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TETRAHYDROISOQUINOLINE DERIVED PRMT5-INHIBITORS

20170298075 · 2017-10-19

    Inventors

    Cpc classification

    International classification

    Abstract

    A compound of formula I wherein: n is 1 or 2: p is 0 or 1; R.sup.1 is optionally one or more halo or methyl groups; R.sup.2a and R.sup.2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.2c and R.sup.2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.3a and R.sup.3b are independently selected from H and Me; R.sup.4 is either H or Me; R.sup.5 is either H or Me; R.sup.6a and R.sup.6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C.sub.5-12 heteroaryl.

    ##STR00001##

    Claims

    1. A compound of formula I: ##STR00246## wherein: n is 1 or 2; p is 0 or 1; R.sup.1 is optionally one or more halo or methyl groups; R.sup.2a and R.sup.2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.2c and R.sup.2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.3a and R.sup.3b are independently selected from H and Me; R.sup.4 is either H or Me; R.sup.5 is either H or Me; R.sup.6a and R.sup.6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C.sub.5-12 heteroaryl.

    2-6. (canceled)

    7. A compound according to claim 1, wherein R.sup.1 represents one to four Me or halo groups.

    8. A compound according to claim 1, wherein: (a) R.sup.2a, R.sup.2b, R.sup.2c and R.sup.2d are all H; or (b) R.sup.2a, R.sup.2b, R.sup.2c and R.sup.2d are comprised of three H and one Me or CH.sub.2OH group; or (c) R.sup.2a, R.sup.2b, R.sup.2c and R.sup.2d are comprised of two H and two Me groups.

    9-15. (canceled)

    16. A compound according to claim 1, wherein: (a) R.sup.3a is H and R.sup.3b is Me; or (b) R.sup.3a and R.sup.3b are both H; or (c) R.sup.3a and R.sup.3b are both Me.

    17-22. (canceled)

    23. A compound according to claim 1, wherein: (a) R.sup.6a is H and R.sup.6b is Me; or (b) R.sup.6a and R.sup.6b are both H; or (c) R.sup.6a and R.sup.6b are both Me.

    24-25. (canceled)

    26. A compound according to claim 1 which is of: ##STR00247##

    27-28. (canceled)

    29. A compound according to claim 1, which is a racemate at the carbon atom to which OH is attached.

    30. A compound according to claim 1, which is a single enantiomer at the carbon atom to which OH is attached.

    31-34. (canceled)

    35. A compound according to claim 1 wherein the optional substituents on A are independently selected from the group consisting of: C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, C.sub.3-6 cycloalkyl, C.sub.5-6 heteroaryl, C.sub.5-6 heteroaryl methyl, C.sub.4-6 heterocyclyl, C.sub.4-6 heterocyclyl methyl, phenyl, benzyl, halo, amido, amidomethyl, acylamido, acylamidomethyl, C.sub.1-4 alkyl ester, C.sub.1-4 alkyl ester methyl, C.sub.1-4 alkyl carbamoyl, C.sub.1-4 alkyl carbamoyl methyl, C.sub.1-4 alkylacyl, C.sub.1-4 alkylacyl methyl, phenylcarbonyl, carboxy, carboxymethyl, ether, amino, aminomethyl, sulfonamido, sulfonamino, sulfone, sulfoxide, nitrile and nitrilemethyl and when A is phenyl, the optional substituent may also be a fused C.sub.5-6 N.sub.1-containing heterocyclic ring.

    36. A compound according to claim 1, wherein A is optionally substituted phenyl, wherein the substituents are selected from: C.sub.1-4 alkyl, fluoro, chloro, bromo, acetyl, methoxy, ethoxy, —C(═O)Me, —C(═O)Et, —CH.sub.2C(═O)Me, phenyl, —CF.sub.3, —CF.sub.2H, —CN, —CH.sub.2CN, —OBn, —OPh, —OCF.sub.3, —OCF.sub.2H, —O—(C.sub.6H.sub.4)—CN, —COOH, —CH.sub.2COOH, —C(═O)OMe, —C(═O)NH.sub.2, —C(═O)NMeH, —C(═O)NMe.sub.2, —C(═O)N.sup.iPrH, —C(═O)-piperidinyl, —C(═O)-pyrrolidinyl, —C(═O)-morpholino (which may be bridged or substituted with one or two methyl groups), —C(═O)-azetidinyl, —CH.sub.2C(═O)NH.sub.2, —CH.sub.2C(═O)-azetidinyl, —CH.sub.2C(═O)NMeH, —CH.sub.2C(═O)N.sup.iPrH, —CH.sub.2C(═O)-pyrrolidinyl, —CH.sub.2C(═O)-morpholino, —CH.sub.2-morpholino, —CH.sub.2-methylpiperazinyl, —OCH.sub.2pyridinyl, —OCH.sub.2-methyloxadiazolyl, —CH.sub.2-imidazolyl, —O-tetrahydropyranyl, —CH.sub.2-tetraydropyanyl, —NH-methylpyrazinyl, —CH.sub.2-triazolyl, —NHSO.sub.2Ph, —NHSO.sub.2Me, —SO.sub.2NMePh, —SO.sub.2NMe.sub.2, —SONHEt, —SO.sub.2CF.sub.3, -γ-lactam, —CH.sub.2NHC(═O)Me, —CH.sub.2NHC(═O)OMe, —CH.sub.2NHC(═O)CF.sub.3, morpholino, —CH.sub.2NH.sub.2, —C(═O)Ph, —OCH.sub.2-isoxazolyl, —NH-pyrimidinyl, pyridizinyl, pyrimidinyl, pyridinyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, pyrazinyl, pyridazinyl, methyloxadiazolyl, oxadiazolyl, dimethyloxadiazolyl, isoxazolyl, dimethyltriazolyl, imidazolyl, benzimidazolyl and thiadiazolyl.

    37-42. (canceled)

    43. A compound according to claim 36, wherein: (a) in the ortho position of the phenyl group there is a halo, C.sub.1-4 alkyl, methoxy or ethoxy substituent; or (b) in the meta position of the phenyl group there is a C.sub.1-4 alkyl or C.sub.5-6 heteroaryl substituent; or (c) in the para position of the phenyl group there is an amido or amidomethyl substituent; or (d) the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group; or (e) the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group; or (f) in the meta position of the phenyl group there is an amino substituent.

    44-48. (canceled)

    49. A compound according to claim 1, wherein A is: (a) optionally substituted naphthyl, or (b) optionally substituted C.sub.5-12 heteroaryl selected from the group consisting of: pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridonyl, imidazolyl, benzimidazolyl, imidazopyridinyl and quinolinyl.

    50-65. (canceled)

    66. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00248##

    67. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00249##

    68. A compound according to claim 67, wherein A is selected from one of the following groups: ##STR00250##

    69. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00251##

    70. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00252## ##STR00253## ##STR00254##

    71. A compound according to claim 1, wherein A is selected from phenyl with a para-amido substituent; phenyl with a para-amido substituent, and an ortho-ethoxy group; pyridyl with para ether or amino group, where the ether or amino substituent is a C.sub.5-6 heterocyclic group, with an optional ortho-ethoxy group; and pyridyl with a meta ether group, where the pyridyl N is in the para position.

    72. (canceled)

    73. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

    74. A method of treatment of cancer, comprising administering to a patient in need of treatment, a compound according to a composition according to claim 73.

    75-76. (canceled)

    77. A method of treatment of hemoglobinopathies, comprising administering to a patient in need of treatment, a compound according to a pharmaceutical composition according to claim 73.

    78-79. (canceled)

    Description

    EXAMPLES

    [0365] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

    [0366] Acronyms

    [0367] For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), tert-butyl (tBu), phenyl (Ph), benzyl (Bn), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), and acetyl (Ac).

    [0368] For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), deuterated methanol (d.sub.4-MeOD) ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et.sub.2O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), deuterated chloroform (CDCl.sub.3), diethylamine (DEA), deuterated dimethylsulfoxide (d.sub.6-DMSO), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl, EDCl), meta-chloroperoxybenzoic acid (mCPBA), 1,1′-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et.sub.3N), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (II) (PdCl.sub.2(dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl.sub.2(PPh.sub.3).sub.2), tris(dibenzylideneacetone) dipalladium(0) (Pd.sub.2(dba).sub.3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4), propylphosphonic anhydride (T3P), and 1-hydroxybenzotriazole (HOBt), hexamethylphosphoramide (HMPA), trimethylamine (TEA), dichloroethane (DCE), N-bromosuccinimide (NBS), N—N′-dicyclohexylcarbodiimide (DCC), p-toluenesulfonic acid (TsOH), 4-dimethylaminopyridine (DMAP), 1,1′-carbonyldiimidazole (CDI).

    General Experimental Details

    [0369] Unless otherwise stated the following generalisations apply. .sup.1H NMR spectra were recorded on a Bruker Ultrashield Plus (400 MHz) or a Bruker AVANCE (400 MHz). The multiplicity of a signal is designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz.

    [0370] LCMS data was generated using either an Agilent 6100 Series Single Quad LCMS (LCMS-A), an Agilent 1260 Infinity Series UPLC/MS (LCMS-B), an Agilent 1200 Series G6110A Quadrupole LCMS or Waters 2695 alliance (LCMS-C). Chlorine isotopes are reported as .sup.35Cl, Bromine isotopes are reported as either .sup.79Br Or .sup.81Br or both .sup.79Br/.sup.81Br.

    [0371] LCMS Method A (LCMS-A):

    [0372] Instrument: Agilent 6100 Series Single Quad LC/MS

    [0373] Agilent 1200 Series HPLC

    [0374] Pump: 1200 Series G1311A Quaternary pump

    [0375] Autosampler: 1200 Series G1329A Thermostatted Autosampler

    [0376] Detector: 1200 Series G1314B Variable Wavelength Detector

    [0377] LC Conditions:

    [0378] Reverse Phase HPLC analysis

    [0379] Column: Luna C8 (2) 5 μm 50×4.6 mm 100 Å

    [0380] Column temperature: 30° C.

    [0381] Injection Volume: 5 μL

    [0382] Solvent A: Water 0.1% Formic Acid

    [0383] Solvent B: MeCN 0.1% Formic Acid

    [0384] Gradient: 5-100% solvent B over 10 min

    [0385] Detection: 254 nm or 214 nm

    [0386] MS conditions:

    [0387] Ion Source: Quadrupole

    [0388] Ion Mode: Multimode-ES

    [0389] Drying gas temp: 300° C.

    [0390] Vaporizer temperature: 200° C.

    [0391] Capillary voltage (V): 2000 (positive)

    [0392] Capillary voltage (V): 4000 (negative)

    [0393] Scan Range: 100-1000

    [0394] Step size: 0.1 sec

    [0395] Acquisition time: 10 min

    [0396] LCMS Method B (LCMS-B):

    [0397] Instrument: Agilent 1260 Infinity Series UPLC/MS

    [0398] Pump: 1260 Infinity G1312B Binary pump

    [0399] Autosampler: 1260 Infinity G1367E 1260 HiP ALS

    [0400] Detector: 1290 Infinity G4212A 1290 DAD

    [0401] LC Conditions:

    [0402] Reverse Phase HPLC analysis

    [0403] Column: Poroshell 120 EC-C18 2.7 μm 50×3.0 mm

    [0404] Column temperature: 35° C.

    [0405] Injection Volume: 1 μL

    [0406] Solvent A: Water 0.1% Formic Acid

    [0407] Solvent B: MeCN 0.1% Formic Acid

    [0408] Gradient: 5-100% solvent B over 3.8 min

    [0409] Detection: monitored at 254 nm and 214 nm

    [0410] MS Conditions:

    [0411] Ion Source: Quadrupole

    [0412] Ion Mode: API-ES

    [0413] Drying gas temp: 350° C.

    [0414] Capillary voltage (V): 3000 (positive)

    [0415] Capillary voltage (V): 3000 (negative)

    [0416] Scan Range: 100-1000

    [0417] Step size: 0.1 sec

    [0418] Acquisition time: 5 min

    [0419] LCMS Method C (LCMS-C):

    [0420] Instrument: Agilent 1200 Series G6110A Quadrupole

    [0421] Pump: Binary pump

    [0422] Detector: DAD

    [0423] LC Conditions:

    [0424] Reverse Phase HPLC analysis

    [0425] Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

    [0426] Column temperature: 30° C.

    [0427] Injection Volume: 1-10 μL

    [0428] Solvent A: Water 0.07% Formic acid

    [0429] Solvent B: Methanol

    [0430] Gradient: 30-95% solvent B over 3.5 min (for medium polarity samples) or 10-95% solvent B over 3.7 min (for large polarity samples)

    [0431] Detection: monitored at 254 nm and 214 nm

    [0432] MS Conditions:

    [0433] Ion Source: Quadrupole

    [0434] Ion Mode: ES+

    [0435] Drying gas temp: 350° C.

    [0436] Drying gas flow: 10 L/min

    [0437] Nebulizer pressure: 35 psi

    [0438] Capillary voltage (V): 3500 (positive)

    [0439] Scan Range: 50-900

    [0440] Or

    [0441] Instrument: Waters 2695 alliance

    [0442] Pump: Quaternary Pump

    [0443] Detector: 2996 Photodiode Array Detector

    [0444] MS model: Micromass ZQ

    [0445] LC Conditions:

    [0446] Column: Xbridge-C18, 3.5 μm, 2.1×50 mm

    [0447] Column temperature: 30° C.

    [0448] Injection volume: 1-10 μL

    [0449] Acquisition of wavelength: 214 nm, 254 nm

    [0450] Solvent A: 0.07% HCOOH aqueous solution

    [0451] Solvent B: MeOH

    [0452] Run time: 8 min

    [0453] Gradient: 20-95% solvent B over 5 min

    [0454] Detection: 254 nm and 214 nm

    [0455] MS Condition:

    [0456] Ion source: ES+(or ES−) MS range: 50-900 m/z

    [0457] Capillary: 3 kV Cone: 3 V Extractor: 3 V

    [0458] Drying gas flow: 600 L/hr cone: 50 L/hr

    [0459] Desolvation temperature: 300° C.

    [0460] Source temperature: 100° C.

    [0461] Sample Preparation:

    [0462] The sample was dissolved in methanol, the concentration about 0.1-1.0 mg/mL, then filtered through the syringes filter with 0.22 μm.

    [0463] Preparative RP-HPLC:

    [0464] Agilent 1260 Infinity HPLC system

    [0465] UV detection at 210 nm and 254 nm

    [0466] Gradient or isocratic elution through a Phenomenex Luna C8 (2) column 100 Å Axia (250×21.2 mm; particle size 5 μm)

    [0467] Flow rate: 10 mL/min

    [0468] Gradients are as specified in the individual examples.

    [0469] Analytical thin-layer chromatography was performed on Merck silica gel 60 F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or a basic KMnO.sub.4 dip or Ninhydrin dip.

    [0470] Preparative thin-layer chromatography (prep TLC) was performed using Tklst (China), grand grade: (HPTLC): 8±2 μm>80%; (TLC): 10-40 μm. Type: GF254. Compounds were visualised by UV (254 nm).

    [0471] Flash chromatography was performed using a Biotage Isolera purification system using either Grace or RediSep® silica cartridges.

    [0472] Column chromatography was performed using Tklst (China), grand grade, 100-200 meshes silica gel.

    [0473] Microwave irradiation was achieved using a CEM Explorer SP Microwave Reactor.

    [0474] Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods. Solutions of inorganic acids or bases where made up as aqueous solutions unless stated otherwise.

    [0475] Additional Cartridges used are as follows:

    [0476] Phase Separator:

    [0477] Manufacturer: Biotage

    [0478] Product: ISOLUTE® Phase Separator (3 mL unless otherwise stated)

    [0479] SCX and SCX-2 Cartridges:

    [0480] Manufacturer: Biotage

    [0481] Product: ISOLUTE® SCX 1 g, (6 mL SPE Column unless otherwise stated)

    [0482] Manufacturer: Biotage

    [0483] Product: ISOLUTE® SCX-2 1 g (6 mL Column)

    [0484] Manufacturer: Silicycle

    [0485] Product: SCX-2 500 mg or 5 g

    [0486] Manufacturer: Agilent

    [0487] Product: Bond Elut® SCX 10 g

    [0488] Sample Extraction Cartridge:

    [0489] Manufacturer: Waters

    [0490] Product: Oasis® HLB 35 cc (6 g) LP extraction cartridge

    Intermediate Preparations

    (i) 2-(2-Hydroxy-3-(isoquinolin-3-yl)propyl)isoindoline-1,3-dione (I3)

    [0491] ##STR00063##

    (a) (E)-N-tert-Butyl-1-(2-iodophenyl)methanimine (I1)

    [0492] 2-Iodobenzaldehyde (1.460 g, 6.29 mmol), water (3 mL) and tert-butylamine (1.98 mL, 18.9 mmol) were stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was extracted with diethyl ether (2×5 mL). The combined ether extracts were dried over sodium sulfate and concentrated to give the desired compound as a pale yellow oil (1.45 g, 80%)

    (b) 2-(2-Hydroxypent-4-yn-1-yl)isoindoline-1,3-dione (I2)

    [0493] 2-(1,3-Dioxoisoindolin-2-yl)acetaldehyde (1.00 g, 5.29 mmol), indium powder (1.21 g, 10.6 mmol), THF (10 mL), water (10 mL) and propargyl bromide (80% in toluene, 1.38 mL, 10.6 mmol) were stirred vigorously at room temperature. After four hours, the volatile solvents were removed in vacuo and the aqueous residue diluted with water (100 mL). The aqueous mixture was extracted with DCM (3×100 mL) and the combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated. Chromatography (40 g silica cartridge, 0-60% ethyl acetate in petroleum benzine 40-60° C.) gave the desired compound as a white solid (531 mg, 44%) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90-7.84 (m, 2H), 7.77-7.71 (m, 2H), 4.15-4.07 (m, 1H), 3.93-3.89 (m, 2H), 2.69 (br s, 1H), 2.58-2.43 (m, 2H), 2.09 (t, J=2.7 Hz, 1H); LCMS-B 3.39 min; m/z 212.1 [M−H.sub.2O+H].sup.+; 230.1 [M+H].sup.+; 252.1 [M+Na].sup.+.

    (c) 2-(2-Hydroxy-3-(isoquinolin-3-yl)propyl)isoindoline-1,3-dione (I3)

    [0494] A Schlenk tube was loaded with zinc dust (86 mg, 1.3 mmol) and bis(triphenylphosphine)nickel(II) chloride (21 mg, 5 mol %) and purged with nitrogen. A solution of (E)-N-tert-butyl-1-(2-iodophenyl)methanimine I1 (188 mg, 0.65 mmol) and 2-(2-Hydroxypent-4-yn-1-yl)isoindoline-1,3-dione I2 (150 mg, 0.65 mmol) in dry acetonitrile (15 mL) was added via cannula and the mixture stirred at 80° C. under nitrogen. After 30 minutes, the mixture was cooled to room temperature, filtered through Celite and the Celite washed with acetonitrile (30 mL). The combined filtrates were concentrated in vacuo and the material was subjected to column chromatography (12 g silica cartridge, 0-10% methanol/DCM then 100% methanol). The mixture was loaded in methanol onto a 10 g SCX cartridge, the cartridge washed with methanol (60 mL) and eluted with 2.0 M ammonia in methanol (100 mL). The basic eluate was concentrated in vacuo to a yellow sticky solid. The yellow residue was slurried in ethyl acetate (2×2 mL) and the insoluble material dried in vacuo to give the desired compound (116 mg, 53% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 9.22-9.17 (m, 1H), 8.06-8.01 (m, 1H), 7.88-7.84 (m, 1H), 7.83-7.76 (m, 4H), 7.74-7.69 (m, 1H), 7.65 (s, 1H), 7.62-7.56 (m, 1H), 5.10 (d, J=5.5 Hz, 1H), 4.43-4.31 (m, 1H), 3.76-3.65 (m, 1H), 3.63-3.54 (m, 1H), 3.07-2.90 (m, 2H); LCMS-B: RT 3.26 min; m/z 333.2 [M+H].sup.+.

    (ii) 2-(2-Hydroxy-2-(isoquinolin-3-yl)ethyl)isoindoline-1,3-dione (I5)

    [0495] ##STR00064##

    (a) 2-(2-Hydroxybut-3-yn-1-yl)isoindoline-1,3-dione (I4)

    [0496] A 0.5 M THF solution of ethynyl magnesium bromide (3.33 mL, 1.67 mmol) was cooled to 0° C. under nitrogen. A solution of 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (300 mg, 1.59 mmol) in THF (3 mL) was added cannula and the mixture stirred at 0° C. under nitrogen. After 1.5 hours, the mixture was quenched with a saturated aqueous solution of ammonium chloride (3 mL) and the volatile solvents were removed in vacuo. The residue was diluted with water (10 mL) and DCM (15 mL), the aqueous phase was extracted with DCM (2×15 mL). The combined organic phases were dried over sodium sulfate and concentrated. Chromatography (12 g silica cartridge, 0-60% ethyl acetate in petroleum benzine 40-60° C.) gave the desired compound as a white solid (142 mg, 42%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (dd, J=5.5, 3.1 Hz, 2H), 7.75 (dd, J=5.5, 3.1 Hz, 2H), 4.74-4.66 (m, 1H), 4.08 (dd, J=14.3, 8.0 Hz, 1H), 3.94 (dd, J=14.2, 3.9 Hz, 1H), 2.83 (d, J=7.7 Hz, 1H), 2.49 (d, J=2.1 Hz, 1H); LCMS-B: RT 3.37 min; no product ions detected.

    (b) 2-(2-Hydroxy-2-(isoquinolin-3-yl)ethyl)isoindoline-1,3-dione (I5)

    [0497] A Schlenk tube was loaded with zinc dust (84 mg, 1.3 mmol) and bis(triphenylphosphine)nickel(II) chloride (21 mg, 5 mol %) then flushed with nitrogen. A solution of N-tert-butyl-1-(2-iodophenyl)methanimine (184 mg, 0.641 mmol) and 2-(2-hydroxybut-3-yn-1-yl)isoindoline-1,3-dione I4 (138 mg, 0.641 mmol) in dry acetonitrile (15 mL) was added via cannula, and the mixture stirred at 80° C. under nitrogen. After 30 minutes, the mixture was cooled and filtered through Celite. The celite was washed with acetonitrile (2×20 mL) and the combined filtrates concentrated. Chromatography (12 g silica cartridge, 0-10% methanol/DCM) gave the desired compound as a pale yellow solid (174 mg, 85%). .sup.1H NMR (400 MHz, d.sub.4-DMSO) δ 9.20 (s, 1H), 8.15-8.07 (m, 1H), 8.02-7.97 (m, 1H), 7.96 (s, 1H), 7.91-7.80 (m, 5H), 7.80-7.73 (m, 1H), 7.68-7.61 (m, 1H), 5.91 (d, J=4.9 Hz, 1H), 5.18-5.07 (m, 1H), 4.04-3.95 (m, 1H), 3.92-3.79 (m, 1H); LCMS-B: RT 3.41 min; m/z 319.1 [M+H].sup.+.

    (iii) 4-(Morpholine-4-carbonyl)benzoic acid (I7)

    [0498] ##STR00065##

    (a) Methyl 4-(morpholine-4-carbonyl)benzoate (I6)

    [0499] To an ice-cooled (0° C.) solution of mono-methyl terephthalate (10.0 g, 55.5 mmol) in DCM (100 mL) was added oxalyl chloride (5.7 mL, 67 mmol) and a catalytic amount of DMF (10 drops). The mixture was stirred at 0° C. for 3 hours and the solvent was removed in vacuo. The residue was taken up in DCM (100 mL), cooled to 0° C. and morpholine (5.3 mL, 61 mmol) was added drop-wise followed by triethylamine (9.3 mL, 67 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with a saturated aqueous solution of NaHCO.sub.3 (100 mL). The aqueous layer was extracted with DCM (3×100 mL) and the combined organic layers were washed with 1 M HCl (100 mL), water (100 mL) and brine (25 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo give the desired compound (14.0 g, quantitative) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.09 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 3.93 (s, 3H), 3.87-3.71 (m, 4H), 3.69-3.52 (m, 2H), 3.50-3.25 (m, 2H) COOH peak not observed; LCMS-B: RT 3.35 min, m/z 250 [M+H].sup.+.

    (b) 4-(Morpholine-4-carbonyl)benzoic acid (I7)

    [0500] (i) A suspension of methyl 4-(morpholine-4-carbonyl)benzoate I6 (5.00 g, 20.1 mmol) and LiOH.H.sub.2O (926 mg, 22.1 mmol) in THF (100 mL), MeOH (10 mL) and water (2 mL) was stirred at room temperature for 16 hours. The volatiles were concentrated under reduced pressure and the resulting gum suspended in a 0.5 M aqueous citric acid solution (100 mL). Et.sub.3N (1 mL) was added and the water layer extracted with DCM (3×100 mL). The combined organic fractions were dried over MgSO.sub.4 and the volatiles removed in vacuo to give the product as a white solid (3.55 g, 75%): .sup.1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J=8.5, 2H), 7.53 (d, J=8.5, 2H), 3.95-3.58 (m, 6H), 3.44 (s, 2H); LCMS-B: RT 3.162 min; m/z 236.2 [M+H].sup.+.

    [0501] (ii) Methyl 4-(morpholine-4-carbonyl)benzoate (I6) (6.95 g, 27.9 mmol) was dissolved in THF (100 mL) and a solution of lithium hydroxide monohydrate (1.65 g, 39.4 mmol) in water (50 mL) was added. The mixture was stirred at room temperature for 2 hours. The volatile solvents were removed in vacuo and the aqueous residue diluted with water (50 mL) and 10% w/v aqueous sodium hydrogen sulfate monohydrate (50 mL). The resulting slurry was filtered, the collected solid washed with water (20 mL) and dried under vacuum to give the desired compound (5.77 g, 88% yield) as a white powder. LCMS-B: RT 3.17 min; m/z 236.1 [M+H].sup.+, 258.2 [M+Na]; m/z 234.1 [M−H].sup.−

    (iv) tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12)

    [0502] ##STR00066##

    (a) (S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (I8)

    [0503] (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (5.00 g, 28.2 mmol) was vigorously stirred in 1,4-dioxane (100 mL) and water (50 mL). Sodium bicarbonate (4.74 mg, 56.4 mmol) and Boc anhydride (6.77 g, 31.0 mmol) were added and the mixture was stirred vigorously at room temperature. After 17 hours the mixture was concentrated in vacuo and the residue dissolved in water (200 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (30 mL) was added and the mixture extracted with chloroform (3×200 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (7.50 g, 96% yield) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H].sup.+; m/z 276.1 [M−H].sup.−

    (b) tert-Butyl (S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I9)

    [0504] (S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (I8) (7.50 g, 27.0 mmol) was dissolved in THF (150 mL) and CDI (8.77 g, 54.1 mmol) was added. The mixture was stirred for 30 minutes at room temperature then cooled to 0° C. A solution of sodium borohydride (1.16 g, 30.5 mmol) in water (15 mL) was added dropwise. After 40 minutes the mixture was quenched with acetone (25 mL) and concentrated in vacuo. The residue was partitioned between water (250 mL) and ethyl acetate (200 mL). The separated aqueous phase was extracted with ethyl acetate (2×250 mL), the combined organic extracts washed with 5% w/v aqueous NaHSO.sub.4 (250 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo. The residue was loaded in diethyl ether (50 mL) onto a plug of basic alumina and silica (50 mL each). The plug was eluted with diethyl ether (250 mL) and the eluate evaporated to give the desired compound (5.93 g, 83% yield) as a colourless syrup. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.06 (m, 4H), 4.82-4.59 (m, 1H), 4.57-4.38 (m, 1H), 4.37-4.19 (m, 1H), 3.57-3.40 (m, overlaps with trace solvent), 3.03 (dd, J=16.1, 5.7 Hz, 1H), 2.80 (d, J=16.1 Hz, 1H), 1.50 (s, 9H). LCMS-B: RT 3.66 min; m/z 164.2 [M-Boc+2H].sup.+, 286.2 [M+Na].sup.+

    (c) tert-Butyl (S)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (I10)

    [0505] tert-Butyl (S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I9) (1.50 g, 5.70 mmol), DCM (25 mL) and DMSO (5 mL) were cooled to 0° C. Triethylamine (2.38 mL, 17.1 mmol) was added, followed by pyridine-sulfur trioxide complex (2.72 g, 17.1 mmol). The mixture was stirred at 0° C. for 10 minutes then allowed to come to room temperature. After 2 hours, saturated sodium bicarbonate (75 mL) and water (75 mL) were added, and the mixture extracted with diethyl ether (3×150 mL). The pooled ether extracts were washed with 1:1 water: saturated aqueous NH.sub.4Cl (200 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give the desired compound as a colourless oil which was used without further purification.

    (d) tert-Butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11A) and tert-butyl (S)-3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11B)

    [0506] A solution of tert-butyl (S)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (I10) (5.70 mmol @ 100% conversion) in i-propanol (50 mL) was cooled to 0° C. Nitromethane (1.22 mL, 22.8 mmol) and potassium fluoride (331 mg, 5.70 mmol) were added and the mixture stirred for 18 hours, allowing the temperature to come to room temperature as the ice bath thawed. The mixture was diluted with water (200 mL) and extracted with DCM (3×200 mL). The pooled DCM extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography (40 g silica cartridge, 0-20% ethyl acetate/hexanes) gave two partly overlapping peaks, which were split into early (11A major, colourless syrup, 697 mg, 37% yield) and late (11B minor, colourless syrup, 170 mg, 9% yield) fractions. Overall: 867 mg, 47% yield.

    [0507] Data for major isomer tert-butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I11A:

    [0508] .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.25-7.14 (m, 4H), 4.85-4.49 (m, 5H), 4.44 (dd, J=12.6, 9.3 Hz, 1H), 4.37-3.99 (m, overlaps with solvent), 3.19 (dd, J=15.9, 3.2 Hz, 1H), 2.92 (dd, J=15.8, 5.6 Hz, 1H), 1.51 (s, 9H). LCMS-B: RT 3.71 min; m/z 223.2 [M-Boc+2H].sup.+, 345.2 [M+Na].sup.+; m/z 321.2 [M−H].sup.−

    [0509] Data for minor isomer tert-butyl (S)-3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I11B:

    [0510] .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.25-7.11 (m, 4H), 4.75 (d, J=16.5 Hz, 1H), 4.68-4.48 (m, 4H), 4.42-4.23 (m, overlaps with residual nitromethane), 3.06 (dd, J=16.3, 6.1 Hz, 1H), 2.91 (d, J=16.1 Hz, 1H), 1.50 (s, 9H). LCMS-B: RT 3.70 min; m/z 223.2 [M-Boc+2H].sup.+, 345.2 [M+Na]*; m/z 321.2 [M−H].sup.−

    (e) tert-Butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11A)

    [0511] Copper catalyst used:

    ##STR00067##

    [0512] tert-Butyl (S)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (I10) (1.9 mmol @100% conversion), absolute ethanol (5 mL), nitromethane (1.02 mL, 19.0 mmol) and the copper catalyst (91 mg, 10 mol %) (see above figure, prepared according to Tetrahedron: Asymmetry (2008) 2310-2315) were stirred at room temperature. After 90 hours the mixture was concentrated in vacuo, chromatography (40 g silica cartridge, 0-15% ethyl acetate/hexanes) gave the desired compound (352 mg, 58% yield over two steps). .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.25-7.13 (m, 4H), 4.85-4.68 (m, 1H), 4.65-4.49 (m, 1H), 4.49-4.39 (m, 1H), 4.36-3.96 (m, overlaps with trace solvent), 3.19 (dd, J=15.9, 3.2 Hz, 1H), 2.92 (dd, J=15.9, 5.6 Hz, 1H), 1.51 (s, 9H). LCMS-B: RT 3.25 min; m/z 321.1 [M−H].sup.−

    (f) tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12)

    [0513] tert-Butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11A) (1.54 g, 4.78 mmol), absolute ethanol (75 mL) and 10% Pd/C (53% wetted with water, 1.5 g) were stirred under hydrogen (balloon). After 3 hours the mixture was filtered through celite, the celite was washed with absolute ethanol (100 mL) and the combined filtrates concentrated in vacuo to give the desired compound (1.34 g, 96% yield) as a pale grey-green syrup. LCMS-B: RT 3.27 min, m/z 293.2 [M+H].sup.+

    Alternate Synthesis Method

    (a) (S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (I8)

    [0514] (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (50.0 g, 282 mmol) was vigorously stirred in a mixture of 1,4-dioxane (1000 mL) and water (500 mL). Sodium bicarbonate (47.4 g, 564 mmol) and Boc anhydride (67.7 g, 310 mmol) were added and the reaction was stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue dissolved in water (2000 mL). A 30% w/v aqueous solution of sodium hydrogen sulfate monohydrate (300 mL) was added and the mixture extracted with chloroform (3×1000 mL). The pooled organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired compound (90.0 g, quantitative) as a thick syrup. LCMS-B: RT 3.64 min; m/z 178.1 [M-Boc+2H].sup.+; m/z 276.1 [M−H].sup.−

    (b) tert-Butyl (S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I9)

    [0515] (S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (I8) (54.0 g, 195 mmol) was dissolved in THF (1000 mL) and CDI (63.2 g, 390 mmol) was added. The mixture was stirred for 2 hours at 30° C. then cooled to 0° C. A solution of sodium borohydride (14.7 g, 390 mmol) in water (120 mL) was added dropwise. After 3 hours the mixture was quenched with acetone (300 mL) and concentrated in vacuo. The residue was partitioned between water (1000 mL) and ethyl acetate (1000 mL). The separated aqueous phase was extracted with ethyl acetate (4×500 mL) and the combined organic extracts washed with 5% w/v aqueous NaHSO.sub.4 (1000 mL), brine (500 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (5-20% ethyl acetate/petroleum ether) to give the desired compound (30.4 g, 59% yield) as a yellow syrup. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.06 (m, 4H), 4.82-4.59 (m, 1H), 4.57-4.38 (m, 1H), 4.37-4.19 (m, 1H), 3.57-3.40 (m, overlaps with trace solvent), 3.03 (dd, J=16.1, 5.7 Hz, 1H), 2.80 (d, J=16.1 Hz, 1H), 1.50 (s, 9H). LCMS-B: RT 3.66 min; m/z 164.2 [M−Boc+2H].sup.+, 286.2 [M+Na].sup.+

    (c) tert-Butyl (S)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (I10)

    [0516] tert-Butyl (S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I9) (16 g, 0.06 mol), DCM (250 mL) and DMSO (75 mL) were cooled to 0° C. Triethylamine (25.1 mL, 0.18 mol) was added, followed by pyridine-sulfur trioxide complex (28.6 g, 0.18 mol). The mixture was stirred at 0° C. for 30 minutes then allowed to come to room temperature and stirred at room temperature overnight. Saturated sodium bicarbonate (200 mL) and water (200 mL) were added, and the mixture extracted with diethyl ether (3×300 mL). The pooled ether extracts were washed with 1:1 water: saturated aqueous NH.sub.4Cl (200 mL), dried over sodium sulfate and concentrated in vacuo to give the desired compound (16.0 g) as an orange oil which was used without further purification.

    (e) tert-Butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11A)

    [0517] To a solution of tert-butyl (S)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (I10) (0.06 mol @100% conversion) in absolute ethanol (50 mL) was added a solution of the copper catalyst (6.8 g, 20 mol %) (see above figure, prepared according to Tetrahedron: Asymmetry (2008) 2310-2315) in absolute ethanol (10 mL). The mixture was cooled to 0° C. and nitromethane (36.0 g, 0.6 mol) was added. The reaction was stirred at 0° C. for 3 days, the mixture was concentrated in vacuo and purified by chromatography (5% ethyl acetate/petroleum ether) to give the desired compound (7.5 g, 39% yield over two steps). .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.25-7.13 (m, 4H), 4.85-4.68 (m, 1H), 4.65-4.49 (m, 1H), 4.49-4.39 (m, 1H), 4.36-3.96 (m, overlaps with trace solvent), 3.19 (dd, J=15.9, 3.2 Hz, 1H), 2.92 (dd, J=15.9, 5.6 Hz, 1H), 1.51 (s, 9H). LCMS-B: RT 3.25 min; m/z 321.1 [M−H].sup.−

    (f) tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12)

    [0518] To a solution of tert-butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11A) (7.5 g, 23.3 mmol) in absolute ethanol (100 mL) was added 10% Pd/C (7.5 g) and the reaction was stirred under an atmosphere of hydrogen. After 3 hours, the mixture was filtered through Celite, the Celite was washed with absolute ethanol (200 mL) and the combined filtrates concentrated in vacuo to give the desired compound (5.3 g, 78% yield) as a pale grey solid. LCMS-B: RT 3.27 min, m/z 293.2 [M+H].sup.+

    (v) 2-Methylbenzoic acid (I13)

    [0519] ##STR00068##

    (a) 2-Methylbenzoic acid (I13)

    [0520] Methyl 2-methylbenzoate (0.19 mL, 1.33 mmol) was dissolved in THF (4 mL) and water (0.6 mL) and lithium hydroxide monohydrate (0.34 g, 7.99 mmol) was added. The reaction was then stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the resulting residue diluted with EtOAc (50 mL) followed by 2 M aqueous NaOH (50 mL). The layers were separated and the aqueous layer was acidified with 1 M aqueous HCl (checked by pH paper), then extracted with EtOAc (2×70 mL), washed with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the desired compound (0.010 g, 6% yield) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.05 (dd, J=8.1, 1.5 Hz, 1H), 7.46 (td, J=7.5, 1.5 Hz, 1H), 7.32-7.26 (m, 2H), 2.66 (s, 3H), OH not observed. LCMS-A: RT 5.627 min; mass ion not detected

    (vi) 3-(Pyridazin-4-yl)benzoic acid (I15)

    [0521] ##STR00069##

    (a) 4-Bromopyridazine hydrobromide (I14)

    [0522] Potassium acetate (7.4 g, 75 mmol) and 3-bromofuran (4.0 g, 27 mmol) were stirred in acetic acid (20 mL) and a solution of bromine (1.4 mL, 27 mmol) in acetic acid (10 mL) was added dropwise. After one hour the mixture was filtered, the solids washed with acetic acid (10 mL) and the filtrate concentrated. The mixture was dissolved in ethanol (40 mL) and hydrazine hydrate (4 mL) added. After 3 hours the mixture was added to ethyl acetate (100 mL) and brine (100 mL). The aqueous phase was extracted with further ethyl acetate (100 mL), and the aqueous phases discarded. The pooled ethyl acetate phases were washed with brine (100 mL), and the brine extracted with ethyl acetate (100 mL). The pooled ethyl acetate phases were dried over sodium sulfate and evaporated. The residue was diluted with 1,4-dioxane (20 mL) and treated with 33% HBr in acetic acid (4 mL) dropwise. The dark suspension was filtered, the collected solids washed with 1,4-dioxane (2×20 mL), acetone (20 mL) and air dried to give the desired compound (4.41 g, 68% yield) as a brown solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 9.51 (dd, J=2.5, 1.1 Hz, 1H), 9.15 (dd, J=5.7, 1.0 Hz, 1H), 8.16 (dd, J=5.6, 2.5 Hz, 1H). LCMS-B: RT 2.80 min; m/z 159.0 [M+H].sup.+ for .sup.79Br (free base)

    (b) 3-(Pyridazin-4-yl)benzoic acid (I15)

    [0523] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.50 g, 2.0 mmol), 4-bromopyridazine hydrobromide (I14) (0.58 g, 2.4 mmol), PdCl.sub.2(dppf) DCM complex (83 mg, 5 mol %) and 1,4-dioxane (10 mL) were loaded into a microwave tube. A solution of potassium carbonate (0.83 g, 6.0 mmol) in water (5 mL) was added, the mixture degassed with a stream of nitrogen bubbles then heated in the microwave (120° C./30 minutes). The mixture was cooled, and the volatile solvents removed in vacuo. The aqueous residue was diluted with water to 75 mL, and shaken with DCM (75 mL). The mixture was filtered through celite, the aqueous layer separated and washed with further DCM (75 mL). The DCM extracts were discarded, the aqueous phase was diluted with water (25 mL) and treated with 5% w/v citric acid until pH 3 to pH paper. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the desired compound (312 mg, 78% yield) as a pale brown solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 9.70-9.65 (m, 1H), 9.33-9.28 (m, 1H), 8.38 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.12-8.05 (m, 2H), 7.71 (t, J=7.8 Hz, 1H). Acyl proton not observed. LCMS-B: RT 3.15 min, m/z 201.1 [M+H].sup.+; m/z 199.1 [M−H].sup.−

    (vii) 4-(5-Morpholino-1,3,4-oxadiazol-2-yl)benzoic acid (I17)

    [0524] ##STR00070##

    (a) 4-(5-Bromo-1,3,4-oxadiazol-2-yl)morpholine (I16)

    [0525] 5-Morpholino-1,3,4-oxadiazol-2-amine (250 mg, 1.47 mmol) and copper(II) bromide (492 mg, 2.20 mmol) were stirred in acetonitrile (15 mL) under nitrogen for 5 minutes. tert-Butyl nitrite (0.349 mL, 2.94 mmol) was added and the mixture stirred at room temperature for 17 hours. The mixture was diluted with 0.5M HCl (25 mL) and ethyl acetate (25 mL). The organic phase was separated, and the aqueous phase extracted with further ethyl acetate (2×25 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate and evaporated. Chromatography (12 g silica cartridge, 0-60% ethyl acetate/hexanes) gave the desired compound (104 mg, 30% yield) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.82-3.77 (m, 4H), 3.52-3.48 (m, 4H). LCMS-B: RT 3.22 min; m/z 236.1 [M+H].sup.+ for .sup.81Br

    (b) 4-(5-Morpholino-1,3,4-oxadiazol-2-yl)benzoic acid (I17)

    [0526] 4-(5-Bromo-1,3,4-oxadiazol-2-yl)morpholine (I16) (102 mg, 0.436 mmol), 4-boronobenzoic acid (108 mg, 0.654 mmol), PdCl.sub.2(dppf) DCM complex (18 mg, 5 mol %), and 1,4-dioxane (3 mL) were degassed with a stream of nitrogen bubbles. A 1.0M aqueous solution of cesium carbonate (1.5 mL, 1.5 mmol) was added, the mixture again degassed with a stream of nitrogen bubbles, then heated in a microwave (120° C./30 minutes). The mixture was diluted with water (20 mL) and diethyl ether (20 mL), filtered through celite, the organic phase was discarded and the aqueous phase was concentrated in vacuo. The residue was dissolved in water (10 mL) and the pH adjusted to 1 with 6M HCl. The precipitate was collected by filtration, the supernatant discarded, the solid resuspended in water (5 mL) and again collected by filtration. The collected solid was repeatedly suspended in absolute ethanol (20 mL) and the solvents removed in vacuo (three times) to give the desired compound (115 mg, 96% yield) as a brown solid of approximately 80% purity. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.10-8.05 (m, 2H), 8.02-7.97 (m, 2H), 3.76-3.71 (m, 4H), 3.53 (m, overlaps with solvent). LCMS-B: RT 3.25 min; m/z 276.2 [M+H].sup.+; m/z 274.1 [M−H].sup.−

    (viii) 2-Fluoro-4-(morpholine-4-carbonyl)benzoic acid (I20)

    [0527] ##STR00071##

    (a) (4-Bromo-3-fluorophenyl)(morpholino)methanone (I18)

    [0528] 4-Bromo-3-fluorobenzoic acid (2.19 g, 10.0 mmol), DCM (100 mL), morpholine (2.59 mL, 30.0 mmol), DMAP (122 mg, 10 mol %) and EDCl.HCl (2.876 g, 15.0 mmol) were stirred at room temperature. After 17 hours the mixture was added to 2% w/v sodium hydroxide (100 mL). The separated aqueous phase was extracted with DCM (2×50 mL), the pooled DCM extracts washed with 1 M HCl (75 mL), brine (50 mL), dried over sodium sulfate and evaporated. Chromatography (40 g silica cartridge, 0-60% ethyl acetate/hexanes) gave the desired compound (2.63 g, 91% yield) as a colourless syrup. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.61 (dd, J=8.1, 6.8 Hz, 1H), 7.19 (dd, J=8.5, 1.9 Hz, 1H), 7.08 (ddd, J=8.1, 1.9, 0.7 Hz, 1H), 3.70 (br s, 6H), 3.45 (br s, 2H). LCMS-B: RT 3.49 min; m/z 290.0, 288.1 [M+H].sup.+

    (b) Methyl 2-fluoro-4-(morpholine-4-carbonyl)benzoate (I19)

    [0529] (4-Bromo-3-fluorophenyl)(morpholino)methanone (I18) (2.62 g, 9.09 mmol), dry methanol (20 mL), PdCl.sub.2(dppf) DCM complex (376 mg, 5 mol %) and triethylamine (2.54 mL, 18.2 mmol) were loaded into a Schlenk tube and flushed with nitrogen. The tube was flushed with carbon monoxide and the mixture brought to reflux under carbon monoxide (balloon). After 18 hours the mixture was cooled to room temperature, filtered through celite and the celite washed with methanol (40 mL). The combined filtrates were evaporated, chromatography (40 g silica cartridge, 20-60% ethyl acetate/hexanes) gave the desired compound (2.25 g, 93% yield) as a pale orange solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (t, J=7.3 Hz, 1H), 7.25-7.17 (m, 2H), 3.94 (s, 3H), 3.78 (br s, 4H), 3.63 (br s, 2H), 3.40 (br s, 2H). LCMS-A: RT 5.30 min; m/z 268.1 [M+H].sup.+

    (c) 2-Fluoro-4-(morpholine-4-carbonyl)benzoic acid (I20)

    [0530] Methyl 2-fluoro-4-(morpholine-4-carbonyl)benzoate (I19) (1.00 g, 3.74 mmol) was dissolved in THF (20 mL) and a solution of lithium hydroxide monohydrate (188 mg, 4.49 mmol) in water (10 mL) was added and the mixture was stirred vigorously at room temperature. After 2 hours, the volatile solvents were removed in vacuo and the aqueous residue cooled to 4° C. Cold 3.0 M aqueous HCl (5 mL) was added, the resulting slurry diluted with water (5 mL), filtered, the collected solids washed with water (5 mL) and air dried to give the desired compound (817 mg, 86% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.05-7.99 (m, 1H), 7.32 (s, 1H), 7.30 (dd, J=3.7, 1.4 Hz, 1H), 3.76 (br s, 4H), 3.63 (br s, 2H), 3.42 (br s, 2H). LCMS-B: RT 3.20 min; m/z 254.2 [M+H].sup.+; 276.2 [M+Na].sup.+

    (ix) 3-(Pyrimidin-5-yl)benzoic acid (I21)

    [0531] ##STR00072##

    (a) 3-(Pyrimidin-5-yl)benzoic acid (I21)

    [0532] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (496 mg, 2.00 mmol), 5-bromopyrimidine (382 mg, 2.40 mmol), PdCl.sub.2(dppf) DCM complex (82 mg, 5 mol %) were stirred in 1,4-dioxane (10 mL) under nitrogen and a solution of potassium carbonate (829 mg, 6.00 mmol) in water (5 mL) was added. The mixture was degassed with a stream of nitrogen bubbles and heated in the microwave (120° C./30 minutes). The volatiles were removed in vacuo and the aqueous residue diluted with water (50 mL) and DCM (50 mL). The mixture was filtered through celite, the DCM phase discarded and the aqueous phase extracted with further DCM (2×50 mL). The DCM extracts were again discarded, the aqueous phase was adjusted to pH 3 with 30% w/v aqueous NaHSO.sub.4 and the precipitate collected by filtration and dried under vacuum (40° C./3 hours over P.sub.2O.sub.5) to give the desired compound (137 mg, 34% yield) as a grey solid. LCMS-B: RT 3.25 min; m/z 201.1 [M+H].sup.+

    (x) Lithium 4-((1-acetylpiperidin-4-yl)(methyl)carbamoyl)benzoate (I26)

    [0533] ##STR00073##

    (a) tert-Butyl 4-(4-(methoxycarbonyl)benzamido)piperidine-1-carboxylate (I22)

    [0534] 4-(Methoxycarbonyl)benzoic acid (1.00 g, 5.55 mmol), DCM (25 mL), DMAP (34 mg, 5 mol %), tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride salt (1.45 g, 6.11 mmol) and EDCl.HCl (1.28 g, 6.66 mmol) were stirred at room temperature. After 18 hours the mixture was diluted with 10% w/v NaHSO.sub.4 (50 mL) and DCM (50 mL). The aqueous phase was extracted with further DCM (2×50 mL), the pooled DCM extracts were washed with 1:1 saturated aqueous NaHCO.sub.3: water (50 mL), dried over sodium sulfate and concentrated in vacuo to give the desired compound (1.82 g, 91% yield) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.10-8.06 (m, 2H), 7.83-7.78 (m, 2H), 6.11 (d, J=7.9 Hz, 1H), 4.19-4.04 (m, 3H), 3.94 (s, 3H), 2.98-2.81 (m, 2H), 2.07-1.97 (m, 2H), 1.51-1.35 (m, 11H). LCMS-B: RT 3.63 min; m/z 307.1 [M-.sup.tBu+2H].sup.+, 385.2 [M+Na].sup.+, 263.1 [M-Boc+2H].sup.+, m/z 361.2 [M−H].sup.−

    (b) tert-Butyl 4-(4-(methoxycarbonyl)-N-methylbenzamido)piperidine-1-carboxylate (I23)

    [0535] tert-Butyl 4-(4-(methoxycarbonyl)benzamido)piperidine-1-carboxylate (I22) (1.00 g, 2.76 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. A 60% dispersion (in mineral oil) of sodium hydride (331 mg, 8.28 mmol) and methyl iodide (0.344 mL, 5.52 mmol) were added and the mixture stirred at room temperature. After one hour saturated ammonium chloride (10 mL) was added and the mixture added to water (200 mL). The suspension was extracted with diethyl ether (3×100 mL), the pooled ether phases washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. Chromatography (24 g silica cartridge, 0-60% ethyl acetate/hexanes) gave the desired compound (602 mg, 58% yield) as a white solid. LCMS-B: RT 3.67 min; m/z 321.1 [M-.sup.tBu+2H].sup.+, 277.1 [M-Boc+2H].sup.+, 399.1 [M+Na].sup.+

    (c) Methyl 4-(methyl(piperidin-4-yl)carbamoyl)benzoate hydrochloride salt (I24)

    [0536] tert-Butyl 4-(4-(methoxycarbonyl)-N-methylbenzamido)piperidine-1-carboxylate (I23) (600 mg, 1.59 mmol), 1,4-dioxane (6 mL) and 4.0M HCl in 1,4-dioxane (6 mL) were stirred at room temperature. After 5 hours the resulting precipitate was filtered, washed with further 1,4-dioxane (2×5 mL) and air dried to give the desired compound (444 mg, 89% yield) as a white solid. LCMS-B: RT 3.09 min; m/z 277.1 [M+H].sup.+ (free base)

    (d) Methyl 4-((1-acetylpiperidin-4-yl)(methyl)carbamoyl)benzoate (I25)

    [0537] Methyl 4-(methyl(piperidin-4-yl)carbamoyl)benzoate hydrochloride salt (I24) (200 mg, 0.639 mmol), DCM (5 mL), triethylamine (0.267 mL, 1.92 mmol), DMAP (8 mg, 10 mol %) and acetyl chloride (0.068 mL, 0.96 mmol) were stirred at room temperature. After 17 hours the mixture was diluted with water (5 mL) and DCM (5 mL). The mixture was passed through a phase separation cartridge and the DCM phase concentrated in vacuo. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the desired compound (176 mg, 87% yield) as a pale yellow solid. LCMS-B: RT 3.27 min; m/z 319.1 [M+H].sup.+

    (e) Lithium 4-((1-acetylpiperidin-4-yl)(methyl)carbamoyl)benzoate (I26)

    [0538] Methyl 4-((1-acetylpiperidin-4-yl)(methyl)carbamoyl)benzoate (I25) (170 mg, 0.53 mmol) was dissolved in THF (1 mL) and methanol (0.5 mL). A solution of lithium hydroxide monohydrate (25 mg, 0.59 mmol) in water (0.5 mL) was added and the mixture stirred at room temperature. After 3 hours the mixture was concentrated in vacuo, the residue was dried under vacuum over P.sub.2O.sub.5 to give the desired compound (153 mg, 92% yield) as an off-white solid. LCMS-B: 3.13 min; m/z 305.1 [M-Li+2H].sup.+, m/z 303.1 [M-Li].sup.−

    (xi) Lithium 4-((1-(methoxycarbonyl)piperidin-4-yl)(methyl)carbamoyl)benzoate (I28)

    [0539] ##STR00074##

    (a) Methyl 4-(4-(methoxycarbonyl)-N-methylbenzamido)piperidine-1-carboxylate (I27)

    [0540] Methyl 4-(methyl(piperidin-4-yl)carbamoyl)benzoate hydrochloride salt (I24) (200 mg, 0.639 mmol), DCM (5 mL), triethylamine (0.267 mL, 1.92 mmol), DMAP (8 mg, 10 mol %) and methyl chloroformate (0.074 mL, 0.96 mmol) were stirred at room temperature. After 17 hours the mixture was diluted with water (5 mL) and DCM (5 mL). The mixture was passed through a phase separation cartridge and the DCM phase concentrated in vacuo. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the desired compound (135 mg, 63% yield) as a white solid. LCMS-B: RT 3.40 min; m/z 335.1 [M+H].sup.+

    (b) Lithium 4-((1-(methoxycarbonyl)piperidin-4-yl)(methyl)carbamoyl)benzoate (I28)

    [0541] Methyl 4-(4-(methoxycarbonyl)-N-methylbenzamido)piperidine-1-carboxylate (I27) was dissolved in THF (1 mL) and methanol (0.5 mL). A solution of lithium hydroxide monohydrate (18 mg, 0.43 mmol) in water (0.5 mL) was added and the mixture stirred at room temperature. After 3 hours the mixture was concentrated in vacuo, the residue was dried under vacuum over P.sub.2O.sub.5 to give the desired compound (127 mg, quant yield) as an off-white solid. LCMS-B: RT 3.26 min; m/z 321.3 [M-Li+2H].sup.+; m/z 319.1 [M-Li].sup.−

    (xii) 2-((Tetrahydro-2H-pyran-4-yl)oxy)isonicotinic acid (I29)

    [0542] ##STR00075##

    (a) 2-((Tetrahydro-2H-pyran-4-yl)oxy)isonicotinic acid (I29)

    [0543] A solution of tetrahydro-2H-pyran-4-ol (0.462 g, 4.52 mmol, 2 equiv) in anhydrous DMF (5 mL) was added to a stirring suspension of sodium hydride (60% dispersion in oil, 0.362 g, 9.04 mmol, 4 equiv) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 10 minutes before a solution of 2-fluoroisonicotinic acid (0.319 g, 2.26 mmol, 1 equiv) in DMF (5 mL) was added. The mixture was stirred for a further 16 hours at room temperature. H.sub.2O (˜20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜2 with aqueous HCl (˜2 M). The aqueous was extracted with EtOAc (3×30 mL), the organics were combined, washed with brine, dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The resultant residue was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the desired compound (383 mg, 76% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.31 (dd, J=5.2, 0.8 Hz, 1H), 7.36 (dd, J=5.2, 1.4 Hz, 1H), 7.15 (dd, J=1.3, 0.7 Hz, 1H), 5.21 (tt, J=8.7, 4.1 Hz, 1H), 3.86 (dt, J=11.3, 4.3 Hz, 2H), 3.58-3.45 (m, 2H), 2.06-1.93 (m, 2H), 1.74-1.55 (m, 2H), OH not observed. LCMS-B: RT 3.36 min, m/z 224 [M+H].sup.−.

    (xiii) 2-((1-(Methoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid (I32)

    [0544] ##STR00076##

    (a) 2-((1-(tert-Butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid (I30)

    [0545] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.500 g, 2.48 mmol) in anhydrous DMF (5 mL) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 0.238 g, 5.95 mmol) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 10 minutes before a solution of 2-fluoroisonicotinic acid (0.319 g, 2.26 mmol) in DMF (5 mL) was added. The mixture was stirred for a further 16 hours at room temperature and 4 hours at 60° C. After returning to room temperature, water (˜20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜2 with aqueous HCl (˜2 M). The aqueous was extracted with EtOAc (3×30 mL), the organics were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo. The resultant residue was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a white solid. Analysis by .sup.1H NMR showed an approximate 1:1 mixture of the desired product and the isonicotinic acid starting material. This material was reacted with another equivalent of the Boc-protected hydroxypiperidine anion: A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.500 g, 2.48 mmol) in anhydrous DMF (5 mL) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 0.238 g, 5.95 mmol) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 10 minutes before a solution of the 1:1 product/starting material mixture in DMF (5 mL) was added and stirring was continued for 16 hours. Water (˜20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜2 with aqueous HCl (˜2 M). The aqueous was extracted with DCM (3×30 mL), the organics were combined, dried (MgSO.sub.4) and the solvent removed in vacuo. The resultant residue was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the desired compound (0.419 g, 58% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.34-8.27 (m, 1H), 7.39-7.34 (m, 1H), 7.17-7.13 (m, 1H), 5.27-5.15 (m, 1H), 3.74-3.62 (m, 2H), 3.23-3.11 (m, 2H), 2.00-1.88 (m, 2H), 1.63-1.49 (m, 2H), 1.40 (s, 9H). LCMS-B: RT 3.65 min; m/z 321.2 [M−H].sup.−

    (b) 2-(Piperidin-4-yloxy)isonicotinic acid bis(2,2,2-trifluoroacetic acid) salt (I31)

    [0546] To a solution of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid I30 (141 mg, 0.439 mmol, 1 equiv) in DCM (10 mL) was added TFA (0.5 mL, 6.5 mmol, 15 equiv). The reaction was stirred at room temperature for 16 hours and then dried in vacuo to give a colourless oil. The residue was taken up in diethyl ether:methanol (10 mL, 1:1) and dried in vacuo to give the desired compound (196 mg, quantitative yield) as a white solid. LCMS-B: RT 1.74 min, m/z 223 [M+H].sup.+ (free base)

    (c) 2-((1-(Methoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid (I32)

    [0547] Methylchloroformate (68 μL, 0.87 mmol, 2 equiv) was added drop-wise to a mixture of 2-(piperidin-4-yloxy)isonicotinic acid.bis(2,2,2-trifluoroacetic acid) salt I31 (196 mg, 0.437 mmol, 1 equiv) and sodium hydroxide (73 mg, 1.8 mmol) in water (10 mL). The reaction was stirred at ambient temperature overnight. The aqueous phase was separated and adjusted to pH 1 with a 1M aqueous solution of HCl. The aqueous phase was extracted with EtOAc (3×20 mL), and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and the filtrate concentrated in vacuo. The resultant oil was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the desired compound (103 mg, 84% yield) as a glassy solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.29 (dd, J=5.3, 0.8 Hz, 1H), 7.45 (dd, J=5.3, 1.4 Hz, 1H), 7.36 (dd, J=1.4, 0.8 Hz, 1H), 6.98 (br s, 1H), 5.27 (tt, J=7.4, 3.6 Hz, 1H), 3.86-3.75 (m, 2H), 3.73 (s, 3H), 3.49-3.34 (m, 2H), 2.06-1.95 (m, 2H), 1.86-1.70 (m, 2H)

    (xiv) Lithium 5-(morpholine-4-carbonyl)picolinate (I34)

    [0548] ##STR00077##

    (a) Methyl 5-(morpholine-4-carbonyl)picolinate (I33)

    [0549] 6-(Methoxycarbonyl)nicotinic acid (1.00 g, 5.52 mmol), DCM (30 mL), DMAP (67 mg, 10 mol %), morpholine (1.43 mL, 16.6 mmol) and EDCl.HCl (1.59 g, 8.28 mmol) were stirred together at room temperature. After 18 hours the mixture was diluted with water, the organic phase separated and the aqueous phase extracted with DCM (2×30 mL). The pooled organic extracts were washed with brine and concentrated in vacuo. Chromatography (40 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the desired compound (1.108 g, 80% yield) as a colourless oil that became solid on standing. LCMS-B: RT 3.12 min; m/z 251.2 [M+H].sup.+,

    (b) Lithium 5-(morpholine-4-carbonyl)picolinate (I34)

    [0550] Methyl 5-(morpholine-4-carbonyl)picolinate (I33) (1.11 g, 4.43 mmol) was dissolved in THF (10 mL) and a solution of lithium hydroxide monohydrate (204 mg, 4.87 mmol) in water (5 mL) was added. After 2 hours the mixture was concentrated in vacuo, the residue was dried by evaporation with absolute ethanol (3×100 mL), washed with diethyl ether (100 mL) and dried in vacuo to give the desired compound (0.995 g, 89% yield) as a white solid. LCMS-A: RT 4.01 min; m/z 237.6 [M-Li+2H].sup.+; m/z 235.6 [M-Li].sup.−

    (xv) Lithium 4-(((R)-2-((S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-hydroxyethyl)carbamoyl)benzoate (I36)

    [0551] ##STR00078##

    (a) tert-Butyl (S)-3-((R)-1-hydroxy-2-(4-(methoxycarbonyl)benzamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I35)

    [0552] tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (400 mg, 1.37 mmol), MeCN (10 mL), triethylamine (0.381 mL, 2.74 mmol), 4-(methoxycarbonyl)benzoic acid (246 mg, 1.37 mmol) and HATU (780 mg, 2.05 mmol) were stirred together at room temperature. After 18 hours the mixture was concentrated in vacuo, chromatography (12 g silica cartridge, 0-60% ethyl acetate/hexanes) gave the desired compound (309 mg, 50% yield) as a colourless oil. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.11-8.03 (m, 2H), 7.94-7.84 (m, 2H), 7.22-7.10 (m, 4H), 4.48-4.23 (m, 2H), 3.92 (s, 3H), 3.85-3.70 (m, 1H), 3.68-3.57 (m, 1H), 3.22 (dd, J=16.1, 2.8 Hz, 1H), 2.95 (dd, J=15.9, 5.3 Hz, 1H), 1.56-1.45 (m, 9H). LCMS-B: RT 3.80 min; m/z 355.3 [M-Boc+2H].sup.+; m/z 453.2 [M−H].sup.−

    (b) Lithium 4-(((R)-2-((S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-hydroxyethyl)carbamoyl)benzoate (I36)

    [0553] tert-Butyl (S)-3-((R)-1-hydroxy-2-(4-(methoxycarbonyl)benzamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I35) (307 mg, 0.675 mmol) was dissolved in THF (2 mL) and a solution of lithium hydroxide monohydrate (31 mg, 0.74 mmol) in water (1 mL) was added. After 18 hours the mixture was concentrated in vacuo, the residue was dried by evaporation with absolute ethanol (3×20 mL) to give the crude desired compound (308 mg) as a pale yellow solid. LCMS-B: RT 3.58 min; m/z 439.2 [M-Li+2H].sup.−

    (xvi) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoic acid (I38)

    [0554] ##STR00079##

    (a) Methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoate (I37)

    [0555] To a solution of 4-(methoxycarbonyl)benzoic acid (0.66 g, 3.7 mmol) in DCM (20 mL) was added, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.50 g, 3.4 mmol), DIPEA (0.87 g, 6.7 mmol), HOBt (45 mg, 0.3 mmol) and EDCl (0.77 g, 4.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned against saturated aqueous NaHCO.sub.3 (20 mL×2) and the aqueous layer extracted with DCM (5 mL×2). The combined organic layers were washed with brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The crude residue obtained was purified by column chromatography (1% methanol/DCM) to give the desired compound (0.79 g, 85% yield) as a white solid. LCMS-C: RT 0.61 min; m/z 276.1 [M+H].sup.+

    (b) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoic acid (I38)

    [0556] To a solution of methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoate I37 (0.77 g, 2.8 mmol) in a mixture of THF (20 mL), methanol (2 mL) and water (2 mL) was added LiOH.H.sub.2O (0.59 g, 14 mmol). The resulting mixture was stirred at room temperature overnight, then the solvent was removed and the residue obtained diluted with water (20 mL). The pH of the aqueous solution was adjusted to 6 by addition of 2 M HCl. The aqueous layer was extracted with DCM (20 mL×3) and the combined organic layers washed with brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (0.46 g, 63% yield) as a white solid. LCMS-C: RT 0.83 min; m/z 262.1 [M+H].sup.+

    (xvii) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid (I42)

    [0557] ##STR00080##

    (a) Ethyl-2-ethoxy-4-methylbenzoate (I39)

    [0558] To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 54 mmol) and K.sub.2CO.sub.3 (22.4 g, 162 mmol) in DMSO (70 mL) at 40° C. was added ethyl iodide (12.6 g, 80.8 mmol) drop-wise over a period of 30 minutes. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 minutes. The resulting mixture was stirred for another 8 hours at 40° C., then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL×10) and brine (200 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (10.1 g, 90% yield) as a yellow liquid. LCMS-C: RT 2.70 min; m/z 209.1 [M+H].sup.+

    (b) 3-Ethoxy-4-(ethoxycarbonyl)-benzoic acid (I40)

    [0559] To a solution of ethyl 2-ethoxy-4-methylbenzoate I39 (10.0 g, 48.1 mmol) in a mixture of pyridine (25 mL) and water (75 mL) was added KMnO.sub.4 (22.8 g, 144 mmol). The resulting mixture was heated at 50° C. for 48 hours, then cooled and allowed to stir at room temperature 24 hours. The mixture was filtered and the filter cake washed with hot water. The combined aqueous filtrates were washed with EtOAc (75 mL×3) and acidified with 2M HCl solution. The mixture was extracted with DCM (150 mL×3), the combined DCM layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (5.0 g, 44% yield) as a white solid. LCMS-C: RT 0.25 min; m/z 239.0 [M+H].sup.+

    (c) Ethyl-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoate (I41)

    [0560] To a solution of 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I40 (2.5 g, 10.4 mmol) in DCM (20 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.4 g, 9.5 mmol), HOBt (135.1 mg, 1.0 mmol), DIPEA (2.5 g, 19.0 mmol) and EDCl (2.2 g, 11.4 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned against saturated aqueous NaHCO.sub.3, and extracted with DCM (20 mL×2). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (1% methanol/dichloromethane) to give the desired compound (2.5 g, 80% yield) as a yellow oil. LCMS-C: RT 2.40 min; m/z 334.1 [M+H],

    (d) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid (I42)

    [0561] To a solution of ethyl-4-(3-oxa-8-azabicyclo-[3.2.1]-octane-8-carbonyl)-2-ethoxybenzoate I41 (2.4 g, 7.2 mmol) in a mixture of THF (20 mL), methanol (2 mL) and water (2 mL) was added LiOH.H.sub.2O (1.5 g, 36 mmol). The resulting mixture was stirred at room temperature for 24 hours. The solvent was removed and the residue obtained diluted with water (20 mL), the pH of the aqueous mixture was adjusted to 6 by addition of 2 M HCl. The mixture was extracted with DCM (20 mL×3) and the combined organic layers washed with brine (10 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (1.7 g, 79% yield) as a yellow oil. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.83 (d, J=7.8 Hz, 1H), 7.19 (d, J=1.0 Hz, 1H), 7.10 (dd, J=7.8, 1.3 Hz, 1H), 4.65 (br s, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.97 (br s, 1H), 3.82 (d, J=10.8 Hz, 1H), 3.72 (d, J=11.0 Hz, 2H), 3.59 (d, J=10.9 Hz, 1H), 2.13-1.94 (m, 4H), 1.45 (t, J=7.0 Hz, 3H). LCMS-C: RT 1.20 min; m/z 306.1 [M+H].

    Alternate Synthesis Method

    (a) Ethyl-2-ethoxy-4-methylbenzoate (I39)

    [0562] To a mixture of 2-hydroxy-4-methylbenzoic acid (20 g, 131.5 mmol) and K.sub.2CO.sub.3 (54.5 g, 394.5 mmol) in DMSO (50 mL) was added ethyl iodide (21.5 g, 197.2 mmol) drop-wise over a period of 30 minutes. The reaction was stirred for 2 hours then further ethyl iodide (21.5 g, 197.3 mmol) was added over 30 minutes. The resulting mixture was stirred for another 8 hours at 40° C., then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (150 mL×15) and brine (100 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow oil (27 g, 98%). LCMS-C: RT 2.70 min; m/z 209.1 [M+H].sup.+

    (b) 3-Ethoxy-4-(ethoxycarbonyl)-benzoic acid (I40)

    [0563] To a solution of ethyl 2-ethoxy-4-methylbenzoate I39 (10.0 g, 48.1 mmol) in a mixture of pyridine (25 mL) and water (75 mL) was added KMnO.sub.4 (22.8 g, 144 mmol). The resulting mixture was heated at 50° C. for 48 hours, then cooled and allowed to stir at room temperature for 24 hours. The mixture was filtered and the filter cake washed with hot water, the combined aqueous filtrates were washed with EtOAc (75 mL×3) and acidified with 2M HCl solution. The aqueous was extracted with DCM (150 mL×3), the combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (5.0 g, 44% yield) as a white solid. LCMS-C: RT 0.25 min; m/z 239.0 [M+H].sup.+

    (c) Ethyl-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoate (I41)

    [0564] To a solution of 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I40 (10.0 g, 42 mmol) in DCM (20 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (5.7 g, 38.2 mmol), HOBt (0.52 g, 3.8 mmol), DIPEA (9.8 g, 76.2 mmol) and EDCl (8.8 g, 45.7 mmol). The resulting mixture was stirred at room temperature overnight. The above reaction was repeated from 8.5 g of 3-ethoxy-4-(ethoxycarbonyl) benzoic acid and the two batches combined and worked up together. The reaction was partitioned against saturated aqueous NaHCO.sub.3, and extracted with DCM (200 mL×2). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (50% ethyl acetate/petroleum ether) to give the desired compound (20.5 g, 87%) as a yellow oil. LCMS-C: RT 2.40 min; m/z 334.1 [M+H].sup.+

    (d) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid (I42)

    [0565] To a solution of ethyl-4-(3-oxa-8-azabicyclo-[3.2.1]-octane-8-carbonyl)-2-ethoxybenzoate I41 (20.4 g, 61.2 mmol) in a mixture of THF (150 mL), methanol (15 mL) and water (15 mL) was added LiOH—H.sub.2O (12.9 g, 306.1 mmol). The resulting mixture was stirred at room temperature for 48 hours. The solvent was removed and the residue obtained diluted with water (50 mL), the pH of the aqueous mixture was adjusted to 4 by addition of 2 M HCl. The mixture was extracted with DCM (150 mL×3) and the combined organic layers washed with brine (200 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (16.8 g, 90%) as a white solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.83 (d, J=7.8 Hz, 1H), 7.19 (d, J=1.0 Hz, 1H), 7.10 (dd, J=7.8, 1.3 Hz, 1H), 4.65 (br s, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.97 (br s, 1H), 3.82 (d, J=10.8 Hz, 1H), 3.72 (d, J=11.0 Hz, 2H), 3.59 (d, J=10.9 Hz, 1H), 2.13-1.94 (m, 4H), 1.45 (t, J=7.0 Hz, 3H). LCMS-C: RT 1.20 min; m/z 306.1 [M+H].sup.+.

    (xviii)6-((1-Acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (I47)

    [0566] ##STR00081##

    (a) tert-Butyl (1-acetylpiperidin-4-yl)carbamate (I43)

    [0567] To a solution of tert-butyl piperidin-4-ylcarbamate (5.0 g, 25 mmol) in DCM (80 mL) at 0° C. were added Et.sub.3N (3.8 g, 38 mmol) and Ac.sub.2O (2.6 g, 25 mmol). The resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water (30 mL), separated and the organic layer was washed with saturated NaHCO.sub.3 (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the desired compound (5.6 g, 93% yield) as a pale yellow solid. LCMS-C: RT 1.88 min; m/z 265.1[M+Na].sup.+

    (b) 1-(4-Aminopiperidin-1-yl)ethanone hydrochloride (I44)

    [0568] To a solution of tert-butyl (1-acetylpiperidin-4-yl)carbamate I43 (2.5 g, 10 mmol) in MeOH (10 mL) was added HCl/EtOAc (2 M, 10 mL). The mixture was stirred at room temperature overnight. The solvent was removed to give the desired compound (1.6 g, 89% yield) as a white solid. LCMS-C: RT 0.25 min; m/z 143.1[M+H].sup.+ (free base)

    (c) 1-(4-((6-Chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone (I45)

    [0569] To a solution of 1-(4-aminopiperidin-1-yl)ethanone hydrochloride I44 (1.0 g, 5.6 mmol) in i-PrOH (10 mL) were added DIPEA (2.17 g, 16.8 mmol) and 4,6-dichloropyrimidine (0.83 g, 5.6 mmol). The resulting mixture was stirred at 100° C. in a sealed tube overnight. The solvent was removed under reduced pressure, the residue was diluted with water (50 mL) and the pH adjusted to 12 by addition of 1 M NaOH. The aqueous layer was extracted with DCM (4×50 mL), the combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (100% EtOAc) to give the desired compound (1.3 g, 92% yield) as a yellow oil. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.24 (s, 1H), 6.50 (s, 1H), 4.44-4.41 (m, 1H), 4.17 (m, 1H), 3.94-3.90 (m, 1H), 3.28-3.20 (m, 1H), 2.91-2.84 (m, 1H), 2.12-2.05 (m, 5H), 1.52-1.40 (m, 2H). LCMS-C: RT 0.73 min; m/z 255.1[M+H].sup.+

    (d) Methyl 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylate (I46)

    [0570] To a solution of 1-(4-((6-chloropyrimidin-4-yl)amino)piperidin-1-yl)ethanone I45 (1.7 g, 6.7 mmol) in MeOH (25 mL) were added Et.sub.3N (2.0 g, 20 mmol) and PdCl.sub.2(dppf) (0.24 g, 0.33 mmol). The reaction was then heated at reflux overnight under an atmosphere of carbon monoxide (balloon). The solvent was removed under reduced pressure, the residue was diluted with water (50 mL) and the aqueous layer extracted with DCM (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (0-5% MeOH/DCM) to give the desired compound (1.2 g, 65% yield) as a red solid. LCMS-C: RT 0.49 min; m/z 279.1 [M+H].sup.+

    (e) 6-((1-Acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid (I47)

    [0571] To a solution of methyl 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylate I46 (100 mg, 0.34 mmol) in MeOH (3 mL) was added a solution of NaOH (27 mg, 0.68 mmol) in water (1 mL). The resulting mixture was stirred at room temperature overnight. The pH of the solution was adjusted to pH 6 by addition of 3 M HCl and concentrated. The residue was lyophilized to give the crude desired compound (110 mg) as a yellow solid. LCMS-C: RT 0.28 min; m/z 265.1[M+H].sup.+

    (xix) 3-((1-(Methoxycarbonyl)piperidin-4-yl)oxy)benzoic acid (I48)

    [0572] ##STR00082##

    [0573] Methyl chloroformate (240 μL, 3.10 mmol, 2 equiv) was added drop-wise to a mixture of 3-(piperidin-4-yloxy)benzoic acid hydrochloride (400 mg, 1.55 mmol, 1 equiv) and sodium hydroxide (261 mg, 6.52 mmol, 4.2 equiv) in water (10 mL). The reaction was stirred at ambient temperature overnight, acidified to pH=3 with a 0.5 M aqueous solution of citric acid and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and the filtrate concentrated in vacuo. The crude product was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound (201 mg, 46% yield) as a colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.47 (s, 1H), 7.72-7.68 (m, 1H), 7.61 (dd, J=2.6, 1.5 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.16-7.10 (m, 1H), 4.56 (tt, J=6.9, 3.4 Hz, 1H), 3.77-3.65 (m, 5H), 3.54-3.38 (m, 2H), 1.99-1.87 (m, 2H), 1.84-1.71 (m, 2H). LCMS-B: RT 3.09 min, m/z 280.1 [M+H].sup.+, 278.1 [M−H].sup.−.

    (xx) 2-(Piperidin-4-lox)isonicotinic acid dihydrochloride (I49)

    [0574] ##STR00083##

    [0575] To 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid I30 (1.76 g, 4.15 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added a 4M solution of HCl in 1,4-dioxane (1.35 mL, 5.39 mmol, 1.3 equiv). The reaction was stirred at room temperature for 16 hours then dried in vacuo to give a white solid. The solid was re-suspended in 1,4-dioxane (10 mL) and a 4M solution of HCl in 1,4-dioxane (4 mL, 16 mmol, 3.9 equiv) was added. The reaction was stirred at room temperature for an additional 2 days, and then the solvent was evaporated to give the title compound (1.23 g @ 100% conversion) as a white solid. LCMS-B (hydrophilic method): RT 0.56 min, m/z 221.1 [M−H].sup.− for the free base.

    (xxi) 2-((1-(Isopropoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid (I50 and 2-((1-(Isobutoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid (I51)

    [0576] ##STR00084##

    General Method

    [0577] The desired chloroformate (0.87 mmol, 2 equiv) was added drop-wise to a mixture of 2-(piperidin-4-yloxy)isonicotinic acid dihydrochloride I49 (129 mg, 0.437 mmol, 1 equiv) and sodium hydroxide (73 mg, 1.8 mmol, 4.2 equiv) in water (10 mL). The reaction was stirred at ambient temperature overnight. The pH was adjusted to pH=3 with a 0.5 M aqueous solution of citric acid and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The resultant oil was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-65% EtOAc in petroleum benzine 40-60° C.) to give the title compound.

    TABLE-US-00003 Yield and Intermediate Name and Structure Analytical data I50 [00085]embedded image 114 mg, 85% yield LCMS-B: RT 3.21 min, m/z 309.1 [M + H].sup.+, 331.1 [M + Na].sup.+. I51 [00086]embedded image 46 mg, 16% yield LCMS-B: RT 3.31 min, m/z 323.1 [M + H].sup.+, 345.1 [M + Na].sup.+.

    (xxii) Lithium 4-(4-acetylpiperazine-1-carbonyl)benzoate (I55)

    [0578] ##STR00087##

    (a) tert-Butyl 4-(4-(methoxycarbonyl)benzoyl)piperazine-1-carboxylate I52

    [0579] 4-(Methoxycarbonyl)benzoic acid (500 mg, 2.78 mmol), DCM (25 mL), DMAP (17 mg, 5 mol %), triethylamine (1.16 mL, 8.33 mmol), tert-butyl piperazine-1-carboxylate (569 mg, 3.05 mmol) and EDCl.HCl (585 mg, 3.05 mmol) were stirred at 30° C. overnight. The mixture was diluted with DCM (50 mL) and added to 10% w/v aqueous NaHSO.sub.4 (150 mL). The organic phase was separated, and the aqueous phase extracted with further DCM (50 mL). The pooled organic extracts were washed with water (100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the title compound as a white solid (613 mg, 63% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.09 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 3.94 (s, 3H), 3.74 (br s, 2H), 3.57-3.27 (m, 6H), 1.47 (s, 9H). LCMS-B: RT 3.25 min; m/z 371.1 [M+Na].sup.+; 293.1 [M-.sup.tBu+2H].sup.+; 249.2 [M-Boc+2H].sup.+

    (b) Methyl 4-(piperazine-1-carbonyl)benzoate hydrochloride I53

    [0580] tert-Butyl 4-(4-(methoxycarbonyl)benzoyl)piperazine-1-carboxylate I52 (611 mg, 1.75 mmol) was dissolved in 1,4-dioxane (5 mL) and a 4.0M solution of HCl in 1,4-dioxane (5 mL) was added. The mixture was stirred at 30° C. for 2 hours then concentrated in vacuo to give the title compound as a white solid (511 mg). LCMS-B: RT 0.95 min; m/z 249.1 [M+H].sup.+ for free base.

    (c) Methyl 4-(4-acetylpiperazine-1-carbonyl)benzoate I54

    [0581] Methyl 4-(piperazine-1-carbonyl)benzoate hydrochloride I53 (100 mg, 0.35 mmol), DCM (1.5 mL), triethylamine (0.147 mL, 1.05 mmol), DMAP (0.4 mg, 1 mol %) and acetyl chloride (0.050 mL, 0.70 mmol) were stirred at 30° C. After 17 hours, the mixture was quenched with 10% w/v aqueous NaHSO.sub.4 (1 mL), the organic phase separated and loaded onto a 4 g silica cartridge. Chromatography (0-100% ethyl acetate/hexanes) gave the title compound as a white solid (54 mg, 53% yield). LCMS-B: RT 2.92 min; m/z 291.1 [M+H].sup.+

    (d) Lithium 4-(4-acetylpiperazine-1-carbonyl)benzoate I55

    [0582] Methyl 4-(4-acetylpiperazine-1-carbonyl)benzoate I54 (54 mg, 0.19 mmol) and lithium hydroxide monohydrate (8.6 mg, 0.21 mmol) were stirred in THF (1 mL), water (0.5 mL) and methanol (0.5 mL). After 4 hours, the mixture was concentrated in vacuo, the residue diluted with absolute ethanol (5 mL) and again concentrated in vacuo to give the title compound as a white solid (54 mg). The solid was used without further characterisation or purification.

    (xxiii) Lithium 4-(4-(methoxycarbonyl)piperazine-1-carbonyl)benzoate I57

    [0583] ##STR00088##

    (a) Methyl 4-(4-(methoxycarbonyl)benzoyl)piperazine-1-carboxylate I56

    [0584] Methyl 4-(piperazine-1-carbonyl)benzoate hydrochloride I53 (100 mg, 0.35 mmol), DCM (1.5 mL), triethylamine (0.147 mL, 1.05 mmol), DMAP (0.4 mg, 1 mol %) and methyl chloroformate (0.054 mL, 0.70 mmol) were stirred at 30° C. After 17 hours the mixture was quenched with 10% w/v aqueous NaHSO.sub.4 (1 mL), the organic phase separated and loaded onto a 4 g silica cartridge. Chromatography (0-100% ethyl acetate/hexanes) gave the title compound as a white solid (58 mg, 54% yield). LCMS-B: RT 3.03 min; m/z 307.1 [M+H].sup.+

    (b) Lithium 4-(4-(methoxycarbonyl)piperazine-1-carbonyl)benzoate I57

    [0585] Methyl 4-(4-(methoxycarbonyl)benzoyl)piperazine-1-carboxylate I56 (58 mg, 0.19 mmol) and lithium hydroxide monohydrate (8.7 mg, 0.21 mmol) were stirred in THF (1 mL), water (0.5 mL) and methanol (0.5 mL). After 4 hours, the mixture was concentrated in vacuo, the residue diluted with absolute ethanol (5 mL) and again concentrated in vacuo to give the title compound as a white solid (56 mg). The solid was used without further characterisation or purification.

    (xxiv) 2-(1-Acetylpiperidin-4-yl)oxy)benzoic acid I58

    [0586] ##STR00089##

    [0587] 2-(Piperidin-4-yloxy)benzoic acid hydrochloride (200 mg, 0.78 mmol), DCM (5 mL), triethylamine (0.541 mL, 3.88 mmol) and acetyl chloride (0.221 mL, 3.10 mmol) were stirred at 30° C. After 3 hours, DCM (5 mL) and water (10 mL) were added and the mixture adjusted to pH 1 with 3M aqueous HCl. The organic layer was separated (phase separator cartridge) and concentrated in vacuo. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes, then 0-20% methanol/ethyl acetate) gave the title compound as pale yellow solid (173 mg, 85% yield). LCMS-A: RT 5.24 min; m/z 264.2 [M+H],

    (xxv) Lithium 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate I61

    [0588] ##STR00090##

    (a) Ethyl 4-bromo-2-ethoxy-5-fluorobenzoate I59

    [0589] 4-Bromo-2,5-difluorobenzoic acid (1.00 g, 4.22 mmol) was suspended in DCM (20 mL) and cooled to 0° C. Oxalyl chloride (0.543 mL, 6.33 mmol) and DMF (1 drop) were added and the mixture stirred at room temperature. After one hour, the mixture was concentrated in vacuo, the residue dissolved in DCM (10 mL) and cooled to 0° C. Absolute ethanol (10 mL) was added and the mixture stirred at room temperature. After 15 minutes, the mixture was concentrated in vacuo and the residue taken up in absolute ethanol. Sodium metal (146 mg, 6.33 mmol) was dissolved in absolute ethanol (30 mL) and the solution added to the solution of the ester. After 2 hours, the reaction had a thick precipitate, the mixture was diluted with dry THF (50 mL) and the stir bar replaced with an oversized stir bar. After 19 hours, the mixture was concentrated in vacuo, the residue slurried in ethyl acetate (75 mL) and filtered. The filtrate was concentrated in vacuo and purified by chromatography (12 g silica cartridge, 0-10% ethyl acetate/hexanes) to give the title compound (216 mg, 18% yield) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.57 (d, J=8.6 Hz, 1H), 7.13 (d, J=5.5 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H), 1.37 (t, J=7.1 Hz, 3H). LCMS-B: RT 3.53 min, m/z 245.0 [M-OEt].sup.+ for .sup.79Br

    (b) Ethyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate I60

    [0590] Palladium(II) acetate (8 mg, 5 mol %), xantphos (21 mg, 5 mol %), sodium carbonate (232 mg, 2.19 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride salt (163 mg, 1.09 mmol) and ethyl 4-bromo-2-ethoxy-5-fluorobenzoate I59 (212 mg, 0.728 mmol) were stirred in toluene (2 mL) in a schlenk tube under nitrogen. The tube was flushed with carbon monoxide, and heated to 80° C. under carbon monoxide atmosphere. After 18 hours, the mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The mixture was filtered through Celite and the filtrate concentrated in vacuo. Chromatography (12 g silica cartridge, 0-60% ethyl acetate/hexanes) gave the title compound (41 mg, 16% yield) as a pale yellow film. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.51 (d, J=9.2 Hz, 1H), 7.01 (d, J=5.1 Hz, 1H), 4.75 (d, J=5.8 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.84 (d, J=11.0 Hz, 1H), 3.73-3.68 (m, 2H), 3.64 (d, J=10.9 Hz, 1H), 3.56 (dd, J=11.0, 1.6 Hz, 1H), 2.13-1.90 (m, 4H), 1.45 (t, J=7.0 Hz, 3H), 1.38 (t, J=7.1 Hz, 3H). LCMS-B: RT 3.23 min; m/z 352.1 [M+H].sup.+

    (c) Lithium 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate I61

    [0591] A solution of ethyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate 160 (41 mg, 0.12 mmol) in THF (1 mL) was stirred vigorously, and a solution of lithium hydroxide monohydrate (7.3 mg, 0.18 mmol) in water (0.5 mL) was added. After 4.5 hours, the mixture was concentrated in vacuo, the residue dissolved in absolute ethanol and the mixture again concentrated in vacuo to give the title compound. LCMS-B: RT 2.96 min; m/z 324.1 [M-Li+2H].sup.+; m/z 322.1 [M-Li].sup.−

    (xxvi) 6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxynicotinic acid I65

    [0592] ##STR00091##

    (a) 2-Chloro-6-ethoxypyridine I62

    [0593] To a solution of 2,6-dichloropyridine (5.0 g, 33.8 mmol) in EtOH (50 mL) was added EtONa (9.2 g, 0.14 mol). The mixture was stirred at 60° C. for 24 hours. The solvent was removed and the residue obtained was dissolved in water (100 mL). The aqueous layer was acidified to pH 7 with 2 M HCl, then extracted with DCM (100 mL×2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as yellow oil (4.2 g, 79%). LCMS-C: RT 2.64 min; m/z 158.1 [M+H].sup.+.

    (b) 6-Chloro-2-ethoxynicotinaldehyde I63

    [0594] To a solution of 2-chloro-6-ethoxypyridine I62 (2.0 g, 12.7 mmol) in THF (40 mL) at −78° C. was added t-BuLi (1.6 M in pentane, 8.8 mL, 14.0 mmol) dropwise under N.sub.2. After stirring at the same temperature for 1 hour, DMF (2.8 g, 38.1 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes then warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with 2M HCl (5 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×3) and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as yellow oil (2.0 g, 87%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.17 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.44 (q, J=14.0, 7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H). LCMS-C: RT 2.64 min; m/z 186 [M+H].sup.+; 218.1 [M+MeOH+H].sup.+.

    (c) 6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxynicotinaldehyde I64

    [0595] To a solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.5 g, 10.3 mmol) in toluene (80 mL) was added Et.sub.3N (2.6 g, 25.8 mmol), Xantphos (0.2 g, 0.34 mmol) and Pd(OAc).sub.2 (40 mg, 0.17 mmol). The mixture was degassed three times under N.sub.2 followed by addition of 6-chloro-2-ethoxynicotinaldehyde I63 (1.6 g, 8.6 mmol). The mixture was degassed three times under N.sub.2 and then three times under CO. The reaction was then stirred at 90° C. overnight. Water (80 mL) was added and the mixture was extracted with EtOAc (80 mL×2), the combined organic layers were washed with water (80 mL), brine (80 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (100% petroleum ether to 50% EtOAc in petroleum ether) to give the title compound as a yellow solid (1.1 g, 44%): LCMS-C: RT 2.22 min; m/z 291.1 [M+H].sup.+.

    (d) 6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxynicotinic acid I65

    [0596] To a mixture of 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxynicotinaldehyde I64 (100 mg, 0.34 mmol) in a mixture of t-BuOH (5 mL) and 2-methylbut-2-ene (2 mL) was added a solution of NaH.sub.2PO.sub.4.2H.sub.2O (376 mg, 2.4 mmol) and NaClO.sub.2 (300 mg, 3.3 mmol) in water (5 mL). The resulting mixture was stirred at room temperature for 2 hours after which the solvent was removed under reduced pressure. The residue obtained was dissolved in water and the aqueous layer was acidified to pH 5 with 2 M HCl and extracted with EtOAc (20 mL×4). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (80 mg, 76%). LCMS-C: RT 1.74 min; m/z 307.1 [M+H].sup.+.

    (xxvii) 6-(2-Oxo-2-(piperidin-1-yl)ethyl)nicotinic acid I70

    [0597] ##STR00092##

    (a) Diethyl 2-(5-bromopyridin-2-yl)malonate 166

    [0598] To a solution of 5-bromo-2-iodopyridine (18.0 g, 63.4 mmol) in 1,4-dioxane (100 mL) was added diethyl malonate (20.3 g, 126.8 mmol), Cs.sub.2CO.sub.3 (62.0 g, 190.2 mmol), CuI (1.2 g, 6.3 mmol) and picolinic acid (1.6 g, 12.7 mmol). The resulting mixture was heated to 70° C. and stirred overnight. Water (100 mL) and EtOAc (100 mL) were added and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (3×50 mL) and brine (3×50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/20) to give the title compound as yellow oil (19.6 g, 97%). LCMS-C: RT 2.49 min; m/z 316.0, 318.0 [M+H].sup.+.

    (b) 2-(5-Bromopyridin-2-yl)acetic acid I67

    [0599] To a solution of diethyl 2-(5-bromopyridin-2-yl)malonate 166 (2.1 g, 6.6 mmol) in MeOH (30 mL) was added 2 M NaOH aqueous solution (14 mL, 28 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the residue was dissolved in water (20 mL). The pH of the solution was adjusted to 3-4 by addition of 6 M HCl. The white precipitate formed was collected by filtration, washed with water and dried at 50° C. to give the title compound as a white solid (1.0 g, 70%). LCMS-C: RT 0.78 min; m/z 216.0 [M+H].sup.+.

    (c) 2-(5-Bromopyridin-2-yl)-1-(piperidin-1-yl)ethanone I68

    [0600] To a solution of 2-(5-bromopyridin-2-yl)acetic acid I67 (890 mg, 4.1 mmol) in DCM (5 mL) was added HATU (2.4 g, 6.2 mmol) followed by a solution of piperidine (526 mg, 6.2 mmol) in DCM (5 mL) and DIPEA (1.9 mL, 14.4 mmol). The resulting mixture was stirred at room temperature overnight. Water (15 mL) and DCM (15 mL) were then added, the layers were separated and the aqueous layer extracted with DCM (3×15 mL). The combined organic extracts were washed with saturated NaHCO.sub.3 (3×10 mL) and brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/10) to give the title compound as a white solid (960 mg, 82%). .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 8.59 (d, J=2.4 Hz, 1H), 7.97 (dd, J=8.4, 2.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 3.83 (s, 2H), 3.45-3.40 (m, 4H), 1.58-1.52 (m, 2H), 1.43-1.37 (m, 4H); LCMS-C: RT 2.22 min; m/z 283.1 [M+H].sup.+.

    (d) Methyl 6-(2-oxo-2-(piperidin-1-yl)ethyl)nicotinate I69

    [0601] To a solution of 2-(5-bromopyridin-2-yl)-1-(piperidin-1-yl)ethanone I68 (500 mg, 1.8 mmol) in MeOH (20 mL) was added Pd(dppf)C.sub.2 (65 mg, 0.1 mmol) and triethylamine (394 mg, 3.9 mmol). The resulting mixture was heated at reflux under a carbon monoxide atmosphere overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/1) to give the title compound as a yellow solid (417 mg, 90%). LCMS-C: RT 1.62 min; m/z 263.1 [M+H].sup.+.

    (e) 6-(2-Oxo-2-(piperidin-1-yl)ethyl)nicotinic acid I70

    [0602] To a solution of methyl 6-(2-oxo-2-(piperidin-1-yl)ethyl)nicotinate I69 (390 mg, 1.5 mmol) in a mixture of THF (5 mL), MeOH (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (313 mg, 7.4 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvent was removed and the aqueous layer neutralized with 4 M HCl aqueous solution to a pH of 5-6. The water was removed to give the title crude product which was dissolved in a mixed solution of MeOH/DCM (1/20) and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow oil (338 mg, 91%). The material was carried forward without further purification. LCMS-C: RT 0.55 min; m/z 249.1 [M+H].sup.+.

    (xxviii) 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane I71

    [0603] ##STR00093##

    [0604] To a solution of diisopropylamine (1.41 g, 13.98 mmol) in THF (10 mL) at −20° C. under N.sub.2 was added dropwise n-BuLi (5.82 mL, 13.98 mmol). The mixture was stirred for 30 minutes at −20° C. then cooled to −70° C. and a solution of dihydro-2H-pyran-4(3H)-one (2.0 g, 9.99 mmol) in THF (5 mL) was added. The reaction was then stirred at −70° C. for 30 minutes. A solution of 1,1,1-trifluoro-N-phenylmethanesulfonamide (3.57 g, 9.99 mmol) in THF (5 mL) was added dropwise, the resulting mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/20) to give the triflate intermediate.

    [0605] To a solution of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (993 mg, 3.91 mmol) in DMSO (5 mL) under N.sub.2 was added KOAc (959.8 mg, 9.78 mmol) and Pd(dppf)Cl.sub.2 (71.7 mg, 0.097 mmol). A solution of the triflate intermediate (750 mg) in DMSO (1 mL) was added and the reaction heated at 80° C. overnight. The mixture was diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with saturated NaHCO.sub.3 (3×10 mL) and brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/2) to give the title compound (300 mg) as a white solid which was used without further purification or analysis.

    (xxix) 2-(Tetrahydro-2H-pyran-4-yl)isonicotinic acid I75

    [0606] ##STR00094##

    (a) 2-Chloroisonicotinoyl chloride I72

    [0607] A solution of 2-chloroisonicotinic acid (2.0 g, 12.69 mmol) in thionyl chloride (15 mL) was heated at 80° C. for 3 hours. The mixture was concentrated in vacuo and the residue resuspended in DCM (3×10 mL) and concentrated to remove the excess thionyl chloride to give the title compound as yellow oil (2.2 g, 100%). LCMS-C: (MeOH quench) RT 1.79 min; m/z 172.1 [M+H].

    (b) Benzyl 2-chloroisonicotinate I73

    [0608] To a solution of benzyl alcohol (1.37 g, 12.69 mmol) in DCM (80 mL) was added triethylamine (5.07 g, 50.76 mmol) followed by dropwise addition of 2-chloroisonicotinoyl chloride I72 (2.2 g, 12.69 mmol) and the reaction was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with saturated NaHCO.sub.3 (3×10 mL), brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (3.1 g, 99%) as brown oil. LCMS-C: RT 2.88 min; m/z 248.1 [M+H].sup.+.

    (c) Benzyl 2-(3,6-dihydro-2H-pyran-4-yl)isonicotinate I74

    [0609] To a solution of benzyl 2-chloroisonicotinate I73 (319 mg, 1.29 mmol) in a mixture of toluene (2 mL) and THF (10 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane I71 (300 mg, 1.42 mmol) and 2M Na.sub.2CO.sub.3 aqueous solution (1.29 mL). Pd(dppf)Cl.sub.2 (38 mg, 0.05 mmol) was added and the reaction heated at 100° C. for 3 hours. The mixture was diluted with 1M HCl (20 mL) and extracted with DCM (3×20 mL), the combined organic layers were washed with saturated NaHCO.sub.3 (3×10 mL), brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/5) to give the title compound (60 mg, 6%) as a yellow oil. LCMS-C: RT 2.88 min; m/z 296.2 [M+H].sup.+.

    (d) 2-(Tetrahydro-2H-pyran-4-yl)isonicotinic acid I75

    [0610] To a solution of benzyl 2-(3,6-dihydro-2H-pyran-4-yl)isonicotinate I74 (60 mg, 0.20 mmol) in MeOH (5 mL) was added 10% Pd/C (20 mg). The mixture was stirred under H.sub.2 at room temperature for 1 day. The mixture was filtered and the filtrate concentrated to give the title compound as a yellow oil (30 mg, 71%). LCMS-C: RT 0.52 min; m/z 208.2 [M+H].sup.+.

    (xxx) 4-(2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoic acid I79

    [0611] ##STR00095##

    (a) Ethyl 2-ethoxy-4-methylbenzoate I76

    [0612] To a mixture of 2-hydroxy-4-methylbenzoic acid (20.0 g, 131.5 mmol) and K.sub.2CO.sub.3 (54.5 g, 394.5 mmol) in DMSO (50 mL) at 40° C. was added bromoethane (21.5 g, 197.2 mmol) over 30 minutes. The reaction was then stirred at 40° C. for 2 hours. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40° C. for 8 hours. DCM (200 mL) was added and the mixture was filtered. The organic layer was washed with water (4×150 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (24.1 g, 88%) as a clear oil. LCMS-C: RT 2.77 min; m/z 209.1[M+H].sup.+.

    (b) 2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid I77

    [0613] To a solution of diisopropylamine (1.46 g, 14.4 mmol) in anhydrous THF (20 mL) at −30° C. was added n-BuLi (2.4M in hexane, 5.8 mL, 14.4 mmol) slowly under a nitrogen atmosphere. The mixture was stirred at −30° C. for 30 minutes then cooled to −78° C. and HMPA (4.0 g) was added. A solution of ethyl 2-ethoxy-4-methylbenzoate I76 (2.0 g, 9.6 mmol) in anhydrous THF (5 mL) was then added dropwise and the resulting mixture stirred at −78° C. for 2 hours. CO.sub.2 (g) was bubbled through the mixture until the colour of the anion discharged then for a further 30 minutes. The reaction was allowed to warm to 10° C., then diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The aqueous layer was acidified to pH 2 by addition of 10% aqueous H.sub.2SO.sub.4 and extracted with DCM (2×20 mL). The combined DCM layers were washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (550 mg, 23%) as yellow oil. LCMS-C: RT 2.36 min; m/z 253.1 [M+H].sup.+.

    (c) Ethyl 4-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoate I78

    [0614] A mixture of 2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid I77 (550 mg, 2.2 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride salt (320 mg, 2.1 mmol), EDCl (500 mg, 2.6 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (710 mg, 5.5 mmol) in DCM (10 mL) was stirred at room temperature overnight. Water (20 mL) was added and the reaction mixture extracted with DCM (3×10 mL), the organic layers were combined and washed with saturated aqueous NaHCO.sub.3, water and brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title product (710 mg, 93%) as a yellow oil. LCMS-C: RT 2.38 min; m/z 348.2 [M+H].sup.+.

    (d) 4-(2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoic acid I79

    [0615] To a solution of ethyl 4-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoate I78 (710 mg, 2.0 mmol) in a mixture of THF (5 mL), MeOH (10 mL) and water (5 mL) was added LiOH.H.sub.2O (429 mg, 10.2 mmol). The reaction was stirred at room temperature overnight then the solvent was removed in vacuo. The residue obtained was re-dissolved in water (10 mL) then acidified to pH 2 by addition of 10% aqueous H.sub.2SO.sub.4 solution. The resulting mixture was extracted with DCM (3×10 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (540 mg, 85%) as a yellow solid. LCMS-C: RT 1.20 min; m/z 320.2 [M+H].sup.+.

    (xxxi) 5-Chloro-2-((tetrahydro-2H-pyran-4-yl)oxoisonicotinic acid I81

    [0616] ##STR00096##

    (a) 5-Chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine I80

    [0617] To a solution of tetrahydro-2H-pyran-4-ol (1.0 g, 10 mmol) in DMF (25 mL) at 0° C. was added NaH in mineral oil (60% wt, 1.2 g, 30 mmol) and the mixture was stirred at 0° C. for 30 minutes. 2,5-Dichloropyridine (1.8 g, 12 mmol) was added and the resulting mixture was heated at 60° C. for 2 hours, then cooled to room temperature and allowed to stir overnight. The reaction was partitioned between EtOAc (50 mL) and water and the organic fraction washed with water (3×50 mL) and brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude material obtained was purified by silica gel chromatography (2% EtOAc in petroleum ether) to give the title compound (1.3 g, 62%). LCMS-C: RT 2.65 min; m/z 214.1 [M+H].sup.+.

    (b) 5-Chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)isonicotinic acid I81

    [0618] To a solution of diisopropylamine (284 mg, 2.81 mmol) in anhydrous THF (20 mL) at −5° C. was added n-BuLi (2.4M in hexane, 1.2 mL, 2.81 mmol) slowly under a nitrogen atmosphere. The mixture was then stirred at −15° C. to −5° C. for 30 minutes, then cooled to −78° C. and a solution of 5-chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine I80 (500 mg, 2.34 mmol) in anhydrous THF (5 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 2 hours and then CO.sub.2 (g) was bubbled through the mixture for 15 minutes. Water (10 mL) was added and the mixture extracted with diethyl ether (×2). The aqueous layer was separated and acidified to pH 3 by addition of 10% aqueous H.sub.2SO.sub.4, the aqueous layer was extracted with DCM (×2) and the combined organic layers washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (240 mg, 40%) as a white solid. LCMS-C: RT 1.77 min; m/z 258.2[M+H].sup.+.

    (xxxii) Lithium 6-((1-(methoxycarbonyl)piperidin-4-yl)oxy)pyrimidine-4-carboxylate I86

    [0619] ##STR00097##

    (a) tert-Butyl 4-((6-chloropyrimidin-4-yl)oxy)piperidine-1-carboxylate I82

    [0620] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.2 g, 16.1 mmol) in THF (45 mL) was added NaH in mineral oil (60% wt, 0.97 g, 24.2 mmol) and the mixture was stirred at 60° C. for 1 hour, then cooled to room temperature and a solution of 4,6-dichloropyrimidine (2.0 g, 13.4 mmol) in THF (15 mL) was added. The resulting mixture was then stirred at room temperature for 2 hours. Water (50 mL) was added and the reaction mixture was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (4.3 g, 100%) as a yellow oil. LCMS-C: RT 2.95 min; m/z 314.1 [M+H].sup.+.

    (b) 4-Chloro-6-(piperidin-4-yloxy)pyrimidine dihydrochloride I83

    [0621] A solution of tert-butyl 4-((6-chloropyrimidin-4-yl)oxy)piperidine-1-carboxylate I82 (4.3 g, 13.4 mmol) in HCl/EtOAc (4 M, 40 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was washed with diethyl ether and dried to give the title compound (3.3 g, 86%) as a yellow solid. LCMS-C: RT 0.31 min; m/z 214.1 [M+H].sup.+ for free base.

    (c) Methyl 4-((6-chloropyrimidin-4-yl)oxy)piperidine-1-carboxylate I84

    [0622] To a solution of 4-chloro-6-(piperidin-4-yloxy)pyrimidine dihydrochloride I83 (3.3 g, 11.5 mmol) and Et.sub.3N (5.8 g, 57.6 mmol) in DCM (40 mL) was added methyl chloroformate (1.3 g, 13.8 mmol). The reaction was then stirred at room temperature for 2 hours. Water (100 mL) was added and the aqueous extracted with DCM (×2). The combined organic layers were washed with saturated aqueous NaHCO.sub.3, water, and brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (2.6 g, 83%) as a yellow oil. LCMS-C: RT 2.47 min; m/z 272.1 [M+H].sup.+.

    (d) Methyl 6-((1-(methoxycarbonyl)piperidin-4-yl)oxy)pyrimidine-4-carboxylate I85

    [0623] A mixture of methyl 4-((6-chloropyrimidin-4-yl)oxy)piperidine-1-carboxylate I84 (500 mg, 1.84 mmol), PdCl.sub.2(dppf) (67 mg, 0.09 mmol) and Et.sub.3N (372 mg, 3.68 mmol) in MeOH (10 mL) under an atmosphere of CO (g) was heated at 50° C. for 6 hours. The reaction mixture was concentrated in vacuo and the residue obtained purified by silica gel chromatography (33% EtOAc in petroleum ether) to give the title compound (330 mg, 61%) as a yellow oil. LCMS-C: RT 2.35 min; m/z 296.3 [M+H].sup.+.

    (e) Lithium 6-((1-(methoxycarbonyl)piperidin-4-yl)oxy)pyrimidine-4-carboxylate I86

    [0624] To a solution of methyl 6-((1-(methoxycarbonyl)piperidin-4-yl)oxy)pyrimidine-4-carboxylate 185 (100 mg, 0.34 mmol) in a mixture of THF (1 mL), MeOH (2 mL) and water (1 mL) was added LiOH.H.sub.2O (30 mg, 0.68 mmol). The reaction was stirred at room temperature overnight, then concentrated and the residue was lyophilized to give a crude product (110 mg) as yellow solid which was used in the next step without further purification. LCMS-C: RT 1.21 min; m/z 282.1 [M-Li+2H].sup.+.

    (xxxiii) 2-Ethoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzoic acid I88

    [0625] ##STR00098##

    (a) Ethyl 2-ethoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzoate I87

    [0626] A solution of 2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid (170 mg, 0.67 mmol), pyrrolidine (47.9 mg, 0.67 mmol), EDCl (154 mg, 0.8 mmol), HOBt (9.5 mg, 0.07 mmol) and DIPEA (173 mg, 1.34 mmol) in DCM (5 mL) was stirred at room temperature overnight. Water (5 mL) was added and the reaction mixture was extracted with DCM (3×5 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3, water and brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (170 mg, 83%) as a yellow oil. LCMS-C: RT 2.47 min; m/z 306.1 [M+H].sup.+.

    (b) 2-Ethoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzoic acid I88

    [0627] To a solution of ethyl 2-ethoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzoate I87 (170 mg, 0.56 mmol) in a mixture of THF (2 mL), MeOH (4 mL) and water (2 mL) was added LiOH.H.sub.2O (47 mg, 1.1 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue re-dissolved in water (5 mL) and acidified to pH 2 with 10% aqueous H.sub.2SO.sub.4. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic fractions dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (120 mg, 77%) as a yellow solid. LCMS-C: RT 1.76 min; m/z 278.1 [M+H].sup.+.

    (xxxiv) 2-Ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoic acid I95

    [0628] ##STR00099##

    (a) Methyl 3-hydroxy-2-methylbenzoate I89

    [0629] To a solution of 3-hydroxy-2-methylbenzoic acid (10.0 g, 65.7 mmol) in MeOH (100 mL) was added SOCl.sub.2 (15.6 g, 131.5 mmol) slowly and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue dissolved in DCM (100 mL). The organic solution was washed with saturated aqueous NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (10.7 g, 98%) as a white solid. LCMS-C: RT 1.98 min; m/z 167.1 [M+H].sup.+.

    (b) Methyl 4-bromo-3-hydroxy-2-methylbenzoate I90

    [0630] To a solution of tert-butylamine (2.0 g, 27.1 mmol) in DCM (180 mL) at −70° C. was added a solution of Br.sub.2 (4.2 g, 27.1 mmol) in DCM (10 mL) dropwise and the mixture was stirred at −70° C. for 1 hour. A solution of methyl 3-hydroxy-2-methylbenzoate I89 (4.5 g, 27.1 mmol) in DCM (10 mL) was then added dropwise and the resulting mixture allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of water (30 mL) and the aqueous layer extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude residue obtained was purified by silica gel chromatography (2% EtOAc in petroleum ether) to give the title compound (2.2 g, 33%) as a white solid. LCMS-C: RT 2.46 min; m/z 245.0, 247.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 3.80 (s, 3H), 2.38 (s, 3H).

    (c) Methyl 4-bromo-3-ethoxy-2-methylbenzoate I91

    [0631] To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate I90 (2.1 g, 8.6 mmol) in DMSO (10 mL) was added K.sub.2CO.sub.3 (3.5 g, 25.8 mmol) and ethyl bromide (1.4 g, 12.9 mmol). The reaction was then stirred at 40° C. overnight. Water (30 mL) was added and the aqueous extracted with DCM (3×20 mL). The organic layer was washed with water (10×30 mL), dried (Na.sub.2SO.sub.4), and concentrated to give the title compound (2.2 g, 95%) as a yellow solid. LCMS-C: RT 3.08 min; m/z 273.0, 275.0 [M+H].sup.+.

    (d) 4-Bromo-3-ethoxy-2-methylbenzoic acid I92

    [0632] To a solution of methyl 4-bromo-3-ethoxy-2-methylbenzoate I91 (2.1 g, 10.0 mmol) in a mixture of MeOH (10 mL) and water (0.2 mL) was added NaOH (0.4 g, 20.0 mmol). The reaction was stirred at room temperature overnight then the solvent was removed under reduced pressure. The residue obtained was re-dissolved in water (20 mL) and acidified with 1M HCl to pH 2. The aqueous layer was extracted with DCM (4×20 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (2.4 g, 92%) as a white solid. LCMS-C: RT 2.75 min; m/z 281.0, 283.0 [M+Na].sup.+.

    (e) (4-Bromo-3-ethoxy-2-methylphenyl) (morpholino)methanone I93

    [0633] To a solution of 4-bromo-3-ethoxy-2-methylbenzoic acid I92 (2.4 g, 9.3 mmol) in DCM (500 mL) at 0° C. was added oxalyl chloride (3.5 g, 27.9 mmol) and DMF (0.2 mL). The reaction was stirred for 3 hours then morpholine (1.6 g, 18.6 mmol) and triethylamine (4.1 g, 40.9 mmol) were added and stirring was continued overnight at 0° C. Water (100 mL) was added and the mixture was extracted with DCM (2×100 mL), the combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by silica gel chromatography (1% MeOH in DCM) to give the title compound (720 mg, 24%) as a white solid. LCMS-C: RT 2.48 min; m/z 328.1, 330.1 [M+H].sup.+.

    (f) Methyl 2-ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoate I94

    [0634] To a solution of (4-bromo-3-ethoxy-2-methylphenyl)(morpholino)methanone I93 (720 mg, 2.2 mmol) in MeOH (10 mL) was added PdCl.sub.2(dppf) (81 mg, 0.11 mmol) and TEA (489 mg, 4.8 mmol). The reaction was then heated at reflux overnight under a CO atmosphere. The mixture was concentrated and the residue obtained dissolved in DCM (20 mL), washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by silica gel chromatography (1% MeOH in DCM) to give the title compound (670 mg) as a yellow oil. LCMS-C: RT 2.02 min; m/z 308.2 [M+H].sup.+.

    (g) 2-Ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoic acid I95

    [0635] To a solution of methyl 2-ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoate I94 (670 mg, 2.2 mmol) in a mixture of THF (1 mL), MeOH (10 mL) and water (0.1 mL) was added LiOH.H.sub.2O (275 mg, 6.5 mmol) The reaction was stirred at room temperature overnight, then concentrated under reduced pressure. The residue obtained was re-dissolved in water (20 mL) then acidified with 1M HCl to pH 2. The aqueous mixture was extracted with DCM (10 mL×3) and the combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (310 mg, 48%) as a brown oil. LCMS-C: RT 0.89 min; m/z 294.1 [M+H].sup.+.

    (xxxv) 2-Fluoro-4-(3-oxa-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoic acid I97

    [0636] ##STR00100##

    (a) (3-Fluoro-4-methyl-phenyl)-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone I96

    [0637] To a solution of 3-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.8 g, 11.8 mmol) in DCM (10 mL) were added DIPEA (6.3 mL, 35.4 mmol), EDCl (2.72 g, 14.2 mmol) and HOBt (162.1 g, 1.2 mmol). The mixture was then stirred at room temperature overnight. Saturated aqueous NaHCO.sub.3 (50 mL) was added and the mixture was extracted with DCM (3×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated and the residue was purified by chromatography (5% EtOAc/petroleum ether) to give the title compound as a yellow solid (1.7 g, 58%). LCMS-C: RT 2.30 min; m/z 250.1 [M+H].sup.+.

    (b) 2-Fluoro-4-(3-oxa-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoic acid I97

    [0638] To a solution of (3-fluoro-4-methyl-phenyl)-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone 196 (800 mg, 3.2 mmol) in a mixture of pyridine (6 mL) and H.sub.2O (12 mL) was added KMnO.sub.4 (5.1 g, 32 mmol) and the mixture was stirred at room temperature for 2 days. The resulting suspension was filtered through Celite and the filtrate washed with DCM (3×50 mL). The remaining aqueous layer was acidified to pH 3 by addition of 2M HCl, and extracted with DCM (4×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as an off-white solid (500 mg, 56%). LCMS-C: RT 2.89 min; m/z 280.1 [M+H].sup.+.

    (xxxvi) 6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinic acid I103

    [0639] ##STR00101##

    (a) Ethyl 4-ethoxypicolinate I98

    [0640] A solution of 4-chloropicolinonitrile (5.5 g, 39.7 mmol) in saturated HCl/EtOH solution (80 mL) was stirred at 80° C. for 2 days. The solvent was removed under reduced pressure, saturated aqueous NaHCO.sub.3 (200 mL) was added and the aqueous layer extracted with DCM (3×200 mL). The pooled organic extracts were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (2.6 g, 34%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (d, J=5.6 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 6.93-6.91 (m, 1H), 4.80-4.43 (m, 2H), 4.16-4.11 (m, 2H), 1.46-1.41 (m, 6H). LCMS-C: RT 1.35 min; m/z 196.1[M+H].sup.+.

    (b) Ethyl 5-bromo-4-ethoxypicolinate I99

    [0641] To a solution of ethyl 4-ethoxypicolinate I98 (1.6 g, 8.2 mmol) in concentrated H.sub.2SO.sub.4 (80 mL) was added NBS (2.7 g, 14.8 mmol). The reaction was stirred at room temperature overnight then quenched by addition of saturated aqueous NaHCO.sub.3 (150 mL). The aqueous layer was extracted with DCM (3×130 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a yellow solid (2.0 g, 91%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67 (s, 1H), 7.63 (s, 1H), 4.94-4.40 (m, 2H), 4.29-4.23 (m, 2H), 1.54-1.51 (m, 3H), 1.46-1.42 (m, 3H); LCMS-C: RT 2.59 min; m/z 274.0, 276.0 [M+H].sup.+.

    (c) 5-Bromo-4-ethoxypicolinic acid I100

    [0642] To a solution of ethyl 5-bromo-4-ethoxypicolinate I99 (1.6 g, 6.0 mmol) in a mixture of THF (20 mL), MeOH (2 mL) and H.sub.2O (0.2 mL) was added LiOH.H.sub.2O (1.0 g, 24.0 mmol). The reaction was then stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue obtained dissolved in water (10 mL) and acidified to pH 3 with 1 M HCl. The aqueous phase was extracted with DCM (4×50 mL) and the pooled organic extracts dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a yellow solid (800 mg, 54%). LCMS-C: RT 0.86 min; m/z 246.0, 248.0 [M+H].sup.+

    (d) 3-Oxa-8-azabicyclo[3.2.1]octan-8-yl(5-bromo-4-ethoxypyridin-2-yl)methanone I101

    [0643] To a solution of 5-bromo-4-ethoxypicolinic acid I100 (300 mg, 1.2 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (153 mg, 1.0 mmol) in DCM (5 mL) were added DIPEA (0.72 mL, 4.1 mmol), EDCl (393 mg, 2.0 mmol) and HOBt (15 mg, 0.1 mmol). The mixture was stirred at room temperature overnight, then quenched by addition of saturated aqueous NaHCO.sub.3 (50 mL) and the mixture was extracted with DCM (3×50 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated and the residue obtained purified by chromatography (20% EtOAc/petroleum ether) to give the title compound as a yellow solid (262 mg, 75%). LCMS-C: RT 5.56 min; m/z 340.9, 342.9 [M+H].sup.+

    (e) Methyl 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinate I102

    [0644] To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(5-bromo-4-ethoxypyridin-2-yl)methanone I101 (650 mg, 1.9 mmol) in MeOH (50 mL) was added Et.sub.3N (577 mg, 5.7 mmol) and PdCl.sub.2(dppf) (73 mg, 0.05 mmol). The reaction was then heated at reflux for 2 days under an atmosphere of CO. The solvent was removed under reduced pressure and the residue obtained taken up in water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried over (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by chromatography (33% EtOAc/petroleum ether) to give the title compound as a brown solid (400 mg, 66%). LCMS-C: RT 4.94 min; m/z 320.8 [M+H].sup.+.

    (f) 6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinic acid I103

    [0645] To a solution of methyl 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinate I102 (350 mg, 1.1 mmol) in MeOH (20 mL) was added 1 M aqueous NaOH (2.2 mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue obtained taken up in water (15 mL). The aqueous was acidified to pH 4 by addition of 1M HCl, then extracted with DCM (4×60 mL) and the pooled extracts dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a yellow solid (320 mg, 95%). LCMS-C: RT 0.61 min; m/z 307.1 [M+H].sup.+.

    (xxxvii) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-chlorobenzoic acid 105

    [0646] ##STR00102##

    (a) 3-Oxa-8-azabicyclo[3.2.1]octan-8-yl(3-chloro-4-methylphenyl)methanone I104

    [0647] To a solution of 3-chloro-4-methylbenzoic acid (2.26 g, 13.24 mmol) in DCM (20 mL) was added DIPEA (4.7 g, 36.10 mmol), EDCl (3.5 g, 18.05 mmol), HOBt (190 mg, 1.40 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.8 g, 12.03 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (10 mL) and partitioned against DCM (10 mL). The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts washed with saturated NaHCO.sub.3 (3×5 mL) and brine (3×5 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/10) to give the title compound (3.0 g, 92%) as a white solid. .sup.1HNMR (400 MHz, Methanol-d.sub.4) δ 7.50 (d, J=1.6 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.33 (dd, J=7.6, 1.6 Hz, 1H), 4.61-4.56 (m, 1H), 3.99 (s, 1H), 3.78-3.59 (m, 4H), 2.41 (s, 3H), 2.00-1.99 (m, 4H); LCMS-C: RT 2.51 min; m/z 266.1 [M+H].sup.+

    (b) 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-chlorobenzoic acid I105

    [0648] To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(3-chloro-4-methylphenyl)methanone I104 (500 mg, 1.88 mmol) in a mixture of pyridine (5 mL) and water (15 mL) was added KMnO.sub.4 (1.78 g, 11.28 mmol) in portions. The resulting mixture was heated to 50° C. and stirred for 48 hours. The mixture was filtered and the filtrate was extracted with ethyl acetate (3×5 mL). The pH of the aqueous phase was adjusted to pH 1-2 by addition of concentrated HCl, then extracted with DCM (8×5 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated to give the title compound (340 mg, 61%) as a white solid. LCMS RT 0.88 min; m/z 296.1 [M+H].sup.+.

    (xxxviii) 2-(Trifluoromethyl)-1H-benzo[d]imidazole-6-carboxylic acid I106

    [0649] ##STR00103##

    [0650] A solution of 3,4-diaminobenzoic acid (1.0 g, 6.6 mmol) in TFA (15 mL) was stirred at 70° C. for 16 hours. The reaction mixture was concentrated, the crude material was purified by column chromatography (DCM:methanol=50:1) to give the title compound as an off-white solid (1.3 g, 86%). LCMS-C: RT 1.76 min; m/z 231.1 [M+H].sup.+.

    (xxxix) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(difluoromethyl)benzoic acid I110

    [0651] ##STR00104##

    (a) 4-(Methoxycarbonyl)-2-methylbenzoic acid I107

    [0652] A solution of methyl 4-iodo-3-methylbenzoate (2.0 g, 7.2 mmol) in THF (30 mL) under N.sub.2 was cooled to −20° C., a solution of iso-propylmagnesium chloride (2 M in THF, 4 mL, 8.0 mmol) was added dropwise and the suspension stirred at −20° C. for 1 hour. CO.sub.2 (g) was bubbled through the mixture, and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and water was added, the aqueous layer was washed with DCM (15 mL×3) and the pH adjusted to 3 by addition of 3M HCl. The mixture was extracted with DCM (15 mL×3) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (870 mg, 88%). LCMS-C: RT 2.26 min; m/z 195.1 [M+H].sup.+.

    (b) 2-(Difluoromethyl)-4-(methoxycarbonyl)benzoic acid I108

    [0653] To a solution of 4-(methoxycarbonyl)-2-methylbenzoic acid I107 (450 mg, 2.3 mmol) in MeCN (20 mL) and water (20 mL) was added AgNO.sub.3 (79 mg, 0.5 mmol), Na.sub.2S.sub.2O.sub.8 (552 mg, 2.3 mmol) and Selectfluor@ (4.6 g, 13.9 mmol). The resulting mixture was stirred at 80° C. for 6 hours. Further AgNO.sub.3 (19 mg, 0.003 mmol), Na.sub.2S.sub.2O.sub.8 (138 mg, 0.6 mmol) and Selectfluor@(1.2 g, 3.5 mmol) were added and the resulting mixture was stirred at 80° C. for 3 hours. The pH of the reaction mixture was adjusted to pH 9 by addition of saturated aqueous NaHCO.sub.3 solution and washed with DCM (20 mL×2). The pH of the aqueous fraction that remained was adjusted to 3-4 by addition of 2M HCl solution and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (10 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (180 mg, 41%) as a yellow solid. LCMS-C: RT 2.30 min; m/z 229.1 [M−H].sup.+.

    (c) Methyl4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(difluoromethyl)benzoate I109

    [0654] To a solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (59 mg, 0.4 mmol) in DCM (5 mL) was added 2-(difluoromethyl)-4-(methoxycarbonyl)benzoic acid I108 (100 mg, 0.4 mmol), HOBt (5.3 mg, 0.04 mmol), DIPEA (102 mg, 0.79 mmol) and EDCl (91 mg, 0.5 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned against saturated aqueous NaHCO.sub.3, the organic layer was washed with brine (4 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by prep TLC (DCM:methanol=20:1) to give the title compound as a white solid (45 mg, 35%). LCMS-C: RT 2.40 min; m/z 326.1 [M+H].sup.+.

    (d) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(difluoromethyl)benzoic acid I110

    [0655] To a solution of methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(difluoromethyl) benzoate I109 (42 mg, 0.13 mmol) in a mixture of THF (5 mL), methanol (0.5 mL) and water (0.5 mL) was added LiOH.H.sub.2O (27 mg, 0.65 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was diluted with water (3 mL) and the pH of the aqueous mixture was adjusted to 6 by addition of 2 M HCl. The aqueous solution was extracted with DCM (3 mL×2) and the combined organic layers washed with brine (2 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (49 mg, quantitative yield). LCMS-C: RT 1.95 min; m/z 312.1 [M+H].sup.+.

    (xl) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I112

    [0656] ##STR00105##

    (a) 3-Methoxy-4-(methoxycarbonyl)benzoic acid I111

    [0657] To a mixture of 2-hydroxy-4-methylbenzoic acid (10.0 g, 65.7 mmol) and K.sub.2CO.sub.3 (22.7 g, 164.3 mmol) in DMF (200 mL) at room temperature was added methyl iodide (20.5 g, 144.5 mmol) over a period of 10 minutes. The resulting mixture was stirred at room temperature overnight, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL×10) and brine (200 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the intermediate as a yellow liquid (11.0 g).

    [0658] To a solution of the intermediate in a mixture of pyridine (30 mL) and water (90 mL) was added KMnO.sub.4 (30.37 g, 192.2 mmol). The resulting mixture was heated at 50° C. for 48 hours, then cooled and allowed to stir at room temperature for 24 hours. The mixture was filtered and the filter cake washed with hot water. The combined aqueous filtrates were washed with EtOAc (75 mL×3) and acidified to pH 2 with 2M aqueous HCl solution. The mixture was extracted with DCM (150 mL×3) and the combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (7.0 g, 51% yield over 2 steps): LCMS-C: RT 1.24 min; m/z 211.0 [M+H].sup.+.

    (b) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-methoxybenzoic acid I112

    [0659] To a solution of 3-methoxy-4-(methoxycarbonyl)benzoic acid I111 (0.5 g, 2.4 mmol) in DCM (20 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.38 g, 2.5 mmol), HOBt (0.43 g, 3.2 mmol), triethylamine (0.85 g, 8.4 mmol) and EDCl (0.60 g, 3.2 mmol). The resulting mixture was stirred at room temperature overnight. Saturated aqueous NaHCO.sub.3 was added, the organic layer was separated and the aqueous extracted with DCM (20 mL×2). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (5% methanol in dichloromethane) to give the intermediate as a white solid.

    [0660] To a solution of the intermediate in a mixture of THF (4 mL) and methanol (4 mL) was added aqueous NaOH (2 M, 4 mL). The resulting mixture was then stirred at room temperature for 14 hours. The solvent was removed, and the residue obtained was diluted with water (20 mL). The pH of the aqueous mixture was adjusted to 6 by addition of 2 M aqueous HCl solution. The mixture was extracted with DCM (20 mL×3) and the combined organic layers washed with brine (10 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (0.7 g, quantitative yield over 2 steps). LCMS-C: RT 0.55 min; m/z 292.1 [M+H].sup.+.

    (xli) 2-(1-Acetylioeridin-4-yl)-1H-benzo[d]imidazole-5-carboxylic acid I117

    [0661] ##STR00106##

    (a) Piperidine-4-carboxylic acid hydrochloride I113

    [0662] A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.4 mmol) in saturated EtOAc/HCl solution (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound (720 mg, 99%) as a white solid. LCMS-C: RT 0.72 min; m/z 130.1 [M+H].sup.+ for free base.

    (b) 1-Acetylpiperidine-4-carboxylic acid I114

    [0663] To a mixture of piperidine-4-carboxylic acid hydrochloride I113 (720 mg, 4.3 mmol) and Et.sub.3N (528 mg, 5.2 mmol) in DCM (10 mL) was added Ac.sub.2O (488 mg, 4.8 mmol). The reaction was stirred at room temperature overnight then concentrated and the residue obtained recrystallized from EtOH to give the title compound (400 mg, 54%) as a white solid. LCMS-C: RT 0.73 min; m/z 172.1 [M+H].sup.+.

    (c) Methyl 2-(1-acetylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylate I16

    [0664] A mixture of 1-acetylpiperidine-4-carboxylic acid I114 (200 mg, 1.2 mmol), methyl 3,4-diaminobenzoate (194 mg, 1.2 mmol), EDCl (269 mg, 1.4 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (302 mg, 2.3 mmol) in DCM (5 mL) was stirred at room temperature overnight. The precipitate was collected by filtration and the filter cake dried to give an intermediate compound (182 mg, 49%) as a yellow oil. LCMS-C: RT 4.27 min; m/z 319.9 [M+H].sup.+.

    [0665] A mixture of the intermediate compound (130 mg, 0.41 mmol) in AcOH (5 mL) was heated at 65° C. for 3 hours to form a clear solution. The reaction mixture was neutralised with saturated aqueous NaHCO.sub.3 to pH 6-7 and extracted with DCM (3×10 mL). The combined organic layers were washed with brine and dried (Na.sub.2SO.sub.4). The chemistry was repeated with a further 50 mg of starting material and the product from the two batches combined to give the title compound (110 mg, 65%). LCMS-C: RT 4.28 min; m/z 301.9 [M+H].sup.+.

    (d) 2-(1-Acetylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylic acid I117

    [0666] To a mixture of methyl 2-(1-acetylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxylate I116 (110 mg, 0.36 mmol) in a mixture of THF (1 mL), MeOH (2 mL) and water (1 mL) was added LiOH—H.sub.2O (136 mg, 3.2 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue obtained re-dissolved in water (3 mL) then neutralised by addition of 10% aqueous H.sub.2SO.sub.4 to pH 6. The aqueous solution was lyophilized to give the crude title compound (300 mg) as yellow solid containing some Li.sub.2SO.sub.4 which was used in the next step without purification. LCMS-C: RT 0.30 min; m/z 288.1 [M+H].sup.+.

    (xlii) 2-Ethoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid I120

    [0667] ##STR00107##

    (a) Ethyl 4-(2-acetylhydrazinecarbonyl)-2-ethoxybenzoate I118

    [0668] To a solution of 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I40 (500 mg, 2.1 mmol) in DCM (20 mL) was added DIPEA (960 mg, 7.4 mmol), HOBt (30 mg, 0.2 mmol), EDCl (800 mg, 4.2 mmol) and acetohydrazide (156 mg, 2.1 mmol). The mixture was stirred at room temperature overnight then diluted with DCM (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (100% DCM to 4% MeOH in DCM) to give the title compound as an off-white solid (350 mg, 57%). LCMS-C: RT 4.79 min; m/z 294.9 [M+H].sup.+.

    (b) Ethyl 2-ethoxy-4-(5-methyl-1,3, 4-oxadiazol-2-yl)benzoate I119

    [0669] A mixture of ethyl 4-(2-acetylhydrazinecarbonyl)-2-ethoxybenzoate I118 (330 mg, 1.1 mmol) in POCl.sub.3 (3 mL) was heated at reflux for 1.5 hours. The mixture was poured into ice-water (20 mL) and the aqueous layer extracted with DCM (20 mL×2). The combined organic layers were washed with saturated NaHCO.sub.3 (40 mL×3) and brine (40 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the crude product as a yellow solid (290 mg, 94%). The crude product was used for the next step without purification. LCMS-C: RT 5.40 min; m/z 277.0 [M+H].sup.+.

    (c) 2-Ethoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid I120

    [0670] To a solution of ethyl 2-ethoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoate I119 (270 mg, 1.0 mmol) in MeOH (10 mL) was added a solution of NaOH (193 mg, 4.8 mmol) in water (2 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue obtained suspended in water (5 mL). The pH of the aqueous solution was adjusted to pH 4-5 by addition of 1 M aqueous HCl solution. The solid which precipitated was collected by filtration, washed with water (5 mL) and dried to give the title compound as a yellow solid (110 mg, 45%). LCMS-C: RT 4.77 min, m/z 249.0 [M+H],

    (xliii) 2-Chloro-6-(oxetan-3-yloxy)isonicotinic acid I121

    [0671] ##STR00108##

    [0672] To a mixture of oxetan-3-ol (1.1 g 15.6 mmol) in dry DMF (20 mL) was added NaH (60% in mineral oil, 832 mg, 20.8 mmol) at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 minutes, then 2,6-dichloroisonicotinic acid (2.0 g, 10.4 mmol) was added. The resulting mixture was heated to 50° C. overnight. Water (20 mL) was added and the mixture was acidified with 1 M HCl to form a white suspension. The solid was collected by filtration to give the title compound (2.0 g, 83%) as a white solid. LCMS-C: RT 2.24 min; m/z 230.0, 232.0 [M+H].sup.+

    (xliv) 6-((1-Acetylpiperidin-4-yl)oxy)pyridazine-4-carboxylic acid I124

    [0673] ##STR00109##

    (a) Piperidin-4-ol hydrochloride I122

    [0674] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.9 g, 49.7 mmol, 1.0 eq) in EtOAc (40 mL) was added a saturated solution of HCl in EtOAc (10 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to give the title compound (7.0 g) as a white solid.

    (b) 1-(4-hydroxypiperidin-1-yl) ethanone I123

    [0675] A mixture of piperidin-4-ol hydrochloride salt I122 (1.63 g, 11.9 mmol), acetic anhydride (1.82 g, 17.8 mmol) and K.sub.2CO.sub.3 (4.11 g, 29.7 mmol) in acetone (25 mL) was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the crude title compound (1.6 g) as yellow oil which was used for the next step without further purification. LCMS-C: RT 0.29 min; m/z 144.1 [M+H].sup.+

    (c) 6-((1-Acetylpiperidin-4-yl)oxy)pyridazine-4-carboxylic acid I124

    [0676] To a solution of 1-(4-hydroxypiperidin-1-yl)ethanone I123 (166 mg, 1.16 mmol, 2.0 eq) in DMF (5 mL) at 0° C. was added NaH (60% in mineral oil, 58 mg, 1.45 mmol, 2.5 eq). Methyl 6-chloropyridazine-4-carboxylate (100 mg, 0.58 mmol, 1.0 eq) was added and the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous NaHCO.sub.3 (15 mL) and the aqueous washed with DCM (15 mL×3). The aqueous layer was acidified to pH 5 with 1M HCl and extracted with DCM (15 mL×3), the combined organic fractions were dried (MgSO.sub.4) and concentrated to give the crude title compound (130 mg) as a brown oil. LCMS-C: RT 2.19 min, m/z 266.1 [M+H].sup.+

    (xlv) 1-(Tetrahydro-2H-pran-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid I129

    [0677] ##STR00110##

    (a) Methyl 3-fluoro-2-nitrobenzoate I125

    [0678] To a solution of 3-fluoro-2-nitrobenzoic acid (1.0 g, 5.4 mmol) in DCM (15 mL) and DMF (1 drop) was added (COCl).sub.2 (1.4 g, 10.8 mmol) dropwise. The mixture was stirred at room temperature for 2 hours. Methanol (5 mL) was added dropwise to the mixture and stirring was continued for 1 hour. The solvent was removed and the residue was dissolved in DCM (50 mL), the organic layer was washed with saturated NaHCO.sub.3 (50 mL), water (50 mL) and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a colourless solid (1.0 g, 93%). LCMS-C: RT 2.30 min; m/z 222.0 [M+Na].sup.+.

    (b) Methyl 2-nitro-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate I126

    [0679] To a solution of methyl 3-fluoro-2-nitrobenzoate I125 (100 mg, 0.5 mmol) in MeCN (5 mL) were added tetrahydro-2H-pyran-4-amine (50 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol). The mixture was heated at 50° C. overnight. The solvent was removed and the residue diluted with EtOAc (30 mL). The organic layer was washed with water (30 mL×2) and brine (30 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a brown solid (130 mg, 93%). LCMS-C: RT 2.28 min; m/z 281.1 [M+H].sup.+.

    (c) Methyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate I127

    [0680] To a solution of methyl 2-nitro-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate I126 (130 mg, 0.46 mmol) in EtOH (4 mL) was added 10% Pd/C (20 mg). The mixture was stirred under a hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration through Celite and the filtrate concentrated to give the title compound as a yellow solid (100 mg, 86%). LCMS-C: RT 2.32 min; m/z 251.1 [M+H]f.

    (d) Methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4-carboxylate I128

    [0681] To a solution of methyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate I127 (100 mg, 0.4 mmol) in trimethyl orthoformate (1 mL) was added TsOH.H.sub.2O (8 mg, 0.04 mmol). The reaction was heated at 100° C. for 2.5 hours then cooled to room temperature and poured into water (10 mL). The aqueous layer was extracted with EtOAc (10 mL×2), the combined organic fractions were dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by preparative TLC (6% MeOH/DCM) to give the title compound as a grey solid (45 mg, 43%). LCMS-C: RT 0.33 min; m/z 261.1 [M+H].sup.+.

    (e) 1-(Tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid I129

    [0682] To a solution of methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4-carboxylate I128 (300 mg, 1.1 mmol) in MeOH (5 mL) was added a solution of NaOH (90 mg, 2.2 mmol) in water (1 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue re-suspended in water (5 mL). The pH of the aqueous solution was adjusted to 4-5 by addition of 1 M aqueous HCl solution. The precipitate was collected by filtration, washed with water (5 mL) and dried in air to give the title compound as a grey solid (150 mg, 53%). LCMS-C: RT 0.66 min, m/z 247.1 [M+H].sup.+

    (xlvi) 2-Methyl-1-(tetrahydro-2H-pran-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid I131

    [0683] ##STR00111##

    (a) Methyl 2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4-carboxylate I130

    [0684] To a solution of methyl 2-amino-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate I127 (300 mg, 1.2 mmol) in triethyl orthoacetate (5 mL) was added TsOH.H.sub.2O (23 mg, 0.12 mmol). The mixture was heated at 100° C. for 3 hours then cooled to room temperature and poured into water (50 mL). The aqueous layer was extracted with EtOAc (50 mL×2) and the combined organic fractions washed with brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (2% MeOH/DCM) to give the title compound as a solid (200 mg, 52%). LCMS-C: RT 0.34 min, m/z 275.1 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.96 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.33 (t, J=8.4 Hz, 1H), 4.83-4.66 (m, 1H), 4.16-4.12 (m, 2H), 3.97 (s, 3H), 3.69-3.63 (m, 2H), 2.72 (s, 3H), 2.62-2.51 (m, 2H), 1.90-1.86 (m, 2H).

    (b) 2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid I131

    [0685] To a solution of methyl 2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-4-carboxylate I130 (200 mg, 0.73 mmol) in MeOH (5 mL) was added a solution of NaOH (60 mg, 1.46 mmol) in water (1 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue suspended in water (2 mL). The pH of the aqueous solution was adjusted to 4-5 by addition of 1 M aqueous HCl solution. The aqueous layer was washed with DCM (3 mL×2) and lyophilized to give the title compound as a brown solid (220 mg). The crude product was used in the next step without further purification. LCMS-C: RT 0.31 min, m/z 261.1 [M+H].sup.+

    (xlvii) Lithium 5-((1-(methoxycarbonyl)piperidin-4-yl)oxy)nicotinate I135

    [0686] ##STR00112##

    (a) Methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)nicotinate I132

    [0687] To a solution of methyl 5-hydroxynicotinate (500 mg, 3.3 mmol) in dry THF (10 mL) at 0° C. were added tert-butyl 4-hydroxypiperidine-1-carboxylate (660 mg, 3.3 mmol), DIAD (870 mg, 4.3 mmol) and PPh.sub.3 (950 mg, 3.6 mmol). The mixture was stirred at 0° C. for 1 hour then allowed to warm slowly to room temperature and stirred overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by column chromatography (20% EtOAc/petroleum ether) to give the title compound as yellow oil (580 mg, 58%). LCMS-C: RT 2.77 min, m/z 337.2 [M+H].sup.+

    (b) Methyl 5-(piperidin-4-yloxy)nicotinate dihydrochloride I133

    [0688] A mixture of methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)nicotinate I132 (570 mg, 1.7 mmol) in HCl in diethyl ether (2.0 M, 5 mL) was stirred at room temperature for 3 hours. The solvent was removed to give the title compound as an off-white solid (500 mg, 96%). LCMS-C: RT 0.31 min, m/z 237.1 [M+H].sup.+

    (c) Methyl 5-((1-(methoxycarbonyl)piperidin-4-yl)oxy)nicotinate I134

    [0689] To a solution of methyl 5-(piperidin-4-yloxy)nicotinate dihydrochloride I133 (500 mg, 1.6 mmol) in DCM (10 mL) was added Et.sub.3N (520 mg, 5.1 mmol). Methyl chloroformate (185 mg, 1.9 mmol) was then added dropwise and the mixture stirred at room temperature for 1 hour. The mixture was diluted with DCM (50 mL) and washed with water (50 mL) and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (5% methanol/DCM) to give the title compound as a yellow oil (390 mg, 82%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (d, J=1.6 Hz, 1H), 8.47 (d, J=2.8 Hz, 1H), 7.92 (dd, J=2.8, 1.6 Hz, 1H), 4.80-4.74 (m, 1H), 3.95 (s, 3H), 3.80-3.74 (m, 2H), 3.70 (s, 3H), 3.46-3.40 (m, 2H), 2.04-1.98 (m, 2H), 1.78-1.70 (m, 2H). LCMS-C: RT 2.34 min, m/z 295.1 [M+H].sup.+

    (d) Lithium 5-((1-(methoxycarbonyl)piperidin-4-yl)oxy)nicotinate I135

    [0690] To a solution of methyl 5-((1-(methoxycarbonyl)piperidin-4-yl)oxy)nicotinate I134 (350 mg, 1.2 mmol) in a mixture of THF (3 mL), MeOH (6 mL) and water (1.5 mL) was added LiOH.H.sub.2O (50 mg, 2.4 mmol). The reaction was stirred at room temperature overnight then concentrated under reduced pressure. The residue obtained was re-dissolved in water (3 mL) and lyophilized to give the title compound as a white solid (420 mg). LCMS-C: RT 1.31 min; m/z 281.1 [M-Li+2H].sup.+.

    (xlviii) 5-Methoxynicotinic acid I137

    [0691] ##STR00113##

    (a) Methyl 5-methoxynicotinate I136

    [0692] To a suspension of NaH (60% in mineral oil, 1.46 g, 0.03 mol, washed three times with hexane) in DMF (50 mL) was added methyl-5-hydroxynicotinate (4.0 g, 0.04 mol) portion-wise, keeping the temperature below 10° C. After 30 minutes, methyl iodide (3.87 g, 0.03 mol) was added dropwise over 20 minutes. The mixture was stirred at room temperature for 3 hours, then quenched with MeOH and concentrated in vacuo. The residue was dissolved in chloroform and partitioned against saturated NaHCO.sub.3 and brine. The organic layer was separated and the aqueous layer was extracted with chloroform, the combined organic fractions were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue obtained was purified by flash silica gel chromatography (petroleum ether/EtOAc=5/1 then 3/1) to give the title compound (1.0 g, 23%) as a white solid. LCMS-C: RT 1.16 min; m/z 168.1 [M+H].

    (b) 5-Methoxynicotinic acid I137

    [0693] To a solution of methyl 5-methoxynicotinate I136 (300 mg, 1.79 mmol) in a mixture of THF (4 mL) and methanol (4 mL) was added NaOH (2 M aqueous solution, 3 mL). The resulting mixture was stirred at room temperature for 14 hours. The solvent was removed and the residue obtained diluted with water (20 mL). The pH of the aqueous mixture was adjusted to 6 by addition of a 2 M aqueous HCl solution. The mixture was extracted with DCM (20 mL×3) and the combined organic layers washed with brine (10 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (230 mg, 84%). LCMS-C: RT 0.36 min; m/z 154.1 [M+H].sup.+.

    (il) Alternate synthesis of (S)-tert-Butyl 3-((R)-2-(6-chloronicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A19

    [0694] ##STR00114##

    [0695] To a solution of (S)-tert-butyl 3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (500 mg, 1.71 mmol, 1.0 eq) in DCM (10 mL) at 0° C. was added Et.sub.3N (520 mg, 5.13 mmol, 3.0 eq) and 6-chloronicotinoyl chloride (301 mg, 1.71 mmol, 1.0 eq). The reaction was stirred at room temperature under a nitrogen atmosphere overnight. Saturated aqueous NaHCO.sub.3 (50 mL) was added and the resulting mixture extracted with DCM (3×50 mL). The combined organic fractions were dried (Na.sub.2SO.sub.4) and concentrated and the crude residue purified by chromatography (25% EtOAc/petroleum ether) to give the title compound (510 mg, 69%) as a white solid. LCMS-C: RT 2.87 min; m/z 454.2 [M+Na].sup.+.

    (l) 5-Isopropoxynicotinic acid I39

    [0696] ##STR00115##

    (a) Methyl 5-isopropoxynicotinate I38

    [0697] A mixture of DCC (1.62 g, 7.84 mmol) and CuCl (129 mg, 1.31 mmol) in isopropanol (20 mL) was heated at 60° C. After 13 hours, 5-hydroxynicotinic acid methyl ester (1.0 g, 6.53 mmol) and benzene (20 mL) were added and the reaction heated at 105° C. for 24 hours. The mixture was diluted with chloroform and filtered. The organic filtrate was washed with saturated NaHCO.sub.3(15 mL), water and brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash silica gel chromatography (EtOAc/petroleum ether=1/6) gave the title compound (300 mg, 24%) as a white solid. LCMS-C: RT 2.32 min; m/z 196.1 [M+H].sup.+.

    (b) 5-Isopropoxynicotinic acid I39

    [0698] To a solution of methyl 5-isopropoxynicotinate I38 (300 mg, 1.54 mmol) in a mixture of THF (2 mL) and methanol (4 mL) was added NaOH (2M aqueous solution, 2 mL). The resulting mixture was stirred at room temperature for 14 hours. The solvent was removed, and the residue diluted with water (20 mL). The pH of the aqueous mixture was adjusted to 6 by addition of a 2 M aqueous HCl solution. The mixture was extracted with DCM (20 mL×3) and the combined organic layers washed with brine (10 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (250 mg, 90%) as a white solid. LCMS-C: RT 0.88 min; m/z 182.1 [M+H].sup.+.

    Example 1: N-(2-Hydroxy-3-(1,2,3,4-tetrahydroisoquinolin-3-yl)propyl)-4-(morpholine-4-carbonyl)benzamide (1)

    [0699] ##STR00116##

    (a) 1-Amino-3-(isoquinolin-3-yl)propan-2-ol (A1)

    [0700] 2-(2-Hydroxy-3-(isoquinolin-3-yl)propyl)isoindoline-1,3-dione I3 (114 mg, 0.343 mmol) and absolute ethanol (5 mL) were brought to 80° C. Hydrazine hydrate (0.25 mL, 8.0 mmol) was added and the mixture stirred at 80° C. After two hours, the heterogeneous mixture was cooled to room temperature, diluted with cold absolute ethanol (5 mL) and filtered. The collected solids were washed with cold ethanol (2 mL) and the combined filtrates were concentrated. The residue was dissolved in absolute ethanol and concentrated in vacuo three times to give the desired compound as a pale yellow syrup (70 mg, quant.). The material was taken onto the next step without further purification. .sup.1H NMR (400 MHz, d.sub.4-methanol) δ 9.19 (s, 1H), 8.22-8.16 (m, OH), 8.08-8.02 (m, 1H), 7.89-7.83 (m, 1H), 7.79-7.73 (m, 1H), 7.71 (s, 1H), 7.66-7.59 (m, 1H), 4.11-4.03 (m, 1H), 3.12-2.97 (m, 2H), 2.85-2.77 (m, 1H), 2.73-2.64 (m, 1H). LCMS-B: RT 1.55 min; m/z 203.2 [M+H].sup.+.

    (b) N-(2-Hydroxy-3-(isoquinolin-3-yl)propyl)-4-(morpholine-4-carbonyl)benzamide A2

    [0701] 1-Amino-3-(isoquinolin-3-yl)propan-2-ol A1 (70 mg, 0.35 mmol), DMF (2.5 mL), DIPEA (0.121 mL, 0.69 mmol), 4-(morpholine-4-carbonyl)benzoic acid I7 (90 mg, 0.38 mmol) and HATU (197 mg, 0.52 mmol) were stirred at room temperature. After 3 hours, the mixture was added to 2% w/v sodium hydroxide (50 mL) and extracted with DCM (3×30 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. Chromatography (12 g silica cartridge, 0-10% methanol/DCM) gave the desired compound as a white solid (88 mg, 61%). .sup.1H NMR (400 MHz, d.sub.4-methanol) δ 9.18 (s, 1H), 8.09-8.02 (m, 1H), 7.93-7.85 (m, 3H), 7.78-7.72 (m, 2H), 7.66-7.58 (m, 1H), 7.53-7.46 (m, 2H), 4.35-4.27 (m, 1H), 3.77 (br s, 3H), 3.66-3.57 (m, 3H), 3.55-3.47 (m, 2H), 3.22-3.14 (m, 1H), 3.11-3.04 (m, 1H); LCMS-B: RT 3.16 min; m/z 420.3 [M+H].sup.+; m/z 418.1 [M−H].sup.−.

    (c) N-(2-Hydroxy-3-(1,2,3,4-tetrahydroisoquinolin-3-yl)propyl)-4-(morpholine-4-carbonyl)benzamide (1)

    [0702] N-(2-Hydroxy-3-(isoquinolin-3-yl)propyl)-4-(morpholine-4-carbonyl)benzamide A2 (20 mg, 0.048 mmol) and nickel(II) chloride hexahydrate (14 mg, 0.057 mmol) were dissolved in methanol (2 mL). The mixture was stirred at room temperature and sodium borohydride (22 mg, 0.57 mmol) was added in one portion. After 30 minutes, the mixture was quenched with 3M HCl (0.5 mL) and concentrated in vacuo. The residue was suspended in methanol and applied to a 1 g SCX cartridge. The cartridge was washed with methanol (15 mL) and eluted with 2M ammonia in methanol (15 mL). The basic eluate was concentrated in vacuo. The residue and nickel(II) chloride hexahydrate (14 mg, 0.057 mmol) were dissolved in methanol (2 mL). The mixture was stirred at room temperature and sodium borohydride (22 mg, 0.57 mmol) was added in one portion. After one hour the mixture was quenched with 3M HCl (0.5 mL) and concentrated in vacuo. The residue was suspended in methanol and applied to 2×1 g SCX cartridges. The cartridges were each washed with methanol (15 mL) and eluted with 2M ammonia in methanol (15 mL). The combined basic eluate was concentrated in vacuo to give the desired compound as a colourless syrup (8 mg, 41%). LCMS-B: RT 3.18 min; m/z 424.3 [M+H].sup.+.

    Example 2: N-(2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide (2)

    [0703] ##STR00117##

    (a) 2-Amino-1-(isoquinolin-3-yl)ethan-1-ol (A3)

    [0704] 2-(2-Hydroxy-2-(isoquinolin-3-yl)ethyl)isoindoline-1,3-dione I5 (50 mg, 0.16 mmol) was dissolved in ethanol (1 mL) and hydrazine hydrate (0.050 mL, 0.79 mmol) was added. The mixture was heated at 80° C. for 3 hours and allowed to cool. The mixture was filtered and the solid was washed with further ethanol (2 mL). The combined filtrates were concentrated to give the desired compound as a yellow syrup (32 mg, >100% yield). The material was carried forward without further purification: LCMS-B: RT 2.06 min; m/z 189.2 [M+H].sup.+.

    (b) N-(2-Hydroxy-2-(isoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide (A4)

    [0705] 2-Amino-1-(isoquinolin-3-yl)ethan-1-ol A3 (32 mg, 0.16 mmol), DMF (1 mL), 4-(Morpholine-4-carbonyl)benzoic acid I7 (48 mg, 0.20 mmol), DIPEA (0.059 mL, 0.34 mmol) and HATU (97 mg, 0.26 mmol) were stood at room temperature. After 3 hours, the mixture was diluted with 2% w/v aqueous sodium hydroxide (10 mL) and extracted with chloroform (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. Chromatography (4 g silica cartridge, 0-10% methanol/chloroform) gave the desired compound as an off-white solid (29 mg, 45% yield over two steps): .sup.1H NMR (400 MHz, d.sub.4-methanol) δ 9.23 (s, 1H), 8.12-8.06 (m, 1H), 7.97-7.89 (m, 2H), 7.88-7.82 (m, 2H), 7.80-7.73 (m, 1H), 7.70-7.62 (m, 1H), 7.53-7.44 (m, 2H), 5.17-5.08 (m, 1H), 3.93-3.86 (m, 1H), 3.84-3.71 (m, 5H), 3.62 (br s, 2H), 3.42 (br s, 2H); LCMS-B: RT 3.15 min, m/z 406.2 [M+H].sup.+

    (c) N-(2-Hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide (2)

    [0706] N-(2-Hydroxy-2-(isoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide A4 (10 mg, 0.025 mmol) and nickel(II) chloride hexahydrate (7.0 mg, 0.030 mmol) were dissolved in methanol (1 mL) and sodium borohydride (12 mg, 0.30 mmol) was added. The black suspension was stirred at room temperature. The reaction was quenched with 1.25 M HCl in methanol (0.5 mL) and concentrated in vacuo. The residue was suspended in methanol (1 mL) and loaded onto a 1 g SCX cartridge. The cartridge was washed with methanol (10 mL) then eluted with 2.0 M ammonia in methanol (10 mL). The basic eluate was concentrated and the material was dissolved in methanol (1 mL. Nickel(II) chloride hexahydrate (7.0 mg, 0.030 mmol) and sodium borohydride (12 mg, 0.30 mmol) were added and the mixture stirred for 1.5 hours. The reaction was quenched with 1.25 M HCl in methanol (0.5 mL) and concentrated in vacuo. The residue was suspended in methanol (1 mL) and loaded onto a 1 g SCX cartridge. The cartridge was washed with methanol (10 mL) then eluted with 2.0 M ammonia in methanol (10 mL). The basic eluate was concentrated to give the desired compound as a white solid (6.1 mg, 60%). LCMS-B: RT 3.16 min; m/z 410.3 [M+H].sup.+.

    Examples 3-29, 57-89, 111-120 and 126 (Table A)

    [0707] ##STR00118##

    [0708] Method AA:

    [0709] The respective carboxylic acid (0.070 mmol), triethylamine (0.019 mL, 0.14 mmol), tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (20 mg, 0.068 mmol), DMF (0.5 mL) and HATU (39 mg, 0.10 mmol) were stood at room temperature. After 17 hours, water (1.5 mL) and DCM (1 mL) were added, the mixture agitated then passed through a phase separation cartridge. The collected DCM phase was diluted with 4.0 M HCl in 1,4-dioxane (1 mL), stood for 2 hours then loaded onto a 0.5 g SCX cartridge. The cartridge was washed with methanol (10 mL) then eluted with 2M ammonia in methanol (10 mL). The basic eluate was concentrated to afford the amide product.

    [0710] Method AB:

    [0711] To a solution of the respective acid (0.17 mmol, 1 equiv) in DMF (2 mL) and MeCN (2 mL) were added DIPEA (89 μL, 0.51 mmol, 3 equiv), HATU (97 mg, 0.26 mmol, 1.5 equiv) and a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (50 mg, 0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stirred at room temperature for 16 hours, then quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL). DCM was added and the mixture stirred and then passed through a phase separation cartridge (aqueous phase extracted ×3 with DCM). The combined organic filtrates were dried in vacuo to give a yellow oil which was taken up in 4.0 M HCl in 1,4-dioxane (1 mL) and stirred at room temperature for 2 days. The reaction was dried in vacuo and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia). The basic eluate was concentrated to afford the amide product.

    [0712] Method AC:

    [0713] To a solution of the respective acid (0.17 mmol, 1 equiv) in DMF (2 mL) and MeCN (5 mL) was added DIPEA (89 μL, 0.51 mmol, 3 equiv), HATU (98 mg, 0.26 mmol, 1.5 equiv) and tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (50 mg, 0.17 mmol, 1 equiv). The reaction was stirred for 16 hours at room temperature, then quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (3×5 mL) utilizing a phase separation cartridge. The organic filtrates were dried in vacuo to give a yellow oil which was taken up in 4.0 M HCl in 1,4-dioxane and stirred at room temperature for 16 hours. The reaction was dried in vacuo and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia). The basic eluate was concentrated to afford the amide product.

    [0714] Method AD:

    [0715] To a solution of the respective acid (0.17 mmol, 1 equiv), DIPEA (89 μL, 0.51 mmol, 3 equiv) and HATU (98 mg, 0.26 mmol, 1.5 equiv) was added a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (50 mg, 0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stood at room temperature for 16 hours, quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (×3) utilizing a phase separation cartridge. The organic filtrates were reduced under a stream of air, DCM:TFA (2 mL, 1:1) was added and the reaction stood at room temperature for the specified time. The reaction mixture was concentrated under a stream of air and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give the crude product which was further purified by column chromatography (12 g SiO.sub.2 cartridge, 50-100% EtOAc (modified by the addition of 1% v/v of 3.5 M methanolic ammonia) in petroleum benzine 40-60° C. followed by 0-50% MeOH in EtOAc modified by the addition of 1% v/v of 2.0 M methanolic ammonia) and then by preparative reversed phase HPLC (5-100% acetonitrile in water, 0.1% TFA). The product fractions were combined and dried in vacuo to give the amide product as a TFA salt.

    [0716] Method AE:

    [0717] To a solution of the respective acid (33 mg, 0.17 mmol, 1 equiv) in DMF (2 mL) was added DIPEA (104 μL, 0.595 mmol, 3 equiv), HATU (113 mg, 0.297 mmol, 1.5 equiv) and a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stirred at room temperature for 16 hours then quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (×3) utilizing a phase separation cartridge. The organic filtrates were dried in vacuo to give a yellow oil which was taken up in DCM (5 mL), TFA (1 mL) was subsequently added and the reaction was stirred at room temperature for 2 hours. The mixture was dried in vacuo and purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give the crude amide product as a brown oil. This material was further purified by column chromatography (12 g silica cartridge, 50-100% EtOAc (modified by the addition of 1% v/v of 3.5 M methanolic ammonia) in petroleum benzine 40-60° C. followed by 0-50% MeOH in EtOAc modified by the addition of 1% v/v of 2.0 M methanolic ammonia). The product-containing fractions were combined and stirred in EtOAc and a 1 M aqueous solution of NaOH (4 mL) for 2 hours. DCM was added and the mixture stirred and then passed through a phase separation cartridge (3 repeats). The organic filtrates were dried in vacuo and the residue purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give a yellow oil. The oil was further purified by preparative reversed phase HPLC (5-85% acetonitrile in water, 0.1% TFA). The product fractions were combined and dried in vacuo to give the amide product as a TFA salt.

    [0718] Method AF:

    [0719] tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (60 mg, 0.21 mmol), MeCN (2 mL), DIPEA (0.071 mL, 0.41 mmol), the respective acid (48 mg, 0.21 mmol) and HATU (117 mg, 0.31 mmol) were stirred at room temperature. After 18 hours the mixture was concentrated in vacuo, chromatography (4 g silica cartridge, 0-100% ethyl acetate/hexanes then 100% ethyl hexanes) gave the intermediate as a colourless syrup. This intermediate was dissolved in 1,4-dioxane (2.5 mL) and 4.0 M HCl in 1,4-dioxane (2.5 mL) was added. After 2 hours the mixture was diluted with diethyl ether (50 mL), the solvent decanted, the fine precipitate washed with diethyl ether (2×50 mL) and dried in vacuo to give the amide product.

    [0720] Method AG:

    [0721] tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I12) (50 mg, 0.17 mmol), MeCN (1.5 mL), DMF (0.5 mL), DIPEA (0.060 mL, 0.34 mmol), the respective acid (41 mg, 0.17 mmol) and BOP (113 mg, 0.26 mmol) were stirred at room temperature. After 18 hours the mixture was added to water (50 mL) and extracted with ethyl acetate (3×25 mL). The pooled ethyl acetate phases were washed with brine (2×30 mL), dried over sodium sulfate and concentrated in vacuo. Chromatography (4 g silica cartridge, 0-10% methanol/DCM) gave the intermediate as a pale yellow oil. This intermediate was dissolved in 1,4-dioxane (2 mL), and a solution of 4.0 M HCl in 1,4-dioxane (2 mL) was added. The mixture was stirred at room temperature for 3 hours, the solvent removed from the precipitate by decantation and the solid washed with diethyl ether (3×5 mL). The solid was dried in vacuo to give the amide product.

    [0722] Method AH:

    [0723] The respective carboxylic acid (0.068 mmol), triethylamine (0.019 mL, 0.14 mmol), tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (20 mg, 0.068 mmol), DMF (0.5 mL) and HATU (39 mg, 0.10 mmol) were stood at room temperature. After 17 hours, water (1.5 mL) and DCM (1 mL) were added, the mixture agitated then passed through a phase separation cartridge. The collected DCM phase was diluted with 4.0 M HCl in 1,4-dioxane (1 mL), stood for 17 hours, then loaded onto a 1 g SCX cartridge. The cartridge was washed with methanol (6 mL) then eluted with 7 M ammonia in methanol (6 mL). The basic eluate was concentrated to afford the desired compound.

    [0724] Method AI:

    [0725] To a solution of the respective acid (0.17 mmol, 1 equiv), DIPEA (89 μL, 0.51 mmol, 3 equiv) and HATU (98 mg, 0.26 mmol, 1.5 equiv) was added a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (50 mg, 0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stood at room temperature for 16 hours, quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (×3) utilizing a phase separation cartridge. The organic filtrates were reduced under a stream of air, DCM:TFA (2-4 mL, 1:1) was added and the reaction stood at room temperature for the specified time (see Table A). The reaction mixture was concentrated under a stream of air and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give the desired compound.

    [0726] Method AJ:

    [0727] The respective acid or lithium salt (0.068 mmol), triethylamine (0.019 mL, 0.14 mmol), tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (20 mg, 0.068 mmol), DMF (0.5 mL) and HATU (39 mg, 0.10 mmol) were stood at room temperature. After 17 hours, water (1.5 mL) and DCM (1.5 mL) were added, the mixture agitated then passed through a phase separation cartridge. The collected DCM phase was treated with 0.1 g Dowex 50×8 resin, H.sup.+-form, the mixture filtered and the filtrate diluted with 4.0 M HCl in 1,4-dioxane (2 mL). The mixture was stood for 3 hours then loaded onto a 1 g SCX cartridge. The cartridge was washed with methanol (15 mL) then eluted with 2 M ammonia in methanol (15 mL). The basic eluates were concentrated to afford the desired compound.

    [0728] Method AK:

    [0729] The crude lithium salt (0.059 mmol @ 100% conversion), triethylamine (0.016 mL, 0.12 mmol) and HATU in DMF (0.5 mL) were stood for two minutes then tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (17 mg, 0.059 mmol) was added. After 17 hours, the mixture was diluted with water and DCM (1.5 mL each), the DCM phase separated with a phase separation cartridge and treated with Dowex 50W×8 resin (H.sup.+-form, 200-400 mesh, 100 mg). The suspension was filtered and the collected beads washed with DCM (0.5 mL). The DCM filtrate was diluted with 4.0 M HCl/1,4-dioxane (2 mL) and stood at room temperature. After one hour, the mixture was diluted with methanol (2 mL) and loaded onto a 1 g SCX cartridge. The cartridge was washed with methanol (15 mL) and eluted with 2 M ammonia in methanol (10 mL). The basic eluate was concentrated to afford the desired compound.

    [0730] Method AL:

    [0731] To a solution of the respective acid (1.0 eq) or lithium salt and tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (1.0 eq) in DCM were added DIPEA (3.0 eq), HOBt (0.1 eq), and EDCl.HCl (2.0 eq). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with DCM (3 times). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by prep TLC (DCM:MeOH=20:1) to give the Boc protected intermediate. A solution of the Boc protected intermediate (1.0 eq) in saturated HCl/EtOAc solution or saturated HCl/diethyl ether solution was stirred at room temperature for 2-3 hours. The mixture was concentrated and the residue washed with diethyl ether to give the desired product. In some cases, the HCl salt is not pure enough, in such cases the crude product was added to aqueous saturated NaHCO.sub.3 solution. The resulting mixture was extracted with DCM (3 times). The organic layers were combined, dried (Na.sub.2SO.sub.4) and concentrated to give the residue which was purified by prep TLC (DCM:MeOH=15:1) to give the desired product.

    [0732] Method AM:

    [0733] To a solution of the respective lithium salt (1.0 eq) and tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (1.2 eq) in DMF were added Et.sub.3N (10.0 eq), T3P® (2.0 eq), and DMAP (0.5 eq). The resulting mixture was then stirred at room temperature for 1 hour. Water was added to the reaction mixture and the aqueous layer extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by prep TLC (DCM:MeOH=20:1) to give the Boc protected intermediate.

    [0734] A solution of the Boc protected intermediate (1.0 eq) in saturated HCl/EtOAc solution or saturated HCl/diethyl ether solution was stirred at room temperature for 2-3 hours. The mixture was concentrated and the residue was washed with diethyl ether to give the desired product.

    TABLE-US-00004 TABLE A Ex Name and Structure Analytical data Method 3 [00119]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 4.468 min; m/z 297.2 [M + H].sup.+ AA Stirred for 3 hours with HCl/1,4- dioxane. Elution with 7M ammonia in methanol. 4 [00120]embedded image   2-Chloro-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 4.484 min; m/z 331.1 [M + H].sup.+ AA Stirred for 3 hours with HCl/1,4- dioxane. Elution with 7M ammonia in methanol. 5 [00121]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (trifluoromethyl)benzamide LCMS-A: RT 4.600 min; m/z 365.2 [M + H].sup.+ AA Stirred for 3 hours with HCl/1,4- dioxane. Elution with 7M ammonia in methanol. 6 [00122]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (trifluoromethoxy)benzamide LCMS-A: RT 4.681 min; m/z 381.2 [M + H].sup.+ AA Stirred for 3 hours with HCl/1,4- dioxane. Elution with 7M ammonia in methanol. 7 [00123]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- methoxybenzamide LCMS-A: RT 4.546 min; m/z 327.2 [M + H].sup.+ AA Stirred for 3 hours with HCl/1,4-dioxane. Elution with 7M ammonia in methanol. 8 [00124]embedded image   2-Ethoxy-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 4.649 min; m/z 341.2 [M + H].sup.+ AA Stirred for 3 hours with HCl/1,4- dioxane. Elution with 7M ammonia in methanol. 9 [00125]embedded image   2-Fluoro-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 4.463 min; m/z 315.2 [M + H].sup.+ Stirred for 3 hours with HCl/1,4- dioxane. Elution with 7M ammonia in methanol. 10 [00126]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- methylbenzamide LCMS-A: RT 4.519 min; m/z 311.2 [M + H].sup.+ Stirred for 3 hours with HCl/1,4-dioxane. Elution with 7M ammonia in methanol. Carboxylic acid: I13 12 [00127]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-3- (pyridazin-4-yl)benzamide LCMS-B: RT 3.12 min; m/z 375.2 [M + H].sup.+ AA Carboxylic acid: I15 13 [00128]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(5- morpholino-1,3,4-oxadiazol-2- yl)benzamide LCMS-B: RT 3.18 min; m/z 450.2 [M + H].sup.+ AA Carboxylic acid: I17 14 [00129]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- phenyloxazole-4-carboxamide LCMS-B: RT 3.36 min; m/z 364.2 [M + H].sup.+ AA 15 [00130]embedded image   2-Fluoro-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-4-(morpholine-4- carbonyl)benzamide LCMS-B: RT 3.14 min; m/z 428.3 [M + H].sup.+ AA Carboxylic acid: I20 16 [00131]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- phenylthiazole-4-carboxamide LCMS-B: RT 3.39 min; m/z 380.2 [M + H].sup.+ AA 17 [00132]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-1- (pyridin-3-yl)-1H-pyrazole-4- carboxamide dihydrochloride salt LCMS-B: RT 3.10 min; m/z 364.2 [M + H].sup.+ (free base) AA Precipitated from HCl/1,4-dioxane, collected, washed with MeOH and dried to give the title compound. 18 [00133]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-3- (pyrimidin-5-yl)benzamide LCMS-B: RT 3.20 min; m/z 375.1 [M + H].sup.+ AA Carboxylic acid: I21 19 [00134]embedded image   N.sup.1-(1-Acetylpiperidin-4-yl)-N.sup.4-((R)-2- hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-N.sup.1 methylterephthalamide LCMS-B: RT 3.19 min; m/z 479.2 [M + H].sup.+ AA Carboxylic acid (as lithium salt): I26 20 [00135]embedded image   Methyl 4-(4-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)-N- methylbenzamido)piperidine-1- carboxylate LCMS-B: RT 3.15 min; m/z 450.2 [M − CO.sub.2].sup.+ AA Carboxylic acid (as ithium salt): I28 21 [00136]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (piperidin-4-yloxy)isonicotinamide LCMS-B: RT 3.19 min, m/z 397 [M + H].sup.+ AB Carboxylic acid: I30 22 [00137]embedded image   3-(Difluoromethyl)-N-((R)-2-hydroxy-2- ((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-B: RT 3.30 min, m/z 347 [M + H].sup.+ AC Reaction carried out on 0.14 mmol scale of amine 23 [00138]embedded image   2-(Difluoromethyl)-N-((R)-2-hydroxy-2- ((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-B: RT 3.23 min, m/z 347 [M + H].sup.+ AC Reaction carried out on 0.14 mmol scale of amine 24 [00139]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-3- (morpholine-4-carbonyl)benzamide LCMS-B: RT 3.07 min, m/z 410 [M + H].sup.+ AC 25 [00140]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(5- methyl-1,3,4-oxadiazol-2- yl)benzamide LCMS-B: RT 3.19 min, m/z 379 [M + H].sup.+ AC 26 [00141]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- ((tetrahydro-2H-pyran-4- yl)oxy)isonicotinamide bis(2,2,2- trifluoroacetic acid) salt .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.23 (dd, J = 5.3, 0.8 Hz, 1H), 7.36-7.14 (m, 6H), 5.25 (tt, J = 8.3, 4.0 Hz, 1H), 4.54- 4.32 (m, 2H), 4.29-4.20 (m, 1H), 3.95 (dt, J = 11.5, 4.6 Hz, 2H), 3.71-3.50 (m, 5H), 3.30- 3.15 (m, 2H), 2.13-2.02 (m, 2H), 1.80-1.68 (m, 2H). LCMS-B: RT 2.80 min, m/z 398 [M + H].sup.+ (free base), 396 [M − H].sup.− (free base) AD Carboxylic acid: I29 Treatment with TFA for 24 hours. 27 [00142]embedded image   Methyl 4-((4-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)pyridin-2- yl)oxy)piperidine-1-carboxylate bis(2,2,2-trifluoroacetic acid) salt .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.23 (dd, J = 5.3, 0.7 Hz, 1H), 7.35-7.15 (m, 6H), 5.27 (tt, J = 7.5, 3.6 Hz, 1H), 4.57- 4.32 (m, 2H), 4.29-4.21 (m, 1H), 3.84-3.72 (m, 2H), 3.68- 3.50 (m, 3H), 3.46-3.34 (m, 2H), 3.29-3.15 (m, 2H), 2.06-1.95 (m, 2H), 1.80- 1.66 (m, 2H). LCMS-B: RT 2.83 min, m/z 455 [M + H].sup.+ (free base) AE Carboxylic acid: I32 28 [00143]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4- (morpholine-4-carbonyl)benzamide hydrochloride .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 9.42 (d, J = 10.7 Hz, 1H), 9.01-8.90 (m, 1H), 8.81 (t, J = 5.9 Hz, 1H), 7.95-7.89 (m, 2H), 7.51-7.46 (m, 2H), 7.30- 7.18 (m, 4H), 5.98 (s, 1H), 4.44-4.34 (m, 1H), 4.24- 4.15 (m, 2H), 3.76-3.23 (m, overlaps with solvent), 3.19- 3.04 (m, 3H). LCMS-A: RT 1.67 min; m/z 410.2 [M + H].sup.+ (free base) AF Carboxylic acid: 17 29 [00144]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-5- (morpholine-4-carbonyl)picolinamide dihydrochloride salt LCMS-B: RT 3.11 min; m/z 411.3 [M + H].sup.+ (free base) AG Carboxylic acid (as lithium salt): I34 57 [00145]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-6- (2,2,2-trifluoroethoxy)nicotinamide LCMS-B: RT 2.923 min; m/z 396.1 [M + H].sup.+ AH 58 [00146]embedded image   6-(Cyclopropylmethoxy)-N-((R)-2- hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)nicotinamide LCMS-B: RT 2.905 min; m/z 368.2 [M + H].sup.+ AH 59 [00147]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-6- isopropoxynicotinamide LCMS-B: RT 2.892 min; m/z 356.2 [M + H].sup.+ AH 60 [00148]embedded image   Methyl 4-(3-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)phenoxy)piperidine- 1-carboxylate LCMS-B: RT 2.91 min, m/z 454.2 [M + H].sup.+ AI Treatment with TFA overnight. Carboxylic acid: I48 61 [00149]embedded image   Isopropyl 4-((4-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)pyridin-2- yl)oxy)piperidine-1-carboxylate LCMS-B: RT 2.99 min, m/z 483.3 [M + H].sup.+ AI Treatment with TFA overnight. Carboxylic acid: I50 62 [00150]embedded image   Isobutyl 4-((4-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)pyridin-2- yl)oxy)piperidine-1-carboxylate LCMS-B: RT 3.04 min, m/z 497.2 [M + H].sup.+ AI Treatment with TFA overnight. Carboxylic acid: I51 63 [00151]embedded image   N-((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (2,2,2-trifluoroethoxy)isonicotinamide LCMS-B: RT 2.90 min, m/z 396.1 [M + H].sup.+, 394.1 [M − H].sup.− AI Treatment with TFA for 4 hours. 64 [00152]embedded image   N-((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- isopropoxyisonicotinamide LCMS-B: RT 2.86 min, m/z 356.2 [M + H].sup.+, 354.2 [M − H].sup.− AI Treatment with TFA for 4 hours. 65 [00153]embedded image   2-(2-Amino-2-oxoethoxy)-N-((R)-2- hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 1.64, 1.79 min; m/z 370.2 [M + H].sup.+ AJ 66 [00154]embedded image   4-(4-Acetylpiperazine-1-carbonyl)-N- ((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 1.75 min; m/z 451.3 [M + H].sup.+ AJ Lithium salt: I55 67 [00155]embedded image   Methyl 4-(4-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)benzoyl)piperazine- 1-carboxylate LCMS-A: RT 4.48 min; m/z 467.3 [M + H].sup.+ AJ Lithium salt: I57 68 [00156]embedded image   2-((1-Acetylpiperidin-4-yl)oxy)-N-((R)- 2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-A: RT 4.55 min; m/z 438.3 [M + H].sup.+ AJ Carboxylic acid: I58 69 [00157]embedded image   4-((3-Oxa-8-azabicyclo[3.2.1]octane- 8-carbonyl)-2-ethoxy-5-fluoro-N-((R)- 2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-B: RT 2.88 min; m/z 498.2 [M + H].sup.+ AK Lithium salt: I61 70 [00158]embedded image   6-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-2-ethoxy-N-((R)-2-hydroxy- 2-((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)nicotinamide .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.44 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.17- 7.08 (m, 4H), 4.70-4.64 (m, 2H), 4.54-4.46 (m, 2H), 4.14 (s, 2H), 3.99-3.95 (m, 1H), 3.91-3.87 (m,1H), 3.81-3.67 (m, 4H) 3.61-3.55 (m, 1H), 3.18-3.13 (m, 1H), 2.99-2.97 (m, 2H), 2.09-1.97 (m, 4H), 1.44 (t, J = 7.2 Hz, 3H). LCMS-C: RT 4.77 min, m/z 481.0 [M + H].sup.+ AL Carboxylic acid: I65 71 [00159]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- methoxyisonicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.36 (d, J = 6.0 Hz, 1H), 7.58-7.57 (m, 2H), 7.31-7.21 (m, 4H), 4.51-4.47 (m, 1H) 4.39-4.31 (m, 2H), 4.12(s, 3H), 3.71-3.66 (m, 2H), 3.60- 3.56 (m, 1H), 3.36-3.32 (m, 1H), 3.24-3.19 (m, 1H). LCMS-C: RT 2.64 min, m/z 328.0 [M + H].sup.+ for free base AL 72 [00160]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-6-(2- oxo-2-(piperidin-1- yl)ethyl)nicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 9.24 (s, 1H), 8.87 (dd, J = 8.0, 1.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.31-7.21 (m, 4H), 4.51-4.32 (m, 3H), 3.74- 3.69 (m, 2H), 3.63-3.56 (m, 5H), 3.37-3.31 (m, 2H), 3.30 (m, 1H), 3.25-3.19 (m, 1H), 1.76-1.66 (m, 4H), 1.60-1.55 (m, 2H). LCMS-C: RT 0.98 min, m/z 423.3 [M + H].sup.+ for free base AL Carboxylic acid: I70 73 [00161]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (tetrahydro-2H-pyran-4- yl)isonicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.87-8.85 (m, 1H), 8.39 (s, 1H), 8.28 (m, 1H), 7.30- 7.23 (m, 4H), 4.52-4.35 (m, 3H), 4.12 (d, J = 10.8 Hz, 2H), 3.76-3.58 (m, 5H), 3.40-3.38 (m, 2H), 3.24-3.20 (m, 1H), 2.01-1.98 (m, 4H). LCMS-C: RT 0.61 min, m/z 382.3 [M + H].sup.+ for free base AL Carboxylic acid: I75 74 [00162]embedded image   4-(2-(3-Oxa-8-azabicyclo[3.2.1]octan- 8-yl)-2-oxoethyl)-2-ethoxy-N-(R)-2- hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.94 (d, J = 8.0 Hz, 1H), 7.16-7.07 (m, 4H), 7.06-6.97 (m, 2H), 4.51 (d, J = 5.8 Hz, 1H), 4.31 (d, J = 5.6 Hz, 1H), 4.27-4.19 (m, 2H), 4.03 (d, J = 4.6 Hz, 2H), 3.89-3.83 (m, 1H), 3.81- 3.72 (m, 3H), 3.63-3.52 (m, 4H), 3.40 (d, J = 11.0 Hz, 1H), 2.99-2.94 (m, 1H), 2.91- 2.81 (m, 2H), 2.04-1.96 (m, 2H), 1.92-1.83 (m, 2H), 1.48 (t, J = 7.0 Hz, 3H). LCMS-C: RT 1.92 min, m/z 494.4 [M + H].sup.+ AL Carboxylic acid: I79 75 [00163]embedded image   5-Chloro-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)isonicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.17 (s, 1H), 7.32-7.22 (m, 4H), 6.92 (s, 1H), 5.26- 5.18 (m, 1H),4.51-4.35 (m, 2H), 4.30-4.26 (m, 1H), 3.97- 3.89 (m, 2H), 3.71-3.51 (m, 5H), 3.25-3.14 (m, 2H), 2.11-1.99 (m, 2H), 1.79- 1.68 (m, 2H). LCMS-C: RT 3.56 min, m/z 432.2 [M + H].sup.+ for free base AL Carboxylic acid: I81 76 [00164]embedded image   Methyl 4-((6-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)pyrimidin-4- yl)oxy)piperidine-1-carboxylate dihydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.80 (s, 1H), 7.40 (s, 1H), 7.32-7.24 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 5.46-5.40 (m, 1H), 4.49- 4.34 (m, 2H), 4.28-4.23 (m, 1H), 3.85-3.75 (m, 2H), 3.72- 3.68 (m, 3H), 3.67-3.62 (m, 1H), 3.59-3.53 (m, 1H), 3.45-3.34 (m, 3H), 3.26- 3.18 (m, 2H), 2.08-2.00 (m, 2H), 1.81-1.72 (m, 2H). LCMS-C: RT 3.79 min, m/z 456.2 [M + H].sup.+ for free base AM Lithium salt: I86 77 [00165]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)isonicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.02 (d, J = 6.2 Hz, 2H), 8.46 (d, J = 6.3 Hz, 2H), 7.33-7.20 (m, 4H), 4.51 (d, J = 15.6 Hz, 1H), 4.41- 4.34 (m, 2H), 3.78-3.70 (m, 2H), 3.65-3.58 (m, 1H), 3.39-3.33 (m, 1H), 3.27- 3.19 (m, 1H). LCMS-C: RT 0.33 min, m/z 298.1 [M + H].sup.+ for free base AL 78 [00166]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)nicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.33 (s, 1H), 9.02 (d, J = 8.0, Hz, 1H), , 9.00 (d, J = 5.6, Hz, 1H), 8.18 (dd, J = 8.0, 5.6 Hz, 1H), 7.35- 7.18 (m, 4H), 4.50 (d, J = 15.7 Hz, 1H), 4.42-4.32 (m, 2H), 3.79-3.70 (m, 2H), 3.67- 3.57 (m, 1H), 3.39-3.33 (m, 1H), 3.27-3.19 (m, 1H). LCMS-C: RT 0.34 min, m/z 298.2 [M + H].sup.+ for free base AL 79 [00167]embedded image   2-Ethoxy-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-4-(2-oxo-2-(pyrrolidin-1- yl)ethyl)benzamide hydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J = 8.0 Hz, 1H), 7.32-7.20 (m, 4H), 7.05 (s, 1H), 6.95 (d, J = 7.9 Hz, 1H), 4.49-4.36 (m, 2H), 4.29-4.17 (m, 3H), 3.78- 3.69 (m, 3H), 3.65-3.52 (m, 4H), 3.44 (t, J = 6.8 Hz, 2H), 3.29-3.10 (m, 2H), 2.01- 1.85 (m, 4H), 1.43 (t, J = 6.8 Hz, 3H). LCMS-C: RT 2.02 min, m/z 452.2 [M + H].sup.+ for free base AL Carboxylic acid: I88 80 [00168]embedded image   2-Ethoxy-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-3-methyl-4-(morpholine-4- carbonyl)benzamide hydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.63 (d, J = 7.7 Hz, 1H), 7.33-7.20 (m, 4H), 7.07 (d, J = 7.8 Hz, 1H), 4.44 (m, 2H), 4.25 (m, 1H), 4.02-3.92 (m, 2H), 3.84- 3.70 (m, 5H), 3.68-3.52 (m, 4H), 3.23 (m, 3H), 2.25 (s, 3H), 1.44-1.29 (m, 4H). LCMS-C: RT 1.10 min, m/z 468.3 [M + H].sup.+ for free base AL Carboxylic acid: I95 81 [00169]embedded image   4-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-2-fluoro-N-((R)-2-hydroxy-2- ((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide hydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.87-7.83 (m, 1H), 7.42- 7.37 (m, 2H), 7.31-7.21 (m, 4H), 4.64 (s, 1H), 4.53-4.27 (m, 3H), 3.94 (s, 1H), 3.85- 3.56 (m, 7H), 3.56-3.28 (m, 1H, overlap), 3.21 (dd, J = 17.2, 4.4 Hz, 1H), 2.07-2.01 (m, 4H). LCMS-C: RT 0.48 min, m/z 454.3 [M + H].sup.+ for free base AL Carboxylic acid: I97 82 [00170]embedded image   6-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-4-ethoxy-N-((R)-2-hydroxy- 2-((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)nicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.97 (s, 1H), 7.74 (s, 1H), 7.31-7.22 (m, 4H), 4.68 (s, 1H), 4.54-4.48 (m, 3H), 4.47-4.27 (m, 3H), 3.86-3.59 (m, 7H), 3.56-3.29 (m, 1H, obscured by solvent), 3.20 (dd, J = 16.8, 4.0 Hz, 1H), 2.09-2.08 (m, 4H), 1.49 (t, J = 6.8 Hz, 3H). LCMS-C: RT 3.18 min, m/z 481.1 [M + H].sup.+ for free base AL Carboxylic acid: I103 83 [00171]embedded image   4-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-2-chloro-N-((R)-2-hydroxy-2- ((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.61-7.57 (m, 2H), 7.51- 7.49 (m, 1H), 7.17-7.09 (m, 4H), 4.63 (s, 1H), 4.15 (s, 2H), 4.01-3.94 (m, 2H), 3.82- 3.80 (m, 1H), 3.72-3.64 (m, 3H), 3.59-3.56 (m, 2H), 3.21- 3.17 (m, 1H), 3.00-2.99 (m, 2H), 2.06-2.01 (m, 4H). LCMS-C: RT 3.25 min, m/z 470.2 [M + H].sup.+ AL Carboxylic acid: I105 84 [00172]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (trifluoromethyl)-1H- benzo[d]imidazole-6-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.28 (s, 1H), 7.96-7.93 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.32-7.21 (m, 4H), 4.51- 4.35 (m, 2H), 4.30-4.26 (m, 1H), 3.71-3.58 (m, 3H), 3.28- 3.26 (m, 1H). LCMS-C: RT 3.51 min, m/z 405.1 [M + H].sup.+ for free base AL Carboxylic acid: I106 85 [00173]embedded image   4-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-3-(difluoromethyl)-N-((R)-2- hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)benzamide .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.22 (s, 1H), 8.10(d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.24-7.14 (m, 4H), 7.02-6.88 (m, 1H), 4.69 (s, 1H), 4.32-4.22 (m, 2H), 4.15- 4.14 (m, 1H), 3.83-3.80 (m, 1H), 4.74-3.66 (m, 4H), 3.61- 3.48 (m, 2H), 3.42-3.37 (m, 1H), 3.20-3.07 (m, 2H), 2.09- 1.99 (m, 4H). LCMS-C: RT 2.05 min, m/z 486.2 [M + H].sup.+ AL Carboxylic acid: I110 86 [00174]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- (trifluoromethyl)isonicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.88 (d, J = 4.8 Hz, 1H), 8.23 (s, 1H), 8.07 (d, J = 4.8 Hz, 1H), 7.31-7.21 (m, 4H), 4.51-4.47 (m, 1H), 4.39-4.31 (m, 2H), 3.71-3.66 (m, 2H), 3.61-3.56 (m, 1H), 3.37 (m, 1H), 3.24-3.19 (m, 1H). LCMS-C: RT 3.43 min, m/z 366.3 [M + H].sup.+ for free base AL 87 [00175]embedded image   4-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-2-methoxybenzamide hydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 7.96 (d, J = 7.6 Hz, 1H), 7.31-7.22 (m, 5H), 7.17 (dd, J = 8.0, 1.2 Hz, 1H), 4.65 (br s, 1H), 4.96-4.36 (m, 2H), 4.28- 4.24 (m, 1H), 3.97 (s, 3H), 3.84-3.81 (m, 1H), 3.75-3.71 (m, 3H), 3.67-3.56 (m, 4H), 3.27-3.23 (m, 2H), 2.08-1.98 (m, 4H). LCMS-C: RT 1.03 min, m/z 466.2 [M + H].sup.+ for free base. AL Carboxylic acid: I112 88 [00176]embedded image   2-(1-Acetylpiperidin-4-yl)-N-((R)-2- hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.33 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.37-7.19 (m, 4H), 4.77-4.69 (m, 1H), 4.53- 4.29 (m, 3H), 4.20-4.10 (m, 1H), 3.75-3.57 (m, 4H), 3.28- 3.11 (m, 2H), 2.93-2.69 (m, 2H), 2.38-2.22 (m, 2H), 2.17 (s, 3H), 2.00-1.80 (m, 2H). LCMS-C: RT 0.34 min, m/z 462.3 [M + H].sup.+ AL Carboxylic acid: I117 89 [00177]embedded image   2-Ethoxy-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-4-(5-methyl-1,3,4-oxadiazol- 2-yl)benzamide .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.05 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.24-7.21 (m, 3H), 7.18-7.16 (m, 1H), 4.32- 4.27(m, 4H), 4.18-4.13 (m, 1H), 3.78-3.72 (m, 1H), 3.64- 3.58(m, 1H), 3.48-3.43(m, 1H), 3.21-3.08 (m, 2H), 2.63 (s, 3H), 1.48 (t, J = 6.8 Hz, 3H). LCMS-C: RT 3.57 min, m/z 423.2 [M + H].sup.+ AL Carboxylic acid: I120 111 [00178]embedded image   6-Amino-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)nicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.43(s, 1H), 8.34(d, J = 8.8 Hz, 1H), 7.30-7.20 (m, 4H), 7.06 (d, J = 8.8 Hz, 1H), 4.50-4.46 (m, 1H), 4.38-4.27 (m, 2H), 3.67-3.63 (m, 2H), 3.56-3.53 (m, 1H), 3.27-3.18 (m, 2H). LCMS-C: RT 0.25 min, m/z 313.2 [M + H].sup.+ (free base) AL 112 [00179]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-1H- indazole-5-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.38 (s, 1H), 8.18 (s, 1H), 7.91 (dd, J = 8.8, 1.2 Hz, 1H), 7.60 (d, J = 8.8, 1H), 7.31-7.20 (m, 4H), 4.50-4.46 (m, 1H), 4.39-4.35 (m, 1H), 4.31-4.27 (m, 1H), 3.71-3.58 (m, 3H), 3.36-3.33 (m, 1H), 3.27-3.22 (m, 1H). LCMS-C: RT 2.65 min, m/z 337.2 [M + H].sup.+ (free base) AL 113 [00180]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-1H- benzo[d]imidazole-5-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 9.49 (s, 1H), 8.43 (s, 1H), 8.15(d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31- 7.21 (m, 4H), 4.52-4.35 (m, 3H), 3.75-3.59 (m, 3H), 3.38- 3.33 (m, 1H), 3.27-3.22 (m, 1H). LCMS-C: RT 0.28 min, m/z 337.1 [M + H].sup.+ (free base) AL 114 [00181]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-1H- benzo[d][1,2,3]triazole-5-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.48 (s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 8.8, 1H), 7.31-7.21 (m, 4H), 4.51- 4.47 (m, 1H), 4.39-4.35 (m, 1H), 4.31-4.28 (m, 1H), 3.72- 3.59 (m, 3H), 3.37-3.33 (m, 1H), 3.27-3.22 (m, 1H). LCMS-C: RT 2.72 min, m/z 338.1 [M + H].sup.+ (free base) AL 115 [00182]embedded image   2-Chloro-N-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)-6-(oxetan-3- yloxy)isonicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.05 (s, 1H), 7.87 (s, 1H), 7.33-7.22 (m, 4H), 5.67 (t, J = 8.0 Hz, 1H), 5.14-5.06 (m, 1H), 5.00-4.93 (m, 1H), 4.50 (d, J = 15.5 Hz, 1H), 4.40- 4.31 (m, 2H), 4.11-4.05 (m, 1H), 3.91-3.86 (m, 1H), 3.76-3.65 (m, 1H), 3.62- 3.54 (m, 1H), 3.37-3.33 (m, 2H), 3.23-3.16 (m, 1H). LCMS-C: RT 0.26 min, m/z 404.1, 406.1 [M + H].sup.+ (free base) AL Carboxylic acid: I121 116 [00183]embedded image   6-((1-Acetylpiperidin-4-yl)oxy)-N-((R)- 2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3- yl)ethyl)pyridazine-4-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 9.48 (s, 1H), 8.09 (s, 1H), 7.29-7.23 (m, 4H), 4.51- 4.35 (m, 3H), 3.90-3.58 (m, 8H), 3.26-3.16 (m, 2H), 2.25- 2.05 (m, 5H), 1.96-1.87 (m, 2H) LCMS-C: RT 0.56 min, m/z 440.2 [M + H].sup.+ (free base) AL Carboxylic acid: I124 117 [00184]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-1- (tetrahydro-2H-pyran-4-yl)-1H- benzo[d]imidazole-4-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 9.47 (s, 1H), 8.25 (d, J = 8 Hz, 1H), 8.17 (d, J = 7.2 Hz, 1H), 7.76-7.72 (m, 1H), 7.32-7.21 (m, 4H), 4.51-4.36 (m, 3H), 4.16 (d, J = 11.2 Hz, 2H), 3.82-3.63 (m, 5H), 3.40- 3.25 (m, overlap), 2.25 (br s, 4H). LCMS-C: RT 3.25 min, m/z 421.2 [M + H].sup.+ (free base) AL Carboxylic acid: I129 118 [00185]embedded image   Methyl 4-((5-(((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)carbamoyl)pyridin-3- yl)oxy)piperidine-1-carboxylate dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.82 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 7.31-7.21 (m, 4H), 4.95 (br s, 1H), 4.52- 4.34 (m, 3H), 3.81-3.70 (m, 7H), 3.62-3.57 (m, 1H), 3.47- 3.42 (m, 2H), 3.37-3.31 (m, 1H, overlap), 3.24-3.21 (m, 1H), 2.06 (br s, 2H), 1.79 (br s, 2H). LCMS-C: RT 3.55 min, m/z 455.2 [M + H].sup.+ (free base) AL Lithium salt: I135 119 [00186]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-2- methyl-1-(tetrahydro-2H-pyran-4-yl)- 1H-benzo[d]imidazole-4-carboxamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.27 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.32-7.21 (m, 4H), 4.99-4.93 (m, 1H), 4.51-4.35 (m, 3H), 4.19-4.15 (dd, J = 11.6, 4.0 Hz, 2H), 3.80-3.62 (m, 5H), 3.40-3.25 (m, 2H, overlap), 3.02 (s, 3H), 2.65-2.55 (m, 2H), 2.05-2.02 (m, 2H). LCMS-C: RT 2.89 min, m/z 435.2 [M + H].sup.+ (free base) AL Carboxylic acid: I131 120 [00187]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-5- methoxynicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.88 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 7.31-7.21 (m, 4H), 4.52-4.49 (m, 1H), 4.39-4.3 (m, 2H), 4.10 (s, 3H), 3.75-2.72 (m, 2H), 3.63-3.58 (m, 1H), 3.37-3.33 (m, 1H), 3.26-3.20 (m, 1H). LCMS-C: RT 0.52 min, m/z 328.1 [M + H].sup.+ (free base) AL Carboxylic acid: I137 126 [00188]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-5- isopropoxynicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol- d.sub.4) δ 8.80 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 7.31-7.21 (m, 4H), 4.54 (d, J = 7.6 Hz, 1H), 4.39-4.34 (m, 2H), 3.74- 3.69 (m, 2H), 3.62-3.57 (m, 1H), 3.39-3.33 (m, 1H), 3.25- 3.20 (m, 1H), 3.13-3.07 (m, 1H), 1.46 (d, J = 6.0, 6H). LCMS-C: RT 1.63 min, m/z 357.0 [M + H].sup.+ AL Carboxylic acid: I139

    Examples 30-47, 56 & 90-97 (Table B)

    [0735] ##STR00189##

    [0736] General Method BA:

    [0737] Lithium 4-(((R)-2-((S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-hydroxyethyl)carbamoyl)benzoate (I36) (30 mg, 0.067 mmol), the respective amine (0.067 mmol), triethylamine (0.028 mL, 0.20 mmol), DMF (0.5 mL) and HATU (38 mg, 0.10 mmol) were stood at room temperature. After 18 hours the mixture was diluted with water (1.5 mL) and DCM (1 mL). The mixture was passed through a phase separator cartridge and the collected DCM phase was diluted with 4.0 M HCl in 1,4-dioxane (1 mL). After 4 hours the mixture was diluted with methanol (1 mL) and loaded onto a 0.5 g SCX cartridge. The cartridge was washed with methanol (10 mL) and eluted with 2M ammonia in methanol (5 mL). The basic eluate was concentrated to give the amide products.

    [0738] General Procedure BB:

    [0739] To a solution of the respective amine (0.20 mmol, 1 equiv) in DMF (1 mL) and MeCN (5 mL) were added a pre-stirred solution of lithium 4-(((R)-2-((S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-hydroxyethyl)carbamoyl)benzoate (I36) (69 mg, 0.20 mmol, 1 equiv), DIPEA (104 μL, 0.60 mmol, 3 equiv) and HATU (114 mg, 0.30 mmol, 1.5 equiv) in DMF (1 mL). The reaction was stirred at room temperature for 16 hours. The mixture was quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (3×5 mL) utilizing a phase separation cartridge. The organic filtrates were dried in vacuo to give an oil which was taken up in 2M HCl in 1,4-dioxane (2 mL) and stirred at room temperature for 20 hours. The reaction was dried in vacuo and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia), then concentrated to give the amide products.

    [0740] General Procedure BC

    [0741] Lithium 4-(((R)-2-((S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-hydroxyethyl)carbamoyl)benzoate I36 (30 mg, 0.067 mmol), the respective amine or amine hydrochloride (0.067 mmol), triethylamine (0.028 mL, 0.20 mmol), DMF (0.5 mL) and HATU (38 mg, 0.10 mmol) were stood at room temperature. After 18 hours, the mixture was diluted with water (1.5 mL) and DCM (1 mL). The mixture was passed through a phase separator cartridge and the DCM filtrate diluted with 4 M HCl/1,4-dioxane (1 mL). After 4 hours, the mixture was diluted with methanol (1 mL) and loaded onto a 1 g SCX cartridge. The cartridge was washed with methanol (20 mL) and eluted with 2 M ammonia in methanol (12 mL). The basic eluate was concentrated to give the desired compound.

    TABLE-US-00005 TABLE B Ex Structure LCMS Method 30 [00190]embedded image   4-(4-(Difluoromethyl)-4-hydroxypiperidine-1- carbonyl)-N-((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)benzamide LCMS-B: RT 3.20 min; m/z 474.2 [M + H].sup.+ BA 31 [00191]embedded image   N.sup.1-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-N.sup.4-((tetrahydro-2H- pyran-4-yl)methyl)terephthalamide LCMS-B: RT 3.18 min; m/z 438.2 [M + H].sup.+ BA 32 [00192]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(4- (hydroxymethyl)piperidine-1-carbonyl)benzamide LCMS-B: RT 3.14 min; m/z 438.2 [M + H].sup.+ BA 33 [00193]embedded image   4-(4-(Ethylsulfonyl)piperazine-1-carbonyl)-N-((R)-2- hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-B: RT 3.21 min; m/z 501.2 [M + H].sup.+ BA 34 [00194]embedded image   N.sup.1-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-N.sup.4-(1- (methylsulfonyl)piperidin-4-yl)terephthalamide hydrochloride LCMS-B: RT 3.14 min; m/z 501.2 [M + H].sup.+ (free base) BA Precipitated from HCl/1,4- dioxane, collected, washed with MeOH and dried to give the title compound. 35 [00195]embedded image   N.sup.1-(1-Acetylpiperidin-4-yl)-N.sup.4-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)terephthalamide LCMS-B: RT 3.11 min; m/z 465.3 [M + H].sup.+ BA 36 [00196]embedded image   4-(cis-Hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)- N-((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)benzamide LCMS-B: RT 3.12 min; m/z 436.3 [M + H].sup.+ BA 37 [00197]embedded image   4-(1,1-Dioxidothiomorpholine-4-carbonyl)-N-((R)-2- hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-B: RT 3.13 min; m/z 458.2 [M + H].sup.+ BA 38 [00198]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(3-methoxy-8- azabicyclo[3.2.1]octane-8-carbonyl)benzamide LCMS-B: RT 3.26 min; m/z 464.2 [M + H].sup.+ BA 39 [00199]embedded image   N.sup.1-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-N.sup.4-isopropyl-N.sup.4- methylterephthalamide LCMS-B: RT 3.28 min; m/z 396.2 [M + H].sup.+ BA 40 [00200]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(1,4-oxazepane-4- carbonyl)benzamide LCMS-B: RT 3.20 min; m/z 424.2 [M + H].sup.+ BA 41 [00201]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(4-methyl-3- oxopiperazine-1-carbonyl)benzamide LCMS-B: RT 3.12 min; m/z 437.2 [M + H].sup.+ BA 42 [00202]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(3-hydroxy-8- azabicyclo[3.2.1]octane-8-carbonyl)benzamide LCMS-B: RT 3.19 min; m/z 450.2 [M + H].sup.+ BA 43 [00203]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(3- hydroxypiperidine-1-carbonyl)benzamide LCMS-B: RT 3.10 min, m/z 424 [M + H].sup.+ BB 44 [00204]embedded image   N.sup.1-(4,4-Difluorocyclohexyl)-N.sup.4-((R)-2-hydroxy-2-((S)- 1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)terephthalamide LCMS-B: RT 3.32 min, m/z 458 [M + H].sup.+ BB 45 [00205]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(4- hydroxypiperidine-1-carbonyl)benzamide LCMS-B: RT 3.10 min, m/z 424 [M + H].sup.+ BB 46 [00206]embedded image   4-(4-(Difluoromethyl)piperidine-1-carbonyl)-N-((R)-2- hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3- yl)ethyl)benzamide LCMS-B: RT 3.29 min, m/z 458 [M + H].sup.+ BB 47 [00207]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(3- hydroxypyrrolidine-1-carbonyl)benzamide LCMS-B: RT 3.10 min, m/z 410.2 [M + H].sup.+ BB 56 [00208]embedded image   N.sup.1-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-N.sup.4-(pyridin-2- ylmethly)terephthalamide LCMS-B: RT 3.12 min; m/z 431.2 [M + H].sup.+ BA 90 [00209]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(pyrrolidine-1- carbonyl)benzamide LCMS-B: RT 2.81 min; m/z 394.2 [M + H].sup.+ BC 91 [00210]embedded image   4-(7-Azabicyclo[2.2.1]heptane-7-carbonyl)-N- ((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)benzamide LCMS-B: RT 2.88 min; m/z 420.2 [M + H].sup.+ BC 92 [00211]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(4- methoxypiperidine-1-carbonyl)benzamide LCMS-B: RT 2.82 min; m/z 438.2 [M + H].sup.+ BC 93 [00212]embedded image   N-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-4-(1,2- oxazinane-2-carbonyl)benzamide LCMS-B: RT 2.83 min; m/z 410.2 [M + H].sup.+ BC 94 [00213]embedded image   4-(2-Oxa-5-azabicyclo[2.2.1]heptane-5- carbonyl)-N-((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)benzamide LCMS-B: RT 2.75 min; m/z 422.2 [M + H].sup.+ BC Racemic bridged amine used 95 [00214]embedded image   N.sup.1-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-N.sup.4- ((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)terephthalamide LCMS-B: RT 2.74 min; m/z 472.2 [M + H].sup.+ BC 96 [00215]embedded image   4-(6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-6- carbonyl)-N-((R)-2-hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)benzamide LCMS-B: RT 2.78 min; m/z 443.2 [M + H].sup.+ BC 97 [00216]embedded image   N.sup.1-((R)-2-Hydroxy-2-((S)-1,2,3,4- tetrahydroisoquinolin-3-yl)ethyl)-N.sup.4- isopropylterephthalamide LCMS-B: RT 2.80 min; m/z 382.2 [M + H].sup.+ BC

    Example 48: 4-Chloro-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide

    [0742] ##STR00217##

    (a) tert-Butyl (S)-3-((R)-2-(4-chlorobenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A5)

    [0743] To a solution of 4-chlorobenzoic acid (0.058 g, 0.37 mmol) in DCM (10 mL) were added DIPEA (129 mg, 1.02 mmol) and HATU (0.14 g, 0.37 mmol). The mixture was stirred for 30 minutes, then tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (0.10 g, 0.34 mmol) was added. The resulting mixture was stirred at room temperature overnight, diluted with DCM (40 mL) and washed with water (50 mL), saturated NaHCO.sub.3 (50 mL), water (50 mL), and brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep TLC (5% methanol/DCM) to give the title compound (100 mg, 68% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.81-7.77 (m, 2H), 7.54-7.44 (m, 2H), 7.17-7.14 (m, 4H), 4.86-4.79 (m, 1H), 4.44-4.29 (m, 2H), 3.81-3.61 (m, 2H), 3.23-3.08 (m, 2H), 2.97-2.92 (m, 1H), 1.52-1.49 (m, 9H); LCMS-C: RT 3.09 min; m/z 453.2 [M+Na].sup.+,

    (b) 4-Chloro-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide (48)

    [0744] A mixture of tert-butyl (S)-3-((R)-2-(4-chlorobenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A5 (0.10 g, 0.23 mmol) in HCl/EtOAc (2 M, 4 mL) was stirred at room temperature overnight. The solvent was removed and the residue was diluted with saturated NaHCO.sub.3 (15 mL). The aqueous layer was extracted with DCM (4×20 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep TLC (10% methanol/DCM) to give the title compound (35 mg, 46% yield) as an off-white solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.86-7.84 (d, 2H, J=8.4 Hz), 7.49-7.47 (d, 2H, J=8.4 Hz), 7.26-7.16 (m, 4H), 4.38-4.26 (m, 2H), 4.19-4.15 (m, 1H), 3.67-3.44 (m, 3H), 3.24-3.10 (m, 2H); LCMS-C: RT 1.93 min; m/z 331.1 [M+H].sup.+

    Example 49: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride

    [0745] ##STR00218##

    (a) tert-Butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A6)

    [0746] To a mixture of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (100 mg, 0.342 mmol), 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoic acid I38 (98.7 mg, 0.378 mmol), HOBt (5 mg, 0.03 mmol) and DIPEA (88.4 mg, 0.7 mmol) in DCM (5 mL) was added EDCl.HCl (80.9 mg, 0.422 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was washed with sodium bicarbonate (6 mL) and the aqueous phase was extracted with DCM (2×3 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep TLC (7% methanol/dichloromethane) to give the title compound (58 mg, 32% yield) as an off-white solid. LCMS-C: RT 2.75 min, m/z 558.3 [M+Na].sup.+

    (b) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride (49)

    [0747] tert-Butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A6 (55 mg, 0.10 mmol) was dissolved in ethyl acetate (3 mL), and HCl in EtOAc (2 M, 1.5 mL) was added. The mixture was stirred at room temperature overnight. The solid was collected by filtration and dissolved in water (5 mL), the aqueous solution was washed with diethyl ether (3 mL) and the remaining aqueous phase was freeze-dried to give the title compound (40 mg, 83% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.01-7.93 (m, 2H), 7.63-7.57 (m, 2H), 7.33-7.19 (m, 4H), 4.61-4.69 (m, 1H), 4.52-4.43 (m, 1H), 4.43-4.25 (m, 2H), 3.97-3.91 (m, 1H), 3.86-3.77 (m, 1H), 3.76-3.61 (m, 4H), 3.61-3.53 (m, 2H), 3.31-3.28 (m, 1H), 3.26-3.19 (m, 1H), 2.11-1.93 (m, 4H); LCMS-C: RT 3.14 min; m/z 436.2 [M+H].sup.+ (free base)

    Example 50: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride

    [0748] ##STR00219##

    (a) tert-Butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A7)

    [0749] To a mixture of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (0.30 g, 1.0 mmol), 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I42 (0.34 g, 1.1 mmol), HOBt (0.014 g, 0.10 mmol) and DIPEA (0.27 g, 2.1 mmol) in dichloromethane (5 mL) was added EDCl.HCl (0.24 g, 1.2 mmol). The resulting mixture stirred overnight at room temperature. The mixture was washed with saturated sodium bicarbonate (6 mL) and the aqueous layer extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (2% methanol/dichloromethane) to give the title compound (0.23 g, 38% yield) as an off-white solid. LCMS-C: RT 2.86 min, m/z 580.4 [M+H].sup.+

    (b) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride (50)

    [0750] tert-Butyl (3 S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A7 (0.22 g, 0.4 mmol) was dissolved in ethyl acetate (5 mL) and HCl/EtOAc (2 M, 2.5 mL) was added. The mixture was stirred at room temperature overnight. The solid was collected by filtration and rinsed with ethyl acetate (20 mL). The solid was dried under vacuum to give the title compound (0.13 g, 72% yield) as an off-white solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.98-7.96 (m, 1H), 7.30-7.22 (m, 5H), 7.18-7.15 (m, 1H), 4.64 (br s, 1H), 4.51-4.36 (m, 2H), 4.29-4.20 (m, 3H), 3.95 (br s, 1H), 3.84-3.78 (m, 1H), 3.75-3.55 (m, 6H), 3.23-3.15 (m, 2H), 2.05-1.95 (m, 4H), 1.47-1.38 (m, 3H); LCMS-C: RT 3.51 min; m/z 480.3 [M+H].sup.+ (free base)

    Alternate Synthesis Method

    (a) tert-Butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A7)

    [0751] To a mixture of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (2.7 g, 9.2 mmol), 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I42 (3.1 g, 10.2 mmol), HOBt (0.13 g, 0.9 mmol) and DIPEA (4.8 g, 36.9 mmol) in dichloromethane (40 mL) was added EDCl.HCl (3.6 g, 18.5 mmol). The resulting mixture stirred overnight at room temperature. The mixture was washed with saturated sodium bicarbonate (20 mL) and the aqueous layer extracted with dichloromethane (2×15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (50% ethyl acetate/petroleum ether) to give the title compound (2.9 g, 55%) as an off-white solid. LCMS-C: RT 2.86 min, m/z 580.4 [M+H].sup.+

    (b) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride (50)

    [0752] tert-Butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A7 (2.9 g, 5.0 mmol) was dissolved in HCl/EtOAc (2 M, 100 mL). The mixture was stirred at room temperature overnight then the solvent removed. The solid was washed with diethyl ether (2×30 mL) then taken up in water (40 mL) and lyophilized to give the title compound (2.35 g, 98%) as a yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.98-7.96 (m, 1H), 7.30-7.22 (m, 5H), 7.18-7.15 (m, 1H), 4.64 (br s, 1H), 4.51-4.36 (m, 2H), 4.29-4.20 (m, 3H), 3.95 (br s, 1H), 3.84-3.78 (m, 1H), 3.75-3.55 (m, 6H), 3.23-3.15 (m, 2H), 2.05-1.95 (m, 4H), 1.47-1.38 (m, 3H); LCMS-C: RT 3.51 min; m/z 480.3 [M+H].sup.+ (free base)

    Example 51: 6-((1-Acetylpiperidin-4-yl)amino)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)pyrimidine-4-carboxamide dichloride

    [0753] ##STR00220##

    (a) tert-Butyl (S)-3-((R)-2-(6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A8)

    [0754] To a solution of 6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxylic acid I47 (95 mg, 0.34 mmol) in DCM (5 mL) were added tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (99 mg, 0.34 mmol), HOBt (4 mg, 0.03 mmol), DIPEA (220 mg, 1.70 mmol) and EDCl.HCl (130 mg, 0.678 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL), the organic layer was washed with saturated aqueous NaHCO.sub.3 (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep TLC (0-10% MeOH/DCM) to give the title compound (50 mg, 26%) as a yellow solid. LCMS-C: RT 2.72 min; m/z 539.3 [M+H].sup.+

    (b) 6-((1-Acetylpiperidin-4-yl)amino)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)pyrimidine-4-carboxamide dichloride (51)

    [0755] A mixture of tert-butyl (S)-3-((R)-2-(6-((1-acetylpiperidin-4-yl)amino)pyrimidine-4-carboxamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A8 (50 mg, 0.093 mmol) in HCl/EtOAc (2 M, 3 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the solid washed with EtOAc (10 mL) to give the title compound (35 mg, 46% yield) as a pale yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.68 (s, 0.70H), 8.57 (s, 0.21H), 7.99 (s, 0.20H), 7.41 (s, 0.68H), 7.30-7.21 (m, 4H), 4.58-4.35 (m, 5H), 4.05-3.99 (m, 1H), 3.73-3.68 (m, 2H), 3.60-3.55 (m, 1H), 3.35-3.31 (m, 3H, overlapped), 2.97-2.86 (m, 1H), 2.15-2.04 (m, 5H), 1.67-1.54 (m, 2H). LCMS-C: RT 3.04 min; m/z 439.3 [M+H].sup.+ (free base)

    Example 52: N—((S)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride

    [0756] ##STR00221##

    (a) tert-Butyl (S)-3-((S)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A9)

    [0757] Analogous to the preparation of I12, treatment of tert-butyl (S)-3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I11B) with Pd/C in the presence of hydrogen gave the title compound. LCMS-B: RT 3.24 min, m/z 293.3 [M+H].sup.+

    (b) N—((S)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride (52)

    [0758] Analogous to the preparation of 28, coupling of tert-butyl (S)-3-((S)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A9) with 4-(morpholine-4-carbonyl)benzoic acid 17, followed by treatment with HCl in 1,4-dioxane gave the title compound. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 9.17 (d, J=11.3 Hz, 1H), 8.97 (d, J=11.1 Hz, 1H), 8.80 (t, J=5.8 Hz, 1H), 7.99-7.89 (m, 2H), 7.52-7.44 (m, 2H), 7.31-7.17 (m, 4H), 4.39-4.21 (m, 3H), 3.18-3.08 (m, 2H), 3.01 (dd, J=17.0, 11.3 Hz, 2H) Some protons obscured by residual solvent. LCMS-B: RT 3.13 min; m/z 410.3 [M+H].sup.+ (free base); m/z 408.3 [M−H].sup.− (free base)

    Example 53: N—((S)-2-hydroxy-2-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride

    [0759] ##STR00222##

    (a) (R)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (A10)

    [0760] Analogous to the preparation of I8, treatment of (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid with Boc anhydride gave the title compound. LCMS-B: RT 3.61 min; m/z 300.2 [M+Na].sup.+; 178.2 [M-Boc+2H].sup.+; m/z 276.2 [M−H].sup.−

    (b) tert-Butyl (R)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A11)

    [0761] Analogous to the preparation of I9, treatment of (R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (A10) with CDI and sodium borohydride gave the title compound. LCMS-B: RT 3.66 min; m/z 164.2 [M-Boc+2H].sup.+

    (c) tert-Butyl (R)-3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A12A) and tert-butyl (R)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A12B)

    [0762] Analogous to the preparation of intermediates I11A and I11B, oxidation of tert-butyl (R)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A11) followed by treatment with nitromethane and potassium fluoride gave the title compounds. Data for major isomer tert-butyl (R)-3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A12A:

    [0763] .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.24-7.14 (m, 4H), 4.84-4.68 (m, 1H), 4.65-4.49 (m, 1H), 4.49-4.40 (m, 1H), 4.36-3.98 (m, 3H), 3.19 (dd, J=15.9, 3.2 Hz, 1H), 2.92 (dd, J=15.8, 5.6 Hz, 1H), 1.51 (s, 9H). LCMS-B: RT 3.72 min; m/z 223.2 [M-Boc+2H].sup.+; m/z 321.3 [M−H].sup.−

    [0764] Data for minor isomer tert-butyl (R)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A12B:

    [0765] .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.23-7.12 (m, 4H), 4.75 (d, J=16.4 Hz, 1H), 4.61-4.49 (m, 1H), 4.42-4.22 (m, 4H), 3.06 (dd, J=16.3, 6.1 Hz, 1H), 2.91 (d, J=16.4 Hz, 1H), 1.49 (s, 9H). LCMS-B: RT 3.73 min; m/z 223.2 [M-Boc+2H].sup.+; m/z 321.1 [M−H].sup.−

    (d) tert-Butyl (R)-3-((S)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A13)

    [0766] Analogous to the preparation of I12, treatment of tert-butyl (R)-3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A12A) with Pd/C in the presence of hydrogen gave the title compound. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.21-7.08 (m, 4H), 4.84-4.73 (m, 1H), 4.37-4.08 (m, 2H), 3.42-3.30 (m, overlaps with solvent), 3.18 (dd, J=16.0, 2.6 Hz, 1H), 2.91 (dd, J=16.0, 5.6 Hz, 1H), 2.70-2.54 (m, 1H), 1.51 (s, 9H). LCMS-B RT 3.34 min; m/z 293.3 [M+H].sup.+, 237.2 [M-.sup.tBu+2H].sup.+, 193.2 [M-Boc+2H].sup.+

    (e) N—((S)-2-Hydroxy-2-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride (53)

    [0767] Analogous to the preparation of 28, coupling of tert-butyl (R)-3-((S)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A13) with 4-(morpholine-4-carbonyl)benzoic acid I7, followed by treatment with HCl with 1,4-dioxane gave the title compound. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 9.48-9.38 (m, 1H), 9.03-8.89 (m, 1H), 8.81 (t, J=5.7 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.30-7.18 (m, 4H), 5.98 (d, J=5.2 Hz, 1H), 4.44-4.33 (m, 1H), 4.21 (d, J=15.1 Hz, 2H), 3.17-3.08 (m, overlaps with solvent), 1.31-1.22 (m, 4H). LCMS-B: RT 3.12 min; m/z 410.3 [M+H].sup.+ (free base); m/z 408.2 [M−H].sup.− (free base)

    Example 54: N—((R)-2-Hydroxy-2-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride

    [0768] ##STR00223##

    (a) tert-Butyl (R)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A14)

    [0769] Analogous to the preparation of I12, treatment of tert-butyl (R)-3-((R)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A12B) with Pd/C in the presence of hydrogen gave the title compound. LCMS-A: RT 4.65 min, m/z 293.2 [M+H].sup.+

    (b) N—((R)-2-Hydroxy-2-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride (54)

    [0770] Analogous to the preparation of 28, coupling of tert-butyl (R)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (A14) with 4-(morpholine-4-carbonyl)benzoic acid 17, followed by treatment with HCl in 1,4-dioxane gave the title compound. LCMS-B: RT 3.11 min; m/z 410.3 [M+H].sup.+ (free base)

    Example 55: 4-(3-Oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide

    [0771] ##STR00224##

    (a) Ethyl (3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxybenzoate A16

    [0772] To a solution of the acid 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I40 (73 mg, 0.31 mmol, 1 equiv) in DMF (2 mL) and MeCN (5 mL) was added DIPEA (160 μL, 0.917 mmol, 3 equiv), HATU (174 mg, 0.458 mmol, 1.5 equiv) and the amine; 3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (50 mg, 0.31 mmol, 1 equiv) and the reaction was stirred overnight at room temperature. The mixture was quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried in vacuo and the resultant oil was purified by column chromatography (24 g SiO.sub.2 cartridge, 0-65% EtOAc in petroleum benzine 40-60° C.) to give the title compound (88 mg, 83% yield) as a yellow oil. LCMS-B: RT 3.28 min, m/z 348 [M+H].sup.+

    (b) 4-(3-Oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxybenzoic acid A17

    [0773] To a solution of ethyl (3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxybenzoate A16(88 mg, 0.25 mmol, 1 equiv) in THF:H.sub.2O:MeOH (3:1:0.5, 9 mL) was added LiOH—H.sub.2O (32 mg, 0.76 mmol, 3 equiv). The reaction was stirred at room temperature for 16 hours before the reaction was quenched by the addition of a 0.5 M aqueous solution of citric acid (10 mL). The solution was extracted with EtOAc (3×15 mL), the combined organic layers were washed with water (30 mL), brine (30 mL), dried over MgSO.sub.4 and evaporated in vacuo. The resultant crude was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (55 mg, 68% yield) as a colourless oil. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.84 (d, J=7.8 Hz, 1H), 7.14 (d, J=1.3 Hz, 1H), 7.05 (dd, J=7.8, 1.4 Hz, 1H), 4.52 (s, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.07-3.99 (m, 1H), 3.93-3.72 (m, 3H), 3.60 (s, 1H), 2.02-1.95 (m, obscured by EtOAc solvent), 1.92-1.78 (m, 2H), 1.75-1.64 (m, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.40-1.27 (m, 2H). LCMS-B: RT 3.00 min, m/z 320.2 [M+H].sup.+

    (c) 4-(3-Oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide 55

    [0774] To a solution of 4-(3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxybenzoic acid A17 (55 mg, 0.17 mmol, 1 equiv), DIPEA (90 μL, 0.52 mmol, 3 equiv) and HATU (98 mg, 0.26 mmol, 1.5 equiv) in DMF (2 mL) was added a solution of the amine tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (50 mg, 0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stirred at room temperature overnight, then quenched with a saturated aqueous solution of NaHCO.sub.3 (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over MgSO.sub.4 and concentrated in vacuo. DCM:TFA (4 mL, 1:1) was added and the reaction stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and then purified by solid-phase extraction (2×1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give the crude product which was further purified by column chromatography (12 g SiO.sub.2 cartridge, 50-100% EtOAc modified by the addition of 1% v/v of 3.5 M methanolic ammonia in petroleum benzine 40-60° C. followed by 0-20% MeOH in EtOAc modified by the addition of 1% v/v of 2.0 M methanolic ammonia). The product fractions were combined and dried in vacuo to give title compound (19 mg, 22% yield) as a glassy yellow solid. .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 8.02 (d, J=7.9 Hz, 1H), 7.15-7.07 (m, 5H), 7.08-6.98 (m, 1H), 4.52 (s, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.07-3.98 (m, 3H), 3.91-3.81 (m, 3H), 3.83-3.72 (m, 2H), 3.63-3.52 (m, 2H), 3.02-2.90 (m, 1H), 2.92-2.79 (m, 2H), 2.65-2.52 (m, 1H), 2.04-1.95 (m, 2H), 1.92-1.76 (m, 2H), 1.74-1.63 (m, 1H), 1.48 (t, J=7.0 Hz, 3H). LCMS-B: RT 2.89 min, m/z 494.3 [M+H].sup.+

    [0775] Determination of Stereochemistry

    ##STR00225##

    [0776] The amine I12 (30 mg, 0.10 mmol), DCM (1 mL) and triethylamine (0.028 mL, 0.21 mmol) and (1S)-(+)-10-camphorsulfonyl chloride (26 mg, 0.10 mmol) were stood at room temperature. After three hours the mixtures was purified by chromatography (4 g silica cartridge, 0-100% ethyl acetate/hexanes then 0-100% methanol/ethyl acetate) to give the camphorsulfonamide (20 mg, 39% yield). LCMS-B: RT 3.95 min m/z (positive ion) 407.3 [M-Boc+2H]

    [0777] Crystals of the sulfonamide S1 were grown by vial-in-vial vapour diffusion (S1 dissolved in ethyl acetate, sealed in a larger vial with hexane) over approximately five months. The crystals were studied by X-ray crystallography by the Monash University X-ray Diffraction Service, and a structure obtained. The structure unambiguously confirms the relative and absolute stereochemistry of the tetrahydroisoquinoline and alcohol stereocentres in the product of the preceding nitroaldol reaction. The following table sets out the data derived from the structure:

    TABLE-US-00006 Empirical formula C26H38N2O6S Formula weight 506.64 Temperature 123(2) K Wavelength 1.54184 Å Crystal system, space group Monoclinic, P 21 Unit cell dimensions a = 11.7820(6) Å alpha = 90° b = 7.0492(5) Å beta = 100.331(5)° c = 16.1515(12) Å gamma = 90° Volume 1319.69(15) Å.sup.3 Z, Calculated density 1.275 Mg/m.sup.3 Absorption coefficient 1.440 mm.sup.−1 F(000) 544 Crystal size 0.25 × 0.08 × 0.05 mm Theta range for data collection 2.78 to 66.92° Limiting indices −14 <= h <= 13, −8 <= k <= 8, −19 <= l <= 19 Reflections collected/unique 13367/4558 [R(int) = 0.0667] Completeness to theta = 66.92 98.8% Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.00000 and 0.72746 Refinement method Full-matrix least-squares on F{circumflex over ( )}2 Data/restraints/parameters 4558/3/329 Goodness-of-fit on F{circumflex over ( )}2  1.070 Final R indices [I > 2sigma(I)] R1 = 0.0413, wR2 = 0.1047 R indices (all data) R1 = 0.0445, wR2 = 0.1093 Absolute structure parameter −0.012(16) Largest diff, peak and hole 0.248 and −0.395 e .Math. Å.sup.−3

    Example 98: 6-Chloro-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)nicotinamide hydrochloride 98

    [0778] ##STR00226##

    (a) tert-Butyl (S)-3-((R)-2-(6-chloronicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A19 and tert-butyl (S)-3-((R)-2-(6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)nicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A18

    [0779] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.766 g, 3.81 mmol) in anhydrous THF (25 mL) under an atmosphere of nitrogen was added NaH (60% dispersion in mineral oil, 0.457 g, 11.42 mmol) in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 20 minutes, cooled to 0° C. and methyl 6-chloronicotinate (0.300 g, 1.748 mmol) was added in anhydrous THF (5 mL). The mixture was allowed to warm to room temperature and was then heated at reflux for 48 hours. The reaction was quenched with water (20 mL) and the resulting mixture was allowed to stir at room temperature for 24 hours, then acidified to pH 3 (checked with pH paper) by addition of 0.5 M aqueous citric acid and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (70 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo then purified by column chromatography (Isolera Biotage, 24 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.). The resulting residue was dissolved in DMF (4 mL) and Et.sub.3N (0.074 mL, 0.527 mmol) followed by HATU (0.080 g, 0.211 mmol) were added. The mixture was then stirred at room temperature for 10 minutes before tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (0.046 g, 0.158 mmol) was added. The reaction was stirred at room temperature for 20 hours, then diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO.sub.3 (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product. This material was purified by column chromatography (Isolera Biotage, 12 g SiO.sub.2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compounds A19 (0.008 g, 19% yield) and A18 (20 mg, 66% yield) as colourless gums.

    [0780] A19: LCMS-B: RT 3.346 min, m/z 430.1 [M−H].sup.−

    [0781] A18: LCMS-B: RT 3.532 min, m/z 597.3 [M+H].sup.+

    (b) 6-Chloro-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)nicotinamide hydrochloride 98

    [0782] tert-Butyl (S)-3-((R)-2-(6-chloronicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A19 (0.020 g, 0.035 mmol) was dissolved in 1,4-dioxane (2 mL) and 4 M HCl in 1,4-dioxane solution (0.43 mL) was added and the reaction was then stirred at room temperature for 20 hours. The precipitate formed in the reaction mixture was allowed to sediment on the bottom of the flask. Solvent was carefully removed with a pipette, diethyl ether (˜2 mL) was added and then removed with a pipette. The diethyl ether wash was repeated 4 times and the residue dried on high-vacuum to give the title compound (0.008 g, 52% yield) as an off-white solid. LCMS-B: RT 2.753 min, m/z 332.1 [M+H].sup.+ for free base.

    Example 99: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(piperidin-4-yloxy)nicotinamide trihydrochloride 99

    [0783] ##STR00227##

    [0784] tert-Butyl (S)-3-((R)-2-(6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)nicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A18 (0.008 g, 75% purity, 0.010 mmol) was dissolved in 1,4-dioxane (1 mL) and 4 M HCl in 1,4-dioxane solution (0.13 mL) was added and the reaction was then stirred at room temperature for 20 hours. The precipitate formed in the reaction mixture was allowed to sediment on the bottom of the flask. Solvent was carefully removed with a pipette, diethyl ether (˜2 mL) was added and then removed with a pipette. The diethyl ether wash was repeated 4 times and the residue dried on high-vacuum to give the title compound (0.004 g, 75% yield) as an off-white solid. LCMS-B: RT 1.739 min, m/z 397 [M+H] for free base.

    Example 100: Methyl 4-((5-(((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate 100

    [0785] ##STR00228##

    (a) 6-((1-(Methoxycarbonyl)piperidin-4-yl)oxy)nicotinic acid A18

    [0786] Methyl 4-hydroxypiperidine-1-carboxylate (0.45 g, 2.84 mmol) was dissolved in anhydrous THF (10 mL) under an atmosphere of nitrogen. Sodium tert-butoxide (0.55 g, 5.67 mmol) was added in portions and the resulting mixture was stirred at room temperature for 20 minutes. 6-Fluoronicotinic acid (0.20 g, 1.42 mmol) was then added and the mixture was heated at 60° C. for 20 hours. The reaction was quenched with water (20 mL), then acidified to pH 3 (checked with pH paper) by addition of 0.5 M aqueous citric acid and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (70 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography (Isolera Biotage, 12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (0.068 g, 17% yield, 80% purity) as a white solid. LCMS-B: RT 3.030 min, m/z 279.1 [M−H].sup.−

    (b) tert-Butyl (S)-3-((R)-1-hydroxy-2-(6-((1-(methoxycarbonyl)piperidin-4-yl)oxy)nicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A20

    [0787] 6-((1-(Methoxycarbonyl)piperidin-4-yl)oxy)nicotinic acid A18 (80% purity, 0.063 g, 0.178 mmol) was dissolved in DMF (4 mL) and Et.sub.3N (0.075 mL, 0.535 mmol) followed by HATU (0.102 g, 0.268 mmol) were added. The mixture was then stirred at room temperature for 10 minutes before tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (0.052 g, 0.178 mmol) was added. The reaction was then stirred at room temperature for 20 hours then diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO.sub.3(50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product. This was purified by column chromatography (Isolera Biotage, 12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (0.050 g, 50% yield) as a colourless gum. LCMS-B: RT 3.385 min, m/z 555.3 [M+H].sup.+

    (c) Methyl 4-((5-(((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate 100

    [0788] tert-Butyl (S)-3-((R)-1-hydroxy-2-(6-((1-(methoxycarbonyl)piperidin-4-yl)oxy)nicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A20 (0.05 g, 0.09 mmol) was dissolved in 1,4-dioxane (2.5 mL) and 4 M HCl in 1,4-dioxane solution (1.13 mL) was added and the reaction was then stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was taken up in EtOAc (50 mL) and 1 M aqueous NaOH (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL), the combined organics were washed with brine (70 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the title compound (0.023 g, 56% yield) as an off-white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (dd, J=2.6, 0.7 Hz, 1H), 8.10 (dd, J=8.7, 2.5 Hz, 1H), 7.16-7.01 (m, 4H), 6.83 (dd, J=8.7, 0.8 Hz, 1H), 5.35-5.28 (m, 1H), 4.09-3.97 (m, 2H), 3.89 (dt, J=7.0, 4.7 Hz, 1H), 3.84-3.76 (m, 2H), 3.70 (s, 3H), 3.68-3.62 (m, 1H), 3.54 (dd, J=13.8, 7.0 Hz, 1H), 3.44-3.34 (m, 2H), 2.99-2.85 (m, 3H), 2.06-1.97 (m, 2H), 1.78-1.67 (m, 2H). LCMS-B: RT 2.887 min, m/z 455.2 [M+H].sup.+

    Example 101: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-morpholinonicotinamide 101

    [0789] ##STR00229##

    (a) tert-Butyl (S)-3-((R)-1-hydroxy-2-(6-morpholinonicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A21

    [0790] 6-Morpholinonicotinic acid (0.050 g, 0.240 mmol) was dissolved in DMF (4 mL) and Et.sub.3N (0.100 mL, 0.720 mmol) followed by HATU (0.137 g, 0.360 mmol) were added. The mixture was then stirred at room temperature for 10 minutes before tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (0.070 g, 0.240 mmol) was added. The reaction was then stirred at room temperature for 20 hours then diluted with EtOAc (70 mL) and washed with saturated aqueous NaHCO.sub.3 (70 mL), brine (70 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product. This was purified by column chromatography (Isolera Biotage, 12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (0.061 g, 53% yield) as a colourless gum. LCMS-B: RT 3.222 min, m/z 483.3 [M+H].sup.+

    (b) N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-morpholinonicotinamide 101

    [0791] tert-Butyl (S)-3-((R)-1-hydroxy-2-(6-morpholinonicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A21 (0.061 g, 0.126 mmol) was dissolved in 1,4-dioxane (2.5 mL) and 4 M HCl in 1,4-dioxane solution (1.6 mL) was added and the reaction was then stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue was taken up in EtOAc (70 mL) and 1 M aqueous NaOH (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the combined organics were washed with brine (70 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the title compound (0.045 g, 93% yield) as a white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.62 (dd, J=2.5, 0.7 Hz, 1H), 7.99 (dd, J=9.0, 2.5 Hz, 1H), 7.15-7.01 (m, 4H), 6.85-6.79 (m, 1H), 4.10-3.98 (m, 2H), 3.88 (dt, J=6.9, 4.7 Hz, 1H), 3.81-3.74 (m, 4H), 3.66-3.51 (m, 6H), 3.00-2.85 (m, 3H). LCMS-B: RT 2.711 min, m/z 383.1 [M+H].sup.+

    Example 102: 2-((1-Acetylpiperidin-4-yl)oxy)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)isonicotinamide 102

    [0792] ##STR00230##

    (a) 2-((1-Acetylpiperidin-4-yl)oxy)isonicotinic acid A22

    [0793] To a solution of 2-(piperidin-4-yloxy)isonicotinic acid dihydrochloride I49 (0.150 g, 0.508 mmol, 1 equiv) in anhydrous THF (10 mL) and triethylamine (0.319 mL, 2.29 mmol, 4.5 equiv) was slowly added acetyl chloride (0.073 mL, 1.0 mmol, 2 equiv). After the addition, the mixture was stirred overnight at ambient temperature and then at 50° C. for an additional 24 hours. The solvent was removed in vacuo, a 0.5 M aqueous solution of NaOH was added (20 mL) and the solution was stirred for 1 hour. The reaction was acidified to pH=3 with a 0.5 M aqueous citric acid solution, extracted with EtOAc (3×30 mL) and the combined organic extracts washed with water (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated. The crude product was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (75 mg, 56% yield) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (dd, J=5.2, 0.9 Hz, 1H), 7.46 (dd, J=5.3, 1.4 Hz, 1H), 7.37 (s, 1H), 5.34 (tt, J=7.2, 3.6 Hz, 1H), 3.97-3.85 (m, 1H), 3.80-3.67 (m, 1H), 3.65-3.54 (m, 1H), 3.49-3.38 (m, 1H), 2.17 (s, 3H), 2.11-1.93 (m, 2H), 1.93-1.74 (m, 2H), 1.30-1.18 (m, 1H). LCMS-B: RT 0.80 min, m/z 265.1 [M+H].sup.+, 263.1 [M−H].sup.−.

    (b) 2-((1-Acetylpiperidin-4-yl)oxy)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)isonicotinamide 102

    [0794] To a solution of 2-((1-acetylpiperidin-4-yl)oxy)isonicotinic acid A22 (45 mg, 0.17 mmol, 1 equiv), DIPEA (89 μL, 0.51 mmol, 3 equiv) and HATU (98 mg, 0.26 mmol, 1.5 equiv) was added a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (50 mg, 0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stood at room temperature for 16 hours, quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (×3) utilizing a phase separation cartridge. The organic filtrates were reduced under a stream of air, DCM:TFA (4 mL, 1:1) was added and the reaction stood at room temperature overnight. Additional TFA (2 mL) was added and the solution stirred for 2 more days. The reaction mixture was concentrated under a stream of air and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia). The crude product was further purified by column chromatography (12 g SiO.sub.2 cartridge, 50-100% EtOAc (modified by the addition of 1% v/v of 3.5 M methanolic ammonia) in petroleum benzine 40-60° C.) followed by 0-30% MeOH in EtOAc modified by the addition of 1% v/v of 2.0 M methanolic ammonia) to give the title compound (28 mg, 38% yield) as a pale yellow oil. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.23 (d, J=5.3 Hz, 1H), 7.30 (d, J=5.4 Hz, 1H), 7.22-7.03 (m, 5H), 5.36-5.26 (m, 1H), 4.15 (s, 2H), 4.06-3.96 (m, 1H), 3.94-3.83 (m, 1H), 3.83-3.72 (m, 1H), 3.65 (dd, J=13.8, 5.0 Hz, 1H), 3.59-3.44 (m, 3H), 3.21-3.12 (m, 1H), 3.05-2.92 (m, 2H), 2.12 (s, 3H), 2.14-1.94 (m, 2H), 1.88-1.66 (m, 2H). LCMS-B: RT 2.79 min, m/z 439.2 [M+H].sup.+.

    Example 103: 4-(3-Oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide 103

    [0795] ##STR00231##

    [0796] To a solution of lithium 4-(((R)-2-((S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-hydroxyethyl)carbamoyl)benzoate I36 (150 mg, 0.336 mmol, 1 equiv), DIPEA (176 μL, 1.01 mmol, 3 equiv) and HATU (192 mg, 0.504 mmol, 1.5 equiv) in DMF (2 mL) was added a solution of 3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (55 mg, 0.34 mmol, 1 equiv) in MeCN (10 mL). The reaction was stirred at room temperature overnight, quenched with a saturated aqueous solution of NaHCO.sub.3 (15 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over MgSO.sub.4 and concentrated in vacuo. DCM:TFA (8 mL, 1:1) was added and the reaction stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by solid-phase extraction (2×1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia). The basic eluate was dried in vacuo and further purified by column chromatography (12 g SiO.sub.2 cartridge, 50-100% EtOAc (modified by the addition of 1% v/v of 3.5 M methanolic ammonia) in petroleum benzine 40-60° C. followed by 0-20% MeOH in EtOAc modified by the addition of 1% v/v of 3.5 M methanolic ammonia) to give the title compound (26 mg, 17% yield) as a colourless oil. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.34-7.18 (m, 4H), 4.56-4.34 (m, 3H), 4.30-4.23 (m, 1H), 4.03 (d, J=11.7 Hz, 1H), 3.91-3.74 (m, 3H), 3.71-3.52 (m, 4H), 3.38-3.16 (m, obscured by solvent), 2.66-2.52 (m, 1H), 2.02-1.94 (m, 2H), 1.91-1.77 (m, 2H), 1.74-1.64 (m, 1H). LCMS-B: RT 2.83 min, m/z 450.2 [M+H].sup.+

    Example 104: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-2-((tetrahydrofuran-3-yl)oxy)isonicotinamide bis(2,2,2-trifluoroacetate) 104

    [0797] ##STR00232##

    [0798] (a) tert-Butyl (3S)-3-((1R)-1-hydroxy-2-(2-((tetrahydrofuran-3-yl)oxy)isonicotinamido)ethyl)-3, 4-dihydroisoquinoline-2(1H)-carboxylate A23

    [0799] 2-((Tetrahydrofuran-3-yl)oxy)isonicotinic acid (100 mg, 0.48 mmol), tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (140 mg, 0.48 mmol), DMF (1.5 mL), triethylamine (0.200 mL, 1.43 mmol) and HATU (273 mg, 0.72 mmol) were stirred at 30° C. After 2 hours, the mixture was added to water (30 mL) and the precipitate collected by filtration. The solid was washed with water (15 mL) and air-dried. The solid was dissolved in methanol (10 mL) and sodium tert-butoxide (50 mg) was added. After 1.5 hours the mixture was evaporated, chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the title compound (81 mg, 35% yield) as a white solid. LCMS-A: RT 6.39 min; m/z 484.3 [M+H].sup.+

    (b) N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-2-((tetrahydrofuran-3-yl)oxy)isonicotinamide bis(2,2,2-trifluoroacetate) 104

    [0800] tert-Butyl (3S)-3-((1R)-1-hydroxy-2-(2-((tetrahydrofuran-3-yl)oxy)isonicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A23 (32 mg, 0.066 mmol) was taken up in DCM:TFA (1:1, 4 mL) and stirred overnight at room temperature. The solvent was removed in vacuo to give the title compound (14 mg, 35% yield) as a pale brown oil. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.24 (d, J=5.5 Hz, 1H), 7.35-7.14 (m, 6H), 5.61-5.53 (m, 1H), 4.48 (d, J=15.7 Hz, 1H), 4.36 (d, J=15.6 Hz, 1H), 4.25 (td, J=6.5, 3.1 Hz, 1H), 4.07-3.81 (m, 4H), 3.72-3.48 (m, 3H), 3.20 (dd, J=17.0, 4.8 Hz, 1H), 2.70 (s, 1H), 2.36-2.23 (m, 1H), 2.16-2.07 (m, 1H). LCMS-B: RT 2.85 min, m/z 384.2 [M+H].sup.+ for free base.

    Example 105: Methyl (1R,3r,5S)-3-((4-(((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)carbamoyl)pyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 105

    [0801] ##STR00233##

    (a) 2-(((1R,3r,5S)-8-(tert-Butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid A24

    [0802] A solution of endo-8-Boc-3-hydroxy-8-azabicyclo[3.2.1]octane (0.500 g, 2.20 mmol, 1.2 equiv) in anhydrous DMF (5 mL) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 0.293 g, 7.33 mmol, 4 equiv) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 10 minutes before a solution of 2-fluoroisonicotinic acid (0.259 g, 1.83 mmol, 1 equiv) in DMF (5 mL) was added. The mixture was then stirred for a further 16 hours at room temperature. H.sub.2O (˜20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜3 with a 0.5 M solution of aqueous citric acid. The aqueous layer was extracted with EtOAc (3×30 mL), the organic layers were combined, washed with brine, dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The resulting residue was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (328 mg, contaminated with starting material endo-8-Boc-3-hydroxy-8-azabicyclo[3.2.1]octane) as a white solid. The impure material was carried through to the next step without further purification and analysis.

    (b) 2-(((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid dihydrochloride A25

    [0803] To 2-(((1R,3r,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid A24 (328 mg) in 1,4-dioxane (20 mL) was added a 4 M solution of HCl in 1,4-dioxane (1.42 mL, 5.65 mmol). The reaction was then stirred at room temperature overnight. A further 5 mL of 4 M solution of HCl in 1,4-dioxane (20 mmol) was added and the reaction was stirred at 35° C. for an additional 24 hours before the reaction was dried in vacuo to give the impure title compound (300 mg) as a white solid. LCMS-B: RT 0.42 min, m/z 249.1 [M+H].sup.+ for the free base.

    (c) 2-(((1R,3r,5S)-8-(Methoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid A26

    [0804] Methyl chloroformate (72 μL, 0.93 mmol) was added drop-wise to a mixture of impure 2-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid dihydrochloride A25 (150 mg) and sodium hydroxide (75 mg, 1.9 mmol) in water (10 mL). The reaction was stirred at ambient temperature overnight, acidified to pH=3 with a 0.5 M aqueous solution of citric acid and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and the filtrate concentrated in vacuo. The resulting oil was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound (98 mg, 69% yield) as a white solid. LCMS-B: RT 3.09 min, m/z 307.1 [M+H].sup.+.

    (d) Methyl (1R,3r,5S)-3-((4-(((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)carbamoyl)pyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 105

    [0805] To a solution of 2-(((1R,3r,5S)-8-(methoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid A26 (0.17 mmol, 1 equiv), DIPEA (89 μL, 0.51 mmol, 3 equiv) and HATU (98 mg, 0.26 mmol, 1.5 equiv) was added a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (50 mg, 0.17 mmol, 1 equiv) in DMF (2 mL). The reaction was stood at room temperature for 16 hours, quenched with a saturated aqueous solution of NaHCO.sub.3 (5 mL) and extracted with DCM (×3) utilizing a phase separation cartridge. The organic filtrates were reduced under a stream of air, DCM:TFA (4 mL, 1:1) was added and the reaction stood at room temperature overnight. The reaction mixture was concentrated under a stream of air and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give the crude product. This was further purified by column chromatography (12 g SiO.sub.2 cartridge, 50-100% EtOAc (modified by the addition of 1% v/v of 3.5 M methanolic ammonia) in petroleum benzine 40-60° C. followed by 0-30% MeOH in EtOAc modified by the addition of 1% v/v of 2.0 M methanolic ammonia) to give the title compound. LCMS-B: RT 2.90 min, m/z 481.2 [M+H].sup.+.

    Example 106: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(difluoromethyl)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide 106

    [0806] ##STR00234##

    (a) tert-Butyl (S)-3-((R)-2-(2-(difluoromethyl)-4-(methoxycarbonyl)benzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A27

    [0807] To a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (191 mg, 0.65 mmol) in DCM (5 mL) was added 2-(difluoromethyl)-4-(methoxycarbonyl)benzoic acid I108 (150 mg, 0.65 mmol), HOBt (8.8 mg, 0.065 mmol), DIPEA (337 mg, 2.6 mmol) and EDCl (260 mg, 1.3 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO.sub.3 solution, the organic layer was washed with brine (3 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by prep TLC (DCM:methanol=50:1) to give the title compound as a white solid (89 mg, 27%). LCMS-C: RT 3.07 min; m/z 527.2 [M+Na].sup.+.

    (b) tert-Butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(difluoromethyl)-benzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A28

    [0808] To a solution of tert-butyl (S)-3-((R)-2-(2-(difluoromethyl)-4-(methoxycarbonyl)benzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A27 (80 mg, 0.16 mmol) in a mixture of THF (5 mL), methanol (0.5 mL) and water (0.5 mL) was added LiOH.H.sub.2O (33.3 mg, 0.79 mmol). The resulting mixture was then stirred at room temperature overnight. The solvent was removed, and the residue was diluted with water (5 mL). The pH of the aqueous mixture was adjusted to 6 by addition of a 2 M HCl solution, then extracted with DCM (3 mL×3). The combined organic layers were washed with brine (2 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give an off-white solid (76 mg). A solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (23 mg, 0.15 mmol) in DCM (5 mL) was added to the intermediate (75 mg), HOBt (2.1 mg, 0.015 mmol), DIPEA (79 mg, 0.61 mmol) and EDCl (59 mg, 0.3 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with NaHCO.sub.3 solution, the organic layer was washed with brine (3 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by prep TLC (DCM:methanol=50:1) to give the title compound as a white solid (51 mg, 57%): LCMS-C: RT 2.88 min; m/z 608.3 [M+Na].sup.+.

    (c) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(difluoromethyl)-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide 106

    [0809] A solution of tert-butyl (3S)-3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(difluoromethyl)-benzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A28 (45 mg, 0.077 mmol) in saturated HCl/EtOAc solution (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with NaHCO.sub.3 solution and the organic layer washed with brine (3 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by prep TLC (DCM:methanol=40:1) to give the crude compound. The product was washed with diethyl ether (4 mL×2) then taken up in methanol (4 drops) and water (4 mL) and lyophilized to give the title compound as an off-white solid (9 mg). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (s, 1H), 7.76-7.70 (m, 2H), 7.24-7.10 (m, 5H), 4.66 (s, 1H), 4.27-4.19 (m, 2H), 4.09-4.08 (m, 1H), 3.93-3.92 (m, 1H), 3.84-3.81 (m, 1H), 3.73-3.51 (m, 6H), 3.13-3.03 (m, 2H), 2.06-2.01 (m, 4H). LCMS-C: RT 3.46 min; m/z 486.0 [M+H].sup.+.

    Example 107: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide 107

    [0810] ##STR00235##

    (a) 6-Chloropyrimidine-4-carbonyl chloride A29

    [0811] To a solution of 6-hydroxypyrimidine-4-carboxylic acid (1.0 g, 7.1 mmol) in EtOAc (20 mL) was added oxalyl chloride (3.6 g, 28.4 mmol) dropwise. The mixture was stirred at room temperature for 30 minutes then DMF (0.1 mL) was added and the mixture heated at reflux overnight. The solvent was removed to give the crude product as an oil (1.2 g, 95%) which was used without purification. LCMS-C of a MeOH quench: RT 0.64 min; m/z 173.0, 175.0 [M+H].sup.+.

    (b) (S)-tert-Butyl3-((R)-2-(6-chloropyrimidine-4-carboxamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A30

    [0812] To a solution of (S)-tert-butyl 3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (500 mg, 1.7 mmol) and Et.sub.3N (688 mg, 6.8 mmol) in DCM (20 mL) at 0° C. was added a solution of 6-chloropyrimidine-4-carbonyl chloride A29 (300 mg, 1.7 mmol) in DCM (4 mL) dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with DCM (50 mL) and the organic layer washed with water (50 mL) and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (100% petroleum ether to 25% EtOAc in petroleum ether) to give the title compound as an off-white solid (420 mg, 57%). LCMS-C: RT 2.96 min; m/z 455.1, 457.2 [M+Na].sup.+.

    (c) 6-Chloro-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)pyrimidine-4-carboxamide dihydrochloride A31

    [0813] A mixture of (S)-tert-butyl3-((R)-2-(6-chloropyrimidine-4-carboxamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A30 (100 mg, 0.23 mmol) in saturated HCl/EtOAc (3 mL) was stirred at room temperature for 3 hours. The solvent was removed to give the crude product as a yellow solid (100 mg, 94%). The crude product was without further purification. LCMS-C: RT 0.69 min; m/z 333.2 [M+H].sup.+

    (d) N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide 107

    [0814] To a solution of 6-chloro-N—((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)pyrimidine-4-carboxamide dihydrochloride A31 (85 mg, 0.23 mmol) in i-PrOH (5 mL) were added oxetan-3-amine (20 mg, 0.28 mmol) and Et.sub.3N (93 mg, 0.92 mmol). The mixture was heated at 60° C. overnight. The solvent was removed under reduced pressure and the residue obtained dissolved in water (15 mL). The pH was adjusted to pH 8-9 by addition of solid NaHCO.sub.3. The aqueous layer was extracted with 10% MeOH/DCM (30 mL×5). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated. The solid was washed with diethyl ether (10 mL×2) to give the title compound as a white solid (27 mg, 29%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.69-8.68 (m, 1H), 8.52-8.49 (m, 2H), 7.13-7.01 (m, 5H), 5.11 (d, J=5.2 Hz, 1H), 5.00 (br s, 1H), 4.82 (t, J=6.8 Hz, 2H), 4.48-4.45 (m, 2H), 3.94-3.82 (m, 2H), 3.68-3.59 (m, 2H), 3.32-3.29 (m, 1H, obscured by solvent), 2.83-2.59 (m, 4H); LCMS-C: RT 2.88 min; m/z 370.3 [M+H].sup.+.

    Example 108: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide 108

    [0815] ##STR00236##

    (a) (S)-7-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A32

    [0816] To a solution of (S)-2-amino-3-(p-tolyl)propanoic acid (500 mg, 2.8 mol) in 48% aqueous HBr (5 mL) was added formaldehyde (0.82 mL, 22.3 mmol) gradually at 40° C. The mixture was then stirred at 75° C. for 5 hours. The reaction was cooled to 0° C., filtered and washed with DCM (2×10 mL). The solid was collected to provide the title compound as a white solid (440 mg, 82%). LCMS-C: RT 1.40 min; m/z 192.2 [M+H].sup.+.

    (b) (S)-tert-Butyl 3-(hydroxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A33

    [0817] (S)-7-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A32 (700 mg, 3.7 mmol) was stirred vigorously in 1,4-dioxane (10 mL) and water (5 mL). NaHCO.sub.3 (922 mg, 11 mmol) and Boc.sub.2O (880 mg, 4.0 mmol) were added and the reaction was stirred vigorously. After 6 days, the mixture was concentrated in vacuo and the residue dissolved in water (20 mL). A 30% w/v aqueous solution of NaHSO.sub.4 (30 mL) was added and the mixture extracted with DCM (3×50 mL). The pooled organic extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a yellow oil. This material was dissolved in THF (150 mL) and CDI (579 mg, 3.6 mmol) was added. The mixture was stirred for 3 hours at room temperature then cooled to 0° C. A solution of NaBH.sub.4 (135 mg, 3.6 mmol) in water (4 mL) was added dropwise. The mixture was stirred vigorously at room temperature for 3 hours then concentrated in vacuo. The residue was partitioned between water (20 mL) and ethyl acetate (20 mL) and the aqueous phase extracted with ethyl acetate (2×20 mL), the combined organic extracts washed with 5% w/v aqueous NaHSO.sub.4 (20 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (5% EtOAc/petroleum ether) to give the title compound as a pale oil (262 mg, 26% yield over 2 steps): LCMS-C: RT 2.91 min; m/z 300.2 [M+Na]

    (c) tert-Butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A34

    [0818] To a solution of (S)-tert-butyl 3-(hydroxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A33 (280 mg, 1.0 mmol) in a mixture of DCM (10 mL) and DMSO (2 mL) at 0° C. was added triethylamine (306 mL, 3.0 mmol) and pyridine-sulfur trioxide complex (482 mg, 3.0 mmol). The mixture was stirred at 0° C. for 10 minutes then allowed warm to room temperature and stirred a further 4 hours. The reaction was quenched by addition of saturated aqueous NaHCO.sub.3 (20 mL) and water (20 mL), and the aqueous layer extracted with diethyl ether (3×150 mL). The pooled organic extracts were washed with 1:1 water: saturated aqueous NH.sub.4Cl (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude intermediate as an orange oil which was used without further purification.

    [0819] A solution of N.sup.1,N.sup.2-bis(4-chlorobenzyl)benzene-1,2-diamine (44 mg, 0.12 mmol) and Cu(OAc).sub.2.H.sub.2O (20 mg, 0.1 mmol) in ethanol (5 mL) was stirred at 23° C. for 1 hour. A solution of the crude intermediate from above (275 mg) in ethanol (5 mL) was then added to the catalyst solution and the mixture was cooled to 0° C. and stirred for 30 minutes. CH.sub.3NO.sub.2 (600 mg, 10.0 mmol) was added and stirring continued at 0° C. for 5 days. The mixture was concentrated and the residue purified by chromatography (5% EtOAc/petroleum ether) to give the title compound (160 mg, 48% yield over 2 steps) as a yellow oil. LCMS-C: RT 2.92 min; m/z 359.2 [M+Na].sup.+

    (d) tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A35

    [0820] To a solution of tert-butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A34 (160 mg, 0.47 mmol) in absolute ethanol (10 mL) was added 10% Pd/C (50% wet with water, 160 mg). The reaction was stirred vigorously under a hydrogen atmosphere overnight. The mixture was filtered through Celite and the Celite washed with absolute ethanol (40 mL). The pooled filtrates were concentrated in vacuo to give the title compound as a yellow solid (110 mg, 76%): LCMS-C: RT 2.21 min; m/z 307.2 [M+H].sup.+

    (e) (3S)-tert-Butyl 3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A36

    [0821] To a solution of 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I42 (110 mg, 0.36 mmol) and tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A35 (110 mg, 0.36 mmol) in DCM (10 mL) were added DIPEA (186 mg, 1.44 mmol), HOBt (11 mg, 0.072 mmol), and EDCl.HCl (138 mg, 0.72 mmol). The resulting mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture and the aqueous extracted with DCM (3×20 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by column chromatography (DCM:MeOH=50:1) to give the title compound as a yellow oil (140 mg, 65%): LCMS-C: RT 3.10 min; m/z 594.3 [M+H].sup.+.

    (f) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide 108

    [0822] A solution of (3S)-tert-butyl 3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A36 (140 mg, 0.23 mmol) in saturated HCl/EtOAc solution (10 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue obtained suspended in saturated aqueous NaHCO.sub.3 solution (20 mL). The aqueous mixture was extracted with DCM (3×20 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give a crude residue which was purified by prep TLC (DCM:MeOH=10:1) to give the title compound as a white solid (50 mg, 43%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.99 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 7.17-7.06 (m, 3H), 6.99 (s, 1H), 4.64 (s, 1H), 4.32-4.22 (m, 4H), 4.15-4.11 (m, 1H), 3.96 (br s, 1H), 3.83-3.81 (m, 1H), 3.74-3.70 (m, 3H), 3.62-3.57 (m, 2H), 3.45-3.40 (m, 1H), 3.16-3.04 (m, 2H), 2.30 (s, 3H), 2.07-2.00 (m, 4H), 1.44 (t, J=7.2 Hz, 3H). LCMS-C: RT 2.16 min, m/z 494.3 [M+H].sup.+.

    Example 109: N-((1R)-1-Hydroxy-1-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)propan-2-yl)-4-(morpholine-4-carbonyl)benzamide hydrochloride 109

    [0823] ##STR00237##

    (a) tert-Butyl (3S)-3-((1S)-1-hydroxy-2-nitropropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A37A and tert-butyl (3S)-3-((1R)-1-hydroxy-2-nitropropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A37 B

    [0824] tert-Butyl (S)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate I10 (3.55 mmol @ 100% conversion), absolute ethanol (10 mL), nitroethane (2.53 mL, 35.5 mmol) and the copper catalyst (see above figure, prepared according to Tetrahedron: Asymmetry (2008) 2310-2315) (169 mg, 10 mol %) were stirred at room temperature. After four days the mixture was concentrated in vacuo, chromatography (12 g SiO.sub.2 cartridge, 0-20% ethyl acetate/hexanes) gave title compounds A37A (pale yellow syrup, 231 mg) and A37B (brighter yellow syrup, 306 mg).

    [0825] Data for tert-butyl (3S)-3-((1S)-1-hydroxy-2-nitropropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A37A:

    [0826] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.29-6.99 (m, 4H), 5.03-3.95 (m, overlaps with solvent), 3.16 (dd, J=16.2, 2.4 Hz, 1H), 2.93 (dd, J=15.9, 5.6 Hz, 1H), 1.65-1.37 (m, 12H).

    [0827] Data for tert-butyl (3S)-3-((1R)-1-hydroxy-2-nitropropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A37B:

    [0828] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.23-7.09 (m, 4H), 4.99-4.64 (m, overlaps with solvent), 4.37-3.95 (m, overlaps with solvent), 3.14 (dd, J=15.5, 6.2 Hz, 1H), 2.84 (dd, J=15.5, 6.2 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.50 (s, 9H). LCMS-A: 6.58 min; m/z 237.2 [M-Boc+2H].sup.+

    [0829] Determination of Stereochemistry for A37A and A37B:

    ##STR00238##

    [0830] The ring stereocentre *1 is set in the starting material, (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. Based on .sup.1H NMR coupling constants for nitro compounds A37A and A37B and comparison to the known related systems (i.e. I11A and I11B) coupling constants (configuration which is confirmed by X-ray), stereocentre *2 in compound A37A has been assigned syn with respect to the heteroatoms (i.e. *1,*2=S,S) and compound A37B has been assigned anti with respect to the heteroatoms (i.e. *1,*2=S,R).

    [0831] The stereochemistry at *3 has been left undefined, however a single signal is observed for the methyl group in the .sup.1H NMR for A37B, so A37B (and by extension A37A) are presumed to be a single diastereomers.

    (b) tert-Butyl (3S)-3-((1R)-1-hydroxy-2-(4-(morpholine-4-carbonyl)benzamido)propyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A38

    [0832] tert-Butyl (3S)-3-((1S)-1-hydroxy-2-nitropropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A37A (231 mg, 0.69 mmol), absolute ethanol (10 mL), Pd/C (50% wet with water, 200 mg) were stirred under hydrogen. After 18 hours, the mixture was filtered through Celite and the Celite washed with absolute ethanol (20 mL). The combined filtrates were evaporated to give the crude amine which was used in the next step without purification.

    [0833] The amine (164 mg), 4-(morpholine-4-carbonyl)benzoic acid I7 (126 mg, 0.535 mmol), acetonitrile (5 mL), DMF (1 mL), DIPEA (0.186 mL, 1.07 mmol) and HATU (305 mg 0.803 mmol) were stirred at room temperature. After 18 hours, the mixture was quenched with water (1 mL) and the acetonitrile removed in vacuo. The aqueous residue was diluted with water (25 mL) and DCM (25 mL). The DCM phase was separated and concentrated in vacuo. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the title compound as an off white solid after trituration with DCM/hexanes (48 mg, 13% yield over 2 steps). LCMS-B: RT 3.25 min; m/z 424.2 [M-Boc+2H].sup.+

    (c) N-((1R)-1-Hydroxy-1-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)propan-2-yl)-4-(morpholine-4-carbonyl)benzamide hydrochloride 109

    [0834] tert-Butyl (3S)-3-((1R)-1-hydroxy-2-(4-(morpholine-4-carbonyl)benzamido)propyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A38 (48 mg, 0.091 mmol), 1,4-dioxane (2 mL) and 4.0 M HCl in 1,4-dioxane (2 mL) were stood at room temperature. After 1.5 hours the mixture was diluted with diethyl ether (50 mL), the solvent decanted from the precipitate and the precipitate washed with further diethyl ether (2×50 mL). The diethyl ether extracts were discarded and the precipitate was dried in vacuo to give the title compound as a white solid (8.7 mg, 21% yield). LCMS-B: RT 2.75 min; m/z 424.2 [M+H].sup.+ for free base.

    Example 110: N-((1S)-1-Hydroxy-1-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)propan-2-yl)-4-(morpholine-4-carbonyl)benzamide hydrochloride 110

    [0835] ##STR00239##

    (a) tert-Butyl (3S)-3-((1S)-2-amino-1-hydroxypropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A39

    [0836] tert-Butyl (3S)-3-((1R)-1-hydroxy-2-nitropropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A37B (306 mg, 0.91 mmol), absolute ethanol (10 mL) and Pd/C (50% wet with water, 200 mg) were stirred under hydrogen. After 18 hours, the mixture was filtered through Celite and the Celite washed with absolute ethanol (20 mL). The combined filtrates were evaporated to give the title compound as a colourless syrup (250 mg, 90% yield). LCMS-A: RT 4.76 min; m/z 307.2 [M-Boc+2H].sup.+

    (b) tert-Butyl (3S)-3-((1S)-1-hydroxy-2-(4-(morpholine-4-carbonyl)benzamido)propyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A40

    [0837] tert-Butyl (3S)-3-((1S)-2-amino-1-hydroxypropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A39 (153 mg, 0.499 mmol), 4-(morpholine-4-carbonyl)benzoic acid I7 (117 mg, 0.499 mmol), acetonitrile (5 mL), DMF (1 mL), DIPEA (0.174 mL, 0.999 mmol) and HATU (285 mg 0.749 mmol) were stirred at room temperature. After 18 hours, the mixture was quenched with water (1 mL) and the acetonitrile removed in vacuo. The aqueous residue was diluted with water (25 mL) and DCM (25 mL). The DCM phase was separated and concentrated in vacuo. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the title compound as an off white solid after trituration with DCM/hexanes (96 mg, 37% yield). LCMS-B: RT 3.20 min; m/z 424.2 [M-Boc+2H].sup.+; 468.2 [M-tBu+2H].sup.+; 524.3 [M+H].sup.+

    (c) N-((1S)-1-Hydroxy-1-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)propan-2-yl)-4-(morpholine-4-carbonyl)benzamide hydrochloride 110

    [0838] tert-Butyl (3S)-3-((1S)-1-hydroxy-2-(4-(morpholine-4-carbonyl)benzamido)propyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A40 (96 mg, 0.183 mmol), 1,4-dioxane (2 mL) and 4.0 M HCl in 1,4-dioxane (2 mL) were stood at room temperature. After 1.5 hours, the mixture was diluted with diethyl ether (50 mL), the solvent decanted from the precipitate and the precipitate washed with further diethyl ether (2×50 mL). The diethyl ether extracts were discarded and the precipitate was dried in vacuo to give the title compound as a white solid (46 mg, 55% yield). LCMS-B: RT 2.75 min; m/z 424.3 [M+H].sup.+ for free base.

    Example 121: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(methylamino)nicotinamide dihydrochloride 121

    [0839] ##STR00240##

    (a) (S)-tert-Butyl 3-((R)-1-hydroxy-2-(6-(methylamino)nicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A41

    [0840] To a solution of (S)-tert-butyl 3-((R)-2-(6-chloronicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A19 (50 mg, 0.12 mmol, 1.0 eq) in EtOH (1 mL) was added a solution of methylamine in THF (2M, 0.23 mL), and the reaction was heated in the microwave at 130° C. for 3 hours. The solvent was removed and the residue purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (25 mg, 49%) as a white solid. LCMS-C: RT 2.36 min; m/z 427.2 [M+H].sup.+

    (b) N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(methylamino)nicotinamide dihydrochloride 121

    [0841] To a solution of (S)-tert-butyl 3-((R)-1-hydroxy-2-(6-(methylamino)nicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A41 (20 mg, 0.07 mmol, 1.0 eq) in diethyl ether (2 mL) was added a solution of saturated HCl in diethyl ether (2 mL). The reaction was stirred at room temperature for 2 hours then concentrated and the residue obtained was washed with diethyl ether to give the title compound (15 mg, 79%) as a yellow solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.44 (s, 1H), 8.30 (br s, 1H), 7.30-7.21 (m, 4H), 7.10 (d, J=8.8 Hz, 1H), 4.51-4.30 (m, 3H), 3.69-3.64 (m, 2H), 3.58-3.53 (m, 1H), 3.35-3.28 (m, 1H, overlap), 3.24-3.18 (m, 1H), 3.09 (s, 3H). LCMS-C: RT 0.65 min; m/z 327.2 [M+H].sup.+ (free base)

    Example 122: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)nicotinamide dihydrochloride 122

    [0842] ##STR00241##

    (a) (S)-tert-Butyl 3-((R)-1-hydroxy-2-(6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)nicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A42

    [0843] A solution of (S)-tert-butyl 3-((R)-2-(6-chloronicotinamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A19 (50 mg, 0.12 mmol, 1.0 eq) and (tetrahydro-2H-pyran-4-yl)methanamine (55 mg, 0.48 mmol, 4.0 eq) in tert-butanol (1 mL) was heated in the microwave at 170° C. for 4 hours. The solvent was removed and the crude residue purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (10 mg, 16%) as a white solid. LCMS-C: RT 2.53 min; m/z 511.3 [M+H].sup.+

    (b) N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)nicotinamide dihydrochloride I22

    [0844] To a solution of (S)-tert-butyl 3-((R)-1-hydroxy-2-(6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)nicotinamido)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A42 (10 mg, 0.02 mmol, 1.0 eq) in diethyl ether (2 mL) was added a solution of saturated HCl in diethyl ether (2 mL). The reaction was stirred at room temperature for 2 hours then concentrated and the residue obtained was washed with diethyl ether to give the title compound (7 mg, 78%) as a yellow solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.41 (s, 1H), 8.32-8.28 (m, 1H), 7.33-7.21 (m, 4H), 7.15-7.13 (m, 1H), 4.50-4.47 (m, 1H), 4.39-4.35 (m, 1H), 4.30-4.26 (m, 1H), 3.99-3.96 (m, 2H), 3.69-3.64 (m, 2H), 3.57-3.52 (m, 1H), 3.47-3.41 (m, 2H), 3.35-3.33 (m, overlap), 3.23-3.18 (m, 1H), 2.03-1.94 (m, 1H), 1.78-1.75 (m, 2H), 1.45-1.34 (m, 4H). LCMS: RT 2.45 min; m/z 411.2 [M+H].sup.+ (free base)

    Example 123: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((S)-2-hydroxy-2-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride 123

    [0845] ##STR00242##

    (a) Alternate Synthesis of (R)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A10

    [0846] A mixture of (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.0 g, 16.9 mmol, 1.0 eq) in 1,4-dioxane (60 mL) and water (30 mL) was vigorously stirred. NaHCO.sub.3 (2.8 g, 33.8 mmol, 2.0 eq) and Boc.sub.2O (4.1 g, 18.6 mmol, 1.1 eq) were added and the reaction stirred vigorously at room temperature for 6 days. The mixture was concentrated in vacuo and the residue was dissolved in water (100 mL). A 30% w/v aqueous solution of NaHSO.sub.4 (30 mL) was added and the mixture extracted with CHCl.sub.3 (3×200 mL). The pooled organic extracts were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (3.9 g, 85%) as an oil. LCMS-C: RT 2.65 min; m/z 300.1 [M+Na].sup.+

    (b) Alternate Synthesis of (R)-tert-Butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A11

    [0847] (R)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A10 (3.7 g, 13.5 mmol, 1.0 eq) was dissolved in THF (10 mL). CDI (4.4 g, 27.2 mmol, 2.0 eq) was added and the mixture was stirred for 30 minutes at room temperature then cooled to 0° C. A solution of NaBH.sub.4 (616 mg, 16.3 mmol, 1.2 eq) in water (8 mL) was added dropwise and the reaction stirred vigorously at 0° C. for 4 hours. The reaction was quenched with acetone (20 mL) and concentrated in vacuo. The residue was suspended in water (100 mL) and extracted with ethyl acetate (4×50 mL), the combined organic extracts were washed with 5% w/v aqueous NaHSO.sub.4 (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by chromatography (5%-17% EtOAc/petroleum ether) to give the title compound (1.0 g, 28%) as a pale yellow oil. LCMS-C: RT 2.68 min; m/z 286.1 [M+Na].sup.+

    (c) (R)-tert-Butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A43

    [0848] To a solution of (R)-tert-butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A11 (1.0 g, 3.8 mmol, 1.0 eq) in a mixture of DCM (25 mL) and DMSO (5 mL) at 0° C. was added triethylamine (1.15 g, 11.4 mmol, 3.0 eq) and pyridine-sulfur trioxide complex (1.8 g, 11.4 mmol, 3.0 eq). The mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature. After 3 hours, saturated sodium bicarbonate (50 mL) and water (50 ml) were added and the mixture extracted with diethyl ether (3×150 mL). The pooled ether extracts were washed with 1:1 water: saturated aqueous NH.sub.4Cl (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the crude product as an orange oil which was used in the next step directly without further purification.

    (d) Alternate synthesis of (R)-tert-Butyl 3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A12A

    [0849] To a solution of (R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A43 (3.8 mmol @ 100% conversion) in i-propanol (50 mL) at 0° C. was added nitromethane (928 mg, 15.2 mmol, 4.0 eq) and potassium fluoride (221 mg, 3.8 mmol, 1.0 eq). The reaction was allowed to warm to room temperature and stirred for 2 days. The reaction was diluted with NaHCO.sub.3 (50 mL) and water (200 mL) and extracted with diethyl ether (100 mL×3). The organic layers were washed with brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column (5% EtOAc/petroleum ether) to give the title compound (345 mg, 29%) as a pale yellow oil. LCMS-C: RT 2.67 min; m/z 345.1 [M+Na].sup.+

    (e) Alternate synthesis of (R)-tert-Butyl 3-((S)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A13

    [0850] To a solution of (R)-tert-butyl 3-((S)-1-hydroxy-2-nitroethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A12A (345 mg, 0.15 mmol) in absolute ethanol (25 mL) was added 10% Pd/C (50% wet with water, 350 mg) and the mixture was stirred vigorously under hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite and the Celite washed with absolute ethanol (30 mL). The pooled filtrates were concentrated to give the title compound (260 mg, 83%) as a yellow solid: LCMS-C: RT 2.10 min; m/z 293.2 [M+H].sup.+

    (f) (3R)-tert-Butyl 3-((1S)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A44

    [0851] To a mixture of 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I42 (59 mg, 0.19 mmol, 1.1 eq) and (R)-tert-butyl 3-((S)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A13 (51 mg, 0.175 mmol, 1.0 eq) in DCM (5 mL) were added DIPEA (90 mg, 0.70 mmol, 4.0 eq), HOBt (3 mg, 0.02 mmol, 0.1 eq), and EDCl.HCl (67 mg, 0.35 mmol, 2.0 eq). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with saturated aqueous NaHCO.sub.3 (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by preparative TLC (5% MeOH/DCM) to give the title compound (80 mg, 79%) as a white solid. LCMS-C: RT 2.88 min; m/z 580.3 [M+H].sup.+

    (g) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((S)-2-hydroxy-2-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride 123

    [0852] To a solution of (3R)-tert-butyl 3-((1S)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A44 (70 mg, 0.12 mmol, 1.0 eq) in diethyl ether (5 mL) was added a solution of saturated HCl in diethyl ether (5 mL) and the reaction was stirred at room temperature overnight. The mixture was concentrated and the residue washed with diethyl ether to give the title compound (57 mg, 92%) as a yellow solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.97 (d, J=8.0 Hz, 1H), 7.32-7.22 (m, 5H), 7.15 (d, J=8.0 Hz, 1H), 4.64 (s, 1H), 4.49-4.37 (m, 2H), 4.27-4.22 (m, 3H), 3.95 (br s, 1H), 3.83-3.57 (m, 7H), 3.34-3.27 (m, overlap), 3.22-3.16 (m, 1H), 2.06-2.00 (m, 4H), 1.43 (t, J=6.8 Hz, 3H). LCMS-C: RT 2.05 min, m/z 480.3 [M+H].sup.+ (free base)

    Example 124: N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)isonicotinamide 124

    [0853] ##STR00243##

    (a) 2-((1-Acetylpiperidin-4-yl)methoxy)isonicotinic acid A45

    [0854] A solution of (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methanol (253 mg, 1.38 mmol, 1.3 equiv) in anhydrous DMF (5 mL) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 0.170 g, 24.0 mmol, 4 equiv) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 10 minutes before a solution of 2-fluoroisonicotinic acid (0.150 g, 1.06 mmol, 1 equiv) in DMF (5 mL) was added. The mixture was then stirred overnight. H.sub.2O (˜10 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜3 with a 0.5 M solution of aqueous citric acid. The aqueous was extracted with EtOAc (3×30 mL), the organics were combined, washed with brine, dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The resultant residue was purified by column chromatography (Biotage Isolera, 12 g SiO.sub.2 cartridge, 0-55% EtOAc in petroleum benzene 40-60° C.) to give the title compound (172 mg, 53% yield) as a white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.23 (dd, J=5.2, 0.8 Hz, 1H), 7.40 (dd, J=5.2, 1.4 Hz, 1H), 7.24 (dd, J=1.3, 0.7 Hz, 1H), 5.08 (tt, J=8.0, 3.9 Hz, 1H), 3.10 (q, J=9.9 Hz, 2H), 3.01-2.88 (m, 2H), 2.70-2.59 (m, 2H), 2.12-1.96 (m, 2H), 1.91-1.70 (m, 2H). LCMS-B: RT 2.99 min, m/z 305.1 [M+H].sup.+.

    b) N—((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)isonicotinamide 124

    [0855] To a solution of 2-((1-acetylpiperidin-4-yl)methoxy)isonicotinic acid A45 (70 mg, 0.23 mmol, 1 equiv), DIPEA (120 μL, 0.69 mmol, 3 equiv) and HATU (131 mg, 0.345 mmol, 1.5 equiv) in DMF (4 mL) was added a solution of tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I12 (67 mg, 0.23 mmol, 1 equiv) in DMF (2 mL). The reaction was stood at room temperature overnight, quenched with a saturated aqueous solution of 1 M NaOH (5 mL) and stirred for 3 hours. The solution was extracted with DCM (3×10 mL) utilizing a phase separation cartridge. The organic filtrates were reduced under a stream of air, DCM:TFA (8 mL, 1:1 v/v) was added and the reaction stood at room temperature overnight. The reaction mixture was concentrated under a stream of air and then purified by solid-phase extraction (1 g SCX-2 cartridge, 3 column volumes of methanol followed by 3 column volumes of 0.2 M methanolic ammonia) to give the title compound (62 mg, 56% yield) as a white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.21 (dd, J=5.3, 0.8 Hz, 1H), 7.27 (dd, J=5.3, 1.5 Hz, 1H), 7.16-7.08 (m, 4H), 7.07-7.02 (m, 1H), 5.15-5.04 (m, 1H), 4.09-3.95 (m, 2H), 3.93-3.84 (m, 1H), 3.65 (dd, J=13.8, 4.6 Hz, 1H), 3.53 (dd, J=13.8, 7.2 Hz, 1H), 3.16-3.02 (m, 2H), 3.02-2.81 (m, 5H), 2.71-2.50 (m, 2H), 2.03 (d, J=8.1 Hz, 2H), 1.89-1.70 (m, 2H). LCMS-B: RT 2.87 min, m/z 479.2 [M+H].sup.+.

    Example 125: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-6-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride 125

    [0856] ##STR00244## ##STR00245##

    (a)(S)-6-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride A46

    [0857] To a solution of (S)-2-amino-3-(m-tolyl)propanoic acid (1.0 g, 5.6 mmol) in concentrated HCl (10 mL) was added formaldehyde (1.5 mL, 37-40% gradually at 40° C. The mixture was heated at 100° C. for 3 hours, then cooled to 0° C. and the solid precipitate was collected by filtration and washed with dichloromethane (40 mL). The solid was dried to give the title compound as a grey solid (300 mg), purity about 70%: LCMS-C: RT 2.93 min; m/z 192.1 [M+H].sup.+ (free base).

    (b) (S)-2-(tert-Butoxycarbonyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A47

    [0858] To a vigorously stirred suspension of (S)-6-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride A46 (300 mg, 1.3 mmol) in a mixture of 1,4-dioxane (20 mL) and water (10 mL) at 40° C. was added NaHCO.sub.3 (316 mg, 4.0 mmol) and Boc.sub.2O (316 mg, 1.5 mmol) and the reaction was stirred for 7 days. The mixture was concentrated in vacuo and the residue dissolved in water (10 mL). A 30% w/v aqueous solution of NaHSO.sub.4 (20 mL) was added and the mixture extracted with DCM (4×40 mL). The pooled organic extracts were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as an off-white solid (530 mg, 100%): LCMS-C: RT 2.89 min; m/z 192.2 [M-Boc+2H].sup.+, 314.2 [M+Na].sup.+.

    (c) (S)-tert-Butyl 3-(hydroxymethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A48

    [0859] To a solution of (S)-2-(tert-butoxycarbonyl)-7-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A47 (530 mg, 1.8 mmol) in THF (10 mL) was added CDI (590 mg, 3.6 mmol). The reaction was stirred for 2 hours at room temperature then cooled to 0° C. A solution of NaBH.sub.4 (138 mg, 3.6 mmol) in water (15 mL) was added dropwise and the mixture stirred vigorously at room temperature for 3 hours. The reaction was concentrated in vacuo and the residue obtained partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts dried (Na.sub.2SO.sub.4) and concentrated. The residue was purification by chromatography (5% EtOAc/petroleum ether) to give the title compound as a white solid (207 mg, 41%). LCMS-C: RT 2.91 min; m/z 300.3 [M+Na].sup.+

    (d) (S)-tert-Butyl 3-formyl-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A49

    [0860] To a solution of (S)-tert-butyl 3-(hydroxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A48 (250 mg, 0.9 mmol) in a mixture of DCM (10 mL) and DMSO (3 mL) at 0° C. was added triethylamine (304 mL, 3.0 mmol) and pyridine-sulfur trioxide complex (477 mg, 3.0 mmol). The mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature. After 4 hours, saturated sodium bicarbonate (20 mL) and water (20 ml) were added and the mixture was extracted with diethyl ether (5×30 mL). The pooled ether extracts were washed with 1:1 water: saturated aqueous NH.sub.4Cl (20 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the crude product as an orange oil which was used in next step without purification. LCMS-C: RT 2.96 min; m/z 330.2 [M+MeOH+Na].sup.+

    (e) tert-butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A50

    [0861] A solution of N,N-bis(4-chlorobenzyl)benzene-1,2-diamine (40 mg, 0.11 mmol) and Cu(OAc).sub.2.H.sub.2O (18 mg, 0.09 mmol) in ethanol (2 mL) was stirred at room temperature for 1 hour. A solution of (S)-tert-butyl 3-formyl-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A49 (260 mg, 0.9 mmol) in ethanol (3 mL) was added, the reaction mixture was cooled to 0° C. and stirred for 30 minutes, CH.sub.3NO.sub.2 (541 mg, 9.0 mmol) was added and stirring continued at 0° C. for 2 days. The mixture was concentrated and the residue was purified by preparative TLC (25% EtOAc/petroleum ether) to give the title compound (50 mg, 17%) as an oil. LCMS-C: RT 2.92 min; m/z 359.3 [M+Na].sup.+

    (f) tert-Butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A51

    [0862] A mixture of tert-butyl (S)-3-((R)-1-hydroxy-2-nitroethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A50 (50 mg, 0.15 mmol) and 10% Pd/C (50% wet with water, 80 mg) in absolute ethanol (5 mL) was stirred vigorously under hydrogen atmosphere for 3 days. The catalyst was removed by filtration through Celite and the Celite was washed with absolute ethanol (50 mL). The pooled filtrates were concentrated to give the title compound as a yellow solid (20 mg, 43%). LCMS-C: RT 2.42 min; m/z 307.2 [M+H].sup.+

    (g) (3S)-tert-Butyl 3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A52

    [0863] To a solution of 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I42 (77 mg, 0.25 mmol) and tert-butyl (S)-3-((R)-2-amino-1-hydroxyethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A51 (70 mg, 0.23 mmol) in DCM (10 mL) were added DIPEA (119 mg, 0.92 mmol), HOBt (3 mg, 0.02 mmol) and EDCl.HCl (111 mg, 0.58 mmol). The resulting mixture was stirred at room temperature overnight. A saturated aqueous solution of NaHCO.sub.3 (30 mL) was added and the aqueous layer extracted with DCM (3×30 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound as a yellow oil (56 mg, 41%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.07-8.02 (m, 1H), 7.21 (s, 1H), 7.16-7.13 (m, 1H), 7.02-6.98 (m, 3H), 4.64 (br s, 1H), 4.39-4.23 (m, 4H), 3.96 (br s, 1H), 3.85-3.56 (m, 7H), 3.19-3.13 (m, 2H), 2.92-2.87 (m, 1H), 2.29 (s, 3H), 2.05-2.00 (m, 4H), 1.50-1.43 (m, 12H). LCMS-C: RT 6.01 min; m/z 594.0 [M+H].sup.+.

    (h) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—((R)-2-hydroxy-2-((S)-6-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide hydrochloride 125

    [0864] A solution of (3S)-tert-butyl 3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate A52 (56 mg, 0.23 mmol) in diethyl ether (5 mL) at 0° C. was added a solution of saturated HCl in diethyl ether (5 mL) and the reaction stirred for 3 hours. The mixture was concentrated and the residue washed with diethyl ether to give the title compound (25 mg, 52%) as an off-white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.96 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 7.17-7.10 (m, 4H), 4.64 (br s, 1H), 4.39-4.21 (m, 5H), 3.96 (br s, 1H), 3.83-3.80 (m, 1H), 3.73-3.69 (m, 3H), 3.63-3.58 (m, 3H), 3.26-3.22 (m, 1H), 3.16-3.11 (m, 1H), 2.32 (s, 3H), 2.07-2.00 (m, 4H), 1.43 (t, J=6.8 Hz, 3H). LCMS-C: RT 2.12 min, m/z 494.1 [M+H].sup.+ (free base).

    Assays

    [0865] PRMT5 Biochemical Assay

    [0866] Compounds of the invention may be tested for in vitro activity in the following assay: A histone H4 derived peptide is used as substrate (amino acid sequence: Ser-Gly-Arg-Gly-Lys-Gly-Gly-Lys-Gly-Leu-Gly-Lys-Gly-Gly-Ala-Lys-Arg-His-Arg-Lys-Val-N H.sub.2). Full-length PRMT5 enzyme (NCBI Reference sequence NP_006100.2) was co-expressed with His.sub.6-MEP50 in insect cells and purified via Nickel immobilized metal affinity and gel filtration chromatography (“the enzyme”).

    [0867] The 6 μL assay reactions are run in Greiner brand black 384-well low volume plates. All reactions contained assay buffer (phosphate buffered saline, 0.01% (v/v) Tween-20, 0.01% (w/v) albumin from chicken egg white, 1 mM dithiothreitol, 200 nM peptide substrate, 1 μM S-Adenosyl methionine, and 15 ng/reaction enzyme, with the enzyme being omitted from negative control reactions. Compounds were added in a volume of 100 nL from dilution series prepared in DMSO, positive and negative control reactions receiving the same volume DMSO without compound. The plates were sealed with adhesive seals and incubated for 4 hours at 37° C. Reaction progress was measured using the Transcreener™ EPIGEN methyltransferase assay (BellBrook Labs, Madison, Wis.) as recommended by the manufacturer. To each reaction 2 μL detection mix were added, containing coupling enzymes, fluorescence polarisation tracer, and AMP antibody. Plates were incubated for 90 min before being read on a PerkinElmer EnVision™ plate reader in fluorescence polarisation mode. IC.sub.50 values were obtained from the raw readings by calculating percent inhibition (%1) for each reaction relative to controls on the same plate (% I=(I−CN)/(CP−CN) where CN/CP are the averages of the negative/positive reactions, respectively), then fitting the % I data vs. compound concentration [I] to % I=(A+((B−A)/(1+((C/[I])̂D)))) where A is the lower asymptote, B is the upper asymptote, C is the IC.sub.50 value, and D is the slope.

    TABLE-US-00007 Example Number IC.sub.50 (μM) 1 4.686 2 0.763 53 22.020

    [0868] PRMT5 Biomarker Assay

    [0869] Compounds of the invention may be tested for potency to inhibit symmetrical dimethylation of arginine in the following assay:

    [0870] The cell line TE11 was seeded at a density of 12,000 cells per well in 96 well tissue culture plates in DME medium and 10% foetal bovine serum, and allowed to adhere overnight under standard culture conditions (37° C., 5% CO.sub.2). Compound dilutions prepared in DMSO were added to the medium, with negative control wells reserved for treatment with DMSO only and positive controls receiving a potent PRMT5 inhibitor. The concentration of the inhibitor had been previously determined to give maximum inhibition of the methylation. After incubation for 72 h, cells were washed twice in ice-cold PBS, lysed in lysis buffer (20 mM Tris pH 7.4, 135 mM NaCl, 1.5 mM MgCl.sub.2, 1 mM EGTA, 10% glycerol and 1% Triton-X100), centrifuged at 15,000×g and the supernatants collected for subsequent analysis. The methylation level was determined using the EpiQuik™ Global Di-Methyl Histone H4R.sup.3 Quantification ELISA Kit (Epigentek, Farmingdale, N.Y.) as per the manufacturer's recommendations; in parallel the total protein amount in the lysate was quantified using a Lowry protein assay. The methylation level was corrected for the total protein amount of each sample, normalised to the controls, and the data fitted against a four-parameter logistic model to determine the 50% inhibitory concentration (IC.sub.50).

    TABLE-US-00008 Example Number IC.sub.50 (μM) 1 0.956 2 0.0072

    [0871] Revised PRMT5 Biochemical Assay

    [0872] Compounds of the invention may be tested for in vitro activity in the following assay: A histone H4 derived peptide is used as substrate (amino acid sequence: Ser-Gly-Arg-Gly-Lys-Gly-Gly-Lys-Gly-Leu-Gly-Lys-Gly-Gly-Ala-Lys-Arg-His-Arg-Lys-Val-N H.sub.2). Full-length PRMT5 enzyme (NCBI Reference sequence NP_006100.2) was co-expressed with His.sub.6-MEP50 in insect cells and purified via Nickel immobilized metal affinity and gel filtration chromatography (“the enzyme”).

    [0873] The 6 μL reactions are run in Greiner brand black 384-well low volume assay plates. All reactions contained assay buffer (phosphate buffered saline, 0.01% (v/v) Tween-20, 0.01% (w/v) albumin from chicken egg white, 1 mM Dithiothreitol, 1 μM peptide substrate, 1 μM S-Adenosyl methionine, and 15 ng/reaction enzyme, with the enzyme being omitted from negative control reactions. Compounds were added in a volume of 100 nL from dilution series prepared in DMSO, positive and negative control reactions receiving the same volume DMSO without compound. The plates were sealed with adhesive seals and incubated for 4 hours at 37 degree Celsius. Reaction progress was measured using the Transcreener™ EPIGEN methyltransferase assay (BellBrook Labs, Madison, Wis.) as recommended by the manufacturer. To each reaction 2 μL detection mix were added, containing coupling enzymes, fluorescence polarisation tracer, and AMP antibody. Plates were incubated for 90 minutes before being read on a PerkinElmer EnVision™ plate reader in fluorescence polarisation mode. IC.sub.50 values were obtained from the raw readings by calculating percent inhibition (%1) for each reaction relative to controls on the same plate (% I=(I−CN)/(CP−CN) where CN/CP are the averages of the negative/positive reactions, respectively), then fitting the %1 data vs. compound concentration [I] to % I=(A+((B−A)/(1+((C/[I])̂D)))) where A is the lower asymptote, B is the upper asymptote, C is the IC.sub.50 value, and D is the slope.

    TABLE-US-00009 Example Number IC.sub.50 (μM) 3 8.359 4 8.786 5 51.058 6 45.752 7 19.988 8 16.534 9 12.536 10 22.495 12 0.663 13 0.551 14 2.331 15 0.383 16 0.662 17 1.266 18 2.103 19 0.912 20 11.687 21 0.070 22 2.153 23 5.140 24 3.688 25 1.701 26 0.053 27 0.044 28 0.180 29 0.535 30 0.139 31 0.204 32 0.511 33 0.305 34 1.680 35 0.152 36 0.148 37 0.105 38 0.599 39 0.846 40 0.705 41 1.389 42 0.212 43 0.967 44 1.245 45 0.500 46 0.230 47 3.368 48 0.192 49 0.038 50 0.019 51 0.061 52 3.333 53 21.191 54 82.115 55 0.016 56 0.383 57 0.594 58 0.657 59 0.593 60 3.302 61 0.104 62 0.102 63 0.245 64 0.261 65 2.287 66 0.329 67 0.307 68 2.256 69 1.298 70 0.121 71 0.939 72 0.585 73 2.268 74 0.338 75 1.202 76 0.262 77 8.759 78 1.695 79 0.168 80 0.161 81 0.051 82 0.106 83 0.065 84 0.124 85 0.279 86 3.822 87 0.057 88 0.187 89 0.203 90 0.947 91 0.123 92 0.310 93 0.759 94 0.780 95 9.706 96 1.377 97 18.654 98 0.230 99 0.127 100 0.066 101 0.104 102 0.068 103 0.065 104 0.147 105 0.038 106 0.212 107 0.546 108 0.017 109 0.688 110 1.491 111 4.665 112 2.308 113 2.742 114 5.486 115 2.834 116 1.114 117 0.487 118 0.502 124 0.070 125 0.232

    [0874] Revised PRMT5 Biomarker Assay

    [0875] Compounds of the invention may be tested for potency to inhibit symmetrical dimethylation of arginine in the following assay:

    [0876] The cell line TE11 was seeded at a density of 6,000 cells per well in 96 well optical quality tissue culture plates in DME medium and 10% foetal bovine serum, and allowed to adhere for 5 hours under standard culture conditions (37 degree Celsius, 5% CO.sub.2). Compound dilutions prepared in DMSO were added to the medium, with negative control wells reserved for treatment with DMSO only and positive controls receiving a potent PRMT5 inhibitor compound at 1 μM concentration. After incubation for 72 hours, the cells were fixed with 3.7% formaldehyde in PBS for 30 minutes at room temperature, washed with phosphate buffer saline and blocked with Odyssey blocking buffer (LI-COR, Lincoln, Nebr.). Rabbit anti-Di-Methyl Histone H4 Arginine 3 specific antibody (Epigentek) in Odyssey blocking buffer was added and incubated for 14 hours at 4 degree Celsius. After washing, anti-rabbit secondary antibody labelled with Alexa647 dye (LifeTechnologies) and Hoechst 33342 (1 μg/mL, SigmaAldrich) were added for 1 hour incubation. Plates were washed and read on a PerkinElmer Envision 2103 in fluorescence intensity scanning mode (24 scans across the well area). The methylation level information was corrected for the number of cells as expressed by the Hoechst 33342 stain, converted to percent inhibition relative to controls on the same plate and the data fitted against a four-parameter logistic model to determine the 50% inhibitory concentration (IC.sub.50 plate-reader based). Alternatively, the plates were imaged on a PerkinElmer Phenix high content imaging platform. Using a Columbus image analysis pipeline, individual nuclei were located by Hoechst 33342 stain and the methylation level was calculated from the Alexa647-related intensity in the same area. The resulting mean intensity per cell was directly converted to percent inhibition as outlined above (IC.sub.50, imager based).

    TABLE-US-00010 IC.sub.50 - plate- reader based Example Number (μM) 3 1.460 8 2.325 15 0.023 21 0.087 26 0.015 27 0.007 28 0.012 37 0.254 49 0.006 50 0.0003 51 0.015 55 0.0004 69 0.003 74 0.005 80 0.003 81 0.003 83 0.004 84 0.081 102 0.005 103 0.004 108 0.001

    TABLE-US-00011 IC50 - image based Example Number (μM) 26 0.003 49 0.001 50 0.0003 55 0.0002 79 0.003 82 0.008 100 0.011 101 0.010 104 0.012 105 0.001 106 0.005