MODULATORS OF G PROTEIN-COUPLED RECEPTOR 88

Abstract

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: (I) wherein Ring A, Ring B, Ring C, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, L, m, n, and p are as defined herein. The compounds are modulators of G-protein coupled receptor 88 (GPR88). Also disclosed are pharmaceutical compositions comprising the compounds; and the compounds for use in the treatment of diseases mediated by GPR88, including Tourette's Syndrome, Huntington's Disease (HD), Addiction, Parkinson's Disease (PD), Schizophrenia, Alzheimer's disease, and Attention Deficit Hyperactivity Disorder (ADHD).

##STR00001##

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ##STR00212## wherein: i) -L- is selected from the group consisting of ##STR00213## Ring A is selected from the group consisting of: a 5-10 membered cycloalkyl, a 5-10 membered cycloalkenyl, a 5-6 membered aromatic ring system, a 5-6 membered heteroaromatic ring system, an 8-membered bicyclic heterocyclic ring system and an 8-10 membered bicyclic heteroaromatic ring system; Ring B is selected from the group consisting of: a 5-8 membered cycloalkyl, a 5-6 membered aromatic and a 5-6 membered heteroaromatic ring; Ring C is selected from the group consisting of: a 5-6 membered aromatic and a 5-6 membered heteroaromatic ring; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; R.sub.1 is selected from the group consisting of: hydrogen, substituted or unsubstituted C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl and substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl C.sub.1-C.sub.2 alkyl; wherein each substituent is independently selected from the group consisting of OR.sub.c, nitrile or halo; wherein each R.sub.c is independently selected from the group consisting of H, Me, Et and cyclopropyl; R.sub.2 is selected from the group consisting of: substituted or unsubstituted C.sub.1-C.sub.6 alkyl, substituted or unsubstituted C.sub.2-C.sub.6 alkenyl, substituted or unsubstituted C.sub.2-C.sub.6 alkynyl; substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl; substituted or unsubstituted C.sub.1-C.sub.6 alkoxy, substituted or unsubstituted C.sub.3-C.sub.6 cycloalkoxy; substituted or unsubstituted C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkyl; substituted or unsubstituted C.sub.3-C.sub.6 cycloalkoxy-C.sub.1-C.sub.6 alkyl; substituted or unsubstituted C.sub.1-C.sub.6 haloalkyl, substituted or unsubstituted C.sub.2-C.sub.6 haloalkenyl, substituted or unsubstituted C.sub.2-C.sub.6 haloalkynyl; substituted or unsubstituted C.sub.3-C.sub.6 cyclohaloalkyl; substituted or unsubstituted C.sub.1-C.sub.6 haloalkoxy, substituted or unsubstituted C.sub.3-C.sub.6 cyclohaloalkoxy; substituted or unsubstituted C.sub.1-C.sub.6 haloalkoxy-C.sub.1-C.sub.6 alkyl, substituted or unsubstituted C.sub.3-C.sub.6 cyclohaloalkoxy-C.sub.1-C.sub.6 alkyl, substituted or unsubstituted C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 haloalkyl, substituted or unsubstituted C.sub.3-C.sub.6 cycloalkoxy-C.sub.1-C.sub.6 haloalkyl, substituted or unsubstituted C.sub.1-C.sub.6 haloalkoxy-C.sub.1-C.sub.6 haloalkyl, substituted or unsubstituted C.sub.3-C.sub.6 cyclohaloalkoxy-C.sub.1-C.sub.6 haloalkyl, SO.sub.2R.sub.d, and NR.sub.eR.sub.e; wherein R.sub.d is C.sub.1-4 alkyl; wherein each R.sub.e is independently selected from the group consisting of H and C.sub.1-4 alkyl; wherein each substituent is independently selected from the group consisting of OR.sub.e, ?O, NR.sub.eR.sub.e, nitrile, halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, and a substituted or unsubstituted monocyclic, bicyclic or bridged 3-8 membered cycloalkyl or heterocycloalkyl ring, wherein each R.sub.e is independently selected from the group consisting of H and C.sub.1-4 alkyl; wherein each substituent of the monocyclic, bicyclic or bridged 3-8 membered cycloalkyl or heterocycloalkyl ring is independently selected from the group consisting of OH, nitrile, halo, methyl or methoxy; each R.sub.3 is independently selected from the group consisting of: halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy or CN; each R.sub.4 is independently selected from the group consisting of: halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy or CN; each R.sub.5 is independently selected from the group consisting of: halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy, CN, or ?-C(O)NR.sub.eR.sub.e; R.sub.a and R.sub.b are each independently selected from the group consisting of: hydrogen, halogen, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy; or wherein R.sub.a and R.sub.b, together with the atom to which they are bonded, form a 3-membered to 6-membered cycloalkyl or heterocycloalkyl ring comprising O or NR.sub.f, wherein R.sub.f is H or methyl; provided that the compound is not: ##STR00214## or ii) -L-, Ring A, Ring B, Ring C, m, p, R.sub.2, R.sub.3, R.sub.5, R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.e and R.sub.f are as defined above under i), R.sub.1 is a C.sub.1 or C.sub.2 alkylenyl residue, n is 1 or 2, and one R.sub.4 moiety is a C.sub.1 alkylenyl residue and, when present, the other R.sub.4 moiety is as defined above under i), wherein the C.sub.1 alkylenyl R.sub.4 moeity is bonded to a carbon atom in Ring A that is ortho to the carbon atom of Ring A having the amide residue, and, together with the atoms to which they are bonded, the R.sub.1 and R.sub.4 moieties form a 5- or 6-membered ring; and/or iii) -L-, Ring A, Ring B, Ring C, n, p, R.sub.1, R.sub.4, R.sub.5, R.sub.a, R.sub.b, R.sub.c and R.sub.f are as defined above under i), m is 1 or 2; R.sub.2 is selected from the group consisting of: substituted or unsubstituted OC.sub.1-2 alkylenyl, wherein the oxygen atom is connected to Ring B; wherein each substituent is independently selected from the group consisting of OH, nitrile, halo, methyl or methoxy; one R.sub.3 moiety is an O residue and, when present, the other R.sub.3 moiety is as defined above under i); wherein, together with the atoms to which they are bonded, the R.sub.2 moiety and O R.sub.3 moiety form a 5- or 6-membered ring.

2. The compound of claim 1, wherein R.sub.1 is selected from the group consisting of: hydrogen, substituted or unsubstituted C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl and substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl C.sub.1-C.sub.2 alkyl; wherein each substituent is independently selected from OR.sub.c and nitrile; and wherein each R.sub.c is independently selected from the group consisting of H, Me, Et and cyclopropyl.

3. The compound of claim 2, wherein R.sub.1 is selected from the group consisting of: hydrogen, substituted or unsubstituted C.sub.1-C.sub.4 alkyl and substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl C.sub.1-C.sub.2 alkyl; wherein each substituent is independently selected from OR.sub.c and nitrile; and wherein each R.sub.c is independently selected from the group consisting of H, Me, Et and cyclopropyl.

4. The compound of claim 2, wherein R.sub.1 is selected from the group consisting of: hydrogen and substituted or unsubstituted C.sub.1-C.sub.4 alkyl and substituted or unsubstituted C.sub.3 cycloalkyl C.sub.1 alkyl; wherein each substituent is independently selected from OR.sub.c and nitrile; and wherein each R.sub.c is independently selected from the group consisting of H and Me.

5. The compound of claim 2, wherein R.sub.1 is selected from the group consisting of: ##STR00215##

6. The compound of any preceding claim, wherein n is 1.

7. The compound of any preceding claim, wherein each R.sub.4 is independently selected from the group consisting of: halogen, C.sub.1-C.sub.2 alkyl, and C.sub.1-C.sub.2 alkoxy.

8. The compound of claim 7, wherein R.sub.4 is methyl.

9. The compound of any of claims 1 to 5, wherein n is 0.

10. The compound of claim 1, wherein R.sub.1 is a C.sub.1 or C.sub.2 alkylenyl residue and one R.sub.4 moiety is a C.sub.1 alkylenyl residue wherein the C.sub.1 alkylenyl R.sub.4 moeity is bonded to a carbon atom in Ring A that is ortho to the carbon atom of Ring A having the amide residue, and, together with the atoms to which they are bonded, the R.sub.1 and R.sub.4 moieties form a 5- or 6-membered ring.

11. The compound of any preceding claim, wherein R.sub.2 is selected from the group consisting of: substituted or unsubstituted C.sub.1-C.sub.4 alkyl; substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl; substituted or unsubstituted C.sub.1-C.sub.4 alkoxy, substituted or unsubstituted C.sub.3-C.sub.4 cycloalkoxy; substituted or unsubstituted C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; substituted or unsubstituted C.sub.1-C.sub.4 haloalkyl; substituted or unsubstituted C.sub.1-C.sub.4 haloalkoxy; SO.sub.2R.sub.d; and NR.sub.eR.sub.e.

12. The compound of claim 11, wherein R.sub.2 is selected from the group consisting of: substituted or unsubstituted C.sub.1-C.sub.4 alkyl; substituted or unsubstituted C.sub.1-C.sub.4 alkoxy, substituted or unsubstituted C.sub.3-C.sub.4 cycloalkoxy; substituted or unsubstituted C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; substituted or unsubstituted C.sub.1-C.sub.4 haloalkyl; substituted or unsubstituted C.sub.1-C.sub.4 haloalkoxy; SO.sub.2R.sub.d; and NR.sub.eR.sub.e.

13. The compound of claim 11, wherein R.sub.2 is selected from the group consisting of: ##STR00216##

14. The compound of any preceding claim, wherein m is 1.

15. The compound of any preceding claim, wherein each R.sub.3 is independently selected from the group consisting of: halogen, C.sub.1-C.sub.2 alkyl, and C.sub.1-C.sub.2 alkoxy.

16. The compound of claim 15, wherein R.sub.3 is halo.

17. The compound of any of claims 1 to 13, wherein m is 0.

18. The compound of any of claims 1 to 10, wherein R.sub.2 is a substituted or unsubstituted OC.sub.1 alkylenyl residue, wherein the oxygen atom is connected to Ring B; and one R.sub.3 moiety is an O residue, wherein together with the atoms to which they are bonded, the OC.sub.1 alkylenyl and O residues form a 5-membered ring.

19. The compound of any preceding claim, wherein p is 1.

20. The compound of any preceding claim, wherein each R.sub.5 is independently selected from the group consisting of: halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, CN or C(O)NR.sub.eR.sub.e.

21. The compound of any of claims 1 to 18, wherein p is 0.

22. The compound of any preceding claim, wherein Ring A is selected from the group consisting of: a 6 membered aromatic and heteroaromatic ring, optionally wherein Ring A is phenyl.

23. The compound of any of claims 1 to 21, wherein Ring A is a 5 or 8 membered cycloalkyl ring system, optionally wherein Ring A is bicyclo-[1.1.1]-pentyl.

24. The compound of any preceding claim, wherein Ring B is selected from the group consisting of: a 5 or 6 membered cycloalkyl, a 5 or 6 membered aromatic and a 5 or 6 membered heteroaromatic ring, optionally phenyl, pyridinyl or pyrimidinyl.

25. The compound of any preceding claim, wherein Ring C is selected from the group consisting of: a 6 membered aromatic and a 6 membered heteroaromatic ring, optionally phenyl or pyridinyl.

26. The compound of any preceding claim, wherein R.sub.a and R.sub.b are each independently selected from the group consisting of: hydrogen, halogen, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkoxy; or wherein R.sub.a and R.sub.b, together with the atom to which they are bonded, form a 3-membered to 4-membered cycloalkyl or heterocycloalkyl ring comprising O or NR.sub.f, wherein R.sub.f is H or methyl.

27. The compound of claim 26, wherein R.sub.a and R.sub.b are each independently selected from the group consisting of: hydrogen and methyl.

28. A pharmaceutical formulation comprising a compound of any of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. A compound of any of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use as a medicament.

30. A compound of any of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by GPR88.

31. A compound of any of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of Tourette's Syndrome, Huntington's Disease (HD), Addiction, Parkinson's Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and/or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer's disease and basal ganglia disorders.

Description

EXAMPLES

General Schemes

Abbreviations

[0285] app: apparent; aq: aqueous; br: broad; ca.: circa; d: doublet; Chloroform-d (deuterated chloroform); DMSO-d6 (deuterated dimethylsulfoxide); Methanol-d4 (deuterated methanol); DAST (diethylaminosulfur trifluoride); DCM: dichloromethane; dioxane: 1,4-dioxane; MeCN (Acetonitrile); DIPEA: diisopropylethylamine; DMF: dimethylformamide; Et.sub.3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: hours; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl isouronium hexafluorophosphate(V); HPLC: high performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiplet; M: molar, molecular ion; MeCN: acetonitrile; MeOH: methanol; min: minutes; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; PE (petroleum ether); q: quartet; RT: room temperature (ca. 20? C.); s: singlet, solid; t: triplet; TBAF: tetrabutylammonium fluoride; TBME: tert-butyl methyl ether; TEA (triethylamine); TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra performance liquid chromatography; UV: ultraviolet; ESI (electrospray atmospheric pressure ionization); g (gram); h (hour); nm (nanometer); .sup.1H NMR (proton nuclear magnetic resonance); Hz (hertz); LC-MS (liquid chromatography-mass spectrometry); mg (milligrams); MHz (megahertz); min (minutes); mL (millilitres), mmol (millimoles); ppm (parts per million); Rt (retention time); RT (room temperature); TLC (thin layer chromatography); v/v (volume/volume); m/z (mass charge ratio); HCl (hydrochloric acid); K.sub.3PO.sub.4 (potassium phosphate tribasic); HOAc (acetic acid); HCl (hydrochloric acid); CuCl (Copper(I) chloride); SOCI.sub.2 (thionyl chloride); Pd/C (Palladium on carbon); Cs.sub.2CO.sub.3 (cesium carbonate); NH.sub.4Cl (ammonium chloride); Fe (Iron); DIPEA (N,N-diisopropylethylamine); NBS (N-Bromosuccinimide); MW (microwave); NH.sub.4Cl (Ammonium chloride); Pd(dppf)Cl.sub.2 ([1,1Bis(diphenylphosphino)ferrocene]dichloropalladium); NaH (sodium hydride); DMAP (4-Dimethylaminopyridine); LiOH (Lithium hydroxide); NaH (Sodium hydride); Aq (aqueous); HPLC: high performance liquid chromatography; M: molar, molecular ion.

[0286] Other abbreviations are intended to convey their generally accepted meaning.

[0287] Examples of the invention were prepared following one of the general Schemes below, using the appropriate reagents for the target compound.

##STR00074##

Reagents: (a) Pd(dppfCl.sub.2, K.sub.3PO.sub.4, ArB(OH).sub.2, 1,4-dioxane-water 100? C.; (b) Carboxylic acid, HATU, DIPEA, MeCN RT or 50? C.
Suzuki coupling of I-1 produced I-2. This was reacted with carboxylic acid in the presence of HATU to afford amide I-3.

##STR00075##

Reagents: (a) Carboxylic acid, HATU, DIPEA, MeCN RT (b) Pd(dppfCl.sub.2, K.sub.3PO.sub.4, ArB(OH).sub.2, 1,4-dioxane-water 100? C.
I-1 was reacted with 2-(4-fluorophenoxy)-2-methylpropanoic acid in the presence of HATU to produce amide I-4. This was coupled with an arylboronic acid or arylboronic ester under Pd catalysis to afford I-5.

##STR00076##

Reagents: alkyl halide, sodium hydride, THF 0? C.-RT.
Intermediate I-6 was alkylated with an alkyl halide in the presence of sodium hydride to afford I-7.

##STR00077##

Reagents: Pd/C, H.SUB.2., EtOH

[0288] Intermediate I-8 was hydrogenated to afford I-9.

##STR00078##

Reagents: (a) MeMgBr, Et.sub.2O (b) NaH, Mel, THF (c) AcOHH.sub.2O (d) TsCl, pyridine, DCM (e) ArNH.sub.2, Kl, NEt.sub.3, MeCN (f) RCO.sub.2H, HATU, DIPEA, MeCN
Grignard addition to aldehyde I-10 gave alcohol I-11 which was alkylated to give ether I-12. Acetal deprotection gave diol I-13 which was tosylated to give I-14. Nucleophilic substitution with aniline I-2 afforded amine I-15 which underwent amide coupling to furnish I-16.

##STR00079##

Reagents: a) Pd(dppf)Cl.sub.2, ArB(OH).sub.2, K.sub.3PO.sub.4, dioxane-water (b) oxalyl chloride, DMF, RCO.sub.2H.
Intermediate I-17 was coupled to aryl boronic ester to give intermediate I-18 which was coupled with an acid chloride to furnish I-19

##STR00080##

Reagents: a) RCO.sub.2H, HATU, DIPEA, MeCN (b) Pd(dppf)Cl.sub.2, ArB(OH).sub.2, K.sub.3PO.sub.4, dioxane-water
Intermediate I-20 underwent amide coupling to give I-21 which was coupled via Suzuki reaction to afford I-22.

##STR00081##

Reagents: (a) Carboxylic acid, HATU, DIPEA, MeCN RT (b) Pd(dppfCl.sub.2, K.sub.3PO.sub.4, ArB(OH).sub.2, 1,4-dioxane-water 100? C.
I-1 was reacted coupled to carboxylic acid to give amide I-23. This was coupled with an arylboronic acid or arylboronic ester under Pd catalysis to afford I-24.

##STR00082##

Reagents: MeMgBr, THF

[0289] Methyl magnesium bromide was added to ester I-25 to afford tertiary alcohol I-26.

##STR00083##

Reagents: (a) RCO.sub.2H, HATU, DIPEA, MeCN (b) MeOCH.sub.2BF.sub.3K, Pd(dppf)Cl.sub.2, K.sub.3PO.sub.4, 1,4-dioxane-water 100? C.
Amine I-27 underwent amide coupling to afford I-28 which was reacted with methoxymethyl potassium trifluoroboronate under palladium catalysis to give I-29.

[0290] General Experimental Conditions

[0291] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Reaction mixtures were magnetically stirred and reactions performed at room temperature (ca. 20? C.) unless otherwise indicated.

[0292] Column chromatography was performed on an automated flash chromatography system, such as a CombiFlash R.sub.f system, using pre-packed silica (40 ?m) cartridges, unless otherwise indicated.

[0293] .sup.1H NMR spectra were recorded using a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe?. Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. The spectra were recorded at 298 K unless otherwise indicated.

[0294] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC? H-Class system, equipped with ACQUITY PDA Detector and ACQUITY QDa Mass Detector, running one of the analytical methods described below.

[0295] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below.

[0296] Preparative HPLC purifications were performed either using a Waters X-Select CSH C18, 5 ?m, 19?50 mm column using a gradient of MeCN and water, both modified with 0.1% v/v formic acid, or on a Waters X-Bridge BEH C18, 5 ?m, 19?50 mm column using a gradient of MeCN and 10 mM ammonium bicarbonate(aq). Fractions were collected following detection by UV at a single wavelength measured by a variable wavelength detector.

[0297] Nomenclature of structures was generated using Structure to Name conversion from ChemDraw? Professional 19 (PerkinElmer).

[0298] Analytical Methods

[0299] Method 1Acidic 3 Min Method

[0300] Column: Waters ACQUITY UPLC? CSH C18, 1.7 ?m, 2.1?30 mm at 40? C.

[0301] Detection: UV at 254 nm unless otherwise indicated, MS by electrospray ionisation

[0302] Solvents: A: 0.1% v/v Formic acid in water, B: 0.1% v/v Formic acid in MeCN

[0303] Gradient:

TABLE-US-00001 Time % A % B Flow rate (ml/min) 0.00 95 5 0.77 0.11 95 5 0.77 2.15 5 95 0.77 2.56 5 95 0.77 2.83 95 5 0.77 3.00 95 5 0.77

[0304] Method 2Basic 3 Min Method

[0305] Column: Waters ACQUITY UPLC? BEH C18, 1.7 ?m, 2.1?30 mm at 40? C.

[0306] Solvents: A: 10 mM ammonium bicarbonate(aq), B: MeCN

[0307] (other parameters the same as Method 1)

[0308] Method 3Acidic 4 Min Method

[0309] Column: Waters X-Select CSH C18, 2.5 ?m, 4.6?30 mm at 40? C.

[0310] Detection: UV at 254 nm unless otherwise indicated, MS by electrospray ionisation

[0311] Solvents: A: 0.1% v/v Formic acid in water, B: 0.1% v/v Formic acid in MeCN

[0312] Gradient:

TABLE-US-00002 Time % A % B Flow rate (ml/min) 0.0 95.0 5.0 2.5 3.0 5.0 95.0 2.5 3.01 5.0 95.0 4.5 3.6 5.0 95.0 4.5 3.7 95.0 5.0 2.5 4.0 95.0 5.0 2.5

[0313] Method 4Basic 4 Min Method

[0314] Column: Waters X-Bridge BEH C18, 2.5 ?m, 4.6?30 mm at 40? C.

[0315] Solvents: A: 10 mM ammonium bicarbonate(aq), B: MeCN

[0316] (other parameters the same as Method 3)

[0317] Chiral SFC Method 1

[0318] Waters UPC.sup.2 using anIH 4.6?250, Sum column, flow rate 4 mL/min.sup.?1 eluting with 30% MeOH (0.1% Ammonia), 70% CO.sub.2 at a wavelength 210-400 nm and BPR 120 Bar.

[0319] Chiral SFC Method 2

[0320] Waters UPC.sup.2. Chiralpak IC 4.6?250, 5 um, flow rate 4 mL/min.sup.?1 eluting with 50% MeOH (0.1% Ammonia), 50% CO.sub.2 at a wavelength 210-400 nm and BPR 120 Bar.

[0321] Chiral SFC Method 3

[0322] Waters UPC.sup.2 using an IC 4.6?250, 5 um column, flow rate 4 mL/min.sup.?1 eluting with 35% MeOH (0.1% Ammonia), 65% CO.sub.2 at a wavelength 210-400 nm and BPR 120 Bar.

[0323] Chiral SFC Method 4

[0324] Waters UPC.sup.2 using an IC 4.6?250, Sum column, flow rate 4 mL/min.sup.?1 eluting with 40% IPA (0.1% Ammonia), 60% CO.sub.2 at a wavelength 210-400 nm and BPR 120 Bar.

[0325] Chiral SFC Method 5

[0326] Waters UPC.sup.2 using a Phenomenex Lux C4 4.6?250, 5 um, flow rate 4 mL/min.sup.?1 eluting with 35-% IPA (0.1% Ammonia), 65% CO.sub.2 at a wavelength 210-400 nm and BPR 120 Bar.

[0327] Preparative HPLC Generic Methods:

[0328] HPLC Instruments: Shimadzu 20AP UV detector: SPD-20A. UV wavelength: 214 nm and 254 nm.

[0329] Conditions 1: Mobile phase A: water; Mobile phase B: acetonitrile.

[0330] Conditions 2: Mobile phase A: water with 0.1% trifluoroacetic acid; Mobile phase B: acetonitrile.

[0331] Conditions 3: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile.

[0332] Conditions 4: Mobile phase A: water with 0.1% ammonium hydroxide; Mobile phase B: acetonitrile.

[0333] Column: Agilent 10 Prep-C18 250?21.2 mm. Column temperature: Ambient

[0334] LC gradient: 20% to 85% in 20 min; then 85% to 100% in 0.01 min; then hold 100% for 5 min; then 100% to 20% in 0.01 min; hold at 20% for 5 min.

[0335] LC Flow rate: 20 mL/min binary pump.

[0336] Nomenclature of structures was generated using Structure to Name conversion from ChemDraw? Professional 17 (PerkinElmer).

[0337] Analytical Methods as follows:

[0338] Method 5Acidic Method (Shimadzu 3 Min)

[0339] Column: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Agilent Poroshell 120 EC-C18, 2.7 ?m, 4.6?50 mm column

[0340] Detection: 2020, Quadrupole LC/MS, Ion Source: API-ESI, TIC: 100-900 m/z, Drying gas flow: 15 L/min, Nebulizer pressure: 1.5 L/min, Drying gas temperature: 250? C., Vcap: 4500V. Samples were dissolved in methanol at 1?10 ?g/mL, then filtered through a 0.22 ?m filter membrane. Injection volume: 1?10 ?L.

[0341] Detector: 214 nm, 254 nm. Detection wavelength: 214 nm, 254 nm.

[0342] Solvents: A: 0.05% v/v Formic acid in water, B: 0.05% v/v Formic acid in MeCN

[0343] Gradient:

TABLE-US-00003 T (min) A (%) B (%) Flow rate (mL/min) 0.00 80 15 1.5 0.28 80 15 1.5 2.38 10 90 1.5 2.39 0 100 1.5 2.69 0 100 1.5 2.70 85 15 1.5 3.00 85 15 1.5

[0344] Method 6Acidic 5 Min Method (Shimadzu 5 Min)

[0345] Column: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Agilent Poroshell 120 EC-C18, 2.7 ?m, 4.6?50 mm column.

[0346] Detection: 2020, Quadrupole LC/MS, Ion Source: API-ESI, TIC: 100-900 m/z, Drying gas flow: 15 L/min, Nebulizer pressure: 1.5 L/min, Drying gas temperature: 250? C., Vcap: 4500V. Samples were dissolved in methanol at 1?10 ?g/mL, then filtered through a 0.22 ?m filter membrane. Injection volume: 1?10 ?L.

[0347] Detection wavelength: 214 nm, 254 nm.

[0348] Solvents: A: 0.05% formic acid in water (v/v), B: 0.05% formic acid in MeCN (v/v).

[0349] Gradient:

TABLE-US-00004 T (min) A (%) B (%) Flow rate (mL/min) 0.00 80 15 1.0 0.50 80 15 1.0 4.00 15 85 1.0 4.01 0 100 1.0 4.50 0 100 1.0 4.51 85 15 1.0 5.00 85 15 1.0

[0350] Method 7Acidic Method (Waters QDa 3 Min)

[0351] Column: Waters QDa, Binary Pump, Diode Array Detector. Waters CORTECS UPLC, C18, 1.6 ?m, 2.1?50 mm column.

[0352] Detection: QDa, Quadrupole LC/MS, Ion Source: API-ES, TIC: 70-900 m/z, Fragmentor: 70, Drying gas flow: 12 L/min, Nebulizer pressure: 36 psi, Drying gas temperature: 350? C., Vcap: 3000V. Samples were dissolved in methanol at 1?10 ?g/mL, then filtered through a 0.22 ?m filter membrane. Injection volume: 1?10 ?L. Detector: 214 nm, 254 nm.

[0353] Solvents: A: 0.05% Formate in water (v/v), B: 0.05% Formate in MeCN (v/v).

[0354] Gradient:

TABLE-US-00005 T (min) A (%) B (%) Flow rate(mL/min) 0.00 80 20 0.6 1.80 20 80 0.6 2.65 20 80 0.6 2.80 80 20 0.6 3.00 80 20 0.6

[0355] Compound Synthesis: The compounds of the invention may be prepared by methods well known to those skilled in the art, and as described in the synthetic experimental procedures shown below.

Example 1: (rac-trans)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclo propane-1-carboxamide

[0356] ##STR00084##

Step 1: 4-(methoxymethyl)-[1,1-biphenyl]-4-amine

[0357] To a degassed solution of 4-bromoaniline (2.00 g, 11.6 mmol), (4-(methoxymethyl)phenyl)boronic acid (2.10 g, 12.7 mmol) and 1,1-bis(diphenylphosphino) ferrocenedichloro palladium(II) dichloromethane complex (420 mg, 574 ?mol) in 1-4, dioxane (30 mL) was added a solution of K.sub.3PO.sub.4 (6.20 g, 29.2 mmol) in water (10 mL). The mixture was degassed then heated to 90? C. for 18 h. The mixture was filtered through celite washing with EtOAc (25 mL) then poured into 10 wt % aq. citric acid (100 mL). The phases were separated and the aqueous phase extracted with EtOAc (2?25 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford title amine (1.32 g, 5.9 mmol, 51%, 95% purity) as a beige solid. UPLC-MS (Method 1) m/z 214.4 (M+H).sup.+ at 0.85 min.sup.?1H NMR (500 MHz, DMSO-d6) ? 7.54-7.48 (m, 2H), 7.38-7.32 (m, 2H), 7.32-7.24 (m, 2H), 6.66-6.60 (m, 2H), 5.21 (s, 2H), 4.40 (s, 2H), 3.28 (s, 3H).

Step 2: (rac-trans)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclo propane-1-carboxamide

[0358] To a solution of 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (120 mg, 563 ?mol) and (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (110 mg, 675 ?mol) in MeCN (5 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.29 mL, 1.7 mmol) and HATU (321 mg, 844 ?mol). The mixture was heated at 50? C. for 18 h. The reaction mixture was cooled to RT, diluted with DCM (5 mL) and sat. NaHCO.sub.3 (2 mL), stirred for 10 min then passed through a hydrophobic frit. 10 wt % aqueous citric acid (2 mL) was added to the organics, stirred for 10 min, the mixture was passed through a hydrophobic frit and concentrated under reduced pressure to afford a brown oil. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford title amide (150 mg, 0.41 mmol, 74%, 99% purity) as a white solid. UPLC-MS (Method 2) m/z 359.4 (M+H).sup.+ at 1.43 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.38 (s, 1H), 8.47 (d, J=4.8 Hz, 1H), 7.73-7.66 (m, 3H), 7.65-7.58 (m, 4H), 7.46 (d, J=7.9 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.20 (ddd, J=7.5, 4.9, 1.1 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 2.58 (ddd, J=8.7, 6.0, 3.8 Hz, 1H), 2.41 (ddd, J=8.1, 5.4, 3.8 Hz, 1H), 1.53-1.46 (m, 2H). The trans isomers of N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40 00, 120 bar. The column was IH 10?250 mm, 5 um, flow rate 15 mL/min at 30% MeOH (0.1% Ammonia), 70% CO.sub.2 to afford: First eluting isomer (Example 18) Chiral SFC (method 1) 2.18 min, >99% ee.

[0359] Second eluting isomer (Example 19) Chiral SFC (method 1) 4.04 min, >99% ee.

[0360] The following examples were prepared by methods analogous to Example 1, substituting appropriate starting materials and intermediates where necessary:

TABLE-US-00006 Example Structure Name/Analytical Data 2 [00085] 2-(4-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)-2-methylpropanamide UPLC-MS (Method 2) m/z 394.4 (M + H).sup.+, at 1.77 min. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.11 (s, 1H), 7.88 ? 7.74 (m, 2H), 7.72 ? 7.56 (m, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.23 ? 7.10 (m, 2H), 7.08 ? 6.92 (m, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 1.52 (s, 6H). 4 [00086] N-(4-(methoxymethyl)-[1,1- biphenyl]-4-yl)-2-methyl-2- phenoxypropanamide UPLC-MS (Method 1) m/z 376.2 (M + H).sup.+, at 2.73 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 7.74 ? 7.64 (m, 2H), 7.61 ? 7.49 (m, 4H), 7.40 (d, J = 8.1 Hz, 2H), 7.35 ? 7.26 (m, 2H), 7.17 ? 7.06 (m, 1H), 7.06 ? 6.97 (m, 2H), 4.50 (s, 2H), 3.42 (s, 3H), 1.61 (s, 6H).

Example 3: 2-(4-chlorophenoxy)-N-(4-methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0361] ##STR00087##

[0362] To a solution of 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (50 mg, 0.23 mmol) and 2-(4-chlorophenoxy)-2-methylpropanoic acid (55 mg, 0.26 mmol) in MeCN (2.0 mL) were added HATU (98 mg, 0.26 mmol) and DIPEA (0.12 mL, 0.70 mmol) and the reaction was stirred at RT for 3 h. The mixture was diluted with DCM (15 mL) and 10 wt % aq. citric acid (10 mL), stirred for 10 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford 2-(4-chlorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (89 mg, 0.21 mmol, 92%, 99% purity) as a cream solid. UPLC-MS (Method 1) m/z 410.4/412.4 (M+H).sup.+, at 1.91 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.10 (s, 1H), 7.81-7.74 (m, 2H), 7.62 (dd, J=8.5, 3.1 Hz, 4H), 7.38 (d, J=8.3 Hz, 2H), 7.36-7.34 (m, 2H), 6.99-6.92 (m, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 1.56 (s, 6H).

[0363] The following examples were prepared by methods analogous to Example 3, substituting appropriate starting materials and intermediates where necessary:

TABLE-US-00007 Example Structure Name/Analytical Data 6 [00088] 2-(4-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl) propenamide UPLC-MS (Method 1) m/z 380.7 (M + H).sup.+, at 1.65 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.20 (s, 1H), 7.75 ? 7.69 (m, 2H), 7.66 ? 7.59 (m, 4H), 7.38 (d, J = 8.1 Hz, 2H), 7.18 ? 7.10 (m, 2H), 7.04 ? 6.96 (m, 2H), 4.85 (q, J = 6.7 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H). 7 [00089] N-(4-(methoxymethyl)-[1,1- biphenyl]-4-yl)-2-methyl-2-(pyridin-2- yloxy)propanamide UPLC-MS (Method 1) m/z 377.5 (M + H).sup.+, at 1.65 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 9.61 (s, 1H), 8.05 (ddd, J = 5.0, 2.0, 0.8 Hz, 1H), 7.72 (ddd, J = 8.3, 7.1, 2.0 Hz, 1H), 7.69 ? 7.63 (m, 2H), 7.63 ? 7.57 (m, 2H), 7.59 ? 7.52 (m, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.93 (ddd, J = 7.1, 5.0, 1.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.66 (s, 6H). 8/34/35 [00090] (rac-trans)-N-(3-(4- propylphenyl)bicyclo[1.1.1]pentan-1- yl)-2-(pyridin-2-yl)cyclopropane-1- carboxamide UPLC-MS (Method 1) m/z 369.2 (M + Na).sup.+, at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.77 (s, 1H), 8.42 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.66 (app td, J = 7.6, 1.9 Hz, 1H), 7.40 (app dt, J = 7.8, 1.1 Hz, 1H), 7.17 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.14 ? 7.07 (m, 4H), 2.46 ? 2.38 (m, 1H), 2.20 (s, 6H), 2.12 ? 2.04 (m, 1H), 1.60 ? 1.49 (m, 2H), 1.33 (dd, J = 7.8, 6.3 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 2 protons not observed (under DMSO solvent peak). The trans isomers were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 ? 400 nm, 40? C., 120 bar. The column was IG 10 ? 250 mm, 5 um, flow rate 15 mL/ min at 30% MeOH (0.1% Ammonia), 70% CO.sub.2 to afford: First eluting isomer (Example 34), Chiral SFC (method 1) 2.19 min, >99% ee Second eluting isomer (Example, 35) Chiral SFC (method 1) 3.04 min, >99% ee 9 [00091] 2-(4-fluorophenoxy)-2-methyl-N-(3- (4-propylphenyl)bicyclo[1.1.1] pentan-1-yl)propenamide UPLC-MS (Method 1) m/z 404.2 (M + Na).sup.+, at 1.99 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.70 (s, 1H), 7.17 ? 7.08 (m, 6H), 6.98 ? 6.90 (m, 2H), 2.23 (s, 6H), 1.60 ? 1.49 (m, 2H), 1.37 (s, 6H), 0.87 (t, J = 7.3 Hz, 3H). 2 protons not observed (under DMSO solvent peak). 40 [00092] 2-(4-fluorophenoxy)-N-(5-(4- (methoxymethyl)phenyl)pyridin-2-yl)- 2-methylpropanamide UPLC-MS (Method 1) m/z 395.4 (M + H).sup.+, at 1.78 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.02 (s, 1H), 8.67 (app t, J = 1.7 Hz, 1H), 8.16 (d, J = 1.7 Hz, 2H), 7.74 ? 7.68 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.19 ? 7.11 (m, 2H), 7.08 ? 7.00 (m, 2H), 4.46 (s, 2H), 3.31 (s, 3H), 1.53 (s, 6H). 45/120/121 [00093] (rac-trans)-N-(5-(4- (methoxymethyl)phenyl)pyridin-2-yl)- 2-(pyridin-2-yl)cyclopropane-1- carboxamide UPLC-MS (Method 1) 360.3 (M + H).sup.+, at 1.01 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 9.12 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 4.7 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 8.6, 2.4 Hz, 1H), 7.57 ? 7.49 (m, 3H), 7.42 (d, J = 8.0 Hz, 2H), 7.29 ? 7.26 (m, 1H), 7.03 (dd, J= 7.2, 5.1 Hz, 1H), 4.51 (s, 2H), 3.42 (s, 3H), 2.74 ? 2.66 (m, 1H), 2.39 ? 2.32 (m, 1H), 1.78 ? 1.70 (m, 1H), 1.70 ? 1.61 (m, 1H). The enantiomers were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 ? 400 nm, 40? C., 120 bar. The column was IC 10 ? 250 mm, 5 um, flow rate 15 mL/ min at 35% MeOH (neutral) 65% CO.sub.2 to afford: First eluting isomer (Example 120), Chiral SFC (method 3) 2.66 min, >99% ee Second eluting isomer (Example 121), Chiral SFC (method 3) 3.20 min, >99% ee

Example 5: (rac-trans)-N-((2R,3R)-2-hydroxy-3-methoxybutyl)-N-(4-methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0364] ##STR00094##

Step 1: 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol

[0365] To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (2.00 g, 15.4 mmol) in Et.sub.2O (20 mL) cooled to 78? C. was added dropwise methylmagnesium bromide (10.2 mL, 3 molar, 30.7 mmol), the mixture was allowed to warm slowly to RT and stirred for 18 h. The reaction mixture was quenched by drop-wise addition of sat. aq. NH.sub.4Cl (15 mL) and stirred for 15 min. The mixture was extracted with EtOAc (3?50 mL), the combined organics were washed with brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford a colourless oil. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford title alcohol (2.06 g, 13 mmol, 87%, 95% purity, 3:1 mixture of diastereoisomers) as a colourless oil. NMR data for major isomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 4.75 (d, J=5.3 Hz, 1H), 3.95 (dd, J=8.0, 6.2 Hz, 1H), 3.76 (dd, J=8.1, 6.0 Hz, 1H), 3.71 (dt, J=7.3, 6.1 Hz, 1H), 3.52-3.42 (m, 1H), 1.30 (s, 3H), 1.25 (d, J=0.7 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H).

Step 2: (2R)-3-methoxybutane-1,2-diol

[0366] To a solution of 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol (2.05 g, 14.0 mmol) and Mel (1.32 mL, 21.0 mmol) in THE (20 mL) cooled to 0? C. was added portionwise NaH (617 mg, 60% Wt, 15.4 mmol). After stirring for 30 min, a solution of Mel (1.32 mL, 21.0 mmol) in THE (2.0 mL) was added drop-wise and the mixture was allowed to warm to RT and stirred for 18 h. The reaction mixture was quenched by addition of sat. aq. NH.sub.4Cl (50 mL) and extracted with EtOAc (3?25 mL). The combined organics were washed with brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford a yellow oil. AcOH/water (4:1, 2.5 mL) was added and the mixture was stirred at RT for 2 h, then concentrated under reduced pressure and azeotroped with toluene (2?10 mL). The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford title diol (775 mg, 6.1 mmol, 44%, 95% Purity, 3:1 mixture of diastereoisomers) as a yellow oil. NMR data for major isomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 3.98 (dd, J=8.3, 6.6 Hz, 1H), 3.87 (q, J=6.3 Hz, 1H), 3.71 (dd, J=8.1, 6.1 Hz, 1H), 3.28 (s, 1H), 3.26 (s, 3H), 1.32 (d, J=2.6 Hz, 3H), 1.26 (d, J=2.9 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H).

Step 3: (2R,3R)-2-hydroxy-3-methoxybutyl 4-methylbenzenesulfonate

[0367] To a solution of (2R,3R)-3-methoxybutane-1,2-diol (290 mg, 2.41 mmol) in DCM (20 mL) and pyridine (2 ml) cooled to 0? C. was added drop-wise a solution of 4-methylbenzenesulfonyl chloride (506 mg, 2.66 mmol) in DCM (2.0 mL) and the mixture was stirred for 18 h. The mixture was diluted with 10 wt % aq. citric acid (50 mL) and extracted with DCM (2?25 mL). The combined organics were washed with water (20 ml), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford (2R,3R)-2-hydroxy-3-methoxybutyl 4-methylbenzenesulfonate (150 mg, 0.54 mmol, 22%, 98% purity, 3:1 mixture of diastereoisomers) as a colourless oil.

[0368] UPLC-MS (Method 1) m/z 274.9 (M+H).sup.+, at 1.15 min. NMR data for major isomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.79 (dd, J=8.4, 1.9 Hz, 2H), 7.51-7.42 (m, 2H), 5.26 (d, J=5.9 Hz, 1H), 4.02 (dd, J=9.9, 2.9 Hz, 1H), 3.88 (dd, J=9.8, 6.2 Hz, 1H), 3.44 (qd, J=6.2, 2.8 Hz, 1H), 3.09-3.14 (s, 4H), 2.42 (s, 3H), 1.03 (s, 1H). 3H not observed (under DMSO solvent peak)

Step 4: (2R,3R)-3-methoxy-1-((4-(methoxymethyl)-[1,1-biphenyl]-4-yl)amino)butan-2-ol

[0369] A mixture of (2R,3R)-2-hydroxy-3-methoxybutyl 4-methylbenzenesulfonate (100 mg, 365 ?mol), 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (77.7 mg, 365 ?mol), triethylamine (152 ?L, 1.09 mmol) and potassium iodide (60.5 mg, 365 ?mol) in acetonitrile (3.0 mL) was heated at 160? C. for 2 h under microwave irradiation. The mixture was then heated at 160? C. for a further 12 h. The mixture was partitioned between DCM (10 mL) and 0.5 M aq. HCl (10 mL), stirred for 15 min, passed through a hydrophobic frit and concentrated under reduced pressure to afford a brown gum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford title alcohol (10 mg, 32 ?mol, 8.7%, 100% purity, 3:1 mixture of diastereoisomers) as a brown oil. UPLC-MS (Method 1) m/z 330.4 (M+H).sup.+, at 1.28 min. NMR data for major diastereoisomer: .sup.1H NMR (500 MHz, DMSO-d6) ? 9.68 (s, 1H), 7.84-7.78 (m, 2H), 7.62 (ddt, J=7.2, 4.8, 2.1 Hz, 4H), 7.40-7.30 (m, 2H), 5.74 (dd, J=6.5, 2.2 Hz, 1H), 4.44 (d, J=2.2 Hz, 2H), 3.95 (dd, J=6.5, 3.3 Hz, 1H), 3.76-3.68 (m, 3H), 3.35 (s, 1H), 3.22 (d, J=1.7 Hz, 3H), 1.15 (dd, J=6.5, 2.1 Hz, 3H).

Step 5: (rac-trans)-N-((2R,3R)-2-hydroxy-3-methoxybutyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0370] To a solution of (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (9.3 mg, 57 ?mol) and (2R,3R)-3-methoxy-1-((4-(methoxymethyl)-[1,1-biphenyl]-4-yl)amino)butan-2-ol (18 mg, 57 ?mol) in acetonitrile (2.0 mL) was added HATU (22 mg, 57 ?mol) followed by DIPEA (30 ?L, 0.17 mmol) and the mixture was stirred at RT for 18 h. The mixture was diluted with sat. aq. NH.sub.4Cl (10 mL) and DCM (10 mL), stirred for 10 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane, product eluted at 100% EtOAc) to afford title amide (17.9 mg, 38.9 ?mol, 68%, 100% purity, mixture of 4 diastereoisomers 3:3:1:1) as a colourless solid. UPLC-MS (Method 1) m/z 461.7 (M+H).sup.+, at 1.22 min.

Example 10: 2-(4-fluorophenoxy)-2-methyl-N-(4-(trifluoromethyl)-[1,1-biphenyl]-4-yl)propenamide

[0371] ##STR00095##

Step 1: 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide

[0372] To a stirred solution of 2-(4-fluorophenoxy)-2-methylpropanoic acid (268 mg, 1.35 mmol) and 4-iodoaniline (326 mg, 1.49 mmol) in MeCN (5.0 mL) under a nitrogen atmosphere was added N-ethyl-N-isopropylpropan-2-amine (0.71 mL, 4.1 mmol) followed by HATU (617 mg, 1.62 mmol). The reaction mixture was stirred for 5 hours at 50? C. The reaction mixture was cooled to RT, diluted with DCM (5 mL) and sat. aq. NaHCO.sub.3 (2 mL), stirred for 10 min then passed through a hydrophobic frit. 10 wt % aqueous citric acid (2 mL) was added to the organics, stirred for 10 min, the mixture was passed through a hydrophobic frit and concentrated under reduced pressure to afford a brown oil. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methyl propanamide (490 mg, 1.2 mmol, 90%, 99% purity) as a light brown solid. LC-MS (Method 3) m/z 400.1 (M+H).sup.+, at 2.73 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.62 (s, 1H), 7.80-7.58 (m, 2H), 7.52-7.30 (m, 2H), 7.17-6.83 (m, 4H), 1.53 (s, 6H).

Step 2: 2-(4-fluorophenoxy)-2-methyl-N-(4-(trifluoromethyl)-[1,1-biphenyl]-4-yl) propenamide

[0373] 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (51 mg, 0.13 mmol), (4-(trifluoromethyl)phenyl)boronic acid (36 mg, 0.19 mmol), potassium phosphate (67 mg, 0.32 mmol), and Pd(dppf)Cl.sub.2 (9.3 mg, 13 ?mol) were dissolved in 1,4-dioxane (5.0 mL) and water (0.5 mL). The reaction mixture was purged with nitrogen and heated to 95? C. for 3 h. The reaction mixture was filtered through celite and the cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford title amide (48 mg, 0.11 mmol, 90%, 99% purity) as a pale brown solid. LC-MS (Method 3) m/z 418.2 (M+H).sup.+, at 3.00 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.71 (s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.70 (s, 5H), 7.65-7.58 (m, 2H), 7.07-6.95 (m, 4H), 1.57 (s, 6H).

[0374] The following examples were prepared by methods analogous to Example 10, substituting appropriate starting materials and intermediates where necessary:

TABLE-US-00008 Example Structure Name/Analytical Data 11 [00096] 2-(4-fluorophenoxy)-N-(4-methoxy- [1,1-biphenyl]-4-yl)-2- methylpropanamide LC-MS (Method 3) m/z 380.2 (M + H).sup.+, at 2.76 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.63 (s, 1H), 7.71 ? 7.61 (m, 2H), 7.58 ? 7.49 (m, 4H), 7.04 ? 6.92 (m, 6H), 3.85 (s, 3H), 1.56 (s, 6H). 12 [00097] 2-(4-fluorophenoxy)-2-methyl-N-(4- (trifluoromethoxy)-[1,1-biphenyl]-4- yl)propanamide LC-MS (Method 3) m/z 434.2 (M + H).sup.+, at 3.02 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.68 (s, 1H), 7.76 ? 7.64 (m, 2H), 7.63 ? 7.47 (m, 4H), 7.31 ? 7.26 (m, 2H), 7.10 ? 6.88 (m, 4H), 1.57 (s, 6H). 16 [00098] 4-(2-(4-fluorophenoxy)-2- methylpropanamido)-N,N-dimethyl- [1,1-biphenyl]-4-carboxamide LC-MS (Method 3) m/z 421.3 (M + H).sup.+, at 2.36 min. .sup.1H NMR (500 MHz, Methanol-d4) ? 7.78 ? 7.65 (m, 6H), 7.58 ? 7.50 (m, 2H), 7.06 (d, J = 6.4 Hz, 4H), 3.15 ? 3.08 (m, 6H), 1.61 (s, 6H). One exchangeable proton not observed 17 [00099] N-(4-((dimethylamino)methyl)-[1,1- biphenyl]-4-yl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 407.3 (M + H).sup.+, at 1.62 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.68 ? 8.51 (m, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.65 ? 7.55 (m, 4H), 7.50 (d, J = 8.0 Hz, 2H), 7.06 ? 6.93 (m, 4H), 3.92 (s, 2H), 2.57 (s, 6H), 1.57 (s, 6H). 24 [00100] 2-(4-fluorophenoxy)-2-methyl-N-(4- (2-methylpyrimidin-5- yl)phenyl)propenamide LC-MS (Method 3) m/z 366.2 (M + H).sup.+, at 2.17 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.82 (s, 2H), 8.75 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.06 ? 6.91 (m, 4H), 2.77 (s, 3H), 1.56 (s, 6H). 25 [00101] 2-(4-fluorophenoxy)-2-methyl-N-(4- (morpholinomethyl)-[1,1-biphenyl]-4- yl)propenamide LC-MS (Method 3) m/z 449.3 (M + H).sup.+, at 1.65 min. .sup.1H NMR (500 MHz, Methanol-d4) 0 7.74 ? 7.66 (m, 2H), 7.68 ? 7.54 (m, 4H), 7.44 ? 7.40 (m, 2H), 7.06 (dd, J = 6.4, 1.3 Hz, 4H), 3.72 (app t, J = 4.6 Hz, 4H), 3.57 (s, 2H), 2.50 (br s, 4H), 1.60 (s, 6H). One exchangeable proton not observed 26 [00102] N-(4-(6-ethoxypyridin-3-yl)phenyl)-2- (4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 395.2 (M + H).sup.+, at 2.74 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 8.35 (d, J = 2.6 Hz, 1H), 7.77 (dd, J = 8.6, 2.6 Hz, 1H), 7.73 ? 7.64 (m, 2H), 7.57 ? 7.47 (m, 2H), 7.08 ? 6.95 (m, 4H), 6.79 (d, J = 8.6 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 1.54 (s, 6H), 1.42 (t, J = 7.0 Hz, 3H). 27 [00103] 2-(4-fluorophenoxy)-2-methyl-N-(4- (morpholine-4-carbonyl)-[1,1- biphenyl]-4-yl)propenamide UPLC-MS (Method 2) m/z 463.3 (M + H).sup.+, at 2.33 min. .sup.1H NMR (500 MHz, Chloroform-d) 0 8.69 (s, 1H), 7.77 ? 7.65 (m, 2H), 7.65 ? 7.51 (m, 2H), 7.60 ? 7.56 (m, 2H), 7.51 ? 7.44 (m, 2H), 7.07 ? 6.89 (m, 4H), 3.73 ? 3.55 (m, 8H), 1.57 (s, 6H). 30 [00104] N-(4-(2-ethoxypyrimidin-5-yl)phenyl)- 2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 396.3 (M + H).sup.+, at 2.49 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.70 (br s, 3H), 7.81 ? 7.65 (m, 2H), 7.57 ? 7.41 (m, 2H), 7.09 ? 6.93 (m, 4H), 4.46 (q, J = 7.1 Hz, 2H), 1.56 (s, 6H), 1.45 (t, J = 7.1 Hz, 3H). 36/75/76 [00105] (rac-trans)-N-(4-(6-ethoxypyridin-3- yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide LC-MS (Method 3) m/z 360.2 (M + H).sup.+, at 1.66 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.47 (d , J = 5.1 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 7.74 (dd, J = 8.6, 2.6 Hz, 2H), 7.65 ? 7.54 (m, 3H), 7.45 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 7.4, 5.1 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.77 ? 2.66 (m, 1H), 2.35 ? 2.22 (m, 1H), 1.74 (m, 1H), 1.61 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H). The enantiomers were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 ? 400 nm, 40? C., 120 bar. The column was IC 10 ? 250 mm, 5 um, flow rate 15 mL/ min at 35% MeOH (neutral) 65% CO.sub.2 to afford: First eluting isomer (Example 75), Chiral SFC (method 3) 3.04 min, >99% ee Second eluting isomer (Example 76), Chiral SFC (method 3) 4.45 min, >99% ee 37/77/78 [00106] (1R*,2R*)-N-(4-(morpholinomethyl)- [1,1-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide LC-MS (Method 3) m/z 360.2 (M + H)*, at 1.66 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.47 (d , J = 5.1 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 7.74 (dd, J = 8.6, 2.6 Hz, 2H), 7.65 ? 7.54 (m, 3H), 7.45 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 7.4, 5.1 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.77 ? 2.66 (m, 1H), 2.35 ? 2.22 (m, 1H), 1.74 (m, 1H), 1.61 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H). The enantiomers were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 ? 400 nm, 40? C., 120 bar. The column was IH 10 ? 250 mm, 5 um, flow rate 15 mL/ min at 50% IPA (0.1% Ammonia), 50% CO.sub.2 to afford: First eluting isomer (Example 77), Chiral SFC (method 4) 2.79 min, >99% ee Second eluting isomer (Example 78), Chiral SFC (method 4) 4.91 min, >99% ee 38 [00107] 2-(4-fluorophenoxy)-2-methyl-/-(4- (2-(trifluoromethyl)pyrimidin-5- yl)phenyl)propenamide LC-MS (Method 3) m/z 420.2 (M + H).sup.+, at 2.66 min. .sup.1H NMR (500 MHz, Methanol-d4) 0 9.27 (s, 2H), 7.96 ? 7.88 (m, 2H), 7.86 ? 7.79 (m, 2H), 7.11 ? 7.01 (m, 4H), 1.61 (s, 6H). One exchangeable proton not observed 41 [00108] N-(4-cyclopropoxy-[1,1-biphenyl]-4- yl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 406.3 (M + H).sup.+, at 2.93 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.65 (s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.57 ? 7.53 (m, 2H), 7.53 ? 7.49 (m, 2H), 7.16 ? 7.06 (m, 2H), 7.07 ? 6.93 (m, 4H), 3.82 ? 3.72 (m, 1H), 1.57 (s, 6H), 0.83 ? 0.77 m, 4H). 42 [00109] 2-(4-fluorophenoxy)-N-(4-isobutyl- [1,1-biphenyl]-4-yl)-2-methylpropanamide LC-MS (Method 3) m/z 406.3 (M + H).sup.+, at 3.20 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.65 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.06 ? 6.96 (m, 4H), 2.52 (d, J = 7.2 Hz, 2H), 1.95 ? 1.86 (m, 1H), 1.57 (s, 6H), 0.94 (d, J = 6.6 Hz, 6H). 46 [00110] 2-(4-fluorophenoxy)-N-(4- isopropoxy-[1,1-biphenyl]-4-yl)-2- methylpropanamide LC-MS (Method 3) m/z 408.3 (M + H).sup.+, at 2.98 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.64 (s, 1H), 7.71 ? 7.61 (m, 2H), 7.58 ? 7.52 (m, 2H), 7.51 ? 7.43 (m, 2H), 7.08 ? 6.87 (m, 6H), 4.61 ? 4.56 (m, 1H), 1.57 (s, 6H), 1.37 (d, J = 6.0 Hz, 6H). 47/122/ 123 [00111] 2-(4-fluorophenoxy)-2-methyl-N-(4- (1-morpholinoethyl)-[1,1-biphenyl]- 4-yl)propanamide LC-MS (Method 3) m/z 463.3 (M + H).sup.+, at 1.69 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.67 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 7.11 ? 6.90 (m, 4H), 3.73 (br s, 4H), 3.39 (br s, 1H), 2.55 ? 2.44 (m, 4H), 1.56 (s, 6H), 1.42 (br s, 3H). The enantiomers were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 ? 400 nm, 40? C., 120 bar. The column was IC 10 ? 250 mm, 5 um, flow rate 15 mL/ min at 35% MeOH (neutral) 65% CO.sub.2 to afford: First eluting isomer (Example 122), Chiral SFC (method 3) 3.94 min, >99% ee Second eluting isomer (Example 123), Chiral SFC (method 3) 4.90 min, >99% ee 48 [00112] (rac-trans)-N-(4- (dimethylamino)methyl)-[1,1- biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide LC-MS (Method 3) m/z 372.2 (M + H).sup.+, at 0.88 min. .sup.1H NMR (500 MHz, Methanol-d4) ? 8.52 ? 8.39 (m, 1H), 7.80 ? 7.69 (m, 5H), 7.64 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.40 (dt, J = 7.9, 1.1 Hz, 1H), 7.25 (ddd, J = 7.6, 5.0, 1.1 Hz, 1H), 4.08 (s, 2H), 2.69 (br s, 6H), 2.68 ? 2.63 (m, 1H) 2.39 (ddd, J = 8.4, 5.5, 3.9 Hz, 1H), 1.70 ? 1.65 (m, 1H), 1.65 ? 1.58 (m, 1H). One exchangeable proton notobserved 49 [00113] N-(4-(2-(dimethylamino)pyrimidin-5- yl)phenyl)-2-(4-fluorophenoxy)-2- methylpropanamide UPLC-MS (Method 2) m/z 395.3 (M + H).sup.+, at 2.44 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.64 (s, 1H), 8.54 (s, 2H), 7.67 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 7.06 ? 6.93 (m, 4H), 3.24 (s, 6H), 1.56 (s, 6H). 72 [00114] 2-(4-fluorophenoxy)-2-methyl-N-(4- ((4-methylpiperazin-1-yl)methyl)- [1,1-biphenyl]-4-yl)propanamide LC-MS (Method 3) m/z 462.3 (M + H).sup.+, at 1.65 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.10 (s, 1H), 8.16 (s, 1H), 7.85 ? 7.75 (m, 2H), 7.65 ? 7.54 (m, 4H), 7.41 ? 7.30 (m, 2H), 7.20 ? 7.09 (m, 2H), 7.04 ? 6.93 (m, 2H), 3.47 (s, 3H), 2.16 (s, 9H), 1.52 (s, 6H). 79 [00115] N-(4-(6-(dimethylamino)pyridin-3- yl)phenyl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 394.3 (M + H).sup.+, at 1.57 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.62 (s, 1H), 8.42 (dd, J = 2.6, 0.9 Hz, 1H), 7.71 ? 7.58 (m, 3H), 7.55 ? 7.45 (m, 2H), 7.07 ? 6.90 (m, 4H), 6.58 (dd, J = 8.8, 0.9 Hz, 1H), 3.13 (s, 6H), 1.56 (s, 6H). 84 [00116] 2-(4-fluorophenoxy)-2-methyl-N-(4- propyl-[1,1-biphenyl]-4-yl)propanamide LC-MS (Method 3) m/z 392.3 (M + H).sup.+, at 1.65 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.65 (s, 1H), 7.73 ? 7.62 (m, 2H), 7.63 ? 7.54 (m, 2H), 7.56 ? 7.47 (m, 2H), 7.32 ? 7.20 (m, 2H), 7.10 ? 6.93 (m, 4H), 2.63 (dd, J= 8.5, 6.8 Hz, 2H), 1.75 ? 1.65 (m, 2H), 1.57 (s, 6H), 0.98 (t, J = 7.3 Hz, 3H). 85 [00117] (rac-trans)-N-(4-(methylsulfonyl)- [1,1-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide LC-MS (Method 3) m/z 393.2 (M + H).sup.+, at 1.42 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.50 ? 8.38 (m, 1H), 8.06 ? 7.91 (m, 2H), 7.80 (s, 1H), 7.75 ? 7.68 (m, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.63 ? 7.50 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.12 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 3.08 (s, 3H), 2.69 (ddd, J = 9.3, 5.9, 3.6 Hz, 1H), 2.32 ? 2.28 (m, 1H) 1.74 (ddd, J = 9.0, 5.3, 3.7 Hz, 1H), 1.62 (ddd, J = 8.2, 6.1, 3.7 Hz, 1H). 86 [00118] N-(4-(ethoxymethyl)-[1,1-biphenyl]- 4-yl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 408.3 (M + H).sup.+, at 2.87 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 7.79 ? 7.64 (m, 2H), 7.64 ? 7.49 (m, 4H), 7.48 ? 7.32 (m, 2H), 7.08 ? 6.91 (m, 4H), 4.62 ? 4.50 (m, 2H), 3.61 ? 3.55 (m, 2H), 1.57 (d, J = 2.5 Hz, 6H), 1.33 ? 1.19 (m, 3H). 87 [00119] (rac-trans)-N-(4-cyclopropoxy-[1,1- biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide LC-MS (Method 3) m/z 371.2 (M + H).sup.+, at 1.97 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.46 (q, J = 1.6 Hz, 1H), 7.72 ? 7.54 (m, 4H), 7.54 ? 7.45 (m, 4H), 7.31 (d, J = 7.8 Hz, 1H), 7.17 ? 7.02 (m, 3H), 3.82 ? 3.71 (m, 1H), 2.68 (ddd, J = 9.4, 6.0, 3.8 Hz, 1H), 2.27 (dt, J = 8.8, 4.8 Hz, 1H), 1.74 (ddd, J = 9.0, 5.4, 3.7 Hz, 1H), 1.61 (ddd, J = 8.3, 6.0, 3.7 Hz, 1H), 0.80 (d, J = 4.5 Hz, 4H). 88 [00120] N-(4-(benzo[d][1,3]dioxol-5- yl)phenyl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 394.2 (M + H).sup.+, at 2.74 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.65 (s, 1H), 7.73 ? 7.62 (m, 2H), 7.55 ? 7.44 (m, 2H), 7.15 ? 6.96 (m, 6H), 6.96 ? 6.84 (m, 1H), 5.99 (s, 2H), 1.57 (s, 6H). 89 [00121] N-(4-(tert-butoxymethyl)-[1,1- biphenyl]-4-yl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 436.3 (M + H)*, at 3.08 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 7.75 ? 7.62 (m, 2H), 7.65 ? 7.52 (m, 4H), 7.48 ? 7.38 (m, 2H), 7.10 ? 6.93 (m, 4H), 4.49 (s, 2H), 1.57 (s, 6H), 1.32 (s, 9H). 90 [00122] (rac-trans)-N-(4-isopropoxy-[1,1- biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide LC-MS (Method 3) m/z 373.3 (M + H).sup.+, at 2.01 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.53 ? 8.43 (m, 1H), 7.69 ? 7.43 (m, 8H), 7.32 (d, J = 7.8 Hz, 1H), 7.19 ? 7.10 (m, 1H), 7.00 ? 6.87 (m, 2H), 4.62 ? 4.54 (m, 1H), 2.69 (ddd, J = 9.4, 5.9, 3.8 Hz, 1H), 2.30 ? 2.27 (m, 1H), 1.75 (ddd, J = 9.0, 5.4, 3.7 Hz, 1H), 1.63 ? 1.60 (m, 1H), 1.36 (d, J = 6.1 Hz, 6H). 91 [00123] 2-(4-fluorophenoxy)-2-methyl-N-(4- (6-propylpyridin-3- yl)phenyl)propanamide LC-MS (Method 3) m/z 393.3 (M + H).sup.+, at 1.81 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.83 ? 8.62 (m, 2H), 7.80 (dd, J = 7.9, 2.4 Hz, 1H), 7.78 ? 7.65 (m, 2H), 7.61 ? 7.54 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.07 ? 6.92 (m, 4H), 2.89 ? 2.78 (m, 2H), 1.84 ? 1.76 (m, 2H), 1.57 (s, 6H), 1.00 (t, J = 7.3 Hz, 3H). 92 [00124] 2-(4-fluorophenoxy)-N-(4-(6- isopropoxypyridin-3-yl)phenyl)-2- methylpropanamide LC-MS (Method 3) m/z 409.3 (M + H).sup.+, at 2.89 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 8.35 (dd, J = 2.6, 0.7 Hz, 1H), 7.76 (dd, J = 8.6, 2.6 Hz, 1H), 7.73 ? 7.63 (m, 2H), 7.58 ? 7.45 (m, 2H), 7.09 ? 6.91 (m, 4H), 6.74 (dd, J = 8.5, 0.8 Hz, 1H), 5.36 ? 5.31 (m, 1H), 1.56 (s, 6H), 1.37 (d, J = 6.2 Hz, 6H). 93 [00125] N-(3-fluoro-4-(methoxymethyl)-[1,1- biphenyl]-4-yl)-2-(4-fluorophenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 412.3 (M + H).sup.+, at 2.81 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.69 (s, 1H), 7.74 ? 7.63 (m, 2H), 7.59 ? 7.52 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.37 (dd, J = 7.9, 1.8 Hz, 1H), 7.29 ? 7.22 (m, 1H), 7.07 ? 6.93 (m, 4H), 4.56 (d, J = 1.1 Hz, 2H), 3.44 (s, 3H), 1.57 (s, 6H). 94 [00126] N-(4-(6-ethoxypyridin-3-yl)phenyl)-2- (4-methoxyphenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 407.3 (M + H).sup.+, at 2.71 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.77 (s, 1H), 8.40 ? 8.32 (m, 1H), 7.84 ? 7.63 (m, 3H), 7.59 ? 7.44 (m, 2H), 7.03 ? 6.91 (m, 2H), 6.91 ? 6.76 (m, 3H), 4.40 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 1.57 (d, J = 5.9 Hz, 6H), 1.42 (t, J = 7.1 Hz, 3H). 95 [00127] N-(4-(2-(dimethylamino) pyrimidin-5- yl)phenyl)-2-(4-methoxyphenoxy)-2- methylpropanamide LC-MS (Method 3) m/z 407.3 (M + H).sup.+, at 2.40 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.76 (s, 1H), 8.54 (s, 2H), 7.74 ? 7.66 (m, 2H), 7.51 ? 7.40 (m, 2H), 7.01 ? 6.91 (m, 2H), 6.87 ? 6.81 (m, 2H), 3.79 (s, 3H), 3.23 (s, 6H), 1.54 (s, 6H). 109 [00128] (rac-trans)-N-(4-(6-isopropoxypyridin- 3-yl)phenyl)-2-(pyridin-2- yl) cyclopropane-1-carboxamide LC-MS (Method 3) m/z 374.3 (M + H).sup.+, at 1.80 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.52 ? 8.45 (m, 1H), 8.33 (dd, J = 2.6, 0.7 Hz, 1H), 7.74 (dd, J = 8.6, 2.6 Hz, 1H), 7.67 ? 7.54 (m, 4H), 7.53 ? 7.43 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.16 ? 7.09 (m, 1H), 6.73 (dd, J = 8.6, 0.8 Hz, 1H), 5.36 ? 5.29 (m, 1H), 2.69 (ddd, J = 9.4, 5.9, 3.8 Hz, 1H), 2.32 ? 2.29 (m, 1H), 1.75 (ddd, J = 9.0, 5.4, 3.7 Hz, 1H), 1.62 (ddd, J= 8.3, 6.0, 3.7 Hz, 1H), 1.37 (d, J = 6.2 Hz, 6H). 113 [00129] 2-(4-methoxyphenoxy)-2-methyl-N- (4-(morpholinomethyl)-[1,1- biphenyl]-4-yl)propenamide LC-MS (Method 3) m/z 461.3 (M + H).sup.+, at 1.62 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.78 (s, 1H), 7.75 ? 7.65 (m, 2H), 7.58 (dd, J= 8.5, 2.5 Hz, 4H), 7.44 (d, J = 8.0 Hz, 2H), 7.01 ? 6.90 (m, 2H), 6.88 ? 6.78 (m, 2H), 3.93 ? 3.69 (m, 9H), 2.71 (s, 4H), 1.54 (s, 6H). 116 [00130] 2-(4-cyanophenoxy)-N-(4-(6- ethoxypyridin-3-yl)phenyl)-2- methylpropanamide LC-MS (Method 3) m/z 402.3 (M + H).sup.+, at 2.55 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.38 ? 8.31 (m, 1H), 8.23 (s, 1H), 7.76 (dd, J = 8.6, 2.6 Hz, 1H), 7.68 ? 7.55 (m, 4H), 7.54 ? 7.45 (m, 2H), 7.10 ? 7.02 (m, 2H), 6.79 (dd, J = 8.6, 0.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.67 (s, 6H), 1.42 (t, J = 7.1 Hz, 3H). 117 [00131] 2-(4-cyanophenoxy)-N-(4-(2- (dimethylamino)pyrimidin-5- yl)phenyl)-2-methylpropanamide LC-MS (Method 3) m/z 402.3 (M + H).sup.+, at 2.24 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.53 (s, 2H), 8.21 (s, 1H), 7.64 ? 7.54 (m, 4H), 7.50 ? 7.38 (m, 2H), 7.11 ? 6.98 (m, 2H), 3.24 (s, 6H), 1.67 (s, 6H). 119 [00132] 2-(4-fluorophenoxy)-N-(4-(1- methoxyethyl)-[1,1-biphenyl]-4-yl)-2- methylpropanamide LC-MS (Method 3) m/z 408.3 (M + H).sup.+, at 2.82 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 7.70 ? 7.63 (m, 2H), 7.62 ? 7.52 (m, 4H), 7.44 ? 7.32 (m, 2H), 7.06 ? 6.91 (m, 4H), 4.34 (q, J = 6.5 Hz, 1H), 3.26 (s, 3H), 1.57 (s, 6H), 1.47 (d, J = 6.5 Hz, 3H).

Example 13: 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-N,2-dimethylpropanamide

[0375] ##STR00133##

[0376] To a solution of 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (Example 2) (30 mg, 76 ?mol) in THE (2.0 mL) at 0? C. was added NaH (3.7 mg, 60 wt %, 91 ?mol). The reaction mixture was warmed to RT and after 20 min iodomethane (6.2 ?L, 99 ?mol) was added. After stirring for 90 min the mixture was heated at 50? C. and stirred for a further 16 h. After cooling to RT, MeOH (1.0 mL) was added and the mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-N,2-dimethyl propenamide (14 mg, 33 ?mol, 43%, 95% purity) as a pale yellow solid.

[0377] LC-MS (Method 3) m/z 408.2 (M+H).sup.+, at 2.75 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.55 (d, J=8.3 Hz, 2H), 7.57-7.45 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.20-7.00 (m, 2H), 7.00-6.87 (m, 2H), 6.86-6.39 (m, 2H), 4.50 (s, 2H), 3.42 (s, 3H), 3.38 (br s, 3H), 1.59 (br s, 6H).

[0378] The following examples were prepared by methods analogous to Example 13, substituting appropriate starting materials and intermediates where necessary:

TABLE-US-00009 Example Structure Name/Analytical Data 14 [00134] N-ethyl-2-(4-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)-2-methylpropanamide UPLC-MS (Method 3) m/z 422.3 (M + H).sup.+, at 2.87 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.68-7.39 (m, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.15-6.96 (m, 2H), 6.96-6.85 (m, 2H), 6.76-6.43 (m, 2H), 4.50 (s, 2H), 3.75 (br s, 2H), 3.42 (s, 3H), 1.82-1.43 (m, 6H), 1.15 (br s, 3H). 15 [00135] 2-(4-fluorophenoxy)-N-(2- methoxyethyl)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)-2-methylpropanamide UPLC-MS (Method 3) m/z 452.3 (M + H).sup.+, at 2.76 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.55 (d, J = 8.1 Hz, 2H), 7.50-7.42 (m, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.12-7.03 (m, 2H), 6.97-6.86 (m, 2H), 6.77-6.52 (m, 2H), 4.50 (s, 2H), 4.01-3.85 (m, 2H), 3.63-3.48 (m, 2H), 3.42 (s, 3H), 3.36-3.25 (m, 3H), 1.55-1.45 (m, 6H). 22 [00136] 2-(4-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)-2-methyl-N-propylpropanamide LC-MS (Method 3) m/z 436.3 (M + H).sup.+, at 3.03 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.55 (d, J = 8.4 Hz, 2H), 7.45 (br s, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.15-6.95 (m, 2H), 6.96- 6.86 (m, 2H), 6.75-6.43 (m, 2H), 4.50 (s, 2H), 4.06-3.54 (m, 2H), 3.42 (s, 3H), 1.85-1.41 (m, 8H), 0.96-0.69 (m, 3H). 23 [00137] 2-(4-fluorophenoxy)-N-isobutyl-N- (4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methylpropanamide LC-MS (Method 3) m/z 450.3 (M + H).sup.+, at 3.13 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.55 (d, J = 8.2 Hz, 2H), 7.44 (br s, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.12-6.96 (m, 2H), 6.96-6.84 (m, 2H), 6.66-6.45 (m, 2H), 4.50 (s, 2H), 3.73-3.50 (m, 2H), 3.42 (s, 3H), 1.92-1.71 (m, 1H), 1.69-1.44 (m, 6H), 1.00-0.75 (m, 6H). 28 [00138] N-butyl-2-(4-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)-2-methylpropanamide LC-MS (Method 3) m/z 450.4 (M + H).sup.+, at 2.04 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 7.65 (d, J = 8.1 Hz, 2H), 7.60 (br s, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.19-7.02 (m, 4H), 6.87- 6.48 (m, 2H), 4.45 (s, 2H), 4.01- 3.49 (m, 2H), 1.70-1.24 (m, 8H), 1.28-1.10 (m, 2H), 0.94-0.62 (m, 3H). 3 protons not observed, obscured by water signal. 29 [00139] N-(cyclopropylmethyl)-2-(4- fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)-2-methylpropanamide LC-MS (Method 3) m/z 448.3 (M + H).sup.+, at 1.97 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 7.66 (d, J = 8.0 Hz, 2H), 7.60 (br s, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.22-7.06 (m, 4H), 6.90- 6.54 (m, 2H), 4.45 (s, 2H), 3.93- 3.41 (m, 2H), 3.31 (s, 3H), 1.76- 1.28 (m, 6H), 1.06-0.75 (m, 1H), 0.60-0.17 (m, 2H), 0.22-0.01 (m, 2H). 73 & 74 [00140] (rac-trans)-N-(4-(methoxymethyl)- [1,1-biphenyl]-4-yl)-N-methyl-2- (pyridin-2-yl)cyclopropane-1- carboxamide UPLC-MS (Method 2) 373.2 (M + H).sup.+, at 1.41 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.25 (s, 1H), 7.67-7.60 (m, 5H), 7.42-7.34 (m, 5H), 7.13- 7.07 (m, 1H), 4.45 (s, 2H), 3.31 (s, 3H), 3.25 (s, 3H), 2.58 (ddd, J = 8.5, 5.8, 3.9 Hz, 1H), 1.94 (br s, 1H), 1.47 (ddd, J = 8.5, 5.4, 3.1 Hz, 1H), 1.33 (br s, 1H). The trans isomers were separated by preparative chiral SFC to afford: First eluting isomer (Example 73), Chiral SFC (method 2) 3.16 min, >99% ee Second eluting isomer (Example, 74) Chiral SFC (method 2) 3.83 min, >99% ee

Example 20: 2-(4-fluorophenoxy)-2-methyl-N-(4-methyl-[1,1-biphenyl]-4-yl)-N-propylpropanamide

[0379] ##STR00141##

Step 1: 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methyl-N-(2-methylallyl)propenamide

[0380] The title compound was prepared by methods analogous to Example 13, substituting appropriate starting materials and intermediates where necessary to afford 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methyl-N-(2-methylallyl) propanamide (63 mg, 0.13 mmol, 88%, 95% purity) as a pale yellow oil. LC-MS (Method 3) m/z 434.3 (M+H).sup.+, at 2.90 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.61-7.52 (m, 2H), 7.53-7.36 (m, 4H), 7.13-6.96 (m, 2H), 6.96-6.83 (m, 2H), 6.76-6.46 (m, 2H), 6.07-5.74 (m, 1H), 5.31-4.96 (m, 2H), 4.50 (s, 2H), 4.43-4.06 (m, 2H), 3.42 (s, 3H), 1.84-1.40 (m, 6H).

Step 2: N-propyl-2-(4-fluorophenoxy)-N-(4-(methoxynethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0381] To a vial containing palladium (20 mg, 5 wt %, 9.2 ?mol) was added EtOH (ca 0.5 mL) followed by careful addition of a solution of N-allyl-2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (40 mg, 92 ?mol) in EtOH (3.0 mL), then stirred under an atmosphere of hydrogen 1.0 bar at RT. After 2 h the reaction mixture was filtered through a pad of celite and filtrate was concentrated to afford 2-(4-fluorophenoxy)-2-methyl-N-(4-methyl-[1,1-biphenyl]-4-yl)-N-propylpropanamide (37 mg, 94%, 95% purity) as a beige solid. LC-MS (Method 3) m/z 406.3 (M+H).sup.+, at 3.16 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.51-7.38 (m, 4H), 7.26-7.22 (m, 2H), 7.06-6.94 (m, 2H), 6.94-6.83 (m, 2H), 6.72-6.45 (m, 2H), 3.74-3.54 (m, 2H), 2.40 (s, 3H), 0.95-0.76 (m, 3H). 8 aliphatic protons obscured by H.sub.2O signal.

Example 21: 2-(4-fluorophenoxy)-N-isobutyl-2-methyl-N-(4-methyl-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0382] ##STR00142##

[0383] The title compound was prepared by methods analogous to Example 20, substituting appropriate starting materials and intermediates where necessary to afford:

[0384] Step 1: 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methyl-N-(2-methylallyl)propanamide as a pale yellow oil. LC-MS (Method 3) m/z 448.3 (M+H).sup.+, at 2.99 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.57-7.51 (m, 2H), 7.46-7.38 (m, 4H), 7.07-6.97 (m, 2H), 6.94-6.87 (m, 2H), 6.68-6.49 (m, 2H), 4.84-4.80 (m, 1H), 4.69 (s, 1H), 4.50 (s, 2H), 4.43-4.21 (m, 2H), 3.42 (s, 3H), 1.84-1.67 (m, 3H), 1.67-1.51 (m, 6H).

[0385] Step 2: 2-(4-fluorophenoxy)-N-isobutyl-2-methyl-N-(4-methyl-[1,1-biphenyl]-4-yl)-2-methylpropanamide as a beige solid. LC-MS (Method 3) m/z 420.3 (M+H).sup.+, at 3.21 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.50-7.36 (m, 4H), 7.25 (d, J=7.9 Hz, 2H), 7.07-6.95 (m, 2H), 6.95-6.84 (m, 2H), 6.63-6.46 (m, 2H), 3.68-3.47 (m, 2H), 2.40 (s, 3H), 1.89-1.72 (m, 1H), 0.98-0.82 (m, 6H). 6 aliphatic protons obscured by H.sub.2O signal.

Example 31: 2-(4-fluorophenoxy)-1-(6-(4-(methoxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-2-methylpropan-1-one

[0386] ##STR00143##

Step 1: 6-(4-(methoxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline

[0387] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (200 mg, 943 ?mol), (4-(methoxymethyl)phenyl)boronic acid (235 mg, 1.41 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (69.0 mg, 94.3 ?mol) in 1,4-dioxane (10 mL) was added a solution of K.sub.3PO.sub.4 (500 mg, 2.36 mmol) in water (2.4 mL). The mixture was degassed then heated to 100? C. for 18 h. The mixture was filtered through celite washing with EtOAc (25 mL) and treated with sat aq NH.sub.4Cl (30 mL). The phases were separated and the aqueous phase extracted with EtOAc (2?25 mL), combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford 6-(4-(methoxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline (105 mg, 43%, 98% purity) as a beige solid. UPLC-MS (method 1) m/z 254.6 (M+H).sup.+, at 1.18 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 7.52-7.46 (m, 2H), 7.31-7.26 (m, 2H), 7.21-7.15 (m, 2H), 6.49 (d, J=8.1 Hz, 1H), 5.83-5.79 (m, 1H), 4.39 (s, 2H), 3.28 (s, 3H), 3.23-3.17 (m, 2H), 2.72 (t, J=6.3 Hz, 2H), 1.85-1.77 (m, 2H).

Step 2: 2-(4-fluorophenoxy)-1-(6-(4-(methoxyethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-2-methylpropan-1-one

[0388] To a solution of 2-(4-fluorophenoxy)-2-methylpropanoic acid (40 mg, 0.20 mmol) and N,N-dimethylformamide (3 ?L, 17 ?mol) in DCM (2 mL) at 0? C. was added oxalyl dichloride (22 ?L, 0.25 mmol) and the reaction was warmed to rt. To the solution of acid chloride was added a solution of 6-(4-(methoxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline (43 mg, 0.17 mmol) in DCM (5.0 mL) and DIPEA (0.12 mL, 0.67 mmol) and the reaction mixture was stirred at rt. The mixture was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) then further purified by preparative HPLC to afford 2-(4-fluorophenoxy)-1-(6-(4-(methoxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-2-methylpropan-1-one (26 mg, 36%, 100% Purity) as a clear colourless oil. UPLC-MS (Method 1) m/z 434.5 (M+H).sup.+, at 1.98 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.78 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.43-7.36 (m, 3H), 7.32 (br s, 1H), 6.97-6.85 (m, 4H), 4.49 (s, 2H), 4.12-4.06 (m, 2H), 3.41 (s, 3H), 2.81 (t, J=7.1 Hz, 2H), 1.94-1.85 (m, 2H), 1.72 (s, 6H).

Example 32: 2-(4-fluorophenoxy)-1-(5-(4-(methoxymethyl)phenyl)indolin-1-yl)-2-methylpropan-1-one

[0389] ##STR00144##

Step 1: 1-(5-bromoindolin-1-yl)-2-(4-fluorophenoxy)-2-methylpropan-1-one

[0390] To a solution of 5-bromoindoline (150 mg, 757 ?mol) and 2-(4-fluorophenoxy)-2-methylpropanoic acid (150 mg, 757 ?mol) in MeCN (2.0 mL) were added DIPEA (396 ?L, 2.27 mmol) and HATU (302 mg, 795 ?mol) and the reaction was stirred at RT for 3 days. The mixture was diluted with DCM (15 mL) and 10 wt % aq. citric acid (10 mL), stirred for 10 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford 1-(5-bromoindolin-1-yl)-2-(4-fluorophenoxy)-2-methylpropan-1-one (210 mg, 0.55 mmol, 73%, 99% purity) as a cream solid. LC-MS (Method 3) m/z 378.1/380.1 (M+H).sup.+, at 1.95 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.11 (d, J=8.6 Hz, 1H), 7.46-7.42 (m, 1H), 7.40-7.34 (m, 1H), 7.16-7.07 (m, 2H), 6.88-6.80 (m, 2H), 4.26 (t, J=8.3 Hz, 2H), 3.05 (t, J=8.2 Hz, 2H), 1.59 (s, 6H).

Step 2: 2-(4-fluorophenoxy)-1-(5-(4-(methoxymethyl)phenyl)indolin-1-yl)-2-methylpropan-1-one

[0391] To a solution of 1-(5-bromoindolin-1-yl)-2-(4-fluorophenoxy)-2-methylpropan-1-one (70 mg, 0.19 mmol), (4-(methoxymethyl)phenyl)boronic acid (46 mg, 0.28 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (14 mg, 19 ?mol) in 1,4-dioxane (3.0 mL) in microwave vial was added a solution of K.sub.3PO.sub.4 (98 mg, 0.46 mmol) in water (0.50 mL). The mixture was degassed, sealed, and heated under microwave at 130? C. for 2 h. The mixture was filtered through celite washing with EtOAc (25 mL) and treated with sa.t aq. NH.sub.4Cl (30 mL). The phases were separated and the aqueous extracted with EtOAc (2?25 mL), combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford 2-(4-fluorophenoxy)-1-(5-(4-(methoxymethyl)phenyl)indolin-1-yl)-2-methylpropan-1-one (52 mg, 0.12 mmol, 65%, 97% purity) as an orange oil. UPLC-MS (Method 1) m/z 420.5 (M+H).sup.+, at 1.96 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.24 (d, J=8.5 Hz, 1H), 7.64-7.59 (m, 2H), 7.57-7.48 (m, 2H), 7.40-7.35 (m, 2H), 7.16-7.09 (m, 2H), 6.90-6.83 (m, 2H), 4.44 (s, 2H), 4.30 (t, J=8.2 Hz, 2H), 3.10 (t, J=8.2 Hz, 2H), 1.62 (s, 6H). 3H signal obscured by water signal.

Example 33: 2-(4-fluorophenoxy)-N-(2-hydroxyethyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0392] ##STR00145##

Step 1: N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0393] The title compound was prepared by methods analogous to Example 20, substituting appropriate starting materials and intermediates where necessary to afford N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (20 mg, 31 ?mol, 30%, 85% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 552.6 (M+H).sup.+, at 2.35 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.59-7.52 (m, 2H), 7.50-7.37 (m, 4H), 7.08 (s, 2H), 6.90 (s, 2H), 6.67-6.45 (m, 2H), 4.50 (s, 2H), 4.25-3.61 (m, 4H), 3.42 (s, 3H), 1.91-1.41 (m, 6H), 0.86 (s, 9H), 0.07-?0.03 (m, 6H).

Step 2: 2-(4-fluorophenoxy)-N-(2-hydroxyethyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0394] To a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (20 mg, 36 ?mol) in THE (5.0 mL) at rt was added TBAF (1.0M in THF) (54 ?L, 54 ?mol) drop-wise. After 16 h the reaction mixture was treated with MeOH (?1 mL) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford 2-(4-fluorophenoxy)-N-(2-hydroxyethyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (13 mg, 28 ?mol, 78%, 95% purity) as a pale yellow solid. LC-MS (Method 3) m/z 438.4 (M+H).sup.+, at 1.88 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.52 (d, J=7.9 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 6.93-6.86 (m, 2H), 6.86-6.79 (m, 2H), 6.62 (d, J=8.1 Hz, 2H), 4.48 (s, 2H), 4.40 (t, J=5.4 Hz, 2H), 3.45 (t, J=5.5 Hz, 2H), 3.41 (s, 3H), 1.58 (s, 6H). One exchangeable proton not observed.

Example 39: 2-(4-fluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0395] ##STR00146##

Step 1: ethyl-N-(2-(4-fluorophenoxy)-2-methylpropanoyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)glycinate

[0396] To a solution of 2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (200 mg, 508 ?mol) in THE (5.0 mL) at 0? C. was added NaH (40.7 mg, 60% Wt, 1.02 mmol). The mixture was warmed to RT and after 20 min ethyl 2-bromoacetate (169 ?L, 1.52 mmol) was added and reaction was heated at 50? C. After 16 h, the reaction was cooled to RT, treated with MeOH (?1 mL) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford ethyl-N-(2-(4-fluorophenoxy)-2-methylpropanoyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)glycinate (75 mg, 0.13 mmol, 25%, 80% purity) as a pale yellow solid. LC-MS (Method 3) m/z 480.3 (M+H).sup.+, at 1.88 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.53 (d, J=7.9 Hz, 2H), 7.46-7.37 (m, 4H), 7.26-7.20 (m, 2H), 6.94-6.87 (m, 2H), 6.68-6.61 (m, 2H), 4.49 (s, 2H), 4.31 (s, 2H), 4.27-4.20 (m, 2H), 3.42 (s, 3H), 1.56 (s, 6H), 1.35-1.22 (m, 3H).

Step 2: 2-(4-fluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0397] To a solution of ethyl-N-(2-(4-fluorophenoxy)-2-methylpropanoyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)glycinate (43 mg, 90 ?mol) in THE (2.0 mL) at 0? C. was added drop-wise a solution of methylmagnesium bromide (3M in Et.sub.2O) (0.12 mL, 0.36 mmol). The reaction was allowed to warm to RT and stirred for 90 min. The reaction mixture was treated with sat. aq. NH.sub.4Cl (5 mL), extracted with EtOAc (3?10 mL), washed with brine (20 mL), passed through a phase separator, and concentrated. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) then further purified by preparative HPLC to afford 2-(4-fluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide (0.9 mg, 2 ?mol, 2%, 96% purity) as a clear colourless oil. UPLC-MS (Method 1) m/z 466.6 (M+H).sup.+, at 1.79 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.53 (d, J=8.1 Hz, 2H), 7.42 (dd, J=10.4, 8.2 Hz, 4H), 7.08 (d, J=8.4 Hz, 2H), 6.94-6.87 (m, 2H), 6.59-6.53 (m, 2H), 4.50 (s, 2H), 3.81 (s, 2H), 3.43 (s, 3H), 1.58-1.51 (m, 3H), 1.26 (s, 3H), 1.23 (s, 6H). One exchangeable proton not observed.

Example 43: (6-(4-(methoxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)((rac-trans)-2-(pyridin-2-yl)cyclopropyl)methanone

[0398] ##STR00147##

[0399] To a solution of 6-(4-(methoxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline (70 mg, 0.28 mmol) and (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (45 mg, 0.28 mmol) in acetonitrile (4.0 mL) at RT was added HATU (0.12 g, 0.30 mmol) and DIPEA (0.14 mL, 0.83 mmol). After 3 days the reaction was diluted with water (10 mL) and EtOAc (30 mL), washed with sat. aq. NaHCO.sub.3 (10 mL) and brine (10 mL), passed through a hydrophobic frit and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford (6-(4-(methoxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)((rac-trans)-2-(pyridin-2-yl)cyclopropyl)methanone (85 mg, 0.20 mmol, 73%, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 399.4 (M+H).sup.+, at 1.38 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.39 (d, J=4.6 Hz, 1H), 7.59-7.53 (m, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.40-7.33 (m, 3H), 7.33-7.17 (m, 3H), 7.08-7.02 (m, 1H), 4.48 (s, 2H), 3.94-3.87 (m, 1H), 3.87-3.78 (m, 1H), 3.41 (s, 3H), 2.84-2.73 (m, 3H), 2.68-2.61 (m, 1H), 2.06-1.92 (m, 2H), 1.82-1.75 (m, 1H), 1.66-1.58 (m, 1H).

Example 44: (rac-trans)-N-(3-(4-(methoxymethyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0400] ##STR00148##

Step 1: (rac-trans)-N-(3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)

[0401] To a solution of 3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-amine, HCl (100 mg, 364 ?mol) and (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (59.4 mg, 1 Eq, 364 ?mol) in acetonitrile (2.0 mL) at RT was added HATU (152 mg, 401 ?mol) and DIPEA (190 ?L, 1.09 mmol). After 3 days the mixture was diluted with water (10 mL) and EtOAc (30 mL), washed with sat. aq. NaHCO.sub.3 (10 mL) and brine (10 mL), passed through a hydrophobic frit and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford (rac-trans)-N-(3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (118 mg, 0.29 mmol, 80%, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 383.4/385.4 (M+H).sup.+, at 1.25 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.80 (s, 1H), 8.44-8.39 (m, 1H), 7.70-7.63 (m, 1H), 7.52-7.45 (m, 2H), 7.43-7.38 (m, 1H), 7.21-7.14 (m, 3H), 2.46-2.38 (m, 1H), 2.23 (s, 6H), 2.11-2.04 (m, 1H), 1.37-1.30 (m, 2H).

Step 2: (rac-trans)-N-(3-(4-(methoxymethyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0402] To a degassed solution of (rac-trans)-N-(3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (95.0 mg, 248 ?mol), trifluoro(methoxymethyl)-4-borane, potassium salt (75.3 mg, 496 ?mol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (18.1 mg, 24.8 ?mol) in 1,4-dioxane (5.0 mL) was added a solution of Cs.sub.2CO.sub.3 (162 mg, 496 ?mol) in water (0.50 mL). The mixture was de-gassed with nitrogen for 15 min, then sealed and heated at 90? C. After 16 h the reaction mixture was filtered through a pad of celite, the cake was washed with EtOAc (30 mL) and the filtrate was poured into sat. aq. NaHCO.sub.3 (30 mL). The mixture was extracted with EtOAc (3?30 mL), the combined organic phases were dried (phase separator), and concentrated. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford title carboxamide (18 mg, 49 ?mol, 20%, 95% purity) as a brown crystalline solid. UPLC-MS (Method 1) m/z 349.4 (M+H).sup.+, at 0.99 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.47-8.39 (m, 1H), 7.60-7.53 (m, 1H), 7.37-7.12 (m, 5H), 7.11-7.05 (m, 1H), 6.28-6.15 (m, 1H), 4.54-4.37 (m, 2H), 3.43-3.32 (m, 3H), 2.61-2.54 (m, 1H), 2.49-2.29 (m, 6H), 2.09-1.98 (m, 1H), 1.92-1.82 (m, 1H), 1.66-1.58 (m, 1H).

[0403] The enantiomers were separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40? C., 120 bar. The column was Phenomenex Lux C4 10?250 mm, 5 um, flow rate 15 mL/min at 40% IPA (0.1% Ammonia), 60% CO.sub.2 to afford: [0404] First eluting isomer (Example 110), Chiral SFC (method 5) 2.85 min, >99% ee [0405] Second eluting isomer (Example 111), Chiral SFC (method 5) 3.54 min, >99% ee [0406] Third eluting isomer (Example 112), Chiral SFC (method 5)>99% ee

Example 50: (5-(4-(methoxymethyl)phenyl)indolin-1-yl)((rac-trans)-2-(pyridin-2-yl) cyclopropyl)methanone

[0407] ##STR00149##

Step 1: (5-bromoindolin-1-yl)((rac-trans)-2-(pyridin-2-yl)cyclopropyl)methanone

[0408] To a solution of 5-bromoindoline (150 mg, 757 ?mol) and (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (124 mg, 757 ?mol) in MeCN (2.0 mL) were added DIPEA (396 ?L, 2.27 mmol) and HATU (302 mg, 795 ?mol) and the reaction was stirred at RT for 16 h. The mixture was diluted with DCM (15 mL) and 10 wt % aq. citric acid (10 mL), stirred for 10 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford (5-bromoindolin-1-yl)((rac-trans)-2-(pyridin-2-yl)cyclopropyl)methanone (338 mg, 0.54 mmol, 72%, 55% purity) as a cream solid. LC-MS (Method 3) m/z 343.1/345.2 (M+H).sup.+, at 1.16 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.48 (d, J=5.1 Hz, 1H), 8.09-8.03 (m, 1H), 7.78-7.71 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.31-7.27 (m, 2H), 7.26-7.21 (m, 1H), 4.37-4.21 (m, 2H), 3.24-3.13 (m, 2H), 2.80-2.75 (m, 1H), 2.58-2.51 (m, 1H), 1.82-1.75 (m, 1H), 1.74-1.67 (m, 1H).

Step 2: (5-(4-(methoxymethyl)phenyl)indolin-1-yl)((rac-trans)-2-(pyridin-2-yl) cyclopropyl)methanone

[0409] To a solution of (5-bromoindolin-1-yl)((rac-trans)-2-(pyridin-2-yl)cyclopropyl)methanone (100 mg, 55 wt %, 160 ?mol), (4-(methoxymethyl)phenyl)boronic acid (39.9 mg, 240 ?mol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (11.7 mg, 16.0 ?mol) in 1,4-dioxane (3.0 mL) in microwave vial was added a solution of K.sub.3PO.sub.4 (85.0 mg, 401 ?mol) in water (0.50 mL). The mixture was degassed, sealed, and heated at 100? C. for 16 h. The mixture was filtered through celite washing with EtOAc (25 mL) and treated with sat. aq. NH.sub.4Cl (30 mL). The phases were separated and the aqueous extracted with EtOAc (2?25 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford (5-(4-(methoxymethyl)phenyl)indolin-1-yl)((rac-trans)-2-(pyridin-2-yl)cyclopropyl)methanone (54 mg, 0.13 mmol, 83%, 95% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z 385.3 (M+H).sup.+, at 1.23 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.47 (d, J=4.9 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.64-7.57 (m, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.42-7.35 (m, 3H), 7.32 (d, J=7.8 Hz, 1H), 7.16-7.09 (m, 1H), 4.49 (s, 2H), 4.40-4.31 (m, 1H), 4.31-4.22 (m, 1H), 3.41 (s, 3H), 3.32-3.18 (m, 2H), 2.78-2.71 (m, 1H), 2.54-2.47 (m, 1H), 1.80-1.73 (m, 1H), 1.71-1.64 (m, 1H).

Example 51: N-(4-ethoxy-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide

[0410] ##STR00150##

[0411] To a mixture of 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (50 mg, 0.13 mmol), (4-ethoxyphenyl)boronic acid (31 mg, 0.19 mmol) and Pd(dppf)Cl.sub.2 (9.2 mg, 13 ?mol) in dioxane (2.0 mL) was added a solution of potassium phosphate tribasic (80 mg, 0.38 mmol) in water (0.2 mL). The mixture was degassed then heated at 120? C. for 60 min under microwave irradiation. The reaction mixture was poured into 10 wt % aq. citric acid (20 mL) then DCM (10 mL) was added. The mixture was stirred for 15 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford N-(4-ethoxy-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide (35 mg, 89 ?mol, 71%, 97% purity) as a colourless solid. UPLC-MS (Method 1) m/z 394.8 (M+H).sup.+, at 1.73 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.08 (s, 1H), 7.83-7.69 (m, 2H), 7.61-7.53 (m, 4H), 7.21-7.13 (m, 2H), 7.03-6.97 (m, 4H), 4.08 (q, J=7.0 Hz, 2H), 1.54 (s, 6H), 1.36 (t, J=7.0 Hz, 3H).

[0412] The following examples were prepared by methods analogous to Example 51, substituting appropriate starting materials and intermediates where necessary:

TABLE-US-00010 Example Structure Name/Analytical Data 52 [00151] 2-(4-fluorophenoxy)-2-methyl-N-(4- (methylsulfonyl)-[1,1-biphenyl]-4- yl)propenamide UPLC-MS (Method 1) no ionisation at 1.42 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 10.20 (s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.7 H, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.19-7.10 (m, 2H), 7.03-6.93 (m, 2H), 3.24 (s, 3H), 1.53 (s, 6H). 80 [00152] N-(5-(4-((dimethylamino)methyl) phenyl)pyridin-2-yl)-2-(4- fluorophenoxy)-2-methylpropanamide UPLC-MS (Method 1) 408.1 (M + H).sup.+ at 0.97 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 9.93 (s, 1H), 8.66 (t, J = 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 2H), 7.72- 7.63 (m, 2H), 7.47-7.35 (m, 2H), 7.20- 7.12 (m, 2H), 7.09-7.01 (m, 2H), 3.42 (s, 2H), 2.16 (s, 6H), 1.53 (s, 6H). 81 [00153] 2-(4-fluorophenoxy)-2-methyl-N-(5-(4- (morpholinomethyl)phenyl)pyridin-2- yl)propanamide UPLC-MS (Method 1) 450.3 (M + H).sup.+ at 0.97 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 9.98 (s, 1H), 8.65 (dd, J = 2.1, 1.3 Hz, 1H), 8.15 (app t, J = 1.7 Hz, 2H), 7.74-7.63 (m, 2H), 7.46-7.37 (m, 2H), 7.19-7.11 (m, 2H), 7.09- 7.00 (m, 2H), 3.58 (t, J = 4.6 Hz, 4H), 3.50 (s, 2H), 2.37 (t, J = 4.5 Hz, 4H), 1.53 (s, 6H). 82 [00154] (rac-trans)-N-(5-(4- ((dimethylamino)methyl)phenyl)pyridin- 2-yl)-2-(pyridin-2-yl)cyclopropane-1- carboxamide UPLC-MS (Method 1) 373.2 (M + H).sup.+ at 0.48 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 10.85 (s, 1H), 8.63 (dd, J = 2.5, 0.9 Hz, 1H), 8.46 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.08 (dd, J = 8.7, 2.6 Hz, 1H), 7.76- 7.62 (m, 3H), 7.44 (dt, J = 7.8, 1.1 Hz, 1H), 7.41-7.34 (m, 2H), 7.20 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 3.41 (s, 2H), 2.60 (t, J = 7.1 Hz, 2H), 2.16 (s, 6H), 1.56-1.45 (m, 2H). 83 [00155] (rac-trans)-N-(5-(4-(morpholinomethyl) phenyl)pyridin-2-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide UPLC-MS (Method 1) 415.2 (M + H).sup.+ at 0.49 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 10.89 (s, 1H), 8.62 (dd, J = 2.5, 0.8 Hz, 1H), 8.46 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.73- 7.63 (m, 3H), 7.44 (dt, J = 7.9, 1.1 Hz, 1H), 7.42-7.38 (m, 2H), 7.20 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 3.58 (t, J = 4.6 Hz, 4H), 3.50 (s, 2H), 2.60 (dd, J = 7.7, 6.5 Hz, 2H), 2.37 (d, J = 4.8 Hz, 4H), 1.59-1.46 (m, 2H). 105 [00156] 1-(4-fluorophenoxy)-N-(4-(morpholine- 4-carbonyl)-[1,1-biphenyl]-4- yl)cyclopropane-1-carboxamide UPLC-MS (Method 2) 461.3 (M + H).sup.+ at 1.44 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 10.08 (s, 1H), 7.76-7.68 (m, 4H), 7.66-7.60 (m, 2H), 7.49-7.44 (m, 2H), 7.20-7.14 (m, 2H), 7.04- 6.96 (m, 2H), 3.42 (s, 8H), 1.58-1.52 (m, 2H), 1.25-1.19 (m, 2H). 106 [00157] N-(4-(6-ethoxypyridin-3-yl)phenyl)-1- (4-fluorophenoxy)cyclopropane-1- carboxamide UPLC-MS (Method 2) 393.2 (M + H).sup.+ at 1.70 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 10.05 (s, 1H), 8.42 (dd, J = 2.6, 0.8 Hz, 1H), 7.95 (dd, J = 8.7, 2.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.61-7.52 (m, 2H), 7.21-7.12 (m, 2H), 7.05- 6.96 (m, 2H), 6.84 (dd, J = 8.6, 0.7 Hz, 1H), 4.32 (q, J = 7.0 Hz, 2H), 1.59- 1.52 (m, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.25-1.17 (m, 2H). 107 [00158] N-(4-(2-(dimethylamino)pyrimidin-5- yl)phenyl)-1-(4- fluorophenoxy)cyclopropane-1- carboxamide UPLC-MS (Method 2) 393.2 (M + H).sup.+ at 1.56 min. .sup.1H NMR (500 MHz, DMSO- d6) ? 10.03 (s, 1H), 8.64 (s, 2H), 7.72- 7.64 (m, 2H), 7.57-7.50 (m, 2H), 7.21-7.12 (m, 2H), 7.03-6.96 (m, 2H), 3.15 (s, 6H), 1.58-1.50 (m, 2H), 1.25-1.17 (m, 2H).

Example 53: 1-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)cyclopropane-1-carboxamide

[0413] ##STR00159##

[0414] To a solution of 1-(4-fluorophenoxy)cyclopropane-1-carboxylic acid (0.17 mmol) in DMF (0.5 mL) in a 96 well plate were added sequentially a solution of 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (32 mg, 0.15 mmol) in DMF (0.5 mL), followed by a solution of HATU (68 mg, 0.18 mmol) in DMF (0.5 mL) and DIPEA (78 ?L, 0.45 mmol). The reactions were shaken for 20 h then filtered. The crude reaction mixture was purified by preparative HPLC using a Waters X-Bridge BEH C18, 5 ?m, 19?50 mm column using a gradient of MeCN and 10 mM ammonium bicarbonate(aq) then dried in a Genevac to afford the title compound (38.4 mg, 6.04 mmol, 65% yield, 99% purity) as a colourless solid. UPLC-MS (Method 2) m/z 392.2 (M+H).sup.+, at 1.69 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.04 (s, 1H), 7.75-7.66 (m, 2H), 7.64-7.56 (m, 4H), 7.44-7.31 (m, 2H), 7.21-7.11 (m, 2H), 7.04-6.94 (m, 2H), 4.43 (s, 2H), 3.30 (s, 3H), 1.60-1.51 (m, 2H), 1.25-1.16 (m, 2H).

[0415] The following examples were prepared by methods analogous to Example 53, substituting appropriate starting materials and intermediates where necessary:

TABLE-US-00011 Example Structure Name/Analytical Data 54 [00160] (rac-trans)-2-(4-fluorophenyl)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4- yl)cyclopropane-1-carboxamide UPLC-MS (Method 2) m/z 376.2 (M + H).sup.+, at 1.61 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.34 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.65-7.58 (m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.30- 7.22 (m, 2H), 7.18-7.08 (m, 2H), 4.43 (s, 2H), 3.30 (s, 3H), 2.41 (m, 1H), 2.11-1.99 (m, 1H), 1.50 (m, 1H), 1.37 (m, 1H). 55* [00161] 3-(4-fluorophenyl)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2,2-dimethylpropanamide UPLC-MS (Method 2) m/z 392.2 (M + H).sup.+, at 1.70 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 9.37 (s, 1H), 7.77- 7.67 (m, 2H), 7.67-7.58 (m, 4H), 7.38 (d, J = 8.0 Hz, 2H), 7.22-7.14 (m, 2H), 7.13-7.04 (m, 2H), 4.44 (s, 2H), 3.31 (s, 3H), 2.94 (s, 2H), 1.19 (s, 6H). 56* [00162] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2,2-dimethyl-3- phenylpropanamide UPLC-MS (Method 2) m/z 374.5 (M + H).sup.+, at 1.69 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 9.38 (s, 1H), 7.78- 7.69 (m, 2H), 7.68-7.59 (m, 4H), 7.38 (d, J = 8.1 Hz, 2H), 7.24 (m, 2H), 7.22- 7.16 (m, 1H), 7.16-7.09 (m, 2H), 4.44 (s, 2H), 3.31 (s, 3H), 2.95 (s, 2H), 1.20 (s, 6H). 57 [00163] 2-(4-ethylphenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 404.2 (M + H).sup.+, at 1.89 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.09 (s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.70-7.55 (m, 4H), 7.38 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 2.54 (d, J = 7.6 Hz, 2H), 1.52 (s, 6H), 1.13 (t, J = 7.6 Hz, 3H). 58 [00164] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methyl-2-(m- tolyloxy)propenamide UPLC-MS (Method 2) m/z 390.1 (M + H).sup.+, at 1.81 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.07 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.66-7.56 (m, 4H), 7.38 (d, J = 8.2 Hz, 2H), 7.16 (app t, J = 7.9 Hz, 1H), 6.83 (m, 1H), 6.78 (br s, 1H), 6.71 (dd, J = 8.2, 2.5 Hz, 1H), 4.44 (s, 2H), 3.30 (s, 3H), 2.25 (s, 3H), 1.54 (s, 6H). 59 [00165] 2-(4-bromophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 454.0/456.0 (M + H).sup.+, at 1.84 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.10 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.66-7.58 (m, 4H), 7.53-7.44 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 6.96-6.79 (m, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 1.56 (s, 6H). 60 [00166] 2-(4-isopropylphenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 418.2 (M + H).sup.+, at 1.96 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.08 (s, 1H), 7.86- 7.75 (m, 2H), 7.69-7.56 (m, 4H), 7.38 (d, J = 8.3 Hz, 2H), 7.19-7.09 (m, 2H), 6.90-6.80 (m, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 2.82 (hept, J = 6.9 Hz, 1H), 1.53 (s, 6H), 1.15 (d, J = 6.9 Hz, 6H). 61 [00167] (rac-trans)-N-(4-(methoxymethyl)-[1,1- biphenyl]-4-yl)-2-phenylcyclopropane- 1-carboxamide UPLC-MS (Method 2) m/z 358.2 (M + H).sup.+, at 1.61 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.33 (s, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.66-7.55 (m, 4H), 7.37 (d, J = 8.1 Hz, 2H), 7.32- 7.27 (m, 2H), 7.24-7.13 (m, 3H), 4.43 (s, 2H), 3.30 (s, 3H), 2.39 (m, 1H), 2.09 (m, 1H), 1.51 (m, 1H), 1.38 (m, 1H). 62 [00168] 2-(3-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 394.2 (M + H).sup.+, at 1.73 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.11 (s, 1H), 7.82- 7.71 (m, 2H), 7.67-7.55 (m, 4H), 7.42-7.27 (m, 3H), 6.86 (m, 1H), 6.82- 6.71 (m, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 1.58 (s, 6H). 63 [00169] 2-(2,4-difluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 412.1 (M + H).sup.+, at 1.76 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.14 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.3 Hz, 4H), 7.42-7.30 (m, 3H), 7.12 (app td, J = 9.2, 5.6 Hz, 1H), 7.07-7.00 (m, 1H), 4.44 (s, 2H), 3.31 (s, 3H), 1.52 (s, 6H). 64 [00170] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methyl-2-(o- tolylox)propenamide UPLC-MS (Method 2) m/z 390.2 (M + H).sup.+, at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.07 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.69-7.57 (m, 4H), 7.38 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.08 (app t, J = 7.8 Hz, 1H), 6.91 (app t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 4.44 (s, 2H), 3.30 (s, 3H), 2.27 (s, 3H), 1.54 (s, 6H). 65 [00171] 2-(3-chlorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 410.1 (M + H).sup.+, at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.11 (s, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.63 (br d, J 8.3 Hz, 4H), 7.38 (d, J = 8.0 Hz, 2H), 7.33 (app t, J = 8.2 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (app t, J = 2.2 Hz, 1H), 6.90 (dd, J = 8.4, 2.4 Hz, 1H), 4.44 (s, 2H), 3.30 (s, 3H), 1.57 (s, 6H). 66 [00172] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-(4-methoxyphenoxy)-2- methylpropanamide UPLC-MS (Method 2) m/z 406.2 (M + H).sup.+, at 1.70 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.10 (s, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.73-7.58 (m, 4H), 7.38 (d, J = 8.2 Hz, 2H), 6.95- 6.89 (m, 2H), 6.89-6.81 (m, 2H), 4.44 (s, 2H), 3.69 (s, 3H), 3.31 (s, 3H), 1.48 (s, 6H). 67 [00173] 2-(2-chlorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 410.1 (M + H).sup.+, at 1.84 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.61 (s, 1H), 8.05 (ddd, J = 5.0, 2.0, 0.8 Hz, 1H), 7.72 (ddd, J = 8.3, 7.1, 2.0 Hz, 1H), 7.69- 7.63 (m, 2H), 7.63-7.57 (m, 2H), 7.59- 7.52 (m, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.93 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H), 6.90 (dd, J = 8.3, 0.9 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.66 (s, 6H). 68 [00174] 2-(4-cyanophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 401.2 (M + H).sup.+, at 1.89 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.11 (s, 1H), 7.81- 7.75 (m, 2H), 7.75-7.69 (m, 2H), 7.66-7.58 (m, 4H), 7.37 (d, J = 8.2 Hz, 2H), 7.07-7.00 (m, 2H), 4.43 (s, 2H), 3.30 (s, 3H), 1.64 (s, 6H). 69 [00175] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methyl-2-(pyridazin-3- yloxy)propenamide UPLC-MS (Method 2) m/z 378.2 (M + H).sup.+, at 1.22 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 9.39 (s, 1H), 8.05 (dd, J = 3.8, 1.7 Hz, 1H), 7.67-7.57 (m, 7H), 7.47 (dd, J = 9.4, 3.8 Hz, 1H), 7.40-7.36 (m, 2H), 6.90 (dd, J = 9.4, 1.7 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 4H), 1.66 (s, 6H). 70 [00176] 2-(4-ethoxyphenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 420.2 (M + H).sup.+, at 1.79 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.09 (s, 1H), 7.92- 7.78 (m, 2H), 7.68-7.58 (m, 4H), 7.38 (d, J = 8.4 Hz, 2H), 6.93-6.88 (m, 2H), 6.88-6.81 (m, 2H), 4.44 (s, 2H), 3.94 (q, J = 7.0 Hz, 2H), 3.31 (s, 3H), 1.48 (s, 6H), 1.28 (t, J = 7.0 Hz, 3H). 71 [00177] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methyl-2-((5- (trifluoromethyl)pyridin-2- yl)oxy)propenamide UPLC-MS (Method 2) m/z 445.2 (M + H).sup.+, at 1.71 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.68 (s, 1H), 8.49 (m, 1H), 8.10 (dd, J = 8.8, 2.6 Hz, 1H), 7.70- 7.63 (m, 2H), 7.63-7.54 (m, 4H), 7.36 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.72 (s, 6H). 96 [00178] 2-(2,4-dichlorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 445.2 (M + H).sup.+, at 1.96 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.19 (s, 1H), 7.86-7.76 (m, 2H), 7.67 (d, J = 2.6 Hz, 1H), 7.66- 7.60 (m, 4H), 7.42-7.33 (m, 3H), 7.00 (d, J = 8.9 Hz, 1H), 4.44 (s, 2H), 3.31 (s, 3H), 1.57 (s, 6H). 97 [00179] 2-(4-chloro-3-methylphenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 424.3 (M + H).sup.+, at 1.91 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.08 (s, 1H), 7.84-7.72 (m, 2H), 7.67-7.58 (m, 4H), 7.42- 7.35 (m, 2H), 7.32 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 3.0, 0.8 Hz, 1H), 6.77 (dd, J = 8.8, 3.1 Hz, 1H), 4.44 (s, 2H), 3.30 (s, 3H), 2.27 (s, 3H), 1.55 (s, 6H). 98 [00180] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-(3-methoxyphenoxy)-2- methylpropanamide UPLC-MS (Method 2) m/z 406.3 (M + H).sup.+, at 1.71 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.09 (s, 1H), 7.85-7.73 (m, 2H), 7.66-7.58 (m, 4H), 7.41- 7.34 (m, 2H), 7.23-7.13 (m, 1H), 6.60 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 6.53- 6.46 (m, 2H), 4.44 (s, 2H), 3.69 (s, 3H), 3.30 (s, 3H), 1.56 (s, 6H). 99 [00181] 2-(2,6-difluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 412.3 (M + H).sup.+, at 1.77 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.07 (s, 1H), 7.89-7.82 (m, 2H), 7.69-7.60 (m, 4H), 7.43- 7.35 (m, 2H), 7.29-7.10 (m, 3H), 4.44 (s, 2H), 3.31 (s, 3H), 1.51 (s, 6H). 100 [00182] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methyl-2-(3- (trifluoromethyl)phenoxy)propanamide UPLC-MS (Method 2) m/z 466.1 (M + Na).sup.+, at 1.83 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.14 (s, 1H), 7.79- 7.71 (m, 2H), 7.66-7.60 (m, 4H), 7.58- 7.52 (m, 1H), 7.42-7.35 (m, 3H), 7.26 (app t, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.3, 2.5 Hz, 1H), 4.44 (s, 2H), 3.30 (s, 3H), 1.60 (s, 6H). 101 [00183] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-(2-methoxyphenoxy)-2- methylpropanamide UPLC-MS (Method 2) m/z 406.3 (M + H).sup.+, at 1.77 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.09 (s, 1H), 7.86-7.77 (m, 2H), 7.69-7.61 (m, 4H), 7.42- 7.34 (m, 2H), 7.12-7.03 (m, 2H), 6.99 (dd, J = 7.6, 1.2 Hz, 1H), 6.88 (ddd, J = 8.0, 6.2, 2.7 Hz, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.31 (s, 3H), 1.48 (s, 6H). 102 [00184] 4-((1-((4-(methoxymethyl)-[1,1- biphenyl]-4-yl)amino)-2-methyl-1- oxopropan-2-yl)oxy)benzamide UPLC-MS (Method 2) m/z 441.3 (M + Na).sup.+, at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.11 (s, 1H), 7.85- 7.78 (m, 3H), 7.78-7.71 (m, 2H), 7.66- 7.58 (m, 4H), 7.43-7.34 (m, 2H), 7.20 (s, 1H), 6.98-6.90 (m, 2H), 4.43 (s, 2H), 3.30 (s, 3H), 1.60 (s, 6H). 103 [00185] 2-(2-fluorophenoxy)-N-(4- (methoxymethyl)-[1,1-biphenyl]-4-yl)- 2-methylpropanamide UPLC-MS (Method 2) m/z 394.3 (M + H).sup.+, at 1.75 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.15 (s, 1H), 7.87-7.78 (m, 2H), 7.67-7.61 (m, 4H), 7.41- 7.36 (m, 2H), 7.33-7.24 (m, 1H), 7.16- 7.02 (m, 3H), 4.44 (s, 2H), 3.31 (s, 3H), 1.54 (s, 6H). 104 [00186] N-(4-(methoxymethyl)-[1,1-biphenyl]- 4-yl)-2-methyl-2-(4- (trifluoromethyl)phenoxy)propanamide UPLC-MS (Method 2) m/z 444.1 (M + H).sup.+, at 1.81 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.13 (s, 1H), 7.79-7.72 (m, 2H), 7.70-7.65 (m, 2H), 7.65- 7.58 (m, 4H), 7.41-7.34 (m, 2H), 7.11- 7.03 (m, 2H), 4.43 (s, 2H), 3.30 (s, 3H), 1.63 (s, 6H). *These compounds fall outside the scope of the present claims.

Example 108: N-(2-fluoro-4-hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-N,2-dimethylpropanamide

[0416] ##STR00187##

[0417] Step 1: N-(2-fluoro-4-(hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (57 mg, 0.14 mmol), (2-fluoro-4-(hydroxymethyl)phenyl)boronic acid (29 mg, 0.17 mmol), Na.sub.2CO.sub.3 (30 mg, 0.28 mmol) and Pd(dppf.sub.2Cl.sub.2 (10 mg, 14 ?mol) were dissolved in 1,4-dioxane (4 mL) and water (2 mL). The reaction mixture was purged with nitrogen and heated to 80? C. for 4 h. The reaction mixture was filtered through celite and the cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford N-(2-fluoro-4-(hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide (46 mg, 0.11 mmol, 81% yield) as a colourless solid. LC-MS (Method 3) m/z 398.3 (M+H).sup.+, at 2.43 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.69 (s, 1H), 7.71-7.64 (m, 2H), 7.57-7.50 (m, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.24-7.15 (m, 2H), 7.08-6.94 (m, 4H), 4.73 (s, 2H), 1.91 (s, 1H), 1.56 (s, 6H).

Step 2: N-(2-fluoro-4-(hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-N,2-dimethylpropanamide

[0418] To a solution of N-(2-fluoro-4-(hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide (22 mg, 55 ?mol) in THE (3 mL) cooled to 0? C. was added sodium hydride (3.3 mg, 60% wt %, 82 ?mol). After 10 min iodomethane (0.011 mL, 0.18 mmol) was added and the mixture was stirred at 0? C. for 1 hour. The reaction was quenched with saturated aqueous NH.sub.4Cl solution (0.3 mL). The reaction mixture was extracted with EtOAc (2?5 mL), the combined organics were dried over (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (7 mg, 0.02 mmol, 30% yield) as a colourless gum. LC-MS (Method 3) m/z 412.3 (M+H).sup.+, at 2.78 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.61-7.33 (m, 3H), 7.24-7.04 (m, 4H), 6.99-6.50 (m, 4H), 4.74 (s, 2H), 3.39 (s, 3H), 1.75 (s, 1H), 1.56 (s, 6H).

Example 114: N-(2-fluoro-4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide

[0419] ##STR00188##

Step 1: N-(2-fluoro-4-(hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide

[0420] 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (57 mg, 0.14 mmol), (2-fluoro-4-(hydroxymethyl)phenyl)boronic acid (29 mg, 0.17 mmol), Na.sub.2CO.sub.3 (30 mg, 0.28 mmol) and Pd(dppf.sub.2Cl.sub.2 (10 mg, 0.1 Eq, 14 ?mol), were dissolved in 1,4-dioxane (4 mL) and water (2 mL). The reaction mixture was purged with nitrogen and heated to 80? C. for 4 h. The reaction mixture was filtered through celite and the cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (46 mg, 0.11 mmol, 81% yield) as a colourless solid. LC-MS (Method 3) m/z 398.3 (M+H).sup.+, at 2.43 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.69 (s, 1H), 7.71-7.64 (m, 2H), 7.57-7.50 (m, 2H), 7.42 (app t, J=8.0 Hz, 1H), 7.24-7.15 (m, 2H), 7.08-6.94 (m, 4H), 4.73 (s, 2H), 1.91 (s, 1H), 1.56 (s, 6H).

Step 2: N-(3-fluoro-4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide

[0421] To a solution of N-(2-fluoro-4-(hydroxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide (22 mg, 55 ?mol) in THE (3 mL) cooled to 0? C. was added sodium hydride (3.3 mg, 60 wt %, 82 ?mol). After 10 min iodomethane (0.011 mL, 0.18 mmol) was added and the mixture was stirred at 0? C. for 1 hour. The reaction was quenched with saturated aqueous NH.sub.4Cl solution (0.3 mL). The reaction mixture was extracted with EtOAc (2?5 mL). The combined organic layers were collected, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (7 mg, 0.02 mmol, 30% yield) as a colourless gum. LC-MS (Method 3) m/z 412.3 (M+H).sup.+, at 2.78 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.66 (s, 1H), 7.72-7.65 (m, 2H), 7.60-7.51 (m, 2H), 7.41 (app t, J=8.0 Hz, 1H), 7.19-7.11 (m, 2H), 7.08-6.93 (m, 4H), 4.48 (s, 2H), 3.43 (s, 3H), 1.57 (s, 6H).

Example 115: N-(2-fluoro-4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-N,2-dimethylpropanamide

[0422] ##STR00189##

[0423] The title compound was also isolated from example 114, step 2 (3 mg, 0.07 mmol, 10% yield). LC-MS (Method 3) m/z 426.3 (M+H).sup.+, at 2.79 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.57-7.32 (m, 3H), 7.22-7.01 (m, 4H), 6.93-6.64 (m, 4H), 4.49 (s, 2H), 3.43-3.38 (m, 6H), 1.62-1.57 (m, 6H).

Example 118: 2-(4-fluorophenoxy)-N-(4-(5-(methoxymethyl)thiophen-3-yl)phenyl)-2-methylpropanamide

[0424] ##STR00190##

Step 1: methyl 4-(4-(2-(4-fluorophenoxy)-2-methylpropanamido)phenyl)thiophene-2-carboxylate

[0425] 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (40 mg, 99 ?mol), (5-(methoxycarbonyl)thiophen-3-yl)boronic acid (22 mg, 0.12 mmol), Na.sub.2CO.sub.3 (26 mg, 0.25 mmol), and Pd(PPh.sub.3).sub.4 (29 mg, 25 ?mol) were dissolved in 1,4-dioxane (5 mL) The reaction mixture was purged with nitrogen and heated to 80? C. overnight. The reaction mixture was filtered through celite, the cake was washed with EtOAc (20 mL) and filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (18 mg, 39 ?mol, 39% yield) as a brown gum. LC-MS (Method 3) m/z 414.2 (M+H).sup.+, at 2.72 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.67 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.62 (d, J=1.6 Hz, 1H), 7.60-7.55 (m, 2H), 7.03-6.96 (m, 4H), 3.92 (s, 3H), 1.56 (s, 6H).

Step 2: 2-(4-fluorophenoxy)-N-(4-(5-(hydroxymethyl)thiophen-3-yl)phenyl)-2-methylpropanamide

[0426] To a stirred solution of methyl 4-(4-(2-(4-fluorophenoxy)-2-methylpropanamido)phenyl)thiophene-2-carboxylate (14 mg, 34 ?mol) in dry THE (2.5 mL) and methanol (0.1 mL) under a nitrogen atmosphere at 0? C. was added LiBH.sub.4 (0.13 mL, 2 M in THF, 0.27 mmol). The reaction mixture was stirred for 5 hours at RT. The reaction mixture quenched with methanol (2 mL) at 0? C. and stirred for 10 mins then concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (12 mg, 30 ?mol, 88% yield) as a colourless solid. LC-MS (Method 3) m/z 386.2 (M+H).sup.+, at 2.35 min.

Step 3: 2-(4-fluorophenoxy)-N-(4-(5-(methoxymethyl)thiophen-3-yl)phenyl)-2-methylpropanamide

[0427] To a solution of 2-(4-fluorophenoxy)-N-(4-(5-(hydroxymethyl)thiophen-3-yl)phenyl)-2-methylpropanamide (13 mg, 32 ?mol), N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (41 mg, 0.19 mmol), and 4 ? molecular sieves (420 mg) in DCM (3 mL) at RT was added trimethyloxonium tetrafluoroborate (9.5 mg, 64 ?mol). After 2 h the reaction mixture was filtered through a pad of celite, the filter cake was washed with DCM (30 mL), the combined filtrates were passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (6 mg, 0.01 mmol, 40%, yield) as a colourless oil. LC-MS (Method 3) m/z 400.2 (M+H).sup.+, at 2.69 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.64 (s, 1H), 7.71-7.51 (m, 4H), 7.37 (d, J=1.5 Hz, 1H), 7.31-7.27 (m, 1H), 7.11-6.92 (m, 4H), 4.63 (s, 2H), 3.42 (s, 3H), 1.56 (s, 6H).

Example 124: 2-(4-cyanophenoxy)-2-methyl-N-(4-(morpholinomethyl)-[1,1-biphenyl]-4-yl)propenamide

[0428] ##STR00191##

Step 1: 2-(4-cyanophenoxy)-N-(4-iodophenyl)-2-methylpropanamide

[0429] To a stirred solution of 2-(4-cyanophenoxy)-2-methylpropanoic acid (251 mg, 1.22 mmol) and 4-iodoaniline (295 mg, 1.35 mmol) in dry MeCN (8 mL) under a nitrogen atmosphere was added N-ethyl-N-isopropylpropan-2-amine (0.64 mL, 3.7 mmol) followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (558 mg, 1.47 mmol). The reaction mixture was stirred for hours at 50? C. The reaction mixture was cooled to RT, diluted with DCM (5 mL) and sat. NaHCO.sub.3 (2 mL), stirred for 10 min then passed through a hydrophobic frit. 10 wt % aqueous citric acid (2 mL) was added to the organics, stirred for 10 min, the mixture was passed through a hydrophobic frit and concentrated under reduced pressure to afford a brown oil. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford title amide (455 mg, 90% yield) as a yellow solid; LC-MS (method 3) m/z (M+H).sup.+ at 2.54 min.

Step 2: 2-(4-cyanophenoxy)-2-methyl-N-(4-(morpholinomethyl)-[1,1-biphenyl]-4-yl)propenamide

[0430] Step 1 amide (57 mg, 0.14 mmol), (4-(morpholinomethyl)phenyl)boronic acid (46 mg, 0.21 mmol), potassium carbonate (48 mg, 0.35 mmol) and Pd(dppf)Cl.sub.2 (10 mg, 14 ?mol) were dissolved in dioxane (5 mL) and water (0.5 mL). The reaction mixture was purged with nitrogen and heated to 95? C. for 4 h. The reaction mixture was filtered through Celite and the cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure then purified by reversed phase preparative HPLC on a Waters X-Select CSH C18 ODB prep column, 130 ?, 5 ?m, 30 mm?100 mm, flow rate 40 mL min-1 eluting with a 0.1% formic acid in water-MeCN gradient over 12.5 mins. At-column dilution pump gives 2 mL min-1 MeCN over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 15% MeCN; 0.5-10.5 min, ramped from 15% MeCN to 45% MeCN; 10.5-10.6 min, ramped from 45% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN, to afford title amide (40 mg, 63% yield). LC-MS (method 3) 456.3 (M+H).sup.+ at 1.52 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.28 (s, 1H), 7.68-7.52 (m, 8H), 7.46 (d, J=8.1 Hz, 2H), 7.08-6.99 (m, 2H), 3.87 (dd, J=10.9, 6.2 Hz, 6H), 2.83 (s, 4H), 1.68 (s, 6H).

Example 125: N-(4-(6-(dimethylamino)pyridin-3-yl)phenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0431] ##STR00192##

[0432] N-(4-iodophenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (51 mg, 0.14 mmol), (6-(dimethylamino)pyridin-3-yl)boronic acid (36 mg, 0.22 mmol), potassium carbonate (61 mg, 0.44 mmol), and Pd(dppf)Cl.sub.2 (11 mg, 15 ?mol) were dissolved in dioxane (4.5 mL) and water (1.5 mL). The reaction mixture was purged with nitrogen and heated to 85? C. for 3 h. The reaction mixture was filtered through Celite and the cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 ODB prep column, 130 ?, 5 ?m, 30 mm?100 mm, flow rate 40 mL min-1 eluting with a 0.3% ammonia in water-MeCN gradient over 12.5 mins using At-column dilution pump gives 2 mL min-1 MeCN over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 30% MeCN; 0.5-10.5 min, ramped from 30% MeCN to 60% MeCN; 10.5-10.6 min, ramped from 60% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN to afford title amide (25 mg, 70% yield). LC-MS (method 3) m/z 359.3 (M+H).sup.+ at 1.12 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.46-8.35 (m, 2H), 7.73-7.52 (m, 4H), 7.52-7.39 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.09 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 6.59 (d, J=8.9 Hz, 1H), 3.14 (s, 6H), 2.67 (ddd, J=9.3, 6.0, 3.8 Hz, 1H), 2.29-2.19 (m, 1H), 1.73 (ddd, J=8.9, 5.3, 3.6 Hz, 1H), 1.61 (ddd, J=8.3, 6.0, 3.7 Hz, 1H) [One exchangeable proton not observed].

Example 126: N-(4-(2-(dimethylamino)pyrimidin-5-yl)phenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0433] ##STR00193##

[0434] N-(4-iodophenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (55 mg, 0.15 mmol), (2-(dimethylamino)pyrimidin-5-yl)boronic acid (39 mg, 0.23 mmol), potassium carbonate (66 mg, 0.48 mmol) and Pd(dppf)Cl.sub.2 (12 mg, 16 ?mol) were dissolved in dioxane (4.5 mL) and water (1.5 mL). The reaction mixture was purged with nitrogen and heated to 85? C. for 5 h. The reaction mixture was filtered through Celite, the cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 ODB prep column, 130 ?, 5 ?m, 30 mm?100 mm, flow rate 40 mL min.sup.?1 eluting with a 0.3% ammonia in water-MeCN gradient over 12.5 mins. At-column dilution pump gives 2 mL min.sup.?1 MeCN over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 25% MeCN; 0.5-10.5 min, ramped from 25% MeCN to 55% MeCN; 10.5-10.6 min, ramped from 55% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN to afford title amide (30 mg, 53% yield). LC-MS (method 4) m/z 360.1 (M+H).sup.+ at 2.23 min. .sup.1H NMR (500 MHz, Methanol-d4) ? 8.59 (s, 2H), 8.50-8.41 (m, 1H), 7.79-7.66 (m, 3H), 7.58-7.49 (m, 2H), 7.40 (dt, J=7.9, 1.1 Hz, 1H), 7.24 (ddd, J=7.6, 5.0, 1.1 Hz, 1H), 3.24 (s, 6H), 2.66 (ddd, J=8.9, 6.1, 3.9 Hz, 1H), 2.37 (ddd, J=8.3, 5.4, 3.9 Hz, 1H), 1.74-1.59 (m, 2H) [One exchangeable proton not observed].

Example 127: 1-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)cyclobutane-1-carboxamide

[0435] ##STR00194##

[0436] To a stirred solution of 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (137 mg, 637 ?mol) and 1-(4-fluorophenoxy)cyclobutane-1-carboxylic acid (203 mg, 579 ?mol) in dry MeCN (5 mL) under a nitrogen atmosphere was added N-ethyl-N-isopropylpropan-2-amine (0.505 mL, 2.90 mmol) followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (264 mg, 695 ?mol). The reaction mixture was stirred at 50? C. for 3 hrs and then overnight at room temperature. The reaction was cooled to RT, diluted with DCM (5 mL) and sat. NaHCO.sub.3 (2 mL), stirred for 10 min then passed through a hydrophobic frit. 10 wt % aqueous citric acid (2 mL) was added to the organics, stirred for 10 min, the mixture was passed through a hydrophobic frit and concentrated under reduced pressure to afford a brown oil. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford title amide (200 mg, 81% yield) as a yellow solid. LC-MS (method 3) 406.1 (M+H).sup.+ at 3.04 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 7.93 (s, 1H), 7.66-7.44 (m, 6H), 7.45-7.33 (m, 2H), 7.04-6.90 (m, 2H), 6.78-6.68 (m, 2H), 4.49 (s, 2H), 3.41 (s, 3H), 2.91-2.75 (m, 2H), 2.41-2.35 (m, 2H), 2.13-2.03 (m, 1H), 2.03-1.90 (m, 1H).

Example 128: N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methyl-2-(p-tolyloxy) propenamide

[0437] ##STR00195##

[0438] To a solution of 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (50 mg, 0.23 mmol) and 2-methyl-2-(p-tolyloxy)propanoic acid (50 mg, 0.26 mmol) in DMF (2 mL) at RT was added HATU (98 mg, 0.26 mmol) followed by DIPEA (0.12 mL, 0.70 mmol) and the mixture was stirred at RT for 18 h. The mixture was diluted with DCM (10 mL) and 10 wt % aq. citric acid (10 mL), stirred for 10 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford title amide (74 mg, 81% yield) as a colourless solid. UPLC-MS (method 2) m/z 390.2 (M+H).sup.+ at 1.87 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.08 (s, 1H), 7.83-7.77 (m, 2H), 7.66-7.59 (m, 4H), 7.41-7.35 (m, 2H), 7.12-7.05 (m, 2H), 6.87-6.80 (m, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 2.22 (s, 3H), 1.52 (s, 6H).

Example 129: 1-(4-fluorophenoxy)-N-(4-(morpholinomethyl)-[1,1-biphenyl]-4-yl)cyclo propane-1-carboxamide

[0439] ##STR00196##

[0440] To a solution of 1-(4-fluorophenoxy)-N-(4-iodophenyl)cyclopropane-1-carboxamide (50 mg, 0.13 mmol), (4-(morpholinomethyl)phenyl)boronic acid (42 mg, 0.19 mmol)) and Pd(dppf)Cl.sub.2 (9.2 mg, 13 ?mol) in dioxane (1.5 mL) and water (0.5 mL) was added a 1 M aq. solution of potassium phosphate tribasic (0.38 mL, 0.38 mmol). The mixture was degassed and heated under microwave irradiation for 60 min at 120? C. The reaction mixture was filtered through Celite washing with EtOAc (15 mL). The filtrate was washed with water (10 mL), brine (10 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford brown gum (69 mg). The crude product was purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 ODB prep column, 130 ?, 5 ?m, 30 mm?100 mm, flow rate 40 mL min-1 eluting with a 0.3% ammonia in water-MeCN gradient over 12.5 min. At-column dilution pump gives 2 mL min-1 MeCN over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 45% MeCN; 0.5-10.5 min, ramped from 45% MeCN to 75% MeCN; 10.5-10.6 min, ramped from 75% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN to afford title amide (25 mg, 44% yield) as a beige solid. UPLC-MS (method 2) m/z 447.5 (M+H).sup.+ at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.04 (s, 1H), 7.73-7.66 (m, 2H), 7.60-7.55 (m, 4H), 7.35 (d, J=8.0 Hz, 2H), 7.16 (t, J=8.8 Hz, 2H), 7.04-6.96 (m, 2H), 3.57 (t, J=4.6 Hz, 4H), 3.47 (s, 2H), 2.36 (t, J=4.7 Hz, 4H), 1.58-1.51 (m, 2H), 1.21 (q, J=5.0 Hz, 2H).

Example 130: N-(4-cyclopropoxy-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0441] ##STR00197##

[0442] N-(4-iodophenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (54 mg, 0.15 mmol), (4-cyclopropoxyphenyl)boronic acid (31 mg, 0.18 mmol), Na.sub.2CO.sub.3 (39 mg, 0.37 mmol) and Pd(PPh.sub.3).sub.4 (17 mg, 15 ?mol) were dissolved in dioxane (4.5 mL) and water (1.5 mL). The reaction mixture was purged with nitrogen and heated to 90? C. for 4 h. The reaction mixture was filtered through Celite and the cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford trans racemic title amide (41 mg, 75% yield) as a white solid. LC-MS (method 3) 371.2 (M+H).sup.+ at 1.97 min. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.46 (q, J=1.6 Hz, 1H), 7.72-7.54 (m, 4H), 7.54-7.45 (m, 4H), 7.31 (d, J=7.8 Hz, 1H), 7.17-7.02 (m, 3H), 3.82-3.71 (m, 1H), 2.68 (ddd, J=9.4, 6.0, 3.8 Hz, 1H), 2.27 (dt, J=8.8, 4.8 Hz, 1H), 1.74 (ddd, J=9.0, 5.4, 3.7 Hz, 1H), 1.61 (ddd, J=8.3, 6.0, 3.7 Hz, 1H), 0.80 (d, J=4.5 Hz, 4H).

[0443] The isomers were separated by chiral SFC on a Sepiatec with UV detection by DAD at 220 nm, 40? C., 120 bar. The column was IC 10?250 mm, 5 um, flow rate 20 mL/min at 30% MeOH (neutral), 70% CO.sub.2 to afford Example 130 as the second eluting isomer (24 mg) as a colourless solid; SFC (method X) 4.345 min, 97 ee.

Example 131: 2-(4-fluorophenoxy)-N-(4-(isopropoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0444] ##STR00198##

[0445] 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (50 mg, 0.12 mmol), 2-(4-(isopropoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 0.22 mmol), K.sub.2CO.sub.3 (50 mg, 0.36 mmol) and Pd(PPh.sub.3).sub.4 (14 mg, 12 ?mol), were dissolved in DMF (4 mL) The reaction mixture was purged with nitrogen and heated to 80? C. for 3 h. The reaction mixture was filtered through Celite and the cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford title amide (25 mg, 46% yield) as a white solid. m/z 422.2 (M+H)+ (ES+) at 2.99 min; .sup.1H NMR (500 MHz, Chloroform-d) ? 8.65 (s, 1H), 7.79-7.65 (m, 2H), 7.65-7.49 (m, 4H), 7.48-7.37 (m, 2H), 7.10-6.93 (m, 4H), 4.55 (s, 2H), 3.72 (dt, J=12.2, 6.1 Hz, 1H), 1.57 (s, 6H), 1.32-1.18 (m, 6H).

Example 132: N-(4-(cyclopropoxymethyl)-[1,1-biphenyl]-4-yl)-2-(4-fluorophenoxy)-2-methylpropanamide

[0446] ##STR00199##

[0447] 2-(4-fluorophenoxy)-N-(4-iodophenyl)-2-methylpropanamide (70 mg, 0.17 mmol), 2-(4-(cyclopropoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (81 mg, 0.26 mmol, Na.sub.2CO.sub.3 (46 mg, 0.43 mmol) and Pd(PPh.sub.3).sub.4 (20 mg, 17 ?mol) were dissolved in Dioxane (4.5 mL) and water (1.5 mL). The reaction mixture was purged with nitrogen and heated to 90? C. for 3 h. The reaction mixture was filtered through Celite and the cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford title amide (40 mg, 54% yield) as a white solid; LC-MS (method 3) 420.2 (M+H).sup.+ at 3.02 min. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.66 (s, 1H), 7.75-7.61 (m, 2H), 7.61-7.51 (m, 4H), 7.46-7.36 (m, 2H), 7.07-6.90 (m, 4H), 4.59 (s, 2H), 3.41-3.36 (m, 1H), 1.57 (s, 6H), 0.69-0.65 (m, 2H), 0.59-0.44 (m, 2H).

Examples 133 & 134; N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0448] ##STR00200##

[0449] To a solution of trans-N-(4-iodophenyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (80 mg, 0.22 mmol), 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (87 mg, 0.33 mmol) and Pd(dppfCl.sub.2 (16 mg, 22 ?mol) in dioxane (1.4 mL) was added a 1 M aq, solution of potassium phosphate tribasic (0.66 mL, 0.66 mmol). The mixture was degassed and heated under microwave irradiation for 45 min at 120? C. The reaction mixture was filtered through Celite washing with EtOAc (15 mL). The filtrate was washed with water (10 mL), brine (10 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford a brown solid. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford transracemic title amide (89 mg, 99%) yield as a brown solid. UPLC-MS (method 1) 374.3 (M+H).sup.+ at 1.38 min. The product was separated by chiral SFC on a Sepiatec with UV detection by DAD at 220 nm, 40? C., 120 bar. The column was IH 10?250 mm, 5 um, flow rate 20 mL/min at 40% MeOH (neutral), 60% CO.sub.2 to afford (stereochemistry arbitrarily assigned):

[0450] First eluting isomer: Example 133 trans isomer D1 (14.6 mg, 15% yield) as a colourless solid; LC-MS m/z 374.5 (M+H).sup.+ (ES+) at 1.63 min, 99% purity (diode array). SFC (method Y) 2.07 min, 100 ee.

[0451] Second eluting isomer: Example 134 trans isomer D2 (17.1 mg, 18% yield) as a colourless solid. SFC (method Y) 5.09 min, 97 ee.

Example 135: 2-(4-fluorophenoxy)-N-(3-(4-(methoxymethyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-2-methylpropanamide

[0452] ##STR00201##

Step 1: N-(3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-yl)-2-(4-fluorophenoxy)-2-methylpropanamide

[0453] To a solution of 3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-amine, HCl (80 mg, 0.29 mmol) and 2-(4-fluorophenoxy)-2-methylpropanoic acid (58 mg, 0.29 mmol) in MeCN (5 mL) was added HATU (0.12 g, 0.32 mmol) followed by drop-wise addition of N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.87 mmol) and the mixture was stirred at RT for 18 h. The mixture was diluted with DCM (15 mL) and 1 M aq. citric acid (10 mL), stirred for 15 min, passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford title bromide (118 mg, 0.25 mmol, 84%) as a colourless solid. UPLC-MS (method 1) m/z 440.1/442.1 (M+Na).sup.+ at 1.86 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.75 (d, J=16.4 Hz, 1H), 7.54-7.45 (m, 2H), 7.21-7.16 (m, 2H), 7.13 (td, J=9.2, 8.7, 3.0 Hz, 2H), 6.94 (ddt, J=6.8, 4.6, 2.2 Hz, 2H), 2.26 (s, 6H), 1.38 (d, J=3.4 Hz, 6H).

Step 2: 2-(4-fluorophenoxy)-N-(3-(4-(methoxymethyl)phenyl)bicyclo[1.1.1]pentan-1-yl)-2-methylpropanamide

[0454] To a solution of Step 1 bromide (116 mg, 277 ?mol), trifluoro(methoxymethyl)-14-borane, potassium salt (105 mg, 693 ?mol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (20.3 mg, 27.7 ?mol) in 1,4-dioxane (2.5 mL) was added potassium phosphate, tribasic (177 mg, 832 ?mol). The mixture was degassed for 15 min then heated to 80? C. and stirred for 19 h. The mixture was cooled to RT, trifluoro(methoxymethyl)-14-borane, potassium salt (105 mg, 693 ?mol), potassium phosphate, tribasic (177 mg, 832 ?mol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (20.3 mg, 27.7 ?mol) were added. The mixture was degassed for 15 min then heated to 90? C. and stirred for 19 h. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford a yellow oil (75 mg). The product was further purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 ODB prep column, 130 ?, 5 ?m, 30 mm?100 mm, flow rate 40 mL min-1 eluting with a 0.3% ammonia in water-MeCN gradient over 12.5 mins. At-column dilution pump gives 2 mL min.sup.?1 MeCN over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 35% MeCN; 0.5-15.5 min, ramped from 35% MeCN to 65% MeCN; 15.5-15.6 min, ramped from 65% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN to afford title amide (5.9 mg, 4.2% yield) as a colourless solid. UPLC-MS (method 2) m/z 384.4 (M+H).sup.+ at 1.77 min. .sup.1H NMR (500 MHz, DMSO-d6) ? 8.72 (s, 1H), 7.28-7.18 (m, 4H), 7.13 (td, J=9.0, 2.2 Hz, 2H), 6.94 (ddd, J=9.0, 4.6, 2.1 Hz, 2H), 4.37 (s, 2H), 3.26 (s, 3H), 2.25 (s, 6H), 1.38 (d, J=1.8 Hz, 6H).

Example 137: N-(3-(5-propylpyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0455] ##STR00202## ##STR00203##

[0456] Step 1: 1,3-dioxoisoindolin-2-yl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate: A mixture of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (5.0 g, 22.0 mmol), 2-hydroxyisoindoline-1,3-dione (3.60 g, 22.0 mmol), dicyclohexylcarbodiimide (2.8 g, 22.0 mmol) and DMAP (269 mg, 2.2 mmol) in DCM (50 mL) was stirred at RT for 1 h. The resulting mixture was filtered through celite, concentrated and purified by silica gel chromatography (eluting with 1/10 EtOAc/PE) to afford the title compound (11.8 g, 31.7 mmol, 86% yield) as an off-white solid. UPLC-MS (Method 7) m/z 373.10 (M+H).sup.+ at 1.257 min.

[0457] Step 2: Methyl 6-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)nicotinate: A mixture of Step1 carboxylate (1.74 g, 4.67 mmol), methyl 6-bromonicotinate (500 mg, 2.34 mmol), NiBr.sub.2.DME (360 mg, 1.17 mmol), dtbbpy (470 mg, 1.76 mmol) and Zn powder (913 mg, 14.04 mmol) in DMA (6 mL) was heated at 35? C. in a sealed tube for 16 h. The resulting mixture was filtered through celite, concentrated and purified by silica gel chromatography (eluting with ? EtOAc/PE) to afford the title compound (300 mg, 0.94 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) ? 9.13 (d, J=2.1 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.22 (dd, J=8.1, 2.2 Hz, 1H), 3.93 (s, 3H), 2.41 (s, 6H), 1.47 (s, 9H).

[0458] Step 3: tert-butyl (3-(5-(hydroxymethyl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: To a solution of Step 2 carboxylate (318 mg, 0.94 mmol) in THE (25 mL) at 0? C., was added LAH (72 mg, 1.89 mmol). The reaction mixture was stirred at RT for 2 h, then quenched with NaOH (2 M). The reaction mixture was extracted with EtOAc and the organic layer dried over Na.sub.2SO.sub.4, filtered through celite and concentrated to give the crude product. Purification by Biotage Isolera One (C.sub.18 column, eluting with 10 to 90% MeCN/H.sub.2O) afforded the title compound (200 mg, 0.67 mmol, 71% yield) as a grey oil. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.41 (d, J=2.1 Hz, 1H), 7.63 (dd, J=8.0, 2.2 Hz, 1H), 7.57 (s, 1H), 7.23 (d, J=7.9 Hz, 1H), 5.23 (t, J=5.6 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 2.19 (s, 6H), 1.39 (s, 9H).

[0459] Step 4: tert-butyl (3-(5-formylpyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: A mixture of Step 3 carbamate (670 mg, 2.3 mmol), PCC (750 mg, 3.5 mmol) and silica gel (750 mg) in DCM (20 mL) was stirred at 0? C. for 1 h. The mixture was filtered through celite and then concentrated to give the crude product. Purification by Biotage Isolera One (C.sub.18 column, eluting with 10 to 90% MeCN/H.sub.2O) afforded the title compound (230 mg, 0.80 mmol, 35% yield) as a grey oil. UPLC-MS (Method 7) m/z 289.00 (M?H).sup.? at 0.960 min.

[0460] Step 5: tert-butyl (E)-(3-(5-(prop-1-en-1-yl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: A mixture of ethyltriphenylphosphonium bromide (1.48 g, 4.0 mmol) and tBuOK (448 mg, 4.0 mmol) in THE (10 mL) was stirred at RT for 1 h, then Step 4 carbamate (230 mg, 0.80 mmol) was added. The resulting solution was stirred at RT for 2 h, then filtered through the celite and concentrated to give the crude product. Purification by silica gel chromatography (eluting with ? EtOAc/PE) afforded the title compound (100 mg, 0.33 mmol, 41% yield) as a yellow solid. UPLC-MS (Method 7) m/z 301.00 (M?H).sup.? at 1.649 min.

[0461] Step 6: tert-butyl (3-(5-propylpyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: A mixture of Step 5 carbamate (70 mg, 0.24 mmol) and Pd/C (10%, 25 mg) in dry toluene (6 mL) was stirred at RT for 20 mins under an atmosphere of H.sub.2. The mixture was filtered through celite and the solvent was removed in vacuo to afford the title compound (70 mg, 0.24 mmol, 100% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.31 (d, J=2.2 Hz, 1H), 7.54 (dd, J=7.9, 2.3 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 2.53 (d, J=7.4 Hz, 2H), 2.18 (s, 6H), 1.56 (h, J=7.3 Hz, 2H), 1.40 (s, 9H), 0.88 (t, J=7.3 Hz, 3H).

[0462] Step 7: 3-(5-propylpyridin-2-yl)bicyclo[1.1.1]pentan-1-amine: A mixture of Step 6 carbamate (50 mg, 0.17 mmol) and HCl (4 M in EtOAc, 3 mL) was stirred at RT for 30 mins. The solvent was removed in vacuo to afford the title amine (33 mg, 0.16 mmol, 94% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (Method 7) m/z 203.00 (M?H).sup.? at 0.488 min.

[0463] Step 8: N-(3-(5-propylpyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide: A mixture of Step 7 amine (33 mg, 0.16 mmol), (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (28 mg, 0.17 mmol), HATU (80 mg, 0.21 mmol) and DIPEA (62 mg, 0.48 mmol) in DCM (3 mL) was stirred at RT for 30 mins. The solvent was removed in vacuo to give the crude product, which was purified by prep-HPLC to obtained the title compound (9.6 mg, 0.027 mmol, 17% yield) as a white solid. UPLC-MS (Method 7) m/z 348.00 (M+H).sup.+ at 0.835 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.80 (s, 1H), 8.42 (d, J=4.1 Hz, 1H), 8.32 (s, 1H), 7.66 (td, J=7.7, 1.7 Hz, 1H), 7.58-7.51 (m, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.24-7.13 (m, 2H), 2.53 (d, J=7.3 Hz, 2H), 2.43 (td, J=7.5, 3.9 Hz, 1H), 2.26 (s, 6H), 2.08 (s, 1H), 1.56 (q, J=7.4 Hz, 2H), 1.38-1.30 (m, 2H), 0.87 (t, J=7.3 Hz, 3H).

Example 136; N-(3-(5-(methoxymethyl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0464] ##STR00204##

[0465] Step 1: (6-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)pyridin-3-yl)methyl methanesulfonate: To a solution of Example 137 Step 3 carbamate (300 mg, 1.0 mmol) and TEA (210 mg, 2.0 mmol) in DCM (15 mL) at 0? C., was added MsCl (180 mg, 1.6 mmol) and the reaction solution was stirred at RT for 30 mins. The resulting mixture was concentrated to afford the crude product (300 mg, 0.81 mmol, 81% yield) as a brown oil, which was used in the next step without further purification.

[0466] Step 2: tert-butyl (3-(5-(methoxymethyl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: To a solution of Step 1 methanesulfonate (300 mg, 0.81 mmol) in THE (15 mL) at 0? C., was added MeONa (5.4 M in MeOH, 1 mL, 5.2 mmol). The reaction solution was stirred at RT for 1 h. The resulting mixture was concentrated and then purified by Biotage Isolera One (C.sub.1, column, eluting with 10 to 90% MeCN/H.sub.2O) to afford the title compound (210 mg, 0.69 mmol, 85% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.43 (d, J=2.1 Hz, 1H), 7.66 (dd, J=7.9, 2.2 Hz, 1H), 7.59 (s, 1H), 7.31-7.23 (m, 1H), 4.41 (s, 2H), 3.29 (s, 3H), 2.21 (s, 6H), 1.41 (s, 9H).

[0467] Step 3: 3-(5-(methoxymethyl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-amine: Prepared according to the method of step 7 of Example 137

[0468] Step 4: N-(3-(5-(methoxymethyl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide: Prepared according to the method of Step 8 of Example 137 using Step 3 amine and (rac-trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid. UPLC-MS (Method 5) m/z 350.00 (M+H).sup.+ at 0.639 min. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.82 (s, 1H), 8.42 (t, J=3.0 Hz, 2H), 7.66 (dtd, J=7.6, 3.5, 1.9 Hz, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.17 (ddd, J=7.5, 4.8, 1.1 Hz, 1H), 4.41 (s, 2H), 3.28 (s, 3H), 2.46-2.40 (m, 1H), 2.28 (s, 6H), 2.13-2.04 (m, 1H), 1.39-1.30 (m, 2H).

Example 138; 2-((5-fluoropyridin-2-yl)oxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0469] ##STR00205## ##STR00206##

[0470] Step 1: 4-(methoxymethyl)-[1,1-biphenyl]-4-amine: A mixture of 1-bromo-4-(methoxymethyl)benzene (1.0 g, 4.98 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.6 g, 7.46 mmol), K.sub.3PO.sub.4 (2.1 g, 9.95 mmol) and Pd(dppf)Cl.sub.2 (0.36 g, 0.49 mmol) in dioxane/H.sub.2O (v/v=10:1) (20 mL) was heated at 110? C. in a sealed tube for 16 h. The resulting mixture was filtered through celite, concentrated and purified by silica gel chromatography (eluting with ? EtOAc/PE) to afford the title compound (1.02 g, 4.78 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d.sub.6) ? 7.56-7.49 (m, 2H), 7.41-7.28 (m, 4H), 6.69-6.61 (m, 2H), 5.35 (s, 2H), 4.41 (s, 2H), 3.30 (s, 3H).

[0471] Step 2: benzyl 2-hydroxypropanoate: A mixture of (bromomethyl)benzene (10.0 g, 58.47 mmol), 2-hydroxypropanoic acid (5.79 g, 64.3 mmol) and Cs.sub.2CO.sub.3 (19.0 g, 58.47 mmol) in DMF (120 mL) was stirred at RT for 16 hours. The reaction mixture was filtered through celite, concentrated and purified by Biotage Isolera One (C.sub.18 column, eluting with 10 to 90% MeCN/H.sub.2O) to afford the title compound (4.37 g, 24.2 mmol, 41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d.sub.6) ? 7.39 (s, 3H), 7.45-7.31 (m, 2H), 5.47 (d, J=5.8 Hz, 1H), 5.15 (s, 2H), 4.28-4.16 (m, 1H), 1.29 (d, J=6.9 Hz, 3H).

[0472] Step 3: Benzyl 2-((5-fluoropyridin-2-yl)oxy)propanoate: To a solution of Step 2 alcohol (2.16 g, 12.0 mmol), 5-fluoropyridin-2-ol (1.33 g, 10.0 mmol) and PPh.sub.3 (3.93 g, 15.0 mmom) in THF (25 mL) at 0? C., was added DEAD (2.61 g, 15.0 mmol) under atmosphere of N.sub.2. The solution was stirred at RT for 1 h and then the solvent was removed in vacuo to give the crude product. Purification by Biotage Isolera One (C.sub.18 column, eluting with 10 to 90% MeCN/H.sub.2O) afforded the title compound (1.45 g, 5.27 mmol, 53% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.01 (d, J=3.1 Hz, 1H), 7.71 (ddd, J=9.1, 8.0, 3.1 Hz, 1H), 7.34 (dq, J=6.6, 5.6, 4.8 Hz, 3H), 7.27 (dd, J=7.7, 1.8 Hz, 2H), 6.95 (dd, J=9.1, 3.6 Hz, 1H), 5.23 (q, J=7.0 Hz, 1H), 5.14 (s, 2H), 1.52 (d, J=7.0 Hz, 3H).

[0473] Step 4: Benzyl 2-((5-fluoropyridin-2-yl)oxy)-2-methylpropanoate: To a solution of Step 3 ester (400.0 mg, 1.45 mmol) in dry THF (6 mL) at ?78? C., was added NaHMDS (2.0 M in hexane, 1.45 mL, 2.91 mmol) dropwise over 10 min. The resulting solution was stirred at ?78? C. for 30 min then Mel (206.5 mg, 1.45 mmol) was added dropwise over 5 min. The resulting solution was warmed to ?20? C. for 1 h, then quenched with saturated NH.sub.4Cl solution, extracted with EtOAc and concentrated. The crude product was purified by silica gel chromatography (eluting with ? EtOAc/PE) to afford the title compound (145 mg, 0.5 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d.sub.6) ? 7.89 (d, J=3.1 Hz, 1H), 7.75-7.65 (m, 1H), 7.34 (dd, J=5.1, 1.9 Hz, 3H), 7.19 (dd, J=6.8, 2.8 Hz, 2H), 6.89 (dd, J=9.1, 3.6 Hz, 1H), 5.10 (s, 2H), 1.64 (s, 6H).

[0474] Step 5: 2-((5-fluoropyridin-2-yl)oxy)-2-methylpropanoic acid: A mixture of Step 4 ester (445 mg, 1.54 mmol), Pd/C (133 mg, 10%) and methanol (10 mL) was stirred at RT for 1 h under an atmosphere of H.sub.2. The resulting mixture was filtered through celite, concentrated and purified by silica gel chromatography (eluting with 1/10 EtOAc/PE) to afford the title compound (303 mg, 1.52 mmol, 98% yield) as a yellow soild. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.11 (d, J=3.1 Hz, 1H), 7.77-7.67 (m, 1H), 6.89 (dd, J=9.1, 3.6 Hz, 1H), 1.63 (s, 6H).

[0475] Step 6: 2-((5-fluoropyridin-2-yl)oxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide: To a solution of Step 5 acid (145 mg, 0.73 mmol), Step 1 amine (155 mg, 0.73 mmol) and DIPEA (195.5 mg, 1.46 mmol) in DCM (5 mL) at RT, was added HATU (416 mg, 1.10 mmol). The reaction solution was stirred at RT for 16 h, then concentrated to give the crude product. Purification by Biotage Isolera One (C.sub.18 column, eluting with 10 to 90% MeCN/H.sub.2O) afforded the title compound (182 mg, 0.46 mmol, 63% yield) as a yellow solid. UPLC-MS (Method 5) m/z 495.15 (M+H).sup.+ at 0.967 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.64 (s, 1H), 8.05 (d, J=3.0 Hz, 1H), 7.73-7.64 (m, 3H), 7.58 (dd, J=15.5, 8.4 Hz, 4H), 7.36 (d, J=8.1 Hz, 2H), 6.96 (dd, J=9.1, 3.5 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.66 (s, 6H).

Example 139; N-(2-cyanoethyl)-2-(4-fluorophenoxy)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-methylpropanamide

[0476] ##STR00207##

Example 140; N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-methyl-2-(pyridin-2-yloxy)propanamide

[0477] ##STR00208##

[0478] Prepared from 4-(6-ethoxypyridin-3-yl)aniline and 2-methyl-2-(pyridin-2-yloxy)propanoic acid following details for Example 138 Step 6 to give title compound. UPLC-MS (Method 5) m/z 378.10 (M+H).sup.+ at 1.967 min. 1H NMR (400 MHz, DMSO-d.sub.6) ? 9.61 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.04 (dd, J=5.0, 1.8 Hz, 1H), 7.94 (dd, J=8.6, 2.6 Hz, 1H), 7.74-7.63 (m, 3H), 7.53 (d, J=8.5 Hz, 2H), 6.95-6.88 (m, 2H), 6.84 (d, J=8.6 Hz, 1H), 4.32 (q, J=7.0 Hz, 2H), 1.66 (s, 6H), 1.32 (t, J=7.1 Hz, 3H).

Example 141; N-(2-hydroxy-2-methylpropyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (Trans D1)

[0479] ##STR00209##

[0480] Step 1: 1-((4-(methoxymethyl)-[1,1-biphenyl]-4-yl)amino)-2-methylpropan-2-ol: To a solution of 2,2-dimethyloxirane (672.2 mg, 9.38 mmol) in Et.sub.2O (20 mL) at 0? C., was added LiClO.sub.4 (2.99 g, 28.13 mmol).

[0481] The solution was stirred at RT for 15 mins, then 4-(methoxymethyl)-[1,1-biphenyl]-4-amine (1.0 g, 4.69 mmol) was added and the resulting solution was stirred at RT for 16 h. The reaction mixture was concentrated and the crude product was purified by Biotage Isolera One (C.sub.18 column, eluting with 10 to 90% MeCN/H.sub.2O) to afford the title compound (735 mg, 2.57 mmol, 55% yield) as a yellow solid. UPLC-MS (Method 7) m/z 286.00 (M+H).sup.+ at 1.612 min.

[0482] Step 2: N-(2-hydroxy-2-methylpropyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide: Prepared according to the method of Example 138 Step 6 using Step 1 amine and 2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (trans diastereoisomer 1); UPLC-MS (Method 5) m/z 431.10 (M+H).sup.+ at 1.400 min. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.25 (s, 1H), 7.61 (dt, J=20.4, 9.9 Hz, 5H), 7.39 (d, J=7.9 Hz, 5H), 7.11 (s, 1H), 4.44 (s, 2H), 3.77 (q, J=14.3 Hz, 2H), 3.31 (s, 3H), 2.55 (s, 1H), 1.90 (s, 1H), 1.48 (s, 1H), 1.32 (s, 1H), 1.05 (s, 6H).

Example 142; N-(2-hydroxy-2-methylpropyl)-N-(4-(methoxymethyl)-[1,1-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide (Trans D2)

[0483] Prepared as detailed for Example 141 using 2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (trans diastereoisomer 2); UPLC-MS (Method 5) m/z 431.15 (M+H).sup.+ at 1.400 min. 1H NMR (400 MHz, DMSO-d.sub.6) ? 8.41 (s, 1H), 7.89 (s, 1H), 7.60 (d, J=7.8 Hz, 4H), 7.50-7.28 (m, 6H), 4.44 (s, 2H), 3.86-3.69 (m, 2H), 3.31 (s, 3H), 2.65 (d, J=9.8 Hz, 1H), 1.94 (s, 1H), 1.50 (d, J=5.9 Hz, 2H), 1.05 (d, J=4.5 Hz, 6H).

[0484] ADME Properties Testing Procedures

[0485] (i) Plasma Stability (Human, mouse and/or Rat)

[0486] To quantify the degradation of the test compound in plasma over a 1 hour period. The percent of parent compound present at 0, 30 and 60 mins after initiating incubations in plasma is determined. Compounds were taken from 10 mM DMSO stock solutions and added to plasma, which had previously been incubated at 37? C., to give a final concentration of 25 ?M and re-incubated. Aliquots were removed at the appropriate timepoints and quenched with an equal volume of cold acetonitrile. After mixing vigorously, the precipitated protein matter was removed by filtration (Multiscreen Solvinert filter plates, Millipore, Bedford, MA, USA) and the filtrate analysed by reverse phase HPLC with mass spectrometric detection, using single ion monitoring of the [M+H].sup.+ species. Metabolic turnover was determined by comparison of peak areas from the ion chromatograms of the parent before and after incubation and expressed as percent remaining at each timepoint.

[0487] (ii) Microsomal Metabolic Stability (Human, Mouse or Rat)

[0488] Test compound (3 ?M) is incubated with pooled liver microsomes. Test compound is incubated at 5 time points over the course of a 45 min experiment and the test compound is analysed by LC-MS/MS. An intrinsic clearance value (CL.sub.int) with standard error and t % value are calculated.

[0489] Microsomes (final protein concentration 0.5 mg/mL), 0.1M phosphate buffer pH7.4 and test compound (final substrate concentration 3 ?M; final DMSO concentration 0.25%) are pre-incubated at 37 C prior to the addition of NADPH (final concentration 1 mM) to initiate the reaction. The final incubation volume is 50 ?L. A minus cofactor control incubation is included for each compound tested where 0.1 M phosphate buffer pH7.4 is added instead of NADPH (minus NADPH). Two control compounds are included with each species. All incubations are performed singularly for each test compound. Each compound is incubated for 0, 5, 15, 30 and 45 min. The control (minus NADPH) is incubated for 45 min only. The reactions are stopped by transferring 20 ?L of incubate to 60 ?L methanol at the appropriate time points. The termination plates are centrifuged at 2,500 rpm for 20 min at 4 C to precipitate the protein. Following protein precipitation, the sample supernatants are combined in cassettes of up to 4 compounds and analysed using generic LC-MS/MS conditions. From a plot of In peak area ratio (compound peak area/internal standard peak area) against time, the gradient of the line is determined. Subsequently, half-life and intrinsic clearance are calculated using the equations below:

[00001]$\mathrm{Elimination}\mathrm{rate}\mathrm{constant}\left(k\right)=\left(-\mathrm{gradient}\right)$$\mathrm{Half}-\mathrm{life}\left(t_{1/2}\right)\left(\min \right)=\frac{0.693}{k}$$\mathrm{Intrinsic}\mathrm{clearance}\left({\mathrm{CL}}_{int}\right)\left(\mathrm{.Math.L}/\min /\mathrm{mg}\mathrm{protein}\right)=\frac{V?0.693}{t_{1/2}}$$\mathrm{where}$$V=\mathrm{Incubation}\mathrm{volume}\left(\mathrm{.Math.L}\right)/\mathrm{Microsomal}\mathrm{protein}\left(\mathrm{mg}\right)$

[0490] Relevant control compounds are assessed, ensuring intrinsic clearance values fall within the specified limits.

[0491] (iii) Hepatocyte Stability (Human, Mouse, Rat or Dog)

[0492] Test compound (3 ?M) is incubated with cryopreserved hepatocytes in suspension. Samples are removed at 6 time points over the course of a 60 min experiment and test compound is analysed by LC-MS/MS. An intrinsic clearance value (CL.sub.int) with standard error and half-life (t %) are calculated. Cryopreserved pooled hepatocytes are stored in liquid nitrogen prior to use. Williams E media supplemented with 2 mM L-glutamine and 25 mM HEPES and test compound (final substrate concentration 3 ?M; final DMSO concentration 0.25%) are pre-incubated at 37 C prior to the addition of a suspension of cryopreserved hepatocytes (final cell density 0.5?10.sup.6 viable cells/mL in Williams E media supplemented with 2 mM L-glutamine and 25 mM HEPES) to initiate the reaction. The final incubation volume is 500 ?L. A control incubation is included for each compound tested where lysed cells are added instead of viable cells. Two control compounds are included with each species.

[0493] The reactions are stopped by transferring 50 ?L of incubate to 100 ?L methanol containing internal standard at the appropriate time points. The control (lysed cells) is incubated for 60 min only. The termination plates are centrifuged at 2500 rpm at 4? C. for 30 min to precipitate the protein. Following protein precipitation, the sample supernatants are combined in cassettes of up to 4 compounds and analysed using generic LC-MS/MS conditions. From a plot of In peak area ratio (compound peak area/internal standard peak area) against time, the gradient of the line is determined. Subsequently, half-life (t %) and intrinsic clearance (CL.sub.int) are calculated using the equations below:

[00002]$\mathrm{Elimination}\mathrm{rate}\mathrm{constant}\left(k\right)=\left(-\mathrm{gradient}\right)$$\mathrm{Half}-\mathrm{life}\left(t_{1/2}\right)\left(\min \right)=\frac{0.693}{k}$$\mathrm{Intrinsic}\mathrm{clearance}\left({\mathrm{CL}}_{int}\right)\left(\mathrm{.Math.L}/\min /\mathrm{million}\mathrm{cells}\right)=\frac{V?0.693}{t_{1/2}}$$\mathrm{where}$$V=\mathrm{Incubation}\mathrm{volume}\left(\mathrm{.Math.L}\right)/\mathrm{Number}\mathrm{of}\mathrm{cells}$

[0494] Two control compounds for each species are included in the assay and if the values for these compounds are not within the specified limits the results are rejected and the experiment repeated.

[0495] Compounds of the invention are compared to the stability of literature comparison 1; RTI-13951-33 (e.g. see Jin, C et al, J. Med. Chem. 61, 6748-6758, 2018 and references cited therein), Table 1.

##STR00210##

TABLE-US-00012 TABLE 1 Mouse hepatocyte stability data Example Mouse heps Clint (?L/min/10.sup.6 cells) Literature comparison 1 176 (1) 65 (2) 54 (3) 30 (4) 51 (7) 46 (8) 55 (9) 39 (13) 90 (17) 37 (18) 70 (25) 41 (26) 70 (31) 76 (32) 65 (35) 49 (36) 80 (53) 71 (68) 37 (70) 74 (76) 30 (85) 14 (87) 31 (92) 47 (111) 22 (121) 30

[0496] (v) Log D Determinations:

[0497] Log D.sub.(PBS) determinations were performed in 96 well microtitre plates using a miniaturised shake-flask method. In brief, compounds were taken from 10 mM DMSO stock solutions and added to wells containing equal volumes of phosphate buffered saline (10 mM; pH 7.4) (PBS) and 1-octanol (Sigma-Aldrich, Poole, Dorset, UK) to give a final concentration of 50 ?M. The plates were then capped and mixed vigorously for 1 hour on a microtitre plate shaker, after which they were left to stand, allowing the PBS and octanol phases to separate. The PBS layer was analysed by reverse phase HPLC with mass spectrometric detection, using single ion monitoring of the [M+H].sup.+ species. Log D.sub.(PBS) was determined by comparison of the peak area from the ion chromatogram of the compound in the PBS phase with that of a 50 ?M standard of the same compound dissolved in acetonitrile/water (50:50) and calculated using the following formula:

[00003]$\mathrm{Log}D=\mathrm{Log}\left[\frac{\mathrm{AUCstd}-\mathrm{AUCpbs}}{\mathrm{AUCpbs}}\right]$

[0498] Where AUCstd and AUCpbs are the peak areas from the standard and test ion chromatograms respectively. Log D.sub.(PBS) determinations were also made using PBS at pH6.9 and 5.5 by adjusting the pH of the buffer prior to the start of the assay, with 0.1 M HCl

[0499] Biological Investigations

[0500] The following assays can be used to illustrate the commercial utilities of the compounds according to the present invention.

[0501] Biological Assay 1: hGPR88-HEK cAMP Accumulation Assay

[0502] To evaluate the agonist activity of compounds at the hGPR88 receptor, test compounds are dispensed into 384-well white shallow well ProxiPlate assay plates (Perkin Elmer 6008280) using ECHO acoustic dispensing with DMSO backfill. Forskolin, prepared in KRH assay buffer (5 mM KCl, 1.25 mM MgSO.sub.4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH.sub.2PO.sub.4, 1.45 mM CaCl.sub.2 freshly supplemented with 0.05% (w/v) BSA and 0.5 mM IBMX), is dispensed into wells containing test compounds using Thermo Scientific? Multidrop? Combi Reagent Dispenser in 5 ?l volume to provide a final assay concentration of 200 nM (EC.sub.90). Cryopreserved vials of HEK-293 cells expressing human recombinant GPR88 receptor are re-suspended in KRH assay buffer and 5 ?l of cell solution is suspended in test wells at a seeding density of 2500?500 cells per well using the multidrop to provide a final reaction volume of 10 ?l containing 0.5% DMSO. Assay plate is incubated for 30 min at room temperature and the reaction is terminated by addition of 5 ?l of each of the cAMP detection reagents of the cAMP Gi kit (Cisbio Bioassays, 62AM9PEJ), diluted in cell lysis buffer, to each well using the multidrop in the following order: first the cAMP-d.sub.2 conjugate, then the anti-cAMP cryptate conjugate. The plate is further incubated for 1 hour at room temperature before reading the fluorescence emission ratio (665 nm/620 nm) on PHERAstar? FSX (BMG Labtech). Raw counts were converted to cAMP concentrations via a standard curve before EC.sub.50 and E.sub.max determination. Data is expressed as % decrease in forskolin stimulated cAMP compared to cells treated with vehicle alone in the same buffer and on the same plate.

[0503] Supplementary Information

[0504] Cloning of the GPR88 Receptor Gene:

[0505] The coding region encoding the GPR88 receptor was cloned in pEFIN3, a proprietary bicistronic expression vector developed at EPICS, in which the transcription of both the receptor and the gene of selection (neomycin) are under the control of a strong promoter of transcription through an IRES (internal ribosome entry site) sequence (Ghattas et al., 1991, Mol. Cell. Biol. 11, 5848-5859).

[0506] Cell Line Development

[0507] EPICS's proprietary bicistronic expression plasmids containing the coding sequence of the human GPR88 receptor was transfected, using Lipofectamine 2000, in HEK293 cells. After selection with antibiotics, the mix of antibiotic-resistant cells has been frozen and further used in a cAMP assay using 2-PCCA as reference agonist.

[0508] Preparation of Cryovials

[0509] GPR88-HEK cells were grown in standard TC conditions with the supplier's recommended media (EMEM, 10% FBS, 100 IU/ml penicillin, 100 ?g/ml streptomycin, 100 ?g/ml GeneticinGibco ref 10131-027). Cells were harvested between 50-80% confluency by washing flasks once with PBS, then detaching cells with a 10-15 min incubation with Versene (5 mL per 225 cm2 flask). Detached cells were harvested using 5 mL media (without G418) per flask and dissociated by pipetting aggressively against the wall of the flask 10-15 times. Cells were visually inspected under a microscope to ensure adequate dissociation. Cells were counted using AOPI stain, centrifuged at 300?g for 5 min, then resuspended in freezing media (90% media without G418, 10% DMSO) for a final concentration of 2.5?10.sup.6 live cells/mL. Cells were frozen in 0.5 and 1 mL aliquots using a cell freezing container in a ?80? C. freezer overnight. Cells were then stored at ?80? C. until required.

[0510] The results for selected compounds according to the invention are shown in Table 2. The skilled person will realise that the assays described herein exhibit some variability. The variability arises due to the fact that the assay is a cell-based assay (involving batches of cells being thawed for each assay run). The inter assay variability might range by an amount of +/?30%. For that reason, the activity of the compounds is quoted in High/Medium/Low bands rather than as precise results.

TABLE-US-00013 TABLE 2 GRP88 agonist activity (EC.sub.50) wherein High (<1000 nM), Medium (1000 nM to 5000 nM); Low (>5000 nM). In this assay, literature comparison 1 (RTI-13951-33) exhibited a value of 420 nM (lit value e.g. see Jin, C et al, J. Med. Chem. 61, 6748-6758, 2018 and references cited therein is 25 nM). 1 High 2 High 3 High 4 High 5 Low 6 Low 7 Medium 8 High 9 Medium 10 Low 11 Low 12 Low 13 Medium 14 Medium 15 Medium 16 Low 17 Medium 18 High 19 Low 20 Low 21 Low 22 Medium 23 Low 24 Low 25 High 26 High 27 Medium 28 High 29 Medium 30 Medium 31 High 32 Medium 33 Medium 34 Medium 35 High 36 Medium 37 Medium 38 Low 39 Medium 40 Medium 41 Low 42 Low 43 Low 44 Medium 45 Medium 46 High 47 Medium 48 Low 49 High 50 Medium 51 Low 52 Low 53 High 54 Low 55 High 56 Medium 57 High 58 High 59 High 60 High 61 Low 62 High 63 High 64 High 65 High 66 High 67 High 68 High 69 Low 70 High 71 Low 72 Medium 73 Low 74 Low 75 Medium 76 Medium 77 Medium 78 Medium 79 High 80 Medium 81 High 82 Low 83 Medium 84 Low 85 High 86 High 87 High 88 Medium 89 High 90 Medium 91 Medium 92 High 93 Low 94 Medium 95 Medium 96 Low 97 Medium 98 Medium 99 Medium 100 Medium 101 Medium 102 Medium 103 Medium 104 Medium 105 Medium 106 Medium 107 Medium 108 Medium 109 Medium 110 Medium 111 Medium 112 Low 113 Medium 114 Medium 115 High 116 Medium 117 Medium 118 Low 119 Medium 120 Medium 121 Medium 122 Medium 123 High 124 High 125 Low 126 Low 127 High 128 High 129 High 130 Low 131 Low 132 Medium 133 Medium 134 Low 135 Medium 136 Low 137 Medium 138 Medium 139 Low 140 Medium 141 Low 142 Low

[0511] Biological Assay 2: Dopamine Transporter Uptake Assay

[0512] Evaluation of the inhibition of dopamine uptake transporter with 10 M compound is determined in rat striatum synaptosomes following [.sup.3H]dopamine scintillation counting (see Janowsky, A. et al. J. Neurochem., 46, 1272-1276, 1986). Compounds of the invention are compared to the literature comparison 1; RTI-13951-33 and literature comparison 2; 2-PCCA (e.g. see Jin, C et al, J. Med. Chem. 61, 6748-6758, 2018 and references cited therein), Table 3,

##STR00211##

TABLE-US-00014 TABLE 3 Table 3. Off-target selectivity screening vs rat DAT Inhibition of dopamine uptake transporter Example (% inhibition at 10 ?M compound) Literature comparative 1 70 Literature comparative 2 90 (1) 11 (2) 3 (18) 0 (26) 7 (31) 52 (45) 28 (49) 0 (75) 5 (76) 7 (78) 17 (79) 21 (85) 12 (87) 1 (111) 14 (135) 8 (136) 2 (137) 10