Phosphoinositide 3-Kinase Inhibitors for Inhibiting Leukocyte Accumulation

• US 20080287469A1
• Filed: 02/16/2006
• Published: 11/20/2008
• Est. Priority Date: 02/17/2005
• Status: Abandoned Application

• Current Assignee: Joel S. Hayflick, Kamal D. Puri, Thomas G. Diacovo
• Original Assignee: Joel S. Hayflick, Kamal D. Puri, Thomas G. Diacovo
• Inventors: Puri, Kamal D., Hayflick, Joel S., Diacovo, Thomas G.
• Application Number:
  US11/884,566
• Publication Number:
  US 20080287469A1
• Time in Patent Office: Days
• US Class Current: 514/263.21
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention relates generally to phosphoinositide 3-kinases (PI3Ks), and more particularly to methods of inhibiting leukocyte accumulation comprising selectively inhibiting phosphoinositide 3-kinase delta (PI3Kδ) and phosphoinositide 3-kinase gamma (PI3Kγ) activities in endothelial cells. The disclosed methods may be used to treat individuals having an inflammatory condition where leukocytes are found to be accumulating at the site of insult or inflamed tissue. The inflammatory condition may be attributed to or associated with an underlying disorder not typically associated with inflammation, e.g. cancer, coronary vascular disease, etc.

Claims

1-19. -19. (canceled)

20. A method of inhibiting leukocyte accumulation, comprising:

administering at least one selective inhibitor in an amount effective to inhibit p110 delta (p110δ

) and p110 gamma (p110γ

) in endothelial cells, wherein the selective inhibitor is a dual selective inhibitor having a PI3Kγ

IC₅₀ to PI3Kδ

IC₅₀ ratio of between about 10 to 1 and about 1 to 10;

wherein the dual selective inhibitor comprises a compound having formula (IV) or pharmaceutically acceptable salts and solvates thereof;

wherein X¹ is selected from the group consisting of hydrogen, amino, C_1-6alkyl, halo, NO₂, OR^e, CF₃, OCF₃, N(R^e)₂, and CN;

X² is selected from the group consisting of aryl, heteroaryl, cyclopropylmethyl, cyclopentyl, and cyclohexyl;

X³ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, and propargyl;

X⁴ is selected from the group consisting of hydrogen, halo, and amino;

X⁵ is selected from the group consisting hydrogen and halo; and

,

R^e is independently selected from the group consisting of hydrogen, C_1-6alkyl.

21. The method according to claim 20, wherein the dual selective inhibitor is selected from the group consisting of:

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-6-fluoro-3-phenyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(3-fluoro-phenyl)-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-5-chloro-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-propyl]-5-fluoro-3-phenyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-5-chloro-3-phenyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-5-methyl-3-phenyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-(2-hydroxy-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-5-methyl-3-phenyl-3H-quinazolin-4-one;

3-(4-fluoro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

3-(4-fluoro-phenyl)-2-[1-(2-fluoro-9H-purin-6-ylamino)-ethyl)-5-methyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-propyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(2,4-difluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(2,4-difluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-phenyl-5-trifluoromethyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-butyl]-5-methyl-3-phenyl-3H-quinazolin-4-one; and

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-cyclopentyl-5-methyl-3H-quinazolin-4-one.

22-23. -23. (canceled)

24. A method of inhibiting leukocyte accumulation, comprising:

administering at least one selective inhibitor in an amount effective to inhibit p110 delta (p110δ

) and p110 gamma (p110γ

) in endothelial cells,

wherein the at least one selective inhibitor includes a PI3Kγ

selective inhibitor having formula (V) or pharmaceutically acceptable salts and solvates thereof;

wherein X¹ is selected from the group consisting of NR⁶, O, and S;

and wherein when X¹ is NR⁶, then

R⁶ is selected from the group consisting of hydrogen and C_1-3alkyl;

X² is S;

R¹ and R² are both methoxy;

R⁴ and R⁵ are both hydrogen, and

R³ is selected from the group of phenyl and substituted phenyl, wherein substitution groups are selected from the group consisting of C_1-4 alkyl, C_1-4 alkoxy, and halogen;

and wherein when X¹ is O, then

X² is selected from the group consisting of O, O—

C(Me)H—

, O—

C(Et)H—

, OCH₂—

, and O—

C_1-3alkylene;

R¹ is selected from the group consisting of methoxy and chloro;

R², R⁴, and R⁵ are all hydrogen and

R³ is selected from the group consisting of optionally substituted C_3-8cycloalkyl, optionally substituted cyclohexenyl, optionally substituted bicyclo[2.2.1]heptanyl, optionally substituted 4, 5, or 6 membered heterocycloalkyl, optionally substituted decahydronaphthyl, optionally substituted oxetanyl, and optionally substituted tetrahydropyranyl, and wherein said optionally substituted groups are selected from the group consisting of C_1-4alkyl and C_-3alkenyl;

and wherein when X¹ is S, then

X² is selected from the group consisting of S, S—

CH₂—

, S—

CH₂CH₂—

, S—

C_1-4alkylene-, S—

C[C(Me)N(Me)C(O)Me]H—

, O, O—

C_1-4alkylene-, and O—

C_1-4alkyleneC(O)—

;

wherein when X² is S, S—

CH₂—

, S—

CH₂CH₂—

, S—

C_1-4alkylene-, or S—

C[C(Me)N(Me)C(O)Me]H—

,

R¹ is selected from the group consisting of methoxy, ethoxy, and methyl;

R² is selected from the group consisting of hydrogen, methyl, methoxy, CH₃OCH₂—

, CH₃CH₂OCH₂—

, and PhCH₂OCH₂—

;

R⁴ and R⁵ are hydrogen, and

R³ is selected from the group consisting of unsubstituted C_3-8cycloalkyl, optionally substituted phenyl, optionally substituted furanyl, optionally substituted 5-membered heteroaryl, and optionally substituted benzo[1,3]dioxolyl, wherein the substitution groups are selected from the group consisting of cyano, halo, trifluoromethyl, trifluoromethoxy, hydroxyl, C_1-4alkyl, OC_1-4alkyl, dimethylamino, CO₂Me, CH₂CO₂Me, CH₂CH₂CO₂Me, CO₂H, CH₂CO₂H, and CH₂CH₂CO₂H, and

when X² is O, O—

C-i_-4alkylene-, or O—

C_1-4alkyleneC(O)—

, then

R¹ is selected from the group consisting of methyl, methoxy, ethoxy, hydroxyl, —

OCHF₂, and -Ocyclopropyl;

R² is selected from the group consisting of hydrogen, methyl, methoxy, and -Ocyclopropyl;

R⁴ and R⁵ are the same or different and are selected from the group consisting of hydrogen and methyl, and

R³ is an optionally substituted moiety selected from the group consisting of C_3-8cycloalkyl, C_5-8cycloalkenyl, 4-, 5-, and 6-membered heterocycloalkyl, phenyl, naphthyl, 5- and 6-membered heteroaryl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, bicyclo[2.2.1]heptanyl, decahydronaphthyl, pyrimidinyl, pyridinyl, quinolinyl, and indanyl, wherein the substitution groups are selected from the group consisting of halo, cyano, nitro, hydroxyl, OCF₃, CF₃, SO₂Me, C_1-4alkyl, CN(H)NH₂, CH₂CH₂Br, CH₂CH₂S(t-Bu), OC_1-6alkyl, N(H)C(O)Me, NH₂, NMe₂, CH₂C(O)OEt, C(O)C_1-4alkyl, C(O)H, or

the substitution can be of the formula YR⁷ wherein Y is selected from the group of null, O, C_1-6alkylene, O—

C_1-6alkylene, C(O), —

CH(OH)—

, C_1-4alkylene-S—

, C_1-6alkylene-O—

, and C_1-6alkylene-C(O)—

, and

R⁷ is optionally substituted and is selected from the group consisting of phenyl, C_4-7cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiofuranyl, 5- and 6-membered heterocyloalkyl heterocycloalkyl, 1,1-dioxohexahydro-1λ

⁶-thiopyranyl, and wherein the substitutions are selected from the group consisting of halo, cyano, nitro, CF₃, hydroxyl, OCF₃, SO₂Me, C_1-4alkyl, O—

C_1-6alkyl, C(NH)NH₂, NH—

C(O)-Me, NH₂, NMe₂, C(O)—

NH₂, C(O)Me, C(O)—

C_1-4alkyl, C(O)H, C(O)—

C(Me)₂-NH—

C(O)—

O-t-Butyl, CH₂-phenyl, C_5-6cycloalkyl, piperidinyl, CH₂OMe, oxo, and 1,3-dioxolan-2-yl.

25. The method according to claim 24, wherein the PI3Kγ

selective inhibitor is selected from the group consisting of;

3-(4-Hydroxy-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(3-Chloro-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

5-Methoxy-3-(3-methoxy-phenylsulfanyl)-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(4-Isopropyl-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(4-Dimethylamino-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

4-[5-Methoxy-6-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-ylsulfanyl]-benzoic acid;

{4-[5-Methoxy-6-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-ylsulfanyl]-phenyl}-acetic acid;

3-{4-[5-Methoxy-6-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-ylsulfanyl]-phenyl}-propionic acid;

5-Methoxy-6-methyl-3-phenylsulfanyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

5-Methoxy-6-methyl-3-phenethylsulfanyl)-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(2,5-dimethoxy-phenylsulfanyl)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-[5,6-Dimethoxy-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-y-lsufanyl]-benzoic acid methyl ester;

5,6-Dimethoxy-3-(3-methoxy-phenylsulfanyl)-benzo[b]thiophene-2-carb-oxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenethylsulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3-Chloro-phenylsulfanyl)-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

6-Methoxy-3-(3-methoxy-phenylsulfanyl)-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

4-[6-Methoxy-5-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-ylsulfanylmethyl]-benzoic acid;

3-[2-(Acetyl-methyl-amino)-phenyl-propylsulfanyl]-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-Methoxy-6-methoxymethyl-3-phenylsulfanyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

5-Ethoxy-3-phenylsulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-Ethoxy-3-phenethylsulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

{4-[5-Ethoxy-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-ylsulfanyl]-phenyl}-acetic acid;

3-{4-[5-Ethoxy-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-ylsulfanyl]-phenyl}-propionic acid;

5-methoxy-3-o-tolylsulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(2,5-dimethoxy-phenyl-sulfanyl)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

5-Methoxy-6-methyl-3-phenylsulfanyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

5-Methoxy-6-methyl-3-phenethylsulfanyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-cyclohexylmethylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5-ethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-ethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylmethylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-methoxy-6-methoxymethyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-6-ethoxymethyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

6-benzyloxymethyl-3-cyclohexylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopropylmethylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclooctyloxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(2-methyl-cyclohexyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(2-methyl-cyclopentyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(2,4-dimethyl-cyclopentyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(3-methyl-bicyclo[2.2.1]hept-2-ylmethoxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(3-methyl-cyclohexyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,5-dimethyl-cyclohexyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(2-methyl-cyclohexyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(1-cyclopentyl-ethoxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(1-cyclohexyl-propoxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,4-dimethyl-cyclohexyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,5-dimethyl-cyclohexyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(decahydro-naphthalen-2-yloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(1-methyl-cyclomethoxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclobutylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cycloheptyloxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cycloheptylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexyloxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-chloro-3-cycloheptyloxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(tetrahydro-pyran-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(3,3,5,5-tetramethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(3,3,5-trimethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(3,3-dimethyl-cyclohexyloxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-cyclohexyloxy-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(3-methyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-cycloheptyloxy-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-[5-methoxy-6-methyl-2-(2H-tetrazol-5-yl-carbamoyl)-benzo[b]thiophen-3-yloxy-piperidine-1-carboxylic acid tert-butyl ester;

3-(3-cyclohexyl-propoxy)-5-methoxy-6-methyl-benzo[b}thiophene-2-carboxylic acid (2H-tetrazol-5-yl)amide;

3-(1-acetyl-piperidin-4-yloxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

4-[5-methoxy-6-methyl-2-(2H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester;

5-methoxy-6-methyl-3-(1-methyl-cyclopropylmethoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2,2-dichloro-cyclopropylmethoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-cyclohexyloxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-tert-butyl-cyclohexyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-methyl-bicyclo[2.2.1]hept-2-ylmethoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(cyclohex-3-enylmethoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,5-dimethyl-cyclohexyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3-cyclohexyl-propoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-Cyclohexyloxy-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3,3,5-trimethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(tetrahydro-pyran-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

{4-[5-methoxy-6-methyl-2-(2H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-yloxy]-phenyl}-acetic acid ethyl ester;

3-(4-isopropyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclopentyloxy-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-tert-butyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-bromo-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-fluoro-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-chloro-2-fluoro-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(4-trifluoromethoxy-phenoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-[4-(1-carbamoyl-cyclopentyl)-phenoxy]-5-methoxy-6-methyl-benzo[b]-thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-[4-(tetrahydro-pyran-4-yl)-phenoxy]-benzo[b]thiophene-2-carboxylic acid(2H-tetrazol-5-yl)-amide;

3-[4-(1,1-dioxo-hexahydro-1λ

⁶-thiopyran-4-yl)-phenoxy]-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide,

5-methoxy-6-methyl-3-(2-nitro-4-cyclohexyl-phenoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2-chloro-4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2-cyano-4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2-cyclohexylmethoxy-benzyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3-cyano-phenoxy)-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-difluoromethoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-hydroxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-methoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenyl)-5-cyclopropyl-6-methoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-6-cyclopropyl-5-difluoromethyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid methyl-(2H-tetrazol-5-yl)-amide;

3-(2-cyano-4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-((S)-1-methyl-2-phenyl-ethoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-phenyl-propoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(2-methyl-2-phenyl-propoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-o-tolylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(3,4-dichloro-phenylsulfanyl)-5,6-dimethoxy-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-methoxy-phenylsulfanyl)-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

1-ethyl-5,6-dimethoxy-3-phenyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenyl-1-propyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

1-ethyl-5,6-dimethoxy-3-phenyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenyl-1-propyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-o-tolylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(3,4-dichloro-phenylsulfanyl)-5,6-dimethoxy-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-methoxy-phenylsulfanyl)-1H-indole-2-carboxylic acid (2H-tetrazol-5

5,6-dimethoxy-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid(2H-tetrazol-5-yl)-amide;

1-ethyl-5,6-dimethoxy-3-phenyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide; and

5,6-dimethoxy-3-phenyl-1-propyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide.

26-44. -44. (canceled)

45. A method of inhibiting leukocyte tethering to endothelial cells, comprising:

administering at least one selective inhibitor in an amount effective to inhibit p110 delta (p110δ

) and p110 gamma (p110γ

) in endothelial cells,

wherein the selective inhibitor has a PI3Kγ

IC₅₀ to PI3Kδ

IC₅₀ ration [sic, ratio] of between about 10 to 1 and about 1 to 10; and

wherein the dual selective inhibitor comprises a compound having formula (IV) or pharmaceutically acceptable salts and solvates thereof;

wherein X¹ is selected from the group consisting of hydrogen, amino, C_1-6alkyl, halo, NO₂, OR^e, CF₃, OCF₃, N(R^e)₂, and CN;

X² is selected from the group consisting of aryl, heteroaryl, cyclopropylmethyl, cyclopentyl, and cyclohexyl;

X³ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, and propargyl;

X⁴ is selected from the group consisting of hydrogen, halo, and amino;

X⁵ is selected from the group consisting hydrogen and halo; and

,

R^e is independently selected from the group consisting of hydrogen, C_1-6alkyl.

46. The method according to claim 45, wherein the dual selective inhibitor is selected from the group consisting of:

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-6-fluoro-3-phenyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(3-fluoro-phenyl)-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-5-chloro-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-propyl]-5-fluoro-3-phenyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-5-chloro-3-phenyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-5-methyl-3-phenyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-(2-hydroxy-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-5-methyl-3-phenyl-3H-quinazolin-4-one;

3-(4-fluoro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

3-(4-fluoro-phenyl)-2-[1-(2-fluoro-9H-purin-6-ylamino)-ethyl)-5-methyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-propyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(2,4-difluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-(2,4-difluoro-phenyl)-5-methyl-3H-quinazolin-4-one;

2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-phenyl-5-trifluoromethyl-3H-quinazolin-4-one;

2-[1-(2-amino-9H-purin-6-ylamino)-butyl]-5-methyl-3-phenyl-3H-quinazolin-4-one; and

2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-3-cyclopentyl-5-methyl-3H-quinazolin-4-one.

47-48. -48. (canceled)

49. A method of inhibiting leukocyte tethering to endothelial cells, comprising:

administering at least one selective inhibitor in an amount effective to inhibit p110 delta (p110δ

) and p110 gamma (p110γ

) in endothelial cells,

wherein the at least one selective inhibitor includes a PI3Kγ

selective inhibitor having formula (V) or pharmaceutically acceptable salts and solvates thereof;

wherein X¹ is selected from the group consisting of NR⁶, O, and S;

and wherein when X¹ is NR⁶, then

R⁶ is selected from the group consisting of hydrogen and C_1-3alkyl;

X² is S;

R¹ and R² are both methoxy;

R⁴ and R⁵ are both hydrogen, and

R³ is selected from the group of phenyl and substituted phenyl, wherein substitution groups are selected from the group consisting of Ci_-4 alkyl, Ci_-4 alkoxy, and halogen;

and wherein when X¹ is O, then

X² is selected from the group consisting of O, 0-C(Me)H—

, 0-C(Et)H—

, OCH₂—

, and O-Ci_-3alkylene;

R¹ is selected from the group consisting of methoxy and chloro;

R², R⁴, and R⁵ are all hydrogen and

R³ is selected from the group consisting of optionally substituted C_3-scycloalkyl, optionally substituted cyclohexenyl, optionally substituted bicyclo[2.2.1]heptanyl, optionally substituted 4, 5, or 6 membered heterocycloalkyl, optionally substituted decahydronaphthyl, optionally substituted oxetanyl, and optionally substituted tetrahydropyranyl, and wherein said optionally substituted groups are selected from the group consisting of Ci_-4alkyl and C_2-3alkenyl;

and wherein when X¹ is S, then

X² is selected from the group consisting of S, S—

CH₂—

, S—

CH₂CH₂—

, S—

C_1-4alkylene-,

S—

C[C(Me)N(Me)C(O)Me]H—

, O, O—

C_1-4alkylene-, and O—

C_1-4alkyleneC(O)—

;

wherein when X² is S, S—

CH₂—

, S—

CH₂CH₂—

, S—

C_1-4alkylene˜

, or S—

C[C(Me)N(Me)C(O)Me]H—

,

R¹ is selected from the group consisting of methoxy, ethoxy, and methyl;

R² is selected from the group consisting of hydrogen, methyl, methoxy, CH₃OCH₂—

, CH₃CH₂OCH₂—

, and PhCH₂OCH₂—

;

R⁴ and R⁵ are hydrogen, and

R³ is selected from the group consisting of unsubstituted C_3-8cycloalkyl, optionally substituted phenyl, optionally substituted furanyl, optionally substituted 5-membered heteroaryl, and optionally substituted benzo[1,3]dioxolyl, wherein the substitution groups are selected from the group consisting of cyano, halo, trifluoromethyl, trifluoromethoxy, hydroxyl, Ci-₄alkyl, OC_1-4alkyl, dimethylamino, CO₂Me, CH₂CO₂Me, CH₂CH₂CO₂Me, CO₂H, CH₂CO₂H, and CH₂CH₂CO₂H, and when X² is O, O—

C_1-4alkylene-, or O—

C_1-4alkyleneC(O)—

, then

R¹ is selected from the group consisting of methyl, methoxy, ethoxy, hydroxyl, —

OCHF₂, and —

Ocyclopropyl;

R² is selected from the group consisting of hydrogen, methyl, methoxy, and -Ocyclopropyl;

R⁴ and R⁵ are the same or different and are selected from the group consisting of hydrogen and methyl, and

R³ is an optionally substituted moiety selected from the group consisting of C_3-8cycloalkyl, C_5-8cycloalkenyl, 4-, 5-, and 6-membered heterocycloalkyl, phenyl, naphthyl, 5- and 6-membered heteroaryl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, bicyclo[2.2.1]heptanyl, decahydronaphthyl, pyrimidinyl, pyridinyl, quinolinyl, and indanyl, wherein the

substitution groups are selected from the group consisting of halo, cyano, nitro, hydroxyl, OCF₃, CF₃, SO₂Me, C_1-4alkyl, CN(H)NH₂, CH₂CH₂Br, CH₂CH₂S(t-Bu), OC_1-6alkyl, N(H)C(O)Me, NH₂, NMe₂, CH₂C(O)OEt, C(O)C_1-4alkyl, C(O)H, or the substitution can be of the formula YR⁷ wherein Y is selected from the group of null, O, C_1-6alkylene, O-d_-6alkylene, C(O), —

CH(OH)—

, C_1-4alkylene-S—

, C_1-6alkylene-O—

, and C_1-6alkylene-C(O)—

, and

R⁷ is optionally substituted and is selected from the group consisting of phenyl, C_4-7cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiofuranyl, 5- and 6-membered heterocycloalkyl, 1,1-dioxohexahydro-1λ

⁶-thiopyranyl, and wherein the substitutions are selected from the group consisting of halo, cyano, nitro, CF₃, hydroxyl, OCF₃, SO₂Me, C_1-4alkyl, O—

C_1-6alkyl, C(NH)NH₂, NH—

C(O)-Me, NH₂, NMe₂, C(O)—

NH₂, C(O)Me, C(O)—

C_1-4alkyl, C(O)H, C(O)—

C(Me)₂-NH—

C(O)—

O-t-Butyl, CH₂-phenyl, C_5-6cycloalkyl, piperdinyl piperidinyl, CH₂OMe, oxo, and 1,3-dioxolan-2-yl.

50. The method according to claim 49, wherein the PI3Kγ

selective inhibitor is selected from the group consisting of;

3-(4-Hydroxy-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(3-Chloro-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

5-Methoxy-3-(3-methoxy-phenylsulfanyl)-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(4-Isopropyl-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(4-Dimethylamino-phenylsulfanyl)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

4-[5-Methoxy-6-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-ylsulfanyl]-benzoic acid;

{4-[5-Methoxy-6-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-ylsulfanyl]-phenyl}-acetic acid;

3-{4-[5-Methoxy-6-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-ylsulfanyl]-phenyl}-propionic acid;

δ

-Methoxy-θ

-methyl-S-phenylsulfanyl-benzotbjthiophenê

-carboxylic acid(1H-tetrazoI-5-yl)-amide;

δ

-Methoxy-δ

-methyl-S-phenethylsulfanyO-benzofb̂

hiophenê

-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-(2,5-dimethoxy-phenylsulfanyl)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-[5,6-Dimethoxy-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen [sic, thiophene?]-3-ylsufanyl]-benzoic acid methyl ester;

5,6-Dimethoxy-3-(3-methoxy-phenylsulfanyl)-benzo[b]thiophene-2-carb-oxylic acid (1H-tetrazol-5-yl)-amide;

δ

,θ

-dimethoxy-S-phenethylsulfanyl-benzô

thiophenê

-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3-Chloro-phenylsulfanyl)-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

6-Methoxy-3-(3-methoxy-phenylsulfanyl)-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

4-[6-Methoxy-5-methyl-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophe-n-3-ylsulfanylmethyl]-benzoic acid;

3-[2-(Acetyl-methyl-amino)-1-phenyl-propylsulfanyl]-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-Methoxy-6-methoxymethyl-3-phenylsulfanyl-benzo[b]thiophene-2-carb-oxylic acid(1H-tetrazol-5-yl)-amide;

5-Ethoxy-3-phenylsulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-Ethoxy-3-phenethylsulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

{4-[5-Ethoxy-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-ylsulfanyl]-phenyl}-acetic acid;

3-{4-[5-Ethoxy-2-(1H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-ylsulfanyl]-phenyl}-propionic acid;

5-methoxy-3-o-tolysulfanyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(2,5-dimethoxy-phenyl-sulfanyl)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid(1H-tetrazol-5-yl)-amide;

δ

-Methoxy-δ

-methyl-S-phenylsulfanyl-benzô

thiophenê

-carboxylic acid(1H-tθ

trazol-5-yl)-amide;

δ

-Methoxy-β

-methyl-S-phenethylsulfanyl-bθ

nzotbJthiophenê

-carboxylic acid(1H-tetrazol-5-yl)-amide;

3-cyclohexylmethylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (1T-1-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5-ethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-ethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylmethylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-5-methoxy-6-methoxymethyl-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfanyl-6-ethoxymethyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazo!-5-yl)-amide;

δ

-benzyloxymethyl-S-cyclohexylsulfanyl-δ

-methoxy-benzo[b]thiophenê

-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylsulfany!-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid

(1H-tetrazol-5-yl)-amide;

3-cyclopentylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopropylmethylsulfanyl-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclooctyloxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(2-methyl-cyclohexyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(2-methyl-cyclopentyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(2,4-dimethyl-cyclopentyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(3-methyl-bicyclo[2.2.1]hept-2-ylmethoxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3˜

(3-methyl-cyclohexyloxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,5-dimethyl-cyclohexyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(2-methyl-cyclohexyloxy)-benzofuran-2-carboxylic acid (1H-tθ

trazol-5-yl)-amide;

3-(1-cyclopentyl-ethoxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(1-cyclohexyl-propoxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,4-dimethyl-cyclohexyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,5-dimethyl-cyclohexyloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(decahydro-naphthalen-2-yloxy)-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-3-(1-methy!-cyclomethoxy)-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclobutylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cycloheptyloxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cycloheptylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclopentylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexyloxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-cyclohexylmethoxy-5-methoxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-chloro-3-cycloheptyloxy-benzofuran-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(tetrahydro-pyran-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(3,3,5,5-tetramethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(3,3,5-trimethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(3,3-dimethyl-cyclohexyloxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-cyclohexyloxy-5-methoxy-6-methy!-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(3-methyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-cycloheptyloxy-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-[5-methoxy-6-methyl-2-(2H-tetrazol-5-yl-carbamoyl)-benzo[b]thiophen-3-yloxy-piperidine piperidine-1-carboxylic acid tert-butyl ester;

3-(3-cyclohexyl-propoxy)-5-methoxy-6-methyl-benzo[b}thiophene-2-carboxylic acid (2H-tetrazol-5-yl)amide;

3-(1-acetyl-piperidin-4-yloxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

4-[5-methoxy-6-methyl-2-(2H-tetrazo!-5-ylcarbamoyl)-benzo[b]thiophene-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester;

5-methoxy-6-methyl-3-(1-methyl-cyclopropylmethoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2,2-dichloro-cyclopropylmethoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-cyclohexyloxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-tert-butyl-cyclohexyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-methyl-bicyclo[2.2.1]hept-2-ylmethoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(cyclohex-3-enylmethoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3,5-dimethyl-cyclohexloxy cyclohexyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3-cyclohexyl-propoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-Cyclohexyloxy-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3,3,5-trimethyl-cyc!ohexyloxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(tetrahydro-pyran-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

{4-[5-methoxy-6-methyl-2-(2H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-yloxy]-phenyl}-acetic acid ethyl ester;

3-(4-isopropyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclopentyloxy-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-tert-butyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-bromo-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-fluoro-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxy!ic acid (2H-tetrazol-5-yl)-amide;

3-(4-chloro-2-fluoro-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-(4-trifluoromethoxy-phenoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-[4-(1-carbamoyl-cyclopentyl)-phenoxy]-5-methoxy-6-methyl-benzo[b]-thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5-methoxy-6-methyl-3-[4-(tetrahydro-pyran-4-yl)-phenoxy]-benzo[b]thiophene-2-carboxylic acid(2H-tetrazol-5-yl)-amide;

3-[4-(1,1-dioxo-hexahydro-1λ

⁶-thiopyran-4-yl)-phenoxy]-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide,

5-methoxy-6-methyl-3-(2-nitro-4-cyclohexyl-phenoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2-chloro-4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2-cyano-4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(2-cyclohexylmethoxy-benzyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

3-(3-cyano-phenoxy)-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-difluoromethoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-hydroxy-6-methyl-benzo[b]thiophenO-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-methoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenyl)-5-cyclopropyl-6-methoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-6-cyclopropyl-5-difluoromethyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(4-cyclohexyl-phenoxy)-5-methoxy-6-mθ

thyl-benzo[b]thiophene-2-carboxylic acid methyl-(2H-tetrazol-5-yl)-amide;

3-(2-cyano-4-cyclohexyl-phenoxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-((S)-1-methyl-2-phenyl-ethoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-phenyl-propoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(2-methyl-2-phenyl-propoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-o-tolylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(3,4-dichloro-phenylsulfanyl)-5,6-dimethoxy-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-methoxy-phenylsulfanyl)-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

1-ethyl-5,6-dimethoxy-3-phenyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenyl-1-propyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

1-ethyl-5,6-dimethoxy-3-phenyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-phenyl-1-propyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-o-tolylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

3-(3,4-dichloro-phenylsulfanyl)-5,6-dimethoxy-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-3-(3-methoxy-phenylsulfanyl)-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

5,6-dimethoxy-1-methyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid (2H-tetrazol-5-yl)-amide;

1-ethyl-5,6-dimethoxy-3-phenyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide; and

5,6-dimethoxy-3-phenyl-1-propyl-1H-indole-2-carboxylic acid (1H-tetrazol-5-yl)-amide.

51-72. -72. (canceled)