6-METHOXY-3,4-DIHYDRO-1H-ISOQUINOLIN COMPOUNDS

Abstract

In an embodiment, the present invention provides a compound of the formula:

##STR00001##

wherein R1 is selected from the group consisting of F and H; R2 is selected from the group consisting of CH.sub.3, CH.sub.3CHCH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; R4 is selected from the group consisting of H and CH.sub.3; R5 is selected from the group consisting of H and CH.sub.3; R6 is selected from the group consisting of H and OH; R7 is selected from the group consisting of

##STR00002##

or a pharmaceutically acceptable salt thereof, and methods of using this compound for positive allosteric modulation of a receptor selected from the group consisting of GLP1, GIP, and glucagon.

Claims

1. A compound of the formula: ##STR00047## wherein R1 is selected from the group consisting of F and H; R2 is selected from the group consisting of CH.sub.3, CH.sub.3CHCH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; R4 is selected from the group consisting of H and CH.sub.3; R5 is selected from the group consisting of H and CH.sub.3; R6 is selected from the group consisting of H and OH; R7 is selected from the group consisting of ##STR00048## or a pharmaceutically acceptable salt thereof.

2. A compound of the claim 1, wherein the compound is of the formula: ##STR00049## wherein R1 is selected from the group consisting of F and H; R2 is selected from the group consisting of CH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; R4 is selected from the group consisting of H and CH.sub.3; R5 is selected from the group consisting of H and CH.sub.3; R6 is selected from the group consisting of H and OH; or a pharmaceutically acceptable salt thereof.

3. The compound as claimed by claim 1 wherein R4 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

4. The compound as claimed by claim 1 wherein R5 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

5. The compound as claimed by claim 1 wherein R6 is H, or a pharmaceutically acceptable salt thereof.

6. The compound as claimed by claim 1 wherein R1 is F, or a pharmaceutically acceptable salt thereof.

7. The compound as claimed by claim 1 wherein R3 is H, or a pharmaceutically acceptable salt thereof.

8. The compound as claimed claim 1 wherein R2 is NHCH.sub.2CH(CH.sub.3).sub.2, or a pharmaceutically acceptable salt thereof.

9. The compound as claimed by claim 1 wherein R2 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

10. The compound as claimed by claim 1 wherein the compound is selected from the group consisting of ##STR00050## or a pharmaceutically acceptable salt thereof.

11. The compound as claimed by claim 10 wherein the compound is ##STR00051## or a pharmaceutically acceptable salt thereof.

12. The compound as claimed by claim 1 wherein the compound is ##STR00052## or a pharmaceutically acceptable salt thereof.

13. The compound as claimed by claim 12 wherein the compound is: ##STR00053## or a pharmaceutically acceptable salt thereof.

14. A compound as claimed by claim 13 wherein the compound is a hydrochloride salt.

15. A compound as claimed by claim 1, wherein the compound is ##STR00054## or a pharmaceutically acceptable salt thereof.

16. A compound as claimed by claim 15 wherein the compound is a hydrochloride salt.

17. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 1 and at least one pharmaceutically acceptable carrier, diluent, or excipient.

18. A method for treating type II diabetes mellitus in a mammal comprising administering to the mammal in need thereof, an effective amount of a compound as claimed by claim 1, or a pharmaceutically acceptable salt thereof.

19. A compound of claim 1, or a pharmaceutically acceptable salt thereof, for use as a positive allosteric modulator of a receptor selected from the group consisting of GLP1, GIP, and glucagon.

20. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 1 for use in therapy.

21. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 1 for use in the treatment of type II diabetes mellitus.

22. Use of a compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 1 in the manufacture of a medicament for the treatment of type II diabetes mellitus.

Description

EXAMPLE 1

2-Fluoro-6-(isobutylamino)-4-[(1R)-2-[1-(4-isopropylphenyl)ethyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-5-yl]phenol; dihydrochloride

[0088] ##STR00018##

[0089] Mix 4-bromo-2-fluoro-6-(isobutylamino)phenol (200 mg, 0.76 mmol) and anhydrous 1,4-dioxane (2 mL). Bubble nitrogen through the mixture for 15 min and add bis(pinacolato)diboron (240 mg, 0.9263 mmol), Pd(dppf)Cl.sub.2.Math.DCM (32 mg, 0.038 mmol) and potassium acetate (116 mg, 1.15 mmol). Bubble nitrogen through the mixture for 5 min, seal the reaction vessel and stir at 90° C. for 17 h. Cool the mixture to ambient temperature and add (1R)-5-bromo-2-[1-(4-isopropylphenyl)ethyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline, Isomer 2 (210 mg, 0.52 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (23 mg, 0.026 mmol) and potassium phosphate tribasic (1M in water, 1.5 mL, 1.5 mmol). Seal the reaction vessel and stir the mixture at 90° C. for 4 h. Cool the reaction mixture to ambient temperature and add EtOAc. Wash the organics with a 5% aqueous citric acid, dry over Na.sub.2SO.sub.4, filter and concentrate in-vacuo. Purify the residue on a SCX column eluting with 2N NH.sub.3 in MeOH. Further purify the product by silica gel chromatography using a gradient of 0 to 30% EtOAc in DCM. Purify the product again by silica gel chromatography using a gradient of 0 to 40% EtOAc in hexanes. Further purify the product by SFC (column: Luna® HILIC (30×150 mm, 5 μm); gradient 10% to 20% of (10 mM NH.sub.4HCO.sub.3 in MeOH, pH 8) in CO.sub.2) to obtain the free base of the title compound (68 mg, 17%) as a white solid. ES/MS m/z: 505 [M+H].sup.+.

[0090] Dissolve the free base of the title compound (68 mg, 0.14 mmol) in ACN (3 mL) and add hydrogen chloride (2M in ether, 0.40 mL, 0.8 mmol). Stir for 2 min and remove solvent with a nitrogen stream at 40° C. Dry in-vacuo for 96 h to obtain the title compound (77 mg, 97%) as a dark brown solid. ES/MS m/z: 505 [M+H].sup.+.

Preparation 8

Diethyl 2-acetamido-2-[(2-chloro-3-methoxy-phenyl)methyl]propanedioate

[0091] ##STR00019##

[0092] Mix 1-(bromomethyl)-2-chloro-3-methoxy-benzene (63.9 g, 271 mmol), diethyl acetamidomalonate (60.1 g, 271 mmol), potassium carbonate (75.0 g, 542 mmol) and potassium iodide (45.0 g, 271 mmol) in ACN (958 mL) and heat the mixture to reflux for 2 h under nitrogen. Add diethyl acetamidomalonate (6.6 g, 29.8 mmol) and reflux for further 36 h. Concentrate solvents to ⅓ of the volume and add water and EtOAc. Separate the organic layer and extract the aqueous layer twice with EtOAc. Combine organic layers, wash with water and saturated aqueous NaCl, dry over Na.sub.2SO.sub.4 and concentrate to obtain the title compound (105.7 g, 100%) as a white foam. ES/MS m/z: 372 [M+H].sup.+.

Preparation 9

5-Chloro-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; hydrochloride

[0093] ##STR00020##

[0094] Mix diethyl 2-acetamido-2-[(2-chloro-3-methoxy-phenyl)methyl]propanedioate (105.6 g, 284 mmol), acetic acid (211 mL) and hydrochloric acid (37% in H.sub.2O, 528 mL, 6400 mmol) and heat the mixture to reflux for 18 h under nitrogen. Cool the mixture to 50° C., add formaldehyde (37% in water, 284 mL, 3790 mmol) dropwise and stir at 100° C. for 2 h. Cool the mixture to 0° C. and stir for 30 min. Filter the resulting solid, wash with water and dry to obtain the title compound (68.8 g, 87%) as a white solid. ES/MS m/z: 242 [M+H].sup.+.

Preparation 10

Methyl 5-chloro-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Isomer 1 and Isomer 2)

[0095] ##STR00021##

[0096] Suspend 5-chloro-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (60.5 g, 218 mmol) in methanol (860 mL) and stir at 5° C. under nitrogen. Add thionyl chloride (77.6 g, 653 mmol) dropwise and reflux the mixture for 20 h under nitrogen. Cool the mixture to ambient temperature and remove the solvents in-vacuo. Triturate the residue with EtOAc, then filter and wash the solid with EtOAc. Dry the solid under vacuum at 40° C. overnight to obtain the hydrochloride salt of the title compound (58.8 g, 92%) as a racemic mixture.

[0097] Suspend a portion of the solid (15.00 g, 49.80 mmol) in saturated aqueous K.sub.2CO.sub.3 (15 mL) and stir at ambient temperature for 30 min. Filter the solid and wash with water. Dry the white solid in-vacuo at 40° C. Dissolve the solid in DCM and filter through a silica plug using a gradient 0 to 5% MeOH in DCM to give the title compound (12.18 g) as a racemic mixture. ES/MS m/z 256 [M+H].sup.+.

[0098] Separate a portion of the racemic mixture (10.15 g) by chiral SFC (column: Chiralpak® IG (25×2 cm, 5 μm); mobile phase: 15% (MeOH+0.2% dimethylethylamine) in CO.sub.2; temperature: ambient; flow rate: 80 g/min; outlet pressure: 120 bar) to obtain Isomer 1 (first-eluting, 2.69 g, 26%) and Isomer 2 (second-eluting, 4.10, 40%) of the title compound. Analytical chiral SFC (column: Chiralpak® IG (10 cm×4.6 mm, 5 μm); mobile phase: 15 to 55% (methanol+0.2% isopropanamine) in CO.sub.2; temperature: 40° C.; flow rate: 4 mL/min; outlet pressure: 120 bar) shows both Isomer 1 (retention time: 1.58 min) is >98% ee and Isomer 2 (retention time: 1.66 min) is 95% ee.

Preparation 11

O2-tert-Butyl O3-methyl 5-chloro-6-methoxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate

[0099] ##STR00022##

[0100] Add di-tert-butyl dicarbonate (3.5 g, 16 mmol) to a solution of methyl 5-chloro-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Isomer 1, 3.6 g, 14 mmol) in DCM (70 mL) and stir at ambient temperature for 4 h. Remove the solvent under reduced pressure and purify the residue by silica gel chromatography using a gradient of 0 to 20% EtOAc in DCM. Wash the solid with hexane and filter to obtain the title compound (4.55 g, 90%) as a white solid. ES/MS m/z: 256 [M+H−BOC].sup.+.

Preparation 12

tert-Butyl 5-chloro-3-(hydroxymethyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0101] ##STR00023##

[0102] Add lithium borohydride (2.0 M in THF, 13 mL, 26 mmol) to a solution of O2-tert-butyl O3-methyl 5-chloro-6-methoxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate (4.55 g, 12.8 mmol) in anhydrous THF (40 mL) at ambient temperature and stir for 6 h. Add water and stir the mixture at ambient temperature for 10 min. Dilute with water and extract twice with EtOAc. Combine the organic layers and wash with water, saturated aqueous NaHCO.sub.3 and saturated aqueous NaCl. Dry the organics over anhydrous Na.sub.2SO.sub.4, filter and concentrate in-vacuo. Dry the residue in-vacuo at ambient temperature for 17 h to obtain the title compound (4.4 g, 100%) as a waxy solid. ES/MS m/z: 272 [M+H−Boc].sup.+.

Preparation 13

tert-Butyl 5-chloro-6-methoxy-3-(methoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0103] ##STR00024##

[0104] Add sodium hydride (60% in oil, 2.1 mg, 0.053 mmol) to a 0° C. solution of tert-butyl 5-chloro-3-(hydroxymethyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (4.4 g, 13 mmol) and iodomethane (8.1 mL, 130 mmol) in anhydrous DMF (87 mL) and stir the reaction for 10 min. Add water dropwise until no gas evolution is observed and partition the mixture between water and ethyl acetate. Wash the organic layer with water and saturated aqueous NaCl, dry over anhydrous Na.sub.2SO.sub.4, filter and concentrate in-vacuo. Purify the residue by silica gel chromatography using a gradient of 0 to 10% EtOAc in DCM to obtain the title compound (4.5 g, 94%) as a waxy solid. ES/MS m/z: 242 [M+H−t-Bu].sup.+.

Preparation 14

4-[6-Methoxy-3-(methoxymethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-phenol;hydrochloride

[0105] ##STR00025##

[0106] Dissolve tert-butyl 5-chloro-6-methoxy-3-(methoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.68 g, 7.84 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.45 g, 9.42 mmol) in 2-methyl-2-butanol (54 mL) in a resealable tube and purge with a nitrogen stream for 30 min while stirring. Add chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,11-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (2.sup.nd generation XPhos precatalyst, 325 mg, 0.39 mmol) and potassium phosphate tribasic (1M in water, 16 mL, 16 mmol), seal the vessel and heat the mixture at 85° C. for 2 h. Allow the mixture to cool to ambient temperature, filter through Celite® and rinse with EtOAc. Wash the organic layer with water and saturated aqueous NaCl, dry over anhydrous Na.sub.2SO.sub.4, filter and concentrate in-vacuo. Purify by silica gel chromatography using a gradient of 0 to 10% EtOAc in DCM. Dissolve the material in DCM (30 mL), add hydrogen chloride (4M in 1,4-dioxane, 10 mL, 40 mmol) and stir the mixture at ambient temperature for 1.5 h. Remove the solvents, then triturate the solid with EtOAc and filter. Wash the solid with EtOAc to obtain the title compound (2.6 g, 91%) as a white solid. ES/MS m/z: 314 [M+H].sup.+.

EXAMPLE 2

4-[2-[(2-Hydroxy-4-isopropyl-phenyl)methyl]-6-methoxy-3-(methoxymethyl)-3,4-dihydro-1H-isoquinolin-5-yl]-2-methyl-phenol; hydrochloride

[0107] ##STR00026##

[0108] Suspend 4-[6-methoxy-3-(methoxymethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-phenol; hydrochloride (157 mg, 0.45 mmol) in DCM (3 mL) and add 4-isopropylsalicylaldehyde (0.11 mL, 0.71 mmol) and triethylamine (0.19 mL, 1.35 mmol). After 20 min add sodium triacetoxyborohydride (294 mg, 1.35 mmol) and stir the mixture at ambient temperature for 16 h. Add 4-isopropylsalicylaldehyde (0.060 mL, 0.39 mmol) and sodium triacetoxyborohydride (151 mg, 0.69 mmol) and stir the mixture for 6 h. Dilute the mixture with DCM and wash with saturated aqueous NH.sub.4C1. Extract the aqueous layer with DCM. Combine the organic layers, dry over Na.sub.2SO.sub.4, filter and concentrate in-vacuo. Purify the residue by silica gel chromatography using a gradient of 0 to 25% EtOAc in DCM. Further purify by chromatography in silica gel eluting with hexane/EtOAc 3:1 followed by 2:1. Load onto a SCX column and elute the compound with 2N NH.sub.3 in MeOH. Dissolve the compound in DCM (1 mL) and add hydrogen chloride (2M in ether, 0.50 mL, 1.0 mmol). Concentrate to dryness and dry under high vacuum at 40° C. for 48 h to obtain the title compound (138 mg, 73%) as a white solid. ES/MS m/z: 462 [M+H].sup.+.

Preparation 15

2-Fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0109] ##STR00027##

[0110] Dissolve 4-bromo-2-fluoro-6-methyl-phenol (24 g, 94 mmol), bis(pinacolato)diboron (28 g, 110 mmol) and potassium acetate (13 g, 130 mmol) in degassed anhydrous 1,4-dioxane (200 mL). Add Pd(dppf)Cl.sub.2.Math.DCM (5 g, 6.0 mmol). Bubble nitrogen through the mixture for 5 min and stir at 85° C. for 2 h. Dilute the reaction mixture with DCM and filter through Celite®. Concentrate the mixture in-vacuo and dilute with EtOAc and water. Separate the layers and wash the organic layer with water, dry over anhydrous MgSO.sub.4, filter and concentrate in-vacuo. Purify the residue by silica gel chromatography using a gradient of 0 to 10% MTBE in hexanes to obtain the title compound (14.5 g, 61%) as a white solid. ES/MS m/z: 251 [M−H].sup.+.

EXAMPLE 3

2-Fluoro-4-[(1R)-2-[1-(4-isopropylphenyl)ethyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-5-yl]-6-methyl-phenol; hydrochloride

[0111] ##STR00028##

[0112] Bubble nitrogen for 5 min through a mixture of (1R)-5-bromo-2-[1-(4-isopropylphenyl)ethyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline (Isomer 2, 31 mg, 0.077 mmol), 2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.12 mmol), potassium phosphate tribasic (1 M aqueous solution, 0.17 mL, 0.17 mmol), and 2-methyl-2-butanol. Add (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1-1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3, 4 mg, 0.5 μmol) and heat the mixture to 100° C. for 3 h. Cool the mixture to room temperature and pour onto a SCX column. Elute the column with MeOH and then NH.sub.3 in MeOH (2 M). Remove the solvent from the NH.sub.3/MeOH elution in-vacuo. Purify the residue by silica gel chromatography using a gradient of 7 to 30% EtOAc in hexanes to obtain the free base of the title compound (28 mg), then add ACN and add hydrogen chloride (2M in diethylether, 0.20 mL, 0.31 mmol). Remove solvents with a nitrogen stream and dry the material at 40° C. under high vacuum overnight to obtain the title compound (26 mg, 85%) as a white solid. ES/MS m/z: 448 [M+H].sup.+.

##STR00029## ##STR00030## ##STR00031##

Preparation 17

2-Benzyloxy-1-bromo-3-fluoro-5-iodo-benzene

[0113] ##STR00032##

[0114] Dissolve 2-bromo-6-fluoro-4-iodo-phenol (3.66 g, 11.5 mmol) and potassium carbonate (3.2 g, 23 mmol) in DMF (23 mL) and stir at rt for 5 min. Add benzyl bromide (2.1 mL, 18 mmol) by syringe and stir at rt for 2 hours. Add AcOEt and water, separate layers and wash the organic layer with water, dry over MgSO.sub.4, filter and concentrate in-vacuo to obtain a brown oil. Purify by flash chromatography eluting with a gradient of 0-20% of DCM in hexane to obtain the title compound (4.53 g, 96% yield) as a white solid.

Preparation 18

tert-Butyl (1R)-6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0115] ##STR00033##

[0116] Combine preparation 4 (1000 mg, 2.81 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1000 mg, 3.94 mmol) and potassium acetate (520 mg, 5.30 mmol) in degassed 1,4-dioxane (20 mL) in a microwave tube. Add tris(benzylideneacetone)dipalladium(0) (160 mg, 0.17 mmol) and tricyclohexylphosphine (120 mg, 0.42 mmol). Degass the mixture for 5 minutes, cap and heat in a microwave at 150° C. for 1 hour. Purify by flash chromatography eluting with a gradient of 0-20% of methyl tert-butyl ether in hexane to obtain the title compound as a yellow oil (942 mg, 75% yield). MS(ESI) m/z: 304 [M+H−(t-Bu)].sup.+.

Preparation 19

tert-Butyl (1R)-5-(4-benzyloxy-3-bromo-5-fluoro-phenyl)-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0117] ##STR00034##

[0118] Dissolve tert-butyl (1R)-6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (3380 mg, 8.38 mmol), 2-benzyloxy-1-bromo-3-fluoro-5-iodo-benzene (4100 mg, 10.07 mmol), sodium carbonate (2.7 g, 25.0 mmol) in 1,4-dioxane (67 mL) and water (17 mL) in a resealable tube. Bubble nitrogen through the solution for 5 minutes and add tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.43 mmol). Cap the tube and stirr at 90° C. for 5 h. Concentrate, adsorbed on Celite® and purify by flash chromatography eluting with a gradient of 0-30% of methyl tert-butyl ether in hexane to obtain the title compound as a white solid (3.07 g, 90% yield).

[0119] MS(ESI) m/z: 502 [M+H−(t-Bu)].sup.+.

Preparation 20

tert-Butyl (1R)-5-(4-benzyloxy-3-fluoro-5-isopropenyl-phenyl)-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0120] ##STR00035##

[0121] Dissolve tert-butyl (1R)-5-(4-benzyloxy-3-bromo-5-fluoro-phenyl)-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (150 mg, 0.27 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.59 mmol), sodium carbonate (85 mg, 0.80 mmol) in 1,4-dioxane (4 mL) and water (0.27 mL) in a resealable tube. Bubble nitrogen for 5 minutes and add tetrakis(triphenylphosphine)palladium(0)) (17 mg, 0.015 mmol), cap and stir at 90° C. for 18 h. Concentrate and adsorbed on Celite®, and purify by flash chromatography eluting with a gradient of 20-60% of methyl tert-butyl ether in hexane to obtain the title compound as a colorless oil (200 mg, 49% yield). MS(ESI) m/z: 418 [M+H−Boc].sup.+.

Preparation 21

tert-Butyl (1R)-5-(3-fluoro-4-hydroxy-5-isopropyl-phenyl)-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0122] ##STR00036##

[0123] Dissolve tert-butyl (1R)-5-(4-benzyloxy-3-fluoro-5-isopropenyl-phenyl)-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (270 mg, 0.25 mmol) in methanol (5 mL), add palladium (10% on C, 400 mg, 0.36 mmol). Stir the mixture under a hydrogen atmosphere (1 atm) at room temperature for 18 hours. Filter over Celite® and wash with ethanol. Remove the solvent in-vacuo to obtain the title compound as a brown oil (134 mg, 60% yield). MS(ESI) m/z: 374 [M+H−(t-Bu)].sup.+.

Preparation 22

2-Fluoro-6-isopropyl-4-[(1R)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]phenol

[0124] ##STR00037##

[0125] Dissolve (1R)-5-(3-fluoro-4-hydroxy-5-isopropyl-phenyl)-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (134 mg, 0.25 mmol) in DCM (1.2 mL), add hydrochloric acid (4M in dioxane, 0.3 mL, 1 mmol). Stir the mixture at room temperature for 2 hours. Remove the solvent and purify by SCX eluting with methanol followed by 2N NH.sub.3 in methanol. Combine the basic fractions and remove the solvent to obtain the title compound (120 mg, 68 mass %, 99% yield). MS(ESI) m/z: 330 [M+H].sup.+

Preparation 23

4-[(1R)-2-[(4,4-Dimethylcyclohexyl)methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-5-yl]-2-fluoro-6-isopropyl-phenol

[0126] ##STR00038##

[0127] Add 4,4-dimethylcyclohexane-1-carbaldehyde (77 mg, 0.49 mmol) to a solution of 2-fluoro-6-isopropyl-4-[(1R)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]phenol (120 mg, 0.25 mmol) in DCM (3 mL). Stir the mixture at room temperature for 30 min and add sodium triacetoxyborohydride (100 mg, 0.47 mmol). Stir the reaction at room temperature for 4 hours. Add water and dichloromethane. Extract the aqueous layer with dichloromethane. Combine the organic layers, wash with saturated aqueous NaCl, dry over anhydrous magnesium sulphate, filter and concentrate in-vacuo. Purify by flash chromatography eluting with a gradient of 0% to 20% acetone in hexane to obtain the title compound as a colorless oil (90 mg, 78% yield). MS(ESI) m/z: 454 [M+H].sup.+

EXAMPLE 4

Synthesis of 4-[(1R)-2-[(4,4-Dimethylcyclohexyl)methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-5-yl]-2-fluoro-6-isopropyl-phenol;hydrochloride

[0128] ##STR00039##

[0129] Dissolve 4-[(1R)-2-[(4,4-dimethylcyclohexyl)methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-5-yl]-2-fluoro-6-isopropyl-phenol (90 mg, 0.19 mmol) in ACN (1 mL), add hydrochloric acid (2 M in diethyl ether, 0.18 mL, 0.36 mmol). Sonicate the mixture at room temperature for 5 minutes. Remove solvents and dry the material at 45° C. in-vacuo for 18 hours to obtain the title compound as a tan solid (90 mg, 94% yield). MS(ESI) m/z: 454 [M+H].sup.+.

Biological Assays

Human GIP Receptor Potentiator Assay

[0130] GIP Receptor (GIPR) functional activity is determined using cAMP formation in an HEK293 clonal cell line expressing human GIPR (NCBI accession number NP_000155). The assay measures compound induced cAMP production in the presence of an EC.sub.20 dose of the GIPR agonist GIP(1-42). The hGIPR receptor expressing cells are treated with 25 pM of GIP(1-42) (Labcyte Echo direct dilution) and a dose response of test compound (10 point concentration-response curve in DMSO, 3-fold Labcyte Echo direct dilution, 384 well plate Corning Cat #3570) in DMEM (Gibco Cat #31053) supplemented with 1× GlutaMAX™ (Gibco Cat #35050), 0.1% bovine casein (Sigma C4765-10ML), 250 μM IBMX (3-Isobutyl-1-methylxanthine, Acros Cat #228420010) and 20 mM HEPES (Gibco Cat #15630) in a 20 μL assay volume (final DMSO concentration is 1.0%). After a 30 min incubation at 37° C., the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). Briefly, cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 μL) followed by the antibody anti-cAMP-Eu.sup.3+-Cryptate, also in cell lysis buffer (10 μL). The resulting competitive assay is incubated for at least 60 min at room temperature, then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665 nm/620 nm*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed. A relative EC.sub.50 value and percent top (E.sub.max) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation. The EC.sub.50 and E.sub.max data when the compounds of Examples 1 and 3 are tested in the cAMP assay described above are shown in Table 1. These data indicate that the compounds of Examples 1 and 3 are positive allosteric modulators of the human GIP receptor.

TABLE-US-00001 TABLE 1 HEK293 GIPR cell line intracellular cAMP response. Example EC.sub.50 (nM) and SEM (n) E.sub.max (%) ± SEM (n) Example 1 11.9 (5.6, n = 4)   101 ± 7 (n = 4) Example 3 37.5 (22.1, n = 4) 91.0 ± 8 (n = 4)

Human GLP-1 Receptor Potentiator Assay

[0131] GLP-1 Receptor (GLP-1R) functional activity is determined using cAMP formation in an HEK293 clonal cell line expressing human GLP-1R (NCBI accession number NP_002053). The assay measures compound induced cAMP production in the presence of an EC.sub.20 dose of the GLP-1R agonist Oxyntomodulin. The GLP-1R expressing cells are treated with 5 nM of the GLP-1R agonist oxyntomodulin (Bachem Cat #H-6058) and a dose response of test compound (10 point concentration-response curve in DMSO, 3-fold Labcyte Echo direct dilution, 384 well plate Corning Cat #3570) in DMEM (Gibco Cat #31053) supplemented with 2 mM L-glutamine (Gibco Cat #25030), 0.25% fetal bovine serum (Gibco Cat #16000-044), 0.05% fraction V bovine serum albumin (Gibco Cat #15260), 1× Penicillin/Streptomycin (HyClone Cat #SV30010), 250 μM IBMX (3-Isobutyl-1-methylxanthine, Acros Cat #228420010) and 20 mM HEPES (HyClone Cat #SH30237.01) in a 20 μL assay volume (final DMSO concentration is 0.56%). After 60 min incubation at room temperature, the resulting increase in intracellular cAMP is quantitatively determined using a custom CisBio cAMP Hybrid HTRF Assay Kit (60MISZZZ). Briefly, cAMP levels within the cell are detected by adding the Dynamic 2 cAMP-d2 conjugate in cell lysis buffer (10 μL) followed by the HiRange antibody anti-cAMP-Eu.sup.3+-Cryptate, also in cell lysis buffer (10 The resulting competitive assay is incubated for at least 60 min at RT, then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665 nm/620 nm*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed. A relative EC.sub.50 value and percent top (E.sub.max) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation. The EC.sub.50 and E.sub.max data when the compound of Example 2 is tested in the cAMP assay described above is shown in Table 2. This data indicates that the compound of Example 2 is a positive allosteric modulator of the human GLP-1 receptor.

TABLE-US-00002 TABLE 2 HEK293 GLP-1R cell line intracellular cAMP response. Example EC.sub.50 (nM) and SEM (n) E.sub.max (%) ± SEM (n) Example 2 15.7 (8.1, n = 10) 181 ± 35 (n = 10)
Certain embodiments contemplated by the invention are the following:

[0132] 1. A compound of the formula:

##STR00040## [0133] wherein [0134] R1 is selected from the group consisting of F and H; [0135] R2 is selected from the group consisting of CH.sub.3, CH.sub.3CHCH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; [0136] R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; [0137] R4 is selected from the group consisting of H and CH.sub.3; [0138] R5 is selected from the group consisting of H and CH.sub.3; [0139] R6 is selected from the group consisting of H and OH; [0140] R7 is selected from the group consisting of

##STR00041##  or [0141] a pharmaceutically acceptable salt thereof.

[0142] 2. A compound of the formula:

##STR00042## [0143] wherein [0144] R1 is selected from the group consisting of F and H; [0145] R2 is selected from the group consisting of CH.sub.3 and —NHCH.sub.2CH(CH.sub.3).sub.2; [0146] R3 is selected from the group consisting of H and —CH.sub.2OCH.sub.3; [0147] R4 is selected from the group consisting of H and CH.sub.3; [0148] R5 is selected from the group consisting of H and CH.sub.3; [0149] R6 is selected from the group consisting of H and OH; or [0150] a pharmaceutically acceptable salt thereof.

[0151] 3. The compound of any one of embodiments 1 to 2 wherein R4 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

[0152] 4. The compound of any one of embodiments 1 to 3 wherein R5 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

[0153] 5. The compound of any one of embodiments 1 to 4 wherein R6 is H, or a pharmaceutically acceptable salt thereof.

[0154] 6. The compound of any one of embodiments 1 to 5 wherein R1 is F, or a pharmaceutically acceptable salt thereof.

[0155] 7. The compound of any one of embodiments 1 to 6 wherein R3 is H, or a pharmaceutically acceptable salt thereof.

[0156] 8. The compound of any one of embodiments 1 to 7 wherein R2 is NHCH.sub.2CH(CH.sub.3).sub.2, or a pharmaceutically acceptable salt thereof.

[0157] 9. The compound of any one of embodiments 1 to 7 wherein R2 is CH.sub.3, or a pharmaceutically acceptable salt thereof.

[0158] 10. The compound of embodiment 1 wherein the compound is selected from the group consisting of

##STR00043## [0159] or a pharmaceutically acceptable salt thereof.

[0160] 11. The compound of embodiment 10 wherein the compound is

##STR00044##

or a pharmaceutically acceptable salt thereof.

[0161] 12. The compound of embodiment 1 wherein the compound is

##STR00045## [0162] or a pharmaceutically acceptable salt thereof.

[0163] 13. The compound of embodiment 12 wherein the compound is:

##STR00046## [0164] or a pharmaceutically acceptable salt thereof.

[0165] 14. A compound of any one of embodiments 1 to 13 wherein the compound is a hydrochloride salt.

[0166] 15. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 14 and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0167] 16. A method for treating type II diabetes mellitus in a mammal comprising administering to the mammal an effective amount of a compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof.

[0168] 17. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 14 for use in therapy.

[0169] 18. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 14 for use in the treatment of type II diabetes mellitus.

[0170] 19. Use of a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 14 in the manufacture of a medicament for the treatment of type II diabetes mellitus.

[0171] 20. A compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 14, for use in positive allosteric modulation of a receptor selected from the group consisting of GLP1, GIP, and glucagon.

[0172] 21. A compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 2 to 14, for use in positive allosteric modulation of a GLP1 receptor.