compounds can be further modified, for example, by reacting the aromatic and heteroaromatic materials e_〇h with the above-described light-coupling conditions (see above) to provide compound 28. Process 10

In some cases, it may be necessary to further modify the compounds described herein. One such example is shown in Scheme 11, whereby a gasifying agent such as tetra-gasified benzyltrimethylammonium is used in DCM at ambient temperature. Treatment of compound 17 primarily provides a gas derivative 29 for 24 h. Conversely, a mixture of iodine compound 30 and o-iodo isomer 31 is also provided as described in Scheme 11 by treatment with iodine and silver sulfate in a solvent such as EtOH. If desired, iodine can be further modified by a variety of methods by those skilled in the art. Such transformations include, but are not limited to, cross-coupling reactions, cyanation reactions, halogen exchange reactions, and carbonylation reactions. The phenolic group can then be further altered as described above (see above). 137610.doc -39- 201028152 17 Process 11 Bn(Me)3N+ IC14

DCM, rt, 24 h OR11 29

In some cases, it may be necessary to further change the ring E. An example of such a transformation is described in Scheme 12, wherein ring E of compound 32 is an aryl or heteroaryl ring. These compounds can be alkylated under basic conditions with RY (R = alkyl, benzyl; Y = Br, Cl, I, OMs, OTosyl) or using light delay coupling conditions with ROH (R = alkyl, benzene Methyl)alkylation to provide ether 33 as previously described (see above). Process 12

Y-R

Cs2C03, DMF (R4) 〇-2

OR11

HO-R

DIAD, Ph3P DCM can also change the E-ring via a cross-coupling reaction. For example, as shown in Scheme 13, when E is an aromatic or heteroaromatic ring, the Suzuki cross-coupling conditions can be used to provide compound 34 (Y = Br, C I, OTf) with an alkyl tanning acid, alkene. The base S acid, the heteroaryl acid, and the aryl acid R5-B(OH) 2 are coupled to provide the product 137610.doc -40 - 201028152 35 ' as described above (see above). You can also use the UUman program (〇rg

Lett. 2002 'p. 1623» coupling aryl halides to heteroatoms such as phenols' such procedures include at elevated temperatures in catalysts such as CuC1, such as 2,2,6,6-tetramethyl-3 The ligand of 5-heptanedione and the presence of a reagent such as Cs2c〇3 are reacted in a suitable solvent such as N-methylpyrrolidone to provide an aryl ether 36. Alternatively, compound 34 (Y = Br, I) can be converted to the corresponding _ acid brew 37 ' and then cross-coupled with the appropriate R5_Y (γ = α, Br, I, OTf) under the aforementioned Suzuki coupling conditions to provide compound 35 (see above) ).

Process 13

(R4) 〇-2 j 36 R7 ° OR6 35 As will be appreciated by those skilled in the art, the compounds described herein can be further modified by a variety of chemical reactions including, but not limited to, substitution, reduction, oxidation. , alkylation, deuteration, cross coupling and hydrolysis reactions. As shown in Scheme 14, when R" is an alkyl group, the pyrazoles and triazole esters 38a and the synthetic intermediates can be readily converted to the corresponding carboxylic acids using methods known to those skilled in the art to 137610.doc -41 · 201028152 acid. For example, the saponification of ester 38a can be achieved in a mixture of a polar solvent such as tetrahydrofuran, dioxane, methanol, ethanol or the like using a base such as lithium hydroxide or aqueous sodium hydroxide to provide the corresponding carboxylic acid 38b. . Further, when R11 is a third butyl group, the esters can be easily converted to a carboxylic acid by treatment with an acid (such as trifluoroacetic acid) which is usually in a 1:1 mixture with dioxane at ambient temperature for 0.5 to 8 h. Acid 3 8b. Process 14 L2 ° (eV (RV2 38a hydrolysis)

As is well known to those skilled in the art, in all processes, product J and all synthetic intermediates can be subjected to recrystallization, wet milling, preparative thin layer chromatography, and silica gel flash chromatography (eg, W. c. Stil丨). Or, reverse phase HPLC purification to remove improper by-products, reagents and solvents. The compounds purified by HPLC can be separated into the corresponding salt forms. Also, in some cases, the final compound! The synthesis intermediate can comprise a mixture of cis and trans isomers, enantiomers or diastereomers. As is well known to those skilled in the art, the cis and trans isomers: enantiomers and diastereomers can be separated by a variety of methods, including crystallization, use of pure palmity. In the case of cis/trans isomers and diastereomers, such methods include normal phase and reverse phase chromatography. The column examples are illustrative of the compounds of formula I and the intermediates used to prepare the compounds of the formula 137610.doc • 42· 201028152 The invention is not to be construed as limiting. The chemical reaction was monitored by LCMS, and the purity and characteristics of the reaction product were determined by [CMS (electrospray ionization) and NMR. The NMR spectrum uses the residual proton solvent signal as an internal reference. The data of iH NMR is based on chemical shift (δ ppm), multiplicity (s== singlet, d=doublet, t=triple bee, quartet, m=multiplet), coupling constant (Hz) and Points reported. On a YMC-Pack Pro C18 column (150 x 20 mm id) or Kromasil 100-10 C8 column (100 x 30 mm id) at an initial flow rate of 4 mL/min for 1.3 5 min, followed by 20 mL/min for 13.6 Min performs preparative HPLC. The gradient used during the faster portion of the operation has been described and all operations are followed by rinsing with 100% organics at 20 mL/min for 5 min. A Fisher 12 〇 V, 3A lamp with a 25 〇 w bulb was used for the reaction of the fluorescent lamp. The gel flash chromatography was performed on a Bi〇tage Horizon or Biotage SP-1 instrument equipped with a UV detector using a prefilled cartridge column. The following examples are provided to enable the invention to be more fully understood. It is not to be taken as limiting the invention in any way. Example 1

137610,doc -43- 201028152 Step A: hexyl-1-(6-gas "bite-2-yl)-5-trimethylmethyl-4-formate to 2-gas-6-fluorenyl Add 2-(ethoxymethylene)-4,4,4 -3 to a solution of bite (1.00 g, 6.97 mmol) and triethylamine (0.971 mL ' 6.97 mmol) in acetonitrile (35 mL) Gas-3-oxobutyrate ethyl acetate (1.36 mL, 6.97 mmol). After 20 min, the reaction mixture was placed in an oil bath of 6 °C. After 30 min, the reaction mixture was cooled to ambient temperature and then concentrated in vacuo. Purification by flash chromatography (30% EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut elut elut (500 MHz, CDC13) δ 8.10 (s, 1H), 7.88 (t, J=7.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 4.38 (q, J=7.〇Hz, 2H), 1.38 (t, J=7.0 Hz, 3H) 〇Step B: l-[6-(2·hydroxyphenyl) 吼_2_基]— Addition of 2-hydroxyphenyl-acid (237 mg, 1.72 mmol) and anti-- to a flask containing the title compound (500 mg, 1.56 mmol). One milk bis(diphenylphosphine) put (11) (112 mg, 0.16 mmol). Acetonitrile (4 mL) and sodium carbonate (3.9 mL, 1% hydrazine aqueous solution, 3.9 mmol) were added, and the mixture obtained was degassed by nitrogen. The reaction mixture was at 70. (: stirring for 3 h' then it was cooled to ambient temperature and poured into water. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuo. EtOAc, followed by 30 to 100 〇 / 己 in the hexane

Purification by EtOAc afforded the title compound: </RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 8.04 (m, 2H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (dd, J=7.5, 1.5 Hz, 1H), 7.38-7.34 (m, 1H), 7.06-7.03 (m, 1H), 6.99-6.95 (m, 1H), 4.40 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.〇Hz, 3H). Step C: l-[6-(2-{[4-(2-Phenylhexyl)benzyl)oxy}phenyl)-palladium-2-yl]_5_(trifluoromethyl)-1Η- The pyrazole-4-formic acid ethyl ester was fed into the vial of the title compound of Example 1 Step B (36.0 mg, 0.095 mmol), carbazide (62.2 mg, 0.191 mmol) and 4-tridecyldiphenylmethyl (33.0 mg) , 0.143 mmol). DMF (0.5 mL) was added and the resulting suspension was stirred vigorously. After 2 h the reaction mixture was diluted with EtOAc and brine. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography (0 to 25% EtOAc in hexanes elute elut elut elut elut elut elut elut elut elut elut elut (500 MHz, CDC13) δ 8.16 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.98 (dd5 J=7.5, 1.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H) , 7.53 (d, J=7.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.29-7.26 (m, 4H), 7.22-7.17 (m, 5H), 7.11 (t, J=7.5 Hz, 1H ), 7.07 (d, J=8.5 Hz, 1H), 5.13 (s, 2H), 4.39 (q, J=7.0 1^, 211), 2.93 (approximately single peak (&amp; 卩?8), 411), 1.39 (1, Bu 7.0 1^, 3H). Step D: l-[6-(2-{[4-(2-Phenylethyl)benzyl)oxy}phenyl)-l-yl-2-yl]-5-(trifluoromethyl)· 1Η-«carbazole-4-carboxylic acid was added to the solution of the title compound of Example 1 Step C (27.0 mg, 0.048 mmol) in 137610.doc -45 - 201028152 1,4-di &quot;digested (2 mL) The hydroxide chain (1.0 mL, 2.0 Μ aqueous solution, 2.0 mmol) was stirred and the mixture was stirred at 60 °C. After 15 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, which was then diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse-phase HPLC (30 to 100% acetonitrile in water </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; D6-DMSO) δ 8.25 (s, 1H), 8.14-8.07 (m, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.42 (t, J =7.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.27-7.14 (m, 8H), 7.09(1;,1=8.0 1^,111), 5.19(8,211),2.86 (Approx. single peak, 41^). Example 2

Step A: l-(6-{2-[(4-Bromobenzyl)oxy]phenyl)pyridine_2-yl)_5•(trifluoromethylindole-4-carboxylic acid) Add 4-bromobenzyl bromide (678 mg, 2 71) to a solution of the title compound (682 mg, 1.81 mmol) in DMF (10 mL)

The mixture was poured into saturated aqueous NHCl and extracted with EtOAc. The organic 137610.doc -46 - 201028152 phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (0 to 25% EtOAc in EtOAc EtOAc EtOAc EtOAc EtOAc 500 MHz, CDC13) δ 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.95 (dd, J=7.5, 1.5 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H) , 7.54 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.39-7.36 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 5.10 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H) . Step B: 5-(Trifluoromethyl)-indole[6-(2-{[4,-(trifluoromethyl)indol-4-yl]methoxy}phenyl) To a flask containing the title compound of Example 2, Step A (40.0 mg, 0.073 mmol), 4-trifluoromethylphenyl succinic acid (21. 〇mg, 0.110) Methyl) (1) (2.6 mg, 0.004 mmol). Degassed acetonitrile (0.5 mL) and sodium carbonate (0.183 mL, 1.0 EtOAc, 0.183 mmol) were added and the mixture was stirred at 70 °C. After 1.5 h, the reaction mixture was cooled to ambient temperature and then transitioned via DCS eluting with DCM. The Suzuki product was used in the next step without further purification: LCMS m/z 612.2 [M+H]+. Step C: S-(Trifluoromethyl)-1-[6·(2-{[4,-(trifluoromethyl)xyl-4-yl]methoxy}phenyl)pyridin-2-yl -1H-pyrazole-4-carboxylic acid The title compound (about 0.073 mmol) from Example 2 Step B was taken from 1-4. A solution of hydrazine (0.50 mL, 2.0 Torr in water, 1.00 mmol) was added to the solution in sm. (0.5 mL), and the mixture was stirred at 50 °C. After 2 h, 137610.doc • 47· 201028152 The reaction mixture was made acidic by the addition of aqueous hydrochloric acid, which was then diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water with 0.1% v/v TFA) afforded the title compound: LCMS m/z 584.1 [M+H] + ; 4 NMR (500 MHz, d6-DMSO ) δ 8.30 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.14 (t, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.80 (d, J =8.0 Hz, 2H), 7.75-7.71 (m, 4H), 7.56 (d, J=8.0 Hz, 2H), 7.46-7.43 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 5.32 (s, 2H). Example 3

Step A: 5-(Trifluoromethyl)-1-(6-{2-[(4-{(Ε)-2-[4-(trifluoromethyl)phenyl)vinyl}benzyl) Ethyloxy]phenyl}acridin-2-yl)-1Η-»carbazole-4-carboxylic acid ethyl ester 2-(4-) was added to a vial containing the title compound (50.0 mg, 0.092 mmol) Trifluoromethylphenyl)vinyl Spentanoic acid (29.6 mg, 0.137 mmol) and trans-di- gas bis(triphenylphosphine)palladium (11) (6.4 mg, 0.009 mmol). Acetonitrile (0.400 mL) and sodium carbonate (0.229 mL, 1.0 Μ water 137610.doc -48 - 201028152 solution, 0.229 mmol) were added and the mixture obtained was degassed by nitrogen. After the reaction vial was capped and placed in a preheated oil bath (7 Torr) for <RTI ID=0.0># </RTI> for 18 h, the reaction mixture was cooled to ambient temperature and poured into water. The mixture was extracted with DCM and the organic phase was concentrated in vacuo. Purification by gelatin chromatography (0 to 30% / EtOAcEtOAcEtOAcEtOAcEtOAc NMR (500 MHz, CDC13) δ 8.16 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.88 (t, J = 7.5 Hz, 1H) , 7.61 (br s, 4H), 7.54 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41-7.39 (m, 1H), 7.37 (d, J=7.5 Hz , 1H), 7.21-7.06 (m, 4H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H). Step B: 5-(Trifluoromethyl)-l-(6-{2-[(4-{2-[4-(trifluoromethyl)phenyl)ethyl}benzyl)oxy]benzene The de-gassed solution of the title compound (24.0 mg, 0.03 8 mmol) in EtOAc (2 mL··········· Platinum oxide (ιν) (8·〇mg) was added thereto. A hydrogen balloon connected to a 3-way adapter was attached to the reaction mixture. The reaction flask was then evacuated and backfilled with hydrogen. After the process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere and stirred vigorously for 45 min. The reaction mixture was filtered and washed with EtOAc over Celite. The mixture was concentrated in vacuo and used without further purification: LCMS m/z 640.6 [M+H]+. To a solution of the hydrogenated product in EtOAc, EtOAc (2 mL), EtOAc (1··········· After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, then diluted with 137610.doc 49- 201028152 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% in EtOAc / EtOAc EtOAc EtOAc EtOAc) -DMSO) δ 8.12 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.26 (d , J=8.5 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.09 (t, J=8.5 Hz, 1H), 5.20 (s, 2H), 2.97-2.94 (m, 2H), 2.91 -2.88 (m, 2H). Example 4

Step A: l-{6-丨2-({4-[(18,28)-2-phenylcyclopropyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-( Trifluoromethyl)_1H_pyrazole_4_carboxylic acid and ({4-[(lR,2R)-2-phenylcyclopropyl]benzyl}oxy)phenyl] 咕 bit_2_基卜5-(Trifluoromethyl)-1Η-«Λ -4- -4-carboxylic acid was fed into a vial. Example 2 Steps The title compound (600 mg, 1.10 mmol), exo/spiral anti-2 -benyl propyl Base acid (356 mg, 2.20 mmol) and tripotassium phosphate (769 mg, 3.62 mmoip), the flask was purged with nitrogen, followed by the addition of toluene (5.00 mL) and water (0.198 mL, 10.98 mmol). Add 137610.doc -50- 201028152 肆(triphenylphosphine)palladium(0)(127 mg, 0.110 mmol)' and the reaction was capped and placed in a preheated oil bath (10 ° C) with vigorous stirring. After 18 h The reaction mixture is cooled to ambient temperature and then purified by flash chromatography (0 to 20% EtO Ac in hexanes then 20 to 1% EtOAc in hexanes) to provide the Suzuki product: LCMS m/z 556·2 [M+H]+. via preparative palmitic HPLC (column column, 30% IPA in heptane, 9 mL/min flow rate, Separation of the enantiomers by separation of the enantiomer tr = 15.03 min; second dissociation enantiomer tr = 22.83 min). Enantiomerically pure ethyl ester at 50 ° C with LiOH (1.5 NaOH, 2.0 Μ aqueous solution, 3.0 mmol) was saponified in dioxane (4 mL). After 1 h, the reaction mixture was acidified by the addition of 2 N HCl, then diluted with 1,4-dioxane and DMF Purified by reverse phase HPLC (50 to 100% acetonitrile in water, both with 0.1% v/v TFA) to afford the title compound: LCMS m/z 544.4 [M+H] + ; !H NMR ( 500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.15-8.09 (m, 2H), 7.73 (dd, J=7.5, 1.5 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.28-7.24 (m, 3H), 7.16-7.15 (m, 5H), 5.20 (s, 2H), 2.17 (t, J=7.0 Hz, 2H), 1.46-1.43 (m, 2H) 〇

Example S

137610.doc 201028152 Step A : l-(6-{2-[(4-Iodophenylmethyl)oxy]phenyl}pyridin-2-yl)-5-(trifluoromethyl)-1Η-pyridyl To a solution of the title compound (304 mg, 0.81 mmol) in EtOAc (EtOAc: EtOAc. Barium carbonate (788 mg ' 2.42 mmol). After 12 h, the reaction mixture was poured with EtOAc EtOAc EtOAc. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. Purification by silica gel flash chromatography (EtOAc to EtOAc (EtOAc:EtOAc) (500 MHz, CDC13) δ 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.94 (dd9 J=7.5, 1.5 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H) , 7.68 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.14-7.12 (m, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 1H), 5.09 (s, 2H), 4.39 (q, J=7.0

Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H). Step B: l-[6_(2-{[4-(4-Vinyloxy)benzyl)oxy}phenylpyridin-2-yl]-5-(tri-Imethyl)·1Η-· Feeding vaporized copper (1) (1.7 mg, 0.017 mmol), cesium carbonate (55.0 mg, 0.169 mmol), 4-chlorophenol (21.7 mg, 0.169 mmol) and Example 5 steps into a vial The title compound (50. 〇 mg, 0.084 mmol) from A. 2,2,6,6-tetramethyl-3,5-dione (0.007 mL, 0.034 mmol) was added and the mixture was then evaporated. Degassed N-decylpyrrolidone (0.170 mL)' and the vial was capped and placed in a preheated oil bath (12 Torr. (:). After 15 h, the reaction mixture was cooled to ambient temperature. Subsequently, it was filtered through DCM 137610.doc -52· 201028152 using DCM and concentrated in vacuo: LCMS m/z 594.3 [M+H]+. To the unpurified coupling product in 1,4-dioxane ( Lithium hydroxide (0.5 mL, 2.0 Torr in water, 1.00 mmol) was added to the solution in 1 mL), and the resulting mixture was taken up at 50 ° C. After 30 min, the reaction mixture was made acidic by adding aqueous hydrochloric acid. It is then diluted with dioxane and passed through a 0.45 micron needle Purification by reverse phase HPLC (50 to 100% acetonitrile in water, EtOAc EtOAc) (s, 1H), 8.15-8.09 (m, 2H), 7.74 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (dd, J=7.5, 1.0 Hz, 1H), 7.47-7.42 (m, 4H) ), 7.29 (d, J=8.0 Hz, 2H), 7.12-7.09 (m, 2H), 7.04-7.00 (m, 3H), 5.22 (s, 2H) 〇Example 6

Step A: 4-[4-(Trifluoromethyl)benzoinyl]methyl benzoate was fed to the flask with methyl 4-hydroxybenzoate (500 mg, 3.29 mmol), copper acetate (11) (895 mg ' 4.93 mm 〇l), 4-trifluorodecylphenyl decanoic acid (2.50 g, 13.15 mmol) and 4 angstrom molecular sieves (5 〇〇 mg). A gas-burning (3 3 mL) and triethylamine (1.83 mL, 13.15 mmol) were added, and the reaction mixture was stirred rapidly under air. After 48 h, the reaction mixture was taken up and concentrated in vacuo. Purification by silica gel flash chromatography (0 to 10% EtOAc in EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc H] + ; 4 NMR (500 MHz, CDC13) δ 8.07-8.05 (m, 2Η), 7.63 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.06-7.04 ( m, 2H), 3.92 (s, 3H). Step B: 4-[4-(Trifluoromethyl)phenoxy]phenyl}methyl-yield EtOAc (EtOAc: EtOAc. °C) DIBAL-H (2.2 mL, 1.50 Μ, 3.29 mmol in heptane) was added to the solution. After 30 min, the reaction mixture was transferred to a 0 ° C bath and kept at this temperature for 45 min then quenched by MeOH (0.5 mL). The resulting mixture was diluted with diethyl ether and sat. sodium tartrate/potassium aqueous solution and the mixture was stirred vigorously until clear phase separation was achieved. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc EtOAc (EtOAc) elut elut elut elut elut elut elut elut </ RTI> </ RTI> <RTIgt; Step C: 5-(Trifluoromethyl)-l-{6-[2-({4-[4-(trifluoromethyl)phenoxy]benzyl}oxy)phenyl]pyridine-2 The title compound (107 mg '0.40 mmol) from Example 1 Step B, the title compound (75.0 mg, 0.20 mmol) and triphenylphosphine (104 mg) To the solution in DCM (1 mL) was added diisopropyl dicarboxylic acid diisopropylacetate (0.077 mL, 0.40 mmol), and the mixture was stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo 137 610.doc - 54 - 201028152. The title compound was obtained by filtration with EtOAc EtOAc EtOAc. Lithium hydroxide (1.0 mL, 2·〇 Μ, 2.00 mmol) in water was added to a solution of the product of the product in 14% dioxane (2 mL), and the mixture was stirred at 50 °C. After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid solution, which was then diluted with dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water with EtOAc EtOAc: EtOAc: EtOAc: EtOAc) DMSO) δ 8.28 (s, 1H), 8.16-8.10 (m, 3H), 7.75-7.70 (m, 4H), 7.51 (d, J=8.5 Hz, 2H), 7.47-7.44 (m, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.15-7.10 (m, 5H), 5.25 (s, 2H). Example 7

Step A: l-[6-(2-{[4-(Hydroxymethyl)benzyl)oxy}phenyl)]-5-(trifluoromethyl)-1Η-pyrazole_4_carboxylic acid Ethyl ester To a solution of the title compound (150 mg &lt;RTI ID=0.0&gt;&gt;&gt; 3 13 mg, 1.19 mmol) 'Addition of azodicarboxylic acid II 137610.doc -55· 201028152 isopropyl ester (0.232 mL, 1 ·19 mmol). The reaction vial was capped and stirred at 60 ° C. 1.5 h After that, the reaction mixture was cooled to ambient temperature and then concentrated in vacuo tolululululululululululululululululu :LCMS m/z 498.1 [Μ+Η] + ; NMR (500 MHz, CDC13) δ 8.13 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.95 (dd, J=8.0, 1.5 Hz , 1H), 7.85 (t, J=7.5 Hz, 1H), 7.51 (d, J=8.5,

Hz, 1H), 7.39-7.28 (m, 5H), 7.11 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 4.98-4.94 (m , 2H), 4.38 (q, ® J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H). Step B: 5-(Trifluoromethyl)-l-(6-{2-[(4-{[4-(trifluoromethyl)phenoxy]methyl}benzyl)oxy]phenyl The title compound (30.0 mg, 0.060 mmol) and 4-hydroxybenzotrifluoride (29·3 mg, 0.181 mmol) of Example 7 Step A Triphenylphosphine (47.5 mg, 0.181 mmol) and diisopropyl azodicarboxylate (0.035 mL, 0.181 mmol) were added to a solution in THF (0.400 mL). The resulting mixture was stirred at 60 °C. After 3.5 h, the reaction mixture was cooled to ambient temperature then concentrated - concentrated in vacuo. Rapid chromatography by gelatin (50% in hexane)

Purification by EtOAc, EtOAc (EtOAc)EtOAc. Step C: 5-(Trifluoromethyl)-1-(6-{2·[(4-{[4-(trifluoromethyl)phenoxy]methyl}benzyl)oxy]phenyl a solution of the title compound (15.0 mg, 0.023 mmol) in 1,4-dioxane (5. 5 mL). Lithium hydroxide (05 mL, 137610.doc • 56-201028152 in water 2.0 Μ, 1.00 mmol) was added thereto, and the resulting mixture was stirred at 50 °C. After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, which was then diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (30 to 100% acetonitrile in water with 0.1% v/v TFA) afforded the title compound: LCMS m/z 614.2 [M+H] + ; H NMR (500 MHz, d6- DMSO) δ 8.29 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.10 (t, J=8.0 Hz, 1H), 7.73 (dd, J=7.5, 1.5 Hz, 1H), 7.70 ( d, J=8.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 5H), 7.27 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 5.25 (s, 2H), 5.18 (s, 2H). Example 8

Step A: 1-[6-(2.Methoxy-5-methylphenyl)pyridin-2-yl]-5-(trifluoromethyl)-1Η-pyrazole_4·ethyl formate Example 1 Step of the title compound (1.50 g, 4.69 mmol) of a flask was charged with 2-decyloxy-5-methylphenyl-p-acid (0.779 g, 4.69 mm 〇1) and anti-digas bis(triphenyl) Palladium (11) (329 mg, 0.469 mmol). B guess (12 mL) and sodium carbonate (u 7 mL, 1.0 Μ aqueous solution Π · 7 mmol) were added and the resulting mixture was degassed by nitrogen. Will 137610.doc •57- 201028152

The reaction mixture was at 7 Torr. (The mixture was stirred for 18 h, then cooled to room temperature and poured into water. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuo. / 〇Et〇Ac, followed by purification in 20% to 1% EtOAc in hexanes to afford the title compound: lcmS m/z 406.4 [M+H] + ; H NMR (500 MHz, CDC13) δ 8.12 (s , 1H), 8.11 (d, J=8.0 Hz, 1H), 7.91 (t, J=8.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H ), 7.19 (dd, J=8.0, 2.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 2,35 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). Step B: l-[6-(2-hydroxy-5-methylphenyl)pyridin-2-yl]-5-(three To a cooled (〇°C) solution of the title compound in Example 8 Step A in EtOAc (1 mL, EtOAc) Medium 1.0 Μ, 11.7 mmol). After 15 min, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the reaction mixture was cooled to the hydrazine, then the saturated NaHC03 aqueous solution (gas evolution) was added dropwise. The title compound was obtained by EtOAc: EtOAc (EtOAc:EtOAc: LCMS m/z 392.6 [M+H] + ; 4 NMR (500 MHz, CDC13) δ 11.78 (s, 1H), 8.17 (s, 1H), 8.07-8.03 (m, 2H), 7.60 (d, J= 1.5 Hz, 1H), 7.48 (dd, J=7.0, 1.5 Hz, 1H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.36 (s, 3H), 1.40 (t, J=7.0 Hz, 3H) 137610.doc -58· 201028152 Step C: 4·[4-(Trifluoromethyl)cyclohexane -1·Alkenyl}ethyl benzoate to 4· diflurocyclocyclohexanone (3.00 g '18·1 mmol) in anhydrous THF (100 mL) in a cooled (_78 &lt;t) solution Bis(trimethyl-stone) guanamine lithium (19.9 mL, 1.0 THF in THF, 19.9 mm 〇1) was added dropwise. After 1 〇min, a solution of 2-[Ν,Ν·bis(trifluoromethylsulfonyl)amino]5-cyclohexyl (7.09 g, 18.1 mmol) in THF (20 mL) The resulting mixture was slowly warmed to ambient temperature overnight, at which time the reaction was quenched by pouring into saturated aqueous NaHC. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated The resulting enol triflate was used without further purification. To a flask containing unpurified enol triflate was added 4 ethyl sulfenyl succinic acid (3.68 g, 18.69 mmol) and trans-di- gas bis(triphenylphosphine) palladium ( 11) (633 mg, 0.903 mmol). Acetonitrile (9 〇 mL) and sodium carbonate (45 mL, 1.0 Μ aqueous solution, 45.0 mmol) were added, and the mixture was then degassed by nitrogen. (: stirring for 1.5 h, then cooling to room temperature ' and pouring into water. The mixture was extracted with Et EtOAc, and the organic phase was concentrated in vacuo. Purification of 10% EtOAc <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; (d, J=8.5 Hz, 2H), 6.20-6.18 (m, 1H), 4.37 (q, J=7.〇Hz, 2H), 2.61-2.18 (m, 6 H), 1.74- 1.68 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H). Step D: 4-[cis-4-(trifluoromethyl)cyclohexyl]benzoic acid ethyl ester and 4_[anti_4-(trifluoromethyl) ) 环 基 】 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹 睹/ Alumina (25.0 mg). A hydrogen balloon attached to a 3-way adapter was attached to the reaction mixture. The reaction flask was then evacuated and backfilled with hydrogen. After the process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere. After vigorous stirring for 1 h, the reaction mixture was washed with EtOAc through celite. Filtration. Concentration of the mixture in vacuo to give a 2:1 (cis: trans) mixture of the isomers. Purified by silica gel flash chromatography (0 to 2% diethyl ether in hexane) Product of the mixture (1:1 cis: trans). A small portion was further purified for characterization. Analytical data for the first isomer (anticyclohexyl compound) on the mash: LCMS m/ z 301.5 [M+H] + ; NMR (500 MHz, d6-DMSO) δ 7.89 (d,J=8.5 Hz, 2H), 7.38 (d,J=8.5 Hz, 2H), 4.29 (q, J=7.0 Hz, 2H), 2.67-2.61 (m, 1H), 2.39- 2.33 (m,1H), 1.97 (approximate doublet, j=13.0 Hz, 2H), 1.88 (approximate doublet, j=13 〇HZ , 2H), 1.59-1.51 (m, 2H), 1.46-1.39 (m, 2H)' 1·31 (t, J=7.0 Hz, 3H). The second isomer on the tannin (cis-cyclohexyl compound) Analytical data: LCMS m/z 301.5 [M+H] + ; NMR (500 MHz, d6-DMSO) δ 7.90 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H) , 4.30 (q, J=7.〇Hz, 2H), 2.87-2.82 (m, 1H), 2.54-2.49 (m, 1H), 1.87-1.82 (m, 2H), 1.77-1.73 (m, 6 H ), 1.31 (t, J=7.〇Hz, 3H)Step E: 4-[opt-4-(trifluoromethyl)cyclohexyl]phenylmethanol and 4_丨anti_4_(trifluoromethyl)cyclohexyl]phenyl-carboxaldehyde

MBAL_H (33 mL), 1.0 Torr in toluene, 33.1 mm, was added to a cooled (〇 ° C) solution of the title compound (2.49 g, 8.28 mmol. 〇l). After 2 h, the reaction mixture was quenched by MeOH (5 mL). The resulting mixture was diluted with diethyl ether and sat. sodium tartrate/potassium aqueous solution and the mixture was stirred vigorously until clear phase separation was achieved. The organic phase is then separated, dried over anhydrous sodium sulfate and evaporated in vacuo tolululululululululululululu For the case: LCMS m/z 241.4 [M-OH]+. Step: F: l-{6-[5-methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl benzylidene) oxy)phenyl] -2-yl }-5-(Trifluoromethyl)-1Η-®Λ -4--4-carboxylic acid and methyl-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl}oxy The title of the title compound (150 mg, 0.383 mmol) of Example 8 Step </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Add a solution of the compound (148 mg, 0.575 mmol) and triphenylphosphine (151 mg '0.575 mmol) in DCM (5 mL) EtOAc (0.112 mL, 0.575 mmol) The resulting mixture was stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc EtOAc (EtOAc) elute elut elut elut elut elut elut elut elut elut : LCMS m/z 632.3 [M+H]+. The second isolating diastereomer is a cis isomer: LCMS m/z 632.3 [M+H]+. Lithium hydroxide (1.0 mL in water 2, hydrazine, 2.00 mmol) was added to a separate solution of the product of the yield in EtOAc, EtOAc (2 mL), and the mixture was stirred at 5 〇C. After 3 〇 min, the reaction mixture was made acidic by the addition of hydrochloric acid water soluble 137610.doc -61 - 201028152, which was then diluted with hydrazine, 4 - dioxane and passed through a 0. 45 micron syringe filter. Purification by reverse phase hplC (60 to 100% / acetonitrile in water &lt;RTI ID=0.0&gt; Analytical data for the trans isomer: LCMS m/z 604.6 [Μ+Η] + ; 4 NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.15-8.08 (m, 2H), 7.69 ( d, J=7.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.24-7.19 (m, 2H), 7.15 (d, J=8.5 Hz, 2H), 5.16 (s, 2H), 2.54-2.49 (m, 1H), 2.36-2.31 (m, 1H), 2.27 (s, 3H), 1.96-1.93 (m, 2H), 1.86-1.84 ( m, 2H), 1.54-1.46 (m, 2H), 1.43-1.35 (m, 2H). Analytical data for cis isomer: LCMS m/z 604.6 [M+H] + ; *H NMR (500 MHz, d6-DMSO) δ 8.27 (s, 1H), 8.14 (d, J = 7.5 Hz, 1H ), 8.10 (t, J=7.5 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.57 (br s, 1H), 7.33 (d, J=8.0 Hz, 2H0, 7.23 (d, J =8.0 Hz, 2H), 7.23-7.22 (m, 1H), 7.16 (d, J=8.5 Hz, 1H), 5.16 (s, 2H), 2.76-2.71 (m, 1H), 2.50-2.48 (m, 1H, blurred due to DMSO signal), 1.82- 1.78 (m, 2H), 1.74-1.71 (m, 6 H). Example 9

137610.doc -62- 201028152 Step A: l_[6-(5-Gas-2-hydroxyphenyl)acridin-2-yl]_5_(trifluoromethyl 1H-pyrazole-4·carboxylate to an example Add a solution of the title compound (1.o g, 2.65 mmol) in EtOAc (EtOAc m. Stir at ambient temperature. After 24 h, the mixture was concentrated in vacuo. EtOAc EtOAc (EtOAc:EtOAc Provided the title compound: LCMS m/z 412.0 [M+H] + ; NMR (500 MHz, CDC13) δ 11.98 (s, 1H), 8.18 (s, 1H), 8.10 (t, J = 8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.78 (br s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.30 (dd, J=9.0, 2.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1-40 (t, J=7.0 Hz, 3H) Step B: l-{6-[5-gas-2-( {4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}ano)phenyl]&quot;bite-2-yl}-5·(trifluoromethyl)-1Η-«Λ Ethyl tetra-4-carboxylate and 1-{6-丨5-chloro-2-({4-indene-4-(trifluoromethyl)cyclohexyl]benzene }oxy).Phenyl]0tfc ate-2-yl}-5-(dimethylmethyl)-111-13⁄43⁄4 ol-4-carboxylic acid hexazone to the title compound of Step 9 Step A (90.0 mg, 0.219 mmol Add the di- isopropyl dicarboxylate (0.064 mL) to a solution of the title compound (85.0 mg, 0.328 mmol) and triphenyl squary (86.0 mg, 0.328 mmol) in DCM (1 mL) , 0.328 mmol), and the mixture was stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo. EtOAc EtOAc EtOAc Purification of 12 to 100% EtOAc) provided the title compound <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; CDC13) δ 8.15 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.31 (dd, J=9.0, 2.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.5 Hz, 1H), 5.12 (s, 2H), 4.39 (q, J=7.〇Hz, 2H), 2.55-2.50 (m, 1H), 2.10-2.01 (m&gt; 5H), 1.50-1.46 (m, 4H), 1.40 (t , J=7.0 Hz, 3H). The second dissolving compound is a cis isomer: [CMS m/z 652.1 [M+H] + ; 'H NMR (500 MHz, CDC13) δ 8.16 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.5, 2.5 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 5.12 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.73-2.70 ( m, 1H), 2.34-2.28 (m, 1H), 1.98-1.89 (m, 4H), 1.80-1.71 (m, 4H), 1.40 (t, J = 7.0 Hz, 3H). Step C: l-{6-[5-chloro-2·({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]bit-2-yl} -5-(trifluoromethyl)carboxylic acid and 1-(6-[5-gas·2-({4-[Ι«-4-(5fluoromethyl)cyclohexyl]benzyl}oxy)benzene a separate solution of the title compound of the pyridin-2-yl}-5-(trifluoromethyl)-1 oxime-pyrazole-4-carboxylic acid to the title compound of Example 9 in 1,4-dioxin (1 mL) Hydrogen chloride (0.5 mL, 2.0 Μ aqueous solution, 1 · 〇〇 mmol) was added thereto, and the resulting mixture was stirred at 5 ° C. After 30 min, the reaction mixture was made acidic by adding aqueous hydrochloric acid, and then 1 4_Dioxane was diluted and passed through a 0.45 micron syringe filter to provide the title compound by reverse phase hplc (65 to 100% acetonitrile in 137610.doc 201028152 in water, each with 0.1% v/v TFA). Analytical data for the isomers: LCMS m/z 624.4 [M+H] + ; 'H NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H) , 8.14 (t, J=8.0 Hz, 1H), 7.77-7.75 (m, 2H), 7.49 (dd, J=9.0, 2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.31 ( d, J=9.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 5.2 2 (s, 2H), 2.52-2.48 (m, 1H, blurred due to residual DMSO peak), 2.35- 2.32 (m, 1H), 1.96-1.94 (m, 2H), 1.87-1.84 (m, 2H), 1.54-

1.46 (m, 2H), 1.44-1.35 (m, 2H). Analytical data for cis isomers············· 8.14 (t, J=8.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.48 (dd, J=9.0, 3.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.31 (d , J=9.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 5.23 (s, 2H), 2.77-2.73 (m, 1H), 2.52-2.48 (m, 1H, due to residual DMSO peak Fuzzy), 1.82-1.78 (m, 2H), 1.74-1.71 (m, 6 H). Example 10

137610.doc -65- 201028152 Step A: 4-(1,4-Dioxaspiro[4.5]indole-7-en-8-yl)benzoic acid ethyl ester to 1,4-cyclohexanedione To a cooled (-78 ° C) solution of mono-ethylene glycol ketal (1.00 g, 6.40 mmol) in anhydrous THF (30 mL) was added dropwise lithium bis(tridecyl decyl) amide (7.7 mL, 1.0 Μ in THF, 7.70 mmol). After 10 min, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]5-chloropyridine (2.51 g, 6.40 mmol) in THF (10 mL) The mixture was slowly warmed to ambient temperature overnight, at which time the reaction was quenched by pouring into saturated aqueous NaHC03. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated To a flask containing unpurified enol triflate (1.36 g, 4.72 mmol) was added 4-ethoxycarbonylphenyl-acid (1.1 〇g, 5.66 mmol) and trans-digas double ( Triphenylphosphine) (11) (33 1 mg, 0.472 mmol). Acetonitrile (24 mL) and sodium carbonate (11.8 mL, 1.0 hydr. aqueous solution, 11.8 mmol) were added, and the mixture obtained was degassed by nitrogen. The reaction mixture was stirred at 70 ° C for 3 h, then cooled to ambient temperature and poured into water. The mixture was extracted with EtOAc and EtOAc evaporated. Purification by gelatin chromatography (0 to 30% EtOAc in EtOAc EtOAc EtOAc EtOAc (500 MHz, CDC13) δ 7.97 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 6.12-6.10 (m, 1H), 4.36 (q, J=7.0 Hz, 2H ), 4.03 (s, 4H), 2.70-2.67 (m, 2H), 2.50-2.48 (m, 2H), 1.93 (t, J=6.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H) 〇Step B: 4-(1,4-Dioxaspiro[4.S] 癸-8-yl)benzoic acid ethyl ester The title compound of Example 10 Step A (907 mg, 3.. 66- 201028152

The solution in EtOAc was degassed by nitrogen. Oxidation (IV) (225 mg, 0.991 mmol) was then added. A 3-way adapter equipped with a hydrogen balloon was mounted on the reaction flask. After 3 vacuum/hydrogen cycles, the reaction mixture was placed under a hydrogen atmosphere. After 1 h, the reaction mixture was filtered with EtOAc EtOAc. Used in the next step • Unpurified product: LCMS m/z 291.0 [M+H]+. Step C: [4-(1,4-Dioxaspiro[4.5]dec-8-yl)phenyl]methyl-yield to the title compound (450 mg, 1.55 mmol) In the cooling (-78. (:) solution was added DIBAL-H (3.10 mL, 1.50 Μ in heptane, 4.65 mmol). After 30 min, the reaction mixture was transferred to a 〇 ° C bath at this temperature The reaction was stopped for 45 min' followed by the addition of MeOH (0.63 mL, 15.5 mmol). The mixture was diluted with diethyl ether and saturated sodium sulphate/potassium and the mixture was quickly stirred until clear phase separation was achieved. The organic phase was separated and dried over anhydrous sodium sulphate and concentrated in vacuo. Purified by flash chromatography (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexane) Compound: LCMS m/z 231.1 [M-OH] + ; NMR (500 MHz, CDC 13) δ 7.29 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 7.5 Hz, 2H), 4.65 (s, 2H), 3.98 (s, 4H), 2.59-2.54 (m, 1H), 1.87-i 1.66 (m, 8H). Step 1): 1-[6-(2-{[4-(1,4- Dioxaspiro[4.5]dec-8-yl)benzylmethyl]oxy}phenyl)pyridin-2-yl]-5-(three The title compound (248 mg '〇·67 mm〇l) of Example 1 Step B, the title compound of Example 10 Step C (248 mg, 1.00 mmol) To a solution of triphenylphosphine 137610.doc-67-201028152 (349 mg, 1.33 mmol) in DCM (3 mL), diisopropyl azodicarboxylate (0.259 mL, 1.33 mmol). The resulting mixture was stirred at ambient temperature. After 5 hours, the reaction mixture was concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut (500 MHz, CDC13) δ 8.15 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.23 (d, J=7.5 Hz, 2H), 7.12-7.06 (m , 2H), 5.12 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.98 (s, 4H), 2.60-2.54 (m, 1H), 1.87-1.65 (m, 8H), 1.39 ( t, J = 7.0 Hz, 3H). Step E: 1-[6-(2-{[4-(4·Sideoxycyclohexyl)benzyl)oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)- A solution of the title compound (300 mg, 0.49 mmol) in EtOAc (EtOAc) (EtOAc) After 2 h, the mixture was cooled to ambient temperature then concentrated in vacuo. The resulting oil was diluted with diethyl ether. then washed sequentially with water, saturated aqueous sodium hydrogen carbonate, water and brine. The organic phase was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc (500 MHz, CDC13) δ 8.14 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.96 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H ), 7.54 (d, J=7.5 Hz, 1H), 137610.doc -68- 201028152 7.40-7.36 (m, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz) , 2H), 7.12 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 5.14 (s, 2H), 4.38 (q, J=7.〇Hz, 2H), 3.04 (dddd, 1=12.0, 12.0, 3.5, 3.5 Hz, 1H), 2.54-2.50 (m, 4H), 2.25-2.21 (m, 2H), 1.99-1.91 (m, 2H), 1.39 (t, J= 7.0 Hz, 3H). Step F: l-[6-(2-{[4-(4-Sideoxycyclohexyl)benzyl)oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)- 1 Η-pyrazole-4-carboxylic acid To a solution of the title compound (20.0 mg, 0.035 mmol) in EtOAc (EtOAc m. Μ, 1.00 mmol), and the resulting mixture was stirred at 50 °C. After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, which was then diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse-phase HPLC (40 to 95% EtOAc in EtOAc EtOAc EtOAc EtOAc) D6-DMSO) δ 8.30 (s,1H), 8.14 (d, J=7.5 Hz, 1H), 8.11 (t, J=7.5 Hz, 1H), 7.73-7.70 (m, 2H), 7.43 (t, J =8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.29-7.26 (m, 3H), 7.09 (t, J=7.5 Hz, 1H), 5.21 (s, 2H), 3.07-3.02 (m, 1H), 2.57 (td, J = 14.0, 5.5 Hz, 2H), 2.26-2.24 (m, 2H), 2.05-2.03 (m, 2H), 1.90-1.82 (m, 2H). Example 11 137610.doc -69- 201028152

Step A: 1-[6-(2·{[4_(4,4-Difluorocyclohexyl)benzyl]oxy}phenyl)acridin-2-yl]-5-(trifluoromethyl) -1 Η-pyrazole-4-carboxylic acid ethyl ester A solution of the title compound @ (87 mg, 0.154 mmol) in DCM (0.75 mL). DAST (0.035 mL, 0.262 mmol) was added followed by ethanol (0.002 mL, 0.03 mmol) and the mixture was stirred at ambient temperature. After 4 h, the reaction mixture was quenched by aqueous saturated sodium hydrogen The organic phase was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. Purification by silica gel chromatography (EtOAc EtOAc (EtOAc) ❿ Step B: 1-[6-(2-{[4-(4,4-Difluorocyclohexyl)benzyl]oxy}phenyl)acridin-2-yl]-5-(trifluoromethyl) The title compound (20.0 mg, 0.034 mmol) from Example 11 Step A was added to a solution of 1,4-dioxalate (1 〇 11 Torr). 0.50 〇 111 [, 2.0 水中 in water, 1.00 mmol), and the resulting mixture was stirred at 50 ° C. After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, then 1,4-dioxane Dilute and pass through a 0.45 micron syringe filter. Purified by reverse phase HPLC (50 to 1 〇〇〇/〇 acetonitrile in water, each with 0·1 ° / 〇 v / v TFA) by 137610.doc -70- 201028152 The title compound is provided: [CMS m/z 558.2 [M+H] + ; 4 NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.15-8.09 (m, 2H), 7.73 (dd, J = 8.0, 1.5 Hz, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 7.0 Hz, 2H), 7.27 (d, J= 8.5 Hz, 1H), 7.23 (d, J=7.0 Hz, 2H), 7.09 (t, J=8.5 Hz, 1H), 5.20 (s, 2H), 2.71-2.66 (m, 1H), 2.11-2.07 ( m, 2H), 2.00-1.83 (m, 4H), 1.67-1.60 (m, 2H).

Step A: l-[6-(2-{[4-(trans-4-methoxycyclohexyl)benzyl)oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl )_1H_pyrazole_4_carboxylic acid and (cis-4-methoxycyclohexyl)benzyloxy]phenyl)acridin-2-yl]_5 (trifluoromethyljun-4-carboxylic acid to the example) Sodium borohydride (29.5 mg, 0.781 mmol) was added to a solution of the title compound (2 EtOAc (EtOAc) After 3 min, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium sulphate, and then extracted with Et.sub.Ac. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum 137610.doc m 201028152. The alcohol was subjected to subsequent work without further purification. LCMS m/z 566.1 [M+H] +. Add to a solution of the unpurified reduction product (64 mg ' 0.113 mmol) in DCM (0.400 mL) 26· One-second butyl® specific bite (0.038 mL '0.170 mmol) and trifluorosulfonium silver acetate (32.0 mg, 0.124 mmol). The solution was cooled to the next generation and added with a block of simmer (0.009 mL ' 0.136 Mm). 30 min The reaction mixture was warmed to ambient temperature and maintained at this temperature for 15 h, then was filtered thru a celite over DCM. The reaction mixture was evaporated in vacuo and used without purification In one step: LCMS m/z 580.3 [M+H]. Add lithium hydroxide (i) to a solution of the crude base (approximately 66 mg ' 0.113 mmol) in 1,4-dioxane (2 mL) _〇〇mL, 2.0 Μ in water, 2·00 mmol), and the resulting mixture was stirred at 50 ° C for 30 min, then the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, followed by 1,4-two The methane is diluted and passed through a 0.45 micron syringe filter. The diastereomers (the main isomer is a transcyclohexyl compound) can be obtained by reverse phase HPLC (40 to 90% in water, acetonitrile, each After purification with 〇·ι〇/0 v/v TFA) was isolated to give the title compound. </ RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; -DMSO) δ 8.30 (s, 1H), 8.15-8.09 (m, 2H), 7.73-7.70 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 1H), 7 .20 (d, J=8.0 Hz, 2H), 7.08 (t, J=7.5 Hz, 1H), 5.19 (s, 2H), 3.24 (s, 3H), 3.16-3.13 (m, 1H), 2.5〇 2.47 (m, 1H), 2.07 (d, J=10 Hz, 2H), 1.79 (d, J=12.5 Hz, 2H), 1.46-1.43 (m, 2H), 1.25-1.17 (m, 2H). Cis-cyclohexyliso 137610.doc • 72- 201028152 Analytical data for the construct: LCMS m/z 552.2 [M+H]+; 4 NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.16- 8.10 (m, 2H), 7.73 (dd, J=7.5, 1.5 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.44-7.41 (m, 1H), 7.33 (d, J=8.0 Hz (2, H), 7.27 , 1H, blurred due to residual water peaks), 3.23 (8, 311), 2.56-2.52 (m, 1H), 1.95-1.92 (m, 2H), 1.69-1.61 (m, 2H), 1.52-1.46 (m , 2H), 1.23-1.17 (m, 2H).

Example 13

Step by step A ·· 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) methyl benzoate into a round bottom flask Feeding 4-bromo-2-mercaptobenzoic acid decyl ester (3.98 g, 17.37 mmol), bis(pinacol. root) shed (4.85 g, 19.11 mmol), potassium acetate (5.12 g, 52.1 mmol) And dichlorobis(diphenylphosphino)ferrocene]palladium(II) digas methane adduct (0.426 g, 0.521 mmol). The flask was purged with nitrogen. Anhydrous DMSO (100 mL) was added and the resulting suspension was degassed by nitrogen. The mixture was then placed in a preheated oil bath (80 ° C) and held at this temperature for 2 h, then cooled to ambient temperature 137610.doc • 73 - 201028152 degrees and then poured into water. The aqueous phase was extracted with diethyl ether and the organic phase was washed with brine. The organic phase was then separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (EtOAc EtOAc: EtOAc (EtOAc) + ; 1h NMR (500 MHz, CDCls) δ 7.87 (d, J = 7.5 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 1.35 (s, 12H). Step B: 4-(l,4_dioxan[4.5]癸_7_lean_s_yl)_2_methylbenzoic acid methyl ester to the enol trifluoromethyl synthesized according to step A of Example 10 The title compound (1.16 g, 4.20 mmol) and the trans-di- gas bis(triphenylphosphine)palladium (π) (134 mg, 0.191 mmol) were added to the flask of the acid ester (1.10 g, 3.82 mmol). ). Acetonitrile (15 mL) and sodium carbonate (9.54 mL, aq. The reaction mixture was stirred at 70 ° C for 15 h, then cooled to ambient temperature and poured into water. The mixture was extracted with EtOAc and EtOAc was evaporated. Purification by gelatin chromatography (0 to 30% EtOAc in hexanes elute elut elut elut elut elut elut elut elut elut elut elut elut , CDC13) δ 7.87 (d, J=8.5 Hz, 1H), 7.27-7.25 (m, 2H), 6.09-6.07 (m, 1H), 4.03 (s, 4H), 3.88 (s, 3H), 2.68- 2.65 (m, 2H), 2.60 (3, H), 2.49-2.47 (m, 2H), 1.94-1.91 (m, 2H). Step C: 4-(1,4-Dioxaspiroline 4.5) 癸-8-yl)-2-methylbenzoic acid methyl ester to the title compound of Example 13 Step B (606 mg, 2. Doc -74- 201028152

Platinum oxide (jvkwO mg) was added to the degassed solution in EtOAc (15 mL). A 3-way adapter connected to a hydrogen balloon was attached to the reaction mixture. The reaction flask was then evacuated and backfilled with hydrogen. After the process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere' followed by vigorous stirring. After 45 min, the reaction mixture was filtered with EtOAc EtOAc. After the mixture was concentrated in vacuo to give the title compound which was used without further purification: LCMS m/z 259.4 [M-CH30]+. Step D: Methyl 2-methyl-4-(4-oxocyclohexyl)benzoate The title compound (61 mg, 2.1 mmol) was obtained. A solution of mL) and water (2.6 mL). After 2 h, the mixture was cooled to ambient temperature and then concentrated in vacuo. The oil obtained was diluted with diethyl ether, and then washed with water, a saturated aqueous sodium hydrogen carbonate solution, water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on EtOAc (EtOAc: EtOAc (EtOAc:EtOAc) (500 MHz, CDC13) δ 7.88 ( (d, J=8.5 Hz, 1H), 7.14-7.10 (m, 2H), 3.88 (s, 3H), 3.05-3.00 (m, 1H), 2.59 (s, 3H ), 2.51 (approximately doubled doublet, J = 8.5, 4.0 . Hz, 4H), 2.24-2.20 (m, 2H), 1.97-1.92 (m, 2H). Step E: Methyl 4-(trans-4-hydroxycyclohexyl)-2-methylbenzoate To a solution of the title compound ( 232 mg, 0.942 mmol After the reaction of the reaction mixture, the reaction mixture was quenched by the addition of a saturated aqueous solution of NH.sub.4Cl. The mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. [M+H]+. Step F: Methyl 4-(trans-4-methoxycyclohexyl)-2-methylbenzoate to a solution of the title compound ( 246 mg, EtOAc. 2,6-Di-t-butylpyridine (0.318 mL, 1.41 mmol) and silver trimellitate (266 mg, 1.04 mmol) were added. The resulting solution was cooled to 〇 ° C and iodine (0.071 mL, 1.. After 30 min, the reaction mixture was warmed to ambient temperature and kept at this temperature for 3 h then filtered and washed with EtOAc. The reaction mixture was concentrated in vacuo. Purification by silica gel flash chromatography (0 to 30% EtOAc in hexanes eluting EtOAc EtOAc EtOAc LCMS m/z 263.17 [M+H] + ; 4 NMR (500 MHz, CDC13) δ 7.85 (d, J=8.5 Hz, 1H), 7.08-7.06 (m, 2H), 3.86 (s, 3H), 3.38 (s, 3H), 3.24-3.17 (m, 1H), 2.58 (s, 3H), 2.49 (dt, J=12.0, 3.5 Hz, 1H), 2.21-2.18 (m, 2H), 1.94-1.92 (m , 2H), 1.54-1.46 (m, 2H), 1.39-1.30 (m, 2H). Step G: [4_(trans-4-methoxycyclohexyl)-2-methylphenyl]methyl-yield was cooled to the title compound (90.0 mg, 0.343 mmol. (-78 ° C) DIBAL-H (1.03 mL, 1.0 Torr in toluene, 1.03 mmol) was added. After 30 min, the reaction mixture was warmed to 〇 ° C. After 2 h, the reaction mixture was quenched with MeOH (0.140 mL). The resulting mixture was diluted with diethyl ether and saturated tartaric acid 137610.doc -76 - 201028152 sodium/potassium, and the mixture was stirred rapidly until a clear phase separation was achieved. The organic phase was then separated, dried over anhydrous sodium sulfate and dried in vacuo. The title compound was obtained in the succintion, which was used without further purification. Step: 【: 1-[6-(2-{丨4-(trans)-4.methoxycyclohexyl)-2-methylbenzyl]oxy}phenyl)pyridin-2-yl] -5-(Trifluoromethyl)-l-pyrazole-4-carboxylic acid ethyl ester was subjected to the title compound of Example 13 Step G and the title compound of Step 1 of Example 1 by using the chemistry described in Example 8 Step F. The title compound was prepared by optical coupling: LCMS m/z 594.7 [Μ+Η]+. Step I: 1-[6-(2-{[4-(trans)-4-methoxycyclohexyl)-2-methylbenzylmethyloxy}phenyl)pyridin-2-yl]-5 - (Trifluoromethyl)-l-pyrazole-4-carboxylic acid The title compound was obtained after the title compound of the title compound of Example 13 was hydrolyzed using the chemistry described in Example 1 Step D: LCMS m/z 566.7 [M +H] + ; NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.08 (t, J = 7.5 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.71-7.68 ( m, 2H), 7.46-7.42 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J=8.0 Hz, 1H), 5.16 (s, 1H), 3.24 (s, 3H), 3.18-3.13 (m, 1H), 2.43-2.40 (m, 1H) , 2.08-2.06 (m, 2H), 1.79-1.76 (m, 2H), 1.48-1.42 (m, 2H), 1.24-1.17 (m, 2H). Example 14 137610.doc -77- 201028152

Step A: l-[6-(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzyl)oxy }Phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1 oxime-pyrazole-4-carboxylic acid ethyl ester was fed into a vial of the product of Example 2 Step A (300 mg, 0.549 mmol), double (pinacol root) two sheds (153 mg, 0.604 mmol), bis(tricyclohexylphosphine)palladium (0) (25.0 mg, 0.037 mmol) and potassium acetate (135 mg ' 1.37 mmol). The mixture was purged with nitrogen, followed by degassed 1,4-dioxane (2.7 mL). The vial was capped and stirred for 15 h then diluted with water and extracted with EtOAc. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. Purification by silica gel flash chromatography (EtOAc EtOAc EtOAc EtOAc (EtOAc) MHz, CDCls) δ 8.19 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.02 (d, J=7.0 Hz, 1H), 7.90 (t, J=8.0 Hz, 1H), 7.85 ( d, J=7.0 Hz, 2H), 7.57 (d, J=8.0 Hz, lH), 7.42 (d, J=7.0 Hz, 2H), 7.39-7.37 (m, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 5.21 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.39 ( s, 12H). 137610.doc -78 * 201028152 Step B: 5-(trifluoromethyl)-1-{6-[2-({4·[6-(trifluoromethyl -3-yl) phenylmethyl} Ethyl-based phenyl] dimethyl-2-yl}-111-吼 -4--4-carboxylate ethyl ester was added to a vial containing the title compound (14.0 mg, 〇. 〇 24 mmol) from the procedure of Example I4. 6-Trifluoromethylpyridine (6.4 mg, hydrazine, hydrazine 28 mmol) and trans-di- gas bis(triphenylphosphine)palladium (11) (1.7 mg, 0. 〇〇 24 mmol). Add acetonitrile (0.500 mL) And sodium carbonate (0.059 mL, 1.0 Torr in water, 0.05 9 mmol) and the mixture was degassed by nitrogen. The reaction vial was capped and placed in a preheated oil bath (70 〇) After 6 h, the reaction mixture was cooled to room temperature and then purified by flash chromatography: LCMS m/z 613.2 [M+H]+. Steps 0:5-(trifluoromethyl)-1- 6-[2-({4-[6-(Trifluoromethyl)indol-3-yl] benzyl}indolyl)phenyl]pyridin-2-yl}-111-pyrazole-4-carboxylic acid To a solution of the title compound of Example 14 Step B in 1,4-dioxane (0.500 <RTI ID=0.0></RTI> <RTIgt; Mixed After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, then diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter by reverse phase HPLC (50 to 100 in water) Purification afforded the title compound: LCMS m/z 585.2 [M+H] + ; 4 NMR (500 MHz, d6-DMSO) δ 9.09 (d, J = 2.0 Hz) , 1H), 8.36 (dd, J=8.0, 2.0 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J=7.0 Hz, 1H), 8.14 (t, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.0, 2.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.47-7.43 (m, 1H), 7.30 (d, J=8.0 Hz, 137610.doc -79· 201028152 1H), 7.11 (t, J=7.5 Hz, 1H) , 5.34 (s, 2H). Example 15

Step A: l-[6-(2-Hydroxy-3-iodophenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester to Example 1 Step B To the suspension of the title compound (2.00 g, 5.30 mmol) The resulting suspension was vigorously stirred at ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc and EtOAc EtOAc. The organic phase was then concentrated in vacuo. Chromatography by gelatin (0 to 15% EtOAc in hexanes followed by 15% EtOAc in hexanes followed by 15 to 1 EtOAc/EtOAc in hexanes. The title compound is isolated from the p-iodo isomer after purification: LCMS m/z 504.5 + ; 4 NMR (500 MHz, CDC 13) δ 13.08 (s, 1 Η), 8.17 (s, 1H), 8.10 (t, J=8.〇Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.86 (dd, J=7.5, 1.5 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H) . Step B: dimethylbenzyloxy) _3_iodophenyl} pyridine - B7610.doc · 80· 201028152 2_yl)-5-(trifluoromethyl)-1Η-«Λ -4--4- The title compound (200 mg, 0.397 mmol), 2,4-dimethylbenzyl alcohol (81. mg, 0.596 mmol) and triphenylphosphine (156 mg '0.596 mmol). To a solution in DCM (2 mL) was added diisopropyldichloroacetic acid diisopropylacetate (0.114 mL, 0.596 mmol) and the mixture was stirred at ambient temperature. After 18 hours, the reaction mixture was concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc EtOAc EtOAc (EtOAc) 500 MHz, CDC13) δ 8.17 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.85-7.81 (m, 2H), 7.60 (d, J=7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.95-6.92 (m, 2H), 4.69 (s, 2H), 4.41 ( q, J=7.0 Hz, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). Step C: 1-(6·{2-[(2,4-dimethylbenzyl)oxy]-3-methylphenylpyridin-2-yl)-5-(trifluoromethyl) -lH-pyrazole-4-carboxylic acid ethyl ester was fed into the vial of the product of Example 15 Step B (40 mg, 0.064 mmol), dimethylcyclotrioxoxime (49 mg, 50% by weight, 0.193 mmol) and Di-vaporized U,-bis(diphenylphosphino)ferrocene-palladium (11) dioxane complex (5.3 mg, 0.006 mmol). Sodium carbonate (0.161 mL, 1.0 Torr aqueous solution, 0.161 mm 〇l) and THF (0.25 mL) were added, and the resulting suspension was degassed by nitrogen. The vial was then capped and placed in a preheated (65 t) oil bath. After 18 h, the reaction mixture was cooled to ambient temperature and then poured into water. The aqueous phase was extracted with EtOAc and EtOAc (EtOAc)EtOAc. Purification by silica gel flash chromatography (EtOAc EtOAc EtOAc (EtOAc) [M+H]+. Step D: 1-(6-{2_[(2,4-dimethylbenzyl)oxy]_3_methylphenyl}indole-2-yl)-5-(trifluoromethyl spit- 4-carboxylic acid To a solution of the title compound (12.0 mg, 0.023 mmol) from EtOAc (EtOAc m. 'And stirring the resulting mixture at 5 (TC. After 30 min) the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, which was then diluted with 1,4-dioxane and passed through a 〇-45 micron syringe filter. Purification by reverse-phase HPLC (40 to 100% EtOAc in EtOAc) eluted with EtOAc: EtOAc: EtOAc 8.30 (s, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.0 , 1.5 Hz, 1H), 7.35-7.32 (m, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.91-6.86 (m, 3H), 4.52 (s, 2H), 2.27 (s, 3H) , 2.21 (s, 3H), 2.06 (s, 3H). Example 16

201028152 Step A: 2-(6-aeropyrazine-2-yl)phenol to 2,6-dichloro-pyrazine (1.00 g ' 6.71 mmol), 2-hydroxyphenyl-fatanoic acid (972 mg, 7.05 mmol) And acetonitrile (2 〇 mL) and sodium carbonate (13.4 mL in water, 1. 〇μ, 13.4 mmol) in a mixture of bis(triphenylphosphine)palladium ((1) 丄mg, 0.671 mmol) And the resulting mixture was degassed by spraying nitrogen. A reflux condenser was placed on the reaction flask, which was then placed in a preheated oil bath (75 EtOAc) and stirred rapidly. After 5 h, the reaction mixture was cooled to room temperature then poured into water and extracted with EtOAc. The organic phase was separated and concentrated in EtOAc EtOAc (EtOAc:EtOAc) [M+H] + ; 4 NMR (500 MHz, CDC13) δ 11.64 (s, 1Η), 9.11 (s, 1H), 8.53 (s, 1H), 7.85 (dd, J=8.0, 1.5 Hz, 1H) , 7.40 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H). Step B: l-[6-(2_hydroxybenzene) Ethyl pyridazine-2-yl]-5-(tri-L-methyl)-1 - oxazole-4-carboxylic acid ethyl ester mp. Hydrazine hydrate (3.25 mL, 35% v/v, 36.3 mmoip) was placed in the reaction flask to assemble a reflux condenser, and the reaction mixture was stirred at 8 ° C. After 12 h, the mixture was cooled to room temperature. , followed by precipitation of a yellow solid. The solid was triturated with hexane and filtered to Washed with water and dried in vacuo: EtOAc (EtOAc: EtOAc (EtOAc) Ethyl (ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate 137610.doc -83 - 201028152 (0·872 g, 3.63 mmol) 〇4环境 at ambient temperature After min, the reaction mixture was placed in a 6 (TC bath and stirred for 3 Torr, at which time the reaction mixture was cooled to ambient temperature and then concentrated in vacuo. EtOAc (EtOAc) Purification of % EtOAc, EtOAc (EtOAc: EtOAc: EtOAc) 1H), 9.35 (s, 1H), 8.85 (s, 1H), 8.23 (s, 1H), 7.93 (dd, J=8.0, 1.5 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H). Step C: l-{6-[5-Gas-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}- 5-(Trifluoromethyl)-indole-&quot;carbazole-4-carboxylic acid and 1_ {6-[5-gas-2·({4-[cis-4-(trifluoromethyl)cyclohexyl)benzene) Methyl}oxy)phenyl] &quot;pyridazine_2-yl}-5-(trifluoromethyl)-1 oxime-pyrazole-4-carboxylic acid The title compound (100.0 mg, 0.264 mmol) Add the azodicarboxylic acid diisopropyl vinegar (0.077 mL) to a solution of the title compound (102 mg, 0.397 mmol) and triphenylphosphine (104 mg, 0.397 mmol) in DCM (7 mL) , 0.397 mmol), and the resulting mixture was stirred at ambient temperature. After 18 hours, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (0 to 20% EtOAc in EtOAc) The first isolating compound is the trans isomer: LCMS m/z 619.2 [M+H] + ; NMR (500 MHz, CDC13) δ 9.44 (s, 1H), 8.85 (s, 1H), 8.17 (s, 1H) ), 8.00 (dd, J=7.5, 1.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.16 - I37610.doc -84- 201028152 7.12(m,2H), 5.18(s,2H), 4.40(q,j=7.0Hz,2H),2.54-2.51 (m, 1H), 2.11-2.00 (m, 5H ), 1.50-1.45 (m, 4H), 1.42 (t, J=7.0 Hz, 3H). The second dissolving compound is a cis isomer: [CMS m/z 619.2 [M+H] + ; 'H NMR (500 MHz, CDC13) δ 9.46 (s, 1H), 8.86 (s, 1H), 8.18 ( s,1H), 8.01 (dd, J=7.5, 1.5 Hz, 1H), 7.47-7.44 (m, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H ), 7.17-7.13 (m, 1H), 5.20 (s, 2H), 4.41 (q, J=7.0 Hz, 2H), 2.74-2.71 (m, 1H), 2.36-2.29 (m, 1H), 2.01- 1.90 (m, 4H), 1.81-1.71 (m, 4H), 1.41 (t, J = 7.0 Hz, 3H). Step D: l-{6-[5-Chloro-2-({4·[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]&quot;Λ- Ethyl}-5-(trifluoromethyl)_1Η-咐•吐-4-carboxylic acid ethyl ester and 1-{6-[5-chloro-2-({4-[cis-4-(trifluoromethyl)) Cyclohexyl]benzyl}oxy)phenyl]&quot;indol-2-yl}-5-(trifluoromethyl)-iH-nbjun-4-carboxylic acid ethyl ester to the title compound of Example 16 Step C A separate hydration clock (0.5 mL, 2.0 Torr aqueous solution, 1.00 mmol) was added to a separate solution in 1,4-bis" (1 mL) and the mixture was stirred at 50 C. After 30 min, the reaction mixture was made acidic by the addition of aqueous hydrochloric acid, which was then diluted with hydrazine, &lt;RTIgt; Purification by reverse phase HPLC (40 to 100% acetonitrile in water, each with ο.% v/v TFA) affords the title compound. Analytical data for the trans isomer: LCMS m/z 591.5 [M+H] + ; !H NMR (500 MHz, d6-DMSO) δ 9.37 (s, 1H), 9.00 (s, 1H), 8.39 (s , 1H), 7.78 (dd, J=7.5, 1.5 Hz, 1H), 7.54- 7.50 (m,1H), 7.37-7.34 (m,3H), 7.22 (d, J=8.0 Hz, 2H), 7.15 ( t, J=7.5 Hz, 1H), 5.23 (s, 2H), 2.55-2.49 (m, 1H), 137610.doc •85· 201028152 2.35-2.32 (m,1H),1.96-1.85 (m,4H) , 1.55-1.36 (m, 4H). Analytical data for cis isomer: LCMS m/z 591.5 [M+H] + ; NMR (500 MHz, d6-DMSO) δ 9.38 (s, 1H), 9.00 (s, 1H), 8.38 (s, 1H ), 7.78 (dd, J=7.5S 1.5 Hz, lH), -54-7.50 (m, 1H), 7.39-7.34 (m, 3H), 7.25 (d, J=8.0 Hz, 2H), 7.15 (t , J=7.5

Hz, 1H), 5.24 (s, 2H), 2.76-2.73 (m, 1H), 2.52-2.48 (m, 1H), 1.82-1.77 (m, 2H), 1.75-1.70 (m, 6 H)-&gt ; Example 17

Step: A. 1-丨4-(2-methoxyphenyl)_i, 3_mouth-flavor_2-yl]_5_(trifluoromethylazole-4-carboxylic acid ethyl ester heated at 80C 1-(amine Base carbon sulfur base) _5_ mercapto- 5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-furoate ethyl ester (470 mg, 1.65 mm 〇l, according to J· Comb·Chem. 2002, 4, 23-32 Preparation) and a solution of 2-di-2'-methoxyacetophenone (377 mg, 1.65 mmol) in ethanol (8 mL). After 1 h, the mixture Cooling to ambient temperature, then concentrating in vacuo. Purified by flash chromatography (purified in hexanes to 55% EtOAc)

The title compound of the title: LCMS m/z 398.5 [M+H] + ; ^ NMR (500 MHz, CD3OD) δ 8.26 (dd, J=7.6, 1.6 Hz, 1H), 8.13 (s, I37610.doc -86 - 201028152 1H), 8.03 (s, 1H), 7.37 (ddd, J=8.9, 6.5, 1.8 Hz, 1H), 7.12-7.01 (m, 2H), 4.42 (q, J=7.〇Hz, 2H) , 4.02 (s, 3H), 1.42 (t, J=7.0 Hz, 3H). Step B: l-[4-(2-Hydroxyphenyl)-l,3-thiazol-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester to step 17 BBr3 (2.67 ml, 1.0 Μ in a DCM, 2.67 mmol) was added dropwise to a solution of the title compound (353 mg, 0.888 mmol). After the addition is complete, the mixture is allowed to warm to ambient temperature. After 1 h, the reaction mixture was quenched with EtOAc EtOAc EtOAc. The organic phase was separated and concentrated in vacuo. The title compound was obtained as a yellow solid: EtOAc (EtOAc: EtOAc) 10.17 (s, 1H), 8.18 (s, 1H), 7.67 (dd, J=8.0, 1.9 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 7.09 (dd, J=8.2, 0.9 Hz , 1H), 6.98 (t, J=7.4 Hz, 1H)' 4.45 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H). Step C: 5-(Trifluoromethyl)-1-[4·(2-{[4,-(trifluoromethyl)androst-4-yl]methoxy}phenyl)-1,3- The title compound was prepared from the title compound from Example 17 Step: mp </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ] + ; !H NMR (500 MHz, d6-DMSO) δ 8.40 (s, 1H), 8.22 (s, 1H), 8.08 (dd, J=7.5, 1.5 Hz, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.40-7.37 (m, 1H), 7.31 (d, J=8.5 Hz, 137610.doc -87- 201028152 1H), 7.11 (t, J=7.5 Hz, 1H), 5.43 (s, 2H). Example 18

Step A: 1_(2-Apyrimidine-4-yl)_5_(Ethyl trifluoromethyl b 1H_pyrazole-4-carboxylate to 2-gas-6-mercaptopyrimidine (10〇g, 6.92 mmol) and Ethylamine (0.964 mL ' 6.92 mmol) in acetonitrile (35 mL) was added 2_(ethoxy-indolyl)-4,4,4-trifluoro-3·Ethyloxybutyrate (1.35) After 5 min, the reaction mixture was placed in a 90 ° C oil bath. After 1 h, the reaction mixture was cooled to ambient temperature and then concentrated in vacuo. Purification afforded the title compound: EtOAc: EtOAc: EtOAc: EtOAc , J=5.5 Hz, 1H), 8.12 (s, 1H), 7.76 (d, J=5.5 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H Step B: l-[2-(2-{[4-(2-Phenylhexyl)benzyl)oxy}phenyl)pyrimidin-4-yl b-5-(trifluoromethyl)-1Η -pyrazole-4-carboxylic acid coupling the title compound of Example 18, Step A, with 2-nonyloxyphenyl-acid eucalyptus, followed by treatment with BBr3 (steps A and B according to Example 8) to give pyrimidinyl 137610.doc-88 - 201028152 Benzene, according to the procedure of Example 1 Steps C and D to give the title compound: LCMS m/z 545.3 [M+H] + ; 'H NMR (500 MHz, d6-DMSO) δ 9.20 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 7.88 (d, J=5.5 Hz, 1H), 7.69 (dd, J=8.0, 2.0 Hz, 1H), 7.50-7.47 (m, 1H), 7.27-2.08 (m, 11H), 5.13 (s, 2H), 2.82 (s, 4H). Example 19

Step A: 2-Ga-6-(2-methoxy-5-methylphenyl)-4-nitroindole according to the procedure described in Example 1, Step B, by 2-methoxy The title compound was prepared by the reaction of -5-methyl-p-yl-acid with 2,6-di-n- 4- pyridine. LCMS m/z 279.5 [M+H] + ; *H NMR (500 MHz, CDC13) δ 8.19 (d, J=8.5 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.44 (d, # J=8-5 Hz, 1H), 7.28 (dd, J=8.5, 2.1 Hz, 1H ), 6.83 (d, J=8.5

Hz, 1H), 3.72 (s, 3H), 2.42 (s, 3H). Step B: l-[6-(2-Methoxy-5-methylphenyl)-4-nitro"acridin-2-yl]indole-1,2-dicarboxylic acid di-t-butyl ester The title compound (1.5 g, 5.4 mmol), 肼-1,2-didecanoic acid di-tert-butyl ester (1.375 g, 5.92 mmol), DPPF (360 mg) was stirred at 10 ° C. , 0.65 mmol), a mixture of Pd2 &lt; Jba3 (0.4 g, 0.43 mmol), Cs2C03 (1.90 g, 5.83 mmol) and 12 mL of toluene. After 20 h, the mixture was cooled to ambient temperature, then 137610.doc -89 - 201028152 was purified by flash chromatography eluting with hexanes (20:1 to 4:1 v/v) as mobile phase to provide the title compound : LCMS m/z 375.6 (corresponding to the value of [M+H] + for the ion missing a B〇c group); 4 NMR (400 MHz, acetone-d6) δ 7.86 (d, J = 2.1 Hz, 1H), 7.26 (dd, J=8.4, 2.1 Hz, 1H), 7.07 (d, J=8.4, 2.1 Hz, 1H), 3.93 (s, 3H), 2.31 (s, 3H), 1.54 (s, 9 H), 1.47 (s, 9 H) 〇Step C: 2-mercapto-6-(2-methoxy-S-methylphenyl)-heart nitro acridine compounding Example 19 Step B Title A mixture of compound (2.0 g, 2.2 mmol), 23 mL 1,4-dioxane and concentrated hydrochloric acid (2 mL). Concentrated _ hydrochloric acid (8 mL) was added dropwise. After 1 h, concentrated hydrochloric acid (4 mL) was added dropwise. After 4 h, the reaction mixture was diluted with water and concentrated to a solid. The solid was washed with EtOAc (EtOAc) EtOAc (EtOAc)麻麻 D ·· 1-[6-(2-methoxy-5-methylphenyl)-4-nitrodept-2-yl]-5-(trifluoromethyl)-1Η-咐•岐4-Methyl oxime ethyl ester The title compound of Example 19, step c, and 2-(ethoxymethylene)-4,4,4-trifluoro-3- side, according to the procedure described in Example 1 Reaction of Ethyl oxybutyrate 6 to provide the title compound: LCMS m/z 451.6 [M+H]+ » Step E: l-[4-mercapto-6-(2-carbamid-5-methylbenzene Ethyl pyridin-2-yl]-5-(trifluoromethyl)-lH-nb tern-4-carboxylic acid ethyl ester. The title compound (1.2 g, 2.7 mmol), DMF A mixture of 15 mL), water (1.5 mL) and vaporized tin(II) dihydrate (1·8 g '7.9 mmol) for 1.5 h reduced the nitro group to the corresponding hydroxylamine. The second addition of vaporized tin(II) dihydrate (2.4 g, 10.6 mmol), 137610.doc -90-201028152 and then heating overnight at 100 °C allowed the reaction to be substantially halted. Water was added and the reaction mixture was extracted with EtOAc-EtOAc. The organic phase was separated and passed through a pad of silicone. Hydrogenation of Pd-black (450 mg, 4.2 mmol) in EtOAc (EtOAc EtOAc (EtOAc) H]+; 4 NMR (400 MHz '-propion-d6) δ 8.09 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.13 (dd , J=8.4 Hz, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.82 ( s, 3H), 2.26 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). Step: F: l-[4-A.6_(2-methoxy-5-methylphenyl)"*唆-2-yl]-5-(trifluoromethyl)-1Η-»Λ嗤-4 -ethyl formate, butyl nitrite (0.68 mL, 0.59 mmol) was added to the title compound (1.2 g, 2.9 mmol) In the solution. The resulting mixture was at 60. (The reaction was quenched with EtOAc (EtOAc) EtOAc (EtOAc (EtOAc) 532.6 [M+H] + ; NMR (500 MHz, CDC13) δ 8.54 (d, J=ll Hz, 1H), 8.15 (s, 1H), 7.98 (d, J=ll Hz, 1H), 7.79 (d , J=2.1 Hz, 1H), 7.25 (dd, J=8.5 Hz, 2.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.93 ( s, 3H), 2.39 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). Step G ·········· -2_基]_5_(Trifluoromethyl)-1Η-pyrazole-4-carboxylic acid ethyl ester 137610.doc •91 · 201028152 The title compound (1 g, 188 mmol) was heated at 80 ° C. And a solution of iodine trimethyl decane (3 6 „^) in 15 mL of chloroform for 7 h. Add a second portion of trimethyl decane (2 mL) and continue heating at 90 ° C overnight. Remove in vacuo Volatile. Toluene was added and the volatiles were removed in vacuo. Finally, anhydrous MeOH was added and the volatiles were removed in vacuo. hexanes: EtOAc (20:1 to EtOAc) Flash chromatography to give the title compound: LCMS m/z: </ </ </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (d, J = ll Hz, 1H), 7.89 (d, J=2 Hz, 1H), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.30 (s, 3H), 1.35 (t, J=7.1 Hz, 3H) Step H: 1-(gas methyl)_4·[reverse]_4_(trifluoroa) The title compound (14 mg, 0.542 mmol) in mp. Thionite gas (〇1 mL, 137 mmol) was added to the solution. The mixture was taken up at ambient temperature for 3 min, then concentrated in vacuo. Purification by flash chromatography (purification in hexanes to 5% EtOAc EtOAc EtOAc EtOAc m/z 241.6 [M-Cl]+. Step I: l-{4-iodomethyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine_2-yl}- 5-(Trifluoromethyl)-1 Η-« oxazole-4-carboxylic acid acetamidine The title compound (150 mg, 137610.doc • 92 - 201028152 0.289 mmol), Example 19, was stirred at room temperature. A mixture of the title compound (100 mg, 0.361 mmol), Cs2C03 (141 mg, 0.434 mmol) and DMF (1 mL) 2NHC1 was added and the reaction mixture was extracted with a mixture of hexanes and EtOAc. The combined organic layers were concentrated and purified with EtOAc EtOAc EtOAc: Step J: l-{4-methyl-6-[5-methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl] bite -2 -yl} - 5 -(di-methyl)-1Η - olfactory 4-carboxylic acid The title compound of Example 19 Step I (20 mg, 0.026 mmol), Pd(PPh3)4 (1〇·7 mg, 0.009 mmol), K2CO3 (11 mg, 0.08 mmol), trimethyl sulfonate (11.6 mg, 0.09 mmol) and two. A mixture of caesar (0.5 mL) was heated in a microwave reactor at 140 ° C for 1 h, cooled, diluted with hexane and dissolved in dioxane through a pad. Remove the solvent in a vacuum. Treated with a mixture of 1,4-dioxane (0,1 mL), MeOH (0.1 mL) and 3 N NaOH (0.1 mL) for 15 min at 50 ° C, followed by a YMC C-18 column Reverse phase HPLC (45 to 95% acetonitrile in water with 0.1% v/v TFA) afforded the title compound: LCMS m/z 618.8 [M+H] + NMR (400 MHz, acetone-d6), δ 8.17 (s, 1H), 8.08 (s, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.48 (s, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.27 (d, J= 8.1 Hz, 2H), 7.20 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 2.43 (s, 3H), 2.29 (s, 3H), 2.59 (m , 1H), 1.96 (m, 2H), 1.67-1.39 (m, 4H). The compounds in Table 1 were prepared using the chemistry described in Examples 1-19. 137610.doc •93· 201028152 Table 1

No. Ri r2 r3 R4 MS 20 -cf3 HH -ch2-^^-ocf3 592.1 [M+H]+ 21 Η HH 546.2 [M+H]+ 22 Η HH -ch2~〇~〇~ci 572.1 [M+Na ] 23 Η HH -ch2~〇_-C^ cf3 584.1 [M+H]+ 24 Me HH 0~cf3 598.7 [M+H]+ 25 Me HH -εΗ2-〇^〇~α 564.6 [M+H] + 26 Me HH -ch2-0~0 528.4 [MH]' 27 Br HH ,CH2^^ 624.5 [M+H]+ 29 cPr HH 'ch2~〇~^^ 584.5 [M+H]+ 30 cf3 HH • Ch2-〇^〇-c, 618.2 [M+H]+ 31 cf3 HH 652.3 [M+H]+ 32 cf3 HH •ch2-0~0_f 602.2 [M+H]+ 137610.doc -94- 201028152

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

H H H H H H H H H H H H H H H

Me HH Me HHHHHHHH Me HHHHHHHHHHHHHH Me HI Cl HI -Ch,2-〇— -ch2-^^-cf3 CH2_0—〇~Me -cH2—〇—〇-〇cF3 cHz^0_0ch2O~0 .&quot;cf3 -ch2- ^^-^^-*cf3 mcf3 &quot;ICF3 584.4 [M+H]+ 568.1 [M+H]+ 618.0 [M+H]+ 562.5 [M+H]+ 610.5 [M+H]+ 510.6 [M +H]+ 522.5 [M+H]+ 552.2 [M+Na] 600.2 [M+H]+ 599.6 [M+H]+ 508.6 [M+H]+ 522.6 [M+H]+ 590.5 [M+H ]+ 590.5 [M+H]+ 730.6 [M+H]+ 750.6 [M+H]+ 137610.doc -95- 201028152

49 H H I 50 cPr H H 51 H H H 52 H H H 53 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

(CH2)2—~~ 〇~cF3 •ch2'~〇—〇~ci 692.9 [M+H]+ 624.2 [M+H]+ 598.2 [M+H]+ 586.2 [M+Na]+ 598.2 [M +H]+ 564.2 [M+H]+ 496.6 [M+H]+ 602.4 [M+H]+ 568.5 [M+H]+ 618.4 [M+H]+ 552.4 [M+H]+ 620.4 [M+ H]+ 510.5 [M+H]+ 602.3 [M+H]+ 566.3 [M-Η]- 137610.doc -96- 201028152 Φ

64 FHH 65 FHH 66 FHH 67 FHH 68 HHH 69 HHH 70 HHH 71 Me HH 72 HHH 73 HHH 74 HHH 75 HHH 76 HHH 77 HHH 78 HHH -ch2-^-o-^&gt; Cl •CH: -CH Η Η C ^&quot;0CF3 -CH2^V&gt;hL(-f cf3 -CH:

Cf3 •CH:

-CH2—^ Bu Cl Cl

Cl

Cf3 cf3

Cf3 •CH·

Η H 'CH2_&lt;C^—^^~0'ΡΓ 618.3 [M+H]+ 552.4 [M+H]+ 620.4 [M+H]+ 602.4 [M+H]+ 562.6 [M+H]+ 584.0 [M+H]+ 618.0 [M+H]+ 598.2 [M+H]+ 548.2 [M+H]+ 548.5 [MH]* 564.4 [MH]· 548.5 [M-Η]' 598.4 [M-Η] ' 568.5 [MH]* 596.2 [M+Na]+ 137610.doc •97- 201028152

79 H H H 80 H H H 81 H H H H H H H H H H H H H 84 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

137610.doc

552.2 [M+H]+ 584.0 [M+H]+ 602.1 [M+Na]+ 617.8 [M+H]+ 617.8 [M+H]+ 612.2 [M+H]+ 580.1 [M+Na]+ 600.0 [M+Na]+ 590.0 [M+H]+ 482.1 [M+H]+ 619.1 [M+H]+ 566.1 [M+H]+ 534.0 [M+H]+ 558.1 [M+Na]+ 544.1 [ M+Na]+ 201028152 ❿

94 Η HH -ch2-^— 468.0 [M+H]+ 95 Me HH (ch2)3-&lt;(^) 488.0 [M+H]+ 96 Me HH 556.1 [M+Na] 97 Me HH -cH2~ (^y 460.0 [M+H]+ 98 Me HH 'CH2HnX^ 511.1 [M+H]+ 99 HHH 625.4 [M+H]+ 100 HHH -CH2-^j^-^)&quot;ICF3 604.4 [M+ H]+ 101 HHH -ch2-^K3^cf3 604.5 [M+H]+ 102 Me HH -ch2-^^— 518.0 [M+Na] 103 cf3 HH -ch2-^&gt;— 536.6 [M+H] + 104 cf3 HH -ch2H^-^ 564.6 [M+H]+ 105 Me HH -ch2H°X tBu 578.6 [M+H]+ 106 Me HH -cn2-^y~&lt;\ 508.6 [M+H]+ 107 cf3 HH -ch2-^-&lt;| 584.5 [M+H]+ 137610.doc -99- 201028152

108 H H H 109 H H H 110 H H H 111 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

-cH2—0*·〇·丨0h -CH2-^—Q-f

cPr 548.0 [M+H]+ 614.1 [M+H]+ 616.2 [M+Na]+ 566.2 [M+Na]+ 570.0 [M+Na]+ 582.0 [M+Na]+ 538.8 [M+H]+ 540.9 [M+H]+ 618.1 [M+H]+ 540.5 [M+H]+ 572.5 [M+H]+ 640.2 [M+H]+ 524.6 [M+H]+ 564.2 [M+H]+ 624.2 [M+H]+ 137610.doc •100- 201028152

AltylO

123 Η 124 Me 125 Η 126 C1 127 Η 128 Η 129 C1 130 C1 131 Η 132 Η 133 C1 134 C1 135 C1 136 Me 137 Me 138 Me 139 Η Η Η -ch2^〇^];o η η -cH2~^ y~(^)~ η η -〇H2~^y~^y~ Η H -CHz^p- cPr Η Η Η Η -ch2hQ^Qd Η Η injury-OK^ Η Η -CH2-〇-〇~ Η Η Η Η -ch2-〇~0~ Η Η -ch2-^^-~' Η Η ·°Η2-〇~〇~^ 510.6 [Μ+Η]+ 530.7 [Μ+Η]+ 546.6 [M+Na ]+ 580.6 [M+Na]+ 536.7 [Μ+Η]+ 536.9 [Μ+Η]+ 568.7 [M-Η]' 568.8 [M-Η]' 548.8 [Μ-Η]·548.8 [M-Η] ' 616.6 [M+Na]+ 630.8 [Μ-Η]' 626.7 [Μ-Η]' 538.8 [Μ+Η]+ 550.9 [Μ+Η]+ 550.9 [Μ+Η]+ 608.8 [Μ+Η]+

137610.doc -101 - 201028152 140 Me HH -CH2—l〇Me 566.6 [M+H]+ 141 Me HH -CH2—^&lt;OMe 586.6 [M+H]+ 142 HHH -ch2O*0.i〇h 550.9 [M-Η]' 143 cPr HH -ch2-^— 508.8 [M+H]+ 144 Cl HH -ch2-^— 500.7 [M-Η]' 145 HHH -CH(Me)— 562.4 [M-Η ]' 146 H Cl H 578.5 [M+H]+ 147 HFH •ch2-〇~〇~〇Me 586.5 [M+Na] 148 HFH 'cH2_〇~^^-〇Me Cl 620.5 [M+Na] 149 HFH 602.6 [M+H]+ 150 HH cPr -ch2-^— 508.8 [M+H]+ 151 HH Cl -ch2-^— 500.7 [M-Η]' 152 Me H Cl -ch2-^— 516.7 [M +H]+ 153 IHH -ch2-^^— 592.7 [MH]' 154 HHI -ch2-^— 592.7 [M-Η]' 155 Me H Cl -ch2^^— 530.7 [M+H]+ 137610.doc -102- 201028152

156 Me H Cl 157 Me H Cl 158 HHH 159 HH Me 160 HH Me 161 -cf3 HH 162 Cl HH -ch2--^~~^—cf3 ch2—Cl —〇Η2^ΟΚ3*,,ν( •ch2 O* 0^cf3 'ch2_O^Z)&quot;icF3

163 H H H 164 H H H 165 H H H 166 Cl H H 167 Cl H H 168 Cl H H 169 Cl H H 170 Cl H H

CHz-〇~〇 ch2~〇_〇_cf3 -ch2H〇~^〇~ci

Cf3 556.7 [M+H]+ 522.6 [M+H]+ 580.0 [M+H]+ 604.9 [M+H]+ 604.9 [M+H]+ 612.6 [M+H]+ 558.5 [M+H]+ 508.6 [M+H]+ 524.5 [M+H]+ 516.6 [M+H]+ 578.4 [MH]' 550.2 [M+H]+ 618.2 [M+H]+ 584.2 [M+H]+ 618.2 [M +H]+ 137610.doc -103- 201028152 171 Η Η Η -CH2-&lt; χ °^0 508.5 [M+H] 172 Η Η Η -ch2H°I 542.4 [M+H] 173 Η Η Η -ch2 _〇~〇517.5 [M+H] 174 Η Η Η 〇~α 551.4 [M+H] 175 Η Η Η -ch2~O~〇~cf3 585.4 [M+H] 176 Me Η Η 558.5 [M+H 177 F Η Η 562.5 [M+H] The compounds of Table 2 were prepared using the chemistry described in Examples 1-9. Table 2

No. Ri r2 r3 R4 MS 178 HH Me -ch2_〇^ 490.2 [M+H] 179 Cl H Me •ch2_〇~^ 524.1 [M+H] 180 HH Me -ch2~〇~o 462.2 [M+H ] 137610.doc -104- 201028152

181 Cl H Me 182 HH Me 183 HH Me 184 HH CF2H 185 HH cf2h 186 HH cf2h 187 Cl H cf2h 188 Cl H cf2h 189 HH cf2h 190 HH cf2h 191 Me H cf2h 192 Me H cf2h 193 HH cf2h 194 HH cf2h 195 HH cf2h 196 HH cf2h •ch2~0~0 'ch2~0~0~ci •ch2~〇~C^_cF3 ch2~〇~X3~ci -ch2~〇~〇~cf3 .ch2-^Q-^0 -ch2 ~h〇~〇~ci ch2_h〇~O_cf3 •ch2~〇~〇~ocF3 -ch2-〇~ cf3 -ch2__〇~(^~cf3

F 496.1 [M+H]+ 496.1 [M+H]+ 529.9 [M+H]+ 532.0 [M+H]+ 566.2 [M+H]+ 526.2 [M+H]+ 566.0 [M+H]+ 600.0 [M+H]+ 582.0 [M+H]+ 566.1 [M+H]+ 580.5 [M+H]+ 546.5 [M+H]+ 580.5 [M+H]+ 546.5 [M+H]+ 584.4 [M+H]+ 550.4 [M+H]+ 137610.doc -105- 201028152 197 HH Et 198 HH iPr 199 HH cPr 200 HH -CH2OMe 201 HH Et 202 HH iPr 203 HH cPr 204 HH -CH2OMe 205 HH cf2h 206 HH cf2h 207 HH Pr 208 HH Ph 209 Cl Cl cf2h 210 Cl H cf2h 211 Cl H cf2h 212 Cl H cf2h -ch2^〇~^〇-cf3 544.5 [M+H]+ -CH^-〇-C^CF3 558.5 [M+H]+ -CH2O~〇~CF3 556.5 [M+H]+ -ch2-〇~〇-cf3 560.5 [M+H]+ w^-O-cF3 558.5 [M+H]+ Speak-^ }·^}-% 572.5 [M+H]+ -CH2-^-〇~CF3 570.5 [M+H]+ -CH2~^)-〇-CF3 574.5 [M+H]+ -CH2^〇^〇 .&quot;CF3 572.6 [M+H]+ 572.6 [M+H]+ •CH^-^-〇-CF3 572.6 [M+H]+ -ch2-^^〇-cf3 606.6 [M+H]+ - CH^-^}-^〇-CF3 648.4 [M+H]+ 614.5 [M+H]+ -ch2-Q^}-.icf3 606.5 [M+H]+ -ch2^〇M^cf3 606.5 [M +H]+ 137610.doc 201028152 213 Cl Cl CF2H -CH2-^^-^)-CF3 640.5 [M+H] 214 HH cf2h 587.0 [M+H] 215 HH cf2h ch2~CD^C^cF 3 587.0 [M+H] The compounds in Table 3 were synthesized using the chemistry described in Examples 1-19. Table 3 No. 216 217 218 219 220 221

❹

MS 589.5 [M+HJ+ 589.5 [M+H]+ 583.5 [M+H]+ 549.5 [M+H]+ 669.9 [M+H]+ 669.9 [M+H]+ 137610.doc -107- 201028152 222 223 224 225 226 227 228 229 230

599.5 [M+H]+ 604.5 [M+H]+ 570.4 [M+H]+ 556.5 [M+H]+ 608.5 [M+H]+ 574.4 [M+H]+ 730.8 [M+H]+ 618.8 [M+H]+ 730.8 [M+H]+ 137610.doc -108- 201028152 231 232 233

234 235

638.8 [M+H]+ 551.1 [M+H]+ 517.2 [M+H]+ 750.9 [M+H]+ 750.9 [M+H]+ Example 236

Step A: l-(6-{2-[(4-Methoxyphenyl)ethynyl]phenylpyridin-2-yl)· 5-(trifluoromethyl)-1Η-pyrazole-4-carboxylic acid The ethyl ester was cooled to 137610.doc • 109- 201028152 in the title compound (374 mg, 0.991 mmol) and pyridine (0.241 mL, 2.97 mmol) in DCM (5 mL). Trifluoromethanesulfonic anhydride (0.25 1 mL, 1.487 mmol) was added. Immediately remove the cooling bath&apos; and the reaction mixture was stirred at ambient temperature for 45 min. then the reaction mixture was poured into water and extracted with DCM. The layers were separated and the organic phase was concentrated in vacuo to give material that was purified for the next step: LCMS m/z 510.0 [Μ+Η]+» Add iodine to the flask containing unpurified trifluoromethanesulfonic acid. Copper (1) (56.1 mg, 0.294 mmol), trans-di- gas bis(triphenylphosphine) (11) (68.9 mg, 0.098 mmol), tetrabutylammonium molybdenum (1.088 g, 2.94 mmol) And 4-methoxyphenylacetylene (195 mg, 1.47 mmol). The flask was purged with nitrogen and acetonitrile (5 mL) was added. The hydrazine mixture was degassed with nitrogen, triethylamine (1.00 mL, 7.17 mmol) was added and the mixture was stirred at ambient temperature for 20 hr. Purification by silica gel flash chromatography (30% EtOAc (EtOAc) elut elut elut elut elut elut elut elut 500 MHz, CDC13) δ 8.32 (d, J=8.0 Hz, 1H), 8.14 (s, 1H), 7.99 (t, J=8.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.65 -7.63 (m, 2H), 7.47-7.39 (m, 2H), 7.33 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 ^

Hz, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0 Hz, 3H). Step B: l-(6-{2-[2-(4-Methoxyphenyl)ethyl]phenyl}pyridin-2-yl)· 5-(trifluoromethyl)-1Η-pyrazole To a degassed solution of the title compound (255 mg, 0.519 mmol) in EtOAc (3 mL) . Install hydrogen to the reaction mixture connected to the 3-way adapter 137610.doc 110- 201028152 Balloon. The reaction flask was then evacuated and backfilled with hydrogen. After the process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere and stirred vigorously. After 2 h, the reaction mixture was filtered with EtOAc EtOAc. The mixture was concentrated in vacuo and used without further purification: LCMS m/z 496.2 [M+H]+. Step C: 5-(Trifluoromethyl)4-(6-(2-12-(4-(1(trifluoromethyl)sulfonyl)oxy}phenyl)ethyl]phenyl}pyridine_ Addition of tribromide to a cooled (〇 ° C) solution of the title compound (177 mg, 0.357 mmol) Boron (1.07 mL, 1.0 Μ, 1.07 mmol in DCM). After 45 min, the reaction mixture was quenched by the addition of saturated aqueous NaHC03, then warmed to ambient temperature. The aqueous phase was extracted with DCM. Dry over sodium sulfate, filter and concentrate in vacuo. EtOAc EtOAc: m. 5 mL) pyridine (0.087 mL, 1.07 mmol) and trifluoromethanesulfonic anhydride (0.091 mL, 0.536 mmol) were added to the solution, and the mixture was warmed to ambient temperature. After 1 h, the reaction mixture was added with saturated aqueous NaHC03. The reaction was quenched and extracted with DCM. EtOAc (EtOAc) Purification of 40 to 100% EtOAc in hexanes afforded the title compound: LCMS m/z 614.2 [M+H]+. Step D: 5-(trifluoromethyl)·ι_[6-(2-{2-[4 ,-(Trifluoromethyl)biphenyl-4-yl]ethyl}phenyl)&quot;bite-2-yl] olfactory-4-carboxylic acid was fed into the vial. Example 236 Step C Compound (60.0 mg , 137610.doc -111- 201028152 0.098 mmol), 4-trimethylsulfonyl benzoic acid (24.2 mg, 0.127 mmol) and trans-digas bis(triphenylphosphine)ie (11) (6.9 mg, 0.010 Add acetonitrile (0.400 mL) and sodium carbonate (0.244 mL, 1.0 水溶液 aqueous solution, 0.244 mmol), and the mixture was degassed with nitrogen. The vial was then capped and placed in preheated (70 ° C) oil. After 15 h, the mixture was diluted with water and DCM, and EtOAc (EtOAc m. To the solution of the unpurified Suzuki product in 1,4-dioxalate (2.0 mL), lithium hydroxide (1_0 mL, 2.0 Μ in water, 2.00 mmol) was added and the mixture was stirred at 50 °C. After 1 h, the reaction was made by adding an aqueous solution of hydrochloric acid. The mixture was acidic, and then it is diluted with 1,4-dioxane and through a 0.45 micron syringe filter. Purification by reverse phase HPLC (60 to 100% acetonitrile in water with 0.1% v/v TFA) afforded the title compound: LCMS m/z 582.4 [M+H] + ; !H NMR (500 MHz, d6- DMSO) δ 8.34 (s, 1H), 8.20 (t, J = 8.0 Hz, 1H), 7.82-7.73 (m, 6 H), 7.50 (d, J=8.0 Hz, 2H), 7.44-7.34 (m, 4H), 6.99 (d, J=8.0 Hz, 2H), 2.97-2.93 (m, 2H), 2.78-2.74 (m, 2H) ° Example 237

137610.doc -112- 201028152 Step A: 1-(2'-Fluoro-2,3,-bipyridin-6-yl)-5-(trifluoromethyl)_1H-pyrazole-4-carboxylic acid ethyl ester Example: Step title compound (100 mg, 〇.3 mmc^), (2-fluoropyridin-3-yl)-acid (66 mg, 0.47 mmol), reversed A mixture of dioxobis(triphenylphosphine)palladium(11) (31 〇mg, 0.05 mmol), Na2C03 (〇·47 mL, 2.0 Μ aqueous solution, 0.94 mmol) and acetonitrile (1 mL). After 50 min, the reaction mixture was cooled to ambient temperature and then concentrated in vacuo. Purification by flash chromatography using hexanes: EtOAc (EtOAc: EtOAc (EtOAc: EtOAc: EtOAc) CDC13) δ 8.63 (m, 1Η), 8.27 (m, 1H), 8.13 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 8.03 (t, J=7.9 Hz, 1H), 7.70 ( d, J = 7.8 Hz, 1H), 7.35 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Step B: 5-(Trifluoromethyl)-i-(2,-{[4,-(trifluoromethyl)indol-4-yl]methoxy}-2,3*-bipyridine-6 -yl)-1Η-pyrazole-4-carboxylic acid

Add KOtBu (15.0 mg, 0.13 mmol), [4·-(trifluoromethyl)biphenyl-4-yl]nonanol (US Patent 2004209936) (36.0 mg, 0.14 mmol) and DMF (0.3 mL) to the vial. ). After 5 min, the title compound (20.0 mg, 0.05 mmol. After 30 min, the reaction mixture was treated with NaOH (0.1 mL, 3 N aqueous solution, 0.3 mmol), MeOH (0.1 mL) and 1,4-dioxane (0.1 mL) at 50 ° C for 20 min » using YMC C -18 column was subjected to reverse phase HPLC (65 to 100% acetonitrile in water, each with 0.1% v/v TFA) to give the title compound: LCMS 137610.doc 113 201028152 m/z 584.9 [M+H] + ; *H NMR (400 MHz, CDC13) δ 8.44 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.27 (dd, J=4.9, 2.0 Hz, 1H), 8.20 ( s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.69 (s, 4H), 7.62-7.53 (m, 5H), 7.10 (dd, J=7.5, 4.9 Hz, 1H), 5.63 (s , 2H). Example 238

Step A: l-(5'-Bromo-2,-fluoro-2,3,-bipyridin-6-yl)-5-(trifluoromethyl)-indole-zolidine-4·carboxylate at 100 A mixture of the title compound (2.0 g, 6.3 mmol), EtOAc (20 mL) and 57% HI (20 mL) After 22 h, the organic phase was washed with brine, water and aqueous NaHCO3 &lt;&quot;&quot;&quot;&quot;&quot; The title compound (LCMS m/z 412, 0 [M+H]+) was obtained by EtOAc (EtOAc: EtOAc (EtOAc) A mixture of the title compounds (about 2:1). The crude mixture obtained above (1.95 g), (5-bromo-2-fluoropyridin-3-yl)carboxamide (1.31 g, 5.96 mmol), hydrazine (triphenylphosphine) was stirred at 1 °C. Palladium (0) (274 mg, 〇237 mmol), Na2C03 (9.5 mL '2 Μ aqueous solution '19 mmol) and acetonitrile (25 mL) for 30 min. Aqueous treatment with hexane-triethyl 137610.doc-114-201028152 amine (19:1 to 7:1 V/V) as mobile phase purification afforded the title compound: lc_m/z 461.0 [M +H] + ; *H NMR (5〇〇MHz, CD2C12) δ 8.78 (dd, J=8.5, 2.5 Hz, 1H), 8.36 (m, 1H), 8.17 (s, 1H), 8.13 (m, 2H) ), 7.80 (m, 1H), 4.41 (q, &gt;7"Hz, 2H),! 42 (t, J=7) Hz, 3H). Step B: l-(2,-Fluoro-5,-methyl-2,3,-bipyridyl-6-yl)_5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid acetamidine at 140° (: The title compound of Example 238, Step 8 (12〇111§, 〇26 mmol), hydrazine (triphenylphosphine), (0) (30.0 mg, 〇〇26 mm〇1), K2C〇3 (72.0) Mg, 0.52 mmol), a mixture of tridecylcyclotriborane (33 〇mg, 〇% mmol) and a chew (1.5 mL) were heated in a microwave reactor for 35 min, cooled and filtered and passed through a gel. Chromatography (hexane _Et 〇Ac, 93:7 to 85:15 v/v) to give the title compound: [CMS m/z 395.1 [M+H]+. Step C: 1-(5'·A Base-2,-{[3·methyl-4,·(trifluoromethyl)biphenyl_4_yl]methoxy]},2,3'- indeed bite-6-yl)-5- (Trifluoromethyl)-111-&quot;111 olfactory-4-carboxylic acid according to the procedure described in the procedure of Example 237, mp. Preparation of the title compound: LCMS m/z 612.9 [Μ+Η] + ; NMR (500 MHz, acetone-d6) δ 8.18 (πι, 2H) ), 7.91 (d, J=8.2 Hz, 2H), 7.80 (m, 3H), 7.63 (m, 2H), 5.66 (s, 2H), 2.51 (s, 3H), 2.37 (s, 3H). Example 239 137610.doc -115- 201028152

Cl

Step by step A. 1-(S,-gas-2,-gas-2,3'-linked®tb bite·6-yl)-5-(trimethylmethyl)_ 1Η_&quot;carbazole-4-carboxylic acid The mixture of the title compound (115 mg, 0.25 mmol), CuCl (74 mg, 0.75 mmol) and DMF (1 mL) was then warmed in a microwave reactor at 170 ° C for 10 min. Diluted with DCM, filtered, concentrated and purified with EtOAc EtOAc (EtOAc: EtOAc (EtOAc) ; 4 NMR (500 MHz, CD2C12) δ 8.64 (dd, J=8.4, 2.6 Hz, 1H), 8.26 (m, 1H), 8.17 (s, 1H), 8.13 (m, 2H), 7.80 (m, 1H) ), 4.41 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). Step B: l-(5,-Chloro-2,-{[3-methyl-4,-(trifluoromethyl)benzene-3-yl]methoxy}-2,3,-bipyridine- 6-yl)-5-(trifluoromethyl)-1 Η-«carbazole-4-carboxylic acid according to the procedure described in Example 237, Step B, mp. -4,-(Trifluoromethyl)biphenyl-4-yl]nonanol (PCT Publication WO2005118542) Reaction Preparation of the title compound: LCMS m/z 632.7 [M+H]+; 'H NMR (500 MHz, acetone -d6) δ 8.22 (m, 2Η), 7.92 (d, J=8.2 Hz, 2H), 7.83 (m, 3H), 7.63 (m, 2H), 5.70 (s, 2H), 2.52 (s, 3H) . Example 240 137610.doc -116- 201028152

Step A: 1-[2,-Fluoro-5,-(trifluoromethyl)_2,3,-indolyl-6-yl]-5-(trifluoromethyl)-1Η-pyrazole-4-carboxylic acid The ethyl ester was heated at 100 ° C with 3-gas-2-fluoro-5-(trifluoromethyl)pyridine (1.30 g, 6.52 mmol), bis(pinacolyl)diboron (2.00 g, 7.87 mmol), A mixture of KOAc (1.52 g, 15, 5 mmol), 260 mg of bis(tricyclohexylphosphine)palladium(0) (260 mg, 0.40 mmol) and 1,4-dioxane (1 〇mL) for 50 min. Water was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate, passed through a pad of silica and concentrated. Hexane was added and the reaction mixture was filtered and concentrated to give crude 2-fluoro-3-(4,4,5,5-tetradecyl-1,3,2-dioxaboromid-2-yl)-5 -(Trifluoromethyl)pyridine. The title compound of Example 1 Step A (1.00 g, 3.1 mmol) was obtained and the crude compound obtained above (2·fluoro-3-(4,4,5,5·tetramethyl-l, 3,2-Dioxaboron-2-yl)-5-(trifluoromethyl) 0-pyridine (2.09 g), trans-di- gas bis(triphenylphosphine)palladium (11) (154 mg ' a mixture of 0.22 mmol), CsF (1.43 g, 9.40 mmol), Na2C03 (3.9 mL, 2.0 M aqueous solution, 7.8 mmol) and acetonitrile (15 mL) for 45 min, water, hexane and EtOAc. Flash chromatography (hexanes: EtOAc, EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc δ 8.96 (dd, J=8.7, 2.5 Hz, 1H), 8.56 (s, 1H), 8.16-8.12 (m, 2H), 8.08 (t, J=7.9 Hz, 1H), 7.79 (dd, J=7.8 , 0.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H) Step B: l-[2,-{[3-methyl-4,- (trifluoromethyl)biphenyl_4_yl]methoxy}-5,-(trifluoromethyl)-2,3,-linked nt pyridine-6-yl]-5-(trifluoromethyl) -1Η-»carbazole-4-carboxylic acid according to the procedure described in Example 237, Step B, by subjecting Example 240, Step A Reaction of the title compound with [3-methyl-4'-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication No. WO2005118542) to give the title compound: LCMS m/z 666.8 [Μ+Η] + ; NMR (500 MHz, 嗣__6) δ (ppm) 8.78 (d, J=2.3 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.26 (m, 2H) , 8.22 (m,1H), 7.92 (d, J=8.2 Hz, 2H), 7.88 (m, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.66 (s, 1H), 7.59 (dd, J=7.9, 1.7 Hz, 1H), 5.80 (s, 2H), 2.54 (s, 3H). Example 241

Step A: l-{6-[2-(hydroxymethyl)phenyl] "Acridine-2-yl}-5-(trifluoromethyl)_ 1Η-pyrazole-4-carboxylic acid ethyl ester 137610.doc -118- 201028152 The title compound (300 mg, 0.94 mmol) of Example 1 Step A in a nitrogen-filled vial at 100 ° C, 2,1-benzoxanzepine-1 (3H)- Alcohol (189 mg, 1.40 mmol), trans-di- gas bis(triphenylphosphine), (11) (94 mg, 0.14 mmol), Na2C03 (1.4 mL, 2.0 EtOAc, 2.8 mmol) and acetonitrile (1.5 mL) The mixture was stirred for 1.5 h, cooled, EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (400 MHz, CDC13) δ 8.16 (s, 1H), 8.06 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.59-7.41 (m, 5H), 4.51 (s , 2H), 4.36 (q, J=7.1 Hz, 2H), 1·40 (t, J=7.1 Hz, 3H). Step B: 5-(Trifluoromethyl)-l-{6-[2-({[4'-(trifluoromethyl)biphenyl-4-yl J-oxy}methyl)phenyl]pyridine- 2-Base}-111-pyrazole-4-carboxylic acid DIAD (0.03 mL, 0.15 mmol) was added dropwise to the title compound (33.0 mg, 0.08 mmol), 4'-(trifluoromethyl). A solution of biphenyl-4-ol (33 mg, 0.14 mmol) and PPh3 (34 mg, 0.13 mmol) in THF (0.5 mL). The reaction mixture was aged for 15 min, concentrated and treated with a mixture of 1,4-dioxane (0.15 mL), MeOH (0.15 mL) and 3 N NaOH (0-15 mL) for 30 min. Reverse phase HPLC (45 to 100% acetonitrile in water, each with 0.1% v/v TFA) afforded the title compound: LCMS m/z 584.2 [M+H] + NMR (500 MHz) , CDC13) δ 8.23 (s, 1H), 8.05 (t, J=7.9 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.74-7.48 (m, 11H), 6.98 (d, J= 8.7 Hz, 2H), 5.28 (s, 2H). Example 242 137610.doc -119- 201028152

Step A: 5-(Trifluoromethyl)-1-(6-{2·[({5-[4-(trifluoromethyl)phenyl]acridin-2-yl}oxy)methyl] Phenyl}indole-2-yl)·1Η-carbazole-4-carboxylic acid to 5- -2-fluoro D ratio (72 mg, 0.41 mmol) and the title compound of Example 241 (80 mg, To a solution of 0.2 mmol) in DMF (1 mL) was added KOtBu (15 mg, 0.22 mmol). After 25 min, the reaction mixture was quenched by the addition of saturated aqueous NH4CI. The reaction mixture was concentrated and purified by flash chromatography ( EtOAc to EtOAc EtOAc EtOAc EtOAc EtOAc 2-yl)oxy]methyl}phenyl)° ratio to the ketone-2-yl]-5-(tris 4 fluorenyl)-1 Η-° ratio. A mixture of 4-ethyl decanoate was obtained according to LCMS: LCMS m/z 548.9 [M+H]+. The above obtained material (3 5 mg), 4-trimethylsulfonylphenyl tanning acid (24 mg, 0.13 mmol), hydrazine (triphenylphosphine) were placed in a nitrogen-filled vial at 112 °C. 0) (15.0 mg, 0.013 mmol), a mixture of Na2C03 (0.128 mL, 2 M aqueous solution, 0.256 mmol) and DME (0.7 mL), min, cooled, concentrated and 3 N NaOH (0.1 mL at 60 ° C) A mixture of MeOH (0.1 mL) and 1,4-dioxane (0.1 mL) was taken for 3 min. Reverse phase HPLC (45 to 137610.doc -120 - 201028152 100% acetonitrile in water, each with 0.1% v/v TFA) was used to give the title compound: LCMS m/z 584.9 [M+H] ] + ; *H NMR (500 MHz, d6-DMSO) δ 8.40 (d, J = 2.4 Hz, 1H), 8.22 (m, 2H), 8.04 (dd, J=8.7, 2.4 Hz, 1H), 7.89 ( d, J=7.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.51 (m, 2H), 6.83 (d, J = 8.5 Hz, 1H). Example 243

Step A: l-[6-(5-Mercapto-2-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acridin-2-yl]·5-(trifluoromethyl) -1 Η-pyrazole-4-carboxylic acid ethyl ester The title compound (2.05 mg, 5.24 mmol) from Example 8 Step B and EtOAc (EtOAc: EtOAc. Trifluoromethanesulfonic anhydride (1.06 mL, 6.29 mmol) was added and the mixture was warmed to ambient. After completion of the reaction, the mixture was quenched with 2 N aqueous HCl solution and the aqueous phase was extracted with hexane: ethyl acetate (3:j v/v). The organic phase was separated, dried over sodium sulfate, taken-up from EtOAc (d. The title compound was used without further purification: LCMS m/z 524.6 [M+H] + ; NMR (500 MHz, CDC13) δ 8.14 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H), 137610.doc • 121 - 201028152 7.81 (d, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.30 (s, 2H), 4.39 ( q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H). Step B: l-(6-{2-[(4-Methoxybenzyl)thio]_5-methylphenylidene-2-yl)-5-(trim-methyl benzo-4-carboxylic acid Ethyl ester to a solution of the title compound (2.74 g, 5.23 mmol), 4-methoxy-l-toluenethiol (0.88 mL, 6.28 mmol) DIEA (1.83 mL, 10.5 mmol), Xantphos (0.61 g' 1.05 mmol) and bis(diphenylhydrazinone) dipalladium (0) (0.48 g '0.52 mmol) were added and the mixture was taken at 9 〇. (: heating down. After 15 h, the reaction mixture was cooled to ambient temperature then diluted with hexanes. The obtained yellow solid was removed by filtration, and the collected organic filtrate was concentrated in vacuo. Purification (5 to 20% ethyl acetate in hexanes) afforded the title compound: EtOAc: EtOAc: EtOAc: (t, J=7.9 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.36 (m, 2H), 7.17 (d, J=8.0 Hz , 1H), 7.04 (d, J=8.5 Hz, 2H) 6.74 (d, J=8.7 Hz, 2H) 4.35 (q, J=7.1 Hz, 2H), 3.87 (s, 2H), 3.73 (s, 3H) ), 2.37 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H) Step C: 1-[6-(2·Siliary-5-methylphenyl)3⁄4 pyridine-2-yl]_5_(trifluoro Methyl)-1Η-°Λ -4- 4-carboxylic acid B and diethyl 1,1»_{dimercapto bis[(5-methyl-2,1-phenylene-6,2-di) </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Anisole (1 η mL, 15 7 mmol) was added to a solution in TFA (15 mL) and the mixture was warmed at 60 ° C. After 5 h, the mixture was cooled to ambient temperature and then concentrated in vacuo. The title compound was obtained as a mixture of the monomer and disulfide dimerization by flash chromatography (5 to 20 <RTI ID=0.0></RTI> <RTIgt; ]+ (monomer), LCMS m/z 406.6 [M+H]+ (dimer); NMR (500 MHz, CD2C12) (dimer) δ 8.14 (s, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.35 (d, J=ll Hz , 1H), 7.13 (dd, J=8.1,1·5 Hz, 1H), 4.36 (q, J=7 .2 Hz, 2H), 2.35 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H) 〇 Step 0: 1-(6-{2-[(4-bromobenzyl)thio] _5-Methylphenyl}-bite-2_yl)-5-(trifluoromethyl)-1 Η-°Λ峻-4-methyl oxime ethyl ester to the title compound of Example 243, Step C (monomer and dimerization) a mixture of 209 mg, about 0.54 mmol) and 4-bromophenylhydrazino bromide (192 mg, 0.77 mmol) in DMF (3 mL). The resulting mixture was stirred for 30 minutes until the monomer was consumed. Sodium borohydride (58 mg, 1.54 mmol) was then added and the reaction mixture was stirred for a further 45 minutes to cleave the disulfide bond of the dimer and form the desired product. Once the reaction was completed, the mixture was cooled to 0 ° C and quenched by the addition of 2 N aqueous HCl. The aqueous phase was extracted with a 3:1 mixture of EtOAc EtOAc. Purification by silica gel flash chromatography (EtOAc EtOAc EtOAc EtOAc (EtOAc) 201028152 δ 8.12 (s, 1Η), 7.96 (t, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.36 (d, J =1.4 Hz, 1H), 7.32 (d, J=8.2 Hz, 3H), 7.16 (dd, J=7.9, 1.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 2H), 4.35 (q, J =7.1 Hz, 2H), 3.81 (s, 2H), 2.37 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Step E: l-{6-[5-Methyl-2-({[4,-(trifluoromethyl)biphenyl-4-yl]methyl}thio)phenyl]pyridin-2-yl 5-(Trifluoromethyl)-1 Η-pyrazole-4-carboxylic acid The title compound (24 mg, 0.04 mmol), 4-(trifluoromethyl)phenyl succinic acid (10.4 mg, 0.06 mmol), anti-di- gas bis(triphenylphosphine) (11) (8.9 mg, 0·01 mmol) and fluorinated (19 mg, 0.13 mmol) in acetonitrile (0.5 mL). Then, sodium carbonate (0.13 mL, 1.0 Torr in water, 0.13 mmol) was added. The resulting mixture was stirred at 901. After 30 minutes, the reaction mixture was cooled to ambient temperature then quenched with EtOAc EtOAc EtOAc. The organic phase was dried over sodium sulfate, taken up in DCM eluting with EtOAc (EtOAc) and concentrated in vacuo. To a solution of the crude reaction product in 1,4-dioxane (0.200 mL) and methanol (0.030 mL), sodium hydroxide (0.040 mL, 1.0 EtOAc. (: heating down. After 15 min, the reaction mixture was cooled to ambient temperature. The reaction mixture was concentrated in vacuo and then acidified with TFA (2 N in DMSO) by reverse phase HPLC (65 to 100% in water) Acetonitrile, each with 0.1% v/v TFA) purified to provide the title compound: LCMS m/z 614.9 [M+H] + ; 4 NMR (500 MHz, CD2C12) δ 8.13 (s, 1H), 7.96 (t, J= 7.9 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.69-7.65 (m, 4H), 7.60 (d, J=8.0 137610.doc -124- 201028152

Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.18 (d, J=8.2 Hz, 3H), 3.94 ( s, 2H), 2.36 (s, 3H). The compounds listed in Table 4 were prepared using the chemistry described in Examples 236-243. Table 4

X r2

No. X Ri 244 CH H 245 CH H 246 CH Cl 247 CH H 248 CH H 249 CH Me 250 CH Me 251 CH H 252 N H -OCH.

❿ MS ([M+H]+) 549.9 595.8 617.8 617.8 597.9 615.8 611.8 548.4 544.9 137610.doc -125- 201028152 253 NH 254 N Cl 255 N Cl 256 N Me 257 N Me 258 N Cl 259 N Cl 260 N Cl 261 N Cl 262 N Cl 263 N Cl 264 N Cl 265 N Cl 266 N Me 267 N CF,

-〇ch2-^V-^-cf3 -〇ch2-^VO-cf3

599.0 620.8 602.8 598.8 582.9 582.9 602.8 636.7 598.8 652.8 578.9 598.8 619.9 600.0 613.0 137610.doc -126- 201028152 268 269 270 • 271 272 ❹ 273 274 275 276 277 278 279 . 280 281 282 CH H CH H CH H CH H CH H CH H CH H CH Me CH Me CH Me CH Me CH Me CH Me CH Me CH Me

-sch2

Cl

-SCH2-^ ^~^ OMe

-SCH2_O~0~CF3

614.9 634.9 618.9 560.9 580.9 564.9 584.8 562.7 628.9 595.0 580.9 632.9 618.9 596.8 596.8 137610.doc -127- 201028152 283 (isomer A) CH Me 284 (isomer B) CH Me 285 CH Me 286 CH Me 287 CH Me 288 CH Me 289 CH Me 290 CH Me 291 CH Cl 292 CH Cl 293 (isomer A) CH Cl 294 (isomer B) CH Cl 295 CH Cl 296 CH Cl 297 CH Cl -sch2 -sch2 -sch2 -sch2— ^ -OK&gt;' -sch2 -sch2-^— -sch2 -sch2—^ -SCH2^ -SCH2

Cf3

Cf3

Cf3

-sch2

Cf3 -sch2

Cf3 p· 635.0 635.0 566.9 566.9 580.9 580.9 498.7 512.7 648.7 594.7 654.8 654.7 518.7 532.8 574.9 137610.doc -128- 201028152

298 CH Cl -sch2-^- 532.8 299 CH Cl -SCH2-H〇-0Me 520.7 Example 300 Step A: 1·(6-{2-[(4-Bromophenyl)(difluoro)methoxy]benzene Ethyl}tbpyridin-2-yl)-5-(trifluoromethyl)-l-pyrazole-4-carboxylic acid ethyl ester to the title compound of Example 1 Step B (5 15 mg, 1.37 mmol) in DMF (5 mL NaH (35.0 mg, 1.46 mmol) was added to the cooled (0 ° C) solution. The reaction vessel was then warmed to ambient temperature for 25 min, followed by the addition of 1-Di-[4-(difluoro)methyl]benzene (445 mg, 1.56 mmol, synthesized according to US Pat. No. 6,399,990) and heated at 60 °C. . After 24 h, the reaction mixture was cooled and quenched with EtOAc EtOAc. Purification by silica gel flash chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc s, 1H), 7.88-7.82 (m, 2H), 7.78 (d, J = 7.1 Hz, 1H), 7.57 (dd, J = 7.8, 0.7 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H ), 7.46-7.41 (m, 2H), 137610.doc -129- 201028152 7.39-7.32 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H) . Step B: 1_丨6-(2-{Difluoroμ,-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)® Λ-2-yl]-5-(three The title compound (5 〇.〇mg, 0.086 mmol), 4-trifluoromethylphenyl ruthenate (Step A. 〇mg, 0.086 mmol), was stirred at 90 ° C under fluoromethyl)-1Η-*Λ君-4- 35 mg, 0.1 8 mmol), trans-di- gas bis(triphenylphosphine) (11) (9.0 mg, 0.013 mmol), Na2C03 (0.1 mL, 2.0 Μ aqueous solution, 0.2 mmol) and MeCN (1 mL) Mixture 35 min »The crude mixture was dried and concentrated in vacuo to a mixture of 0.1 mL of 3 N NaOH, dioxane and MeOH at 5 ° C for 1 〇 min and then using a YMC C-18 column. Reverse phase HPLC (65 to 100% acetonitrile in water, each with 0.1% v/v TFA) afforded the title compound: LCMS m/z 599.9 [MF] + ; 4 NMR (500 MHz, propyl-d6) δ 8.34 ( m, 2Η), 8.03 (d, J=7.6 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.95-7.78 (m, 7 H), 7.69 (d, J=8.5 Hz, 2H) , 7.62 (m, 2H) » Example 301

137610.doc -130- 201028152 Step A: 1-{6-[2-(difluoro{4-[trans-4-(trifluoromethyl)cyclohexyl]phenyl}methoxy)phenyl]pyridine -2-yl}-5-(trifluoromethyl)-1Η-pyrazole-4-carboxylic acid and 1-{6-[2-(difluoro{4-[cis-4-(trifluoromethyl)) ring Benzyl]phenyl}methoxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1 oxime-pyrazole-4-carboxylic acid The title compound of Example 300 Step A was stirred at 90 ° C ( 4〇mg, . 0.068 mmol), 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexene·;[_.yl]-1,3,2- Dioxanthene (38 mg, 0.14 mmol, prepared according to j. Med. Chem., 2006, 49, 3719), trans-di- gas bis(triphenylphosphine)palladium rhodium (11) (12 mg '0.017 mmol) , a mixture of Na2C03 (0.1 mL, 2.0 hydrazine in water, 0.2 mmol), CsF (32 mg, 0.2 mmol) and MeCN (0.5 mL) for 40 min. The crude mixture was dried and the polar material was removed by preparative TLc (5: &lt;EMI&gt; The remaining material was dissolved in Et 〇 H (0.5 mL) and hydrogenated in the presence of about 12 mg of Pd black for 6 hours. The two isomers obtained were separated by preparative TLC (5:1 hexane·EtOAc). For each individual isomer, treat with a mixture of 3 N NaOH (0.1 mL), Ershiyuan• (〇·1 mL) and MeOH (0.1 mL) for 15 min at 50 °C, followed by 9 TFA ( Acidification in DMSO) and reverse phase HPLC (65 to 100% acetonitrile in water, each with ο"% v/v tfa) using a YMC C-18 column to generate trans (from moving on normal phase TLC) The faster hydrolysis of the isomers) and the cis (from the hydrolysis of the slower isomers moving on the normal phase TLC) the title compound. Analytical data of the trans isomer: LCMS (ESI) m/Z 605.8 [M-F], H NMR (500 MHz, propyl-d6) δ 8.27 (s, 1 Η), 8.19 (t J = 7.9 Hz , 1H), 8.01 (d, J=7.8 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 2.65 (m, 1H), 2.32 (m , 1H), 137610.doc -131- 201028152 2.08 (m, 2H), 1.98 (m, 2H), 1.67-1.45 (m, 4H). Analytical data for cis isomer: LCMS m/z 605.8 [MF] + ; NMR (400 MHz, acetone _d6) δ 8.20 (s, 1H), 8.14 (t, J = 7.9 Hz, 1H), 7.96 ( d, J=7.9 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 2.80 (m, 1H), 2.43 (m, 1H), 1.82 (m, 6 H) 〇Example 302

Step A: 5-Bromo-2-(difluoromethyl)benzonitrile was heated at 150 ° C in NMP (50 mL) 4-bromo-1-(difluoromethyl)_2-fluorobenzene (5.0 g , 22 mmol) and a mixture of KCN (4.34 g, 67 mmol) for 16 h. After wet milling with a mixture of water, hexane, EtOAc and DCM, the organic layer was concentrated and purified by flash chromatography using hexane: DCM (4:1 to 4:1.5 v/v) as mobile phase. Title compound: NMR (500 MHz, CD2C12) δ 7.97 (s, 1 Η), 7.93 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 6.95 (t, J = 54.5 Hz , 1H). Step B: 5-Bromo-2-[bromo(difluoro)methyl]benzonitrile The title compound (2.44 g, 10.5 137610.doc -132 - 201028152 mmol), CCl3Br (8) A mixture of mL) and Na2C03 (480 mg, 4.5 mmol) was irradiated with a fluorescent lamp for 3 〇h. Purification by flash chromatography using 8:1 to 6:1 to 4:1 hexanes: DCM as the mobile phase to give the title compound: NMR (500 MHz, CD2C12) δ 8.03 (s, 1 Η), 7.92 (d , J = 8.5 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H) 〇 Step C: 5-bromo-2-[bromo(difluoro)methyl]benzaldehyde to the title compound of Example 302 Step B ( 1.23 g, 3.95 mmol) DIBAL-H (5.14 mL '1.0 Μ, 5.14 mmol in toluene) was added dropwise to a cooled (-78 ° C) solution in toluene (10 mL). HOAc (1.5 mL) was added followed by MeOH (0.5 mL) and 2N HCl. The title compound was obtained by EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) , 1H), 8.22 (d, J=1.6 Hz, 1H), 7.87 (d, J=8.2, 1.6 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H). Step D: l-(6-{2-[(4-Bromo-2-carboxyphenyl)(difluoro)methoxy]phenyl} hexane-2-yl)-5-(trifluoromethyl The title compound was obtained by reacting the title compound of Example 302 Step C with the title compound of Example 1 Step B to afford the title compound: LCMS m/z 592.5 [MF] + ° Step E: 1-(6-{2·[(4-Bromo-2-vinylphenyl)(difluoro)methoxy]phenyl}pyridin-2-yl)-5-(trifluoromethyl)-1Η- Add ethyl n-BuLi (5.5 mL) to a cooled (〇 ° C ) suspension of methyl bromide (5.33 g ' 14.9 mmol) in THF (100 mL). , at 137610.doc •133- 201028152 2·5 Μ ' 13.8 mmol) in hexane. After 40 min of aging, the reaction mixture was warmed to ambient temperature for 25 min. At this time, 7.4 mL of supernatant was added and added. The title compound (270 mg, 0.442 mmol) was obtained from m. Purified by silica gel flash chromatography (5% to 15% EtOAc in hexane) For the title compound: LCMS m/z 590.5 [MF] + ; 4 NMR (500 MHz, CD2C12) δ 8.13 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.45-7.40 (m, 3H), 7.08 (m, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.32 (d, J=11.0) Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). Step F: l-(6-{2-[{2-ethyl-4- [4-(Trifluoromethyl)cyclohexyl]phenyl}(difluoro)methoxy]phenyl}pyridin-2-yl)-5-(trifluoromethyl)-1Η-pyrazole-4-carboxylic acid The title compound was prepared from the title compound of mp. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1H), 8.10 (m, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.58 (m, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.48 (m, 1H), 7.27 (s, 1H), 7.15 (d, 1H), 2.76 (q, J=7.6 Hz, 2H), 2.63 ( m, 1H), 2.31 (m, 1H), 2.07 (m, 2H), 1.99 (m, 2H), 1.67-1.46 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H). Example 303 137610.doc -134- 201028152

CF3 Step a: 1-Bromo-2-[bromo(difluoro)indolyl]benzene. 卜&gt;Smell-2-difluoromethylbenzene (9.6 g, 46.8 mmol) and N-Dimethyldiimide (24.8 g, 139 mmol) of the solution in four gasified carbon (1 mL) was irradiated with a daylight. After 3 days, the reaction mixture was diluted with hexane, the precipitate was removed, and the collected organic filtrate was concentrated in vacuo. Purification by silica gel flash chromatography (100% hexane) afforded the title compound: 4 NMR (500 MHz, CD2C12) δ 7.74 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.0, 1.5

Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.37 (td, J=7.7, 1.3 Hz, 1H). Step B: (2-Bromophenyl)(difluoro)methyl 4,-(trifluoromethyl)biphenyl-4·ylindole-4-1(2-bromophenyl)(difluoro)methoxy Cooling of 4'-(trifluoromethyl)anthracene to 4'-(trifluoromethyl)[1,1'-biphenyl]-4-ol (178 mg, 0.75 mmol) in DMF (0) °C) Sodium hydride (27.0 mg, 1.12 • mmol) was added to the solution. Once the hydrogen evolution has ceased, the reaction mixture is allowed to warm to ambient temperature. The title compound of Example 303, Step A (373 mg, 1.30 mmol) was then added to the reaction flask and the mixture was stirred at 60 °C. After 15 h, the reaction mixture was quenched by the addition of 2 N aqueous HCl. The aqueous phase was extracted with hexane/ethyl acetate (3:1 v/v). The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel flash chromatography (0-20% dioxane in 137610.doc - 135 · 201028152 hexane) afforded the title compound: LCMS m/z 423.5 [MF]+; lU NMR (500 MHz, CD2C12 ) δ 7.85 (dd, J=7.8, 1.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.72 (s, 4H), 7.65 (dd, J=6.8, 1.9 Hz, 2H), 7.45 (d, J = 8.7 Hz, 3H), 7.40 (td, J = 7.7, 1.5 Hz, 1H). Step C C: l-[6_(4,4,5,5-tetramethyl-1,3,2·dioxaboromid-2-yl)pyridine·2-yl]-5-(trifluoromethyl) The title compound (538 mg, 1.68 mmol), bis (pinadol), bis(P. Bis(diphenyl scaly)ferrocene (93 mg, 0.17 mmol), gasified 1-indole-bis(diphenylphosphino)ferrocene (II) and dichasole (137 mg, 0.17) The complex of mmol) and acetic acid off (495 mg, 5.05 mmol) were dissolved in DMSO (10 mL) and the mixture was warmed at 100 °C. After 2 h, the reaction mixture was cooled to ambient temperature then quenched with brine andEtOAc. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel flash chromatography (20% EtOAc EtOAc) elut elut elut elut elut elut elut elut ) δ 8.10 (s,1H), 7.92 (m,2H), 7.57 (dd, J=6.6, 2.5 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz) , 3H), 1.37 (s, 12H). Step D: M6-[2_(difluoro{[4,-(trifluoromethyl)indolyl-4-yl]oxy}methyl)phenyl]® Λ_2-yl}-5-(two The title compound (95.5 mg, 0.22 mmol) from EtOAc (m. Add verse-di- gas bis(triphenylphosphine)palladium (11) (30 mg, 0.04 mmol), cesium fluoride (98 mg, 0.65 mmol) and sodium carbonate (0.90) to the solution in 136- 201028152 (2.0 mL) mL, 1.0 Μ aqueous solution, 0.90 mmol). The resulting mixture was heated at 90 °C. After 1.5 hours, the reaction mixture was cooled to ambient temperature and then quenched with brine and th The organic phase is separated and dried over sodium sulfate. The mixture was then dissolved in DCM through a pad of silica gel and concentrated in vacuo. To a solution of the crude product obtained above in dioxane (0.50 mL) and methanol (0.050 mL), sodium hydroxide (0.100 mL, 1.0 Μ aqueous solution, 0.100 mmol) was added and the mixture was stirred at 50 ° C. . After 15 min, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The mixture was then acidified with TFA (2 M in DMSO). Purification by reverse phase HPLC (65 to 100% acetonitrile in water with 0.1% v/v TFA) afforded the title compound: LCMS m/z 600.8 [MF] + ; ;H NMR (500 MHz, CD2C12) δ 8.10 (s, 1H), 8.02 (t, J=7.9 Hz, 1H), 7.74-7.60 (m, 9 H), 7.53 (dd, J=6.8, 1.9 Hz, 3H), 7.06 (d, J=8_7 Hz , 2H). ^ The compounds in Table 5 were prepared using the chemistry described in Examples 300-303. table 5

No. Ri r2 r3 MS ([MF]+) 304 Me Η -〇cf2-Q&gt;—Q-cf3 613.9 137610.doc -137- 201028152 305 Η H -〇cf2-O-Q-CI 565.9 306 Η H -〇 Cf2~〇~o 538.0 307 Η H •〇cf2_〇~0 524.0 308 Η H -OCF2-Qm^)&quot;ICF3 605.8 309 Η H -〇CF2-Q»-^)-CF3 605.8 310 Η H •〇 cf2-hO^GK 566.0 311 Me H -ocf2-&lt;Q^-ci 504.0 312 Me H OCF2-^》-SEt 530.0 313 Me H -OCFg-^ ^~cPr 510.1 314 Me H -〇cf2_^3~o 552.0 315 Η H -〇cf2-^^-Qkci NC 590.8 316 Η H -〇CF2-^^-^^-CF3 NC 624.8 317 Cl H •〇cf2_〇~0~ci 599.8 318 Η H -〇CF2- ^^-^^ co2h 575.9 319 Cl H -〇CF2-^j&gt;-&lt;^-ICF3 639.9 320 Cl H -〇CF2-^^»*&lt;^)h*CF3 639.9 321 Cl H -〇cF2- 〇_^〇_OMe 595.9 137610.doc -138- 201028152

Example 330

322 Η Η -〇CF2-^^—^^-OMe 561.9 323 Me Η -°CF2—~OMe 576.0 324 Cl Η -0CF2-^^—ζ^-OMe Cl 629.9 325 Η Η -〇CF2-Q—^ -OMe Cl 595.9 326 Me Η -OCF2—~y 丨OMe 582.6 327 Me Br 〇CF2~C^&quot;d)._ICF3 698.5 328 Η Η cF2°~〇^〇_0Me 562.9 329 Η Η -cf2〇^0 ~〇~cf3 618.9

F step is called A · 2 - 4 gas base -6 · gas &quot;tb bite into a 250 ml round bottom flask equipped with a mechanical stirrer, Claisen head and addition funnel. Add 2-gas-6-mercapto 0 to bite ( 4.00 g, 27·9 mmol), Et2O (20 mL) and concentrated hydrochloric acid (12 mL, 146 mmol). A solution of sodium nitrite (2.211 g, 32.0 mmol) in water (28 mL) was added dropwise to a mixture of cold 137610.doc - 139 - 201028152 but (0 ° C). The insoluble material gradually dissolved. After 2 h, the aqueous phase was extracted with diethyl ether (2 x 50 mL). The combined organic phases were dried <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; Step B: 1-(6-Gapyridin-2-yl)-5-(trifluoromethyl)-1Η-1,2,3-triazole-4-carboxylic acid acetamidine to the title compound of Example 330. Methyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoic acid ethyl acetate (0.284 mL, 1.94) in acetonitrile (4 mL) Methyl), then TEA (0.271 mL ' 1.94 mmol) was added and the mixture was heated at 70 °C. After 16 hours, the reaction mixture was taken from EtOAc EtOAc EtOAc. NMR (500 MHz, CD3OD) δ 8.03 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). Step C: 5-(Trifluoromethyl)-1-fluorene 6-(2-{丨4,-(trifluoromethyl)-l-phenyl-4-yl]methoxy}phenyl-2-yl] -1H-1,2,3-Trisin-4--4-carboxylic acid The title compound was obtained from the title compound from Example 330 Step B: mp. H] + ; *H NMR (500 MHz, d6-DMSO) δ 8.29 (d, J = 8.0 Hz, 1H), 8.24 (t, J = 8.0 Hz, 1H), 7.91-7.88 (m, 3H), 7.81 (d, J=8.5 Hz, 2H), 7.75-7.72 (m, 3H), 7.56 (d, J=8.5 Hz, 1H), 7.49-7.45 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.12 (t, J=7.5 137610.doc -140- 201028152

Hz, 1H), 5.33 (s, 2H). The compounds in Table 6 were prepared using the chemistry described in Examples 1 and 330. Table 6

No. Ri R2 MS 331 Η -ch2~〇~〇~ci 551.0 [M+H] 332 Me -ch2~〇^〇~cf3 599.5 [M+H] 333 Me -ch2_^D_^C}_cf3 613.5 [M+ H] 334 Me 617.4 [M+H] F The measurement of soluble uridine cyclase (cGC) activation (based on fine running) is measured by the production of intracellular loop-single guanine (cGMP) The ability of a compound to activate a sGC of heterologous expression in CHO cells was measured to determine the activity of the compound on sGC. Since the cDNA is selected for human sGC subunits ~ and mouth! The CMVie promoter was inserted into the mammalian expression vector using standard molecular biology methods. Standard cell biology methods were used to generate CHO cell lines that stably transfected and overexpressed two sGC subunits. The test compound (5 μM) was dissolved in DMSO and diluted in DMSO to 50 times the desired final concentration for a 3-fold continuous diluent amount reaction curve. Compounds with 3500-4000 cells in 384-well plates (Greiner #784076) at 137610.doc -141 - 201028152 containing 1 nM IBMX (3-isobutyl-1-methylxanthine) 5 μM phosphate buffer Incubation in physiological saline (PBS) in the presence and absence of [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) at 37 ° C Hr. ODQ is used to distinguish between hemoglobin-dependent (HDA) compounds and hemoglobin-independent (HIA) compounds. At the end of the incubation period, the reaction is terminated and the cells are dissolved. The assay kit detects the amount of labeled cGMP removed from its specific antibody by measuring the amount of intracellular cGMP based on the HTRF-based assay kit (CisBio, 62GM2PEC). The inflection point, % maximum activation, and EC5 enthalpy were obtained based on the curve of compound concentration versus % activation. The compound was determined to have an inflection point greater than 10 ® μΜ and at least 20% activation. Measurement of soluble uridine cyclase (cGC) activation (based on enzyme) The activity of the test compound against purified sGC was assessed in a cell-free enzymatic assay for PCASA assay. A human recombinant sGC enzyme with a purity greater than 95% was obtained from Axxora, LLC (San Diego, CA). The compound was incubated with 0.1 ng of sGC enzyme for 1 hr in the presence of the substrate GTP of the enzyme at 37 °C. At the end of the incubation period, the reaction was stopped and the amount of cGMP produced was measured by HTRF-based assay (CisBio, 62GN2PEC), which detects the translocation of fluorophore-labeled cGMP from its specific antibody. the amount. The inflection point, % maximal activation, and EC50 values were obtained based on the curve of compound concentration versus % activation. In this assay, 1-{6-[5-gas-2-({4-[trans-4-(dimethyl)cyclohexyl]-benzyl}oxy)phenyl]° is pyridine- 2-Base}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 9) yielded an inflection point of 11 nM and an EC50 value of 1.7 nM 0 137610.doc • 142-

Claims (9)

201028152 VII. Scope of application: 1. A compound of formula I or a pharmaceutically acceptable salt or hydrate thereof: Wherein: Z1 is selected from the group consisting of CH and N; A is a ring selected from the group consisting of: R7 is selected from the group consisting of: 1) hydrogen, 2) Cw alkyl, wherein the alkyl group may be unsubstituted or substituted with 丨3 氤 137610.doc 201028152 atoms and unsubstituted or 〇c _3 alkyl monosubstituted, 3) C3.6 cycloalkyl, wherein the cycloalkyl group may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with OCu alkyl, and 4) benzene a group wherein the phenyl group is unsubstituted or substituted by CN4 alkyl, -0 (^.4 alkyl, halogen 'CN, N02 &amp; SCCOojCM alkyl, wherein C!·4 alkyl and -OCu alkyl are not Substituted or substituted with 1-3 fluorine atoms; L1 is selected from the group consisting of hydrazine, S, C(R丨2)2; and © cf2; L is selected from the group consisting of: CH2) 2.4, -C(R12)2, -CFz-O and s, with the proviso that when LI is ο or s, L2 is not 〇 or S; R is independently selected from the group consisting of: Hydrogen and C]_3 alkyl, wherein the Cw alkyl group is unsubstituted or substituted with 丨3 fluorine atoms; E is a ring selected from the group consisting of the following rings: 1) 6-10 member aryl ring, _ 2 ) independently selected from 〇, 丨, 2, and 3 &gt;|Atom, 〇 or a group of 〇 atoms and 〇 or 1 s atom, a 5-10 membered heteroaryl ring of 2, 3 or 3 heteroatoms, 3) a C3.8 cycloalkyl ring; Wherein the aryl group, heteroaryl group and C3 s cycloalkyl group are unsubstituted or monosubstituted by rS, and are unsubstituted, monosubstituted by r8 or independently disubstituted by r8; 137610.doc 201028152 in the presence of each person Independently selected from the group consisting of: halogen, Cl-6 alkyl 'wherein the alkyl group may be unsubstituted or substituted with 13 fluorine atoms, -〇-C〗 6 alkyl, wherein the alkyl group may Unsubstituted or substituted by 3 fluorines, substituted by atoms, C3·8 cycloalkyl, which is unsubstituted or substituted with a ruthenium (tetra) atom, -〇_C3-8 cycloalkyl, unsubstituted or via 1-3 Substituted by a fluorine atom, ® CN, and N〇2; R is, at each occurrence, independently selected from the group consisting of: 1) R6, 2) -OR6, 3) C!·6 alkyl, which may be unsubstituted or substituted by 13 fluorine atoms, and unsubstituted or independently selected from the group of the following groups • Monosubstituted. C3_6 ring burning Base, _〇_Ci 4 alkyl, 〇H, =〇, SCCOQdCw alkyl, -OR6 and R6, 4) Cw alkenyl, which may be unsubstituted or substituted by 13 fluorine atoms' and unsubstituted or Monosubstituted groups independently selected from the group consisting of -O-Cw leukoxyl, 〇H, =〇, S(〇)〇2Ci 4 alkyl, -OR6 and R6, 5) 0-Ci_6 alkyl, The alkyl group may be unsubstituted or substituted by a fluorine atom 'and unsubstituted or monosubstituted by a group independently selected from the group consisting of c3_6 cycloalkyl and R6, 137610.doc 201028152 6) -S-C1 _6 leukoxene, 7) a C3_8 cycloalkyl ring which is unsubstituted or monosubstituted, disubstituted or trisubstituted, and unsubstituted or independently selected from the group consisting essentially of a fluoro group and a C. 4 alkyl group. Single group substitution of the group: may be unsubstituted or passed through a fluorine source? Replace it.丨4 alkyl, -O-Cw alkyl, OH, =0, s(〇)0 2Ci 4 alkyl, _〇r6, R6 and NR9R10, 8) C5.8 cycloalkenyl ring 'unsubstituted or Independently selected from a fluorine group And a group of C丨-4 alkyl groups which are monosubstituted, disubstituted or trisubstituted, and unsubstituted or monosubstituted by a group independently selected from the group consisting of 卩U groups: a core which may be unsubstituted or substituted by a fluorine atom Burning base, -0-~burning base, 0H, =〇, s(〇). An alkyl group and a R6, 9&quot; to 6 membered heterocyclyl ring having a hetero atom selected from the group consisting of n and 〇W, and unsubstituted or monosubstituted by a group independently selected from the group : Cl.4 alkyl, 0Ci 4 fluorenyl and hydrazine, and 10) halogen, which may be unsubstituted or substituted with 3 fluorine atoms; R6 is selected from the group consisting of: 1) benzene ring' Monosubstituted or disubstituted aryl, 〇H, CN, unsubstituted or substituted by a fluorine atom, which is unsubstituted or independently selected from the group consisting of: The base may be unsubstituted or substituted by a fluorine atom. 烧~alkyl, N〇2, s(o)0-2Ci 4 alkyl, C2 4 diluted, 〇·1376I0.doc 201028152 C2.4ene a group, NR9R1G and COOH, and 2) a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from N, 0 and S, wherein the heteroaryl ring is unsubstituted and independently selected Mono- or di-substituted from the group of the following groups: halogen, OH, CN, Ci·4 alkyl which may be unsubstituted or substituted by 1 to 3 fluorine atoms, alkyl may be unsubstituted or via 丨3 Fluorine atom Oc丨.4 alkyl, no2, S(0)G.2Cb6 alkyl, S(0)〇_2, C2-6, OC2-6, NR9R10 and c〇〇H; R8 Is selected from the group consisting of: Cm alkyl, wherein the alkyl group may be unsubstituted or substituted with 丨3 fluorine atoms, C2-4 alkenyl, halogen, C3-6 cycloalkyl, wherein the ring The alkyl group may be unsubstituted or substituted by μ fluorine atoms, wherein the alkyl group may be unsubstituted or substituted by 13 gas atoms, 〇_c2.4 cation, no2, SCCOo.aCw alkyl And CN; two: selected: independently selected from the group consisting of hydrogen and Ci. 6 appearance groups; and selected from the group consisting of hydrazine and C -6 alkyl. 2. A compound as claimed in the formula or a salt thereof accepted by the pharmaceutical agent 1, wherein 1376IO.doc 201028152 is selected from the group consisting of: Where E1 is CH or N. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein 5 Λ^^5)〇-1 '(R8)〇-2 It is selected from the group consisting of: 4. The compound of claim 或其 or its pharmaceutically acceptable salt is CH. 5. A compound as claimed in the formula or a pharmaceutically acceptable salt thereof, wherein r7 is selected from the group consisting of ch3, cf3 and cf2h. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of hydrazine and S. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of ch2, CH(eH3), 〇CHzCH2, ch and c^chkH2, the [a is 〇L1 is not 〇. 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein [a 137610.doc 201028152 is selected from the group consisting of CH2 and CF2. 9. A compound of the present invention, or a pharmaceutically acceptable salt thereof, selected from the group consisting of HU, cyclopropyl, n〇2 &amp; cf3 . 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein r4 is selected from the group consisting of Cl and CH3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is a mono-, di- or tri-substituted benzene ring which is unsubstituted or independently selected from the group consisting of: : α, F, even, c(cH3)3 , CF3, -ocf3, -och3, _OCH(CH3)2, and c〇〇H. 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein r5 is selected from the group consisting of: 1) R6, 2) Gw cycloalkyl ring, unsubstituted or independently a mono-, di- or tri-substituted group selected from the group consisting of phenyl, F, CF3, CH3, OH and =0, 3) ° pyridine ring, wherein the point of attachment to the acridinyl ring is a carbon atom, and wherein the pyridyl ring is unsubstituted or monosubstituted with CF3, 4) -CH2-L3-R6, where L3 is -(:4_ or -〇_, 5) -OR6, 6) -OCH2R6, 137610.doc 201028152 8) -CF3, 9) CM, F or Br, 10) -CH3, 11) OCH3, 12) OCF3, 13) -CH=CHR6, and 14) -SCH2CH3. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of C, F, Br, -CH3, -C(CH3)3, och3, ocf3, -sch2ch3, CF, Cl CH3 Cf3 K3f. Cf3 Och3 Och3 O \—CH2CH2-^ ^ \ —ch2〇 —<〉~cf3 ^_ch2o —^-ch2o Bu I -ch2ch2 Cf3 〇cf3 \—ch2ch2 F ^—CH=CH Cf3 137610.doc 201028152 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of: -CH3, 137610.doc -9- 201028152 15. The compound of claim 1 or a pharmaceutical thereof is selected from the group consisting of CF3. And a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of the following rings: R8: CH3, Cl, F, cyclopropyl and 16. ring: 17. A compound as claimed, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen. 18. The compound of claim 1 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 1^6-(2-{[4-(2-phenylethyl)benzene) Methyl]oxy}phenyl)β-pyridyl-2-yl]-5-(trifluoromethyl)_ιη-吼. -4-carboxylic acid, 5-(difluoromethyl)-1-[6-(2-{[4'-(trifluoromethyl)biphenyl-4-yl]nonyloxy}phenyl)* ratio咬-2-yl]-111-° ratio °-4-carboxylic acid, 5-(trifluoromethyl)-1-(6-{2-[(4-{2·[4-(trifluoromethyl)) Phenyl]ethyl}phenylphenyl)-oxy]phenyl}acridin-2-yl)-1Η-indoleazole-4-carboxylic acid, phenylcyclopropyl]benzyl}oxy)phenyl 0-pyridin-2-yl}-5-(trifluoromethyl)-1Η-pyrazole_4_carboxylic acid, 1_{6-[2-({4-[(111,21〇-2_phenyl) Cyclopropyl]benzyl}oxy)phenyl]»pyridin-2-yl}-5-(trifluoromethyl)-1Η-pyrazole-4-furic acid, 1-[6-(2- {[4-(4-Vinylphenoxy)benzyl]oxy}phenyl)"pyridinyl-2_ 137610.doc -10· 201028152 yl]-5-(trifluoromethyl)-1 Η_°嗤-4-carboxylic acid, 5-(trifluoromethyl)-1-{6-[2-({4-[4-(trifluoromethyl)phenoxy]benzyl}oxy)phenyl ]0 than bite-2-*}-1Η-η ratio. Sodium-4-carboxylic acid, 5-(difluoroindolyl)-1-(6-{2-[(4-{[4-(trifluoroantimony) Phenyloxy]methyl} fluorenyl)oxy]phenyl}0 is more than keto-2-yl)-1 Η-η than β -4-carboxylic acid, 1-{6-[5-fluorenyl- 2-( {4-[trans-4-(trifluoromethyl)cyclohexyl]benzoinyl} . oxy)phenyl]° than biti-2-yl}-5-(trifluoromethyl)-1Η-» than sal-4-pyruic acid, 1-{6-[5-mercapto-2·( {4-[cis-4-(trifluoromethyl)cyclohexyl]phenylhydrazino} oxy)phenyl]0-pyridyl b-5-(trimethylsulfonyl)_ιη·pyrazole_4_decanoic acid , 1-{6-[5-chloro-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]phenyl)}oxy)phenyl]pyridin-2-yl}-5- (Trifluoromethyl)_1Η-pyrazole_4_decanoic acid, 1-{6-[5-gas-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl) Oxy)phenyl]° than biti-2-yl}-5-(trifluoromethyl)-ΐΗ-«&gt; than saliva-4-pyruic acid, 1-[6-(2-{[4·( 4-sided oxocyclohexyl)phenylhydrazinyl]oxy}phenyl)π-pyridin-2-yl]-5-(diazyl)-111-0 ratio °--4 decanoic acid, Φ 1 -[6_(2_{[4_(4,4-difluorocyclohexyl)benzyl]oxy}phenyl)"pyridin-2-yl]-5-(trifluoromethyl)-1Η-0 ratio Salivary-4-decanoic acid, 1-[6-(2-{[4-(trans-4-methoxycyclohexyl)benzyl)oxyindole phenyl)anthracene / bite ·2·yl]-5 -(dimethylmethyl)-1 Η-σ than 嗤-4-carboxylic acid, . 1-[6-(2-{[4·(cis-oxycyclohexyl)benzyl]oxy}phenyl) Bite-2-yl]-5-(difluoromethyl)-1Η-° Salivary-4-carboxylic acid, 1-[6-(2-{[4-(trans)-4-methoxycyclohexyl)_2-methylphenylhydrazinyloxy)phenyl)&quot;bipyridine-2 -yl]-5-(trifluoromethyl)_1Η_pyrazole_4_carboxylic acid, 5-(trifluoromethyl)-1-{6-[2-({4·[6-(trifluoromethyl) Pyridine _3·yl]benzene 137610.doc •11· 201028152 methyl}-oxy)phenyl]pyridine^-ylindole-^-pyrazole-4-carboxylic acid, 1-(6-{2-[( 2,4-Dimethylbenzyloxy]-3-mercaptophenyl}»pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, gas -2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl} oxy)phenyl]0 is indole-2-yl}-5-(trifluoromethyl)- 1Η- 11 ratio "• sit-4-ethyl phthalate, {6-[5-gas-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]phenylhydrazinyloxy) Phenyl]°pyrazine-2-yl}-5-(trifluoromethyl)-1Η-嗤嗤_4_capric acid ethyl vinegar, ❹ 5-(trifluoromethyl)-1-[4-(2 -{[4·-(trifluoromethyl)biphenyl·4_yl]decyloxy}phenyl]-1,3-thiazol-2-yl]-1Η-pyrazole-4-furic acid, 1· [2-(2-{[4-(2-Phenylethyl)-methyl]oxy}phenyl) mouth bite_4_yl]-5-(trifluoromethyl)_1Η-pyrazole-4- Tannic acid, 1_{4-methyl-6 -[5-methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl] oxamethyl}-oxy)phenyl]indole is more than 2-yl}-5-( Trifluoromethyl)_ΐΗ-α is more than 〇4·capric acid, 5-(trifluoromethyl)-1-[6-(2-{2-[4'·(trifluoromethyl)) stupid_ 4_yl]ethinyl}phenyl)pyridin-2-yl]-1Η-pyrazole-4-carboxylic acid, 5-(trifluoromethyl)_1_(2'-{[4'-(trifluoromethyl) Biphenyl-4-yl]nonyloxy}_ 2,3·-bipyridyl-6-yl)_1Η-pyrazole·4-decanoic acid, mercapto-2,-{[3-methyl-4' -(Trifluoromethyl)biphenyl_4-yl]methoxy}yl}-2,3·- 吼 -6-6-yl)-5-(tri-II fluorenyl)-1Η-° than 嗤4 _ formic acid, 1-(5,-gas-2,-{[3-methyl-4'-(trifluoromethyl)biphenyl-4-yl]methoxy b 2,3'- bismuth bite _6_yl)-5-(trifluoromethyl) ratio. -4-carboxylic acid, 137610.doc -12- 201028152 1-[2·-{[3-indolyl-4·-(trifluoromethyl)biphenyl-4-yl]methoxy b 5,-( Trifluoromethyl)-2,3,-bipyridyl-6-yl]-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid, 5-(trifluoromethyl)-1-{6 -[2-({[4·-(trifluoromethyl)biphenyl_4.yl]oxy}methyl)phenyl]0 is more than _2-yl}·1Η-0 than sal-4-曱Acid '-5-(trifluoromethyl)-1-(6-{2-[({5-[4-(trifluoromethyl)phenyl)pyrene) _2_yl}oxy)methyl] Phenyl}pyridin-2-yl)-1Η-pyrazole-4-carboxylic acid, 1-{6-[5-methyl-2-({[4·-(trifluoromethyl)biphenyl-4-yl) ]methyl}thio)phenyl]0 than bite-2-yl}·_5-(trimethylmethyl)-1 Η-Β is 0 to 4-butylic acid, 1-[6-(2-{2 Fluoro[4'-(trifluoromethyl)biphenyl-4-yl]nonyloxy}phenyl is more than 2-yl]-5-(trimethylsulfonyl)-1Η_ο than salivary-4-carboxylic acid, 1-{6-[2-(difluoro{4-[trans-4-(trifluoromethyl)cyclohexyl]phenyl}methoxy) benzyl]0 is more than -2-yl}-5-( Trifluoromethyl)-1Η-β than 曱-4-decanoic acid, 1-{6-[2-(difluoro{4-[cis-4-(trifluoromethyl)cyclohexyl;|phenyl}曱Oxy)phenyl]» than bite_2-yl}_5-(difluoromethyl)_ιη_〇 》-4-曱酸, 1-(6-{2-[{2-ethyl-4_[4-(trifluoromethyl)cyclohexyl]phenyl}(difluoro)methoxy]phenyl } η 比 bit-2-yl)-5-(trifluoromethyl)_1Η-bazole-4-carboxylic acid, 1-{6-[2-(difluoro{[4·-(trifluoromethyl)) Biphenyl-4-yl]oxy}methyl)phenyl]0 is more than benzyl-2-yl}-5-(trifluoromethyl)-lH-0 than sal-4-carboxylic acid, and 5-(trifluoro Mercapto)-1-[6-(2-{[4.-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyridin-2-yl]-1Η-1,2, The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein r1 is Η 'Z1 is CH' R7 is CF3 or CF2H, D1 is CH, and L1 is Ο, L2 137610.doc -13- 201028152 is ch2 or cf2, Η〇-' and 丨~〇~. call. 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 1-{6-[5-methyl-2-({4-[anti-4_] (difluoroindolyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)_1H-pyrazolecarboxylic acid, 1-{6-[5-methyl- 2-({4-[cis-4_(difluoromethyl)cyclohexyl]phenylhydrazinyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)_1H•pyrazole·4 · Formic acid, 1-{6-[5-chloro-2-({4-[trans_4_(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5 -(trifluoromethyl)-1Η-pyrazole-4-carboxylic acid, and 1-{6-[5-chloro-2-({4-[cis-trifluoromethyl)cyclohexyl]benzyl}oxyl Phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1Η-pyrazole_4-carboxylic acid. 21. A composition suitable for treating or preventing: cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis 137610.doc.14-201028152, hypertension, thrombosis, restenosis, Myocardial infarction, stroke, cardiac insufficiency, excessive pulmonary pressure, erectile dysfunction, bronchial asthma, chronic renal insufficiency, diabetes, or cirrhosis, the composition comprising an amount of work as required for the treatment or prevention a compound, a stereoisomeric form thereof, or a physiologically acceptable salt thereof, or any of the above, a mixture of two or more, and or a plurality of pharmaceutically acceptable carriers. Φ 22. The use of a compound of the formula 1 of claim 1 , a stereoisomeric form thereof, a physiologically acceptable salt thereof, or a mixture of any two or more of the foregoing, for the preparation of a solubility for activation Ursolic acid cyclase. 23. A composition comprising a compound as claimed in the formula and a compound selected from the group consisting of an angiotensin converting enzyme inhibitor, a blood angiotensin II receptor antagonist, and a neutral peptide chain Dicer inhibitors, lignin antagonists, renin inhibitors, endothelin receptor antagonists, vasodilators, calcium channel blockers, potassium channel activators, diuretics, sympathetic inhibitors, beta-adrenal glands Blocking drugs, alpha adrenergic blockers, central adrenergic agonists, peripheral vasodilators, lipid lowering agents, and metabolic changes. -24. The use of a compound of the formula I according to claim 1 , a stereoisomeric form thereof, a physiologically acceptable salt thereof, or a mixture of any two or more of the foregoing, for use in the preparation of a therapeutic or Drugs for the prevention of cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thrombosis, restenosis, 137610.doc •15- 201028152 · 心肌 myocardial infarction, stroke, heart Insufficiency, excessive lung pressure, erectile dysfunction, bronchial asthma, chronic renal insufficiency, diabetes or cirrhosis. 137610.doc •16· 201028152 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 137610.doc