AU2006279211A1 - Novel substituted 1,2,3-triazolylmethyl-benzothiophene or -indole and their use as leukotriene biosynthesis inhibitors - Google Patents

Description

WO 2007/016784 PCT/CA2006/001306 TITLE OF THE INVENTION Novel substituted 1,2,3-triazolylmethyl-benzothiophene or -indole and their use as leukotriene biosynthesis inhibitors. FIELD OF THE INVENTION 5 The instant invention involves novel compounds which are useful as inhibitors of leukotriene biosynthesis. BACKGROUND OF THE INVENTION Inhibition of leukotriene biosynthesis has been an active area of pharmaceutical research 10 for many years. The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. Leukotrienes are potent contractile and inflammatory mediators derived by enzymatic oxygenation of arachidonic acid by 5-lipoxygenase. One class of leukotriene biosynthesis inhibitors are those known to act through inhibition of 5-lipoxygenase (5-LO). The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4 and 15 LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenases on arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their 20 contribution to various diseases states are also discussed in the book by Rokach. In general, 5-LO inhibitors have been sought for the treatment of allergic rhinitis, asthma and inflammatory conditions including arthritis. One example of a 5-LO inhibitor is the marketed drug zileuton (ZYLOFT@) which is indicated for the treatment of asthma. More recently, it has been reported that 5-LO may be an important contributor to the atherogenic process; see Mehrabian, M. et al., 25 Circulation Research, 2002 Jul 26, 91(2):120-126. Despite significant therapeutic advances in the treatment and prevention of conditions affected by 5-LO inhibition, further treatment options are needed. The instant invention addresses that need by providing novel 5-LO inhibitors which are useful for inhibiting leukotriene biosynthesis. 30 SUMMARY OF THE INVENTION The instant invention relates to compounds of Formula I which are leukotriene biosynthesis inhibitors, methods for their preparation, and methods and pharmaceutical formulations for using these compounds in mammals, especially humans.

WO 2007/016784 PCT/CA2006/001306 N_ N 2 R2

R

3

R

4 The compounds of Formula I are useful as pharmaceutical agents to slow or halt atherogenesis. Therefore, the instant invention provides a method for treating atherosclerosis, which includes halting or slowing the progression of atherosclerotic disease once it has become clinically 5 evident, comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such treatment. The instant invention also provides methods for preventing or reducing the risk of developing atherosclerosis and atherosclerotic disease events, comprising administering a prophylactically effective amount of a compound of Formula I to a patient who is at risk of developing atherosclerosis or having an atherosclerotic disease event. 10 Additionally, the instant invention involves the use of compounds of Formula I as anti asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection. The instant invention provides methods of treatment comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of the above-described treatments. 15 The instant invention further provides the use of a compound of Formula I in combination with other therapeutically effective agents. Additional embodiments will be evident from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION 20 The novel leukotriene biosynthesis inhibitors of the instant invention are compounds of structural Formula I N N N Z R2 R 3

R

4 ' and the pharmaceutically acceptable salts, esters and solvates thereof wherein: 2 WO 2007/016784 PCT/CA2006/001306 Z is selected from the group consisting of 1- S(O)' R -- R1 2 and 2R N A A wherein the numbers "I" and "2" indicate the points of attachment within structural Formula I; A is selected from the group consisting of -Cl and phenyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of (i) -F (ii) -Cl, (iii) 5 -Cl-3alkyl optionally substituted with one or more of halo for example including -CF3, (iv) -OC -3alkyl optionally substituted with one or more of halo for example including -OCHF2 and -OCF3, (v) -OC3-6cycloalkyl, (vi) -C3-6cycloalkyl, (vii) -CH2OH, (viii) -COOR 5 , (ix) -CN and (x) -NR5R5a; n is an integer selected from zero, 1 and 2; 10 RI is selected from the group consisting of (i) -H, (ii) -Br, (iii) -Cl, (iv) -COCl-6alkyl, (v) -COOCl-6alkyl, (vi) -COOC3-6cycloalkyl, (vii) -SO2Cl-6alkyl, (viii) -SO2NR 5

R

5 , (ix) -CONR 5 R5, (x) -CN, (xi) -C -6alkyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of -OH and -F, (xii) phenyl optionally mono- or di substituted with a substituent independently selected at each occurrence from the group consisting of 15 -OH and -F, (xiii) tetrazolyl optionally substituted with methyl, (xiv) 1,2,4-oxadiazolyl optionally substituted with methyl, and (xv) pyridinyl optionally substituted with methyl;

R

2 is selected from the group consisting of -H, -OH, -F, -Cl-3alkyl, -OCl-3alkyl and -OC(O)-Cl-3alkyl;

R

3 is selected from the group consisting of -H, -Cl-6alkyl, -Cl-6alkyl substituted with one or more of fluoro including for example but not limited to -Cl -6perfluoroalkyl such as -CF3 and -CF2CF 3 , 20 -Cl-6alkyl substituted with R 6 , phenyl, -C2-6alkenyl, -C3-6cycloalkyl and -C5-7cycloalkenyl;

R

4 is selected from the group consisting of -H, -Cl-6alkyl, -Cl-6alkyl substituted with one or more of fluoro including for example but not limited to -CI6perfluoroalkyl such as -CF3 and -CF2CF3, -Cl -6alkyl substituted with R 6 , phenyl, -C2-6alkenyl, -C3-6cycloalkyl and -C5-7cycloalkenyl;

R

5 is independently selected at each occurrence from the group consisting of -H, -Cl-6 alkyl and 25 -C3-6cycloalkyl; R5a is independently selected at each occurrence from the group consisting of -H, -Cl-6 alkyl, -C3-6cycloalkyl and -COOR 5 ; and

R

6 is independently selected at each occurrence from the group consisting of -COOR 5 , -C(O)H, -CN,

-CR

5

R

5 0H, -OR 5 , -S-C I-6alkyl and -S- C3-6 cycloalkyl. 30 3 WO 2007/016784 PCT/CA2006/001306 In one embodiment of this invention are compounds within the scope of Formula I having structural Formula Ia wherein the variables are as defined in Formula I: N N R2_ A

R

3

R

4 Ia and the pharmaceutically acceptable salts, esters and solvates thereof. 5 In another embodiment of this invention are compounds within the scope of Formula I having structural Formula lb wherein the variables are as defined in Formula I: N

R

2 A

R

3

R

4 and the pharmaceutically acceptable salts, esters and solvates thereof. Within each of the embodiments defined by Formulas I, Ia and lb is a class of 10 compounds wherein "A" is selected from the group consisting of phenyl and phenyl mono-substituted at the 3- or 4-position, and particularly wherein the substituent at the 3- or 4-position on the phenyl is selected from -Cl and -F, and more particularly wherein the substituent is -F. In a sub-class of each of these classes are compounds wherein R 2 is selected from the group consisting of -H, -OH , -F, -Cl 3alkyl, -OCH3, and -OC(O)CH3; R 3 is selected from the group consisting of -H, -Cl-6alkyl, -CI-6alkyl 15 substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R 4 is selected from the group consisting of -H, -Cl-6alkyl, -C-6alkyl substituted with one or more of fluoro, -Cl-6alkyl substituted with R 6 and -C3-6cycloalkyl. In another sub-class of each class are compounds wherein R 2 is selected from -H and -OH; R 3 is selected from -CH3, -C2H5, -Cl-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R 4 is selected from -CH3, -CH2CH3, -Cl-2alkyl substituted 20 with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCI-4alkyl. In a further sub-class of each class are compounds wherein R 2 is -OH, R 3 is -CH2CH3 and R 4 is -CF3. Within each of the embodiments defined by Formulas I, la and lb is a class of compounds wherein "A" is selected from the group consisting of phenyl and phenyl mono-substituted at the 3- or 4-position, and particularly wherein the substituent at the 3- or 4-position on the phenyl is 25 selected from -Cl and -F, and more particularly wherein the substituent is -F, and R 1 is selected from COOR 5 , -CONRR5, -SO 2

-CI-

6 -alkyl and -SO 2 NR5R5. In a sub-class of each of these classes are compounds wherein R 2 is selected from the group consisting of -H, -OH, -F, -Cl-3alkyl, -OCH3, and 4 WO 2007/016784 PCT/CA2006/001306 OC(O)CH3; R 3 is selected from the group consisting of -H, -CI-6alkyl, -CI6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R 4 is selected from the group consisting of -H, -C1-6alkyl, -C1-6alkyl substituted with one or more of fluoro, -C1-6alkyl substituted with R 6 and -C3 6cycloalkyl. In another sub-class of each class are compounds wherein R 2 is selected from -H and -OH; 5 R 3 is selected from -CH3, -C2H5, -C1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R 4 is selected from -CH3, -CH2CH3, -CI-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCl-4alkyl. In a further sub-class of each class are compounds wherein R 2 is -OH, R 3 is -CH2CH3 and R 4 is -CF3. Within each of the embodiments defined by Formulas I, Ia and Ib is a class of 10 compounds wherein R' is selected from -COOR', -CONRR 5 , -S0 2

-C

1 6 alkyl and -SO 2

NR

5

R

5 . In a sub class of each of these classes are compounds wherein R 2 is selected from the group consisting of -H, OH , -F, -C1-3alkyl, -OCH3, and -OC(O)CH3; R 3 is selected from the group consisting of -H, -CI 6alkyl, -C1-6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R 4 is selected from the group consisting of -H, -C1-6alkyl, -C-6alkyl substituted with one or more of fluoro, 15 C1-6alkyl substituted with R 6 and -C3-6cycloalkyl. In another sub-class of each class are compounds wherein R 2 is selected from -H and -OH; R 3 is selected from -CH3, -C2H5, -C1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R 4 is selected from -CH3, -CH2CH3, -C1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCl-4alkyl. In a further sub-class of each class are compounds wherein R 2 is -OH, R 3 is -CH2CH3 and R 4 is -CF3. 20 Within each of the embodiments defined by Formulas I, Ia and Ib is a class of compounds wherein R 2 is selected from the group consisting of -H, -OH , -F, -Cl-3alkyl, -OCH3, and OC(O)CH3. In a sub-class of this class are compounds wherein R 2 is selected from -H and -OH. In another sub-class of this class are compounds wherein R 2 is -OH. Within each of the embodiments defined by Formulas I, la and Ib is a class of 25 compounds wherein R 3 is selected from the group consisting of -H, -CI-6alkyl, -CI-6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl. In a sub-class of this class are compounds wherein R 3 is selected from -CH3, -C2HS, -C1-2alkyl substituted with fluoro particularly -CF3 and CF2CF3, and cyclopropyl. In another sub-class of this class are compounds wherein R 3 is -CH2CH3. Within each of the embodiments defined by Formulas I, Ia and lb is a class of 30 compounds wherein R 4 is selected from the group consisting of -H, -C1-6alkyl, -C1-6alkyl substituted with one or more of fluoro, -C1-6alkyl substituted with R 6 and -C3-6cycloalkyl. In a sub-class of this class are compounds wherein R 4 is selected from -CH3, -CH2CH3, -C1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOC1-4alkyl. In another sub-class of this class are compounds wherein R 4 is -CF3. 35 Within each of the embodiments defined by Formulas I, Ia and lb is a class of compounds wherein R 2 is selected from the group consisting of -H, -OH , -F, -C1-3alkyl, -OCH3, and 5 WO 2007/016784 PCT/CA2006/001306 OC(O)CH3; R 3 is selected from the group consisting of -H, -C1-6alkyl, -Cl-6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R 4 is selected from the group consisting of -H, -C1-6alkyl, -C1-6alkyl substituted with one or more of fluoro, -C1-6alkyl substituted with R 6 and -C3 6cycloalkyl. In a sub-class of this class are compounds wherein R 2 is selected from -H and -OH; R 3 is 5 selected from -CH3, -C2H5, -C1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R 4 is selected from -CH3, -CH2CH3, -C1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCI-4alkyl. In another sub-class of this class are compounds wherein R 2 is -OH, R 3 is -CH2CH3 and R 4 is -CF3. Compounds in the Examples and in Tables I and 2 which have mass spectral (MS) data 10 or NMR data associated with them were synthetically prepared. Mass spectra were measured by Electron-Spray Ion mass spectroscopy (ESI) or Atmospheric Pressure Chemical Ionization mass spectroscopy (APCI) as noted herein. Examples of compounds within the scope of Formula Ia include but are not limited to those in Table I as well as pharmaceutically acceptable salts, esters and solvates of the compounds. 15 Table 1 / N, N S N R1

F

3 C A HO CH 2

CH

3 Compound # R1 A Formula Mass Spectral Result Ia-1 -S02CH3 4-fluoro-Ph C 2 2

H

20

F

4

N

3 0 3

S

2 ESI (M+H)* 514.0 Ia-2 -SO2CH3 4-cyclohexyl-Ph Ia-3 -Br 4-fluoro-Ph Ia-4 -S02-NH2 4-fluoro-Ph Ia-5 -S02-NH-t-Bu 4-fluoro-Ph Ia-6 -S02CH3 3-fluoro-Ph C 22

H

20

F

4

N

3 0 3

S

2 ESI (M+H)[ 514.3 Ia-7 -CONH2 4-fluoro-Ph Ia-8 -COOCH3 4-fluoro-Ph Ia-9 -CN 4-fluoro-Ph Ia-10 -CONH2 3-fluoro-Ph Ia-1 I -CN 3-fluoro-Ph 6 WO 2007/016784 PCT/CA2006/001306 Compound # RI A Formula Mass Spectral Result Ia-12 CH 3 Ph C 23

H

2 1

F

3

N

7 OS ESI (M+H)* 500.2 N_ N N' N Ia-13 N N Ph C 23

H

21

F

3

N

7 0S ESI (M+H)* 500.1 N C H3 Ia-14 H Ph C 22

H

17

F

3

N

7 0S ESI (M-H)* 484.3 N-N Ia-15 -CONH2 Ph Ia-16 -Cl Ph C 21 Hs 8

CF

3

N

3 0S ESI (M+H)* 452.2 Ia-17 -S02CH3 Ph C 22

H

21

F

3

N

3 0 3

S

2 ESI (M+H)* 496.0 Ia-18 -CHF2 Ph Ia-19 4-F-Ph Ph C 27

H

22

F

4

N

3 0S ESI (M+H)* 512.0 Ia-20 OH Ph C 27

H

24

F

3

N

4 0S ESI (M+H)* 509.3 Ia-21 N OH 3 Ph Ia-22 N- Ph C 26

H

22

F

3

N

4 0S ESI (M+H)* 494.8 Ia-23 -CN Ph C 22 Hi 8

F

3

N

4 0S ESI (M+H)* 443.2 Ia-24 -Br Ph C 21

H

17 BrF 3

N

3 OS ESI (M+H)* 496.2 Ia-25 -H Ph C 21

H

1 9

F

3

N

3 0S ESI (M+H)* 417.9 Ia-26 -COCH3 Ph Ia-27 -CHOHCH3 Ph Ia-28 -CH2OH Ph Ia-29 -C(CH3)20H Ph Ia-30 -CONHCH3 Ph Ia-31 -CON(CH3)2 Ph C 24

H

24

F

3

N

4 0 2 S ESI (M+H)* 489.3 Ia-32 -COOCH3 Ph Ia-33 -S02CH3 Cl C 16 Hl 6 ClF 3

N

3 0 3

S

2 ESI (M+H)* 454.1 Ia-34 -CN Cl Ia-35 -COOCH3 Cl Ia-36 -S02CH3 3-Me-4-fluoro-Ph C 23

H

22

F

4

N

3 0 3

S

2 APCI (M+H)* 528 7 WO 2007/016784 PCT/CA2006/001306 Compound # RI A Formula Mass Spectral Result Ia-37 -S02CH3 4-CH(CH3)2-Ph C 25

H

2 7

F

3

N

3 0 3

S

2 APCI (M+H)- 538 Ia-38 -S02CH3 3-Me-Ph C 2 3

H

2 3

F

3

N

3 0 3

S

2 APCI (M+H)* 510 Ia-39 -S02CH3 4-Me-Ph C 2 3

H

23

F

3

N

3 0 3

S

2 APCI (M+H)* 510 Ia-40 -S02CH3 3,5-difluoro-Ph C 2 2H, 9

F

5

N

3 0 3

S

2 ESI (M+H)* 532.0 Ia-41 -S02CH3 3-Cl-Ph C 22

H

20 C1F 3

N

3 0 3

S

2 APCI (M+H)* 530 Ia-42 -CONH2 3-methoxy-Ph C 23

H

22

F

3

N

4 0 3 S ESI (M+H) 491.3 Ia-43 -CONH2 4-methoxy-Ph C 2 3

H

22

F

3

N

4 0 3 S ESI (M+H)* 491.4 Ia-44 -CONH2 3-Me-Ph C 23

H

22

F

3

N

4 0 2 S APCI (M+H)* 475 Ia-45 -CONH2 4-Me-Ph C 23

H

22

F

3

N

4 0 2 S APCI (M+H)* 475 Compound Ia-4 'H NMR (500 MHz, Acetone): 6 8.15 (s, 1 H), 8.11 (s, 1 H), 7.62-7.53 (in, 2 H), 7.48 (s, 2 H), 7.29 (t, 2 H), 6.88 (s, 2 H), 5.84 (s, 2 H), 5.43 (s, 1 H), 2.37-2.28 (in, 1 H), 2.11-2.03 (in, 1 H), 0.80 (t, 3 H). 5 Compound Ia-5 'H NMR (500 MHz, Acetone): 6 8.17 (s, 1 H), 8.12 (s, 1 H), 7.70-7.60 (in, 2 H), 7.56 (d, 1 H), 7.47 (d, 1 H), 7.26 (t, 2 H), 6.22 (s, 1 H), 5.87 (s, 2 H), 5.44 (s, 1 H), 2.45-2.30 (in, 1 H), 2.12-2.03 (in, 1 H), 1.17 (s, 9H), 0.84 (t, 3 H). Compound Ia-18 10 'H NMR (500 MHz, Acetone): 6 8.17 (s, 1 H), 8.16 (s, 1 H), 7.71-7.47 (in, 7 H), 7.01 (t, 1 H), 5.88 (s, 2 H), 5.42 (s, 1 H), 2.40-2.37 (in, 1 H), 2.12-2.04 (in, 1 H), 0.83 (t, 3 H). Compound Ia-21 H NMR (500 MHz, Acetone): 6 8.18 (s, 1 H), 8.16 (s, 1 H), 7.75-7.65 (in, 4 H), 7.65-7.45 (in, 3 H), 5.89 (s, 2 H), 5.45 (s, 1 H), 2.40-2.30 (in, 1 H), 2.39 (s, 3 H), 2.12-2.04 (in, 1 H), 0.84 (t, 3 H). 15 Examples of compounds within the scope of Formula lb include but are not limited to those in Table 2 as well as pharmaceutically acceptable salts, esters and solvates of the compounds. Table 2 N NR1 N

F

3 C HO CH 2

CH

3 Compound # RI 8 WO 2007/016784 PCT/CA2006/001306 Compound # RI lb-I -CN Ib-2 -CONH2 Ib-3 -COCH3 lb-4 -CH(OH)CH 3 lb-5 -CH2OH Ib-6 -COOCH 3 lb-7 -COOCH 2

CH

3 Compound Ib-3 'H NMR (500 MHz, Acetone): 6 8.06 (s, 1 H), 7.88 (s, 1 H), 7.62 (d, 1 H), 7.56-7.46 (in, 3 H), 7.40-7.32 (m, 3 H), 7.09 (d,, I H), 5.77 (s, 2 H), 5.42 (s, 1 H), 2.55 (s, 3 H), 2.38-2.27 (in, 1 H), 2.05 (s, I H), 0.83 5 (t, 3 H). Compound Ib-4 'H NMR (500 MHz, Acetone): ( 8.06 (s, 1 H), 7.67(s,1H), 7.60 (in, 2 H), 7.42-7.56 (in, 3 H), 7.15 (d, 1 H), 7.02 (d,1H), 6.65 (s, 1 H), 5.77 (s, 2 H), 5.42 (s, 1 H), 4.82 (m,1H), 4.19 (d, 1 H), 2.30 (m, 1 H), 2.08 2.05 (m, I H), 1.42 (d, 3 H), 0.83 (t, 3 H). 10 Compound Ib-5 'H NMR (500 MHz, Acetone): ( 8.06 (s, I H), 7.70 (s, I H), 7.62 (m, 2 H), 7.52 (in, 3 H), 7.20(d, 1 H), 7.12 (d, I H), 6.68 (d, I H), 5.77 (s, 2 H), 5.42 (s, I H), 4.62(d, 2 H), 4.18 (t, 1 H), 2.38-2.27 (in, I H), 2.08 (s, I H), 0.82 (t, 3 H). Compound Ib-7 15 'H NMR (500 MHz, Acetone): ( 8.06 (s, 1 H), 7.85 (s, 1 H), 7.56-7.46 (in, 3 H), 7.45(s, 1 H), 7.40-7.32 (in, 3 H), 7.10 (d, 1 H), 5.78 (s, 2 H), 5.42 (s, 1 H), 4.18 (q, 2 H), 2.35 (in, I H), 2.08 (m, 1 H), 1.18 (t, 3 H), 0.83 (t, 3 H). The compounds of this invention, including compounds referenced as those of "Formula 20 I," "Formula Ia," "Formula Ib," or any other generic structural formulas used herein to describe the compounds of this invention, are intended to encompass compounds falling within the scope of each of these structural formulas including pharmaceutically acceptable salts, esters and solvates thereof where such salts, esters and solvates are possible. Herein, the term "pharmaceutically acceptable salts" refers to non-toxic salts of the 25 compounds employed in this invention which can generally be prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed 9 WO 2007/016784 PCT/CA2006/001306 from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p chlorobenzyl-2-pyrrolidine-l'-yl-methylbenzimidazole, diethylamine, piperazine, morpholine, 2,4,4 trimethyl-2-pentamine and tris(hydroxymethyl)aminomethane. When the compound of the present 5 invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, 10 maleic, phosphoric, sulfuric, and tartaric acids. Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of this invention, pharmaceutically acceptable esters of carboxylic acid derivatives can be employed. Examples of pharmaceutically acceptable esters include, but are not limited to, -Cl-4 alkyl (e.g., methyl, ethyl), pivaloyloxymethyl and -C1-4 alkyl substituted with phenyl, dimethylamino and 15 acetylamino. Acyl derivatives of alcohol groups, such as -0-acetyl, -0-pivaloyl, -O-benzoyl and -0 aminoacyl can similarly be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics of pharmaceutical compounds for use as pro-drugs or sustained-release or formulations. Some of the compounds described herein contain one or more asymmetric centers 20 and can thus occur as racemates, racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. The present invention includes all such possible isomers in racemic, racemic mixture and resolved, enantiomerically pure forms and the pharmaceutically acceptable salts thereof. Furthermore, some of the crystalline forms of compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. 25 In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates and hydrates are likewise encompassed within the scope of this invention. Some of the compounds described herein contain olefinic double bonds. The invention includes both E and Z geometric isomers. Compounds of this invention may be separated into their individual diastereoisomers by, 30 e.g., fractional crystallization from suitable solvents, e.g., methylene chloride/hexanes or EtOAc/hexanes, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, any stereoisomer of a compound of this invention may be obtained by stereospecific 35 synthesis using optically pure starting materials or reagents of known absolute configuration. 10 WO 2007/016784 PCT/CA2006/001306 As used herein "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl, isohexyl and the like. "Cycloalkyl" means a 5 monocyclic saturated carbocyclic ring, having the specified number of carbon atoms, e.g., 3, 4, 5 or 6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C2-6alkenyl" as used herein, refers to a straight or branched 2-6 carbon chain with at least one carbon-carbon double bond. Examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1 -propenyl, 2-butenyl, 2-methyl-2-butenyl, 10 and the like. The term "C5-7 cycloalkenyl" as used herein means a non-aromatic monocyclic ring having from 5 to 7 carbon atoms in the ring with at least one carbon-carbon double bond. The terms "halo" or "halogen" are meant to include fluoro, chloro, bromo and iodo, unless otherwise noted. Fluoro and chloro are preferred, and fluoro is most preferred. The term "optionally" substituted means "unsubstituted or substituted," and therefore, 15 the generic structural formulas described herein encompass compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent. For example, the phrase "tetrazolyl optionally substituted with methyl" encompasses unsubstituted tetrazolyl and tetrazolyl substituted with methyl. Each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when RI is -SO2NR 5

R

5 , R 5 is independently selected at 20 each occurrence and each R5 can be the same or different. Use of the term "substituted" is intended to encompass mono- and poly-substitution on the specified moiety, unless otherwise specified. A mono-substituted moiety has one substituent, while a poly-susbtituted moiety has more than one substituent wherein each carbon atom, as well as heteroatom such as nitrogen if present, that is available for substitution in the moiety may independently be 25 unsubstituted, mono- or poly-substituted such that it results in the creation of a stable structure. For example, "-C -6alkyl optionally substituted with fluoro" includes but is not limited to -CH3, -CH2F, -CHF2, -CF3 and -CH2CF3. The ability of the compounds of this invention to inhibit biosynthesis of the leukotrienes makes them useful for preventing or reversing the symptoms induced by the leukotrienes in a human 30 subject. Accordingly, this invention provides a method for preventing the synthesis, the action, or the release of leukotrienes in a mammal which comprises administering to said mammal a 5-LO inhibitory effective amount of a compound of this invention. Such 5-LO inhibitory activity can be measured using the Human 5-Lipoxygenase Enzyme Assay and 5-Lipoxygenase Human Whole Blood Assay described herein. Since leukotrienes are potent inflammatory mediators, also provided is method of treating an 35 inflammatory condition in a mammal which comprises administering a therapeutically effective amount of a compound of this invention to a mammal in need of such treatment. 11 WO 2007/016784 PCT/CA2006/001306 The inhibition of the mammalian biosynthesis of leukotrienes also indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent or ameliorate atherosclerosis in mammals, and especially in humans. Therefore, the compounds of this invention can be used for the treatment of atherosclerosis comprising administering a therapeutically effective amount 5 of a compound of this invention to a patient in need of such treatment. The method of this invention serves to prevent or slow new atherosclerotic lesion or plaque formation, and to prevent or slow progression of existing lesions or plaques, as well as to cause regression of existing lesions or plaques. Accordingly, one aspect of this invention encompassed within the scope of treatment of atherosclerosis involves a method for halting or slowing the progression of 10 atherosclerosis, including halting or slowing atherosclerotic plaque progression, comprising administering a therapeutically effective amount of a compound of this invention to a patient in need of such treatment. This method includes halting or slowing progression of atherosclerotic plaques existing at the time the instant treatment is begun (i.e., "existing atherosclerotic plaques"), as well as halting or slowing formation of new atherosclerotic plaques in patients with atherosclerosis. 15 Another aspect of this invention encompassed within the scope of treatment of atherosclerosis involves a method for effecting regression of atherosclerosis, including effecting regression of atherosclerotic plaques existing at the time the instant treatment is begun, comprising administering a therapeutically effective amount of a compound of this invention to a patient in need of such treatment. 20 Also provided is a method comprising administering to a patient who has atherosclerosis a compound of this invention with the objective of preventing or reducing the risk of atherosclerotic plaque rupture. Therefore, this invention provides a method for preventing or reducing the risk of atherosclerotic plaque rupture comprising administering a prophylactically effective amount of a compound of this invention to a patient having atherosclerotic plaque. 25 This invention also involves a method for preventing or reducing the risk of developing atherosclerosis, comprising administering a prophylactically effective amount of a compound of this invention to a patient in need of such treatment, including. for example, a patient who is at risk for developing atherosclerosis. Atherosclerosis is characterized by the deposition of atheromatous plaques containing 30 cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries. Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and 35 peripheral vessel disease including erectile dysfunction, are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis" and "atherosclerotic disease." 12 WO 2007/016784 PCT/CA2006/001306 A compound of the instant invention may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease (CHD) event, a cerebrovascular event, and/or intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization 5 procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. The term "atherosclerotic disease event" as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal 10 atherosclerotic disease events are those for whom the potential for recurrence of such an event exists. Accordingly, the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of a compound of this invention to a patient in need of such treatment, such as a patient who is at risk for such an event. The patient in need of such treatment may 15 already have atherosclerotic disease at the time of administration, or may be at risk for developing it. This invention also provides a method for treating, preventing, or ameliorating angina and/or myocardial ischemia, comprising administering a therapeutically or prophylactically effective amount, as appropriate, of a compound of this invention to a patient in need of such treatment. Additionally, the activity of the instant compounds as leukotriene biosynthesis inhibitors 20 makes them useful for treating, preventing, or ameliorating:1) pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skin disorders such as atopic eczema, and the like, 6) cardiovascular disorders such hypertension, platelet aggregation and the like, 7) renal 25 insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiology and 8) migraine or cluster headache, 9) ocular conditions such as uveitis, 10) hepatitis resulting from chemical, immunological or infectious stimuli, 11) trauma or shock states such as burn injuries, endotoxemia and the like, 12) allograft rejection, 13) prevention of side effects associated with therapeutic administration of cytokines such as Interleukin II and tumor necrosis factor, 14) chronic lung 30 diseases such as cystic fibrosis, bronchitis and other small- and large-airway diseases, 15) cholecystitis, 16) multiple sclerosis, 17) proliferation of myoblastic leukemia cells, 18) pulmonary fibrosis, 19) respiratory syncytial virus, 20) acne and 21) sleep apnea. Particularly, the compounds of this invention can be administered to patients, including adult and pediatric patients, for the prophylaxis of asthma and for chronic treatment of asthma. 35 The compounds of this invention can be administered to patients, including adult and pediatric patients, for the treatment of asthma: (1) as an alternative to low-dose inhaled corticosteroids (ICS) for 13 WO 2007/016784 PCT/CA2006/001306 patients with mild persistent asthma, (2) as concomitant therapy with low-dose inhaled corticosteroids (ICS) for patients with mild persistent asthma, or (3) as concomitant therapy in patients with persistent asthma who are inadequately controlled on inhaled corticosteroids (ICS) or on combined ICS/long-acting beta-agonist (LABA) therapy. The compounds can be used for treatment of asthmatic patients including, 5 but not limited to, steroid resistant/non-responder asthmatics, asthmatics for whom leukotriene modifiers have previously failed, smoking asthmatics, and aspirin sensitive asthmatics. The compounds can be administered to patients to: (1) improve FEVI (Forced Expitory Volume in one minute), (2) improve morning and evening PEF (Peak Expitory flow), (3) reduce beta agonist use (measured by puffs/day), (4) reduce inhaled / systemic steroid use. (5) improve daytime 10 asthma symptoms, (6) reduce number of nocturnal awakenings, 7) improve asthma control days, (8) reduce number of asthma exacerbations, wherein an exacerbation is defined as: requiring systemic steroid, an emergency room visit, hospitalization, an unscheduled asthma related doctor visit, decrease in A.M. PEF by >20% or A.M. PEF <180 1/min, increased SABA (short-acting beta-agonist) use >70% from baseline (minimum increase 2 puffs), or increased symptom score of >50%, (9) reduce the 15 number of asthma attacks (measured as % of days with at least one attack over a specified period of total days), wherein the attack is one that requires systemic steroid use, an emergency room visit, hospitalization, or an unscheduled asthma related doctor visit, (10) reduce the number of acute asthma attacks, (11) reduce blood and sputum eosinophils, and/or (12) prevent and treat EIB (exercised induced bronchoconstriction). 20 Additionally, the compounds of this invention can be administered to patients, including adult and pediatric patients, for the relief of symptoms of allergic rhinitis, including seasonal allergic rhinitis. Thus, the compounds of the present invention may also be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis; erosive esophagitis; diarrhea; 25 cerebral spasm; premature labor; spontaneous abortion; dysmenorrhea; ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl 4 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure. Leukotriene biosynthesis inhibitors also act as inhibitors of tumor 30 metastasis and exhibit cytoprotective action. The cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non steroidal anti-inflammatory drugs on the gastrointestinal tract, animal studies show that cytoprotective 35 compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions, and the like. Two assays can be used to measure cytoprotective 14 WO 2007/016784 PCT/CA2006/001306 ability. These assays are: (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140,684. In particular, the compounds of the invention would be useful to reduce the gastric erosion caused by co-administration of a cyclooxygenase-2 selective inhibitor such as rofecoxib (VIOXX@), etoricoxib (ARCOXIATM), and celecoxib (CELEBREX@) and low-dose aspirin. 5 In addition, the compounds of this invention can also be used for the treatment of chronic obstructive pulmonary disease (COPD). As described in S. Kilfeather, Chest, 2002, vol 121, 197, airway neutrophilia in COPD patients is believed to be a contributing source of inflammation and is associated with airway remodeling. The presence of neutrophils is mediated in part by LTB4, and treatment with the instant compounds could be used to reduce neutrophilic inflammation in patients with COPD and reduce 10 the rate of COPD exacerbations. In particular, the compounds of this invention could be used for daily, preferably once-daily, maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema. The term "patient" includes mammals, especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the patient 15 includes both self-administration and administration to the patient by another person. The patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by inhibition of leukotriene biosynthesis. The term "therapeutically effective amount" is intended to mean that amount of a drug or 20 pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The term "prophylactically effective amount" is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. 25 The magnitude of prophylactic or therapeutic dose of a compound of this invention will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. It will also vary according to the age, weight and response of the individual patient. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment to slow progression of existing atherosclerosis, and a 30 prophylactically effective amount, e.g., for prevention of an atherosclerotic disease event or formation of new lesions. In general, the daily dose range for anti-asthmatic, anti-inflammatory, anti-allergic or anti atherosclerotic use and generally, uses other than cytoprotection, lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to I mg per kg, in single or divided doses. On the other hand, it may be necessary to 35 use dosages outside these limits in some cases. 15 WO 2007/016784 PCT/CA2006/001306 In the case where an oral composition is employed, a suitable daily dosage range for anti asthmatic, anti-inflammatory, anti-allergic or anti-atherosclerotic use is, e.g., from about 0.01 mg to about 100 mg of a compound of this invention per kg of body weight per day, and preferably from about 0.1 mg to about 10 mg per kg. For cytoprotective use a suitable daily dosage range is from 0.1 mg to 5 about 100 mg, preferably from about 1 mg to about 100 mg, and more preferably from about 10 mg to about 100 mg, of a compound of this invention per kg of body weight per day. For use where a composition for intravenous administration is employed, a suitable daily dosage range for anti-asthmatic, anti-inflammatory, anti-atherosclerotic or anti-allergic use is from about 0.00 1 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of this invention per kg 10 of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of this invention per kg of body weight per day. For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of this invention in an acceptable ophthalmic formulation may be used. 15 The exact amount of a compound of this invention to be used as a cytoprotective agent will depend on, inter alia, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e.g., gastrointestinal ulcerations vs. nephrotic necrosis), and on the nature of the causative agent. An example of the use of a compound of this invention in avoiding future damage would be co-administration of a compound of this invention with an NSAID that might 20 otherwise cause such damage (for example, indomethacin). For such use, the compound of this invention is administered from 30 minutes prior up to 30 minutes after administration of the NSAID. Preferably it is administered prior to or simultaneously with the NSAID, (for example, in a combination dosage form). The pharmaceutical compositions of the present invention comprise a compound of this invention as an active ingredient and a pharmaceutically acceptable carrier and optionally other 25 therapeutic ingredients. Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. For use in treating or preventing atherosclerosis and related disease events, oral formulation is 30 preferred. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active 35 ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. 16 WO 2007/016784 PCT/CA2006/001306 For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for 5 inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of this invention in suitable propellants, such as fluorocarbons or hydrocarbons. Suitable topical formulations of a compound of this invention include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like. In practical use, the compounds of this invention can be combined as the active 10 ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the 15 case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage 20 unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. In addition to the common dosage forms set out above, the compounds of this invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; and 5,366,738 the 25 disclosures of which are incorporated herein by reference. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such 30 compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, 35 optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally 17 WO 2007/016784 PCT/CA2006/001306 mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet, cachet or capsule contains from about 1 mg to about 500 mg of the active ingredient, for example but not limited to 10 mg, 20mg, 30mg, 40mg, 50 mg and 75mg. The 5 following are examples of representative pharmaceutical dosage forms for the compounds of this invention: Injectable Suspension (I.M.) mg/ml Compound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection to a total volume of 1 ml Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 Providone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500 Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5 Magnesium Stearate 1.5 600 10 Aerosol Per canister Compound of Formula I 24 mg Lecithin, NF Liquid Concentrate 1.2 mg Trichlorofluoromethane, NF 4.025 gm Dichlorodifluoromethane, NF 12.15 gm 18 WO 2007/016784 PCT/CA2006/001306 The instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a compound of this invention with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a compound 5 of this invention with a pharmaceutically acceptable carrier. A therapeutically effective amount of a compound of this invention can be used for the preparation of a medicament useful for treating or preventing any of the medical conditions described herein, in dosage amounts described herein. For example, a compound of this invention can be used for the preparation of a medicament useful for preventing or reducing the risk of developing atherosclerotic 10 disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event. Additionally, a compound of this invention can be used for the preparation of a medicament useful for the treatment of asthma, allergies and allergic conditions, inflammation, COPD or erosive gastritis. The medicament comprised of a compound of this invention may also be prepared with 15 one or more additional active agents, such as those described below. One or more additional active agents may be used in combination with the compounds of this invention in a single dosage formulation, or the active agents of the combination may be administered to the patient in separate dosage formulations, which allows for concurrent or sequential administration of the active agents. Unless otherwise specified, reference herein to compounds of this 20 invention being used in combination with other active agents or used as part of combination therapy or the like encompasses both a single pharmaceutical composition comprised of a compound of this invention with one or more additional active agents, as well as a pharmaceutical composition comprised of a compound of this invention administered as part of a combination therapy with one or more other separately formulated active agents. 25 In addition to the compounds of this invention, the pharmaceutical compositions of the present invention can also contain other active agents (i.e., ingredients) and the pharmaceutical compositions comprised of a compound of this invention may be used for combination therapy with one or more other separately formulated active agents, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. 30 The weight ratio of the compound of this invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of this invention is combined with an NSAID the weight ratio of the compound of said compound to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of this invention and other active 35 ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. 19 WO 2007/016784 PCT/CA2006/001306 NSAIDs can be characterized into five groups: (1) propionic acid derivatives; (2) acetic acid derivatives; (3) fenamic acid derivatives; (4)oxicams; and (5)biphenylcarboxylic acid derivatives; or a pharmaceutically acceptable salt thereof. The propionic acid derivatives which may be used comprise: alminoprofen, 5 benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, and tioxaprofen. Structurally related propionic acid derivatives having similar analgesic and anti inflammatory properties are also intended to be included in this group. Thus, "propionic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a 10 free -CH(CH 3 )COOH or -CH2CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO-Na+ or -CH2CH2COO-Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system. The acetic acid derivatives which may be used comprise: indomethacin, which is a preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, 15 furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac. Structually related acetic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. Thus, "acetic acid derivatives" as defined herein are non narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH2COO-Na+), typically 20 attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system. The fenamic acid derivatives which may be used comprise: flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid. Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. Thus, "fenamic acid derivatives" as defined herein are non-narcotic 25 analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure: aR NHO CO2 H which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO-Na+. The biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and 30 flufenisal. Structurally related biphenyl-carboxylic acid derivatives having similar analgesic and anti inflammatory properties are also intended to be encompassed by this group. Thus, "biphenylcarboxylic 20 WO 2007/016784 PCT/CA2006/001306 acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure: COOH which can bear a variety of substituents and in which the free -COOH group can be in the form of a 5 pharmaceutically acceptable salt group, e.g., -COO-Na+. The oxicams which can be used in the present invention comprise: isoxicam, piroxicam, sudoxicam and tenoxican. Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. Thus, "oxicams" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which have the general formula: OH O N NHR

CH

3 10 (0)2 wherein R is an aryl or heteroaryl ring system. The following NSAIDs may also be used: amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine, beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, 15 di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone, nabumetone, nictindole, 20 nimesulide, orpanoxin, oxametacin, oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaramide HCI, tiflamizole, timegadine, tolpadol, tryptamid, and ufenamate. The following NSAIDs, designated by company code number (see e.g., Pharmaprojects), may also be used: 480156S, AA861, AD 1590, AFP802, AFP860, A177B, AP504, 25 AU8001, BPPC, BW540C, CHINOIN 127, CN1OO, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ON03144, PR823, PV102, PV108, R830, 21 WO 2007/016784 PCT/CA2006/001306 RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1 indancarboxylic acid), TVX2706, U60257, UR2301, and WY41770. Finally, NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid and the phenylbutazones, and pharmaceutically acceptable salts thereof. 5 In addition to indomethacin, other preferred NSAIDs are acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac, and tolmetin. Pharmaceutical compositions and combinations comprising compounds of this invention may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in EP 138,481 (April 24,1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP 140,709 10 (May 8, 1985), which are hereby incorporated herein by reference. The compounds of this invention may also be used in combination with leukotriene antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984) which are hereby incorporated herein by reference and others known in the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification 15 No. 2,058,785 (April 15, 1981), which are hereby incorporated herein by reference. Pharmaceutical compositions and combinations comprising compounds of this invention may also contain as the second active ingredient, or be used in combination therapy with, prostaglandin antagonists such as those disclosed in EP 11,067 (May 28, 1980) or thromboxane antagonists such as those disclosed in U.S. Pat. 4,237,160. They may also contain or be used with histidine decarboxylase 20 inhibitors such as a-fluoromethylhistidine, described in U.S. Pat. 4,325,961. The compounds of this invention may also be advantageously combined with an HI or 112-receptor antagonist, such as for instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine, terfenadine and like compounds, such as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceutical 25 compositions may also contain or be used in combination with a K+/H+ ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of this invention may also be usefully combined with most cell stabilizing agents, such as 1,3-bis(2-carboxychromon-5-yloxy)-2 hydroxypropane and related compounds described in British Patent Specifications 1,144,905 and 1,144,906. Another useful pharmaceutical composition comprises compounds of this invention in 30 combination with serotonin antagonists such as methysergide, the serotonin antagonists described in Nature, 316, 126-131 (1985), and the like. Each of the references referred to in this paragraph is hereby incorporated herein by reference. Other advantageous pharmaceutical combinations comprise the compounds of this invention in combination with anti-cholinergies such as ipratropium bromide and tiotropium, 35 bronchodilators such as the beta agonist salbutamol, metaproterenol, terbutaline, fenoterol, salmeterol, formoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllinate and 22 WO 2007/016784 PCT/CA2006/001306 enprofylline, the calcium antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipine, etc., and the corticosteroids, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, and the like. Particularly, for the prophylaxis and treatment of asthma, compounds of this invention 5 can be used in combination with orally inhaled corticosteroids, such as beclomethasone (e.g. QVAR@ Inhalation Aerosol), budesonide (e.g. Pulmicort Respules), flunisolide (e.g., AEROBID@ and AEROBID@-M Inhaler System), fluticasone (e.g., FLOVENT@ DISKUS@ inhalation powder, FLOVENT@ HFA Inhalation Aerosol), mometasone (e.g., ASMANEX@ TWISTHALER@), and triamcinolone (e.g., AZMACORT@ Inhalation Aerosol), and also with inhaled corticosteroid/LABA 10 products such as fluticasone propionate/salmeterol (e.g., ADVAIR DISKUS@). The instant compounds could also be used in combination with leukotriene receptor antagonists such as montelukast (e.g., SINGULAIR@); phosphodiesterase 4 (PDE4) inhibitors such as roflumilast, N-Cyclopropyl-1-[3-(1 oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and the compounds disclosed in PCT Publication W02003/018579; and Very Late Antigen 4 (VLA4) inhibitors 15 such as the compounds disclosed in U.S. Pat. No. 6,229,011, particularly R411 (N-(2-Chloro-6 methylbenzoyl)-4-[(2,6- dichlorobenzoyl) amino]-L-phenylalanine-2-(diethylamino)ethyl ester which is an ester pro-drug of the active moiety, N-(2-chloro-6-methylbenzoyl)-4- [(2,6-dichlorobenzoyl)amino]-L phenylalanine), and the compounds disclosed in PCT publication W02006/023396. Furthermore, additional active agents such as anti-atherosclerotic agents, anti-diabetes 20 agents, anti-obesity agents and agents used for the treatment of metabolic syndrome, may be used in combination with the compounds of this invention. The additional active agent or agents can be lipid altering compounds such as HMG-CoA reductase inhibitors, or agents having other pharmaceutical activities, or agents that have both lipid-altering effects and other pharmaceutical activities. Examples of HMG-CoA reductase inhibitors useful for this purpose include statins in their lactonized or dihydroxy 25 open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (MEVACOR@; see US Patent No. 4,342,767); simvastatin (ZOCOR@; see US Patent No. 4,444,784); dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof (PRAVACHOL@; see US Patent No. 4,346,227); fluvastatin particularly the sodium salt thereof (LESCOL@; see US Patent No. 5,354,772); atorvastatin, 30 particularly the calcium salt thereof (LIPITOR@; see US Patent No. 5,273,995); pitavastatin also referred to as NK-104 (see PCT international publication number WO 97/23200); and rosuvastatin (CRESTOR®; see US Patent No. 5,260,440). Additional active agents which may be employed in combination with a compound of this invention include but are not limited to HMG-CoA synthase inhibitors; cholesterol absorption inhibitors such as ezetimibe (ZETIA®) which is 1-(4-fluorophenyl)-3(R)-[3(S)-(4 35 fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, described in U.S. Patent No.'s Re. 37721 and 5,846,966 as well as a fixed dose combination of ezetimibe and simvastatin 23 WO 2007/016784 PCT/CA2006/001306 (VYTORIN@); HDL-raising agents such as cholesterol ester transfer protein (CETP) inhibitors, for example JTT-705 (Japan Tobacco Company) and torcetrapib (Pfizer); squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as 5 well as dual inhibitors of ACATI and -2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein Ilb/IIla fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPARy) agonists including the compounds commonly referred to as glitazones for example troglitazone, pioglitazone and rosiglitazone and, 10 including those compounds included within the structural class known as thiazolidinediones as well as those PPARy agonists outside the thiazolidinedione structural class; PPARc agonists such as clofibrate, fenofibrate including micronized fenofibrate and gemfibrozil; PPAR dual aX/y agonists such as muraglitazar; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCI salt; vitamin B12 (also known as cyanocobalamin); folic acid or a pharmaceutically 15 acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; anti-oxidant vitamins such as vitamin C and E and beta carotene; beta-blockers; angiotensin II antagonists such as losartan and losartan with hydrochlorothiazide; angiotensin converting enzyme inhibitors such as enalapril and captopril; calcium channel blockers such as nifedipine and diltiazam; endothelian antagonists; agents that enhance ABC 1 gene expression; FXR and LXR ligands including both inhibitors 20 and agonists; bisphosphonate compounds such as alendronate sodium; and cyclooxygenase-2 inhibitors such as rofecoxib, etoricoxib and celecoxib. Anti-obesity agents can be employed in combination with a compound of this invention including, but not limited to, sibutramine, orlistat, topiramate, naltrexone, bupriopion, phentermine, and phentermine/topiramate combination (QNEXA@); NPY5 antagonists; Acetyl-CoA Carboxylase-l and -2 (ACC) inhibitors; MCHlR antagonists; and CB1 antagonists/inverse 25 agonists such as those described in W003/077847 and W005/000809. Additional anti-diabetes agents which may be employed in combination with a compound of this invention include but are not limited to DPP-4 (dipeptidylpeptidase-4) inhibitors such as sitagliptin (JANUVIA@) and vildagliptin (GALVUS@); sulfonylureas e.g., chlorpropamide, tolazamide, glyburide, glipizide, and glimepiride; biguanides, e.g., metformin; alpha-glucosidase inhibitors e.g., acarbose and miglitol; meglitinides e.g., repaglinide; 30 glucagon-receptor agonists; and glucokinase activators. Compounds of this invention can be tested using the following assays to determine their mammalian leukotriene biosynthesis inhibiting activity. Representative tested compounds of this invention were shown to be inhibitors of leukotriene biosynthesis, with most having an IC 5 0 less than or equal to 4pM in the Human 5-Lipoxygenase Enzyme Assay, described below, with preferred compounds 35 tested in this assay having an IC50 less than or equal to 0.100 pM. The representative tested compounds were also shown to have activity as 5-LO inhibitors in the 5-Lipoxygenase Human Whole Blood Assay, 24 WO 2007/016784 PCT/CA2006/001306 described below, with most having an IC50 less than or equal to 5pM, and preferred compounds having an IC50 of less than or equal to 0.500 pM. Human 5-Lipoxygenase Enzyme Assay The activity of 5-lipoxygenase was measured using a spectrophotometric assay and 5 recombinant human 5-lipoxygenase as a source of enzyme. Human 5-lipoxygenase was purified from Sf9 cells infected with the recombinant baculovirus rvH5LO (8-1) containing the coding sequence for human 5-lipoxygenase as described by Percival et al., (Eur. J. Biochem 210, 109-117, 1992). The enzymatic activity was measured using a spectrophotometric assay from the optimal rate of conjugated diene formation (absorbance at 238 nm) using the procedure described in Riendeau et al. (Biochem. 10 Pharmacol. 38, 2313-2321, 1989) with minor modifications. The incubation mixture contained 25 mM potassium phosphate, pH 7.5, 0.1 mM EDTA, 0.3 mM CaCl 2 , 24 ptg/ml phosphatidylcholine, 0.1 mM ATP, 0.5 mM DTT, 20 pM arachidonic acid (2 pl from a 100-fold solution in ethanol), inhibitor (2 ptl aliquot from a 100-fold solution in DMSO) and an aliquot of purified 5-lipoxygenase. Reactions were initiated by the addition of the purified 5-lipoxygenase and the rate of conjugated diene production was 15 followed for 5 minutes at room temperature. The reaction was performed in a Costar UV plate (Cat. # 3635) and the absorbance changes at 238 nm were recorded with a Molecular Devices UV/VIS 96 well spectrophotometer (Spectra Max 190) using SOFTmax PRO software. Enzymatic activity was calculated from the optimal rate of the reaction by a linear fit of the increase in absorbance at 238 nm over 36 seconds. When the rate of diene formation is low (<0.01 Absorbance Unit/min) the linear fit is 20 performed over 180 seconds. The results are expressed as percentage of inhibition of the reaction rate relative to controls (typically between 0.00 1-0.005 Absorbance Unit/min) containing the DMSO vehicle. 25 WO 2007/016784 PCT/CA2006/001306 5-Lipoxygenase Human Whole Blood Assay Fresh blood is collected in heparinized tubes by venipuncture from volunteers with consent. The subjects have no apparent inflammatory conditions and have not taken any nonsteroidal anti-inflammatory drugs for at least 4 days prior to blood collection. 250 il aliquots of blood are pre 5 incubated with either 0.5 il of vehicle (DMSO) or test compound at 37 0 C for 15 minutes. This is followed by incubation of the blood with 5 pil of either plasma or a 1.25 mM solution of the calcium ionophore A23187 (Sigma, St Louis, Mo, USA) in plasma. The latter solution is prepared by centrifuging approximately 10 mls of blood from each donor and collecting the plasma. A 5OmM stock solution of A23187 in DMSO is diluted 40-fold in plasma to yield a 1.25 mM working solution. Five pls of this 10 working solution is added to each appropriate 250pl-aliquot of blood of the same donor from which the plasma was prepared to give a final concentration of 25 pM of A23187. The blood is then incubated at 37 0 C for 30 minutes. Following incubation, the blood is centrifuged at 1500g at 4 0 C for 10 minutes. Plasma is then collected from all samples and stored at 4'C until time of enzyme immunosorbent assay (EIA). All samples are tested for the production of leukotriene B4 (LTB4) using the LTB4 EIA kit from 15 Assay Designs (Ann Arbor, MI, USA) according to the manufacturer's instructions. Compounds of this invention may be prepared employing general synthetic procedures known in the art. The synthetic routes outlined in the following methods, reaction schemes and Examples are provided for illustrative purposes. 20 Some abbreviations used herein include: Ac = acyl; AIBN = 2,2'-azobisisobutyronitrile; Bz or bz = benzyl; CAN = cerium ammonium nitrate; CDI = 1, '-carbonyl diimidazole; cy cyclohexyl; DAST = diethylaminosulfur trifluoride; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC = 1,3 dicyclohexylcarbodiimide; DCM = dichloromethane; DIBAL = diisobutylaluminum hydride; DIPEA N,N-diisopropylethylamine; DMAP = 4-(dimethylamino)pyridine; DME ethylene glycol dimethyl 25 ether; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; eq = equivalent; EtOH = ethanol; Et20 diethyl ether; Et3N = triethylamine; EtOAc = ethyl acetate; h = hours; 1 H NMR is proton nuclear magnetic resonance; HOAc acetic acid; KHMDS = potassium bis(trimethylsilyl)amide; LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; m-CPBA (or MCPBA) = 3-chloroperoxybenzoic acid; MsCI = methanesulphonyl chloride; MeOH = methanol; NBS = N-bromosuccinimide; NCS = N 30 chlorosuccinimide; NMO = 4-methylmorpholine N-oxide; NMP = 1-methyl-2-pyrrolidinone; OTf = trifluoromethanesulfonate = triflate; 0-THP = 0-tetrahydropyran-2-yl; Ph = phenyl; PPTS = pyridinium p-toluenesulfonate; rt = room temperature; TBAF = tetrabutylammonium fluoride; Tf 2 O = triflic anhydride (also known as trifluoromethanesulfonic anhydride); TFA trifluoro acetic acid; TFAA trifluoracetic anhydride; THF = tetrahydrofuran; TMSCN = trimethylsilyl cyanide. 35 Synthetic procedures used to prepare the compounds of this invention are outlined in Schemes 1-12. The variable "-X" depicted in some of the structures in the Schemes represents one or 26 WO 2007/016784 PCT/CA2006/001306 two substituents on the phenyl ring to which X is attached, wherein the substituents are as defined within the scope of structural Formula I. The term "ligand" used in some of the Schemes below represents the compound: Cys ligand: Cy 5 As shown in Scheme 2, starting material 3-chloro-6-methyl-1 -benzothiophene-2-carbonyl chloride (see T. Higa and A.J. Krubsack, J. Org. Chem, 1976, 41, 3399-3403) is treated with methanol to generate the corresponding methyl ester. Benzylic bromination followed by azide displacement generates the azide intermediate. Copper iodide induced cyclization of the thus formed benzylic azide with 3-(trifluoromethyl)pent- 1 -yn-3-ol (prepared following the reactions outlined in Scheme 1) generates 10 the corresponding triazole. The final aromatic ring is introduced via a Suzuki cross-coupling reaction; the solvent is preferably 1,4-dioxane:water at a ratio of 100:1-1.5, and the reaction is preferably quenched with 2N NaOH when using any intermediate that is stable to NaOH. The methyl ester can be saponified using standard conditions and, in turn, can be coupled with a variety of alcohols or amines using standard protocols to form the corresponding esters or amides. The intermediate carboxylic acid 15 can also be decarboxylated by treatment with copper in refluxing quinoline. The methyl ester substituent of the benzothiophene can be modified into a number of other groups as illustrated in Schemes 3 and 4. For example, the ester can be reduced to the primary alcohol by treatment with DIBAL as highlighted in Scheme 3. This alcohol can be oxidized to the corresponding aldehyde through the action of MnO 2 . Treatment with organometallic reagents, such as 20 methyl lithium, generate the secondary alcohols with in turn can be oxidized by MnO 2 to the corresponding ketone. In addition, as illustrated in Scheme 4, the methyl ester of the 3 chlorobenzothiophene intermediate can be reduced as described above with DIBAL and the resulting alcohol oxidized to the corresponding aldehyde. This aldehyde can be converted into a nitrile by first treating with hydroxylamine followed by CDI. Suzuki cross-coupling of the 2-cyano-3 25 chlorobenzothiophene with a variety of boronic acids can be accomplished following standards methods. Unsubstituted and substituted phenylborinic acids are commercially available or can prepared from the corresponding bromide following standard literature procedures such as that described in Byrant, J.A. et. al., J. Org. Chem. 1990, 55, 4622-4634. The nitrile can be treated with tributyltin azide to provide the corresponding tetrazolyl analog. 30 Scheme 5 outlines an alternative route to the synthesis of the benzothiophene ring system starting from commercially available 4-bromo-2-fluorobenzaldehyde. After formation of the 27 WO 2007/016784 PCT/CA2006/001306 benzothiophene ring system, standard carbonylation conditions convert the aryl bromide into the corresponding methyl ester. Selective bromination of the benzothiophene employing bromine in acetic acid yields the 2-bromobenzothiophene analog. Having introduced the 2-bromo substituent the methyl ester is in turn converted into the triazole ring system following standard conditions as outlined in 5 Scheme 5. Scheme 6 highlights a number of additional transformations of the benzothiophenes that can be accomplished. Scheme 6a illustrates treatment of the methyl ester with excess methyl lithium to generate the corresponding tertiary alcohol. Schemes 6b and 6c highlight two approaches to generate the primary amide by either treating the methyl ester with pre-mixed NH4CI-AlCl3 or, alternatively, 10 oxidation of the corresponding nitrile. The 2-bromobenzothiophene can be converted into a methyl sulphone, as shown in Scheme 6d, by treatment with methyl sulfinic acid sodium salt and Cul in hot DMF. Additional alkyl sulphone adducts can be generated by using the appropriate sulfinic acid sodium salt coupling partner (alkyl-SO2Na). The bromide intermediate can be coupled with a variety of boronic acids or organostannanes to generate the corresponding 2 -aryl or heterocyclic adducts (see Scheme 11). 15 Also, the bromide can be converted into sulphonamides by first generating the 2-lithio species by treatment with BuLi, quenching this anion with sulfur dioxide, chlorination with NCS and finally treatment with an amine. Schemes 6e and 6f illustrate that the sulfur atom of the benzothiophene ring can be oxidized to the corresponding sulfoxide or sulphone by treatment with either hydrogen peroxide or MCPBA, respectively. 20 The synthesis of 2-sulfonamide benzothiophenes is illustrated in Scheme 7. Hydrolysis of the acid chloride followed by decarboxylation generates the 2-hydro-benzothiophene. This intermediate can be deprotonated at the 2-position with the aid of a strong, base such as BuLi, and the resulting anion reacted with sulphur dioxide. Treatment of the resulting sulfinic acid lithium salt with NCS generates the sulphonyl chloride which, in turn, is reacted with an amine, such as tBuNH2, to 25 furnish the corresponding sulphonamide. Cross-coupling of the 3-chlorobenzothiophene and introduction of the triazole ring is carried out as described above. The tert-butyl group can be readily removed by treatment with TFA in dichloromethane to provide the corresponding primary sulphonamide. As shown in Scheme 8, treatment of 2-formylbenzothiophene with a fluorinating agent such as (MeOEt)2NSF3 generates the corresponding difluoride. Elaboration of this intermediate to 30 introduce the triazole unit was performed as previously described. Scheme 9 illustrates the preparation of 2-oxadiazolebenzothiophene analogs. Treatment of the acid chloride, prepared from the corresponding carboxylic acid by standard methods, is reacted with N-hydroxyethanimidamide and the resulting adduct is then heated in pyridine to generate the corresponding oxadiazole ring system. This intermediate can be further elaborated to introduce the 35 triazole unit as previously described. 28 WO 2007/016784 PCT/CA2006/001306 As shown in Scheme 10, chlorination of a benzothiophene, such as methyl 3-phenyl-1 benzothiophene-6-carboxylate, provides the corresponding 2-chloro derivative. The methyl ester can be elaborated to introduce the triazole ring system as previously described. Scheme 12 illustrates the synthesis of 5-LO inhibitors of Formula lb. The phenyl group 5 was N-coupled to methyl 5-methyl-IH-indole-2-carboxylate using standard methods. Benzylic bromination followed by azide displacement provides the corresponding benzylic azide. Exposure of this azide with an alkyne in the presence of Cul generates the triazole ring system. Saponification of the methyl ester provides the carboxylic acid which, under standard conditions, can be transformed into a carboxamide or the corresponding nitrile. Alternatively, the acid can be transformed into a variety of 10 esters or amides by following procedures outlined above in the previous schemes. Scheme 13 illustrates a alternate synthesis of compounds of formula Ia wherein RI is -COOC -6alkyl, -COOC3-6cycloalkyl or -CONR 5

R

5 which is preferred for chiral synthesis of the final products. Starting material 3-chloro-6-methyl-1-benzothiophene-2-carbonyl chloride 2 is made according to the procedure in T. Higa and A.J. Krubsack, J. Org. Chem, 1976, 41, 3399-3403. Compound 2 can be 15 esterified to 3 with an alkyl alcohol, for example methanol, using DMAP at 0 0 C under an inert (e.g. nitrogen) atmosphere using a procedure like that described in Example 1, step 1. In a similar fashion, amide forms of 3 can also be prepared by adding a mixture of an appropriate amine (4 eq, for example NH2C1.-6alkyl) in CH2Cl2 to the carbonyl chloride 2 (leq) under an inert (e.g. nitrogen) atmosphere at 0*C, followed by quenching with water, extraction and solvent evaporation. The aromatic ring is 20 introduced via a Suzuki cross-coupling reaction as described in Scheme 2 and similar to the procedure of Example 1, step 6, to make 4. When preparing 4, it is preferable to use 1,4-dioxane:water at a ratio of 100:1-1.5 as solvent. The reaction is preferably quenched by the addition of 2N NaOH, which serves to remove the excess boronic acid. Benzylic bromination of 4 followed by azide displacement generates the azide 25 intermediate 6, using procedures similar to that described in Scheme 2 and Example 1, steps 2 and 3. The benzylic bromination of 4 (1 eq) can be performed using solvents such as carbon tetrachloride or benzene, employing about 1.1 eq. of NBS, and from about 0.05 to about 0.3 eq. of benzoylperoxide in a single portion or two portions. The azide displacement can be performed using about 1 to 2 eq of sodium azide. 30 The coupled product 10 can be prepared by treating a mixture of 6 (1 eq) and 9 (1.1 eq) at rt in a solvent such as THF under an inert (e.g., nitrogen) atmosphere with DIPEA (5 eq) and copper(I) iodide (1.5 eq) followed by isolation of the product. The product is isolated using standard techniques, e.g., by removing the solvent, re-dissolving in EtOAc and filtering through a silica gel pad. The product can be further purified using flash chromatography such as the COMBI-FLASH@ system (an automated flash 35 chromatography system from Teledyne Isco) as described in many of the examples below. 29 WO 2007/016784 PCT/CA2006/001306 The nitrobenzoyl group is removed by treatment of 10 with base such as sodium hydroxide to obtain 11. For example, sodium hydroxide (2M, 1.7 eq.) is added dropwise to a solution of 10 (1 eq) in 1:1 THF/MeOH at rt followed by stirring until the reaction is complete, then quenching by adding EtOAc and water. The product is isolated using standard techniques, e.g., extracting with 5 EtOAc, washing the combined organic layers with water, a saturated NaHCO3 solution, then brine, drying over a drying agent such as Na2SO 4 , then concentrating the resulting material. The product can be further purified using flash chromatography such as the COMBI-FLASH@ system. For compound 11 where -C(O)Rla = an alkyl ester, additional modifications to the alkyl ester group can be performed as noted in the Schemes above. When -C(O)Rla is an alkyl-substituted amide, such as -NH-t-butyl, the alkyl 10 group can be readily removed by treatment with TFA with or without additional solvent to provide the corresponding primary amine. Scheme 14 illustrates a method for making racemic 1-ethyl-i -(trifluoromethyl)prop-2-yn I-yl 4-nitrobenzoate 8 which can be chromatographically resolved to obtain 9. The chiral intermediate 9 can be used for the chiral synthesis of compounds of this invention as described in Scheme 13. 15 Compound 8 was prepared by adding n-butyllithium (1 eq) to a stirring mixture of ethynyl(trimethyl)silane (1.2 eq) in THF using standard conditions, e.g., at -78'C under an inert (e.g., nitrogen) atmosphere, followed by stirring at -78'C for about an hour and then at rt for about an hour. Then 1,1,1-trifluorobutan-2-one (1 eq) was added dropwise at -78 0 C, the resulting mixture was stirred at rt for about 2 hours, then cooled down again to -78 'C before addition of 4-nitrobenzoyl chloride (1.3 20 eq). The reaction was quenched with saturated NaHCO3 solution, followed by a standard work-up, i.e., separating the organic layer, extracting the aqueous phase with EtOAc, washing the combined organic layers with brine, then drying over Na2SO4. After filtration, tetrabutylammonium fluoride 1 M in THF (1.2 eq) was added dropwise, the resulting mixture was stirred at rt for 2 hours and the reaction was quenched by the addition of brine. The organic layer was separated and the aqueous phase was extracted 25 with EtOAc. The organic layers were combined, washed with brine, and dried over Na2SO4. After evaporation, the crude was purified by COMBI-FLASH@ chromatography system with toluene to afford compound 8. Chiral resolution of 8 was performed using a CHIRALCEL OD@ HPLC column 5cm x 50cm (from Daicel Chemical Industries, Ltd.), eluting with 10% i-PrOH/Hexanes at a flow rate of 70 30 mL/min, at 320 nM; compound 8 was dissolved in pure 20% i-PrOH/CHCl3 ("stock solution") for application to the column. Preferably, just before each injection into the HPLC, the stock solution is slowly mixed with hexane in a ratio of 1:4 stock solution:hexane. Retention time is about 10-12 min for the 1st enantiomer off the column (fraction A) and about 18-20 min for the desired enantiomer 9 (fraction B). 30 WO 2007/016784 PCT/CA2006/001306 For compounds of formula I containing the 1-hydroxy-1-(trifluoromethyl)propyl- moiety attached to the triazolyl ring in the structure, the (S)-stereoisomer of 1-hydroxy-1 (trifluoromethyl)propyl- is preferred: NsN, HO

CF

3 5 Scheme 1 1. n-BuLi/THF

TMS

2. CF 3 HO CF 3 0 3. TBAF/THF 31 WO 2007/016784 PCT/CA2006/001306 Scheme 2 SS 0 MeOH/DMAP s 0NBSICC1 4 /(BzO)2/80O 00 ci CH 2 Ci 2 0 Br NaN 3 /DMF N 3 I / + 0 0 HO CF 3 N- HO,. B OH Huni' N /N HngsbaselTHF HO /0,.

CF

3 Ci Pd(OAC) 2 /iigafld N-s 0 1 ,4-dioxaneIH 2 OlCsF HO 0- / Py

CF

3 /\ ligand: Cy ~ ~X 32 WO 2007/016784 PCT/CA2006/001306 Scheme 3 N- N S o NNN S OH N DIBAL/THF/ HO 0 -8 HO -78 TC

CF

3

CF

3 x NN S OH 1. MnO 2

/CH

2 Ci 2 N MnO 2

/CH

2

CI

2 2. MeLi/THF/-78 OC HO

CF

3 x N N S 0 NX HO

CF

3 x Scheme 4 NNs 0 1. DIBAL/THF/- 78 C N N 2. MnO 2

/CH

2

CI

2 HO O3. NH 2 OH HCI/NaOAc/EtOH

CF

3 CI 4. CDI/CH 2 Cl -NSHO B OH Pd(OAc) 2 /ligand HO CF3 + 1,4-dioxane/H 2 0/CsF HO

CF

3 x 33 WO 2007/016784 PCT/CA2006/001306 Scheme 5 -Br Mg 1. Br S Br F /THF H X O 2. MnO 2

/CH

2

CI

2 3. HSCH 2 COOMe/Cs 2

CO

3 /THF/reflux 4. NaOH/THF/reflux X 5. Cu/quinoline/140 0 C 0 0 CO/PdCl 2 (dppf)-CH 2 Cl2/ S Br2/AcOH/ O MeOH/DMSO/50 C CH 2

CI

2 Br

N

3 X 1. DIBAL/THF/-78 0C S 2. MsCI/Et 3

N/CH

2 CI2/-30 0 C B r Cul/Hunig's base/ 3. NaN 3 /DMF + HO CF 3 THF X N' N S F Br

F

3 E~ x 34 WO 2007/016784 PCT/CA2006/001306 Scheme 6 N S 6a: N- S 0N N" N MeUIlTHF/ N N M 3 OH HO -780 C CF 3

CF

3 XX xx N- NH 2 6b: N- N N N N N NH 4 CI/Me3Ail N O 0 HO HO C 6

H

6

CF

3 CF 3 xx 6c: N- S Na2CO3-H202/ ,N N

NH

2 N' NN -- N N O HO / Acetone/H20 HO HO

CF

3

CF

3 x x 0 6d: N s MeSO 2 Na/Cul/ N N O / N Br / NMP/150 0 C HO

CF

3 CF 3 xx x 0 it N N s N 2 N OH / 6e N~ ' N 2

H

2 0 2 ,TFA N N H HO HO/ Ch 2

CI

2 F

CF

3 \ X - . x 0 0 N__ ,N' N N MPBA NO0 HO HOH C2 3

CF

3 CCF3 x x 35 WO 2007/016784 PCT/CA2006/001306 Scheme 7 COIl C Cu, qunoine

THF-H

2 0 140 0 C C1 C1 S 1. nBuLi, THF, -78 -C 1. NCS, CH 2

C

2 , 0 0 C

SO

2 Li 2. S0 2 (g), excess 2. tBuNH 2 C1 CI S 0 S 1 Pd(OAc) 2 /ligand S 0 S-Ht~ S-NHtBu 0 1,4-dioxane/H 2 0/CsF / N C0 4-FC 6

H

4

B(OH)

2 0 F

N

3 0 OH 1. NBS, Bz 2 O, CC1 4 SNHtBu 3 0 2. NaN 3 THF, DIPEA, CuI F N >S / N 11 N,'N s N N O N S-NHtBu N S-NH 2 TFA HO CH 2

CI

2 HO

F

3 C F 3 C F F 36 WO 2007/016784 PCT/CA2006/001306 Scheme 8 Br F 1. PhMgBr, THF Br F HSCH2CO2Me, Cs2CO3 CHO 2. Dess Martin reagent O THF, 50 *C Br s Br s 0

CO

2 Me iBu 2 AJ, THF, -60 C MnO 2 , CH 2

CI

2 Br S F

(CH

3 0CH 2

CH

2

)

2

NSF

3 / CO, Pd(dppf)C1 2 F

CH

2

C

2 DMSO, MeOH, Et 3 N 0 MeO 1. iBu 2 AIH, CH 2

CI

2

N

3 S F F F 2. MsCI, Et 3 N, CH 2

CI

2 3. NaN 3 OH N N S F 3 F ,_ HO THF, DIPEA, Cul F 3 C 37 WO 2007/016784 PCT/CA2006/001306 Scheme 9 Br sBrs Br CO 2 H oxalyl chloride COOi

CH

2

CI

2 Br s N 1. HONHC(NH)CH 3 \10- N CO, Pd(dppf)C 2 , MeOH

CH

2

CI

2 , DMAP DMSO, Et 3 N 2. pyr, reflux o

N

3 MeO OS N 1. iBu 2 AH, CH 2

C

2 s N 2. MsCI, Et 3 N, CH 2 CI2 ON 3. NaN 3 OH - CF 3 ,NN S N 0_ N THF, DIPEA, Cul HO

F

3 C 38 WO 2007/016784 PCT/CA2006/001306 Scheme 10 O 0 MeO S S02Cl 2 MeO S Cl

CH

2 Cl 2 OH

N

3 S-

C

3 / CF, 1. iBuAIH, CH 2 CI2 Cl 2. MsCl, Et 3 N, CH 2 Ci 2 THF, DIPEA, Cul 3. NaN 3 N Cl HO

F

3 C Scheme 11 N S Pd2(dba) 3 , S -N N'N Ph 3 As, N N N BrDMF N HO H FHC SnBu 3 HO F3C F3C N 39 WO 2007/016784 PCT/CA2006/001306 Scheme 12

C

6

H

5 1, dioxane,

CO

2 Me NBS Br CO 2 Me

CO

2 Me Cul, K 3 P0 4 , N _____ H trans-1,2- CC14 diaminocyclohexane / C

N

3 ~OH NN CO 2 Me N3 CO 2 Me - CF 3 N N NaN 3 N HO/ DMF Cul, THF, DIPEA F 3 C NaOH N'N ' CO 2 H 1) oxalyl chloride, CH 2

CI

2 THF, MeOH, H 2 0 HO 2) NH 3

F

3 C N-N ~N-N" N CONH 2 TFFA NN HF dioxane, pyridine HO 40 WO 2007/016784 PCT/CA2006/001306 Scheme 13 ~ SRC RaH OH ' / 0 SOC12 7- 0 Ria = -OCl- 6 alkyI, -OC 3

-

6 cycIoalkyl I2 or -NR 5

R

5 Rila 7'/ 0 NBS 7- 0 Cl x _ B(0H) 2 x 3 N Br 0sR~ i 2 7 F NaN 3 0 5 6 X 'F/ N~S RC 3 / N I RI N~N 7- 0 NaOH * N / 0 10 O 0 11011 Sch~emel 4 0CF 3 0 2 N

CF

3 Chiral HPLC 0 2 N

CF

3 - , C 3 0 2 N 1 ~ 0 Chiralcel OD 0 7- C8 80 9 0 0 41 WO 2007/016784 PCT/CA2006/001306 EXAMPLE 1 Methyl 6-({4-[I-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-3-phenyl-1 benzothiophene-2-carboxylate N N S 0 0 OH F F\ F 5 Step 1: methyl 3-chloro-6-methyl-1-benzothiophene-2-carboxylate C / To a mixture of methanol (1.582 mL, 39.1 mmol, 1.2 eq) and DMAP (4.78 g, 39.1 mmol, 1.2 eq) in 10 CH 2 Cl 2 (50 mL, 0.652M) stirred at 0 'C under an atmosphere of nitrogen, 3-chloro-6-methyl-1 benzothiophene-2-carbonyl chloride (8 g, 32.6 mmol) was added portionwise. The resulting mixture was stirred at rt for 3 h. The reaction was quenched by passing through a silica gel pad and washed with 20% EtOAC/hexane. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min, to 15% EtOAC/hexane in 20 min, to 20% EtOAC/hexane in 15 20 min) to afford the titled compound. 'H NMR 8 (ppm)(Acetone): 7.88 (1 H, d), 7.84 (1 H, s), 7.45 (1 H, d), 3.95 (3 H, s), 2.53 (3 H, s). Step 2: methyl 6-(bromomethyl)-3-chloro-1-benzothiophene-2-carboxylate Br 0 0 C1 20 To a mixture of methyl 3-chloro-6-methyl-1-benzothiophene-2-carboxylate (3.3 g, 13.71 mmol) in carbon tetrachloride (80 mL, 0.171 M) stirred at reflux under an atmosphere of nitrogen, pre-mixed NBS, 99% (2.68 g, 15.08 mmol, 1.1 eq) and benzoylperoxide (166 mg, 0.686 mmol, 0.05 eq) were added. The resulting mixture was stirred at reflux forl h. The solvent was removed by evaporation and the crude thus obtained was re-dissolved in EtOAc and the mixture was treated by the addition of water. The organic 25 layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were 42 WO 2007/016784 PCT/CA2006/001306 combined, washed with brine, dried over Na2SO 4 . The solvent was removed by evaporation to afford crude the titled compound. Step 3: methyl 6-(azidomethyl)-3-chloro-1-benzothiophene-2-carboxylate

N

3 0 5 CI To a mixture of methyl 6-(bromomethyl)-3-chloro-1-benzothiophene-2-carboxylate (4.2 g, 17.45 mmol) in DMF(150 mL, 0.1 16M) stirred at rt under an atmosphere of nitrogen, sodium azide (854 mg, 13.14 mmol, 1 eq) was added. The resulting mixture was stirred at rt for1 h. The reaction was quenched by the 10 addition of water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 20% EtOAC/hexane in 20 min, to 35% EtOAC/hexane in 20 min) to afford the title compound). 'H NMR 6 (ppm)(Acetone): 8.12 (1 H, s), 8.05 (1 H, d, J = 8.3 Hz), 7.66 (1 H, d, J = 8.4 Hz), 4.71 (2 H, s), 15 3.98 (3 H, s). Step 4: 3-(trifluoromethyl)pent-1-yn-3-ol HO

CF

3 To a mixture of trimethylsilylacetylene (19.4 g, 198 mmol, 1 eq) in THF (500 mL, 0.396M) stirred at 78'C under an atmosphere of nitrogen, n-butyllithium 1.6M hexanes (124 mL, 198 mmol, 1 eq) was 20 added. The resulting mixture was stirred at -78'C fori h. Then 1,1,1-trifluoro-2-butanone (25.0 g, 198 mmol, 1 eq) was added dropwise at -78'C and the resulting mixture was stirred at rt for 2 h. The reaction was quenched by the addition of a saturated NaHCO3 solution at 0 C . The organic layer was separated and the aqueous phase was extracted with ether/hexane (1:1). The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by careful distillation. The crude thus 25 obtained was re-dissolved in THF (200 mL, 1 M) under atmosphere of nitrogen at 0 0 C, tetrabutylammonium fluoride IM THF (238 mL, 238 mmol, 1.2 eq) was added dropwise. The resulting mixture was stirred at rt for 2 h. The reaction was quenched by the addition of brine. The organic layer was separated and the aqueous phase was extracted with hexane. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by careful distillation and residue was 30 purified by distillation (collect the fraction between 100-140 C) to afford the titled compound. 'H NMR 6 (ppm)(Acetone): 5.86 (1 H, s), 3.27 (1 H, s), 1.91-1.81 (2 H, in), 1.15 (3 H, t). 43 WO 2007/016784 PCT/CA2006/001306 Step 5: methyl 3-chloro-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carboxylate N N N 0 OH CI F F F 5 To a mixture of methyl 6-(azidomethyl)-3-chloro-1-benzothiophene-2-carboxylate (3.4 g, 12.07 mmol) and 3-(trifluoromethyl)pent-1-yn-3-ol (1.84 g, 12.07 mmol, 1 eq) in THF (80 mL, 0.15 IM) stirred at rt under an atmosphere of nitrogen, was added N,N-diisopropylethylamine(1O.53 mL, 60.3 mmol, 5 eq) and copper(I) iodide (2.299 g, 12.07 mmol, I eq. The resulting mixture was stirred at rt for over night. After evaporation, the crude thus obtained was re-dissolved in EtOAc and filtered through a layer of 10 silica gel. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 45%EtOAC/hexane in 20 min, to 70% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR 6 (ppm)(Acetone): 8.18 (1 H, s), 8.08 (1 H, s), 8.03 (1 H, d), 7.62 (1 H, d), 5.90 (2 H, s), 5.45 (1 H, s), 3.97 (3 H, s), 2.37-2.30 (1 H, m), 2.09 (1 H, m), 0.84 (3 H, t). 15 Step 6: Methyl 6-({4-[I-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-yl}methyl)-3-phenyl-1 benzothiophene-2-carboxylate To a mixture of methyl 3-chloro-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-IH-1,2,3-triazol-1 yl}methyl)-1-benzothiophene-2-carboxylate (900 mg, 2.074 mmol), phenylboronic acid (0.758 g, 6.22 mmol, 3 eq), 2-(dicyclohexylphosphino-2'-(N,N-dimethyl-amino)bipheny (73.6 mg, 0.187 mmol, 0.09 20 eq), palladium(II) acetate (27.8 mg, 0.124 mmol, 0.06 eq), and cesium fluoride (1.89 g, 12.44 mmol, 6 eq) under an atmosphere of nitrogen, 1,4-Dioxane-water (101 mL, 100:1, 0.021M) was added. The resulting mixture was stirred at rt for1 day. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude 25 thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.16 (s, 1 H), 8.09 (s, 1 H), 7.55-7.49 (m, 3 H), 7.38 (dd, I H),5.87 (s, 2 H), 5.45 (s, I H), 3.75 (s, 3 H), 2.36-2.29 (in, I H), 2.08 (m, I H), 0.83 (t, 3 H). 30 EXAMPLE 2 1,1,1 -trifluoro-2-( 1- { [2-(hydroxymethyl)-3-phenyl-1-benzothien-6-yl]methy1 } -IH-1,2,3-triazol-4 yl)butan-2-ol 44 WO 2007/016784 PCT/CA2006/001306 N N- N Z5 S H W- / OH F F F To a mixture of Methyl 6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-IH-1,2,3-triazol-1-yl}methyl)-3 5 phenyl-1-benzothiophene-2-carboxylate (180 mg, 0.379 mmol) in THF (5 mL, 0.076M) stirred at -78'C under an atmosphere of nitrogen, DIBAL-H (1.011 mL, 1.516 mmol, 4 eq) was added dropwise. The resulting mixture was stirred at -78'C for10 min and rt for 1 h. The reaction was quenched by the addition of silica gel and water, filtration through a pad of silica gel. The solvent was removed by evaporation and the crude thus obtained was purified by triturating with toluene and hexane to afford the 10 titled compound. 1 H NMR (500 MHz, Acetone): 6 8.12 (s, 1 H), 8.02 (s, 1 H), 7.58-7.54 (in, 3 H), 7.48 (in, 3 H), 7.40 (dd, I H), 5.82 (s, 2 H), 5.43 (s, 1 H), 4.85 (d, 2 H), 4.75 (t, 1 H), 2.36-2.29 (in, 1 H), 2.08 (in, 1 H), 0.83 (t, 3 H). EXAMPLE 3 15 6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-IH-1,2,3-triazol-1-yl}methyl)-3-phenyl-1-benzothiophene 2-carbaldehyde NN S /O OH F F F 20 To a mixture of 1,1,1-trifluoro-2-(1-{[2-(hydroxymethyl)-3-phenyl-1-benzothien-6-yl]methyl}-1H-1,2,3 triazol-4-yl)butan-2-ol (150 mg, 0.335 mmol) in CH 2 Cl 2 (50 mL, 0.0067M) stirred at rt under an atmosphere of nitrogen, manganese(IV) oxide (437 mg, 5.03 mmol, 15 eq) was added. The resulting mixture was stirred at rt for 2 h. The reaction was quenched by passing through a silica gel pad and 25 washed with 50% EtOAC/hexane. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 50 % EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. (137 mg, Yield = 92 %). 'H NMR (500 MHz, Acetone): 6 9.95 (s, 1 H), 8.18 (s, 1 H), 8.15 (s, I H), 7.84 (d, 1 H), 7.69-7.61 (in, 5 H), 7.52 (d, 1 H), 5.89 (s, 2 H), 5.46 (s, 1 H), 2.34 (in, 1 H), 2.08 (s, I H), 0.84 (t, 3 H). 45 WO 2007/016784 PCT/CA2006/001306 EXAMPLE 4 1,1,1-trifluoro-2-(1-{{2-(1 -hydroxyethyl)-3-phenyl-1-benzothien-6-yl]methyl -IH-1,2,3-triazol-4 yl)butan-2-ol 5 N N "S OH N OH F F F To a mixture of 1,1,1-trifluoro-2-(1-{[2-(hydroxymethyl)-3-phenyl-1-benzothien-6-yl]methyl}-lH-1,2,3 triazol-4-yl)butan-2-ol (137 mg, 0.308 mmol) in THF (5 mL, 0.062M) stirred at -78'C under an atmosphere of nitrogen, methyllithium (660 uL, 0.924 mmol, 3 eq) was added. The resulting mixture was 10 stirred at -78'C for15 min. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to % EtOAC/hexane in 20 min, to % EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.10 (s, I H), 15 8.02 (s, 1 H), 7.56 (t, 2 H), 7.50-7.44 (in, 5 H), 7.38 (dd, 1 H), 5.81 (s, 2 H), 5.44 (s, 1 H), 5.21-5.17 (in, I H), 4.77 (d, 1 H), 2.32 (in, I H), 2.09 (m, 1 H), 1.47 (d, 3 H), 0.83 (t, 3 H). EXAMPLE 5 1-[6-({4-[1 -hydroxy-1 -(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-3-phenyl-1-benzothien-2 20 yllethanone ' N S 0 OH F F F To a mixture of 1,1,1-trifluoro-2-(1-{{2-(1-hydroxyethyl)-3-phenyl-1-benzothien-6-yl]methyl}-1H-1,2,3 triazol-4-yl)butan-2-ol (52 mg, 0.113 mmol) in CH 2 Cl2 (20 mL, 0.0056M) stirred at rt under an 25 atmosphere of nitrogen, manganese(IV) oxide (147 mg, 1.695 mmol, 15 eq) was added. The resulting mixture was stirred at rt for 3 h. The reaction was quenched by passing through a silica gel pad and washed with 50% EtOAC/hexane. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min, to 40% EtOAC/hexane in 20 min, to 60% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): & 8.16 (s, 1 H), 46 WO 2007/016784 PCT/CA2006/001306 8.06 (s, I H), 7.64-7.57 (in, 3 H), 7.52 (d, 2 H), 7.42 (s, 2 H), 5.86 (s, 2 H), 5.46 (s, 1 H), 2.36-2.29 (in, 1 H), 2.10 (in, 4 H), 0.83 (t, 3 H). EXAMPLE 6 5 6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-IH-1,2,3-triazol-1-yl }methyl)-3-phenyl-1-benzothiophene 2-carboxamide N S 0 N N

NH

2 OH F F F To a mixture of ammonium chloride (225 mg, 4.21 mmol, 10 eq) in benzene (10 mL, 0.042M) stirred at 10 0 0 C under an atmosphere of nitrogen, trimethylaluminum 2M heptane (2.105 mL, 4.21 mmol, 10 eq) was added. The resulting mixture was stirred at rt fori h. Then methyl 6-({4-[ 1 -hydroxy- 1 (trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-3-phenyl-1-benzothiophene-2-carboxylate (200 mg, 0.421 mmol) was added at rt and the resulting mixture was stirred at 60'C for 2 days.The reaction was quenched by the addition of silica gel and water, then filtered through a layer of silica gel, and 15 washed with 80% of EtOAc/hexane.The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 40% EtOAC/hexane in 20 min, to 60% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.15 (s, 1 H), 8.08 (s, I H), 7.66-7.58 (in, 3 H), 7.54 (d, 2 H), 7.43 (in, 2 H), 6.83 (br s, 1 H), 5.89 ( br s, I H), 5.85 (s, 2 H), 5.44 (s, I H), 2.34-2.30 (in, 1 H), 2.08 (m, 1 H), 0.83 (t, 3 H). 20 EXAMPLE 7 6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-N-methyl-3-phenyl-1 benzothiophene-2-carboxamide N

SHN

OH F F\ 25 F To a mixture of methyl amine/THF (1.05 mL, 2.1 mmol, 10 eq) in THF (5 mL, 0.042M) stirred at rt under an atmosphere of nitrogen, trimethylaluminum 2M heptane (1.05 mL, 2.1 mmol, 10 eq) was added. The resulting mixture was stirred at rt for15 min. Then methyl 6-({4-[1-hydroxy-l (trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-3-phenyl-1-benzothiophene-2-carboxylate (100 30 mg, 0.21 mmol) was added at rt and the resulting mixture was stirred at 60'C for 1 day. The reaction 47 WO 2007/016784 PCT/CA2006/001306 was quenched by the addition of SILICA GEL at rt followed by the addition of 4 drops of water. The resulting mixture was filtered through a silica gel pad and washed with 70% EtOAC/hexaneThe solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ ( pure hexane for 4 min , to 60% EtOAC/hexane in 15 min, to 75% EtOAC/hexane in 15 min) to afford the 5 titled compound. 'H NMR (500 MHz, Acetone): 6 8.14 (s, 1 H), 8.07 (s, 1 H), 7.62-7.48 (in, 6 H), 7.42 (d, I H), 6.43 (s, 1 H), 5.84 (s, 2 H), 5.45 (s, 1 H), 2.71 (d, 3 H), 2.37-2.29 (in, 1 H), 2.09 (in, 1 H), 0.83 (t, 3 H). EXAMPLE 8 10 1,1,1-trifluoro-2-(1-{[2-(1-hydroxy-1-methylethyl)-3-phenyl-1-benzothien-6-yl]methyl}-1H-1,2,3-triazol 4-yl)butan-2-ol N OH F F F To a mixture of Methyl 6-({4-[I-hydroxy-1-(trifluoromethyl)propyl]-IH-1,2,3-triazol-1-yl4methyl)-3 15 phenyl-1-benzothiophene-2-carboxylate (66 mg, 0.139 mmol) in THF (5 mL, 0.028M) stirred at -78'C under an atmosphere of nitrogen, methyllithium (261 uL, 0.417 mmol, 3 eq) was added dropwise. The resulting mixture was stirred at -78'C for10 min. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over. The solvent was removed by evaporation and the crude 20 thus obtained was purified by COMBI-FLASH@ ( pure hexane for 4 min , to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.08 (s, I H), 7.96 (s, 1 H), 7.55-7.49 (m, 3 H), 7.34 (d, 2 H), 7.30 (d, I H), 7.02 (d, I H), 5.78 (s, 2 H), 5.42 (s, 1 H), 4.87 (s, 1 H), 2.31 (m, 1 H), 2.11 (in, I H), 1.45 (s, 6 H), 0.82 (t, 3 H). 25 EXAMPLE 9 1 methyl 3-(4-fluorophenyl)-6-({4-[I1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl4methyl) 1 -benzothiophene-2-carboxylate NN S 0 OH F F F F 48 WO 2007/016784 PCT/CA2006/001306 To a mixture of methyl 3-chloro-6-({4-[I-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1 yl 4methyl)-1-benzothiophene-2-carboxylate (900 mg, 2.074 mmol), (4-fluorophenyl)boronic acid (0.87 g, 6.22 mmol, 3 eq) (2902 mg, 20.74 mmol, 10 eq), 2-(dicyclohexylphosphino-2'-(N,N-dimethyl amino)biphenyl (73.6 mg, 0.187 mmol, 0.09 eq), palladium(II) acetate (27.8 mg, 0.124 mmol, 0.06 eq), 5 and cesium fluoride (1.89 g, 12.44 mmol, 6 eq) under an atmosphere of nitrogen, 1,4-Dioxane-water (101 mL, 100:1, 0.021M) was added. The resulting mixture was stirred at rt forl day. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ ( pure hexane for 10 4 min , to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.13 (s, 1 H), 8.07 (s, 1 H), 7.52-7.42 (in, 3 H), 7.28-7.24 (m, 3 H), 5.87 (s, 2 H), 5.46 (s, 1 H), 3.77 (s, 3 H), 2.37-2.30 (in, 1 H), 2.09 (in, 1 H), 0.83 (t, 3 H). EXAMPLE 10 15 3-(3-fluorophenyl)-6-({4-[I-hydroxy-1-(trifluoromethyl)propyl]-1lH-1 ,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carbonitrile -N' N N S -N OH F F F F 20 Step 1: 2-(1-{[3-chloro-2-(hydroxymethyl)-1-benzothien-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1 trifluorobutan-2-ol N' N OH N / OH C F F F To a mixture of methyl 3-chloro-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1 yl}methyl)-1-benzothiophene-2-carboxylate (2.4 g, 5.53 mmol) in THF (100 mL, 0.055M) stirred at 25 78'C under an atmosphere of nitrogen, DIBAL-H (11.06 mL, 16.59 mmol, 3 eq) was added. The resulting mixture was stirred at rt forl h. The reaction was quenched by the addition of silica gel and water, then filtered through a layer of silica gel, and washed with 70% of EtOAc/hexane. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the 30 titled compound. 'H NMR (500 MHz, Acetone): 6 8.12 (s, I H), 8.01 (s, 1 H), 7.80 (d, 1 H), 7.53 (d, 1 49 WO 2007/016784 PCT/CA2006/001306 H), 5.84 (s, 2 H), 5.67 (d, 1 H), 5.45 (s, 1 H), 4.96 (d, 2 H), 2.41-2.29 (in, 1 H), 2.10 (in, I H), 0.86 (t, 3 H). Step 2: 3-chloro-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carbonitrile 5 N N N N _N OH CI F F F To a mixture of 2-(1- {[3 -chloro-2-(hydroxymethyl)- 1 -benzothien-6-yl]methyl } -1H- 1,2,3 -triazol-4-yl) 1,1,1-trifluorobutan-2-ol (2.2 g, 5.42 mmol) in CH 2

CI

2 (50 mL, 0.000108M) stirred at rt under an 10 atmosphere of nitrogen, manganese(IV) oxide (7.04 g, 81 mmol, 15 eq) was added. The resulting mixture was stirred at rt for3 h. The reaction was quenched by passing through a silica gel pad and washed with 50% EtOAC/hexane. After evaporation the crude thus obtained was re-dissolved in EtOH-THF (65 mL, 3.3:1, 0.07M) and hydroxylamine hydrochloride (1151 mg, 16.56 mmol, 3 eq) and sodium acetate (1.334 g, 16.26 mmol, 3 eq) were added. The resulting mixture was stirred at rt for 3 h and quenched by the 15 addition of a saturated NaHCO 3 solution. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . After evaporation, the crude thus obtained was re-dissolved in CH 2 Cl 2 (50 mL) under atmosphere of nitrogen at rt, CDI (1,1'-carbonyldiimidazole) (1.054 g, 6.5 mmol, 1.2 eq)was added. The resulting mixture was stirred at rt for overnight. The solvent was removed by evaporation and the crude thus obtained was 20 purified by COMBI-FLASH@ (pure hexane for 4 min, to 50 % EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the desired the titled compound. 1 H NMR (500 MHz, Acetone): 6 8.20 (s, 1 H), 8.19 (s, 1 H), 8.05 (d, 1 H), 7.70 (t, 1 H), 5.93 (s, 2 H), 5.46 (s, 1 H), 2.38-2.30 (in, 1 H), 2.09 (d, 1 H), 0.83 (t, 3 H). Step 3: 3-(3-fluorophenyl)-6-({4-[I-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl) 25 1 -benzothiophene-2-carbonitrile To a mixture of 3-chloro-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carbonitrile (400 mg, 0.998 mmol), (3-fluorophenyl)boronic acid (1396 mg, 9.98 mmol, 10 eq) , 2-(dicyclohexylphosphino-2'-(N,N-dimethyl-amino)bipheny (83 mg, 0.21 mmol, 0.21 eq), palladium(II) acetate (31.4 mg, 0.14 mmol, 0.14 eq), and cesium fluoride (4542 mg, 29.9 mmol, 30 30 eq) under an atmosphere of nitrogen, 1,4-Dioxane (25 mL, 39.9M) was added. The resulting mixture was stirred at rt forl day. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus obtained was 50 WO 2007/016784 PCT/CA2006/001306 purified by COMBI-FLASH@ (pure hexane for 4 min , to 50% EtOAC/hexane in 20 mi, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.22 (s, I H), 8.19 (s, 1 H), 7.93 (d, I H), 7.73 (d, 1 H), 7.62-7.52 (in, 2 H), 7.44-7.40 (m, 2 H), 5.92 (s, 2 H), 5.46 (s, 1 H), 2.37-2.30 (in, 1 H), 2.08 (in, 1 H), 0.84 (t, 3 H). 5 Example 11 3-(4-fluorophenyl)-6-( 4-[1 -hydroxy-1 -(trifluoromethyl)propyl]-IH-1,2,3-triazol-1 -yl}methyl)- 1 benzothiophene-2-carbonitrile N N N,N-N OH F F F 10 F To a mixture of 3-chloro-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carbonitrile (400 mg, 0.998 mmol), (3-fluorophenyl)boronic acid (0.4 g, 0.998 mmol), (4-fluorophenyl)boronic acid (418 mg, 2.99 mmol, 3 eq), POPd (C 6

HHP

2

O

2 C1 2 Pd, 50.2 mg, 0.1 mmol, 0.1 eq) and cesium carbonate (1.952 g, 5.99 mmol, 6 eq) at rt under an atmosphere of nitrogen, 1,2 15 Dimethoxyethane (16 mL, 0.062M) was added. The resulting mixture was stirred at reflux for 4 h. The reaction was diluted with EtOAc and filtered through a layer of silica gel. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min, to 50 % EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.20 (s, 1 H), 8.19 (s, I H), 7.89 (d, 1 H), 7.79-7.77 (in, 2 H), 7.60 (d, 1 H), 20 7.44 (dd, 2 H), 5.91 (s, 2 H), 5.48 (s, 1 H), 2.37-2.30 (in, 1 H), 2.08-2.06 (in, 1 H), 0.84 (t, 3 H). EXAMPLE 12 3-(3-fluorophenyl)-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carbonitrile 25 N SZO N

NH

2 OH F F F - F To a mixture of 3-(3-fluorophenyl)-6-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1 yl}imethyl)-1-benzothiophene-2-carbonitrile (250 mg, 0.543 mmol) in water-Acetone (10 mL, 1:1.5, 0.054M) stirred at rt under an atmosphere of nitrogen, sodium percarbonate (256 mg, 1.629 mmol, 3 eq) 51 WO 2007/016784 PCT/CA2006/001306 was added. The resulting mixture was stirred at reflux for over night. The reaction was quenched by the addition of water, and was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 5 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.15 (s, 1 H), 8.08 (s, I H), 7.68-7.64 (m, 1 H), 7.51-7.44 (in, 2 H), 7.38-7.32 (in, 3 H), 6.89 (s, 1 H), 6.19 (s, 1 H), 5.85 (s, 2 H), 5.46 (s, I H), 2.36-2.29 (in, I H), 2.09 (d, 12 H), 0.83 (t, 3 H). EXAMPLE 13 10 2-(1-{[2-bromo-3-(4-fluorophenyl)-1-benzothien-6-yl]methyl}-IH-1,2,3-triazol-4-yl)-1,1,1 trifluorobutan-2-ol ,N' N-N / Br OH F F F F 15 Step 1: 6-bromo-3-(4-fluorophenyl)-1-benzothiophene Br - s F To a mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 49.3 mmol) in THF-(100 mL, 0.493M) stirred at 0 0 C under an atmosphere of nitrogen, (4-fluorophenyl)magnesium bromide (54.2 mL, 54.2 mmol, 1.1 eq) was added. The resulting mixture was stirred at rt forI h. The reaction was quenched by the addition of 20 water (3 ml). The resulting mixture was filtered through a layer of silica gel. After evaporation, the crude thus obtained was re-dissolved in CH 2 Cl 2 (100 mL, 0.493M) under an atmosphere of nitrogen at rt, and manganese(IV) oxide (64.2 g, 739 mmol, 15 eq) was added. The resulting mixture was stirred at rt over a weekend. The reaction was quenched by passing through a silica gel pad and washed with 20% EtOAC/hexane . After evaporation, the crude thus obtained was re-dissolved in THF (200 mL, 0.239M) 25 and methyl mercaptoacetate (4.7 mL, 52.6 mmol, 1.1 eq) was added. The resulting mixture was stirred at reflux with cesium carbonate (31.3 g, 96 mmol, 2 eq) overnight. The reaction was quenched by passing through a silica gel pad and washed with 50% EtOAC/hexane . After evaporation, the crude thus obtained was re-dissolved in solvent mixture (200 mL of THF + 200 mL of H20). To the resulting 52 WO 2007/016784 PCT/CA2006/001306 solution at rt,, sodium hydroxide (120 mL, 239 mmol, 5 eq) was added. The resulting mixture was stirred at reflux for 2 h. The reaction was quenched by the addition of 10% HCl. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine and dried over Na 2

SO

4 . After evaporation, the crude thus obtained was re-dissolved in 100 5 mL quinoline and stirred at 160'C with copper (1.52 g, 23.9 mmol, 0.5 eq) overnight. The reaction was quenched by the addition of IN HCl and extracted with EtOAc. The organic layers were combined, washed with brine and dried over Na 2

SO

4 . After evaporation, the crude thus obtained was purified by flash chromatography (pure hexane, silica gel) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.29 (s, 1 H), 7.83 (d, 1 H), 7.74 (s, 1 H), 7.70-7.68 (m, 2 H), 7.64-7.60 (d, I H), 7.33 (t, 2 10 H). Step 2: methyl 3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate 0 O S F To a mixture of 6-bromo-3-(4-fluorophenyl)-1-benzothiophene (8.6 g, 28 mmol) and triethylamine (7.87 15 mL, 56 mmol, 2 eq) in methanol-DMSO (518 mL, 1:2, 0.054M) stirred at rt under an atmosphere of CO (BALLOON), (1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II)-CH 2

C

2 (2287 mg, 2.8 mmol, 0.1 eq) was added. The resulting mixture was stirred at 65'C overnight and cooled down to rt. Then water was added and the resulting mixture was extracted with 50% EtOAc/THF. The combined organic layer was washed with brine, dried over Na 2

SO

4 , and evaporated to dryness. The crude thus 20 obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 15% EtOAC/hexane in 20 min, to 30% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 3 8.72 (s, I H), 8.08 (d, 1 H), 8.00 (d, 1 H), 7.98 (s, 1 H), 7.73-7.71 (m, 2 H), 7.34 (t, 2 H), 3.96 (s, 3 H). Step 3: methyl 2-bromo-3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate 0 Br 25 F 53 WO 2007/016784 PCT/CA2006/001306 To a mixture of methyl 3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate (7.5 g, 26.2 mmol) in acetic acid (61.2 mL, 0.428M) stirred at rt under an atmosphere of nitrogen, bromine/CH 2 Cl (1 M, 52.4 mL, 52.4 mmol, 2 eq) was added. The resulting mixture was stirred at rt for 3 h. The reaction was quenched by the addition of water and was extracted with EtOAc. The organic layers were combined, washed with 5 a Na 2

SO

3 solution and a saturated NaHCO 3 solution, and dried over Na 2

SO

4 . After evaporation, the crude thus obtained was determined to be the titled compound by 'H NMR . 'H NMR (500 MHz, Acetone): 6 8.63 (s, 1 H), 7.99 (d, I H), 7.61 (d, I H), 7.58-7.56 (in, 2 H), 7.39-7.35 (t, 2 H), 3.92 (s, 3 H). Step 4: 2-(1-{[2-bromo-3-(4-fluorophenyl)-1-benzothien-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1 trifluorobutan-2-ol 10 To a mixture of methyl 2-bromo-3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate (9.57 g, 26.2 mmol) in THF (350 mL, 0.075M) stirred at -78'C under an atmosphere of nitrogen, DIBAL-H (52.7 mL, 79 mmol, 3 eq) was added. The resulting mixture was stirred at -78'C for 1 h. The reaction was quenched by the addition of silica gel and water and was passed through a silica gel pad and washed with 30% EtOAC/hexane. The solvent was removed by evaporation and the crude thus obtained was used directly 15 in next step. To a mixture of the alcohol thus obtained (1.6 g, 4.74 mmol) and triethylamine (3.99 mL, 28.4 mmol, 6 eq) in CH 2 Cl 2 (50 mL, 0.095M) stirred at -30'C under an atmosphere of nitrogen, methanesulfonyl chloride (1.108 mL, 14.22 mmol, 3 eq) was added. The resulting mixture was stirred at 30'C for1 h. The reaction was quenched by the addition of a saturated NaHCO 3 solution. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were 20 combined, washed with brine, and dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus obtained was re-dissolved in DMF (25 mL) under atmosphere of nitrogen at rt and sodium azide (3.08 g, 47.4 mmol, 10 eq) was added. The resulting mixture was stirred at rt for 3 h. The reaction was quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried over Na 2

SO

4 . The solvent was removed by evaporation and the crude thus 25 obtained was used directly in next step. To a mixture of the crude obtained (1.6 g, 4.42 mmol) and 3 (trifluoromethyl)pent-1-yn-3-ol (806 mg, 5.3 mmol, 1.2 eq) in THF (29.3 mL, 0.15 IM) stirring at rt under an atmosphere of nitrogen, N,N-diisopropylethylamine (3.86 mL, 22.1 mmol, 5 eq) and copper(I) iodide (842 mg, 4.42 mmol, I eq) was added. The resulting mixture was stirred at rt overnight. The solvent was removed by evaporation and the crude thus obtained was re-dissolved in EtOAc and filtered through a 30 silica gel pad and washed with 60% EtOAC/hexane. The solvent was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 50 % EtOAC/hexane in 20 min, to 65% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 6 8.13 (s, 1 H), 8.04 (s, 1 H), 7.59-7.55 (in, 3 H), 7.44 (d, I H), 7.37 (t, 2 H), 5.81 (d, 2 H), 5.43 (s, I H), 2.37-2.29 (m, I H), 2.11 (s, 1 H), 0.83 (t, 3 H). 35 54 WO 2007/016784 PCT/CA2006/001306 EXAMPLE 14 3-(4-fluorophenyl)-6-({4-[1-hydroxy-I-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1 benzothiophene-2-carboxamide N N N-N S 0

NH

2 OH F F F 5 F To a solution of 2-(1-{[2-bromo-3-(4-fluorophenyl)-1-benzothien-6-yl]methyl}-1H-1,2,3-triazol-4-yl) 1,1,1-trifluorobutan-2-ol (1.2 g, 2.333 mmol) in DMSO (50 mL, 0.046M) stirred at rt under an atmosphere of nitrogen, copper(I) cyanide (418 mg, 4.67 mmol, 2 eq) was added. The resulting mixture was stirred at 150'C for 6 h. The reaction was quenched by the addition of water and was extracted with 10 EtOAc. The organic layers were combined, washed with brine and dried over Na 2

SO

4 . After evaporation, the crude thus obtained was re-dissolved in acetone/H 2 0 (50 mL,1:1 0.047M) under atmosphere of nitrogen at rt, and sodium percarbonate (1.099 g, 7 mmol, 3 eq) was added. The resulting mixture was stirred at reflux for 3 h. The reaction was quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine and dried over Na 2

SO

4 . The solvent 15 was removed by evaporation and the crude thus obtained was purified by COMBI-FLASH@ (pure hexane for 4 min , to 50% EtOAC/hexane in 20 min, to 70 % EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 5 8.15 (s, 1 H), 8.07 (s, 1 H), 7.60-7.58 (in, 2 H), 7.48 7.42 (m, 2 H), 7.39 (t, 2 H), 6.87 (s, I H), 6.08 (s, I H), 5.85 (s, 2 H), 5.44 (s, I H), 2.36-2.29 (m, 2 H), 2.08-2.04 (m, 1 H), 0.83 (t, 3H). 20 The thus obtained racemic material was resolved into the individual enantiomers using HPLC separation with a chiral column. The racemic 3-(4-fluorophenyl)-6-({4-[-hydroxy-1 (trifluoromethyl)propyl]-IH-1,2,3-triazol-1-yl}methyl)-1-benzothiophene-2-carboxamide was dissolved in pure EtOH for injection into the HPLC machine. Chromatography conditions: ChiralPak AD 19x250 mm column, flow rate = 8 mL/min, 254 nm detection, solvent system: 50% isoropanol/hexane. First 25 enantiomer retention time = 17 min, second enantiomer retention time = 27 min. 55 WO 2007/016784 PCT/CA2006/001306 EXAMPLE 15 Methyl 5-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H-indole 2-carboxylate N- 0 N N FF FOH F- N FfX Fb 5 Step 1: methyl 5-methyl-1-phenyl-1H-indole-2-carboxylate 0 To methyl 5-methyl-1H-indole-2-carboxylate (10.0g) in dioxane 250 mL was added iodobenzene (10.03 g), copper iodide (0.468g), potassium phosphate (21.86g) and 1,2-diaminocyclohexane (0.604 mL). The reaction mixture was refluxed for 12 h. The reaction solvent was evaporated to dryness and the residue 10 re-dissolved in dichloromethane then was passed on a plug of SiO 2 and eluted with hexane / EtOAc 10 % to afford the titled product. Step 2: methyl 5-bromomethyl-1-phenyl-IH-indole-2-carboxylate Br 0 -~N To methyl 5-methyl-1-phenyl-1H-indole-2-carboxylate (1.5 g) in CC14 (100 mL) was added NBS (1.05g) 15 and azobis(cyclohexanecarbonitrile) (26 mg). The reaction was refluxed for 2 hours. The reaction was cooled and diluted with hexane and filtered on a pad of celite. The organic extracts were evaporated to dryness and the residue was purified by flash chromatography eluting with toluene to afford the titled product. Step 3: methyl 5-azido-1-phenyl-1H-indole-2-carboxylate 56 WO 2007/016784 PCT/CA2006/001306

N

3 0 N To methyl 5-bromomethyl-l-phenyl-IH-indole-2-carboxylate (1g) in DMF (20 mL) was added sodium azide (0.726 g). The reaction mixture stirred at rt for I h. The reaction was quenched with ammonium chloride saturated solution and extracted with ethyl acetate. The organic fraction was dried over 5 magnesium sulfate and evaporated to dryness. The residue was passed on a plug of SiO2 and eluted with hexane / EtOAc 20 % to afford the titled product. Step 4: methyl 5-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl 1 H-indole-2-carboxylate To a solution of methyl 5-azido-1-phenyl-1H-indole-2-carboxylate (0.85g), in THF (15 mL) and 3 10 (trifluoromethyl)pent-1-yne-3-ol (631 mg) at rt was added DIPEA (2.3 mL) and copper iodide (758 mg). The reaction was stirred at rt overnight. The reaction was quenched with ammonium chloride saturated solution and extracted with ethyl acetate. The organic fraction was dried over magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography eluting with hexane / EtOAc 40 % to afford the titled product. 1H NMR (500 MHz, Acetone):8 8.07 (s, 1 H); 7.86 (s, 1 H); 7.59-7.51 15 (m, 3 H); 7.47 (s, 1 H); 7.42-7.36 (in, 3 H); 7.11 (d,1 H); 5.77 (s, 2 H); 5.44 (s, 1 H); 3.75 (s, 3 H); 2.35 2.28 (in, 1 H); 2.09 (in, I H); 0.83 (t, 3 H). EXAMPLE 16 5-({4-[1-hydroxy-1-(trifluoromethyl)propy1]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H-indole-2 20 carboxamide

N

N - NN N H 2 F OH F F Step 1: 5-(4-[Il-hydroxy-1-(trifluoromethyl)propyl]-IH-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H indole-2-carboxylic acid 57 WO 2007/016784 PCT/CA2006/001306 N- N0 N N N OH FF To methyl 5-({4-[1-hydroxy-1-(trifluoromethyl)propylI]-I H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1 H indole-2-carboxylate (1.2g) in THF/methanol 1/1 (15 mL) and water (3 mL) at rt, was added NaOH (0.21g). The reaction was stirred at rt overnight. The reaction was evaporated to remove THF/methanol, 5 then diluted with water and it was acidified with HCI 10 %. The suspension thus obtained was filtered on a glass filter and air dried. Step 2: 5-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H indole-2-carboxamide To a solution of 5-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H 10 indole-2-carboxylic acid (0.15 g) in CH 2 Cl2/ THF (4mL/1mL) at 0OC was added a trace of DMF followed by oxalyl chloride (0.037mL). The reaction was stirred at rt for 30 min. The reaction was cooled at -78 OC and NH3 (g) was bubbled into the solution. Then the temperature was raised to rt for lh. The reaction mixture was acidified with HCI 10 % and extracted with EtOAc. The extracts were dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography eluting 15 with hexane / EtOAc 80 % to afford the titled product. 1H NMR (500 MHz, Acetone): 6 8.04 (s, 1 H), 7.79 (s, 1 H), 7.54 (dd, 2 H), 7.46 (t, 1 H), 7.39 (t, 2 H), 7.31-7.29 (in, 3 H), 7.15 (d, 1 H), 6.65 (s, 1 H), 5.75 (s, 2 H), 5.41 (s, 1 H), 2.35-2.28 (in, 1 H), 2.08 (in, 1 H), 0.82 (t, 3 H). EXAMPLE 17 20 5-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H-indole-2 carbonitrile N _ N =N F OH F F To a solution of 5-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-phenyl-1H indole-2-carboxamide (0.5 g) and pyridine (0.19 mL) in dioxane (15 mL) at 5 OC was added TFAA (0.16 25 mL). The reaction was stirred at rt for 1h. The reaction mixture was quenched with NH4CI sat. solution 58 WO 2007/016784 PCT/CA2006/001306 and extracted with EtOAc. The extracts were dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography using hexane / EtOAc 10-30 % to afford the titled product. I H NMR (500 MHz, Acetone): 6 8.10 (s, I H), 7.90 (s, 1 H), 7.71 (dd, 2 H), 7.63 (dd, 4 H), 7.49 (dd, 1 H), 7.39 (d, 1 H), 5.80 (s, 2 H), 5.42 (s, 1 H), 2.36-2.29 (m, 1 H), 2.09 (d, 1 H), 0.83 (t, 3 H). 59

Claims (26)

1. A compound of structural Formula I N' N R2 N 5 R3 R 4 and the pharmaceutically acceptable salts, esters and solvates thereof wherein: Z, is selected from the group consisting of 1 'S O)n R1 R 2 and

2 N A A wherein the numbers "1" and "2" indicate the points of attachment within structural Formula I; A is selected from the group consisting of -Cl and phenyl optionally mono- or di-substituted with a 10 substituent independently selected at each occurrence from the group consisting of (i) -F (ii) -Cl, (iii) -Cl-3alkyl optionally substituted with one or more of halo, (iv) -OCl-3alkyl optionally substituted with one or more of halo, (v) -OC3-6cycloalkyl, (vi) -C3-6cycloalkyl, (vii) -CH2OH, (viii) -COOR 5 , (ix) -CN and (x) -NR5R5a; n is an integer selected from zero, 1 and 2; 15 R1 is selected from the group consisting of (i) -H, (ii) -Br, (iii) -Cl, (iv) -COC -6alkyl, (v) -COOCl-6alkyl, (vi) -COOC3-6cycloalkyl, (vii) -SO2CI-6alkyl, (viii) -SO2NR 5 R 5 , (ix) -CONR 5 R5, (x) -CN, (xi) -C -6alkyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of -OH and -F, (xii) phenyl optionally mono- or di substituted with a substituent independently selected at each occurrence from the group consisting of 20 -OH and -F, (xiii) tetrazolyl optionally substituted with methyl, (xiv) 1,2,4-oxadiazolyl optionally substituted with methyl, and (xv) pyridinyl optionally substituted with methyl; R 2 is selected from the group consisting of -H, -OH, -F, -Cl-3alkyl, -OCl-3alkyl and -OC(O)-C1-3alkyl; R 3 is selected from the group consisting of -H, -CI-6alkyl, -Cl-6alkyl substituted with one or more of fluoro, -Cl-6alkyl substituted with R 6 , phenyl, -C2-6alkenyl, -C3-6cycloalkyl and -C5-7cycloalkenyl; 60 WO 2007/016784 PCT/CA2006/001306 R 4 is selected from the group consisting of -H, -CI-6alkyl, -Cl-6alkyl substituted with one or more of fluoro, -CI-6alkyl substituted with R 6 , phenyl, -C2-6alkenyl, -C3-6cycloalkyl and -C5-7cycloalkenyl; R 5 is independently selected at each occurrence from the group consisting of -H, -C1-6 alkyl and -C3-6cYcloalkyl; 5 R5a is independently selected at each occurrence from the group consisting of -H, -C1-6 alkyl, -C3-6cycloalkyl and -COOR5; and R 6 is independently selected at each occurrence from the group consisting of -COOR 5 , -C(O)H, -CN, -CR 5 R 5 0H, -OR 5 , -S-Cl -6alkyl and -S- C3-6 cycloalkyl. 10 2. The compound of claim 1 having structural Formula Ia N/N N S R2_ A R

3 R 4 Ia and the pharmaceutically acceptable salts, esters and solvates thereof. 15 3. The compound of claim 2 wherein A is selected from the group consisting of phenyl and phenyl mono-substituted with a substituent selected from -Cl and -F.

4. The compound of claim 3 wherein R 2 is selected from the group consisting of -H, -OH , -F, -Cl-3alkyl, -OCH3, and -OC(O)CH3; R 3 is selected from the group consisting of -H, 20 -Cl-6alkyl, -Cl-6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R 4 is selected from the group consisting of -H, -CI-6alkyl, -CI-6alkyl substituted with one or more of fluoro, -Cl-6alkyl substituted with R 6 and -C3-6cycloalkyl. .

5. The compound of claim 4 wherein R 1 is selected from -COOR 5 , -CONR 5 R 5 , 25 -S0 2 -C 1 6 alkyl and -SO 2 NR 5 R 5 .

6. The compound of claim I having structural Formula lb 61 WO 2007/016784 PCT/CA2006/001306 N R2 N R A R 3 R 4 and the pharmaceutically acceptable salts, esters and solvates thereof.

7. The compound of claim 6 wherein A is selected from the group consisting of 5 phenyl and phenyl mono-substituted with a substituent selected from -Cl and -F.

8. The compound of claim 7 wherein R 2 is selected from the group consisting of -H, -OH , -F, -Cl-3alkyl, -OCH3, and -OC(O)CH 3 ; R 3 is selected from the group consisting of -H, -Cl-6alkyl, -CI-6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R 4 is 10 selected from the group consisting of -H, -C1-6alkyl, -CI-6alkyl substituted with one or more of fluoro, -Cl-6alkyl substituted with R 6 and -C3-6cycloalkyl. .

9. The compound of claim 8 wherein R 1 is selected from -COOR', -CONR 5 R', -S0 2 -C 16 alkyl and -SO 2 NR 5 R 5 . 15

10. The compound of claim 1 selected from the group consisting of: N 'N N R1 F 3 C A HO CH 2 CH 3 Compound # R1 A Ia-I -S02CH3 4-fluoro-Ph Ia-2 -SO2CH3 4-cyclohexyl-Ph Ia-3 -Br 4-fluoro-Ph Ia-4 -S02-NH2 4-fluoro-Ph Ia-5 -S02-NIH-t-Bu 4-fluoro-Ph Ia-6 -S02CH 3 3-fluoro-Ph Ia-7 -CONH2 4-fluoro-Ph Ia-8 -COOCH3 4-fluoro-Ph Ia-9 -CN 4-fluoro-Ph 62 WO 2007/016784 PCT/CA2006/001306 Compound # Rl A la- 10 -CONH2 3-fluoro-Ph Ia-il -CN 3-fluoro--Ph Ia-12 OH 3 Ph N- N Ia-13 N N Ph la-14 H Ph N-N Ia-15 -CONH2 Ph Ia-16 -Cl Ph Ia- 17 -SO2CH3 Ph Ia- 18 -CHF2 Ph la-19 4-F-Ph Ph la-20 /-N C3 Ph la-21 N O- H 3 Ph Ia-22 N- Ph Ia-23 -CN Ph Ia-24 -Br Ph Ia-25 -H Ph la-26 -COCH3 Ph Ia-27 -CHOHCH3 Ph Ia-28 -CH2OH Ph Ia-29 -C(CH3)20H Ph Ia-30 -CONHCH3 Ph Ia-3 1 -CON(CH3)2 Ph Ia-32 -COOCH3 Ph la-33 -S02CH3 Cl Ia-34 -CN Cl Ia-35 -COOCH3 cl1 63 WO 2007/016784 PCT/CA2006/001306 Compound# RI A Ia-36 -SO2CH3 3-Me-4-fluoro-Ph Ia-37 -S02CH3 4-CH(CH 3 )2-Ph Ia-38 -S02CH3 3-Me-Ph Ia-39 -SO2CH3 4-Me-Ph Ia-40 -SO2CH 3 3,5-difluoro-Ph Ia-41 -SO2CH3 3-Cl-Ph Ia-42 -CONH2 3-methoxy-Ph Ia-43 -CONH2 4-methoxy-Ph Ia-44 -CONH2 3-Me-Ph Ia-45 -CONH2 4-Me-Ph and the pharmaceutically acceptable salts, esters and solvates thereof.

11. The compound of claim 1 selected from the group consisting of: N RN F 3 C N HO CH 2 CH 3 5 Compound # RI Ib-1 -CN Ib-2 -CONH12 Ib-3 -COCH 3 Ib-4 -CH(OH)CH 3 Ib-5 -CH2OH Ib-6 -COOCH3 Ib-7 -COOCH2CH3 and the pharmaceutically acceptable salts, esters and solvates thereof.

12. A method of preventing the synthesis, the action, or the release of leukotrienes in a mammal which comprises administering to said mammal a 5-LO inhibitory effective amount of a 10 compound of claim 1.

13. The method of claim 10 wherein the mammal is a human. 64 WO 2007/016784 PCT/CA2006/001306

14. A method of treating an inflammatory condition in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 5

15. A method for treating atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

16. A method for preventing or reducing the risk of an atherosclerotic disease event 10 comprising administering a prophylactically effective amount of a compound of claim 1 to a patient at risk for having an atherosclerotic disease event..

17. A method for the prophylaxis or treatment of asthma comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment. 15

18. A method for treating the symptoms of allergic rhinitis comprising administering a therapeutically effective amount of a compound of claim I to a patient in need of such treatment.

19. A method for treating COPD comprising administering a therapeutically 20 effective amount of a compound of claim 1 to a patient in need of such treatment.

20. A pharmaceutical composition comprised of a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 25

21. Use of a compound of claim 1 for the preparation of a medicament useful for treating or preventing an inflammatory condition in a mammal.

22. Use of a compound of claim 1 for the preparation of a medicament useful for treating atherosclerosis. 30

23. Use of a compound of claim 1 for the preparation of a medicament useful for preventing or reducing the risk for an atherosclerotic disease event.

24. Use of a compound of claim 1 for the preparation of a medicament useful for 35 the prophylaxis or treatment of asthma. 65 WO 2007/016784 PCT/CA2006/001306

25. Use of a compound of claim I for the preparation of a medicament useful for treating the symptoms of allergic rhinitis.

26. Use of a compound of claim I for the preparation of a medicament useful for 5 treating COPD. 66 WO 2007/016784 PCT/CA2006/001306 AMENDED CLAIMS received by the International Bureau on 19 January 2007 (19.01 .2007) Compound # RI A Ia-36 -S02CH3 3-Me-4-fluoro-Ph Ia-37 -S02CH3 4-CH(C143)2-Ph Ia-3 8 -SQ2CI43 3-Me-Ph Ia-39 -SO2CH3 4-Me-Ph Ia-40 -S0 2 043 3,5-difluoro-Ph Ia-41 -SO2CH3 3-Cl-Ph Ia-42 -001 12 3-methqxy-Ph Ia-43 -. CON112 4-methqoxy-Ph Ta-44 -CONHW2 3-Me-Ph Ia-4S -CONH2 4-Me-Ph and the pharmaceutically acceptable salts, esters and solvates thereof. 11. The compound of claim 1 selected from the group consisting of: N F 3 C;N HO CH 2 CH 3 / Comp ound#N RI Ib-i -CN Ib-2 -CONTI 2 lb-3 -COCH3 1b4 -CH(OH1)CN3q Th-5 -C112011 Ib-6 -COOCH 3 1b-7 -COQCH2CH3 and the pharmaceutically acceptable salts, esters and solvates thereof. 12. A method of preventing the syntliesis 3 the action, or the release of leukbtrienes in a mammal which comprises administering to said mammal a 5-LQ inhibitory effctive amount of a 10 compound of claim 1. 13. The method of claims 12 wherein the m~aIa is a human. 67 WO 2007/016784 PCT/CA2006/001306 14. A method of treating an inflammatory condition in a mammal whichcotnprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 5 15. A method for treating atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment, 16. A method for preventing or reducing the risk of an atherosclerotic disease event 10 comprising administering a prophylactically effective amount of a compound of claim 1 to a patient at risk for having an atherosclerotic disease event.. 17. A method for the prophylaxis or treatment of asthma comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment. 15 18. A method for treating the syrnptoms of allergic rhinitis comprising admn~nistering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment, 19. A method fdr treating COPD comprising administering a therapeutically 20 effective amount of a compound of claim I to a patient in need of such treatment. 20. A pharmaceutical composition comprised of a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 25 21. Use of a compound of claim 1 for the preparation of a medicament for treating or preventing an inflammatory condition in a mammal. 22. Use of a compound of claim 1 for the preparation of a nedicament Stpr' treating atherosclerosis. 30 23. Use of a compound of claim I for the preparation of a medicament for preventing or reducing the risk for an atherosclerotic disease event. 24. Use of a compound of claim 1 for the preparation of a medicament for 35 the prophylaxis or treatment of asthma. 68 WO 2007/016784 PCT/CA2006/001306 25. Use of a compound of claim 1 for the preparation of a medicament for treating the symptoms of allergic rhinitis. 26. Use of a compound of claim 1 for the preparation of a medicament for 5 treating COPD. 69