Tetrahydro-benzo[d]azepine derivatives as GPR120 modulators

Abstract

Novel tetrahydroisoquinoline and tetrahydrobenzazepine compounds of formula (I) capable of modulating the G-protein-coupled receptor GPR120, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as of diabetes, inflammation, obesity and metabolic diseases. ##STR00001##

Claims

1. A compound of formula (I): ##STR00171## wherein Ar is a fused benzo group; m.sub.1 is 1 and m.sub.2 is 2; J is —C(R.sup.21R.sup.22)—; X is —O—, —S— or —C(R.sup.31R.sup.32)—, Y is —O— or —C(R.sup.41R.sup.42)—, Z is —C(R.sup.51R.sup.52)—, and n.sub.1, n.sub.2 and n.sub.3 are independently selected from 0 or 1 with the proviso that at least one of n.sub.1, n.sub.2 and n.sub.3 must be 1 and at least one of X, Y or Z must be —C(R.sup.31R.sup.32)—, —C(R.sup.41R.sup.42)—, or —C(R.sup.51R.sup.52)— respectively; when X and Y are —C(R.sup.31R.sup.32)— and —C(R.sup.41R.sup.42)— respectively, R.sup.31 and R.sup.41 may be combined to form, together with X and Y, a (C.sub.3-C.sub.5)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo; when Y and Z are —C(R.sup.41R.sup.42)— and —C(R.sup.51R.sup.52)— respectively, R.sup.41 and R.sup.51 may be combined to form, together with Y and Z, a (C.sub.3-C.sub.5)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo; when X, Y and Z are —C(R.sup.31R.sup.32)—, —C(R.sup.41R.sup.42)— and —C(R.sup.51R.sup.52)— respectively, R.sup.31 and R.sup.51 may form, together with X, Y and Z a (C.sub.4-C.sub.7)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo; R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.21, R.sup.22, R.sup.31, R.sup.32, R.sup.41, R.sup.42, R.sup.51, and R.sup.52 are independently selected from hydrogen, deuterium, halo, or (C.sub.1-C.sub.3)alkyl optionally substituted by halo; A is —CO.sub.2H, —CO.sub.2R.sup.3, —CH.sub.2OH, tetrazolyl, or 3-hydroxyisoxazol-5-yl; R.sup.3 is (C.sub.1-C.sub.6)alkyl, or (C.sub.1-C.sub.6)cycloalkyl; Ar is optionally substituted 1, 2 or 3 times by W, where W is (C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)alkoxy, (C.sub.2-C.sub.10)dialkylamino, (C.sub.1-C.sub.10)alkylthio, (C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)heterocycloalkyl, halo, (C.sub.1-C.sub.10)haloalkyl, (C.sub.1-C.sub.10)perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl, and when Ar is substituted by a plurality of substituents, each substituent is selected independently; G is an optionally substituted phenyl ring; G is optionally substituted one or more times by B, where B is (C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)alkoxy, (C.sub.2-C.sub.10)dialkylamino, (C.sub.1-C.sub.10)alkylthio, (C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)heterocycloalkyl, halo, (C.sub.1-C.sub.10)haloalkyl, (C.sub.1-C.sub.10)perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, cyano, or E-M where E is —O—, —S— or —N(R.sup.4)— and M is optionally substituted (C.sub.1-C.sub.7)alkyl, (C.sub.3-C.sub.7)cycloalkyl, fluoro(C.sub.1-C.sub.3)alkyl, a 5- to 10-membered heterocyclic group or an optionally substituted 6- to 10-membered aryl group, and when G is substituted by a plurality of substituents, each substituent is selected independently; R.sup.4 is hydrogen, deuterium, or (C.sub.1-C.sub.3)alkyl optionally substituted by halo; or a pharmaceutically acceptable salt thereof, or corresponding N-oxide.

2. A compound according to claim 1 wherein R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.21 and R.sup.22 are hydrogen.

3. A compound according to claim 1 which is a compound of formula (Id): ##STR00172## R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.21 and R.sup.22 are hydrogen; n.sub.1 is 0, Y is —C(R.sup.41R.sup.42)— and Z is —C(R.sup.51R.sup.52), and n.sub.2 and n.sub.3 are independently selected from 0 or 1 with the proviso that at least one of n.sub.2 and n.sub.3 must be 1; when Y and Z are —C(R.sup.41R.sup.42)— and —C(R.sup.51R.sup.52)— respectively, R.sup.41 and R.sup.51 may be combined to form, together with Y and Z, a (C.sub.3-C.sub.6)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo; R.sup.31, R.sup.32, R.sup.41, R.sup.42, R.sup.51, and R.sup.52 are independently selected from hydrogen, deuterium, halo, or (C.sub.1-C.sub.3)alkyl optionally substituted by halo; A is —CO.sub.2H; the phenyl ring is optionally substituted 1, 2 or 3 times by W where W is (C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)alkoxy, (C.sub.2-C.sub.10)dialkylamino, (C.sub.1-C.sub.10)alkylthio, (C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)heterocycloalkyl, halo, (C.sub.1-C.sub.10)haloalkyl, (C.sub.1-C.sub.10)perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl and where when the phenyl ring is substituted by a plurality of substituents, each substituent is selected independently; G is an optionally substituted phenyl ring; G is optionally substituted one or more times by B where B is (C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)alkoxy, (C.sub.2-C.sub.10)dialkylamino, (C.sub.1-C.sub.10)alkylthio, (C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)heterocycloalkyl, halo, (C.sub.1-C.sub.10)haloalkyl, (C.sub.1-C.sub.10)perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, cyano, or E-M where E is —O—, —S— or —N(R.sup.4)— and M is optionally substituted (C.sub.1-C.sub.7)alkyl, (C.sub.3-C.sub.7)cycloalkyl, fluoro(C.sub.1-C.sub.3)alkyl, a 5- to 10-membered heterocyclic group or an optionally substituted 6- to 10-membered aryl group, and where when G is substituted by a plurality of substituents, each substituent is selected independently; R.sup.4 is hydrogen, deuterium, or (C.sub.1-C.sub.3)alkyl optionally substituted by halo; or a pharmaceutically acceptable salt thereof, or corresponding N-oxide.

4. A compound according to claim 3 wherein X—Y—Z-A is —CH.sub.2—CH.sub.2—COOH, —CH.sub.2CH(CH.sub.3)COOH or ##STR00173##

5. A compound according to claim 3 wherein W is optionally substituted (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo or optionally substituted (C.sub.1-C.sub.6)alkoxy, or wherein the phenyl ring is not substituted by W.

6. A compound according to claim 3 wherein G is substituted 1, 2 or 3 times by B.

7. A compound according to claim 1 wherein the compound is selected from the group consisting of: 3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, 3-(3-(5-cyclobutoxy-2-fluorophenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, 3-(3-(5-cyclopropoxy-2-fluorophenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, 3-(3-(3-fluoro-5-isopropoxyphenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, 3-(3-(2-fluoro-5-isopropoxyphenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, 3-(3-(2-fluoro-5-phenoxyphenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, (R)-3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-2-methylpropanoic acid, 2-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylic acid, 3-(3-(5-cyclobutoxy-2-fluorophenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid, and 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoic acid; or a pharmaceutically acceptable salt thereof.

8. A method of treating a subject suffering from or susceptible to, a disease or condition associated with GPR120 activity, which method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound according to formula (I), ##STR00174## wherein Ar is a fused benzo group; m.sub.1 is 1 and m.sub.2 is 2; J is —C(R.sup.21R.sup.22)—; X is —O—, —S— or —C(R.sup.31R.sup.32)—, Y is —O— or —C(R.sup.41R.sup.42)—, Z is —C(R.sup.51R.sup.52)—, and n.sub.1, n.sub.2 and n.sub.3 are independently selected from 0 or 1 with the proviso that at least one of n.sub.1, n.sub.2 and n.sub.3 must be 1 and at least one of X, Y or Z must be —C(R.sup.31R.sup.32)—, —C(R.sup.41R.sup.42)—, or —C(R.sup.51R.sup.52)— respectively: when X and Y are —C(R.sup.31R.sup.32)— and —C(R.sup.41R.sup.42)— respectively, R.sup.31 and R.sup.41 may be combined to form, together with X and Y, a (C.sub.3-C.sub.5)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo; when Y and Z are —C(R.sup.41R.sup.42)— and —C(R.sup.51R.sup.52)— respectively, R.sup.41 and R.sup.51 may be combined to form, together with Y and Z, a (C.sub.3-C.sub.5)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo: when X, Y and Z are —C(R.sup.31R.sup.32), —C(R.sup.41R.sup.42) and —C(R.sup.51R.sup.52)— respectively, R.sup.31 and R.sup.51 may form, together with X, Y and Z a (C.sub.4-C.sub.7)cycloalkyl ring which may be optionally substituted by (C.sub.1-C.sub.3)alkyl or halo; R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.21, R.sup.22, R.sup.31, R.sup.32, R.sup.41, R.sup.42, R.sup.51, and R.sup.52 are independently selected from hydrogen, deuterium, halo, or (C.sub.1-C.sub.3)alkyl optionally substituted by halo: A is —CO.sub.2H, —CO.sub.2R.sup.3, —CH.sub.2OH, tetrazolyl, or 3-hydroxyisoxazol-5-yl; R.sup.3 is (C.sub.3-C.sub.6)alkyl, or (C.sub.1-C.sub.6)cycloalkyl; Ar is optionally substituted 1, 2 or 3 times by W, where W is (C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)alkoxy, (C.sub.2-C.sub.10)dialkylamino, (C.sub.1-C.sub.10)alkylthio, (C.sub.2-C.sub.0)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)heterocycloalkyl, halo, (C.sub.1-C.sub.10)haloalkyl, (C.sub.1-C.sub.10)perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl, and when Ar is substituted by a plurality of substituents, each substituent is selected independently; G is an optionally substituted phenyl ring; G is optionally substituted one or more times by B, where B is (C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)alkoxy, (C.sub.2-C.sub.10)dialkylamino, (C.sub.1-C.sub.10)alkylthio, (C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)heterocycloalkyl, halo, (C.sub.1-C.sub.10)haloalkyl, (C.sub.1-C.sub.10)perhaloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, cyano, or E-M where E is —O—, —S— or —N(R.sup.4)— and M is optionally substituted (C.sub.1-C.sub.7)alkyl, (C.sub.3-C.sub.7)cycloalkyl, fluoro(C.sub.1-C.sub.3)alkyl, a 5- to 10-membered heterocyclic group or an optionally substituted 6- to 10-membered aryl group, and when G is substituted by a plurality of substituents, each substituent is selected independently; R.sup.4 is hydrogen, deuterium, or (C.sub.1-C.sub.3)alkyl optionally substituted by halo; or a pharmaceutically acceptable salt thereof, or corresponding N-oxide; and wherein the disease or condition is selected from the group consisting of type 1 or 2 diabetes, obesity, hyperglycaemia, glucose intolerance, insulin resistance, hyperinsulinaemia, non-alcoholic steatohepatitis (“NASH”), diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy.

9. A method for modulating circulating insulin concentration in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound according to claim 1.

10. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.

11. A process for the preparation of a compound according to claim 1 comprising: reacting a compound of formula (II) ##STR00175## with a compound of formula (III) ##STR00176##

Description

EXAMPLES

(1) General Experimental Conditions

(2) All starting materials and solvents were obtained either from commercial sources or prepared according to literature methods.

(3) Silica gel chromatography was performed on an automated flash chromatography system, such as CombiFlash Companion, CombiFlash Rf system or Reveleris X2 flash system using RediSep® Rf or Reveleris® or the GraceResolv™ pre-packed silica (230-400 mesh, 40-63 μm) cartridges.

(4) Analytical LCMS experiments to determine retention times and associated mass ions were performed using either:

(5) Waters Acquity H-class UPLC system with a QDa mass detector;

(6) Agilent 1200 series HPLC system coupled to an Agilent 6110 or 6120 series single quadrupole mass spectrometer; or

(7) Dionex Ultimate 3000 series HPLC system coupled to an Advion expression CMS using APCI ionization.

(8) Preparative HPLC purifications were performed using a Waters X-Select CSH C18, 5 μm, 19×50 mm column using a gradient of 0.1% formic acid in MeCN and 0.1% aqueous formic acid. Fractions were collected following detection by either UV at a single wavelength measured by a variable wavelength detector on a Gilson 215 or a Varian PrepStar preparative HPLC, or by mass ion and UV detection at a single wavelength measured by a ZQ single quadropole mass spectrometer, with positive and negative ion electrospray, and dual wavelength detection on a Waters FractionLynx LCMS.

(9) NMR spectra were recorded using a Bruker Avance III 400 MHz instrument or a Bruker Avance III HD 500 MHz instrument, using either residual non-deuterated solvent or tetra-methylsilane as reference.

(10) High-resolution mass spectra (HRMS) were obtained on a Bruker micrOTOF-Q II (ESI).

(11) pEC50 data was obtained by the following procedure:

(12) Human GPR120-β Arrestin 2 Bio-Luminescence Resonance Energy Transfer (BRET) Agonist Assay Procedure

(13) HEK293T cells were cultured in growth media composed of DMEM L-glutamine media supplemented with 10% (v:v) fetal bovine serum (FBS) and 1% (v:v) 10,000 units penicillin/10 mgml.sup.−1 streptomycin at 37° C., 5% CO.sub.2. HEK293T cells transiently co-expressing human GPR120 (FFA1) and b-arrestin 2 were generated by transfection with plasmids encoding a construct of hGPR120 (FFA1) fused at its C terminal with enhanced yellow fluorescent protein (eYFP), and another encoding β-arrestin 2 fused to Renilla luciferase (RLuc), using Polyethylenimine (PEI) as the transfection reagent.

(14) Transfected cells were cryopreserved in batches for consistency between replicate assays. Twenty-four hours post transfection, cells were harvested with non-enzymatic cell dissociation buffer and re-suspended in DMEM medium supplemented with 10% DMSO and 10% FBS before being transferred first to −80° C. overnight and then to liquid nitrogen for long-term storage. On the day prior to the assay, cells were thawed at 37° C. and re-suspended in growth media. A 96 well white opaque bottom microtitre plate was then seeded with 40,000 cells in a volume of 100 μl growth media per well and seeded plates were then incubated overnight at 37° C., 5% CO.sub.2. On the day of the BRET experiment, cells were washed twice with BRET assay buffer (Hanks balanced salt solution (HBSS) supplemented with 10 mM HEPES (pH 7.4)), then 80 μl per well of BRET assay buffer was added before the plate was incubated for 30 minutes at 37° C., 5% CO.sub.2. Then, Renilla luciferase substrate coelenterazine h (5 μM) was added to the cells and incubated at 37° C. for 10 minutes before the addition of GPR120 agonist (TUG-891) or test compound for a further 5 minutes at 37° C.

(15) Bio-luminescence at λ 535 nm and λ 475 nm was then measured with a Pherastar FsX instrument, and the λ 535/λ 475 ratio of bio-luminescence was then used to calculate a BRET value. hGPR120 agonist potency values (pEC.sub.50) were calculated by normalising the BRET values to the DMSO vehicle (0% control) and TUG-891 (100% control) and then fitting the normalised data to a 3-parameter concentration-response curve.

Experimental Scheme 1

Compound 1 3-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(16) ##STR00042## ##STR00043##

a) Procedure for the Preparation of 1b

(17) ##STR00044##

(18) A mixture of 6-bromoisoquinoline 1a (5.0 g, 24 mmol), tetrabutylammonium chloride hydrate (0.71 g, 2.4 mmol), Pd-162 (0.48 g, 1.2 mmol), tert-butyl acrylate (3.9 mL, 26 mmol) and N-cyclohexyl-N-methylcyclohexanamine (7.7 mL, 36 mmol) in 1,4-dioxane (100 mL) was stirred at 80° C. for 20 h. The mixture was cooled to RT and then concentrated in vacuo. The residue was partitioned between water (100 mL) and DCM (100 mL) and the resultant white precipitate was collected by filtration. The solid was dissolved in a mixture of methanolic ammonia (1M, 100 mL) and DCM (100 mL) and the solution was washed with water (100 mL). Residual product was extracted from the aqueous solution using DCM (300 mL) and the combined organic phases were passed through a hydrophobic membrane and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to afford (E)-tert-butyl 3-(isoquinolin-6-yl)acrylate 1b as a light brown solid: m/z 256 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.24 (s, J=1.0 Hz, 1H), 8.56 (d, J=5.7 Hz, 1H), 7.97 (dd, J=8.6, 0.8 Hz, 1H), 7.90-7.87 (m, 1H), 7.77 (dd, J=8.6, 1.7 Hz, 1H), 7.73 (d, J=16.1 Hz, 1H), 7.66 (dd, J=5.8, 1.0 Hz, 1H), 6.55 (d, J=16.0 Hz, 1H), 1.56 (s, 9H).

b) Procedure for the Preparation of 1c

(19) ##STR00045##

(20) A mixture of (E)-tert-butyl 3-(isoquinolin-6-yl)acrylate 1b (1.1 g, 4.2 mmol) and platinum on carbon (0.82 g, 0.21 mmol) in AcOH (50 mL) was heated at 50° C. under hydrogen (5 Bar) for 2 h. The mixture was cooled to RT, filtered and the solvent concentrated in vacuo. NaOH solution (2 M) was added until pH was >10, then the product was extracted with EtOAc (600 mL). The organic solution was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% (0.7 M Ammonia/MeOH) in DCM) to afford tert-butyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 1c as a colourless solid: m/z 262 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.98-6.86 (m, 3H), 3.83 (s, 2H), 2.96 (t, J=5.9 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.46 (t, J=7.5 Hz, 2H), 1.37 (s, 9H).

c) Procedure for the Preparation of 1d

(21) ##STR00046##

(22) tert-Butyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 1c (3.0 g, 11 mmol), Cs.sub.2CO.sub.3 (6.0 g, 18 mmol), Pd-176 (1.7 g, 2.2 mmol) and BINAP (1.5 g, 2.4 mmol) were placed in a sealed vial which was then evacuated and backfilled with nitrogen three times. A solution of 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (2 mL, 12 mmol) in 1,4-dioxane (50 mL) was added and the mixture was stirred, under nitrogen at 105° C. After 16 h Cs.sub.2CO.sub.3 (6.0 g, 18 mmol) and DMF (6 mL) were added and the mixture was stirred at 115° C. for 3 h and then cooled to RT and filtered. The filtrate was diluted with EtOAc (200 mL) and then washed with 20% NaCl solution (200 mL). The organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-20% EtOAc in isohexane) to afford tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 1d: m/z 440 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.08-6.97 (m, 4H), 6.84 (dd, J=7.2, 2.7 Hz, 1H), 6.80-6.72 (m, 1H), 4.28 (s, 2H), 3.46 (t, J=5.8 Hz, 2H), 2.97 (t, J=5.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 1.43 (s, 9H).

d) Preparation of Compound 1 3-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(23) ##STR00047##

(24) A solution of tert-butyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 1d (3.0 g, 6.8 mmol) in DCM (10 mL) was treated with TFA (6.0 mL, 78 mmol) and the mixture was stirred at RT for 2 h and then concentrated in vacuo. Residual solvents were removed by co-evaporation with toluene (10 mL) and then the product was purified by reverse-phase flash chromatography (15-75% MeCN in Water, 0.1% formic acid, C18) to afford 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 1 as a cream solid: m/z 384 [M+H].sup.+ (ES.sup.+), 382 [M−H].sup.− (ES.sup.−). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.13 (s, 1H), 7.29 (dd, J=12.5, 8.8 Hz, 1H), 7.13-7.00 (m, 4H), 6.98-6.89 (m, 1H), 4.25 (s, 2H), 3.41 (t, J=5.8 Hz, 2H), 2.89 (t, J=5.8 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.56-2.51 (m, 2H).

(25) Human GPR12 pEC.sub.50: 7.4

(26) The following compounds were prepared using appropriate starting materials in analogous procedure to that described in Experimental Scheme 1. Where the starting materials are not described in the literature, their synthesis is described below.

(27) TABLE-US-00001 hGPR120 Compound Structure [M + H]+ NMR pEC50 2 400 (DMSO-d.sub.6) δ 7.10-7.05 (m, 1H), 7.05-6.97 (m, 3H), 6.48 (dd, J = 7.5, 2.9 Hz, 1H), 6.34 (dt, J = 8.8, 3.1 Hz, 1H), 4.76 (tt, J = 6.9, 4.4 Hz, 1H), 4.19 (s, 2H), 4.04 (tt, J = 6.9, 4.2 Hz, 1H), 3.37-3.34 (m, 2H), 3.16 (s, 3H), 2.84 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 2.39-2.32 (m, 2H), 2.29-2.19 (m, 2H). 6.8 3 388 (DMSO-d.sub.6) δ 12.13 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.07-6.99 (m, 2H), 6.50- 6.42 (m, 1H), 6.30 (dt, J = 6.5, 2.5 Hz, 1H), 4.64 (quint, J = 7.2 Hz, 1H), 4.23 (s, 2H), 3.40 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 7.7 Hz, 2H), 2.44-2.30 (m, 2H), 2.05-1.92 (m, 2H), 1.76 (q, J = 10.2 Hz, 1H), 1.68- 1.54 (m, 1H). 8 4 0 374 (Methanol-d.sub.4) δ 7.31-7.24 (m, 2H), 7.19-7.10 (m, 2H), 7.06-6.98 (m, 4H), 6.97-6.88 (m, 4H), 4.23 (s, 2H), 3.42 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 7.7 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H). 6.8 5 353 (DMSO-d.sub.6) δ 7.72 (dd, J = 4.9, 1.6 Hz, 1H), 7.24 (dd, J = 7.7, 1.7 Hz, 1H), 7.04- 6.99 (m, 2H), 6.91 (dd, J = 7.6, 4.9 Hz, 1H), 5.9-5.88 (m, 1H), 5.21-5.06 (m, 2H), 4.36 (t, J = 6.4 Hz, 2H), 4.16 (s, 2H), 3.34 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 2.50- 2.45 (m, 2H). 5.1 6 391 (DMSO-d.sub.6) δ 12.13 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.14-7.05 (m, 4H), 7.04- 6.97 (m, 1H), 4.40 (s, 2H), 3.63 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.57-2.50 (m, 2H). 7.1 7 371 (DMSO-d.sub.6) δ 12.12 (s, 1H), 7.43 (dd, J = 12.8, 8.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.07-6.98 (m, 2H), 6.08 (dd, J = 8.4, 1.7 Hz, 1H), 4.97 (quint, J = 7.3 Hz, 1H), 4.58 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 2.51-2.46 (m, 2H), 2.44-2.31 (m, 2H), 2.10-1.94 (m, 2H), 1.84- 1.70 (m, 1H), 1.73-1.57 (m, 1H). 7.8 8 372 (DMSO-d.sub.6) δ 12.12 (s, 1H), 8.19 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 5.23 (quint, J = 7.7 Hz, 1H), 4.74 (s, 2H), 3.88 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.57-2.48 (m, 2H, overlapping with DMSO peak), 2.52-2.40 (m, 2H, overlapping with DMSO peak), 2.23-2.07 (m, 2H), 1.89-1.78 (m, 1H), 1.80- 7.2 1.63 (m, 1H). 9 392 (CDCl.sub.3) δ 7.35-7.28 (m, 2H), 7.11-7.05 (m, 1H), 7.03-6.94 (m, 6H), 6.72 (dd, J = 7.4, 2.9 Hz, 1H), 6.55-6.49 (m, 1H), 4.24 (s, 2H), 3.43 (t, J = 5.8 Hz, 2H), 3.01-2.88 (m, 4H), 2.67 (t, J = 7.8 Hz, 2H) 7.7
Intermediate 1 (I-1)

(28) ##STR00056## ##STR00057##
Step 1:

(29) Sodium tetrahydroborate (0.6 g, 16 mmol) was added portionwise to a solution of 3-(benzyloxy)cyclobutanone I-1a (2.8 g, 16 mmol) in MeOH (50 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Sat. NaHCO.sub.3 solution (70 mL) was added and the product was extracted with EtOAc (300 mL). The organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to afford (1s,3s)-3-(benzyloxy)cyclobutanol 1-1b as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.32-7.16 (m, 5H), 4.34 (s, 2H), 3.84 (dtd, J=7.9, 7.2, 6.5 Hz, 1H), 3.56 (tt, J=7.0, 6.2 Hz, 1H), 2.65 (dtd, J=9.4, 6.6, 3.0 Hz, 2H), 1.86 (dtd, J=9.4, 7.6, 2.9 Hz, 2H).

(30) Step 2:

(31) NaH (60% w/w in oil, 0.6 g, 14 mmol) was added to a solution of (1s,3s)-3-(benzyloxy)cyclobutanol I-1b (1.7 g, 9.4 mmol) in THE (30 mL) at 0° C. The mixture was stirred for 15 min before MeI (0.7 mL, 11 mmol) was added. The mixture was stirred at 0° C. for a further 15 min then warmed to RT and stirred for 16 h. Sat. NaHCO.sub.3 solution (100 mL) was added and the product was extracted with DCM (300 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to afford (((1s,3s)-3-methoxycyclobutoxy)methyl)benzene I-1c as a colourless oil: m/z 193 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.31-7.16 (m, 5H), 4.35 (s, 2H), 3.66-3.56 (m, 1H), 3.48-3.39 (m, 1H), 3.16 (s, 3H), 2.61-2.51 (m, 2H), 1.92-1.81 (m, 2H).

(32) Step 3:

(33) A mixture of (((1s,3s)-3-methoxycyclobutoxy)methyl)benzene 1-1c (1.4 g, 7.3 mmol) and Pd/C (JM Type 39, 10%, 50% w/w) (0.155 g, 0.073 mmol) in EtOH (50 mL) was stirred at RT under an atmosphere of hydrogen (5 Bar) for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0-60% EtOAc in isohexane) to afford (1s,3s)-3-methoxycyclobutanol I-1d as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.92 (quint, J=7.2 Hz, 1H), 3.46 (quint, J=6.8 Hz, 1H), 3.23 (s, 3H), 2.79-2.64 (m, 2H), 2.01 (s, 1H), 1.91-1.79 (m, 2H).

(34) Step 4:

(35) A mixture of (1s,3s)-3-methoxycyclobutanol I-1d (0.15 g, 1.5 mmol), 3-bromo-4-fluorophenol I-1e (0.28 g, 1.5 mmol), Ph.sub.3P (0.39 g, 1.5 mmol) and DIAD (0.286 ml, 1.469 mmol) in THE (20 mL) was heated at 80° C. for 2 days. The reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by silica gel chromatography (0-20% EtOAc in isohexane) to afford 2-bromo-1-fluoro-4-((1r,3r)-3-methoxycyclobutoxy)benzene I-1 as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.95 (dd, J=9.0, 8.1 Hz, 1H), 6.88 (dd, J=5.6, 3.0 Hz, 1H), 6.62 (ddd, J=9.0, 3.8, 3.0 Hz, 1H), 4.69 (tt, J=6.7, 4.5 Hz, 1H), 4.05 (tt, J=6.8, 4.5 Hz, 1H), 3.20 (s, 3H), 2.45-2.25 (m, 4H).

(36) Intermediate 2 (I-2)

(37) ##STR00058## ##STR00059##
Step 1:

(38) A mixture of 4,5-difluoro-2-nitrophenol I-2a (2.2 g, 13 mmol), bromocyclobutane (2.4 mL, 25 mmol), TBAI (4.7 g, 13 mmol) and Cs.sub.2CO.sub.3 (4.1 g, 13 mmol) in DMF (10 mL) was stirred at 90° C. for 16 h. The mixture was cooled to RT, diluted with water (100 mL) and the product was extracted with TBME (300 mL). The organic solution was washed with brine (50 mL) and dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to afford 1-cyclobutoxy-4,5-difluoro-2-nitrobenzene I-2b as a light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.83 (dd, J=9.6, 8.1 Hz, 1H), 6.74 (dd, J=11.5, 6.5 Hz, 1H), 4.69 (quint, J=7.5 Hz, 1H), 2.56-2.42 (m, 2H), 2.36-2.21 (m, 2H), 2.01-1.86 (m, 1H), 1.81-1.66 (m, 1H).

(39) Step 2:

(40) A mixture of 1-cyclobutoxy-4,5-difluoro-2-nitrobenzene I-2b (1.3 g, 5.6 mmol), NH.sub.4Cl (3.0 g, 56 mmol) and iron (1.6 g, 28 mmol) in MeOH (30 mL) was stirred at 90° C. for 1 h, then cooled to RT and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL). Residual product was extracted from the aqueous solution with EtOAc (100 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-100% EtOAc in isohexane) to afford 2-cyclobutoxy-4,5-difluoroaniline I-2c as a red oil: m/z 200 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 6.53-6.42 (m, 2H), 4.61-4.49 (m, 1H), 3.74-3.63 (m, 2H), 2.50-2.37 (m, 2H), 2.24-2.10 (m, 2H), 1.92-1.80 (m, 1H), 1.76-1.61 (m, 1H).

(41) Step 3:

(42) Br.sub.2 (0.3 mL, 6 mmol) was added dropwise to a solution of 2-cyclobutoxy-4,5-difluoroaniline I-2c (1.0 g, 5 mmol) in AcOH (35 mL). The reaction was stirred at RT for 16 h and then sat. Na.sub.2S.sub.2O.sub.3 solution (50 mL) was added. The product was extracted with EtOAc (125 mL) and the organic solution was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to afford 2-bromo-6-cyclobutoxy-3,4-difluoroaniline I-2d as a yellow solid: m/z 278 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.49 (dd, J=11.4, 7.1 Hz, 1H), 4.57 (quint, J=7.1 Hz, 1H), 4.11 (s, 2H), 2.52-2.39 (m, 2H), 2.25-2.11 (m, 2H), 1.95-1.83 (m, 1H), 1.78-1.61 (m, 1H).

(43) Step 4:

(44) Isoamyl nitrite (0.73 mL, 5.4 mmol) was added to a solution of 2-bromo-6-cyclobutoxy-3,4-difluoroaniline I-2d (0.75 g, 2.7 mmol) in THF (10 mL) and the mixture was stirred at 70° C. for 16 h and then cooled to RT. Water (50 mL) was added and the product was extracted with DCM (150 mL). The organic solution was passed through a hydrophobic membrane and then concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to afford 1-bromo-5-cyclobutoxy-2,3-difluorobenzene I-2 as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.74 (ddd, J=4.9, 3.0, 2.2 Hz, 1H), 6.59 (ddd, J=11.5, 6.1, 3.0 Hz, 1H), 4.60-4.49 (m, 1H), 2.50-2.37 (m, 2H), 2.21-2.07 (m, 2H), 1.94-1.81 (m, 1H), 1.76-1.61 (m, 1H).

(45) Intermediate 3 (I-3)

(46) ##STR00060##

(47) A solution of cyclobutanol (125 μL, 1.60 mmol) in dry THE (1 mL) was added dropwise to a suspension of NaH (60% w/w in oil, 65 mg, 1.6 mmol) in dry THF (5 mL) under nitrogen. The mixture was stirred at RT for 10 min before a solution of 2,4-dichloro-5-fluoropyrimidine I-3a (250 mg, 1.5 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at RT for 16 h then partitioned between sat. aq. NH.sub.4Cl (50 mL) and EtOAc (100 mL). The organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in isohexane) to afford 2-chloro-4-cyclobutoxy-5-fluoropyrimidine 1-3 as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.19 (d, J=2.3 Hz, 1H), 5.41-5.28 (m, 1H), 2.60-2.44 (m, 2H), 2.35-2.16 (m, 2H), 1.99-1.85 (m, 1H), 1.82-1.65 (m, 1H).

(48) Intermediate 4 (I-4)

(49) ##STR00061##

(50) A vial was charged with 3-bromo-4-fluorophenol I-1e (300 mg, 1.57 mmol), copper(I) iodide (30 mg, 0.157 mmol), 2-picolinic acid (39 mg, 0.314 mmol), anhydrous potassium phosphate tribasic (0.67 g, 3.14 mmol) and anhydrous DMSO (3.1 mL). The vial was evacuated and back filled with argon (4×). Iodobenzene (641 mg, 3.14 mmol) was added and the mixture was heated at 90° C. for 36 h. The reaction mixture was cooled to RT, diluted with 2 mL water and the product was extracted with EtOAc (4×). The combined organic phases were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuo. The residue was purified by chromatography on silica (petroleum ether) to afford 2-bromo-1-fluoro-4-phenoxybenzene as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.39-7.33 (m, 2H), 7.19 (dd, J=5.7, 2.9 Hz, 1H), 7.16-7.11 (m, 1H), 7.11-7.06 (m, 1H), 7.01-6.97 (m, 2H), 6.96-6.90 (m, 1H).

Experimental Scheme 2

Compound 10 3-(2-(3-(Trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(51) ##STR00062##

a) Procedure for the Preparation of 10a

(52) ##STR00063##

(53) tert-Butyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 1c (100 mg, 0.4 mmol), NaO.sup.tBu (60 mg, 0.62 mmol), 1-bromo-3-(trifluoromethoxy)benzene (100 mg, 0.4 mmol) and RuPhos precatalyst G3 (10 mg, 12 μmol) were placed in a sealed vial which was then evacuated and backfilled with nitrogen three times. 1,4-Dioxane (2 mL) was added and the vial was again evacuated and backfilled with nitrogen three times. The mixture was stirred, under nitrogen at 85° C. for 30 min and then cooled to RT and AcOH (50 μL, 0.9 mmol) was added. The mixture was diluted with sat. aq. NH.sub.4Cl (5 mL) and the product was extracted with EtOAc (5 mL). The organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to afford tert-butyl 3-(2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 10a: m/z 422 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26 (d, J=16.5 Hz, 1H). 7.12-6.99 (m, 3H), 6.87 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J=8.0 Hz, 1H), 4.39 (s, 2H), 3.56 (t, J=5.9 Hz, 2H), 2.96 (t, J=5.9 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 1.42 (s, 9H).

b) Procedure for the Preparation of Compound 10 3-(2-(3-(Trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(54) ##STR00064##

(55) A solution of tert-butyl 3-(2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 10a (60 mg, 0.14 mmol) in DCM (200 μL) was treated with TFA (100 μL, 0.14 mmol) and the mixture was stirred at RT for 2 h and then concentrated in vacuo. Residual solvents were removed by co-evaporation with 10% (7N NH.sub.3 in MeOH) in DCM and then the product was purified by silica gel chromatography (0-50% EtOAc in isohexane) to afford 3-(2-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 10 as a white solid: m/z 366 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.15 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.09-7.02 (m, 2H), 6.98 (dd, J=8.5, 2.5 Hz, 1H), 6.87 (s, 1H), 6.65 (d, J=7.8 Hz, 1H), 4.39 (s, 2H), 3.55 (t, J=5.9 Hz, 2H), 2.87 (t, J=5.9 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.56-2.51 (m, 2H).

(56) Human GPR120 pEC.sub.50: 6.8

(57) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 2. Where the starting materials are not described in the literature, their synthesis is described below.

(58) TABLE-US-00002 hGPR120 Example Structure [M + H]+ NMR pEC50 11 386 (CDCl.sub.3) δ 7.17 (d, J = 8.7, 1H), 6.99-6.92 (m, 3 H), 6.53 (d, J 2.8, 1 H), 6.35 (dd, J 8.7, 2.8, 1H), 4.59-4.44 (m, 1 H), 4.14 (s, 2 H), 3.30 (t, J 5.8, 2 H), 2.92 (t, J 5.8, 2 H), 2.86 (t, J 7.8, 2 H), 2.61 (dd, J 8.4, 7.2, 2 H), 2.38-2.24 (m, 2 H), 2.07 (dtd, J 12.6, 10.0, 7.9, 2 H). 7.3 12 352 (CDCl.sub.3) δ 7.08 (t, J 8.2, 1 H), 7.03-6.90 (m, 3 H), 6.49 (ddd, J 8.3, 2.4, 0.8, 1 H), 6.37 (t, J 2.4, 1 H), 6.20 (ddd, J 8.1, 2.3, 0.8, 1 H), 4.63- 4.46 (m, 1 H), 4.29 (s, 2 H), 3.45 (t, J 5.9, 2 H), 2.90-2.81 (m, 4 H), 2.60 (dd, J 8.4, 7.2, 2 H), 2.44-2.27 (m, 2 H), 2.10 (dtd, J 12.6, 10.0, 7.9, 2 H) 6.8 13 370 (CDCl.sub.3) δ 6.97-6.90 (m, 3 H), 6.85 (dd, J 12.2, 8.8, 1 H), 6.42 (dd, J 7.4, 2.9, 1 H), 6.23 (dt, J 8.8, 3.1, 1 H), 4.54- 4.40 (m, 1 H), 4.18 (s, 2 H), 3.35 (t, J 5.8, 2 H), 2.92-2.78 (m, 4 H), 2.61 (dd, J 8.4, 7.2, 2 H), 2.33 (dddt, J 9.5, 8.1, 6.8, 2.7, 2 H), 2.15- 1.99 (m, 2 H), 1.83- 1.69 (m, 1 H), 1.66- 1.51 (m, 1 H). 7.7 14 366 (DMSO-d.sub.6) δ 12.13 (s, 1H), 7.09-6.98 (m, 4H), 6.55 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 8.2, 2.5 Hz, 1H), 4.62 (quint, J = 7.1 Hz, 1H), 4.00 (s, 2H), 3.11 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.56-2.52 (m, 2H), 2.44-2.32 (m, 2H), 2.17 (s, 3H), 2.11-1.93 (m, 2H), 1.82-1.70 (m, 1H), 1.70-1.55 (m, 1H). 7.3 15 386 (DMSO-d.sub.6) δ 7.06 (d, J = 7.9 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H), 4.21 (s, 2H), 3.42 (t, J = 5.8 Hz, 2H), 2.99 (s, 2H), 2.82 (t, J = 5.7 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 1.44 (s, 6H). 6.2 16 0 350 (DMSO-d.sub.6) δ 12.11 (s, 1H), 7.43 (td, J = 8.0, 7.5, 0.9 Hz, 1H), 7.26 (dd, J = 8.4, 2.6 Hz, 1H), 7.21-7.12 (m, 2H), 7.10- 6.96 (m, 3H), 4.43 (s, 2H), 3.59 (t, J = 5.9 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.54-2.50 (m, 2H). 6.3 17 307 (DMSO-d.sub.6) δ 7.62-7.57 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.09-7.00 (m, 4H), 4.50 (s, 2H), 3.63 (t, J = 5.9 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H). 5.1 18 324 (DMSO-d.sub.6) δ 12.19 (s, 1H), 8.16 (d, J = 6.2 Hz, 1H), 7.27-7.21 (m, 1H), 7.16 (d, J = 7.0 Hz, 2H), 6.72 (d, J = 6.3 Hz, 1H), 4.77 (s, 2H), 3.89 (s, 2H), 2.96-2.82 (m, 4H), 2.06 (tt, J = 7.9, 4.9 Hz, 1H), 1.10-0.95 (m, 4H). 4.6 19 370 (CDCl.sub.3) δ 7.10-7.00 (m, 3H), 6.23 (dt, J = 12.2, 2.2 Hz, 1H), 6.17 (t, J = 1.8 Hz, 1H), 5.97 (dt, J = 10.5, 2.1 Hz, 1H), 4.65-4.56 (m, 1H), 4.35 (s, 2H), 3.50 (t, J = 5.9 Hz, 2H), 2.96- 2.90 (m, 4H), 2.68 (t, J = 7.8 Hz, 2H), 2.49- 2.39 (m, 2H), 2.22- 2.10 (m, 2H), 1.91- 1.80 (m, 1H), 1.75- 1.62 (m, 1H) 7.6 20 374 (DMSO-d.sub.6) δ 12.14 (s, 1H), 7.41-7.32 (m, 2H), 7.21 (t, J = 8.2 Hz, 1H), 7.15-7.08 (m, 2H), 7.04 (d, J = 6.8 Hz, 2H), 7.01- 6.96 (m, 2H), 6.81- 6.75 (m, 1H), 6.66 (t, J = 2.3 Hz, 1H), 6.30 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H), 4.34 (s, 2H), 3.51 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H). 7.6 21 353 (DMSO-d.sub.6) δ 12.11 (s, 1H), 7.49-7.40 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.08-6.99 (m, 2H), 6.33 (dd, J = 8.0, 3.9 Hz, 1H), 5.96 (d, J = 7.8 Hz, 1H), 5.11-5.00 (m, 1H), 4.58 (s, 2H), 3.76 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.41 (dddt, J = 9.5, 7.9, 6.9, 2.6 Hz, 2H), 2.10-1.96 (m, 2H), 7.4 1.85-1.72 (m, 1H), 1.72- 1.59 (m, 1H). 22 367 (DMSO-d.sub.6) δ 12.11 (s, 1H), 7.71 (dd, J = 8.4, 7.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 6.8 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.61 (s, 2H), 3.77 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H). 6.5 23 358 (DMSO-d.sub.6) δ 12.12 (s, 1H), 7.72-7.63 (m, 2H), 7.50-7.42 (m, 2H), 7.40- 7.34 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.20 (t, J = 2.1 Hz, 1H), 7.18- 7.13 (m, 1H), 7.07-6.97 (m, 4H), 4.43 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H). 6.4 24 376 (DMSO-d.sub.6) δ 12.11 (s, 1H), 7.72-7.67 (m, 2H), 7.51-7.43 (m, 2H), 7.43- 7.34 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.08- 7.04 (m, 2H), 7.02 (t, J = 1.9 Hz, 1H), 6.83- 6.79 (m, 1H), 6.77 (d, J = 1.8 Hz, 1H), 4.46 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H). 6.4 25 396 (DMSO-d.sub.6) δ 12.13 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 6.6 Hz, 2H), 6.49 (d, J = 2.1 Hz, 2H), 6.25 (d, J = 1.1 Hz, 1H), 4.38 (s, 2H), 3.77 (s, 3H), 3.54 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.57-2.52 (m, 2H, overlapping with DMSO peak) 7.2
Intermediate 5 (I-5)

(59) ##STR00080##

(60) A mixture of solution of 3-bromo-4-methylphenol I-5a (250 mg, 1.3 mmol), K.sub.2CO.sub.3 (380 mg, 2.8 mmol), KI (10 mg, 60 μmol) and bromocyclobutane (0.2 mL, 2 mmol) in DMF (3 ml) was stirred at 95° C. for 16 h, then cooled to RT and 20% w/w NaCl solution (50 mL) was added. The product was extracted with EtOAc (20 mL), the organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to afford 2-bromo-4-cyclobutoxy-1-methylbenzene I-5 as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.12 (dd, J=8.4, 0.8 Hz, 1H), 7.02 (d, J=2.6 Hz, 1H), 6.70 (dd, J=8.4, 2.6 Hz, 1H), 4.66-4.54 (m, 1H), 2.52-2.39 (m, 2H), 2.33 (d, J=0.6 Hz, 3H), 2.24-2.08 (m, 2H), 1.94-1.80 (m, 1H), 1.78-1.61 (m, 1H).

(61) Intermediate 6 (I-6)

(62) ##STR00081##

(63) A mixture of solution of 3-bromo-4-chlorophenol I-4a (0.3 g, 1.446 mmol), K.sub.2CO.sub.3 (0.50 g, 3.6 mmol) and bromocyclobutane (0.16 mL, 1.7 mmol) in DMF (5 ml) was stirred at 100° C. for 16 h, then cooled to RT and sat. NaHCO.sub.3 solution (15 mL) was added. The product was extracted with MTBE (90 mL), the organic solution was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc in isohexane) to afford 2-bromo-1-chloro-4-cyclobutoxybenzene I-4 as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31-7.21 (m, 1H), 7.03 (d, J=2.8 Hz, 1H), 6.68 (dd, J=8.9, 2.9 Hz, 1H), 4.61-4.50 (m, 1H), 2.47-2.35 (m, 2H), 2.19-2.05 (m, 2H), 1.90-1.78 (m, 1H), 1.74-1.59 (m, 1H).

Experimental Scheme 3

Compound 26 3-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoic Acid

(64) ##STR00082## ##STR00083##

a) Procedure for the Preparation of 26a

(65) ##STR00084##

(66) A flask was charged with 6-bromoisoquinoline 1a (500 mg, 2.4 mmol), Pd(OAc).sub.2 (22 mg, 0.10 mmol), tri(o-tolyl)phosphine (52 mg, 0.17 mmol), DIPEA (0.84 mL, 4.8 mmol) and DMF (4.8 mL). The flask was evacuated and backfilled with argon three times before the addition of methyl methacrylate (0.5 mL, 0.2 mmol). The mixture was stirred at 80° C. for 2.5 h and then cooled to RT, diluted with EtOAc and filtered. The filtrate was diluted with water and extracted with EtOAc (×3). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo onto celite. Purification by silica gel chromatography (25-50% EtOAc in pet. ether) afforded a mixture of methyl 3-(isoquinolin-6-yl)-2-methylacrylate 26a (contaminated with the minor isomer methyl 2-(isoquinolin-6-ylmethyl)acrylate) as a yellow oil that was used in the next step without further purification: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.25 (s, 1H), 8.55 (d, J=5.8 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.80 (d, J=12.1 Hz, 2H), 7.67-7.56 (m, 2H), 3.86 (s, 3H), 2.18 (d, J=1.5 Hz, 3H); ESI-HRMS calculated for C.sub.14H.sub.14NO.sub.2 (M+H.sup.+) 228.1019, found 228.1024.

b) Procedure for the Preparation of 26b

(67) ##STR00085##

(68) A mixture of methyl 3-(isoquinolin-6-yl)-2-methylacrylate and methyl 2-(isoquinolin-6-ylmethyl)acrylate 26a (278 mg, 1.22 mmol) and 5% Pt/C (239.2 mg, 61 μmol Pt) in AcOH (12 mL) was heated at 50° C. under an atmosphere of H.sub.2. After 22 h the mixture was cooled to RT and filtered through a plug of celite, washing through with EtOAc. The filtrate was concentrated in vacuo and the oil was partitioned between EtOAc and sat. Na.sub.2CO.sub.3 (30 mL). The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo to give methyl 2-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 26b as a yellow oil that was used without further purification: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93-6.91 (m, 2H), 6.88 (s, 1H), 3.98 (s, 2H), 3.65 (s, 3H), 3.12 (t, J=6.0 Hz, 2H), 3.01-2.93 (m, 1H), 2.76 (t, J=5.8 Hz, 2H), 2.75-2.66 (m, 1H), 2.59 (dd, J=13.3, 7.8 Hz, 1H), 1.14 (d, J=6.9 Hz, 3H); ESI-HRMS calculated for C.sub.14H.sub.20NO.sub.2 (M+H.sup.+) 234.1489, found 234.1494.

c) Procedure for the Preparation of 26c

(69) ##STR00086##

(70) Methyl 2-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 26b (110 mg, 0.48 mmol), Cs.sub.2CO.sub.3 (310 mg, 0.96 mmol), Pd.sub.2(dba).sub.3 (45 mg, 49 μmol), BINAP (60.9 mg, 98 μmol), 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (140 mg, 0.54 mmol) and DMF (3.7 mL) were placed in a sealed vial which was then evacuated and back filled with argon three times. The mixture was heated at 90° C. for 24 h and then cooled to room temperature and filtered through a plug of silica (EtOAc as eluent). The filtrate was diluted with water and the product was extracted with EtOAc. The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (1-5% EtOAc in pet. ether) to give methyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoate 26c as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.06-6.94 (m, 4H), 6.85-6.80 (m, 1H), 6.79-6.73 (m, 1H), 4.27 (s, 2H), 3.65 (s, 3H), 3.45 (t, J=5.9 Hz, 2H), 3.04-2.94 (m, 3H), 2.78-2.68 (m, 1H), 2.66-2.59 (m, 1H), 1.16 (d, J=6.9 Hz, 3H); ESI-HRMS calculated for C.sub.21H.sub.22F.sub.4NO.sub.3 (M+H.sup.+) 412.1530, found 412.1519.

d) Procedure for the Preparation of Compound 26 3-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoic Acid

(71) ##STR00087##

(72) A mixture of methyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoate 26c (81 mg, 0.20 mmol) and LiOH.H.sub.2O (35 mg, 0.84 mmol) in THF (1.5 mL) and water (1.5 mL) was stirred at 45° C. for 5 h. The reaction mixture was cooled to RT and acidified (pH 1) by the addition of 1 M HCl (aq). The product was extracted with EtOAc and the organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (38% EtOAc with 0.01% AcOH in pet. ether) to afford 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoic acid 26 as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.06-6.97 (m, 4H), 6.83 (dd, J=7.2, 2.7 Hz, 1H), 6.79-6.74 (m, 1H), 4.27 (s, 2H), 3.45 (t, J=5.8 Hz, 2H), 3.09-3.01 (m, 1H), 2.98 (t, J=5.8 Hz, 2H), 2.81-2.72 (m, 1H), 2.68-2.60 (m, 1H), 1.19 (d, J=6.9 Hz, 3H); ESI-HRMS calculated for C.sub.20H.sub.20F.sub.4NO.sub.3 (M+H.sup.+) 398.1374, found 398.1383.

(73) Human GPR120 pEC.sub.50: 7.1

(74) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 3.

(75) TABLE-US-00003 hGPR120 Example Structure [M + H]+ NMR pEC50 27 384 (CDCl.sub.3) δ 7.05-6.88 (m, 4H), 6.52-6.47 (m, 1H), 6.33-6.27 (m, 1H), 4.59- 4.50 (m, 1H), 4.25 (s, 2H), 3.41 (t, J = 5.8 Hz, 2H), 3.08-3.00 (m, 1H), 2.94 (t, J = 5.7 Hz, 2H), 2.80-2.70 (m, 1H), 2.66- 2.58 (m, 1H), 2.44-2.34 (m, 2H), 2.19-2.07 (m, 2H), 1.89-1.78 (m, 1H), 1.72-1.59 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H) 7.0

Experimental Scheme 4

Compound 28 3-(2-(3-Isopropoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(76) ##STR00089## ##STR00090##

a) Procedure for the Preparation of 28a

(77) ##STR00091##

(78) A flask was charged with 6-bromoisoquinoline 1a (5.1 g, 24 mmol), Pd(OAc).sub.2 (58 mg, 0.26 mmol), tri(o-tolyl)phosphine (156 mg, 0.513 mmol), DMF (33 mL) and DIPEA (8.4 mL, 48 mmol). The flask was evacuated and backfilled with argon three times before the addition of ethyl acrylate (3.9 mL, 37 mmol) and heated at 90° C. for 18 h. The reaction was cooled to RT, diluted with EtOAc and filtered through a short plug of silica. The filtrate was diluted with water and the product was extracted with EtOAc. The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by recrystallisation from EtOAc to give ethyl (E)-3-(isoquinolin-6-yl)acrylate 28a as light yellow crystals: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.25 (s, 1H), 8.57 (d, J=5.7 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.90 (s, 1H), 7.83 (d, J=16.1 Hz, 1H), 7.78 (dd, J=8.6, 1.6 Hz, 1H), 7.66 (d, J=5.8 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.14H.sub.14NO.sub.2 (M+H.sup.+) 228.1019, found 228.1024.

b) Procedure for the Preparation of 28b

(79) ##STR00092##

(80) Ethyl (E)-3-(isoquinolin-6-yl)acrylate 28a (3.1 g, 14 mmol) was dissolved in glacial AcOH (130 mL) and under a blanket of argon, 5% Pt/C (2.3 g, 0.58 mmol) was added. The flask was evacuated and backfilled with H.sub.2 three times and the mixture was stirred at 50° C. under an atmosphere of H.sub.2. After 18 h the mixture was cooled to RT, filtered through a plug of celite, washing through with EtOAc. The filtrate was concentrated in vacuo, then the residue was dissolved in DCM and concentrated in vacuo. The resulting oil was cooled to 0° C. and 4 M HCl in dioxane (12 mL) was added. The mixture was stirred for 5 min where after white precipitate formed. The solid was resuspended in DCM and concentrated in vacuo to give ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride 28b as a white solid: 1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (br s, 2H), 7.13-6.96 (m, 3H), 4.27 (br s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.39 (br s, 2H), 3.09 (br s, 2H), 2.90 (t, J=7.7 Hz, 2H), 2.59 (t, J=7.7 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.14H.sub.20NO.sub.2 (M+H.sup.+) 234.1489, found 234.1493.

c) Procedure for the Preparation of 28c

(81) ##STR00093##

(82) Ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride 28b (136.2 mg, 0.50 mmol), Cs.sub.2CO.sub.3 (586 mg, 1.8 mmol), XPhos Pd G4 precatalyst (12.4 mg, 14.5 μmol), 1-bromo-3-isopropoxybenzene (119.5 mg, 0.55 mmol) and dioxane (2 mL) were placed in a sealed vial which was then evacuated and back filled with argon three times. The mixture was stirred at 90° C. for 18 h then cooled to RT. The mixture was filtered through a plug of silica, washing through with EtOAc and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0-8% EtOAc in pet. ether) to give ethyl 3-(2-(3-isopropoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 28c as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.16 (t, J=8.2 Hz, 1H), 7.09-6.97 (m, 3H), 6.55 (dd, J=8.2, 2.0 Hz, 1H), 6.49 (t, J=2.1 Hz, 1H), 6.37 (dd, J=8.1, 1.9 Hz, 1H), 4.61-4.50 (m, 1H), 4.36 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.52 (t, J=5.8 Hz, 2H), 2.97-2.87 (m, 4H), 2.60 (t, J=7.8 Hz, 2H), 1.34 (d, J=6.1 Hz, 6H), 1.24 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.23H.sub.30NO.sub.3 (M+H.sup.+) 368.2220, found 368.2233.

d) Procedure for the Preparation of Compound 28 3-(2-(3-Isopropoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(83) ##STR00094##

(84) A mixture of ethyl 3-(2-(3-isopropoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 28c (120 mg, 0.32 mmol) and LiOH.H.sub.2O (54 mg, 1.3 mmol) in THF (5 mL) and water (5 mL) was stirred at RT for 18 h. The mixture was acidified (pH 4) by the addition of 1 M HCl (aq) and the product was extracted with EtOAc. The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-22% (0.01% AcOH in EtOAc) in pet. ether) to afford 3-(2-(3-isopropoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 28 as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.16 (t, J=8.2 Hz, 1H), 7.10-6.99 (m, 3H), 6.56 (dd, J=8.1, 2.1 Hz, 1H), 6.50 (t, J=2.3 Hz, 1H), 6.37 (dd, J=8.0, 2.2 Hz, 1H), 4.61-4.50 (m, 1H), 4.36 (s, 2H), 3.53 (t, J=5.9 Hz, 2H), 2.93 (dd, J=11.9, 6.7 Hz, 4H), 2.68 (t, J=7.8 Hz, 2H), 1.34 (d, J=6.1 Hz, 6H); ESI-HRMS calculated for C.sub.21H.sub.26NO.sub.3 (M+H.sup.+) 340.1907, found 340.1917.

(85) Human GPR120 pEC.sub.50: 6.3

(86) The following compound was prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 4.

(87) TABLE-US-00004 hGPR120 Compound Structure [M + H]+ NMR pEC50 29 346/348 (DMSO-d.sub.6) δ 7.22- 6.75 (m, 6H), 4.13 (s, 2H), 3.80 (s, 3H), 3.28 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.46 (d, J = 7.6 Hz, 2H). 6.0

Experimental Scheme 5

Compound 30 3-(2-(3,5-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)propanoic Acid

(88) ##STR00096## ##STR00097##

a) Procedure for the Preparation of 24b

(89) ##STR00098##

(90) tert-Butyl (E)-3-(isoquinolin-7-yl)acrylate 30b) was prepared from 7-bromoisoquinoline (5 g, 24 mmol) 30a using a procedure essentially the same as for compound 1a: m/z 256 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.30 (s, 1H), 8.58 (d, J=5.7 Hz, 1H), 8.07 (s, 1H), 7.91 (dd, J=8.6, 1.7 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.78 (d, J=16.0 Hz, 1H), 7.69 (dt, J=5.8, 1.0 Hz, 1H), 6.55 (d, J=16.0 Hz, 1H), 1.58 (s, 9H).

b) Procedure for the Preparation of 30c

(91) ##STR00099##

(92) tert-Butyl 3-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanoate 30c was prepared from tert-butyl (E)-3-(isoquinolin-7-yl)acrylate 30b (5 g, 19.6 mmol) using a procedure essentially the same as for compound 1c: m/z 262 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.97-6.86 (m 2H), 6.81-6.75 (m, 1H), 3.91 (d, J=1.0 Hz, 2H), 3.05 (t, J=6.0 Hz, 2H), 2.77 (t, J=7.9 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.48-2.39 (m, 2H), 1.36 (s, 9H).

c) Procedure for the Preparation of Compound 30 3-(2-(3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)propanoic Acid

(93) ##STR00100##

(94) RuPhos G3 Precatalyst (10 mg, 12 μmol) and NaO.sup.tBu (75 mg, 0.78 mmol) were placed in a sealed vial which was then evacuated and backfilled with nitrogen three times. A solution of tert-butyl 3-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanoate 30c (100 mg, 0.4 mmol) and 1-bromo-3,5-dimethylbenzene (55 μL, 0.41 mmol) in 1,4-dioxane (2 mL) was added and the mixture was stirred, under nitrogen at 90° C. The mixture was cooled to RT and AcOH (55 μL, 0.96 mmol) was added. The mixture was partitioned between EtOAc (5 mL) and sat. NH.sub.4Cl solution (5 mL) and the organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-20% EtOAc in isohexane) to afford a mixture of the title compound and its tert-butyl ester. The mixture was dissolved in DCM (2 mL), treated with TFA (1 mL, 13 mmol) for 16 h and then concentrated in vacuo. Partial oxidation of the heterocycle was observed and so the residue was dissolved in DCM (5 mL), sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added and the mixture was stirred at RT for 10 min and then concentrated in vacuo. The product was purified by reverse-phase flash chromatography (15-75% MeCN in water with 0.1% formic acid) to afford 3-(2-(3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)propanoic acid 30 as a yellow gum: m/z 310 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.12 (s, 1H), 7.09-6.97 (m, 3H), 6.60 (d, J=1.4 Hz, 2H), 6.39 (s, 1H), 4.29 (s, 2H), 3.46 (t, J=5.9 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.57-2.51 (m, 2H), 2.21 (s, 6H).

(95) Human GPR120 pEC.sub.50: 5.8

(96) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 5.

(97) TABLE-US-00005 Com- hGPR120 pound Structure [M + H]+ NMR pEC50 31 01 349/348 (DMSO-d.sub.6) δ 12.14 (s, 1H), 7.11-6.99 (m, 3H), 6.59 (t, J = 2.0 Hz, 1H), 6.42 (t, J = 2.2 Hz, 1H), 6.35 (t, J = 1.9 Hz, 1H), 4.36 (s, 2H), 3.74 (s, 3H), 3.51 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.55-2.51 (m, 2H). 5.6 32 02 366 (DMSO-d.sub.6) δ 7.91 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 7.8, 1.9 Hz, 1H), 7.36-7.25 (m, 2H), 6.94 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 6.89 (t, J = 2.2 Hz, 1H), 6.79 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 4.77-4.65 (m, 1H), 3.95 (dd, J = 7.0, 6.1 Hz, 2H), 3.13 (t, J = 6.5 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.55-2.41 (m, 2H), 5.2 2.14 (dtdd, J = 12.5, 9.8, 6.7, 2.7 Hz, 2H), 1.92-1.80 (m, 1H), 1.80-1.66 (m, 1H) —COOH not observed, 1 CH.sub.2 under DMSO peak 33 03 384 (Chloroform-d) δ 7.12-6.94 (m, 4H), 6.86-6.72 (m, 2H), 4.28 (s, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.02-2.87 (m, 4H), 2.68 (t, J = 7.7 Hz, 2H). 5.9

Experimental Scheme 6

Compound 34 2-(2-(5-Cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-1-carboxylic Acid

(98) ##STR00104##

a) Procedure for the Preparation of 34a

(99) ##STR00105##

(100) A solution of trimethylsulfoxonium iodide (13 g, 59 mmol) in DMSO (75 mL) was added dropwise to a suspension of NaH (60% w/w in oil, 2.1 g, 53 mmol) in DMSO (40 mL) under nitrogen. The mixture was stirred at RT for 1 h before the dropwise addition of a solution of (E)-tert-butyl 3-(isoquinolin-6-yl)acrylate 1b (10 g, 36 mmol) in DMSO (50 mL). The mixture was stirred at RT for 16 h, then partitioned between 20% w/w NaCl soln (1 L) and TBME (1 L). The organic solution was washed with 20% w/w NaCl soln (1 L), dried over MgSO.sub.4, filtered and concentrated in vacuo. The resultant oil was purified by silica gel chromatography (10-30% EtOAc in isohexane) to afford tert-butyl 2-(isoquinolin-6-yl)cyclopropanecarboxylate 34a as a colourless solid: m/z 270 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.21 (s, 1H), 8.49 (d, J=5.9 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.56 (s, 1H), 7.34 (dd, J=8.5, 1.7 Hz, 1H), 2.68-2.59 (m, 1H), 2.05-1.95 (m, 1H), 1.72-1.63 (m, 1H), 1.51-1.46 (m, 9H), 1.43-1.31 (m, 1H).

b) Procedure for the Preparation of 34b

(101) ##STR00106##

(102) A mixture of tert-butyl 2-(isoquinolin-6-yl)cyclopropanecarboxylate 34a (2 g, 7.4 mmol) and Pt—C 5% (50% w/w with water J&M type 117) (500 mg, 0.06 mmol) in AcOH (20 mL) was stirred under an atmosphere of hydrogen (5 Bar) at RT for 18 h and then filtered. The filtrate was concentrated in vacuo and the residue was partitioned between 1N NaOH (50 mL) and EtOAc (100 mL). The organic solution was dried over MgSO.sub.4, filtered and concentrated in vacuo to give tert-butyl 2-(1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 34b as a colourless oil that crystallised on standing: m/z 274 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.92 (d, J=7.9 Hz, 1H), 6.91-6.80 (m, 2H), 3.97 (s, 2H), 3.12 (t, J=6.0 Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.43-2.33 (m, 1H), 1.84-1.74 (m, 1H), 1.54-1.46 (m, 1H), 1.46 (s, 9H), 1.23-1.14 (m, 1H), —NH not observed.

c) Procedure for the Preparation of 34c

(103) ##STR00107##

(104) A flask containing Cs.sub.2CO.sub.3 (3.7 g, 11 mmol), BINAP (0.2 g, 0.4 mmol) and Pd-176 [BINAP Pd(allyl)]Cl.0.5C7H8 (0.2 g, 0.3 mmol) was evacuated and backfilled with nitrogen (3 times). A solution of tert-butyl 2-(1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 34b (2.1 g, 7.5 mmol) and 2-bromo-4-cyclobutoxy-1-fluorobenzene (2.0 g, 8.3 mmol) in 1,4-dioxane (25 mL) was added and the flask was once again evacuated and backfilled with nitrogen (4 times). The resultant mixture was heated at 95° C. (internal temperature) for 16 h, then cooled to RT and partitioned between 20% w/w NaCl soln. (100 mL) and EtOAc (200 mL). The organic solution was washed with 20% w/w NaCl soln. (10 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in isohexane) to afford tert-butyl 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 34c as a thick colourless oil: m/z 438 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93 (d, J=7.8 Hz, 1H), 6.90-6.78 (m, 3H), 6.49 (s, 1H), 6.25 (d, J=8.7 Hz, 1H), 4.47 (quint, J=7.2 Hz, 1H), 4.19 (s, 2H), 3.36 (t, J=5.8 Hz, 2H), 2.88 (s, 2H), 2.39-2.26 (m, 3H), 2.13-1.98 (m, 2H), 1.83-1.68 (m, 2H), 1.67-1.50 (m, 1H), 1.48-1.38 (m, 1H), 1.39 (s, 9H), 1.16-1.09 (m, 1H).

c) Procedure for the Preparation of 34 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic Acid

(105) ##STR00108##

(106) To a solution of tert-butyl 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 34c (2.5 g, 5.8 mmol) in DCM (20 mL) was added TFA (5 mL, 65 mmol) and sodium triacetoxyborohydride (0.25 g, 1.2 mmol). The resultant mixture was stirred at RT for 3 h and then partitioned between DCM (25 mL) and water (50 mL). Residual product was extracted from the aqueous phase with further DCM (150 mL). The combined organics were washed with brine (50 mL), passed through a hydrophobic frit and then concentrated in vacuo. The residue was purified by silica gel chromatography (30-100% (1:1 DCM/EtOAc) in isohexane) to afford 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 34 as an off white solid and racemic mixture of trans enantiomers: m/z 382 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.08 (d, J=7.9 Hz, 1H), 7.02 (dd, J=12.6, 8.8 Hz, H),6.99-6.92 (m, 2H), 6.47 (dd, J=7.5, 3.0 Hz, 1H), 6.36 (dt, J=8.8, 3.1 Hz, 1H), 4.61 (quint, J=7.1 Hz, 1H), 4.18 (s, 2H), 3.34 (t, =5.8 Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.43-2.27 (m, 3H), 2.06-1.92 (m, 2H), 1.81-1.69 (m, 2H), 1.69-1.49 (m, 1H), 1.46-11.36 (m, 1H), 1.36-1.26 (m, 1H), —COOH not observed.

(107) Human GPRD120 pEC.sub.50: 6.8

(108) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 6.

(109) TABLE-US-00006 hGPR120 Compound Structure [M + H]+ NMR pEC50 35 09 396 (CDCl.sub.3) δ 7.08-7.00 (m, 2H), 6.97-6.85 (m, 3H), 6.83-6.75 (m, 1H), 4.29 (s, 2H), 3.53-3.41 (m, 2H), 2.99 (t, J = 5.9 Hz, 2H), 2.64- 2.53 (m, 1H), 1.95-1.85 (m, 1H), 1.65 (dt, J = 9.6, 4.9 Hz, 1H), 1.44-1.35 (m, 1H), —COOH not observed. 7.0 36 0 400 (DMSO-d.sub.6) δ 12.27 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00- 6.91 (m, 2H), 6.50-6.40 (m, 1H), 6.28 (dt, J = 6.8, 2.4 Hz, 1H), 4.63 (quint, J = 7.1 Hz, 1H), 4.23 (s, 2H), 3.39 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.45-2.29 (m, 3H), 2.05-1.90 (m, 2H), 1.82-1.70 (m, 2H), 1.68- 1.54 (m, 1H), 1.44-1.36 (m, 1H), 1.36-1.26 (m, 1H). 7.0 37 383 (DMSO-d.sub.6) δ 12.27 (s, 1H), 7.42 (dd, J = 12.8, 8.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.99-6.90 (m, 2H), 6.07 (dd, J = 8.4, 1.7 Hz, 1H), 4.96 (quint, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.71 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 2.41-2.28 (m, 3H), 2.07- 1.94 (m, 2H), 1.85-1.70 (m, 2H), 1.70-1.57 (m, 1H), 1.45-1.35 (m, 1H), 1.35- 1.25 (m, 1H). 7.4

Experimental Scheme 7

Compound 38 2-(2-(3-Phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-1-carboxylic Acid

(110) ##STR00112##

a) Procedure for the Preparation of 38a

(111) ##STR00113##

(112) A vial containing Cs.sub.2CO.sub.3 (0.21 g, 0.64 mmol), tert-butyl 2-(1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 34b (0.12 g, 0.42 mmol) and RuPhos Pd G3 (11 mg, 0.013 mmol) was evacuated under vacuum and backfilled with nitrogen 3 times. A solution of 1-bromo-3-phenoxybenzene (0.12 g, 0.47 mmol) in 1,4-dioxane (2 mL) was added and the vial was once again evacuated under vacuum and backfilled with nitrogen 3 times. The resultant mixture was heated at 90° C. for 16 h, then cooled to RT and water (5 mL) was added. The product was extracted with DCM (15 mL) and the organic solution was passed through a hydrophobic membrane and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in isohexane) to afford tert-butyl 2-(2-(3-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 38a as a thick colourless oil: m/z 422 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.38-7.29 (m, 2H), 7.22 (t, J=8.2 Hz, 1H), 7.12-7.00 (m, 4H), 6.91 (d, J=8.6 Hz, 2H), 6.72 (d, J=7.1 Hz, 1H), 6.65 (s, 1H), 6.44 (d, J=7.5 Hz, 1H), 4.37 (s, 2H), 3.53 (t, J=5.8 Hz, 2H), 2.93 (t, J=5.5 Hz, 2H), 2.45-2.36 (m, 1H), 1.86-1.73 (m, 1H), 1.52 (dt, J=9.5, 4.8 Hz, 1H), 1.47 (s, 9H), 1.26-1.18 (m, 1H).

b) Procedure for the Preparation of Compound 38 2-(2-(3-Phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic Acid

(113) ##STR00114##

(114) A solution tert-butyl 2-(2-(3-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate 38a (125 mg, 0.28 mmol) in DCM (2 mL) was treated with sodium triacetoxyborohydride (60 mg, 0.28 mmol) and TFA (1 mL, 13 mmol) and the mixture was stirred at RT for 1 h. Water (2 mL) was added and the product was extracted with DCM (15 mL). The organic solution was passed through a hydrophobic membrane and then concentrated in vacuo. The product was purified by reverse-phase flash chromatography (25-100% MeCN in water with 0.1% formic acid) to afford 2-(2-(3-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 38 as a colourless solid: m/z 386 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.30 (s, 1H), 7.41-7.32 (m, 2H), 7.20 (t, J=8.2 Hz, 1H), 7.15-7.07 (m, 2H), 7.01-6.94 (m, 4H), 6.77 (dd, J=8.3, 2.4 Hz, 1H), 6.65 (t, J=2.3 Hz, 1H), 6.29 (dd, J=7.9, 2.2 Hz, 1H), 4.34 (s, 2H), 3.50 (t, J=5.9 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.37-2.29 (m, 1H), 1.80-1.72 (m, 1H), 1.39 (dt, J=9.2, 4.6 Hz, 1H), 1.35-1.26 (m, 1H).

(115) Human GPR120 pEC.sub.50: 7.2

Experimental Scheme 8

Compounds 34-isomer1 and 34-isomer2 2-(2-(5-Cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-1-carboxylic Acid

(116) ##STR00115##

a) Procedure for the Preparation of 34d

(117) ##STR00116##

(118) Oxalyl chloride (0.5 mL, 6 mmol) and DMF (1 drop) were sequentially added to a solution of 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 34 (1.9 g, 4.7 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, then warmed to RT and stirred for a further 2 h. The mixture was concentrated in vacuo to provide 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarbonyl chloride 34d as a yellow foam that was used directly in the next step without purification or analysis.

b) Procedure for the Preparation of 34e: Isomer 1 and Isomer 2

(119) ##STR00117##

(120) A solution of (S)-4-isopropyloxazoidin-2-one (1.3 g, 9.9 mmol) in THF (20 mL) was cooled to −78° C. and n-BuLi (2.5 M in hexane, 3.8 mL, 9.5 mmol) was added dropwise keeping internal temperature below −40° C. The mixture was stirred at −78° C. for 30 min, warmed to 0° C. and then cooled back down to −78° C. A solution of 2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarbonyl chloride 34d (1.9 g, 4.7 mmol) in THE (20 mL) was added dropwise keeping the internal temp below −55° C. The resultant mixture was stirred at −78° C. for 30 min, then at −40° C. for 60 min. The reaction was quenched by the addition of sat. NH.sub.4Cl (25 mL) and the product was extracted with EtOAc (100 mL). The organic solution was washed with brine (25 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-35% EtOAc in isohexane) to afford (S)-3-(2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarbonyl)-4-isopropyloxazolidin-2-one 34e isomer 1 and isomer 2 as thick colourless oils: Isomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.05-6.87 (m, 4H), 6.53 (s, 1H), 6.36-6.27 (m, 1H), 4.60-4.51 (m, 2H), 4.50-4.41 (m, 1H), 4.34-4.18 (m, 4H), 3.60-3.51 (m, 1H), 3.42 (t, J=5.8 Hz, 2H), 2.95 (t, J=5.9 Hz, 2H), 2.65-2.55 (m, 1H), 2.46-2.32 (m, 2H), 2.21-2.07 (m, 2H), 1.91-1.77 (m, 1H), 1.78-1.68 (m, 1H), 1.73-1.58 (m, 1H), 1.46-1.34 (m, 1H), 0.92 (t, J=6.8 Hz, 6H).

(121) Isomer 2: m/z 493 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 1H NMR (400 MHz, Chloroform-d) 7.12-6.87 (m, 4H), 6.58 (s, 1H), 6.33 (d, J=8.8 Hz, 1H), 4.55 (p, J=7.2 Hz, 1H), 4.51-4.43 (m, 1H), 4.33-4.18 (m, 4H), 3.61-3.51 (m, 1H), 3.45 (t, J=5.9 Hz, 2H), 2.97 (s, 2H), 2.69-2.59 (m, 1H), 2.47-2.30 (m, 2H), 2.22-2.07 (m, 2H), 1.84 (q, J=10.5 Hz, 1H), 1.75-1.60 (m, 2H), 1.44-1.34 (m, 1H), 0.91 (dd, J=11.9, 7.0 Hz, 6H).

c) Procedure for the Preparation of 34: Isomer 1 and Isomer 2

(122) Isomer 1: hydrogen peroxide 27% (w/w) (90 μl, 0.793 mmol) was added dropwise to a solution of LiOH (14 mg, 0.585 mmol) in water (0.1 ml) at room temperature. The resulting solution was stirred for 30 min and then cooled to 0° C. This cooled solution was added dropwise to a cooled solution of (S)-3-(2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarbonyl)-4-isopropyloxazolidin-2-one 34e isomer 1 (95 mg, 0.193 mmol) in THF (0.3 ml). The reaction mixture was stirred for 60 minutes at 0° C. then room temperature for a further 60 minutes. Sodium sulfite (100 mg, 0.793 mmol) in water (0.3 ml) was added and the reaction mixture stirred for a further 10 min. The mixture was acidified to pH 5 with 1 M HCl and the product was extracted with EtOAc (2×5 ml). The combined organic phases were washed with brine (5 ml), dried with MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (0-50% EtOAc in isohexane) to afford 34 isomer 1 as a colourless solid: m/z 382 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.28 (s, 1H), 7.09 (d, J=7.9 Hz, 1H), 7.03 (dd, J=12.6, 8.8 Hz, 1H), 6.99-6.93 (m, 2H), 6.48 (dd, J=7.5, 3.0 Hz, 1H), 6.37 (dt, J=8.8, 3.1 Hz, 1H), 4.61 (p, J=7.1 Hz, 1H), 4.18 (s, 2H), 3.35 (t, J=5.9 Hz, 2H), 2.84 (t, J=5.9 Hz, 2H), 2.44-2.29 (m, 3H), 2.08-1.92 (m, 2H), 1.83-1.70 (m, 2H), 1.74-1.53 (m, 1H), 1.45-1.35 (m, 1H), 1.37-1.25 (m, 1H

(123) Human GPR120 pEC.sub.50: 6.8

(124) Isomer 2: 34 isomer 2 was prepared from (S)-3-(2-(2-(5-cyclobutoxy-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarbonyl)-4-isopropyloxazolidin-2-one 34e isomer 2 using a procedure essentially the same as for 34 isomer 1 to afford 34 isomer 2 as a colourless solid: m/z 382 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.23 (s, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.03 (dd, J=12.6, 8.8 Hz, 1H), 7.00-6.92 (m, 2H), 6.48 (dd, J=7.5, 2:9 Hz, 1H), 6.37 (dt, J=8.8, 3.2 Hz, 1H), 4.61 (p, J=7.1 Hz, 1H), 4.18 (s, 2H), 3.35 (t, J=5.8 Hz, 2H), 2.84 (t, J=5.9 Hz, 2H), 2.44-2.29 (m, 3H), 2.00 (dtd, J=12.6, 10.0, 7.9 Hz, 2H), 1.83-1.69 (m, 2H), 1.70-1.53 (m, 1H), 1.45-1.36 (m, 1H), 1.37-1.27 (m, 1H).

(125) Human GPR120 pEC.sub.50: 7.1

(126) The following compounds were prepared using appropriate starting materials in analogous procedure to that described in Experimental Scheme 8.

(127) TABLE-US-00007 hGPR120 Compound Structure [M + H]+ NMR pEC50 35 Isomers Isomer 1: 396 Isomer 2: 396 Isomer 1: (Methanol-d.sub.4) δ 7.20-7.02 (m, 2H), 6.96 (d, J = 6.9 Hz, 3H), 6.85 (d, J = 8.9 Hz, 1H), 4.25 (s, 2H), 3.44 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.1 Hz, 4H), 2.49-2.36 (m, 1H), 1.82 (dt, J = 9.0, 4.8 Hz, 1H), 1.51 (dt, J = 9.4, 4.8 Hz, 1H), 1.40-1.30 (m, 1H), —COOH not observed. Isomer 2: (Methonol-d.sub.4) δ 7.20-7.05 (m, 2H), 6.96 (d, J = 6.7 Hz, 3H), 6.85 (d, J = 8.6 Hz, 1H), 4.25 (s, 2H), 3.44 (t, J = 5.9 Hz, 2H), 2.95 (t, J = 5.9 Hz, 2H), 2.48-2.38 (m, 1H), 1.86-1.75 (m, 1H), 1.56-1.46 (m, 1H), 1.39-1.31 (m, 1H), —COOH not observed. Isomer 1: 6.6 Isomer 1: 6.8 36 Isomers Isomer 1: 400 Isomer 2: 400 Isomer 1: (DMSO-d.sub.6) δ 7.08 (d, J = 7.9 Hz, 1H), 6.98-6.90 (m, 2H), 6.50-6.39 (m, 1H), 6.28 (dt, J = 6.6, 2.4 Hz, 1H), 4.63 (quint, J = 7.1 Hz, 1H), 4.22 (s, 2H), 3.39 (t, J = 5.9 Hz, 2H, overlapping with H2O peak), 2.84 (t, J = 5.8 Hz, 2H), 2.45-2.24 (m, 3H), 2.04-1.89 (m, 2H), 1.82-1.70 (m, 2H), 1.70-1.53 (m, 1H), 1.46-1.33 (m, 1H), 1.33-1.22 (m, 1H), —COOH not observed. Isomer 2: (DMSO-d.sub.6) δ 7.08 (d, J = 7.9 Hz, 1H), 6.99-6.92 (m, 2H), 6.49-6.41 (m, 1H), 6.28 (dt, J = 6.7, 2.3 Hz, 1H), 4.63 (quint, J = 7.1 Isomer 1: 6.9 Isomer 1: 7.1 Hz, 1H), 4.22 (s, 2H), 3.39 (d, J = 11.7 Hz, 2H, overlapping with H2O peak), 2.84 (t, J = 5.9 Hz, 2H), 2.44-2.26 (m, 3H), 2.05-1.90 (m, 2H), 1.81-1.70 (m, 2H), 1.68-1.53 (m, 1H), 1.42-1.33 (m, 1H), 1.31-1.21 (m, 1H), —COOH not observed.

Experimental Scheme 9

(128) Compounds 38-Isomer 1 and 38-Isomer 2

(129) ##STR00120##

(130) 2-(2-(3-Phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 38 (55 mg, 0.14 mmol) was purified by preparative HPLC (ChiralPak IA column, 15 mL/min, 10% EtOH in isohexane (0.2% TFA)) to afford 2-(2-(3-Phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 38 isomer 1 and isomer 2 as tan solids: Isomer 1: m/z 386 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (500 MHz, DMSO) δ 7.40-7.33 (m, 2H), 7.20 (t, J=8.2 Hz, 1H), 7.14-7.08 (m, 2H), 7.01-6.99 (m, 1H), 6.99-6.95 (m, 3H), 6.80-6.75 (m, 1H), 6.65 (t, J=2.3 Hz, 1H), 6.33-6.27 (m, 1H), 4.34 (s, 2H), 3.50 (t, J=5.9 Hz, 2H), 2.85 (t, J=5.9 Hz, 2H), 2.32 (ddd, J=4.1, 6.4, 9.1 Hz, 1H), 1.77 (ddd, J=4.1, 5.3, 8.3 Hz, 1H), 1.39 (ddd, J=4.2, 5.3, 9.2 Hz, 1H), 1.29 (ddd, J=4.2, 6.4, 8.3 Hz, 1H) —COOH not observed.

(131) Human GPR120 pEC50: 7.3

(132) Isomer 2: m/z 386 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (500 MHz, DMSO) δ 7.40-7.33 (m, 2H), 7.20 (t, J=8.2 Hz, 1H), 7.14-7.08 (m, 2H), 7.01-6.98 (m, 1H), 6.98-6.95 (m, 3H), 6.80-6.74 (m, 1H), 6.65 (t, J=2.3 Hz, 1H), 6.32-6.28 (m, 1H), 4.34 (s, 2H), 3.50 (t, J=5.9 Hz, 2H), 2.85 (t, J=5.9 Hz, 2H), 2.33 (ddd, J=4.0, 6.4, 9.2 Hz, 1H), 1.77 (ddd, J=4.1, 5.2, 8.3 Hz, 1H), 1.39 (ddd, J=4.2, 5.3, 9.2 Hz, 1H), 1.30 (ddd, J=4.2, 6.4, 8.3 Hz, 1H) —COOH not observed.

(133) Human GPR120 pEC50: 7.4

(134) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 9.

(135) TABLE-US-00008 hGPR120 Compound Structure [M + H]+ NMR pEC50 37 Isomers Isomer 1: 383 Isomer 2: 383 Isomer 1: (DMSO-d.sub.6) δ 7.42 (dd, J = 12.8, 8.4 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00- 6.91 (m, 2H), 6.08 (dd, J = 8.4, 1.7 Hz, 1H), 4.96 (quint, J = 7.3 Hz, 1H), 4.58 (s, 2H), 3.71 (t, J = 5.8 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 2.45- 2.27 (m, 3H), 2.09-1.93 (m, 2H), 1.83-1.70 (m, 2H), 1.73-1.56 (m, 1H), 1.43- 1.32 (m, 1H), 1.34-1.21 (m, 1H), —COOH not observed. Isomer 2: (DMSO-d.sub.6) δ 7.41 (dd, J = 12.8, 8.4 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.98- 6.89 (m, 2H), 6.07 (dd, J = 8.4, 1.7 Hz, 1H), 4.95 (quint, J = 7.3 Hz, 1H), 4.57 (s, 2H), 3.71 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.43- 2.21 (m, 3H), 2.09-1.93 (m, 2H), 1.83-1.69 (m, 2H), Isomer 1: 7.2 Isomer 1: 7.2 1.72-1.55 (m, 1H), 1.36 (dt, J = 9.2, 4.7 Hz, 1H), 1.29- 1.20 (m, 1H), —COOH not observed.

Experimental Scheme 10

Compound 393-(2-(5-Cyclobutoxy-2-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(136) ##STR00122## ##STR00123##

a) Procedure for the Preparation of 39b

(137) ##STR00124##

(138) A solution of 4-bromo-3-fluorobenzaldehyde 39a (5.0 g, 25 mmol), 2,2-dimethoxyethanamine (2.7 mL, 25 mmol) in anhydrous toluene (60 mL) was heated for two days at 135° C. using Dean stark apparatus. The reaction mixture was cooled to RT, concentrated in vacuo, diluted with MeOH and cooled to 0° C. under argon. Sodium borohydride (2.8 g, 74 mmol) was added portionwise and the mixture was stirred for 30 min at 0° C., then warmed to RT and stirred overnight. The reaction mixture was concentrated in vacuo, diluted with water and the product was extracted with EtOAc. The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford N-(4-bromo-3-fluorobenzyl)-2,2-dimethoxyethan-1-amine 39b as orange oil that was used in the next step without further purification.

b) Procedure for the Preparation of 39c

(139) ##STR00125##

(140) Triethylamine (6.7 mL, 48 mmol) and DMAP (150 mg, 1.2 mmol) were added to a solution of N-(4-bromo-3-fluorobenzyl)-2,2-dimethoxyethan-1-amine 39b (7.0 g, 24 mmol) in anhydrous DCM (70 mL), under argon at 0° C. After 10 min tosyl chloride (4.8 g, 25 mmol) was added and the mixture was warmed to RT and stirred overnight. The mixture was diluted with DCM and washed with water and brine. The organic solution was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc in pet. ether) to give N-(4-bromo-3-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide 39c as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74-7.69 (m, 2H), 7.45 (dd, J=8.1, 7.1 Hz, 1H), 7.32 (d, J=7.9 Hz, 2H), 6.98 (dd, J=9.4, 2.0 Hz, 1H), 6.91 (dd, J=8.2, 1.5 Hz, 1H), 4.41 (s, 2H), 4.35 (t, J=5.3 Hz, 1H), 3.25 (s, 6H), 3.22 (d, J=5.3 Hz, 2H), 2.45 (s, 3H); ESI-HRMS calculated for C.sub.18H.sub.21BrFNO.sub.4SNa (M+Na.sup.+) 468.0251, found 468.0268.

c) Procedure for the Preparation of 39d

(141) ##STR00126##

(142) A suspension of anhydrous aluminum chloride (10.4 g, 78.0 mmol) in anhydrous DCM (100 mL) was cooled to −20° C., under argon before, a solution of N-(4-bromo-3-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide 39c (7.0 g, 16 mmol) in anhydrous dichloromethane (100 mL) was added. The mixture was warmed to RT and stirred for 2 days then concentrated in vacuo. The residue was cooled to 0° C. and water was added slowly, followed by 2 M potassium hydroxide solution (pH>10). The mixture was diluted with EtOAc and filtered through a pad of celite. The layers were separated and residual product was extracted from the aqueous phase with EtOAc (3×). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-35% EtOAc in pet. ether) to afforded 6-bromo-7-fluoroisoquinoline 39d as a pale brown solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.21 (s, 1H), 8.55 (d, J=5.8 Hz, 1H), 8.12 (d, J=6.5 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.59 (d, J=5.8 Hz, 1H); ESI-HRMS calculated for C.sub.9H.sub.6BrFN (M+H.sup.+) 225.9668, found 225.9664.

d) Procedure for the Preparation of 39e

(143) ##STR00127##

(144) A vial was charged with 6-bromo-7-fluoroisoquinoline 39d (1.2 g, 5.3 mmol), Pd(OAc).sub.2 (30 mg, 0.1 mmol), tris(o-tolyl)phosphine (8 mg, 0.3 mmol), anhydrous DMF (6 mL) and DIPEA (6 mL). The vial was evacuated and back filled with nitrogen three times before ethyl acrylate (0.69 mL, 6.4 mL) was added and the mixture was heated overnight at 100° C. under argon. The mixture was cooled to RT and water was added. The product was extracted with EtOAc and the combined organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc in pet. ether) to afford ethyl (E)-3-(7-fluoroisoquinolin-6-yl)acrylate 39e as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.21 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.02 (d, J=7.0 Hz, 1H), 7.90 (d, J=16.2 Hz, 1H), 7.64 (t, J=9.0 Hz, 2H), 6.76 (d, J=16.2 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.14H.sub.13FNO.sub.2 (M+H.sup.+) 246.0925, found 246.0931.

e) Procedure for the Preparation of 39f

(145) ##STR00128##

(146) A mixture of ethyl (E)-3-(7-fluoroisoquinolin-6-yl)acrylate 39e (1.9 g, 7.8 mmol), acetic acid (38 mL) and Pt—C (0.7 g, 0.2 mmol, 5% w/w) was heated overnight at 70° C. under atmosphere of hydrogen (balloon). The mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was partitioned between EtOAc, added sat. NaHCO.sub.3 solution (100 mL). The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was dissolved in DCM and treated with 4 M HCl in dioxane solution (4.5 mL) at 0° C., then concentrated in vacuo to afford ethyl 3-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride 39f as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 10.18 (s, 2H), 7.03 (d, J=7.3 Hz, 1H), 6.80 (d, J=9.9 Hz, 1H), 4.30 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.42 (s, 2H), 3.10 (t, J=5.8 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H), NH.sub.2.sup.+ not observed; ESI-HRMS calculated for C.sub.14H.sub.19FNO.sub.2 (M+H.sup.+) 252.1394, found 252.1400.

f) Procedure for the Preparation of 39g

(147) ##STR00129##

(148) A vial under argon was charged with ethyl 3-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride 39f (100 mg, 0.4 mmol), Cs.sub.2CO.sub.3 (450 mg, 1.4 mmol), Pd.sub.2(dba).sub.3 (16 mg, 0.017 mmol), SPhos (20 mg, 0.05 mmol), 2-bromo-4-cyclobutoxy-1-fluorobenzene (115 mg, 0.470 mmol) and anhydrous dioxane (1.4 mL). The vial was sealed, evacuated and back filled with argon three times, then heated at 100° C. for 48 h. The mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5% EtOAc in pet. ether) to yield ethyl 3-(2-(5-cyclobutoxy-2-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 39g as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 6.97 (d, J=7.6 Hz, 1H), 6.91 (dd, J=12.2, 8.8 Hz, 1H), 6.76 (d, J=10.4 Hz, 1H), 6.47 (dd, J=7.4, 2.9 Hz, 1H), 6.31 (dt, J=8.8, 3.1 Hz, 1H), 4.55 (p, J=6.8 Hz, 1H), 4.21 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.40 (t, J=5.9 Hz, 2H), 2.91 (dt, J=11.5, 6.7 Hz, 4H), 2.63-2.56 (m, 2H), 2.45-2.33 (m, 2H), 2.19-2.07 (m, 2H), 1.89-1.78 (m, 1H), 1.72-1.61 (m, 1H), 1.24 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.24H.sub.27F.sub.2NO.sub.3Na (M+Na.sup.+) 438.1851, found 438.1854.

g) Procedure for the Preparation of 39 3-(2-(5-cyclobutoxy-2-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(149) ##STR00130##

(150) A mixture of ethyl 3-(2-(5-cyclobutoxy-2-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 39g (36 mg, 0.087 mmol) and LiOH.H.sub.2O (11 mg, 0.26 mmol) in THF (0.6 mL) and water (0.3 mL) was stirred at RT overnight. The mixture was cooled to 0° C. and 1 M HCl (aq) was added until the mixture was acidified to pH 1. The mixture was warmed to RT and the product was extracted with EtOAc. The organic solution was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc (with 1% AcOH) in pet. ether) to provide 3-(2-(5-cyclobutoxy-2-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 39 as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.97 (d, J=7.6 Hz, 1H), 6.92 (dd, J=12.2, 8.8 Hz, 1H), 6.77 (d, J=10.4 Hz, 1H), 6.47 (dd, J=7.3, 2.9 Hz, 1H), 6.31 (dt, J=8.8, 3.1 Hz, 1H), 4.55 (p, J=6.8 Hz, 1H), 4.22 (s, 2H), 3.40 (t, J=5.8 Hz, 2H), 2.92 (dt, J=11.4, 6.7 Hz, 4H), 2.68 (t, J=7.7 Hz, 2H), 2.44-2.35 (m, 2H), 2.19-2.07 (m, 2H), 1.89-1.78 (m, 1H), 1.74-1.59 (m, 1H), —COOH not observed; ESI-HRMS calculated for C.sub.22H.sub.24F.sub.2NO.sub.3 (M+H.sup.+) 388.1719, found 388.1715.

(151) Human GPR120 pEC50: 7.2

(152) The following compounds were prepared using appropriate starting materials in analogous procedure to that described in Experimental Scheme 13. Where the starting materials are not described in the literature, their synthesis is described below.

(153) TABLE-US-00009 hGPR120 Compound Structure [M + H]+ NMR pEC50 40 402 (CDCl.sub.3) δ 7.04 (dd, J = 11.9, 8.8 Hz, 1H), 6.85 (dd, J = 7.1, 2.7 Hz, 1H), 6.81 (s, 1H), 6.80-6.74 (m, 2H), 4.24 (s, 2H), 3.41 (t, J = 5.7 Hz, 2H), 2.96 (t, J = 5.7 Hz, 2H), 2.91 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H) —COOH not observed 7.5 41 392 (CDCl.sub.3) δ 7.35-7.29 (m, 2H), 7.22 (t, J = 8.2 Hz, 1H), 7.11-7.05 (m, 1H), 7.04- 7.00 (m, 2H), 6.79 (s, 1H), 6.78-6.72 (m, 2H), 6.69 (t, J = 2.3 Hz, 1H), 6.44 (dd, J = 8.0, 1.8 Hz, 1H), 4.35 (s, 2H), 3.52 (t, J = 5.8 Hz, 2H), 2.97-2.87 (m, 4H), 2.66 (t, J = 7.7 Hz, 2H) —COOH not observed 7.5
Intermediate 7 (I-7)

(154) ##STR00133##
Step 1:

(155) N-(4-Bromo-2-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzene sulfonamide I-7b was prepared from 4-bromo-2-fluorobenzaldehyde I-7a using a procedure essentially the same as for 39c (Scheme 10): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72-7.61 (m, 2H), 7.35-7.23 (m, 4H), 7.16 (d, J=1.8 Hz, 1H), 4.45 (s, 2H), 4.38 (t, J=5.3 Hz, 1H), 3.25 (s, 8H), 2.43 (s, 3H); ESI-HRMS calculated for C.sub.18H.sub.21BrFNO.sub.4SNa (M+Na.sup.+) 468.0251 found 468.0262.

(156) Step 2:

(157) 6-Bromo-8-fluoroisoquinoline I-7c was prepared from N-(4-bromo-2-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzene sulfonamide I-7b using a procedure essentially the same as for 39d (Scheme 10): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.48 (s, 1H), 8.62 (d, J=5.8 Hz, 1H), 7.79 (s, 1H), 7.57 (dd, J=5.8, 1.3 Hz, 1H), 7.38 (dd, J=9.5, 1.6 Hz, 1H); ESI-HRMS calculated for C.sub.9H.sub.6BrFN (M+H.sup.+) 225.9662 found 225.9672.

(158) Step 3:

(159) Ethyl (E)-3-(8-fluoroisoquinolin-6-yl)acrylate I-7d was prepared from 6-bromo-8-fluoroisoquinoline I-7c using a procedure essentially the same as for 39e (Scheme 10): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.52 (s, 1H), 8.65 (d, J=5.8 Hz, 1H), 7.78 (dd, J=16.0, 1.1 Hz, 1H), 7.70 (s, 1H), 7.68 (dd, J=5.8, 1.3 Hz, 1H), 7.42 (dd, J=11.1, 1.3 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.14H.sub.13FNO.sub.2 (M+H.sup.+) 246.0925 found 246.0919.

(160) Step 4:

(161) Ethyl 3-(8-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride I-7 was prepared from ethyl (E)-3-(8-fluoroisoquinolin-6-yl)acrylate I-7d using a procedure essentially the same as for 39f (Scheme 10): m/z 252 [M+H].sup.+ (APCI.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.27 (br s, 2H), 6.85-6.79 (m, 2H), 4.32 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.49-3.41 (m, 2H), 3.17 (t, J=5.8 Hz, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

Experimental Scheme 11

Compound 423-(2-(3-Cyclobutoxy-5-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(162) ##STR00134##

a) Procedure for the Preparation of 42a

(163) ##STR00135##

(164) A vial, under argon, was charged with ethyl 3-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride 39f (125 mg, 0.43 mmol), Cs.sub.2CO.sub.3 (425 mg, 1.3 mmol), Xphos Pd G4 (10 mg, 0.03 mmol), 1-bromo-3-cyclobutoxy-5-fluorobenzene (120 mg, 0.50 mmol) and anhydrous dioxane (2.2 mL). The vial was sealed, evacuated and back filled with argon three times and heated at 100° C. After 22 h the mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc (with 1% AcOH) in pet. ether) to afford ethyl 3-(2-(3-cyclobutoxy-5-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 42a as an amorphous solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.97 (dd, J=12.4, 5.8 Hz, 1H), 6.80 (d, J=10.3 Hz, 1H), 6.22 (dt, J=12.1, 2.2 Hz, 1H),6.16 (t, J=1.8 Hz, 1H), 5.98 (dt, J=10.5, 2.1 Hz, 1H), 4.64-4.55 (m, 1H), 4.31 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.49 (t, J=5.9 Hz, 2H), 2.90 (dt, J=11.5, 6.7 Hz, 4H), 2.61 (t, J=7.7 Hz, 2H), 2.47-2.38 (m, 2H), 2.21-2.10 (m, 2H), 1.90-1.80 (m, 1H), 1.74-1.63 (m, 1H), 1.23 (t, J=7.1 Hz, 3H); ESI-HRMS calculated for C.sub.24H.sub.28F.sub.2NO.sub.3 (M+H.sup.+) 416.2032 found 416.2037.

b) Procedure for the Preparation of 42 3-(2-(3-Cyclobutoxy-5-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(165) ##STR00136##

(166) 3-(2-(3-Cyclobutoxy-5-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 42 was prepared from ethyl 3-(2-(3-cyclobutoxy-5-fluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 42a using a procedure essentially the same as for compound 39: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.99 (d, J=7.5 Hz, 1H), 6.81 (d, J=10.2 Hz, 1H), 6.22 (d, J=12.1 Hz, 1H), 6.16 (s, 1H), 6.02-5.95 (m, 1H), 4.60 (p, J=7.2 Hz, 1H), 4.31 (s, 2H), 3.50 (t, J=5.8 Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 2.88 (t, J=5.7 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H), 2.48-2.38 (m, 2H), 2.22-2.09 (m, 2H), 1.91-1.80 (m, 1H), 1.75-1.61 (m, 1H), —COOH not observed; ESI-HRMS calculated for C22H24F2NO3 (M+H.sup.+) 388.1719 found 388.1715.

(167) Human GPR120 pEC50: 6.5

(168) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 11.

(169) Where the starting materials are not described in the literature, their synthesis is described below.

(170) TABLE-US-00010 hGPR120 Compound Structure [M + H]+ NMR pEC50 43 386 (CDCl.sub.3) δ 7.10-6.99 (m, 3H), 6.51 (app t, J = 1.9 Hz, 1H), 6.27 (app t, J = 2.2 Hz, 1H), 6.23 (app t, J = 1.9 Hz, 1H), 4.65-4.56 (m, 1H), 4.34 (s, 2H), 3.50 (t, J = 5.9 Hz, 2H), 2.96-2.90 (m, 4H), 2.68 (t, J = 7.8 Hz, 2H), 2.48-2.39 (m, 2H), 2.22-2.08 (m, 2H), 1.91- 1.80 (m, 1H), 1.75-1.61 (m, 1H), —COOH not observed. 7.7
Intermediate 8 (I-8)

(171) ##STR00138##

(172) A vial was charged with K.sub.2CO.sub.3 (2.07 g, 15 mmol), DMF (5 mL), 3-bromo-5-chlorophenol I-8a (1.57 g, 7.5 mmol) and KI (620 mg, 3.75 mmol) and the mixture was stirred at RT for 10 min. Bromocyclobutane (1.06 ml, 11.3 mmol) was added and the mixture was heated at 90° C. for 20 h. The reaction was cooled to RT, filtered through a plug of silica (EtOAc), diluted with water and the product was extracted with EtOAc (×3). The combined organic phases were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (pet. ether) to afford 1-bromo-3-chloro-5-cyclobutoxybenzene I-8 as a colourless oil: 1H NMR (400 MHz, CDCl.sub.3) δ 7.08-7.06 (m, 1H), 6.86-6.84 (m, 1H), 6.74-6.73 (m, 1H), 4.63-4.54 (m, 1H), 2.49-2.40 (m, 2H), 2.20-2.08 (m, 2H), 1.93-1.82 (m, 1H), 1.75-1.62 (m, 1H)

Experimental Scheme 12

Compound 44 3-(2-(6-Cyclobutoxy-3,5-difluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(173) ##STR00139##

a) Procedure for the Preparation of 44a

(174) ##STR00140##

(175) A vial was charged with ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate hydrochloride 28c (103 mg, 0.38 mmol), Cs.sub.2CO.sub.3 (259 mg, 0.79 mmol), 2-cyclobutoxy-3,5,6-trifluoropyridine I-9 (116 mg, 0.57 mmol) and DMF (1 mL). The mixture was heated at 100° C. for 20 h. The reaction was cooled to RT and filtered through a plug of silica (eluent EtOAc). The filtrate was diluted with water and the product was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (0-5% EtOAc in pet. ether) to afford ethyl 3-(2-(6-cyclobutoxy-3,5-difluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 44a as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.12 (dd, J=11.0, 8.9 Hz, 1H), 7.08-6.96 (m, 3H), 5.16-5.05 (m, 1H), 4.55 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.69 (t, J=5.9 Hz, 2H), 2.97-2.88 (m, 4H), 2.63-2.58 (m, 2H), 2.47-2.38 (m, 2H), 2.25-2.13 (m, 2H), 1.90-1.80 (m, 1H), 1.75-1.63 (m, 1H), 1.24 (t, J=7.1 Hz, 3H);

b) Procedure for the Preparation of 44 3-(2-(6-Cyclobutoxy-3,5-difluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic Acid

(176) ##STR00141##

(177) 3-(2-(6-Cyclobutoxy-3,5-difluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 44 was prepared from ethyl 3-(2-(6-cyclobutoxy-3,5-difluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate 44a using a procedure essentially the same as for compound 29. The product was purified by column chromatography (0-25% (0.01% AcOH in EtOAc) in pet. ether) to afford 3-(2-(6-Cyclobutoxy-3,5-difluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid 44 as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.13 (dd, J=11.0, 8.9 Hz, 1H), 7.09-6.97 (m, 3H), 5.16-5.05 (m, 1H), 4.55 (s, 2H), 3.70 (t, J=5.9 Hz, 2H), 2.95-2.89 (m, 4H), 2.71-2.64 (m, 2H), 2.46-2.37 (m, 2H), 2.25-2.13 (m, 2H), 1.90-1.80 (m, 1H), 1.75-1.62 (m, 1H)—COOH not observed; ESI-HRMS calcd for C.sub.21H.sub.23F.sub.2N.sub.2O.sub.3 (M+H.sup.+) 389.1671, found 389.1671.

(178) Human GPR120 pEC.sub.50: 7.6

(179) Intermediate 9 (I-9)

(180) ##STR00142##

(181) A vial was charged with K.sub.2CO.sub.3 (1.10 g, 7.94 mmol), MeCN (10 mL), 2,3,5,6-tetrafluoropyridine I-9a (0.66 mL, 6.6 mmol), cyclobutanol (0.52 mL, 6.6 mmol) and the mixture was stirred at RT for 18 h. An additional portion of cyclobutanol (0.4 mL, 5.1 mmol) was added and the mixture was heated at 120° C. for 3 days. The reaction was cooled to RT, filtered through a plug of silica (eluent EtOAc) and concentrated in vacuo. The residue was purified by chromatography on silica (pet. ether) to afford 2-cyclobutoxy-3,5,6-trifluoropyridine I-9 as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.36 (td, J=8.1, 7.2 Hz, 1H), 5.17-5.09 (m, 1H), 2.53-2.43 (m, 2H), 2.25-2.12 (m, 2H), 1.92-1.81 (m, 1H), 1.75-1.62 (m, 1H)

Experimental Scheme 13

Compound 45 3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid

(182) ##STR00143##

a) Procedure for the Preparation of 45b and 45c

(183) ##STR00144##
Step 1a:

(184) NaN.sub.3 (0.36 g, 5.6 mmol) was cautiously added to a solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one 45a (1.0 g, 4.4 mmol) in methanesulfonic acid (5 mL) at 0° C. The reaction mixture was warmed to RT overnight. The mixture was poured onto a mixture of 1 M KOH and ice and the product was extracted with EtOAc. The organic solution was washed with brine, dried over Na.sub.2SO.sub.4 and filtered. The solution was concentrated in vacuo to provide a 1:1 mixture of 7-bromo-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one and 7-bromo-1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one that was taken on without purification.

(185) Step 1b:

(186) Borane.dimethylsulfide complex (1 M, 8.9 mL, 8.9 mmol) was added dropwise to a solution of the mixture obtained in step 1a in DME (5 mL) at 0° C. The mixture was heated at reflux, under argon overnight then cooled to 0° C. The reaction was quenched by the addition of MeOH and the solution was concentrated in vacuo to afford a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine which was taken on to the next step without purification.

(187) Step 1c:

(188) The mixture from step 1b was dissolved in anhydrous DCM (10 mL) and the solution was cooled to 0° C. before the sequential addition of Et.sub.3N (1.2 g, 12 mmol), DMAP (57 mg, 0.47 mmol) and di-tert-butyl dicarbonate (1.3 g, 6.1 mmol). The mixture was stirred at RT overnight, then the product was extracted with DCM. The organic solution was washed with 1M HCl and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in pet. ether) to yield tert-butyl 7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45b and tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 45c as clear oils: 45b: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.27-7.23 (m, 2H), 6.98 (d, J=7.9 Hz, 1H), 3.53 (q, J=5.4 Hz, 4H), 2.88-2.79 (m, 4H), 1.47 (s, 9H); ESI-HRMS calculated for C.sub.15H.sub.20BrNNaO.sub.2 (M+Na.sup.+) 348.0570 found 348.0572. 45c: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.32 (br s, 1H), 7.30-7.25 (m, 2H), 4.35 (br s, 2H), 3.70 (br s, 2H), 2.96-2.89 (m, 2H), 1.78 (s, 2H), 1.41 (s, 9H). 3.73-3.61 (m, 2H), 2.93-2.87 (m, 2H), 1.81-1.70 (m, 2H), 1.38 (s, 9H); ESI-HRMS calculated for C.sub.15H.sub.20BrNNaO.sub.2 (M+Na.sup.+) 348.0570, found 348.0558.

d) Procedure for the Preparation of 45d

(189) ##STR00145##

(190) tert-Butyl 7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45b (170 mg, 0.52 mmol), palladium (II) acetate (2.9 mg, 2.5 mol %) and tri-o-tolylphosphine (7.9 mg, 5.0 mol %) were placed in a sealed vial, which was then evacuated and back-filled with argon three times. Ethyl acrylate (63 mg, 0.63 mmol) and a solution of DMF: DIPEA (1:1, 2 ml) were added and the mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction was cooled to RT and water was added. The product was extracted with diethylether. The combined organic phases were washed with 1M HCl, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in pet. ether) to afford tert-butyl (E)-7-(3-ethoxy-3-oxoprop-1-en-1-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45d as a clear oil: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.66 (d, J=16.0 Hz, 1H), 7.34-7.29 (m, 2H), 7.15 (d, J=7.7 Hz, 1H), 6.42 (d, J=16.0 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.58 (d, J=6.6 Hz, 4H), 2.98-2.84 (m, 4H), 1.47 (d, J=7.2 Hz, 9H), 1.36 (t, J=7.1 Hz, 3H); ESI-HRMS calcd for C.sub.20H.sub.27NNaO.sub.4 (M+Na.sup.+) 368.1832, found 368.1846.

e) Procedure for the Preparation of 45e

(191) ##STR00146##

(192) Pd/C (110 mg, 10 mol %) was added to a solution of tert-Buty (E)-7-(3-ethoxy-3-oxoprop-1-en-1-yl)-1,3,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45d (712 mg, 2.06 mmol) in MeOH (5 ml). The mixture was flushed with argon for 15 minutes and stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (0-20% EtOAc/petroleum ether) to afford tert-butyl 7-(3-ethoxy-3-oxopropyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45e as a clear oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.04-6.99 (m, 1H), 6.97-6.92 (m, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.52 (broad s, 4H), 2.91-2.80 (m, 6H), 2.61-2.56 (m, 2H), 1.47 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); ESI-HRMS calcd for C.sub.20H.sub.29NNaO.sub.4 (M+Na.sup.+) 370.1989, found 370.1999.

f) Procedure for the Preparation of 45f

(193) ##STR00147##
Step 1.

(194) tert-Butyl 7-(3-ethoxy-3-oxopropyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45e (570 mg, 1.6 mmol) was added to a solution of HCl in 1,4-dioxane (4 M, 10 ml). The mixture was stirred at room temperature for 16 h and then concentrated in vacuo to afford ethyl 3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoate hydrochloride, which was taken on to the next step without purification.

(195) Step 2.

(196) A vial under argon was charged with ethyl 3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoate hydrochloride (30 mg, 0.11 mmol), 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (41 mg, 0.16 mmol), cesium carbonate (121 mg, 0.37 mmol), Pd-BINAP G4 precatalyst (5 mg, 4 mol %) and anhydrous dioxane (2 ml). The vial was sealed, evacuated and back filled with argon three times, then heated at 100° C. for 48 h. The reaction was cooled and water was added. The product was extracted with EtOAc (3×). The combined organic phases were washed with brine and dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc in petroleum ether) to afford ethyl 3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoate 45f as a clear oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.08-7.02 (m, 1H), 7.01-6.96 (m, 3H), 6.79-6.74 (m, 1H), 6.74-6.68 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.35-3.29 (m, 4H), 3.06-3.00 (m, 4H), 2.94-2.88 (m, 2H), 2.64-2.58 (m, 2H), 1.24 (t, J=7.1 Hz, 3H); ESI-HRMS calcd for C.sub.22H.sub.24F.sub.4NO.sub.3 (M+H.sup.+) 426.1687, found 426.1678.

f) Procedure for the Preparation of 45 3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic Acid

(197) ##STR00148##

(198) A solution of aqueous lithium hydroxide (0.6 M, 0.5 ml) was added to a solution of ethyl 3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoate 45f (8 mg, 0.02 mmol) in THF (1 ml) and the mixture was stirred for 16 h at RT. 1M HCl was added until the mixture was acidified to pH 3. The product was extracted with EtOAc (3×) and the combined organic phases were washed with brine and dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford 3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoic acid as an amorphous solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.07 (d, J=7.7 Hz, 1H), 7.04-6.96 (m, 3H), 6.79-6.74 (m, 1H), 6-74-6.68 (m, 1H), 3.36-3.29 (m, 4H), 3.07-3.00 (m, 4H), 2.93 (t, J=7.8 Hz, 2H), 2.68 (t, J=7.8 Hz, 2H), COOH not observed; ESI-HRMS calcd for C.sub.20H.sub.20F.sub.4NO.sub.3 (M+H.sup.+) 398.1374, found 398.1383.

(199) Human GPR120 pEC.sub.50: 7.6

(200) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 13.

(201) Where the starting materials are not described in the literature, their synthesis is described below.

(202) TABLE-US-00011 hGPR120 Compound Structure [M + H]+ NMR pEC50 46 384 (CDCl.sub.3) δ 7.01 (d, J = 8.2 Hz, 1H), 7.01-6.97 (m, 2H), 6.92-6.86 (m, 1H), 6.46-6.41 (m, 1H), 6.30- 6.24 (m, 1H), 4.59-4.50 (m, 1H), 3.31-3.25 (m, 4H), 3.06-3.00 (m, 4H), 2.96-2.90 (m, 2H), 2.72-2.65 (m, 2H), 2.45-2.36 (m, 2H), 2.20- 2.08 (m, 2H), 1.88-1.80 (m, 1H), 1.70-1.60 (m, 1H), COOH not observed 7.1 47 0 370 (CDCl.sub.3) δ 7.08-7.03 (m, 1H), 7.03-6.89 (m, 3H), 6.62-6.56 (m, 2H), 3.69-3.63 (m, 1H), 3.32-3.24 (m, 4H), 3.06-2.99 (m, 4H), 2.92 (t, J = 7.8 Hz, 2H), 2.71-2.63 (m, 2H), 0.74 (d, J = 4.5 Hz, 4H) COOH not observed 6.8 48 372 (CDCl.sub.3) δ 7.09-7.04 (m, 1H), 7.02-6.96 (m, 2H), 6.94-6.87 (m, 1H), 6.52-6.46 (m, 1H), 6.41-6.35 (m, 1H), 4.48-4.37 (m, 1H), 3.32- 3.24 (m, 4H), 3.07-2.99 (m, 4H), 2.93 (t, J = 7.8 Hz, 2H), 2.72-2.65 (m, 2H), 1.31 (d, J = 5.8 Hz, 6H), COOH not observed 6.7 49 372 (CDCl.sub.3) δ 7.05-7.00 (m, 1H), 6.98-6.93 (m, 2H), 6.20-6.13 (m, 2H), 6.05-5.99 (m, 1H), 4.54-4.44 (m, 1H), 3.63-3.56 (m, 4H), 2.97- 2.87 (m, 6H), 2.71-2.63 (m, 2H), 1.34 (d, J = 6.1 Hz, 6H), COOH not observed. 6.4 50 406 (CDCl.sub.3) δ 7.35-7.27 (m, 2H), 7.11-6.92 (m, 7H), 6.68-6.61 (m, 1H), 6.53-6.45 (m, 1H), 3.34-3.24 (m, 4H), 3.08-2.97 (m, 4H), 2.92 (t, J = 7.8 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), COOH not observed 7.6
Intermediate 10 (I-10)

(203) ##STR00154##

(204) Bromocyclopropane (0.94 g, 7.8 mmol) was added to a solution of 3-bromo-4-fluorophenol I-1e (1 g, 5.2 mmol) and potassium carbonate (904 mg, 6.54 mmol) in anhydrous MeCN (5 ml). The resultant mixture was heated at reflux for 16 h. The mixture was concentrated in vacuo and water was added. The product was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in pet. ether) to give 2-bromo-4-cyclopropoxy-1-fluorobenzene I-10 as a clear oil: m/z 229.9 [M.sup.79Br] and 231.9 [M.sup.81Br] (ES.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.21 (m, 1H), 7.05-6.98 (m, 1H), 6.94-6.88 (m, 1H), 3.71-3.65 (m, 1H), 0.82-0.71 (m, 4H);

Experimental Scheme 14

Compound 51 (R)-3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-2-methylpropanoic Acid

(205) ##STR00155##

a) Procedure for the Preparation of 51a

(206) ##STR00156##

(207) tert-Butyl 7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45b (130 mg, 0.4 mmol), PdCl.sub.2 (3.5 mg, 0.020 mmol), tri-O-tolylphosphine (12 mg, 0.040 mmol) and anhydrous THF (2.0 mL) were added to a sealed vial. The vial was evacuated and back-filled with argon 3 times. A solution of (S)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide in THF (0.5 M, 1.6 mL, 0.8 mmol) was added and the mixture was heated at reflux. After 3 h, the reaction mixture was cooled to RT, filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (1-15% EtOAc in pet. ether) to afford tert-butyl (R)-7-(3-methoxy-2-methyl-3-oxopropyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 51a as a light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.02 (d, J=7.5 Hz, 1H), 6.94-6.87 (m, 2H), 3.65 (s, 3H), 3.58-3.48 (m, 4H), 2.98 (dd, J=13.4, 6.7 Hz, 1H), 2.90-2.80 (m, 4H), 2.76-2.66 (m, 1H), 2.60 (dd, J=13.4, 7.8 Hz, 1H), 1.48 (s, 9H), 1.15 (d, J=6.9 Hz, 3H); ESI-HRMS calcd for C.sub.20H.sub.29NO.sub.4Na (M+Na.sup.+) 370.1994, found 370.1991.

b) Procedure for the Preparation of 51b

(208) ##STR00157##

(209) A solution of HCl in dioxane (4 M, 0.51 mL, 2.04 mmol) was added to a solution of tert-butyl (R)-7-(3-methoxy-2-methyl-3-oxopropyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 51a (71 mg, 0.20 mmol) in anhydrous dioxane (0.5 mL) at 0° C. The reaction mixture was warmed to RT for 16 h. The reaction mixture was concentrated in vacuo to afford methyl (R)-2-methyl-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoate hydrochloride 51b as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.97 (s, 2H), 7.06 (d, J=7.6 Hz, 1H), 7.01-6.97 (m, 1H), 6.96-6.92 (m, 1H), 3.64 (s, 3H), 3.43-3.29 (m, 4H), 3.28-3.14 (m, 4H), 2.98 (dd, J=13.3, 6.9 Hz, 1H), 2.76-2.66 (m, 1H), 2.62 (dd, J=13.3, 7.5 Hz, 1H), 1.15 (d, J=6.9 Hz, 3H); ESI-HRMS calcd for C.sub.15H.sub.22NO.sub.2 (M+H.sup.+) 248.1645, found 248.1656.

c) Procedure for the Preparation of 51c

(210) ##STR00158##

(211) A vial under argon was charged with methyl (R)-2-methyl-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)propanoate hydrochloride 51 b (53 mg, 0.19 mmol), 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (68 mg, 0.26 mmol) cesium carbonate (186 mg, 0.57 mmol), Pd-BINAP G4 precatalyst (7 mg, 4 mol %) and anhydrous dioxane (2 ml). The vial was sealed, evacuated and back filled with argon three times, then heated at 100° C. for 48 h. The reaction was cooled and water was added. The product was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in pet. ether) to afford methyl (R)-3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-2-methylpropanoate 51c as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.05 (d, J=7.6 Hz, 1H), 7.00 (dd, J=12.2, 8.8 Hz, 1H), 6.96-6.92 (m, 2H), 6.76 (dd, J=7.3, 2.6 Hz, 1H), 6.74-6.69 (m, 1H), 3.65 (s, 3H), 3.32 (dd, J=5.2, 2.8 Hz, 4H), 3.06-2.96 (m, 5H), 2.78-2.68 (m, 1H), 2.61 (dd, J=13.4, 7.8 Hz, 1H), 1.16 (d, J=6.9 Hz, 3H); ESI-HRMS calcd for C.sub.22H.sub.23F.sub.4NO.sub.3Na (M+Na.sup.+) 448.1506, found 448.1510.

d) Procedure for the Preparation of 51 (R)-3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-2-methylpropanoic Acid

(212) ##STR00159##

(213) (R)-3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-2-methylpropanoic acid 51 was prepared from methyl (R)-3-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-2-methylpropanoate 51c using a procedure essentially the same as for compound 45: 1H NMR (400 MHz, CDCl.sub.3) δ 7.06 (d, J=7.4 Hz, 1H), 7.03-6.94 (m, 3H), 6.76 (dd, J=7.2, 2.6 Hz, 1H), 6.74-6.68 (m, 1H), 3.36-3.27 (m, 4H), 3.08-2.99 (m, 5H), 2.81-2.71 (m, 1H), 2.66-2.58 (m, 1H), 1.19 (d, J=6.9 Hz, 3H), COOH not observed; ESI-HRMS calcd for C.sub.21H.sub.22F.sub.4NO.sub.3 (M+Na.sup.+) 412.1530, found 412.1535.

(214) Human GPR120 pEC.sub.50: 6.3

Experimental Scheme 15

Compound 52 2-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylic Acid

(215) ##STR00160##

a) Procedure for the Preparation of 52a

(216) ##STR00161##

(217) To a solution of trimethylsulfoxonium iodide (0.22 g, 1.0 mmol) in DMSO (5 ml) was added sodium hydride (0.04 g, 0.89 mmol) portion wise. The reaction was stirred at RT for 1 h. A solution of tert-butyl (E)-7-(3-ethoxy-3-oxoprop-1-en-1-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 45d (0.22 g, 0.64 mmol) in DMSO (5 ml) was added dropwise and the reaction was stirred at RT for 20 h. In a separate flask sodium hydride (0.05 g, 1.3 mmol) was added portionwise to a solution of trimethylsulfoxonium iodide (0.31 g, 1.4 mmol) in DMSO (5 ml). This mixture was stirred for 1 h before adding to the original reaction mixture dropwise. The resultant mixture was stirred at RT for 20 h. Brine (20% w/w, 100 ml) was added and the product was extracted with TBME (4×50 ml). The combined organic phases were washed with brine (20% w/w, 70 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/isohexane) to afford tert-butyl 7-(2-(ethoxycarbonyl)cyclopropyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate 52a as a colourless oil: m/z 260 [M-CO.sub.2.sup.tBu] (ES.sup.+); .sup.1H NMR (500 MHz, CDCl.sub.3) δ δ 7.04 (d, J=7.6 Hz, 1H), 6.92-6.85 (m, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.55 (s, 4H), 2.87 (s, 4H), 2.49 (ddd, J=9.2, 6.5, 4.1 Hz, 1H), 1.96-1.85 (m, 1H), 1.62-1.56 (m, 1H), 1.50 (s, 9H), 1.31-1.28 (m, 4H).

b) Procedure for the Preparation of 52b

(218) ##STR00162##

(219) To a solution of tert-butyl 7-(2-(ethoxycarbonyl)cyclopropyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate 52a (0.124 g, 0.345 mmol) in DCM (5 ml) was added TFA (0.266 ml, 3.45 mmol). The resultant mixture was stirred at RT for 1 h. The reaction mixture was diluted with MeOH (20 ml) and MP-carbonate resin (4.1 g, 2.98 mmol/g) was added and the mixture was stirred for 15 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield ethyl 2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylate 52b as a colourless oil: m/z 260 [M+H.sup.+] (ES.sup.+); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.09-7.04 (m, 1H), 6.93-6.88 (m, 2H), 4.28 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.21-3.10 (m, 4H), 3.10-3.03 (m, 4H), 2.49 (ddd, J=9.1, 6.5, 4.1 Hz, 1H), 1.90 (ddd, J=8.4, 5.3, 4.1 Hz, 1H), 1.60 (ddd, J=9.2, 5.3, 4.6 Hz, 1H), 1.34-1.26 (m, 4H).

c) Procedure for the Preparation of 52c

(220) ##STR00163##

(221) A via was charged with cesium carbonate (85 mg, 0.26 mmol), BINAP (3 mg, 5 μmol) and Pd-176 (4.35 mg, 5.21 μmol) The vial was sealed, evacuated and back filled with nitrogen three times. A solution of ethyl 2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylate 52b (0.045 g, 0.174 mmol) and 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (49.4 mg, 0.191 mmol) in dioxane (2 ml) was added and the vial was evacuated and back filled with nitrogen three times. The reaction was heated at 90° C. for 16 h. An additional portion of Pd-176 (4 mg, 5 μmol) and cesium carbonate (85 mg, 0.26 mmol) was added and the mixture was heated at 100° C. for 20 h. The reaction was cooled and water (2 ml) was added. The product was extracted with DCM (3×5 ml). The combined organics phases were passed through a hydrophobic membrane and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-10% EtOAc/isohexane) to afford ethyl 2-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylate 52c as a colourless oil: m/z 438 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.11-7.06 (m, 1H), 7.03 (dd, J=12.1, 8.8 Hz, 1H), 6.93-6.89 (m, 2H), 6.80-6.77 (m, 1H), 6.76-6.71 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.39-3.29 (m, 4H), 3.09-3.00 (m, 4H), 2.51 (ddd, J=9.2, 6.5, 4.2 Hz, 1H), 1.91 (ddd, J=8.4, 5.3, 4.2 Hz, 1H), 1.61 (ddd, J=9.2, 5.3, 4.5 Hz, 1H), 1.34-1.31 (m, 1H), 1.31 (t, J=7.1 Hz, 3H).

d) Procedure for the Preparation of 52 2-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylic Acid

(222) ##STR00164##

(223) To a solution of ethyl 2-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylate 52c (0.03 g, 0.069 mmol) in THE (2 ml) and MeOH (1 ml) was added a solution of lithium hydroxide (4.93 mg, 0.206 mmol) in water (1 ml). The resultant mixture was stirred at 40° C. for 2 h. The reaction was cooled and concentrated in vacuo. Water (5 ml) was added and the pH was adjusted to 1 with 1 M HCl (0.5 ml). The crude was extracted with DCM (2×5 ml). The combined organics phases were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (C18, 15-75% MeCN in water, 0.1% Formic Acid) to afford 2-(3-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)cyclopropanecarboxylic acid 52 as a colourless solid: m/z 410.3 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.28 (s, 1H), 7.24 (dd, J=8.8, 12.7 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.99-6.93 (m, 2H), 6.92 (dd, J=2.0, 7.7 Hz, 1H), 6.89-6.83 (m, 1H), 3.31-3.25 (m, 4H), 2.99-2.94 (m, 4H), 2.33 (ddd, J=4.0, 6.5, 9.2 Hz, 1H), 1.77 (ddd, J=4.0, 5.3, 8.3 Hz, 1H), 1.39 (ddd, J=4.2, 5.3, 9.2 Hz, 1H), 1.31 (ddd, J=4.2, 6.5, 8.3 Hz, 1H);

(224) Human GPR120 pEC.sub.50: 6.9

(225) The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 15.

(226) TABLE-US-00012 hGPR120 Compound Structure [M + H]+ NMR pEC50 53 396 (DMSO-d.sub.6) δ 12.30 (s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.03-6.94 (m, 2H), 6.91 (dd, J = 2.0, 7.7 Hz, 1H), 6.43 (dd, J = 3.0, 7.6 Hz, 1H), 6.32 (dt, J = 3.1, 8.8 Hz, 1H), 4.61 (p, J = 7.2 Hz, 1H), 3.25-3.14 (m, 4H), 3.02- 2.88 (m, 4H), 2.43-2.29 (m, 3H), 2.08-1.94 (m, 2H), 1.76 (ddd, J = 4.1, 5.3, 8.4 Hz, 2H), 1.69-1.56 (m, 1H), 1.39 (ddd, J = 4.2, 5.3, 9.3 Hz, 1H), 1.31 (ddd, J = 4.2, 6.4, 8.3 Hz, 1H). 7.0

Experimental Scheme 16

Compound 54 3-(2-(2-Fluoro-5-(trfluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoic Acid

(227) ##STR00166##

a) Procedure for the Preparation of 54a

(228) ##STR00167##

(229) tert-Butyl (E)-7-(3-ethoxy-3-oxoprop-1-en-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 54 a was prepared from tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 45c using a procedure essentially the same as for compound 45d: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67-7.61 (m, 1H), 7.34-7.29 (m, 2H), 7.21-7.17 (m, 1H), 6.45-6.38 (m, 1H), 4.42 (s, 1H), 4.37 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.75-3.64 (m, 2H), 2.98-2.92 (m, 2H), 1.82-1.73 (m, 2H), 1.39 (s, 9H), 1.33 (t, J=7.1 Hz, 3H); ESI-HRMS calcd for C.sub.20H.sub.27NNaO.sub.4 (M+Na.sup.+) 368.1832, found 368.1846.

b) Procedure for the Preparation of 54b

(230) ##STR00168##

(231) Pd/C (14.6 mg, 10 mol %) was added to a solution of tert-butyl (E)-7-(3-ethoxy-3-oxoprop-1-en-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 54a (112 mg, 0.32 mmol) in EtOAc (5 ml). The mixture was flushed with argon for 15 minutes and stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (0-20% EtOAc in pet. ether) to afford tert-butyl 7-(3-ethoxy-3-oxopropyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate 54b as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ δ 7.04-6.99 (m, 1H), 6.97-6.92 (m, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.52 (s, 4H), 2.91-2.80 (m, 6H), 2.61-2.56 (m, 2H), 1.47 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); ESI-HRMS calcd for C.sub.20H.sub.29NNaO.sub.4 (M+Na.sup.+) 370.1989 found 370.1999.

c) Procedure for the Preparation of 54c

(232) ##STR00169##

(233) Step 1.

(234) tert-Butyl 7-(3-ethoxy-3-oxopropyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 54b (60 mg, 0.17 mmol) was added to a solution of HCl in dioxane (4 M, 2 ml). The mixture was stirred at RT for 16 h and then concentrated in vacuo to afford ethyl 3-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoate hydrochloride, which was taken on to the next step without purification.

(235) Step 2.

(236) A vial under argon was charged with afford ethyl 3-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoate hydrochloride (20 mg, 0.07 mmol), 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (27 mg, 0.11 mmol), cesium carbonate (68 mg, 0.21 mmol), Pd-BINAP G4 precatalyst (3 mg, 4 mol %) and anhydrous dioxane (2 ml). The vial was sealed, evacuated and back filled with argon three times, then heated at 100° C. for 48 h. The reaction was cooled and water was added. The product was extracted with EtOAc (3×). The combined organic phases were washed with brine and dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc in pet. ether) to afford ethyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoate 54c as a colourless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.15-7.11 (m, 1H), 7.00-6.89 (m, 3H), 6.72-6.67 (m, 1H), 6-57-6.52 (m, 1H), 4.47 (s, 2H), 4.14-4.07 (m, 2H), 3.69-3.63 (m, 2H), 3.01-2.95 (m, 2H), 2.91-2.85 (m, 2H), 2.61-2.55 (m, 2H), 1.97-1.89 (m, 2H), 1.20 (t, J=7.1 Hz, 3H); ESI-HRMS calcd for C.sub.22H.sub.24F.sub.4NO.sub.3 (M+H.sup.+) 426.1687, found 426.1676.

d) Procedure for the Preparation of 54 3-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoic Acid

(237) ##STR00170##

(238) 3-(2-(2-Fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoic acid 54 was prepared from ethyl 3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)propanoate 54c using a procedure essentially the same as for compound 45: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.14 (d, J=7.1 Hz, 1H), 7.00-6.89 (m, 3H), 6.73-6.68 (m, 1H), 6.58-6.53 (m, 1H), 4.47 (s, 2H), 3.69-3.63 (m, 2H), 3.01-2.96 (m, 2H), 2.89 (t, J=7.8 Hz, 2H), 2.96-2.61 (m, 2H), 1.98-1.90 (m, 2H); ESI-HRMS calcd for C.sub.20H.sub.20F.sub.4NO.sub.3 (M+H.sup.+) 398.1374 found 398.1391.

(239) Human GPR120 pEC.sub.50: 6.7