AMINOINDANE-, AMINOTETRAHYDRONAPHTHALENE- AND AMINOBENZOCYCLOBUTANE-DERIVED PRMT5-INHIBITORS

20170313713 · 2017-11-02

Inventors

Cpc classification

International classification

Abstract

A compound of formula (1a), (1b) or (1c) wherein: n is 1 or 2; R.sup.N is H or Me; R.sup.1 is optionally one or more halo or methyl groups; R.sup.1 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 (if present) 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.4a is selected from OH, —NH.sub.2, —C(═O)NH.sub.2, and —CH.sub.2OH; R.sup.4b is either H or Me; R.sup.5 is either H or 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 Ia, Ib or Ic: ##STR00286## wherein: n is 1 or 2; R.sup.N is H or Me; 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 (if present) 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.4a is selected from OH, —NH.sub.2, —C(═O)NH.sub.2, and —CH.sub.2OH; R.sup.4b is either H or Me; R.sup.5 is either H or 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 (if present) are all H; or (b) of formula Ia or Ib, wherein 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) of formula Ia or Ib, wherein R.sup.2a, R.sup.2b, R.sup.2c and R.sup.2d are comprised of two H and two Me groups; or (d) of formula Ic, wherein R.sup.2a is H and R.sup.2b is a Me or CH.sub.2OH group; or (e) of formula Ic, wherein R.sup.2a and R.sup.2b are each a Me or CH.sub.2OH group.

9-17. (canceled)

18. 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.

19.-25. (canceled)

26. A compound according to claim 1 which is of formula Ia1, Ib1 or Ic1: ##STR00287##

27. A compound according to claim 1 which is of formula Ia2, Ib2 or Ic2: ##STR00288##

28. A compound according to claim 1, wherein the compound is a racemate at the carbon atom to which R.sup.4b and R.sup.4a are attached.

29. A compound according to claim 1, wherein the compound is a single enantiomer at the carbon atom to which R.sup.4b and R.sup.4a are attached.

30-31. (canceled)

32. 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.

33. 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, —CFH, —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, —SO.sub.2NHEt, —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.

34-39. (canceled)

40. A compound according to claim 33, 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 heteroayl 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 an ethoxy 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.

41-45. (canceled)

46. 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.

47-63. (canceled)

64. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00289##

65. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00290##

66. A compound according to claim 65, wherein A is selected from one of the following groups: ##STR00291##

67. A compound according to claim 1, wherein A is selected from one of the following groups: ##STR00292## ##STR00293##

68. A compound according to claim 1, wherein A is selected from one of the following groups: phenyl, with a para-amido substituent and an optional ortho-ethoxy substituent; phenyl, with a para-ether substituent; 6-amino-3-pyridyl; 5-amino-3-pyridyl; and 2-amino-4-pyridyl.

69. (canceled)

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

71. A method of treatment of cancer, comprising administering to a patient in need of treatment, a compound according to a composition according to claim 70.

72.-73. (canceled)

74. 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 70.

75.-76. (canceled)

Description

EXAMPLES

[0300] 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.

Acronyms

[0301] 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).

[0302] 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 or TEA), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 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), hexamethylphosphoramide (HMPA), 1,2-dichloroethane (DCE), benzyl (Bn) and 1-hydroxybenzotriazole (HOBt).

[0303] In addition, TLC refers to thin layer chromatography.

General Experimental Details

[0304] Unless otherwise stated the following generalisations apply. .sup.1H NMR spectra were recorded on a Bruker Ultrashield Plus (400 MHz), a Bruker AVANCE (400 MHz) or a Bruker Avance DRX300 (300 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.

[0305] LCMS data was generated using either an Agilent 6100 Series Single Quad LCMS (LCMS-A), an Agilent 1260 Infinity Series UPLC/MS (LCMS-B), a Agilent 1200 Series G6110A Quadrupole LCMS (LCMS-C), a Waters 2695 alliance (LCMS-D) or a Finnigan instrument (LCMS-E). Chlorine isotopes are reported as .sup.35Cl, Bromine isotopes are reported as either .sup.79Br or .sup.81Br or both .sup.79Br/.sup.81Br.

LCMS Method A (LCMS-A):

Instrument: Agilent 6100 Series Single Quad LC/MS

Agilent 1200 Series HPLC

[0306] Pump: 1200 Series G1311A Quaternary pump

Autosampler: 1200 Series G1329A Thermostatted Autosampler

Detector: 1200 Series G1314B Variable Wavelength Detector

[0307] LC conditions:
Reverse Phase HPLC analysis

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

[0308] Column temperature: 30° C.

Injection Volume: 5 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: MeCN 0.1% Formic Acid

[0309] Gradient: 5-100% solvent B over 10 min

Detection: 254 nm or 214 nm

[0310] MS conditions:

Ion Source: Quadrupole

Ion Mode: Multimode-ES

[0311] Drying gas temp: 300° C.
Vaporizer temperature: 200° C.
Capillary voltage (V): 2000 (positive)
Capillary voltage (V): 4000 (negative)

Scan Range: 100-1000

[0312] Step size: 0.1 sec
Acquisition time: 10 min

LCMS Method B (LCMS-B):

Instrument: Agilent 1260 Infinity Series UPLC/MS

[0313] Pump: 1260 Infinity G1312B Binary pump

Autosampler: 1260 Infinity G1367E 1260 HiP ALS

Detector: 1290 Infinity G4212A 1290 DAD

[0314] LC conditions:
Reverse Phase HPLC analysis

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

[0315] Column temperature: 35° C.

Injection Volume: 1 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: MeCN 0.1% Formic Acid

[0316] Gradient: 5-100% solvent B over 3.8 min
Detection: monitored at 254 nm and 214 nm
MS conditions:

Ion Source: Quadrupole

Ion Mode: API-ES

[0317] Drying gas temp: 350° C.
Capillary voltage (V): 3000 (positive)
Capillary voltage (V): 3000 (negative)

Scan Range: 100-1000

[0318] Step size: 0.1 sec
Acquisition time: 5 min

LCMS Method C (LCMS-C):

Instrument: Agilent 1200 Series G6110A Quadrupole

[0319] Pump: Binary pump

Detector: DAD

[0320] LC conditions:
Reverse Phase HPLC analysis

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

[0321] Column temperature: 30° C.

Injection Volume: 1-10 μL

[0322] Solvent A: Water 0.07% Formic acid

Solvent B: Methanol

[0323] 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)
Detection: monitored at 254 nm and 214 nm
MS conditions:

Ion Source: Quadrupole

Ion Mode: ES+

[0324] Drying gas temp: 350° C.
Drying gas flow: 10 L/min
Nebulizer pressure: 35 psi
Capillary voltage (V): 3500 (positive)

Scan Range: 50-900

LCMS Method D (LCMS-D)

Instrument: Waters ZQ 3100 Mass Detector

Waters 2545-Pump

Waters SFO System Fluidics Organizer

Waters 2996 Diode Array Detector

Waters 2767 Sample Manager

[0325] LC conditions:
Reverse Phase HPLC analysis

Column: XBridge™ C18 5 μm 4.6×100 mm

Injection Volume: 10 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: MeCN 0.1% Formic Acid

[0326] Gradient: 10-100% B over 10 min
Flow rate: 1.5 mL/min

Detection: 100-600 nm

[0327] MS conditions

Ion Source: Single-quadrupole

[0328] Ion Mode: ES positive

Source Temp: 150° C.

Desolvation Temp: 350° C.

[0329] Detection: Ion counting

Capillary (KV): 3.00

Cone (V): 30

Extractor (V): 3

RF Lens (V): 0.1

Scan Range: 100-1000 Amu

Scan Time: 0.5 sec

[0330] Acquisition time: 10 min

Gas Flow: 100 L/h

Desolvation: 650 L/h

LCMS Method E (LCMS-E)

Instrument: Finnigan LCG Advantage Max

Finnigan Surveyor LC Pump

Finnigan Surveyor Autosampler

Finnigan Surveyor PDA Detector

[0331] LC conditions:
Reverse Phase HPLC analysis

Column: Gemini 3 μm C18 20×4.0 mm 110 Å

Injection Volume: 10 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: MeCN 0.1% Formic Acid

[0332] Gradient: 10-100% B over 10 min

Detection: 100-600 nm

[0333] MS conditions
Ion Source: Ion trap
Ion Mode: ES positive

Temp: 300° C.

[0334] Detection: Ion counting

Scan Range: 80-1000 Amu

Scan Time: 0.2 sec

[0335] Acquisition time: 10 min

Preparative Mass-Directed LC

Instrument:

Waters ZQ 3100-Mass Detector

Waters 2545-Pump

Waters SFO System Fluidics Organizer

Waters 2996 Diode Array Detector

Waters 2767 Sample Manager

[0336] LC conditions:
Reverse Phase HPLC analysis

Column: XBridge™ C18 5 μm 19×50 mm

Injection Volume 500 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: MeCN 0.1% Formic Acid

[0337] Gradient: 25-100% B over 10 min
Flow rate: 19 mL/min

Detection: 100-600 nm

[0338] MS conditions:

Ion Source: Single-quadrupole

[0339] Ion Mode: ES positive

Source Temp: 150° C.

Desolvation Temp: 350° C.

[0340] Detection: Ion counting

Capillary (KV)-3.00

Cone (V): 30

Extractor (V): 3

RF Lens (V): 0.1

Scan Range: 100-1000 Amu

Scan Time: 0.5 sec

[0341] Acquisition time: 10 min

Gas Flow

Desolvation L/hour-650

Cone L/hour-100

Preparative RP-HPLC:

[0342] Agilent 1260 Infinity HPLC system
UV detection at 210 nm and 254 nm
Gradient or isocratic elution through a Phenomenex Luna C8 (2) column 100 Å Axia (250×21.2 mm; particle size 5 μm)
Flow rate: 10 mL/min
Gradients are as specified in the individual examples.

[0343] 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.

[0344] 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).

[0345] Flash chromatography was performed using a Biotage Isolera purification system using either Grace or RediSep® silica cartridges.

[0346] Column chromatography was performed using Tklst (China), grand grade, 100-200 meshes silica gel.

[0347] Microwave irradiation was achieved using a CEM Explorer SP Microwave Reactor.

[0348] Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods.

[0349] Additional Cartridges used are as follows:

Phase Separator:

Manufacturer: Biotage

[0350] Product: ISOLUTE Phase Separator (3 mL unless otherwise stated)
SCX and SCX-2 cartridges:

Manufacturer: Biotage

[0351] Product: ISOLUTE SCX 1 g, (6 mL SPE Column unless otherwise stated)

Manufacturer: Biotage

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

Manufacturer: Silicycle

Product: SCX-2 500 mg or 5 g

Manufacturer: Agilent

Product: Bond Elut® SCX 10 g

Sample Extraction Cartridge:

[0352] Manufacturer: Waters Product: Oasis® HLB 35 cc (6 g) LP extraction cartridge

Intermediate Preparations

(i) 1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I2)

[0353] ##STR00062##

(a) 2-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (I1)

[0354] A mixture of N-glycidylphthalimide (2.00 g, 9.84 mmol) and 2-aminoindane (1.57 g, 11.8 mmol) in ethanol (50 mL) was stirred at 80° C. for 24 hours. The volatiles were removed in vacuo and the residue was purified by column chromatography (2×40 g SiO.sub.2 cartridges, 0-20% MeOH (containing 1% v/v 2 M NH.sub.3 in MeOH) in DCM) then (40 g SiO.sub.2 cartridge, 0-10% MeOH (containing 1% v/v 2 M NH.sub.3 in MeOH) in DCM) to give the desired compound as a brown solid (1.69 g, 51%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87-7.81 (m, 2H), 7.74-7.69 (m, 2H), 7.20-7.15 (m, 2H), 7.15-7.11 (m, 2H), 3.99-3.92 (m, 1H), 3.84-3.70 (m, 2H), 3.64-3.55 (m, 1H), 3.18-3.10 (m, 2H), 2.82 (dd, J=12.2, 3.8 Hz, 1H), 2.75 (dd, J=15.6, 6.1 Hz, 2H), 2.65 (dd, J=12.2, 7.3 Hz, 1H).

(b) 1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I2)

[0355] A solution of 2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isoindoline-1,3-dione I1 (1.69 g, 5.02 mmol) in EtOH (35 mL) and DCM (35 mL) was treated with hydrazine hydrate (50-60%, 0.94 mL, 15.0 mmol) and the mixture was stirred for 96 hours at room temperature under nitrogen. The suspension was filtered through Celite and the filtrate solvent was concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge (Agilent HF Bond Elut-SCX, 10 g cartridge). The cartridge was washed with methanol (5 column volumes) and the product was eluted with 2 M NH.sub.3 in MeOH (5 column volumes). The solvent was removed in vacuo to give the desired product as a brown oil (1.00 g, 97%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.23-7.17 (m, 2H), 7.16-7.11 (m, 2H), 3.69-3.57 (m, 2H), 3.21-3.11 (m, 2H), 2.85-2.72 (m, 4H), 2.68-2.54 (m, 2H).

(ii) (S)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I4)

[0356] ##STR00063##

(a) (R)-2-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (I3)

[0357] (S)—N-glycidylphthalimide (2.20 g, 10.8 mmol) and 2-aminoindane (1.70 g, 13.0 mmol) were dissolved in ethanol (45 mL) and the reaction was heated under nitrogen at 80° C. for 22 hours. The volatiles were removed under reduced pressure and the resulting dark residue was purified by column chromatography (40 g SiO.sub.2, 0-20% methanol/DCM) to give the desired compound (1.80 g, 51%); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.84-7.77 (m, 2H), 7.71-7.64 (m, 2H), 7.20-7.06 (m, 4H), 4.01 (m, 1H), 3.84-3.68 (m, 2H), 3.64-3.55 (m, 1H), 3.18-3.10 (m, 2H), 2.85-2.77 (m, 2H), 2.74-2.61 (m, 2H).

(b) (S)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I4)

[0358] A mixture of (R)-2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isoindoline-1,3-dione I3 (1.84 g, 5.47 mmol) and hydrazine monohydrate (380 μL, 7.67 mmol) in ethanol (16 mL) and DCM (16 mL) was stirred at room temperature for 20 hours. The resulting solid was filtered off through Celite, washed with DCM (20 mL) and concentrated under reduced pressure. The residue was dissolved in methanol (15 mL) and the solution applied evenly to SCX cartridges (3×5 g). The cartridges were washed with methanol (20 mL for each cartridge) and eluted with a 2 M solution of ammonia in methanol (20 mL for each cartridge). After concentration of the combined ammonia eluates, the resulting compound was subjected to another round of purification by SCX cartridge, as described, to give the desired compound (950 mg, 84%); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.18-7.09 (m, 4H), 3.62 (m, 2H), 3.15-3.09 (m, 2H), 2.76-2.66 (m, 4H), 2.62-2.51 (m, 2H).

(iii) (R)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I6)

[0359] ##STR00064##

(a) (S)-2-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (I5)

[0360] (R)—N-Glycidylphthalimide (2.50 g, 12.30 mmol) and 2-aminoindane (1.97 g, 14.7 mmol) were dissolved in ethanol (50 mL) and the reaction was heated under nitrogen at 80° C. for 72 hours. The ethanol was removed under reduced pressure and the dark residue was purified by column chromatography (40 g SiO.sub.2, 0-10% methanol/DCM) to give the desired compound (1.22 g, 29%).

(b) (R)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I6)

[0361] A mixture of (S)-2-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isoindoline-1,3-dione I5 (1.22 g, 3.63 mmol) and hydrazine monohydrate (252 μL, 5.09 mmol) in ethanol (13 mL) and DCM (13 mL) was stirred at room temperature for 20 hours. The resulting solid was filtered through Celite and washed with ethanol (20 mL). The volatiles were removed under reduced pressure. The residue was dissolved in methanol (15 mL) and the solution applied evenly to SCX cartridges (3×5 g). The cartridges were washed with methanol (20 mL) and eluted with a 2 M solution of ammonia in methanol (20 mL). The combined ammonia eluates were concentrated in vacuo to give the desired compound (740 mg, 99%).

(iv) 4-((1-Methyl-1H-pyrazol-4-yl)oxy)benzoic acid (I7)

[0362] ##STR00065##

[0363] 5-Hydroxy-1-methylpyrazole (0.250 g, 2.55 mmol) was added portion-wise to a stirring suspension of methyl 4-fluorobenzoate (0.35 mL, 2.7 mmol) and potassium carbonate (0.70 g, 5.1 mmol) in DMSO (10 mL) at room temperature. The resulting suspension was heated at 150° C. overnight. Water (50 mL) was added and the resulting solution was stirred for 4 hours. The reaction was cooled to room temperature, water (50 mL) was added and extracted with EtOAc (3×30 mL). The organic layers were discarded. The aqueous layer was acidified with 6 M HCl (2 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (3×30 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a pale yellow oil. The oil was purified by column chromatography (24 g SiO.sub.2 cartridge, 50-100% EtOAc (with 1% v/v AcOH) in petroleum benzine 40-60° C.) to give the desired compound as a colourless solid (327 mg, 59%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 7.95-7.86 (m, 2H), 7.81 (s, 1H), 7.42 (s, 1H), 7.09-7.00 (m, 2H), 3.82 (s, 3H), LCMS-B RT 2.98 min; m/z 219.1 [M+H].sup.+; 217.1 [M−H].sup.−.

(v) (R)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol (I10)

[0364] ##STR00066##

(a) N-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-inden-2-amine I9

[0365] To a solution of 2,3-dihydro-1H-inden-2-amine (20.0 g, 150.2 mmol) in ethanol (300 mL) was added 2,4-dimethoxybenzaldehyde (25.0 g, 150.2 mmol). The reaction mixture was stirred at 70° C. for 2 h, then the reaction cooled to 0° C. and NaBH.sub.4 (11.4 g, 300.3 mmol) was added. The resulting mixture was stirred at 0° C. for 30 min and poured into water (150 mL), CH.sub.2Cl.sub.2 (150 mL) was added and the resulting mixture filtered. The filtrate was concentrated under reduced pressure and the aqueous mixture extracted with EtOAc (50 mL×3). The organic layer was washed with brine (80 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow oil (41 g, 96%): LCMS: RT 1.45 min; m/z 284.2 [M+H].sup.+.

(b) (R)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10

[0366] To a solution of N-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-inden-2-amine I9 (30.0 g, 105.9 mmol) in ethanol (400 mL) was added (R)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (22.6 g, 111.1 mmol). The resulting mixture was heated at reflux overnight then N.sub.2H.sub.4.H.sub.2O (15.9 g, 317.6 mmol) was added. The resulting mixture was heated at reflux a further 4 h, then the reaction cooled and the precipitate removed by filtration. The filter cake was rinsed with ethanol (100 mL×2) and the filtrate concentrated under reduced pressure. The residue obtained was dissolved in CH.sub.2Cl.sub.2 (200 mL), washed with saturated aqueous NaHCO.sub.3 solution (80 mL×3) and brine (80 mL×3), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow oil (35.7 g, 95%): .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.21-7.19 (d, 1H), 7.15-7.14 (m, 2H), 7.09-7.07 (m, 2H), 6.53-6.47 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.78-3.75 (m, 1H), 3.65-3.63 (m, 3H), 3.02-2.99 (m, 4H), 2.69-2.64 (m, 1H), 2.51-2.42 (m, 3H); LCMS: RT 0.46 min; m/z 357.2 [M+H].sup.+.

(vi) (S)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol (I11)

[0367] ##STR00067##

[0368] To a solution of N-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-inden-2-amine I9 (10.0 g, 35.2 mmol) in ethanol (150 mL) was added (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (7.5 g, 36.9 mmol). The resulting mixture was heated at reflux overnight then the reaction cooled and N.sub.2H.sub.4.H.sub.2O (4.9 g, 97.4 mmol) added. The resulting mixture was heated at reflux for a further 4 h, then filtered and the filter cake rinsed with ethanol (20 mL). The filtrate was concentrated and the residue obtained dissolved in CH.sub.2Cl.sub.2 (200 mL), washed with saturated aqueous solution of NaHCO.sub.3 (80 mL×3) and brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow oil (11.4 g, 87%): .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.21-7.15 (m, 3H), 7.10-7.07 (m, 2H), 6.55-6.54 (m, 1H), 6.50-6.48 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.80-3.70 (m, 2H), 3.63-3.61 (m, 2H), 3.03-2.95 (m, 4H), 2.83-2.60 (m, 1H), 2.58-2.51 (m, 3H); LCMS: RT 0.52 min; m/z 357.2 [M+H].sup.+.

(vii) 1-Amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol (I12)

[0369] ##STR00068##

[0370] To a solution of N-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-inden-2-amine I9 (10.0 g, 35.2 mmol) in ethanol (150 mL) was added 2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (7.5 g, 37.1 mmol). The resulting mixture was heated at reflux overnight, then cooled to room temperature and N.sub.2H.sub.4.H.sub.2O (4.9 g, 97.4 mmol) added. The resulting mixture was heated at reflux for a further 3 h. The reaction was cooled to RT, filtered and the filter cake rinsed with ethanol (50 mL). The filtrate was concentrated then dissolved in CH.sub.2Cl.sub.2, washed with a saturated aqueous solution of NaHCO.sub.3 (80 mL×3) and brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as yellow oil (10.5 g, 83%): LCMS: RT 0.53 min; m/z 357.2 [M+H].sup.+.

(viii) (R)-4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid (I4)

[0371] ##STR00069##

(a) (R)-Methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)benzoate I13

[0372] To a solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino) propan-2-ol I10 (25.0 g, 70.2 mmol) in CH.sub.2Cl.sub.2 (500 mL) was added 4-(methoxycarbonyl)benzoic acid (I3.9 g, 77.2 mmol), DIPEA (18.1 g, 140.4 mmol), HOBt (0.95 g, 7.0 mmol) and EDCl (16.2 g, 84.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was partitioned with a saturated solution of NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2 (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (100% CH.sub.2Cl.sub.2 to 1% methanol in CH.sub.2Cl.sub.2) to give the desired compound as a yellow oil (19.8 g, 55%): LCMS: RT 2.30 min; m/z 519.3 [M+H].sup.+.

(b) (R)-4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid I14

[0373] To a solution of (R)-methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-carbamoyl)benzoate I13 (17.4 g, 33.7 mmol) in a mixture of THF (250 mL) methanol (12 mL) and water (12 mL) was added LiOH.H.sub.2O (7.0 g, 168.3 mmol). The reaction was stirred at room temperature for 48 h. The solvent was removed and the residue diluted with water (200 mL). The pH of the mixture was adjusted to pH 6 by addition of 3 M aqueous HCl. The mixture was extracted with CH.sub.2Cl.sub.2 (150 mL×3). The combined organic layers were washed with brine (100 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a white solid (9.4 g, 56%): LCMS: RT 2.34 min; m/z 505.3 [M+H].sup.+.

(ix) 4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid (I16)

[0374] ##STR00070##

(a) Methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)benzoate I15

[0375] To a solution of 4-(methoxycarbonyl)benzoic acid (1.6 g, 9.0 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added HATU (4.7 g, 12.3 mmol) and DIPEA (2.2 g, 16.8 mmol). The mixture was stirred at room temperature for 1 h then 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I12 (4.0 g, 11.2 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water (100 mL) was added and the phases were separated. The organic layer was washed with a saturated aqueous solution of NaHCO.sub.3 (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0.7% methanol in CH.sub.2Cl.sub.2) to give the byproduct as a yellow oil (1.4 g) further elution (4% methanol in CH.sub.2Cl.sub.2) gave the desired compound as a yellow oil (2.8 g, 48%). LCMS: RT 2.33 min; m/z 519.3 [M+H].sup.+.

(b) 4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl) carbamoylbenzoic acid I16

[0376] To a solution of (R)-methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-carbamoyl)benzoate I15 (2.6 g, 5.0 mmol) in a mixture of THF (40 mL), methanol (2 mL) and water (2 mL) was added LiOH.H.sub.2O (1.1 g, 25.1 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue obtained diluted with water (50 mL). The pH of the aqueous mixture was adjusted to 6 by addition of 4 M aqueous HCl solution, then extracted with CH.sub.2Cl.sub.2 (100 mL×3). The combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a white solid (1.6 g, 64%). LCMS: RT 2.19 min; m/z 505.3 [M+H].sup.+.

(x) 2-(4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)phenyl)acetic acid (I18)

[0377] ##STR00071##

(a) Methyl 2-(4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl) carbamoyl)phenyl)acetate I17

[0378] To a solution of 4-(2-methoxy-2-oxoethyl)benzoic acid (1.0 g, 5.1 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added HATU (2.7 g, 7.1 mmol) and DIPEA (1.2 g, 9.7 mmol). The mixture was stirred at room temperature for 1 h, then 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I12 (2.3 g, 6.4 mmol) was added. The resulting mixture was stirred at room temperature overnight, then diluted with water (80 mL). The organic layer was separated, washed with a saturated aqueous NaHCO.sub.3 solution (100 mL), brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0.5% methanol in CH.sub.2Cl.sub.2) to give the desired compound as a yellow oil (0.92 g, 27%): LCMS: RT 2.24 min; m/z 533.4 [M+H].sup.+.

(b) 2-(4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)phenyl)acetic acid I18

[0379] To a solution of methyl 2-(4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)phenyl)acetate I17 (1.5 g, 2.8 mmol) in a mixture of THF (20 mL), methanol (2 mL) and water (2 mL) was added LiOH.H.sub.2O (0.6 g, 1.4 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed, and the residue diluted with water (50 mL). The pH of the aqueous solution was adjusted to 6 by addition of 4 M aqueous HCl solution. The aqueous mixture was extracted with CH.sub.2Cl.sub.2 (10 mL×3) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow oil (0.63 g, 42%): LCMS: RT 2.16 min; m/z 519.3 [M+H].sup.+.

(xi) (R)-4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)-3-ethoxybenzoic acid (I25)

[0380] ##STR00072## ##STR00073##

(a) Ethyl-4-bromo-2-ethoxybenzoate I19

[0381] To a mixture of 4-bromo-2-hydroxybenzoic acid (20.0 g, 92.6 mmol) and K.sub.2CO.sub.3 (38.4 g, 277.9 mmol) in dimethylsulfoxide (50 mL) at 40° C. was added ethyl bromide (15.2 g, 138.9 mmol) dropwise over 30 min. The reaction was stirred for 2 h then further ethyl bromide (15.2 g, 138.9 mmol) was added over 30 min. The reaction was stirred a further 8 h then diluted with CH.sub.2Cl.sub.2 (150 mL) and filtered. The filtrate was washed with water (200 mL×10) and brine (200 mL×3), dried over Na.sub.2SO.sub.4 and concentrated to give the desired compound as a brown solid (24.3 g, 96%): LCMS: RT 2.93 min; m/z 273.0 [M+H].sup.+.

(b) 4-Bromo-2-ethoxybenzoic acid I20

[0382] To a solution of ethyl 4-bromo-2-ethoxybenzoate I19 (24.1 g, 88.6 mmol) in a mixture of THF (150 mL), methanol (15 mL) and water (15 mL) was added LiOH.H.sub.2O (18.6 g, 44.3 mmol). The resulting mixture was stirred at room temperature for 24 h. The solvent was removed, and the residue was diluted with water (200 mL). The pH of the aqueous mixture was adjusted to 6 by addition of 2 M aqueous HCl solution. The aqueous mixture was extracted with CH.sub.2Cl.sub.2 (150 mL×3) and the combined organic layers washed with brine (100 mL×3), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow solid (19.8 g, 92%): LCMS: RT 2.47 min; m/z 246.9 [M+H].sup.+ for .sup.81Br.

[0383] To a solution of 4-bromo-2-ethoxybenzoic acid I20 (16.4 g, 67.2 mmol) in acetonitrile (75 mL) was added benzyl bromide (13.8 g, 80.7 mmol) and K.sub.2CO.sub.3 (18.6 g, 134.4 mmol). The resulting mixture was stirred at 40° C. overnight. The reaction mixture was filtered and concentrated. The residue obtained was diluted with CH.sub.2Cl.sub.2 (50 mL) and washed with water (100 mL×2). The organic layer was washed with brine (70 mL×3), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (1% EtOAc in petroleum ether) to give the desired compound as a light yellow oil (20.9 g, 93%): LCMS: RT 3.31 min; m/z 334.9 [M+H].sup.+.

(d) 1-Benzyl 4-methyl 2-ethoxyterephthalate I22

[0384] To a solution of benzyl 4-bromo-2-ethoxybenzoate I21 (20.0 g, 59.9 mmol) in methanol (100 mL) was added Pd(dppf)Cl.sub.2 (2.2 g, 3 mmol) and TEA (13.3 g, 131.7 mmol). The resulting mixture was heated at reflux overnight under an atmosphere of carbon monoxide. The reaction mixture was concentrated and the residue obtained diluted with water and extracted with CH.sub.2Cl.sub.2 (50 mL×3). The combined organic layers were washed with brine (60 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (2% EtOAc in petroleum ether) to give the desired compound as a white solid (15.1 g, 81%): LCMS: RT 3.03 min; m/z 315.1 [M+H].sup.+.

(e) 2-Ethoxy-4-(methoxycarbonyl)benzoic acid I23

[0385] To a solution of 1-benzyl 4-methyl 2-ethoxyterephthalate I22 (14.9 g, 47.4 mmol) in THF (100 mL) was added 10% Pd/C (1.5 g). The resulting mixture was stirred at room temperature overnight under H.sub.2 atmosphere. The reaction mixture was filtered through celite, and the filter cake washed with THF (50 mL). The filtrate was concentrated and the residue diluted with water. The pH of the aqueous solution was adjusted to 6 by addition of a 2 M aqueous HCl solution. The resultant mixture was extracted with CH.sub.2Cl.sub.2 (50 mL×3) and the combined organic layers washed with brine (50 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a white solid (10.2 g, 96%): LCMS: RT 2.13 min; m/z 225.0 [M+H].sup.+.

(f) Methyl (R)-4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl) carbamoyl)-3-ethoxybenzoate I24

[0386] To a solution of 2-ethoxy-4-(methoxycarbonyl)benzoic acid I23 (3.8 g, 17.0 mmol) in CH.sub.2Cl.sub.2 (40 mL) was added (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10 (5.5 g, 15.1 mmol), HOBt (208.6 mg, 1.5 mmol), DIPEA (4.0 g, 30.9 mmol) and EDCl (3.7 g, 18.5 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned with saturated aqueous NaHCO.sub.3 solution and extracted with CH.sub.2Cl.sub.2 (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by column chromatography (1% methanol in CH.sub.2Cl.sub.2) to give the desired compound as a yellow oil (6.6 g, 76%): LCMS: RT 2.41 min; m/z 563.2 [M+H].sup.+.

(g) (R)-4-((3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)-3-ethoxybenzoic acid I25

[0387] To a solution of methyl (R)-4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)-3-ethoxybenzoate I24 (6.5 g, 11.6 mmol) in a mixture of THF (40 mL), methanol (4 mL) and water (4 mL) was added LiOH.H.sub.2O (2.4 g, 57.8 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated, 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 aqueous was then extracted with CH.sub.2Cl.sub.2 (10 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 as a white solid (6.3 g, 98%): LCMS: RT 2.26 min; m/z 549.3 [M+H].sup.+.

(xii) 4-(Morpholine-4-carbonyl)benzoic acid (I27)

[0388] ##STR00074##

(a) Methyl 4-(morpholine-4-carbonyl)benzoate I26

[0389] To a solution of mono-methyl terephthalate (10.0 g, 55.9 mmol) in dichloromethane (500 mL) at 0° C. was added oxalyl chloride (8.5 g, 66.6 mmol) and a catalytic amount of DMF (0.5 mL). The mixture was stirred at 0° C. for 3 h. Morpholine (9.7 g, 111.0 mmol) was added followed by triethylamine (7.9 g, 77.7 mmol), the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with a saturated aqueous solution of NaHCO.sub.3 (250 mL). The aqueous layer was extracted with dichloromethane (3×250 mL) and the combined organic layers washed with 0.5 M aqueous HCl solution (100 mL), water (200 mL) and brine (100 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a solid which was crystallized (petroleum ether: ethyl acetate=20:1) to give the desired compound (11.3 g, 82%) as a yellow solid. LCMS: RT 1.11 min; m/z 250.1 [M+H].sup.+

(b) 4-(Morpholine-4-carbonyl)benzoic acid I27

[0390] To a solution of methyl 4-(morpholine-4-carbonyl)benzoate I26 (10.5 g, 42.1 mmol) in a mixture of THF (200 mL), MeOH (20 mL) and water (2 mL) was added LiOH.H.sub.2O (1.9 g, 46.3 mmol) and the reaction stirred at room temperature for 24 h. The solvents were removed under reduced pressure and the resulting gum suspended in a 0.5 M aqueous citric acid solution (250 mL). The aqueous layer extracted with dichloromethane (3×250 mL) and the combined organic fractions dried (MgSO.sub.4) and concentrated in vacuo to yield the product as a tan solid (8.8 g, 88%). LCMS: RT 0.48 min; m/z 236.1 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ=8.23-8.04 (d, 2H), 7.67-7.48 (d, 2H), 3.79 (br s, 2H), 3.75-3.68 (m, 2H), 3.68-3.61 (m, 2H), 3.49-3.40 (m, 2H).

(xiii) 3-(Morpholine-4-carbonyl)benzoic acid I29

[0391] ##STR00075##

(a) Methyl 3-(morpholine-4-carbonyl)benzoate I28

[0392] Morpholine (958 μL, 11.1 mmol, 1 equiv), mono-methyl isopthalate (2.00 g, 11.1 mmol, 1 equiv), MeCN (50 mL), DIPEA (5.80 mL, 33.3 mmol, 3 equiv) and HATU (4.64 g, 12.2 mmol, 1.1 equiv) were stirred at room temperature. After two hours the mixture was quenched with 5% w/v aqueous sodium carbonate solution (50 mL) and the organic solvents removed in vacuo. The aqueous residue was extracted with ethyl acetate (3×50 mL), and the pooled organic extracts washed with water (2×50 mL), dried over sodium sulfate and concentrated. Chromatography (40 g silica cartridge, 0-50% ethyl acetate in petroleum benzine) and collection of the suspected product fractions gave the desired compound (2.72 g, 98% yield) as a pale brown oil. LCMS-B: RT=3.32 min, m/z=250 [M+H].sup.+.

(b) 3-(morpholine-4-carbonyl)benzoic acid I29

[0393] LiOH.H.sub.2O (1.37 g, 32.7 mmol, 3 equiv) was added to a solution of I28 (2.72 g, 10.9 mmol) in MeOH (20 mL) and water (10 mL), the resulting suspension was stirred for 16 hours at room temperature. The volatiles were removed in vacuo to give a white solid. Water was added followed by a 0.5 M aqueous solution of citric acid until the solution was at pH 4. The mixture was stirred for 30 minutes before it was extracted with EtOAc (3×70 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO.sub.4) and concentrated in vacuo to give the desired compound (1.74 g, 68% yield) as a white solid. LCMS-B: RT=3.19 min, m/z=236 [M+H].sup.+, 234 [M−H].sup.−.

(xiv) 2-(2-Cyclopropylacetyl)isoindoline-5-carboxylic acid I32

[0394] ##STR00076##

(a) 1-(5-Bromoisoindolin-2-yl)-2-cyclopropylethanone I30

[0395] To a solution of 2-cyclopropylacetic acid (96 mg, 0.96 mmol) in dichloromethane (10 mL) was added HOBt (212.8 mg, 1.39 mmol), DIPEA (421.2 mg, 3.26 mmol) and EDCl (266.4 mg, 1.39 mmol). The mixture was stirred at 0° C. for 20 min then a solution of 5-bromoisoindoline (190 mg, 0.96 mmol) in dichloromethane (5 mL) was added. The resulting mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture extracted with dichloromethane (20 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (Petroleum ether: ethyl acetate=10:1) to give the desired product (145 mg, 68%) as a yellow oil. LCMS: RT 2.69 min; m/z 280.2 [M+H].sup.+.

(b) Methyl 2-(2-cyclopropylacetyl)isoindoline-5-carboxylate I31

[0396] To a solution of 1-(5-bromoisoindolin-2-yl)-2-cyclopropylethanone I30 (140 mg, 0.5 mmol) in methanol (10 mL) was added triethylamine (111.1 mg, 1.1 mmol) and Pd(dppf)Cl.sub.2 (18.3 mg, 0.025 mmol,). The mixture was heated at reflux under a carbon monoxide atmosphere overnight. The mixture was concentrated to give the crude product which was purified by column chromatography (Petroleum ether: ethyl acetate=10:1) to give the desired product (103 mg, 79%) as a yellow oil. LCMS: RT 2.38 min; m/z 260.3 [M+H].sup.+

[0397] To a solution of 2-(2-cyclopropylacetyl)isoindoline-5-carboxylic acid I31 (97 mg, 0.37 mmol) in mixture of THF (8 mL), methanol (0.8 mL), and water (0.08 mL) was added LiOH.H.sub.2O (77.7 mg, 1.85 mmol). The resulting mixture was stirred at room temperature for 3 days. The mixture was concentrated to give the crude product which was dissolved in water and washed with dichloromethane (10 mL). The aqueous layer was neutralized by addition of a 0.5 M aqueous HCl solution (10 mL) and the solution extracted with dichloromethane (20 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (50 mg, 55%) as a pale solid. LCMS: RT 2.11 min; m/z 246.3 [M+H].sup.+

(xv) 2-(2-Cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid I35

[0398] ##STR00077##

(a) 1-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-cyclopropylethanone I33

[0399] To a solution of 2-cyclopropylacetic acid (201.2 mg, 2.01 mmol) in DCM (30 mL) was added DIPEA (1.4 g, 8.8 mmol), HOBt (445.5 mg, 2.91 mmol) and EDCl (557.8 mg, 2.91 mmol). The mixture was stirred at 0° C. for 20 min then 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (500 mg, 2.01 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water (20 mL) and the solution extracted with DCM (30 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give the desired product (420 mg, 71%) as a yellow oil. LCMS: RT 2.59 min; m/z 294.0 [M+H].sup.+.

(b) Methyl 2-(2-cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate I34

[0400] To a solution of 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-cyclopropylethanone I33 (400 mg, 1.36 mmol) in MeOH (10 mL) was added triethylamine (303.0 mg, 3.0 mmol), and Pd(dppf)Cl.sub.2 (49.9 mg, 0.068 mmol). The mixture was heated at reflux under a carbon monoxide atmosphere overnight. The solvent was removed under reduced pressure to give the crude product which was purified by column chromatography (Petroleum ether: ethyl acetate=5:1) to give the desired product (160 mg, 79%) as a yellow oil. LCMS: RT 2.47 min; m/z 274.3 [M+H].sup.+

[0401] To a solution of methyl 2-(2-cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate I34 (150 mg, 0.54 mmol) in a mixture of THF (8 mL), methanol (0.8 mL), and water (0.08 mL) was added LiOH.H.sub.2O (69.3 mg, 1.65 mmol). The resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated to give the crude product which was diluted with water and washed with dichloromethane (10 mL). The water layer was neutralized by addition of a 0.5 M aqueous HCl solution (10 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (70 mg, 50%) as a pale solid. LCMS: RT 2.20 min; m/z 260.1 [M+H].sup.+

(xvi) 2-(2-Cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid I38

[0402] ##STR00078##

(a) 1-(6-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-cyclopropylethanone I36

[0403] To a solution of 2-cyclopropylacetic acid (236.2 mg, 2.36 mmol) in DCM (30 mL) was added DIPEA (1.03 g, 8.0 mmol), HOBt (523.6 mg, 3.42 mmol) and EDCl (655.6 mg, 3.42 mmol). The mixture was stirred at 0° C. for 20 min then 6-bromo-1,2,3,4-tetrahydroisoquinoline (500 mg, 2.01 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water (20 mL) and the aqueous layer extracted with DCM (30 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give the desired product (580 mg, 83%) as a yellow oil. LCMS: RT 2.69 min; m/z 294.0 [M+H].sup.+

(b) Methyl 2-(2-cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate I37

[0404] To a solution of 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-cyclopropylethanone I36 (560 mg, 1.90 mmol) in MeOH (30 mL) was added triethylamine (422.2 mg, 4.18 mmol), and Pd(dppf)Cl.sub.2 (69.7 mg, 0.095 mmol). The mixture was heated at reflux under a carbon monoxide atmosphere overnight. The mixture was concentrated to give the crude product which was purified by column chromatography (Petroleum ether: ethyl acetate=5:1) to give the desired product (280 mg, 54%) as a pale oil. LCMS: RT 2.45 min; m/z 274.1 [M+H].sup.+

[0405] To a solution of methyl 2-(2-cyclopropylacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate I37 (200 mg, 0.73 mmol) in mixture of THF (10 mL), methanol (1 mL), and water (0.1 mL) was added LiOH.H.sub.2O (94.0 mg, 2.26 mmol). The resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated to give the crude product. Water was added and the aqueous layer washed with dichloromethane (10 mL). The aqueous layer was neutralized by addition of a 0.5 M aqueous HCl solution (10 mL) and the solution was extracted with dichloromethane (20 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (170 mg, 89%) as a yellow solid. LCMS: RT 2.15 min; m/z 260.3 [M+H].sup.+

(xvii) 2-Acetyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid I41

[0406] ##STR00079##

(a) 1-(6-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethanone I39

[0407] To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (456.0 mg, 2.15 mmol) in DCM (20 mL) was added triethylamine (326.0 mg, 3.22 mmol) and acetic anhydride (219.5 mg, 2.15 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 3 h, then allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with a saturated aqueous NaHCO.sub.3 solution (20 mL×2), the organic layer separated, dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (500 mg, 91%) as an orange oil. LCMS: RT 2.41 min; m/z 254.0 [M+H].sup.+

(b) Methyl 2-acetyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate I40

[0408] To a solution of 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethanone I39 (500 mg, 1.97 mmol) in MeOH (30 mL) was added triethylamine (437.0 mg, 4.33 mmol), and Pd(dppf)Cl.sub.2 (71.9 mg, 0.098 mmol). The mixture was heated at reflux under a carbon monoxide atmosphere overnight. The mixture was concentrated to give the crude product which was purified by column chromatography (Petroleum ether: ethyl acetate=2:1) to give the desired product (360 mg, 78%) as an orange oil. LCMS: RT 2.07 min; m/z 234.1 [M+H].sup.+

[0409] To a solution of methyl 2-acetyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate I40 (200 mg, 0.86 mmol) in a mixture of THF (10 mL), methanol (1 mL), and water (0.1 mL) was added LiOH.H.sub.2O (108.3 mg, 2.58 mmol). The resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated to give the crude product which was diluted with water and washed with dichloromethane (10 mL). The aqueous layer was neutralized by addition of a 0.5 M aqueous HCl solution (10 mL) and the solution extracted with dichloromethane (20 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (100 mg, 53%) as a white solid. LCMS: RT 3.01 min; m/z 220.1 [M+H].sup.+

(xviii) 2-Acetyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid I44

[0410] ##STR00080##

(a) 1-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethanone I42

[0411] To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (500 mg, 2.0 mmol), triethylamine (650 mg, 6.4 mmol) and DMAP (25 mg, 0.2 mmol) in DCM (20 mL) at 0° C. was added acetic anhydride (210 mg, 2.1 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was washed with NaHCO.sub.3 solution (20 mL×2) and the organic layer dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (350 mg, 70%) as a clear oil. LCMS: RT 3.03 min; m/z 254.1 [M+H].sup.+

(b) Methyl 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate I43

[0412] To a solution of 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethanone I42 (350 mg, 1.385 mmol) in MeOH (30 mL) was added triethylamine (307.1 mg, 2.25 mmol), and Pd(dppf)Cl.sub.2 (50.6 mg, 0.069 mmol). The mixture was heated at reflux under a carbon monoxide atmosphere overnight. The mixture was concentrated to give the crude product which was purified by column chromatography (Petroleum ether: ethyl acetate=3:1) to give the desired product (150 mg, 46%) as an orange oil. LCMS: RT 2.35 min; m/z 234.3 [M+H].sup.+

[0413] To a solution of methyl 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate I43 (150 mg, 0.64 mmol) in a mixture of THF (10 mL), methanol (1 mL), and water (0.1 mL) was added LiOH.H.sub.2O (80.6 mg, 1.92 mmol). The resulting mixture was stirred at room temperature for 1 day. The mixture was concentrated to give the crude product which was diluted with water and washed with dichloromethane (10 mL). The water layer was neutralized by addition of a 0.5 M aqueous HCl solution (10 mL) and the solution was extracted with dichloromethane (20 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the desired product (80 mg, 57%) as a yellow oil. LCMS: RT 1.57 min; m/z 220.1 [M+H].sup.+

(xix) 6-(Piperidine-1-carbonyl)nicotinic acid I47

[0414] ##STR00081##

(a) (5-Bromopyridin-2-yl)(piperidin-1-yl)methanone I45

[0415] To a solution of 5-bromopicolinic acid (5.0 g, 25.0 mmol) in DCM (250 mL) was added HATU (11.4 g, 30.0 mmol) and Et.sub.3N (8.8 g, 88.0 mmol). The mixture was stirred at room temperature for 30 min then piperidine (2.6 g, 30.0 mmol) was added and the resulting mixture stirred at room temperature overnight. Water (200 mL) was added and the organic layer separated. The aqueous layer was extracted with DCM (2×200 mL) and the combined organic fractions washed with brine (200 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0-30% EtOAc/petroleum ether) to give the desired compound as yellow oil (6.0 g, 90%): LCMS: RT 2.21 min, m/z 269.1; 271.1 [M+H].sup.+ for .sup.79Br and .sup.81Br respectively

(b) Methyl 6-(piperidine-1-carbonyl)nicotinate I46

[0416] To a solution of (5-bromopyridin-2-yl)(piperidin-1-yl)methanone I45 (4.0 g, 14.9 mmol) in MeOH (50 mL) was added Et.sub.3N (3.3 g, 32.8 mmol) and PdCl.sub.2(dppf) (410 mg, 0.75 mmol). The resulting mixture was heated at reflux under a CO balloon overnight. The solvent was removed and the residue diluted with water (50 mL). The aqueous layer was extracted with DCM (3×50 mL) and the combined organic layers washed with brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0-30% EtOAc/petroleum ether) to give the desired compound as a yellow solid (650 mg, 18%): LCMS: RT 1.86 min, m/z 249.1 [M+H].sup.+.

[0417] To a solution of methyl 6-(piperidine-1-carbonyl)nicotinate I46 (600 mg, 2.4 mmol) in MeOH (5 mL) was added a solution of NaOH (193 mg, 4.8 mmol) in water (0.5 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue resuspended in water. The pH of the aqueous solution was adjusted to pH 4 by addition of a 4 M aqueous HCl solution. The aqueous layer was extracted with DCM (5×50 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow solid (300 mg, 53%): LCMS: RT 0.96 min, m/z 235.1 [M+H].sup.+

(xx) 2-Propoxybenzoic acid I49

[0418] ##STR00082##

(a) Propyl 2-propoxybenzoate I48

[0419] To a mixture of 2-hydroxybenzoic acid (5.0 g, 36.2 mmol), NaI (0.5 g, 3.6 mmol) and K.sub.2CO.sub.3 (13.4 g, 0.11 mol) in DMSO (10 mL) at 36° C. was added 1-bromopropane (6.7 g, 54.3 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h, then further 1-bromopropane (6.7 g, 54.3 mmol) was added over a period of 30 min. The resulting mixture was stirred at 36° C. overnight then diluted with DCM (50 mL) and filtered. The solid was washed with DCM (2×50 mL) and the filtrate washed with water (5×100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as colorless oil (7.4 g, 93%): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78-7.76 (m, 1H), 7.43-7.39 (m, 1H), 6.96-6.92 (m, 2H), 4.27-4.24 (m, 2H), 4.00-3.96 (m, 2H), 1.89-1.72 (m, 4H), 1.07-1.00 (m, 6H): LCMS: RT 2.26 min, m/z 223.1 [M+H].sup.+

(b) 2-Propoxybenzoic acid I49

[0420] To a solution of propyl 2-propoxybenzoate I48 (1.0 g, 4.5 mmol) in a mixture of THF (10 mL), MeOH (2 mL) and water (2 mL) was added LiOH.H.sub.2O (0.95 g, 22.5 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue diluted with water (10 mL). The aqueous layer was washed with DCM (2×10 mL) and the pH adjusted to 2 by addition of a solution of concentrated HCl. The aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as yellow oil (300 mg, 53%): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.98 (brs, 1H), 8.19-8.17 (m, 1H), 7.56-7.52 (m, 1H), 7.14-7.10 (m, 1H), 7.05-7.03 (m, 1H), 4.23-4.20 (m, 2H), 1.99-1.90 (m, 2H), 1.12-1.08 (m, 3H): LCMS: RT 2.15 min, m/z 181.1 [M+H].sup.+

(xxi) 2-Isopropoxybenzoic acid I51

[0421] ##STR00083##

(a) Isopropyl 2-isopropoxybenzoate I50

[0422] To a mixture of 2-hydroxybenzoic acid (5.0 g, 36.2 mmol), K.sub.2CO.sub.3 (13.4 g, 0.11 mol) and NaI (0.5 g, 3.6 mmol) in DMSO (10 mL) at 36° C. was added 2-bromopropane (6.7 g, 54.3 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h, then further 2-bromopropane (6.7 g, 54.3 mmol) was added dropwise over 30 min. The resulting mixture was stirred at 36° C. overnight. The mixture was diluted with DCM (50 mL) and the solids removed by filtration. The filter cake was washed with DCM (2×50 mL) and the combined filtrates washed with water (5×100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a colorless oil (2.3 g, 29%): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.70-7.68 (m, 1H), 7.40-7.36 (m, 1H), 6.97-6.91 (m, 2H), 5.28-5.21 (m, 1H), 4.61-4.55 (m, 1H), 1.36-1.34 (m, 12H): LCMS: RT 2.19 min, m/z 223.1 [M+H].sup.+

(b) 2-Isopropoxybenzoic acid I51

[0423] To a solution of propyl 2-isopropoxybenzoate I50 (1.0 g, 4.5 mmol) in a mixture of THF (10 mL), i-PrOH (1 mL) and water (0.1 mL) was added LiOH.H.sub.2O (0.95 g, 22.5 mmol). The resulting mixture was stirred at room temperature for 3 days. The solvent was removed and the residue diluted with water (20 mL). The aqueous layer was washed with DCM (20 mL) and the pH adjusted to 2 by addition of concentrated HCl. The aqueous layer was extracted with DCM (3×20 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as yellow oil: (600 mg, 75%): .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.85-7.82 (m, 1H), 7.47-7.43 (m, 1H), 7.07-7.05 (m, 1H), 6.99-6.96 (m, 1H), 4.72-4.65 (t, 1H), 1.33-1.31 (m, 6H): LCMS: RT 2.15 min, m/z 181.1 [M+H].sup.+

(xxii) 2-(2,2,2-Trifluoroethoxy)benzoic acid I52

[0424] ##STR00084##

[0425] To a solution of 2,2,2-trifluoroethanol (4.8 g, 47.9 mmol) in DMF (30 mL) was added sodium tert-butoxide (2.8 g, 28.7 mmol) at 0° C. The solution was stirred at room temperature for 1 h then 2-chlorobenzoic acid (3.0 g, 19.2 mmol) and CuBr (247 mg, 1.7 mmol) were added. The reaction was heated at 120° C. for 5 hours under nitrogen, then 20% v/v aqueous HCl solution was added. The resulting mixture was extracted with CH.sub.2Cl.sub.2 (60 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (2% MeOH/in CH.sub.2Cl.sub.2) to give the crude product (1.8 g). 100 mg of this material was further purified by prep TLC (EtOAc:petroleum ether=1:1) to give the desired compound (67 mg, 29%) as a white solid: .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.65-7.63 (m, 1H), 7.51-7.47 (m, 1H), 7.18-7.16 (m, 1H), 7.10-7.06 (m, 1H), 4.77-4.70 (m, 2H); LCMS: RT 3.60 min; m/z 221.1[M+H].sup.+.

(xxiii) 4-((3R,5R)-3,5-Dimethylmorpholine-4-carbonyl)benzoic acid I54

[0426] ##STR00085##

(a) Methyl 4-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)benzoate I53

[0427] To a solution of 4-(methoxycarbonyl)benzoic acid (285 mg, 1.6 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added DIPEA (594 mg, 4.6 mmol) and HATU (608 mg, 1.6 mmol) and the mixture stirred for 1 h. (3R,5R)-3,5-dimethylmorpholine (200 mg, 1.3 mmol) was added and the reaction stirred at room temperature for 2 days. The mixture was diluted with water (50 mL) and extracted with CH.sub.2Cl.sub.2 (3×30 mL). The combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (20% EtOAc in petroleum ether) to give the desired compound as a white solid (200 mg, 55%): .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.11-8.10 (m, 2H), 7.61-7.59 (m, 2H), 3.93 (s, 3H), 3.92-3.89 (m, 4H), 3.53-3.49 (m, 2H), 1.29-1.27 (s, 6H); LCMS: RT 2.22 min; m/z 278.1[M+H].sup.+.

(b) 4-((3R,5R)-3,5-Dimethylmorpholine-4-carbonyl)benzoic acid I54

[0428] To a solution of methyl 4-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)benzoate I53 (180 mg, 0.65 mmol) in a mixture of THF (5 mL), MeOH (0.5 mL) and water (0.05 mL) was added LiOH.H.sub.2O (100 mg, 2.34 mmol) and the resulting mixture stirred at room temperature overnight. The solvent was removed and the residue diluted with water (5 mL). The aqueous solution was acidified to pH 3 by addition of a 1M aqueous HCl solution and extracted with CH.sub.2Cl.sub.2 (3×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a white solid (150 mg, 88%): .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.12-8.10 (m, 2H), 7.60-7.58 (m, 2H), 3.93-3.89 (m, 4H), 3.53-3.49 (m, 2H), 1.29-1.28 (m, 6H); LCMS RT 1.67 min; m/z 264.1 [M+H].sup.+.

(xxiv) 2-Methoxy-4-(2-morpholino-2-oxoethyl)benzoic acid I59

[0429] ##STR00086##

(a) Methyl 2-methoxy-4-methylbenzoate I55

[0430] To a solution of 2-hydroxy-4-methylbenzoic acid (I0.0 g, 66 mmol) in acetone (500 mL) was added K.sub.2CO.sub.3 (18.0 g, 131 mmol). Me.sub.2SO.sub.4 (22 g, 178 mmol) was then added dropwise and the resulting mixture heated at reflux for 14 hours. The mixture was poured into cold water and extracted with EtOAc (70 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated and the residue was purified by column chromatography (1% EtOAc in petroleum ether) to give the desired compound as a yellow liquid (7.6 g, 64%). LCMS: RT 2.31 min; m/z 181.1 [M+1].sup.+.

(b) 2-(3-Methoxy-4-(methoxycarbonyl)phenyl)acetic acid I56

[0431] To a solution of diisopropylamine (1.3 g, 13.3 mmol) in dry THF (50 mL) at −50° C. was added n-BuLi (2.5M in hexane, 5.4 mL, 13.3 mmol) dropwise under nitrogen atmosphere. The mixture was stirred at −50° C. for 30 min and then HMPA (2.4 g, 13.3 mmol) was added, followed by methyl 2-methoxy-4-methylbenzoate I55 (2.0 g, 11.1 mmol). The resultant mixture was stirred at −78° C. for 2 h then CO.sub.2 gas was bubbled through the mixture. During the course of the addition, the reaction mixture became pale, the mixture was stirred for another 30 min then poured into a solution of 1M aqueous HCl (100 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0-1% methanol in dichloromethane) to give the desired compound (270 mg, 11%) as colorless oil. LCMS RT 1.50 min; m/z 225.1 [M+H].sup.+.

[0432] To a solution of 2-(3-methoxy-4-(methoxycarbonyl)phenyl)acetic acid I56 (135 mg, 0.6 mmol) in dichloromethane (5 mL) with a catalytic amount of DMF (1 mL) was added oxalyl chloride (99 mg, 0.8 mmol). The mixture was stirred at room temperature overnight then the reaction mixture was concentrated to give the desired product which was used for the next step without further purification.

(d) Methyl 2-methoxy-4-(2-morpholino-2-oxoethyl)benzoate I58

[0433] To a solution of methyl 4-(2-chloro-2-oxoethyl)-2-methoxybenzoate I57 (146 mg, 0.6 mmol) in dichloromethane (5 mL) was added DIPEA (155 mg, 1.2 mmol) and morpholine (63 mg, 0.7 mmol). The reaction was stirred at room temperature overnight then the reaction mixture was partitioned with water, washed with water (2×20 mL) and brine and concentrated to afford the crude product. The residue was purified by column chromatography (0-10% EtOAc in petroleum ether) to give the desired compound (67 mg, 38%) as a colorless oil. LCMS: RT 1.16 min; m/z 294.1 [M+H].sup.+.

(e) 2-Methoxy-4-(2-morpholino-2-oxoethyl)benzoic acid I59

[0434] To a solution of Methyl 2-methoxy-4-(2-morpholino-2-oxoethyl)benzoate I58 (67 mg, 0.2 mmol) in a mixture of THF (3 mL), MeOH (0.3 mL) and water (0.3 mL) was added LiOH.H.sub.2O (19 mg, 0.5 mmol). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue was dissolved in water and the pH adjusted to 2 by addition of a 1M aqueous HCl solution. The aqueous mixture was extracted with dichloromethane (3×5 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound which was used for the next step without further purification. LCMS: RT 0.41 min; m/z 280.1 [M+H].sup.+.

(xxv) 1-Oxa-7-azaspiro[3.5]nonane I60

[0435] ##STR00087##

[0436] Benzyl 1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 3.8 mmol) and 10% Pd/C (100 mg) in methanol (10 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate concentrated. The residue was used for the next step without further purification. LCMS: RT 0.30 min; m/z 128.1 [M+H].sup.+.

(xxvi) 4-(2-Methoxy-2-oxoethyl)benzoic acid I61

[0437] ##STR00088##

[0438] To a solution of 4-(carboxymethyl)benzoic acid (5.0 g, 27.7 mmol) in methanol (60 mL) was added thionyl chloride (0.1 mL, 1.3 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by chromatography (dichloromethane) to give the desired compound (3.0 g, 57%) as a white solid. LCMS: RT 2.00 min; m/z 195.1 [M+H].sup.+.

(xxvii) 4-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)benzoic acid I64

[0439] ##STR00089##

(a) 2-(4-Bromophenyl)-1-(pyrrolidin-1-yl)ethanone I62

[0440] To a solution of 2-(4-bromophenyl)acetic acid (2.0 g, 4.3 mmol) in THF (10 mL) was added HATU (3.6 g, 4.7 mmol), DIPEA (2.2 g, 8.6 mmol) and pyrrolidine (0.64 g, 4.5 mmol). The solution was stirred at room temperature overnight then poured into a 1 M aqueous solution of HCl (20 mL). The aqueous layer was extracted with dichloromethane, washed with water and brine, dried (Na.sub.2SO.sub.4), concentrated and the residue obtained purified by column chromatography (0-2% methanol in dichloromethane) to give the desired compound (2.0 g, 84%) as a white solid.

(b) Methyl 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzoate I63

[0441] A solution of 2-(4-bromophenyl)-1-(pyrrolidin-1-yl)ethanone I62 (1.15 g, 4.3 mmol), Pd(dppf)Cl.sub.2 (157 mg, 0.2 mmol) and triethylamine (953 mg, 9.4 mmol) in methanol (60 mL) under a CO (g) atmosphere was heated at reflux overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (dichloromethane) to give the desired compound (130 mg, 13%) as an orange oil. LCMS: RT 2.11 min; m/z 248.1 [M+H].sup.+.

[0442] To a solution of methyl 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzoate I63 (130 mg, 0.53 mmol) in a mixture of THF (2 mL), methanol (0.2 mL) and water (0.2 mL) was added LiOH.H.sub.2O (27 mg, 0.63 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and then acidified to pH 4 by the addition of a 1 M aqueous HCl solution. The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined organic fractions dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (67 mg, 54%) which was used for the next step without further purification. LCMS: RT 3.31 min; m/z 234.1 [M+H].sup.+.

(xxviii) 4-(2-Morpholino-2-oxoethyl)benzoic acid I67

[0443] ##STR00090##

(a) 2-(4-Bromophenyl)-1-morpholinoethanone I65

[0444] To a solution of 2-(4-bromophenyl)acetic acid (500 mg, 2.3 mmol) in dichloromethane (50 mL) was added morpholine (243 mg, 2.8 mmol), HATU (1.06 g, 2.8 mmol) and Et.sub.3N (810 mg, 8.0 mmol). The reaction was stirred at room temperature overnight. Water was added and the organic phase separated, washed with water (100 mL) and brine, dried (Na.sub.2SO.sub.4), concentrated and the residue purified by chromatography (0-50% EtOAc in petroleum ether) to give the desired compound (500 mg, 76%) as a yellow solid. LCMS: RT 2.21 min; m/z 284.0 [M+H].sup.+.

(b) Methyl 4-(2-morpholino-2-oxoethyl)benzoate I66

[0445] A solution of 2-(4-bromophenyl)-1-morpholinoethanone I65 (446 mg, 1.6 mmol), Pd(dppf)Cl.sub.2 (62 mg, 0.08 mmol) and triethylamine (377 mg, 3.7 mmol) in methanol (60 mL) under a CO (g) atmosphere was heated at reflux overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (0-10% EtOAc in petroleum ether) to give the desired compound (329 mg, 80%) as an orange oil. LCMS: RT 1.43 min; m/z 264.1 [M+H].sup.+.

[0446] To a solution of methyl 4-(2-morpholino-2-oxoethyl)benzoate I66 (329 mg, 3.8 mmol) in a mixture of THF (10 mL), methanol (1 mL) and water (1 mL) was added LiOH.H.sub.2O (319 mg, 7.6 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and the residue dissolved in water. The pH of the solution was adjusted to 4 by addition of a 1 M aqueous HCl solution and the aqueous mixture was extracted with dichloromethane (2×25 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound (118 mg, 38%) as a yellow solid. LCMS: RT 2.67 min; m/z 250.1 [M+H].sup.+.

(xxix) 1-Benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid I68

[0447] ##STR00091##

[0448] To a suspension of NaH (60% dispersion in mineral oil, 1.1 g, 25.3 mmol) in THF (16 mL) at 0° C. was added 2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.78 g, 5.6 mmol). The reaction was stirred at 0° C. for 30 min then benzyl bromide (1.9 g, 11.2 mmol) and DMF (2 mL) were added. The resulting mixture was stirred at room temperature overnight, water (2 mL) was added and the pH of the aqueous layer adjusted to 4 by addition of a 3 M aqueous HCl solution. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (10 mL×2) and the combined organic layers washed with brine (15 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow liquid (219.1 mg, 17%): LCMS: RT 1.81 min; m/z 230.1 [M+H].sup.+.

(xxx) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I72

[0449] ##STR00092##

(a) Ethyl-2-ethoxy-4-methylbenzoate I69

[0450] To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K.sub.2CO.sub.3 (22.4 g, 161.7 mmol) in dimethylsulfoxide (70 mL) at 40° C. was added and ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 h at 40° C., then diluted with CH.sub.2Cl.sub.2 (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 as a yellow liquid (10.1 g, 90%): LCMS: RT 2.70 min; m/z 209.1 [M+H].sup.+.

(b) 3-Ethoxy-4-(ethoxycarbonyl)-benzoic acid I70

[0451] To a solution of ethyl 2-ethoxy-4-methylbenzoate I69 (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, 144.2 mmol). The resulting mixture was heated at 50° C. for 48 h, then cooled and allowed to stir at room temperature for 24 h. 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 aqueous HCl solution. The mixture was extracted with CH.sub.2Cl.sub.2 (150 mL×3). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a white solid (5.0 g, 44%): LCMS: RT 0.25 min; m/z 239.0 [M−H].sup.+.

[0452] To a solution of 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I70 (2.5 g, 10.4 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.42 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 with saturated aqueous NaHCO.sub.3, and extracted with CH.sub.2Cl.sub.2 (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 in dichloromethane) to give the desired compound as a yellow oil (2.5 g, 80%): LCMS: 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 I72

[0453] To a solution of ethyl-4-(3-oxa-8-azabicyclo-[3.2.1]-octane-8-carbonyl)-2-ethoxybenzoate I71 (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 h. 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 CH.sub.2Cl.sub.2 (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 as a yellow oil (1.7 g, 79%): .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: RT 1.20 min; m/z 306.1 [M+H].sup.+.

(xxxi) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoic acid I74

[0454] ##STR00093##

(a) Methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoate I73

[0455] To a solution of 4-(methoxycarbonyl)benzoic acid (664 mg, 3.7 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (500 mg, 3.4 mmol), DIPEA (865.9 mg, 6.7 mmol), HOBt (45 mg, 0.3 mmol) and EDCl (771.4 mg, 4.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned against with aqueous NaHCO.sub.3 (20 mL×2) and the aqueous layer extracted with CH.sub.2Cl.sub.2 (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 in CH.sub.2Cl.sub.2) to give the desired compound as a white solid (786.9 mg, 85%): LCMS: 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 I74

[0456] To a solution of methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoate I73 (770 mg, 2.8 mmol) in a mixture of THF (20 mL), methanol (2 mL) and water (2 mL) was added LiOH.H.sub.2O (587.8 mg, 14.0 mmol). The resulting mixture was stirred at room temperature overnight, then the solvent removed and the residue obtained diluted with water (20 mL). The pH of the aqueous solution was adjusted to 6 by addition of a 2 M aqueous HCl solution. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (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 (460 mg, 63%) as a white solid: LCMS: RT 0.83 min; m/z 262.1 [M+H].sup.+.

(xxxii) 2-Methoxy-4-(morpholine-4-carbonyl)benzoic acid I78

[0457] ##STR00094##

(a) (4-Bromo-3-hydroxyphenyl)(morpholino)methanone I75

[0458] To a solution of 4-bromo-3-hydroxybenzoic acid (6.0 g, 27.6 mmol) in THF (300 mL) was added HATU (12.6 g, 33.2 mmol), DIPEA (4.3 g, 33.2 mmol) and morpholine (3.6 g, 44.2 mmol). The solution was stirred at room temperature overnight then poured into a solution of 1 M aqueous HCl (400 mL). The aqueous layer was extracted with dichloromethane, washed with water and brine, dried (Na.sub.2SO.sub.4), concentrated and the residue purified by column chromatography (0-5% methanol/dichloromethane) to give the desired compound (5.9 g, 75%) as a white solid.

(b) (4-Bromo-3-methoxyphenyl)(morpholino)methanone I76

[0459] To a solution of (4-bromo-3-hydroxyphenyl)(morpholino)methanone I75 (8.6 g, 30.0 mmol) in DMF (120 mL) was added iodomethane (5.1 g, 36.1 mmol) and K.sub.2CO.sub.3 (6.2 g, 45.1 mmol). The solution was stirred at room temperature overnight then poured into water (600 mL). The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with water and brine, dried (Na.sub.2SO.sub.4), concentrated and the residue was purified by column chromatography (0-2% methanol in dichloromethane) to give the desired compound (7.5 g, 83%) as a white solid.

[0460] To a solution of (4-bromo-3-methoxyphenyl)(morpholino)methanone I76 (300 mg, 1.0 mmol) in methanol (10 mL) was added triethylamine (222 mg, 2.2 mmol) and Pd(dppf)Cl.sub.2 (37 mg, 0.05 mmol). The mixture was heated at reflux under a CO atmosphere overnight. The reaction mixture was concentrated and the residue diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic layer was washed with brine, dried (Na.sub.2SO.sub.4), concentrated and the residue was purified by column chromatography (0-5% methanol in dichloromethane) to give the desired compound (200 mg, 80%) as a red oil. LCMS: RT 0.97 min, m/z 280.1 [M+H].sup.+

(d) 2-Methoxy-4-(morpholine-4-carbonyl)benzoic acid I78

[0461] To a solution of methyl 2-methoxy-4-(morpholine-4-carbonyl)benzoate I77 (200 mg, 0.7 mmol) in a mixture of methanol (0.1 mL), THF (1 mL) and water (0.1 mL) was added LiOH.H.sub.2O (33 mg, 0.8 mmol). The mixture was stirred at room temperature overnight then poured into water (20 mL) and acidified to pH 6 by addition of a 1 M aqueous HCl solution. The mixture was extracted with dichloromethane (10 mL×6) and the combined organic layers washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by column chromatography (0-10% methanol in dichloromethane) to give the desired compound (152 mg, 80%) as a white solid. LCMS: RT 0.41 min, m/z 266.1 [M+H].sup.+

(xxxiii) 6-(3-Oxa-8-aza bicyclo[3.2.1]octane-8-carbonyl)-2-ethoxynicotinic acid I82

[0462] ##STR00095##

(a) 2-Chloro-6-ethoxypyridine I79

[0463] 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 h. The solvent was removed and the residue was dissolved in water (100 mL). The aqueous layer was acidified to pH 7 with 2 M aqueous 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: RT 2.64 min; m/z 158.1 [M+H].sup.+.

(b) 6-Chloro-2-ethoxynicotinaldehyde 180

[0464] To a solution of 2-chloro-6-ethoxypyridine 179 (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 h, DMF (2.8 g, 38.1 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature and stirred for 30 min. The reaction mixture was quenched with 2M aqueous 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 (m, 2H), 1.38 (m, 3H). LCMS: RT 2.64 min; m/z 186 [M+H].sup.+; 218.1 [M+MeOH+H].sup.+.

[0465] 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 I80 (1.6 g, 8.6 mmol). The mixture was degassed three times under N.sub.2 and then three times under CO. The mixture was 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: 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 I82

[0466] To a mixture of 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxynicotinaldehyde I81 (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 h. 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 aqueous 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: RT 1.74 min; m/z 307.1 [M+H].sup.+.

(xxxiv) 2-Ethoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid I85

[0467] ##STR00096##

(a) Ethyl 4-(2-acetylhydrazinecarbonyl)-2-ethoxybenzoate I83

[0468] To a solution of 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I70 (500 mg, 2.1 mmol) in CH.sub.2Cl.sub.2 (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 CH.sub.2Cl.sub.2 (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 (0-4% v/v MeOH in CH.sub.2Cl.sub.2) to give the title compound as an off-white solid (350 mg, 57%). LCMS: 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 I84

[0469] A mixture of ethyl 4-(2-acetylhydrazinecarbonyl)-2-ethoxybenzoate I83 (330 mg, 1.1 mmol) in POCl.sub.3 (3 mL) was heated at reflux for 1.5 h. The mixture was poured into ice-water (20 mL) and the aqueous layer extracted with CH.sub.2Cl.sub.2 (20 mL×2). The combined organic layers were washed with a saturated aqueous NaHCO.sub.3 solution (40 mL×3), 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. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J=8.4 Hz, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.57 (m, 1H), 4.41-4.35 (m, 2H), 4.23-4.17 (m, 2H), 2.63 (s, 3H), 1.49 (m, 3H), 1.39 (m, 3H). LCMS: RT 5.40 min; m/z 277.0 [M+H].sup.+.

[0470] To a solution of ethyl 2-ethoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoate I84 (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 was 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: RT 4.77 min, m/z 249.0 [M+H].sup.+

(xxxv) 3-(Methylcarbamoyl)benzoic acid I87

[0471] ##STR00097##

(a) Methyl 3-(methylcarbamoyl)benzoate I86

[0472] To a solution of isophthalic acid (2.0 g, 12 mmol) in DCM (40 mL) with a catalytic amount of DMF (5 drops) at 0° C. under N.sub.2 atmosphere was added oxalyl chloride (3.81 g, 30 mmol) dropwise. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated under vacuum and the residue was dissolved in DCM (20 mL). 2 M methylamine in tetrahydrofuran solution (9 mL, 18 mmol) was then added dropwise and the reaction stirred at room temperature overnight. The reaction was quenched with MeOH (20 mL), stirred for 30 min then the solvent removed under vacuum. The residue was dissolved in DCM (20 mL) and water (10 mL) and the aqueous layer extracted with DCM (3×5 mL). The combined organic extracts were washed with saturated aqueous NaHCO.sub.3 (3×10 mL) and brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/3 v/v) to give the title compound as a white solid (155 mg, 7%): .sup.1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 8.42 (s, 1H), 8.10-8.07 (m, 2H), 7.62 (m, 1H), 3.88 (s, 3H), 2.80 (m, 3H); LCMS RT 0.91 min; m/z 194.1 [M+H].sup.+.

(b) 3-(Methylcarbamoyl)benzoic acid I87

[0473] To a solution of methyl 3-(methylcarbamoyl)benzoate I86 (150 mg, 0.78 mmol) in a mixture of THF (4 mL), MeOH (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (163 mg, 3.88 mmol). The resulting mixture was stirred at room temperature overnight. The organic solvent was removed under vacuum and the aqueous acidified to a pH of 1-2 by addition of 3M aqueous HCl solution. The precipitate which formed was collected by filtration, and dried to give the title compound as a white solid (115 mg, 82%). LCMS RT 1.74 min; m/z 180.1 [M+H].sup.+.

(xxxvi) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-chlorobenzoic acid I89

[0474] ##STR00098##

(a) 3-Oxa-8-azabicyclo[3.2.1]octan-8-yl(3-chloro-4-methylphenyl)methanone I88

[0475] 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. The mixture was diluted with water (10 mL) and partitioned with DCM (10 mL). The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts washed with saturated aqueous 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.1H NMR (400 MHz, MeOD) δ 7.50 (d, J=1.6 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.33 (m, 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 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 I89

[0476] To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(3-chloro-4-methylphenyl)methanone I88 (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 48 h. The mixture was filtered and the filtrate was extracted with ethyl acetate (3×5 mL). The pH of the aqueous phase was adjusted pH 1-2 by addition of concentrated HCl, and 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.+.

(xxxvii) 2-Ethoxy-5-methyl-4-(morpholine-4-carbonyl)benzoic acid I96

[0477] ##STR00099##

(a) Methyl 2-hydroxy-4-methylbenzoate I90

[0478] To a solution of 2-hydroxy-4-methylbenzoic acid (4.0 g, 26.2 mmol) in methanol (40 mL) was added SOCl.sub.2 (4.6 g, 39.4 mmol). The mixture was stirred at 50° C. for 1 d. The mixture was concentrated to give the crude product which was dissolved in CH.sub.2Cl.sub.2 (50 mL) and the mixture was washed with water (20 mL) and saturated aqueous NaHCO.sub.3 solution (20 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a brown oil (4.2 g, 96%): LCMS: RT 2.74 min; m/z 167.1 [M+H].sup.+.

(b) Methyl 5-bromo-2-hydroxy-4-methylbenzoate I91

[0479] To a solution of methyl 2-hydroxy-4-methylbenzoate I90 (2.2 g, 13.24 mmol) in chloroform (20 mL) was added Br.sub.2 (2.09 g, 13.24 mmol) dropwise. The mixture was stirred at 0° C. for 1 h. The reaction was quenched by addition of sodium sulfite (30 mL, 1 M aqueous solution) and the aqueous layer extracted with CH.sub.2Cl.sub.2 (30 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as yellow oil (3.1 g, 96%): LCMS: RT 3.20 min; m/z 245.0 [M+H].sup.+.

[0480] To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate I91 (3.1 g, 12.7 mmol) in DMSO (10 mL) at 40° C. was added K.sub.2CO.sub.3 (5.26 g, 38.1 mmol) and ethyl bromide (2.07 g, 14.05 mmol) dropwise. The mixture was stirred at 40° C. for 2 h. Further ethyl bromide (2.07 g, 14.05 mmol) was then added dropwise and the resulting mixture was stirred at 40° C. for 8 h. The reaction was quenched with water (20 mL) and extracted with CH.sub.2Cl.sub.2 (30 mL×3). The organic layer was washed with water (20 mL×10), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as brown oil (2.5 g, 73%): LCMS: RT 2.86 min; m/z 273.0 [M+H].sup.+.

(d) 2-Bromo-5-ethoxy-4-(methoxycarbonyl)benzoic acid I93

[0481] To a solution of methyl 5-bromo-2-ethoxy-4-methylbenzoate I92 (2.5 g, 9.19 mmol) in pyridine (5 mL) and water (15 mL) was added KMnO.sub.4 (4.3 g, 27.57 mmol). The mixture was stirred at 50° C. for 24 hours, then at room temperature for 2 days. The mixture was filtered through celite, the precipitate was resuspended in 70° C. hot water and filtered again. The aqueous solution was washed with EtOAc (30 mL), then acidified with 2M aqueous HCl solution. The mixture was extracted with CH.sub.2Cl.sub.2 (50 mL×5) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a white solid (610 mg, 23%). LCMS: RT 2.26 min; m/z 303.1 [M+H].sup.+.

(e) Methyl 5-bromo-2-ethoxy-4-(morpholine-4-carbonyl)benzoate I94

[0482] To a solution of 2-bromo-5-ethoxy-4-(methoxycarbonyl)benzoic acid I93 (600 mg, 1.98 mmol) in CH.sub.2Cl.sub.2 (10 mL) at 0° C. was added oxalyl chloride (377 mg, 2.97 mmol) and DMF (0.01 mL). The mixture was stirred at 0° C. for 3 h then morpholine (344.9 mg, 3.96 mmol) was added to the mixture, followed by triethylamine (280 mg, 2.77 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was poured into water (30 mL) and the aqueous layer extracted with CH.sub.2Cl.sub.2 (50 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated and the residue was purified by column chromatography (CH.sub.2Cl.sub.2: methanol=100:1 v/v) to give the title compound as red oil (790 mg, 95%): LCMS: RT 2.30 min; m/z 372.0 [M+H].sup.+.

(f) Methyl 2-ethoxy-5-methyl-4-(morpholine-4-carbonyl)benzoate I95

[0483] To a solution of methyl 5-bromo-2-ethoxy-4-(morpholine-4-carbonyl)benzoate I94 (360 mg, 0.97 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (268.1 mg, 1.94 mmol), methyl boronic acid (116 mg, 1.94 mmol) and Pd(PPh.sub.3).sub.4 (56 mg, 0.05 mmol). The resulting mixture was heated at 100° C. under N.sub.2 for 1 day. Water (20 mL) was added to the mixture, and the aqueous extracted with CH.sub.2Cl.sub.2 (20 mL×3). The organic layer was washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (CH.sub.2Cl.sub.2: methanol=100:1 v/v) to give the title compound as yellow oil (100 mg, purity about 80%). LCMS: RT 2.08 min; m/z 308.1[M+H].sup.+.

(g) 2-Ethoxy-5-methyl-4-(morpholine-4-carbonyl)benzoic acid I96

[0484] To a solution of methyl 2-ethoxy-5-methyl-4-(morpholine-4-carbonyl)benzoate I95 (100 mg, 0.32 mmol) in a mixture of THF (10 mL), methanol (1 mL) and water (0.1 mL) was added LiOH.H.sub.2O (41 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated and the residue diluted with water (20 mL). The pH of the aqueous mixture was adjusted to 6 by addition of 1 M aqueous HCl solution and the aqueous layer extracted with CH.sub.2Cl.sub.2 (20 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated and the crude product purified by preparative TLC (CH.sub.2Cl.sub.2: methanol=10:1 v/v) to give the title compound as a white solid (20 mg, 45%). LCMS: RT 0.85 min; m/z 294.1 [M+H].sup.+.

(xxxviii) 6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinic acid I102

[0485] ##STR00100##

(a) Ethyl 4-ethoxypicolinate I97

[0486] A solution of 4-chloropicolinonitrile (5.5 g, 39.7 mmol) in a saturated solution of HCl in EtOAc (80 mL) was stirred at 80° C. for 2 days. The solvent was removed under reduced pressure. Saturated aqueous NaHCO.sub.3 solution (200 mL) was added and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×200 mL). The combined 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: RT 1.35 min; m/z 196.1[M+H].sup.+.

(b) Ethyl 5-bromo-4-ethoxypicolinate 198

[0487] To a solution of ethyl 4-ethoxypicolinate 197 (1.6 g, 8.2 mmol) in concentrated H.sub.2SO.sub.4 (80 mL) was added N-bromosuccinimide (2.7 g, 14.8 mmol). The reaction was stirred at room temperature overnight and then quenched by addition of a saturated aqueous NaHCO.sub.3 solution (150 mL). The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×130 mL) and the combined organic layers were 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: RT 2.59 min; m/z 274.0 [M+H].sup.+ for .sup.79Br, 276.0 [M+H].sup.+ for .sup.81Br.

[0488] To a solution of ethyl 5-bromo-4-ethoxypicolinate I98 (1.6 g, 6.0 mmol) in a mixture of THF (20 mL), CH.sub.3OH (2 mL) and H.sub.2O (0.2 mL) was added LiOH.H.sub.2O (1.0 g, 24.0 mmol). The reaction was stirred at room temperature for 2 d. The solvent was removed under reduced pressure and the residue was dissolved in water (10 mL) and acidified to pH 3 with 1M aqueous HCl. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (4×50 mL) and the combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a yellow solid (800 mg, 54%). LCMS: RT 0.86 min; m/z 246.0 [M+H].sup.+ for .sup.79Br, 248.0 [M+H].sup.+ for .sup.81Br.

(d) 3-Oxa-8-azabicyclo[3.2.1]octan-8-yl(5-bromo-4-ethoxypyridin-2yl)methanone I100

[0489] To a solution of 5-bromo-4-ethoxypicolinic acid I99 (300 mg, 1.2 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane (153 mg, 1.0 mmol) hydrochloride salt in CH.sub.2Cl.sub.2 (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. The reaction was quenched by addition of saturated aqueous NaHCO.sub.3 solution (50 mL) and the mixture was extracted with CH.sub.2Cl.sub.2 (3×50 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated and the residue was purified by silica gel chromatography (20% EtOAc in petroleum ether v/v) to give the title compound as a yellow solid (262 mg, 75%). LCMS: RT 5.56 min; m/z 340.9 [M+H].sup.+ for .sup.79Br, 342.9 [M+H].sup.+ for .sup.81Br.

(e) Methyl 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinate I101

[0490] To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(5-bromo-4-ethoxypyridin-2-yl)methanone I100 (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 stirred under a CO atmosphere and heated at reflux for 2 days. The solvent was removed under reduced pressure and the residue was taken up in water (100 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL). The combined organic layers were dried over (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel chromatography (33% EtOAc in petroleum ether v/v) to give the title compound as a brown solid (400 mg, 66%). LCMS: 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 I102

[0491] To a solution of methyl 6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethoxynicotinate I101 (350 mg, 1.1 mmol) in CH.sub.3OH (20 mL) was added NaOH (2.2 mL of a 1 M aqueous solution) and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in water (15 mL). The aqueous was acidified to pH 4 by addition of 1M aqueous HCl. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (4×60 mL) and the combined extracts were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound as a yellow solid I102 (320 mg, 95%). LCMS: RT 0.61 min; m/z 307.1 [M+H].sup.+.

(xxxix) 2-Ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoic acid I109

[0492] ##STR00101##

(a) Methyl 3-hydroxy-2-methylbenzoate I103

[0493] 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 solution, dried (Na.sub.2SO.sub.4) and concentrated to give the title product (10.7 g, 98%) as white solid. LCMS: RT 1.98 min; m/z 167.1 [M+H].sup.+.

(b) Methyl 4-bromo-3-hydroxy-2-methylbenzoate I104

[0494] 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 h. A solution of methyl 3-hydroxy-2-methylbenzoate I103 (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 v/v) to give the title product (2.2 g, 33%) as a white solid. LCMS: RT 2.46 min; m/z 245.0 [M+H].sup.+ for .sup.79Br, 247.0 [M+H].sup.+ for .sup.81Br. .sup.1H NMR (400 MHz, d.sub.6-DMSO) 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).

[0495] To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate I104 (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 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 product (2.2 g, 95%) as a yellow solid. LCMS: RT 3.08 min; m/z 273.0 [M+H].sup.+ for .sup.79Br, 275.0 [M+H].sup.+ for .sup.81Br.

(d) 4-Bromo-3-ethoxy-2-methylbenzoic acid I106

[0496] To a solution of methyl 4-bromo-3-ethoxy-2-methylbenzoate I105 (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 and then the solvent was removed under reduced pressure. The residue obtained was dissolved in water (20 mL) and acidified with 1 M aqueous 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 product (2.4 g, 92%) as a white solid. LCMS: RT 2.75 min; m/z 281.0 [M+Na].sup.+ for .sup.79Br, 283.0 [M+Na].sup.+ for .sup.81Br.

(e) (4-Bromo-3-ethoxy-2-methylphenyl)(morpholino)methanone I107

[0497] To a solution of 4-bromo-3-ethoxy-2-methylbenzoic acid I106 (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 h 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 was purified by silica gel chromatography (1% MeOH in DCM v/v) to give the title compound (720 mg, 24%) as a white solid which was used without further purification. LCMS: RT 2.48 min; m/z 328.1 [M+H].sup.+ for .sup.79Br, 330.1 [M+H].sup.+[M+H].sup.+ for .sup.81Br.

(f) Methyl 2-ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoate I108

[0498] To a solution of (4-bromo-3-ethoxy-2-methylphenyl)(morpholino)methanone I107 (720 mg, 2.2 mmol) in MeOH (10 mL) was added PdCl.sub.2(dppf) (81 mg, 0.11 mmol) and triethylamine (489 mg, 4.8 mmol). The reaction was stirred under a CO atmosphere and heated at reflux overnight. The mixture was concentrated and the residue was 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 v/v) to give the title product (670 mg, 80% purity by HPLC) as yellow oil. LCMS: RT 2.02 min; m/z 308.2 [M+H].sup.+.

(g) 2-Ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoic acid I109

[0499] To a solution of methyl 2-ethoxy-3-methyl-4-(morpholine-4-carbonyl)benzoate I108 (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 and then concentrated under reduced pressure. The residue was dissolved in water (20 mL) then acidified with 1 M aqueous 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 product (310 mg, 48%) as brown oil. LCMS: RT 0.89 min; m/z 294.1 [M+H].sup.+.

(xl) 2-Fluoro-4-(3-oxa-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoic acid I111

[0500] ##STR00102##

(a) (3-Fluoro-4-methyl-phenyl)-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone I110

[0501] 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 salt (1.8 g, 11.8 mmol) in CH.sub.2Cl.sub.2 (10 mL) were added DIPEA (6.3 mL, 35.4 mmol), EDCl (2.72 g, 14.2 mmol) and HOBt (162.1 mg, 1.2 mmol). The mixture was stirred at room temperature overnight. A saturated aqueous NaHCO.sub.3 solution (50 mL) was added and the mixture was extracted with CH.sub.2Cl.sub.2 (3×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in petroleum ether v/v) to give the title compound as a yellow solid (1.7 g, 58%). LCMS: 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 I111

[0502] To a solution of (3-fluoro-4-methyl-phenyl)-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone I110 (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 stirred at room temperature for 2 days. The resulting suspension was filtered through Celite and the filtrate washed with CH.sub.2Cl.sub.2 (3×50 mL). The remaining aqueous layer was acidified to pH 3 by addition of 2 M aqueous HCl, and extracted with CH.sub.2Cl.sub.2 (4×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the title compound I111 as an off-white solid (500 mg, 56%). LCMS: RT 2.89 min; m/z 280.1 [M+H].sup.+.

(xli) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I115

[0503] ##STR00103##

(a) Methyl 2-methoxy-4-methylbenzoate I112

[0504] 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 min. The resulting mixture was stirred at room temperature overnight, then diluted with CH.sub.2Cl.sub.2 (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 title compound as a yellow liquid (11.0 g, 93%).

(b) 3-Methoxy-4-(methoxycarbonyl)benzoic acid I113

[0505] To a solution of methyl 2-methoxy-4-methylbenzoate I112 (10.0 g, 48.05 mmol) 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 h, then cooled and allowed to stir at room temperature for 24 h. 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 a 2 M aqueous HCl solution. The mixture was extracted with CH.sub.2Cl.sub.2 (150 mL×3). 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, 61%). LCMS: RT 1.24 min; m/z 211.0 [M+H].sup.+.

[0506] To a solution of 3-methoxy-4-(methoxycarbonyl)benzoic acid I113 (500 mg, 2.10 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (377 mg, 2.52 mmol), HOBt (426 mg, 3.15 mmol), triethylamine (850 mg, 8.4 mmol) and EDCl (602 mg, 3.15 mmol). The resulting mixture was stirred at room temperature overnight. Saturated aqueous NaHCO.sub.3 solution was added. The organic layer was separated and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (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 v/v) to give the title compound as a white solid (800 mg, 59%).

(d) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-methoxybenzoic acid I115

[0507] To a solution of methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-methoxybenzoate I114 (0.9 g, 2.9 mmol) in a mixture of THF (4 mL) and methanol (4 mL) was added aqueous NaOH solution (2 M, 4 mL). The resulting mixture was stirred at room temperature for 14 h. The solvent was removed, and the residue 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 CH.sub.2Cl.sub.2 (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, 83%): LCMS: RT 0.55 min; m/z 292.1 [M+H].sup.+.

(xlii) (R)-tert-butyl(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117

[0508] ##STR00104##

(a) (R)-tert-Butyl(2,3-dihydro-1H-inden-2-yl)(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)carbamate I116

[0509] A mixture of 2,3-dihydro-1H-inden-2-amine (5.0 g, 24.61 mmol) and (R)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.91 g, 36.91 mmol) in EtOH (100 mL) was heated at reflux overnight. After cooling to room temperature, triethyamine (9.94 g, 98.44 mmol) and (Boc).sub.2O (10.74 g, 49.22 mmol) were added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column (EtOAc/Pet. Ether=1/4, v/v) to give the title compound (5.4 g, 50%) as an oil.

(b) (R)-tert-butyl(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117

[0510] A mixture of (R)-tert-butyl(2,3-dihydro-1H-inden-2-yl)(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)carbamate I116 (4.4 g, 10.08 mmol) and NH.sub.2NH.sub.2.H.sub.2O (80%, 1.89 g, 30.24 mmol) in EtOH (100 mL) was heated at reflux for 4 h. After cooling to room temperature, the mixture was filtered and the filtercake was washed with EtOH (50 mL). The filtrate was concentrated and then dissolved in CH.sub.2Cl.sub.2, washed with saturated aqueous solution NaHCO.sub.3 (80 mL×3) and brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (3.1 g, crude) as a yellow oil, which was used for the next step without further purification. LCMS: RT 2.17 min; m/z 307.2 [M+H].sup.+.

(xliii) 4-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoic acid I121

[0511] ##STR00105##

(a) Ethyl 2-ethoxy-4-methylbenzoate I118

[0512] 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 min. The reaction was stirred at 40° C. for 2 h. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40° C. for 8 h. DCM (200 mL) was added and the mixture was filtered. The organic layer was separated washed with water (150 mL×4), dried (Na.sub.2SO.sub.4) and concentrated to give the title product (24.1 g, 88%) as clear oil. LCMS: RT 2.77 min; m/z 209.1[M+H].sup.+.

(b) 2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid I119

[0513] To a solution of diisopropylamine (1.46 g, 14.4 mmol) in dry THF (20 ml) at −30° C. was added n-BuLi (2.4 M in hexane, 5.8 mL, 14.4 mmol) slowly under nitrogen atmosphere. The mixture was stirred at −30° C. for 30 min then cooled to −78° C. and HMPA (4.0 g) added. A solution of ethyl 2-ethoxy-4-methylbenzoate I118 (2.0 g, 9.6 mmol) in dry THF (5 mL) was then added dropwise and the resultant mixture stirred at −78° C. for 2 h. CO.sub.2 (g) was then bubbled through the mixture for a further 30 min until the colour disappeared. The reaction was allowed to warm to 10° C. then was diluted with water (20 mL) and extracted with ether (20 mL×2). The aqueous layer was acidified to pH 2 by addition of 10% aqueous H.sub.2SO.sub.4 and the mixture extracted with DCM (20 mL×2). 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: RT 2.36 min; m/z 253.1[M+H].sup.+.

[0514] A mixture of 2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid I119 (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 DIEA (710 mg, 5.5 mmol) in DCM (10 mL) was stirred at room temperature for overnight. Water (20 mL) was added and the reaction mixture extracted with DCM (10 mL×3), 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 yellow oil. LCMS: 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 I121

[0515] To a solution of ethyl 4-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoate I120 (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 removed under vacuum. The residue obtained was 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 (10 mL×3) and the organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the title product (540 mg, 85%) as yellow solid. LCMS: RT 1.20 min; m/z 320.2 [M+H].sup.+.

(xliv) (S)-tert-butyl(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I123

[0516] ##STR00106##

(a) (S)-tert-butyl(2,3-dihydro-1H-inden-2-yl)(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)carbamate I122

[0517] A mixture of 2,3-dihydro-1H-inden-2-amine (5.0 g, 24.61 mmol) and (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.91 g, 36.91 mmol) in EtOH (100 mL) was heated at reflux overnight. After cooling to room temperature, triethylamine (9.94 g, 98.44 mmol) and (Boc).sub.2O (10.74 g, 49.22 mmol) were added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel column chromatography (EtOAc/petroleum ether=1/4 v/v) to give the title compound (5.4 g, 50%) as an oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88-7.82 (m, 4H), 7.16-7.09 (m, 4H), 6.28 (d, J=4.4 Hz, 1H), 4.51 (br s, 1H), 4.05-3.97 (m, 1H), 3.61-3.38 (m, 3H), 3.32-3.09 (m, 5H), 1.31 (s, 9H).

(b) (S)-tert-butyl(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I123

[0518] A mixture of (S)-tert-butyl(2,3-dihydro-1H-inden-2-yl)(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)carbamate I122 (5.0 g, 11.46 mmol) and NH.sub.2NH.sub.2.H.sub.2O (80%, 2.2 g, 34.37 mmol) in EtOH (100 mL) was heated at reflux for 4 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EtOH (50 mL). The filtrate was concentrated and then dissolved in CH.sub.2Cl.sub.2, washed with saturated aqueous solution NaHCO.sub.3 (80 mL×3), brine (20 mL×2), dried (Na.sub.2SO.sub.4) and concentrated to give the title compound (3.4 g, crude) as a yellow oil, which was used for the next step without further purification. LCMS: RT 1.99 min; m/z 307.2 [M+H].sup.+.

Example 1: 4-Chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide (1)

[0519] ##STR00107##

[0520] A solution of 4-chlorobenzoic acid (0.057 g, 0.36 mmol) in N,N-dimethylformamide (2 mL) containing N,N-diisopropylethylamine (0.230 mL, 1.31 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.095 g, 0.49 mmol) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 0.095 g, 0.49 mmol) was stirred at room temperature for 20 minutes. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.068 g, 0.33 mmol) in DCM (1 mL) was added and stirred at room temperature for 20 hours under a nitrogen atmosphere. Water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with water (2×20 mL), brine, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting residue was suspended in diethyl ether, sonicated for 10 seconds, filtered and dried to give the desired compound as cream coloured solid (0.090 g, 79%). .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 7.81 (d, J=8.55 Hz, 2H), 7.47 (d, J=8.55 Hz, 2H), 7.20-7.10 (m, 4H), 3.98-3.90 (m, 1H), 3.68-3.59 (m, 1H), 3.48 (d, J=5.37 Hz, 2H), 3.20 (ddd, J=15.7, 7.15, 4.0 Hz, 2H), 2.84-2.76 (m, 3H), 2.73-2.66 (m, 1H). LCMS-D: RT 4.85 min; m/z 345 [M+H].sup.+.

Example 2: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide (2)

[0521] ##STR00108##

(a) tert-Butyl (2-hydroxy-3-(4-(morpholine-4-carbonyl)benzamido)propyl)carbamate (A1)

[0522] To a solution of 4-(4-morphlinylcarbonyl)benzoic acid I27 (400 mg, 1.70 mmol) in DCM (15 mL) was added N,N-diisopropylethylamine (1.19 mL, 6.80 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (489 mg, 2.55 mmol) and 1-hydroxybenzotriazole hydrate (390 mg, 2.55 mmol) and the mixture was stirred at room temperature for 20 minutes. The solution was cooled to 0° C. and N-Boc-1,3-diamino-2-propanol (356 mg, 1.87 mmol) was added. After stirring at 0° C. for 10 minutes, the mixture was stirred at room temperature for 20 hours whilst under a nitrogen atmosphere. Water (15 mL) and DCM (20 mL) were added. The aqueous phase was extracted with DCM (2×30 mL) and the combined organic extracts were washed with brine (60 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to give the desired compound (450 mg, 65%). LCMS-D: RT 4.60 min; m/z 408 [M+H].sup.+.

(b) N-(3-Amino-2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride (A2)

[0523] A solution of tert-butyl (2-hydroxy-3-(4-(morpholine-4-carbonyl)benzamido)propyl)carbamate A1 (450 mg, 1.10 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (1.38 mL, 5.52 mmol) and 1,4-dioxane (5 mL) was heated at 60° C. for 2 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure to give the desired compound (271 mg, 72%).

[0524] N-(3-amino-2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide hydrochloride A2 (about 200 mg) was dissolved in methanol (6 mL) and applied to an SCX cartridge (5 g). The cartridge was washed with methanol (40 mL) and eluted with 2 M ammonia in methanol (20 mL). The ammonia wash was concentrated to give the free base (163 mg, 0.53 mmol). The material was dissolved in 1,2-dichloroethane (10 mL) and THF (5 mL) and diisopropylethyl amine (92.4 μL, 0.53 mmol) was added. To the resulting solution, was added 2-indanone (76.5 mg, 0.18 mmol), sodium triacetoxyborohydride (592 g, 2.65 mmol, 95%) and glacial acetic acid (61 μL, 1.06 mmol). The mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The solution was made basic using 10 M aqueous NaOH, then water (15 mL) and ethyl acetate (15 mL) were added. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with water (20 mL), brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The material was purified by column chromatography (SiO.sub.2, 0-20% methanol/DCM) to give the desired compound (77 mg, 34%); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.83 (d, J=8.4 Hz, 2H), 7.64 (m, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.17 (m, 4H), 3.92 (br m, 3H), 3.77 (m, 3H), 3.66 (m, 4H), 3.45-3.37 (m, 3H), 3.19 (dd, J=15.7, 7.2 Hz, 2H), 2.96-2.84 (m, 3H), 2.73 (dd, J=12.2, 7.6 Hz, 1H). LCMS-D: RT 4.15 min; m/z 424.3 [M+H].sup.+.

Example 3: (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxamide (3)

[0525] ##STR00109##

[0526] A solution of 4-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-thiazole-5-carboxylic acid (101 mg, 0.352 mmol) in DCM (4.0 mL) containing N,N-diisopropylethylamine (0.184 mL, 1.06 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole hydrate (70 mg, 0.46 mmol) was stirred for 20 minutes. 1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I4 (65 mg, 0.32 mmol) in DCM (1 mL) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (15 mL) and DCM (15 mL) were added. The aqueous phase was extracted with DCM (2×15 mL) and the combined organic extracts were washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in methanol and applied to an SCX cartridge (1 g). The cartridge was washed with methanol (10 mL) and eluted with 2M ammonia in ethanol (10 mL). The ammonia solution was concentrated under vacuum and the residue purified by preparative HPLC to afford the desired compound (67 mg, 40%); .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 8.51 (br s, 1H), 8.12 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.26-7.16 (m, 4H), 4.11 (m, 2H), 3.57-3.47 (m, 2H), 3.44-3.35 (m, 2H), 3.25-3.11 (m, 3H), 3.10-2.99 (m, 1H), 2.69 (s, 3H). LCMS Method-D: RT 5.42 min; m/z 476.19 [M+H].sup.+.

Example 4

General Procedure A

[0527] ##STR00110##

[0528] A solution of appropriate carboxylic acid (0.220 mmol-0.590 mmol, 1 equiv.) in DCM (2-10 mL) containing N,N-diisopropylethylamine (3 equiv.), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.3 equiv.) and 1-hydroxybenzotriazole hydrate (1.3 equiv.) was stirred for 20 minutes. (S)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I4 (0.9 equiv.) in DCM (1 mL) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (15 mL) and DCM (15 mL) were added. The aqueous phase was extracted with DCM (2×15 mL) and the combined organic extracts were washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in methanol and applied to an SCX cartridge (1 g). The cartridge was washed with methanol (10 mL) and eluted with 2 M ammonia in ethanol (10 mL). The ammonia solution was concentrated under vacuum and the residue purified by preparative-HPLC (Waters) to afford the desired compound.

General Procedure B

[0529] ##STR00111##

[0530] A solution of appropriate carboxylic acid (0.209-0.889 mmol, 1 equiv.) in DCM (2-10 mL) containing N,N-diisopropylethylamine (3 equiv.), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.3 equiv.) and 1-hydroxybenzotriazole hydrate (1.3 equiv.) was stirred for 20 minutes. (S)-1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I6 (0.9 equiv.) in DCM (1 mL) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in methanol and applied to an SCX cartridge (1 g). The cartridge was washed with methanol (10 mL) and eluted with 2 M ammonia in ethanol (10 mL). The ammonia solution was concentrated under vacuum and the residue purified by preparative-HPLC (Waters) to afford the desired compound.

TABLE-US-00003 Starting Material Structure LCMS Method 4 [00112] embedded image 52.5 mg, 0.279 mmol [00113] LCMS Method-D: RT 4.77 min; m/z 377.3 [M + H].sup.+. A Reaction solvent: DCM (2.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-1-phenyl- 1H-pyrazole-4-carboxamide 5 [00114] 101 mg, 0.487 mmol [00115] LCMS Method-D: RT 4.40 min; m/z 396.30 [M + H].sup.+. A Reaction solvent: DCM (4.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-5-(1,3- dimethyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide 6 [00116] embedded image 103 mg, 0.470 mmol [00117] LCMS Method-D: RT 4.98 min; m/z 408.34 [M + H].sup.+. A Reaction solvent: DCM (4.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-5-(4- methoxyphenyl)isoxazole-3-carboxamide 7 [00118] 134 mg, 0.611 mmol [00119] LCMS Method-D: RT 4.95 min; m/z 407.34 [M + H].sup.+. A Reaction solvent: DCM (5.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-3-(4- methoxyphenyl)isoxazole-5-carboxamide 8 [00120] embedded image 52.0 mg, 0.222 mmol [00121] LCMS Method-D: RT 4.68 min; m/z 423.33 [M + H].sup.+. A Reaction solvent: DCM (2.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-((4- methyl-1,2,5-oxadiazol-3-yl)methoxy)benzamide 9 [00122] 105 mg, 0.509 mmol [00123] LCMS Method-D: RT 4.90 min; m/z 395.4 [M + H].sup.+. A Reaction solvent: DCM (4.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-1-(4- fluorophenyl)-1H-pyrazole-4-carboxamide 10 [00124] embedded image 51.0 mg, 0.229 mmol [00125] LCMS Method-D: RT 5.12 min; m/z 411.3 [M + H].sup.+. A Reaction solvent: DCM (2.0 mL) (R)-1-(3-Chlorophenyl)-N-(3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-1H-pyrazole-4-carboxamide 11 [00126] 100 mg, 0.480 mmol [00127] LCMS Method-D: RT 4.03 min; m/z 397.2 [M + H].sup.+. A Reaction solvent: DCM (4.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-6-morpholinonicotinamide 12 [00128] embedded image 58.0 mg, 0.284 mmol [00129] LCMS Method-D: RT 4.33 min; m/z 393.3 [M + H].sup.+. A Reaction solvent: DCM (4.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(5- methyl-1,3,4-oxadiazol-2-yl)benzamide 13 [00130] 100 mg, 0.458 mmol [00131] LCMS Method-D: RT 4.55 min; m/z 407.3 [M + H].sup.+. A Reaction solvent: DCM (4.0 mL) (R)-N-(3-((2,3-Dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-((1- methyl-1H-pyrazol-4-yl)oxy)benzamide 14 [00132] embedded image 108 mg, 0.690 mmol [00133] LCMS Method-D: RT 4.83 min; m/z 345.3 [M + H].sup.+. B Reaction solvent: DCM (10 mL) (S)-4-Chloro-N-(3-((2,3-dihydro-1H- inden-2-yl)amino)-2-hydroxypropyl)benzamide 15 [00134] 162 mg, 0.689 mmol [00135] LCMS Method-D: RT 4.17 min; m/z 424.3 [M + H].sup.+. B Reaction solvent: DCM (7 mL) (S)-N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)- 2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide 16 [00136] embedded image 185 mg, 0.889 mmol [00137] LCMS Method-D: RT 4.13 min; m/z 397.4 [M + H].sup.+. B Reaction solvent: DCM (7.0 mL) (S)-N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-6-morpholinonicotinamide 17 [00138] 42.6 mg, 0.209 mmol [00139] LCMS Method-D: RT 4.33 min; m/z 393.3 [M + H].sup.+. B Reaction solvent: DCM (5.0 mL) (S)-N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)- 2-hydroxypropyl)-4-(5-methyl-1,3,4- oxadiazol-2-yl)benzamide 18 [00140] embedded image 77.0 mg, 0.353 mmol [00141] LCMS Method-D: RT 4.57 min; m/z 407.4 [M + H].sup.+. B Reaction solvent: DCM (7.0 mL) (S)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-4-((1-methyl-1H- pyrazol-4-yl)oxy)benzamide

Example 5: 4-((3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid (19)

[0531] ##STR00142##

(a) Methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoate (A3)

[0532] A solution of 4-(methoxycarbonyl)benzoic acid (1.95 g, 10.8 mmol) in DCM (15 mL) containing N,N-diisopropylethylamine (11.5 mL, 66.2 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.50 g, 28.7 mmol) and 1-hydroxybenzotriazole hydrate (4.39 g, 28.7 mmol) was stirred for 20 minutes. 1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (I2) (2.10 g, 10.2 mmol) in DCM (1 mL) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in methanol (7 mL) and loaded on to an SCX cartridge. The cartridge was washed with methanol (30 mL) and eluted with 2 M ammonia in ethanol (20 mL). The ammonia solution was concentrated under vacuum and the residue was purified by column chromatography (SiO.sub.2, 0-30% ethyl methanol/DCM) to give desired compound (644 mg, 16%): LCMS Method-D: RT 4.57 min; m/z 369.3 [M+H].sup.+.

(b) 4-((3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid (19)

[0533] To a solution of methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl) benzoate A3 (481 mg, 1.31 mmol) in THF (15 mL) and water (6 mL) was added LiOH (47 mg, 1.96 mmol) in water (1 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and dissolved in water (2 mL). The material was applied to a desalting column (10 g, Phenomenex, Strata-XL Polymeric reversed phase). The column was washed with water (20 mL) and eluted with methanol (20 mL). The methanol eluate was concentrated to give the desired compound (395 mg, 85%). LCMS Method-D: RT 4.17 min; m/z 355.4 [M+H].sup.+.

Example 6: 4-(Azetidine-1-carbonyl)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide (20)

[0534] ##STR00143##

[0535] A solution of 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid 19 (95 mg, 0.27 mmol) in DCM (7 mL) containing N,N-diisopropylethylamine (201 μL, 1.15 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole hydrate (54 mg, 0.35 mmol) was stirred for 20 minutes. Azetidine (18 μL, 0.27 mmol) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired compound (32 mg, 30%); .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 8.43 (br s, 1H), 7.95 (m, 2H), 7.73 (m, 2H), 7.29-7.19 (m, 4H), 4.38 (t, J=7.7 Hz, 2H), 4.24-4.08 (m, 4H), 3.61-3.50 (m, 2H), 3.47-3.38 (m, 2H), 3.29-3.13 (m, partially obscured by solvent), 3.10-3.03 (m, 1H). LCMS Method-D: RT 4.22 min; m/z 394.4 [M+H].sup.+.

Example 7: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(pyrrolidine-1-carbonyl)benzamide (21)

[0536] ##STR00144##

[0537] A solution of 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid I9 (102 mg, 0.29 mmol) in DCM (7 mL) containing N,N-diisopropylethylamine (201 μL, 1.15 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg, 0.37 mmol) and 1-hydroxybenzotriazole hydrate (57 mg, 0.37 mmol) was stirred for 20 minutes. Pyrrolidine (24 μL, 0.29 mmol) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The material was dissolved in DCM (7 mL) containing N,N-diisopropylethylamine (201 μL, 1.15 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg, 0.37 mmol) and 1-hydroxybenzotriazole hydrate (57 mg, 0.37 mmol). The mixture was stirred for 20 minutes. Pyrrolidine (119 μL, 1.44 mmol) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired compound (7 mg, 6%); .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 8.54 (br s, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.29-7.19 (m, 4H), 4.11 (m, 2H), 3.64 (m, 2H), 3.53 (m, 2H), 3.47-3.38 (m, 4H), 3.28-3.00 (m, 4H), 2.09-1.89 (m, 4H). LCMS Method-D: RT 4.37 min; m/z 408.4 [M+H].sup.+.

Example 8: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(piperidine-1-carbonyl)benzamide (22)

[0538] ##STR00145##

[0539] A solution of 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid 19 (105 mg, 0.296 mmol) in DCM (7 mL) containing N,N-diisopropylethylamine (206 μL, 1.19 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (74 mg, 0.39 mmol) and 1-hydroxybenzotriazole hydrate (59 mg, 0.39 mmol) was stirred for 20 minutes. Piperidine (29 μL, 0.30 mmol) was added and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired compound (76 mg, 61%). .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 8.39 (br s, 1H), 7.95 (m, 2H), 7.51 (m, 2H), 7.29-7.19 (m, 4H), 4.14 (m, 2H), 3.74 (m, 2H), 3.62-3.51 (m, 2H), 3.49-3.42 (m, 2H), 3.40-3.37 (m, 2H), 3.29-3.13 (m, 3H), 3.10-3.03 (m, 1H), 1.72 (br m, 4H), 1.56 (br m, 2H); LCMS Method-D: RT 4.58 min; m/z 422.3 [M+H].sup.+.

Example 9: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-[1,1′-biphenyl]-4-carboxamide (24)

[0540] ##STR00146##

[0541] A solution of 4-biphenylcarboxylic acid (0.074 g, 0.37 mmol) in DCM (4 mL) containing N,N-diisopropylethylamine (0.132 mL, 1.01 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.098 g, 0.51 mmol) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 0.098 g, 0.509 mmol) was stirred at room temperature for 20 minutes. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.070 g, 0.339 mmol) in DCM (2 mL) was added. The mixture was then stirred at room temperature for 20 hours whilst under a nitrogen atmosphere. Water was added and the resulting mixture formed a white precipitate which was filtered and dried. The white solid was washed with diethyl ether and collected by filtration to give the desired compound as an amorphous white solid (0.105 g, 80%). LCMS Method-D: RT 5.28 min; m/z 387.4 [M+H].sup.+.

Example 10: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)[1,1′-biphenyl]-3-carboxamide (25)

[0542] ##STR00147##

[0543] A solution of 3-biphenylcarboxylic acid (0.074 g, 0.37 mmol) in DCM (4 mL) containing N,N-diisopropylethylamine (0.132 mL, 1.01 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.098 g, 0.51 mmol) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 0.098 g, 0.51 mmol) was stirred at room temperature for 20 minutes. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.070 g, 0.34 mmol) in DCM (2 mL) was added. The mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Water and DCM were added. The aqueous phase was extracted with DCM (2×15 mL) and the combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-10% methanol in DCM) to give the desired product as an amorphous white solid (0.026 g, 19%). LCMS Method-D: RT 5.28 min; m/z 387.4 [M+H].sup.+.

Example 11: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-[1,1′-biphenyl]-2-carboxamide (26)

[0544] ##STR00148##

[0545] A solution of 2-biphenylcarboxylic acid (0.074 g, 0.373 mmol) in DCM (4 mL) containing N,N-diisopropylethylamine (0.132 mL, 1.01 mmol, 3 equiv.), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.098 g, 0.509 mmol, 1.5 equiv) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 0.098 g, 0.509 mmol) was stirred at room temperature for 20 minutes. After this time, a solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.070 g, 0.339 mmol) in DCM (2 mL) was added. The mixture was then stirred at room temperature for 20 hours whilst under a nitrogen atmosphere. Water and DCM were added. The aqueous phase was extracted with DCM (2×15 mL) and the combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product was purified by column chromatography (12 g SiO.sub.2 Cartridge, 0-10% methanol in DCM) to give the desired product as an amorphous solid (0.060, 45%). LCMS Method-D: RT 4.92 min; m/z 387.3 [M+H].sup.+.

Example 12: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-fluoro-4-(morpholine-4-carbonyl)benzamide (27)

[0546] ##STR00149##

(a) (4-Bromo-3-fluorophenyl)(morpholino)methanone (A6)

[0547] 4-Bromo-3-fluorobenzoic acid (2.19 g, 10.0 mmol), morpholine (2.59 mL, 30.0 mmol), DMAP (122 mg, 10 mol %) and EDCl.HCl (2.88 g, 15.0 mmol) in DCM (100 mL), were stirred at room temperature. After 17 hours, the mixture was added to 2% w/v aqueous sodium hydroxide (100 mL) and the separated aqueous phase was extracted with DCM (2×50 mL). The combined organic extracts were washed with 1 M HCl (75 mL), brine (50 mL), dried over sodium sulfate and concentrated. Chromatography (40 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) gave the desired compound as a colourless syrup (2.63 g, 91%): .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 (A7)

[0548] (4-Bromo-3-fluorophenyl)(morpholino)methanone A6 (2.62 g, 9.09 mmol), dry methanol (20 mL), PdCl.sub.2(dppf).DCM (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 concentrated and chromatography (40 g silica cartridge, 20-60% ethyl acetate/petroleum benzine 40-60° C.) gave the desired compound as a pale orange solid (2.25 g, 93%). .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.+.

[0549] Methyl 2-fluoro-4-(morpholine-4-carbonyl)benzoate A7 (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. The mixture was stirred vigorously at room temperature. After two hours, the volatile solvents were removed in vacuo. The aqueous residue was cooled to 4° C. and 3.0 aqueous HCl (5 mL) cooled to 4° C. was added. The resulting slurry was diluted with water (5 mL) and filtered. The collected solids were washed with water (5 mL) and air dried to give the desired compound as a white solid (817 mg, 86%). .sup.1H NMR (400 MHz, d.sub.4-methanol) 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.+.

(d) N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-fluoro-4-(morpholine-4-carbonyl)benzamide (27)

[0550] A mixture of 2-fluoro-4-(morpholine-4-carbonyl)benzoic acid A8 (0.057 g, 0.23 mmol) and triethylamine (0.14 mL, 0.97 mmol) in DCM (5 mL) was cooled to 0° C. under a nitrogen atmosphere and isobutyl chloroformate (32 μL, 0.24 mmol) was added dropwise. The mixture was stirred for 45 minutes at 0° C. and allowed to settle. The liquid phase was transferred via syringe to a solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.050 g, 0.24 mmol) in DCM (10 mL) at 0° C. After 1.25 hours, the mixture was diluted with DCM (10 mL) and aqueous sodium hydroxide (2 M, 25 mL) and the separated aqueous phase was extracted with DCM (2×25 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (24 g SiO.sub.2 cartridge, 0-10% MeOH (containing 1% v/v 2 M NH.sub.3 in MeOH) in DCM) to give a white solid. The solid was dissolved in a minimal amount of DCM and the product was precipitated by the addition of cyclohexane. The precipitate was vacuum filtered and air dried to give the desired compound as a white solid (0.020 g, 20%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.46 (t, J=5.7 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.42-7.35 (m, 1H), 7.35-7.29 (m, 1H), 7.25-7.19 (m, 2H), 7.18-7.12 (m, 2H), 5.38 (s, 1H), 3.95-3.74 (m, 2H), 3.71-3.48 (m, 6H), 3.23-3.10 (m, 2H), 3.00-2.82 (m, 3H), 2.81-2.69 (m, 1H), residual H.sub.2O obscured peaks in the alkyl region; LCMS-B: RT 3.20 min; m/z 442.3 [M+H].sup.+.

Example 13: N-(3-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-chlorobenzamide (28)

[0551] ##STR00150##

(a) tert-Butyl (3-(4-chlorobenzamido)-2-hydroxypropyl)carbamate (A9)

[0552] A solution of 4-chlorobenzoic acid (3.00 g, 19.2 mmol) in DCM (40 mL) containing N,N-diisopropylethylamine (10.01 mL, 57.5 mmol,), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.77 g, 25.0 mmol) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 4.76 g, 25.0 mmol) was stirred at room temperature for 20 minutes. N-Boc-1,3-diamino-2-propanol (4.01 g, 21.1 mmol) was added and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Water was added and the aqueous phase was extracted with DCM (2×20 mL). The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified using column chromatography (120 g SiO.sub.2 Cartridge, 0-30% methanol in DCM) to give of the desired compound as a white foam (3.44 g, 54%). .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ 8.47 (t, J=5.50 Hz, 1H), 7.88 (d, J=8.58 Hz, 2H), 7.54 (d, J=8.58 Hz, 2H), 6.70 (t, J=5.58 Hz, 1H), 4.93 (d, J=5.06 Hz, 1H), 3.66-3.61 (m, 1H), 3.30-3.26 (m, 1H), 3.26-3.11 (m, 1H), 3.04-2.50 (m, 2H), 1.38 (s, 9H).

(b) N-(3-Amino-2-hydroxypropyl)-4-chlorobenzamide hydrochloride (A10)

[0553] A solution of tert-butyl (3-(4-chlorobenzamido)-2-hydroxypropyl)carbamate A9 (3.44 g, 10.5 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (10.4 mL, 41.9 mmol) and 1,4-dioxane (15 mL) was heated at 50° C. for 2.5 hours. The solvent was evaporated under reduced pressure to give the desired compound product as a white foam (2.77 g, 99%). .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ 8.80 (t, J=5.61 Hz, 1H), 7.91 (d, J=6.78 Hz, 2H), 7.55 (d, J=8.55 Hz, 2H), 3.95-3.82 (m, 1H), 3.57-3.23 (m, 5H), 3.02-2.85 (m, 1H), 2.77-2.60 (m, 1H).

[0554] To a solution of N-(3-amino-2-hydroxypropyl)-4-chlorobenzamide hydrochloride A10 (0.070 g, 0.26 mmol) in 1,2-dichloroethane (1 mL) and methanol (1 mL) was added N,N-diisopropylethylamine (0.046 mL, 0.26 mmol), 5-bromo-1H-inden-2 (3H)-one (0.067 g, 0.32 mmol), acetic acid (0.024 mL, 0.40 mmol), and sodium triacetoxyborohydride (0.224 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with 2.5 M aqueous sodium hydroxide and DCM. The aqueous phase was extracted with DCM (2×15 mL) and the combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by silica column chromatography (12 g SiO.sub.2 Cartridge, 0-15% methanol in DCM) to give the desired compound as a light brown solid (0.040 g, 35%): LCMS RT 4.41 min; m/z 424.7 [M+H].sup.+.

Example 14: 4-Chloro-N-(4-((2,3-dihydro-1H-inden-2-yl)amino)-3-hydroxybutyl)benzamide (29)

[0555] ##STR00151##

(a) 2-(But-3-en-1-yl)isoindoline-1,3-dione (A11)

[0556] A mixture of potassium phthalimide (500 mg, 2.70 mmol), acetonitrile (5 mL) and 4-bromobut-1-ene (0.548 mL, 5.40 mmol) was stirred at 90° C. After 18 hours, the mixture was cooled to room temperature, filtered and the collected solids were washed with ethyl acetate (5 mL). The combined filtrates were concentrated and column chromatography (12 g silica cartridge, 0-100% ethyl acetate/hexanes) gave the desired compound as a white solid (431 mg, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87-7.80 (m, 2H), 7.73-7.67 (m, 2H), 5.86-5.72 (m, 1H), 5.11-4.99 (m, 2H), 3.77 (t, J=7.1 Hz, 2H), 2.49-2.40 (m, 2H). LCMS-B: RT 3.71 min; m/z 202.1 [M+H].sup.+.

(b) 2-(2-(Oxiran-2-yl)ethyl)isoindoline-1,3-dione (A12)

[0557] A mixture of 2-(but-3-en-1-yl)isoindoline-1,3-dione A11 (428 mg, 2.13 mmol), chloroform (5 mL) and 70-75% mCPBA (629 mg, 2.55 mmol) was stirred at room temperature. After 18 hours, the mixture was quenched with 10% w/v aqueous sodium thiosulfate (2.5 mL) and was stirred vigorously for 5 minutes. The mixture was diluted with a saturated aqueous solution of sodium bicarbonate (5 mL), water (20 mL) and chloroform (10 mL). The separated aqueous phase was extracted with chloroform (2×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the desired compound as a white solid (451 mg, 98%). The material was carried forward without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88-7.82 (m, 2H), 7.74-7.69 (m, 2H), 3.97-3.80 (m, 2H), 3.03-2.94 (m, 1H), 2.74-2.68 (m, 1H), 2.47-2.41 (m, 1H), 2.04-1.93 (m, 1H), 1.90-1.79 (m, 1H). LCMS-B: RT 3.43 min; m/z 218.1 [M+H].sup.+

[0558] A mixture of 2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione A12 (100 mg, 0.460 mmol), dry acetonitrile (2 mL), 2-aminoindane (64 mg, 0.48 mmol) and calcium triflate (78 mg, 50 mol %) was stirred at room temperature. After two hours, the mixture was concentrated in vacuo and purified by column chromatography (12 g SiO.sub.2 cartridge, 0-20% methanol/DCM) to give the desired compound as a colourless solid (139 mg, 86%). .sup.1H NMR (400 MHz, DMSO) δ 7.92-7.77 (m, 2H), 7.32-7.11 (m, 6H), 4.04-3.96 (m, 1H), 3.28 (dd, J=16.6, 7.7 Hz, overlaps with solvent), 2.92 (dd, J=16.6, 5.1 Hz, 2H); LCMS-B: m/z 351.2 [M+H].sup.+.

(d) 4-Amino-1-((2,3-dihydro-1H-inden-2-yl)amino)butan-2-ol (A14)

[0559] A mixture of 2-(4-((2,3-dihydro-1H-inden-2-yl)amino)-3-hydroxybutyl)isoindoline-1,3-dione A13 (137 mg, 0.391 mmol), ethanol (2 mL) and hydrazine hydrate (0.2 mL) was stirred at 80° C. After three hours, the mixture was cooled to room temperature, the resulting slurry filtered and the collected solids washed with cold ethanol (2 mL). The combined filtrates were concentrated to give the title compound as a white solid (101 mg, >100% yield). The material was carried forward without further purification.

(e) 4-Chloro-N-(4-((2,3-dihydro-1H-inden-2-yl)amino)-3-hydroxybutyl)benzamide (29)

[0560] A mixture of 4-amino-1-((2,3-dihydro-1H-inden-2-yl)amino)butan-2-ol A14 (44 mg, 0.20 mmol), MeCN (2 mL), DIPEA (0.070 mL, 0.40 mmol) and 4-chlorobenzoyl chloride (0.026 mL, 0.20 mmol) was stirred at room temperature. After 18 hours, methanol (0.1 mL) was added and the mixture loaded onto a 5 g SCX cartridge. The cartridge was washed with methanol (40 mL) then eluted with 3.5 M ammonia in methanol (40 mL). The basic eluate was concentrated in vacuo, and preparative TLC (5% methanol/DCM) gave the desired compound as a colourless syrup (7 mg, 9% yield). .sup.1H NMR (400 MHz, d.sub.4-methanol) δ 7.83-7.78 (m, 2H), 7.49-7.45 (m, 2H), 7.21-7.10 (m, 4H), 3.86-3.76 (m, 1H), 3.75-3.64 (m, 1H), 3.61-3.44 (m, 2H), 3.26-3.16 (m, 2H), 2.88-2.79 (m, 3H), 2.76-2.67 (m, 1H), 1.87-1.77 (m, 1H), 1.75-1.64 (m, 1H).

Example 15: 4-Chloro-N-(2-hydroxy-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)propyl)benzamide (30)

[0561] ##STR00152##

(a) 2-(2-Hydroxy-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)propyl)isoindoline-1,3-dione (A15)

[0562] A mixture of N-(2,3-epoxypropyl)phthalimide (0.471 g, 2.31 mmol) and 1,2,3,4-tetrahydro-2-naphthalenamine (0.310 g, 2.10 mmol) in ethanol (3 mL) was heated at reflux for 20 hours under a nitrogen atmosphere. The volatiles were removed in vacuo. The material was adsorbed directly onto silica gel and the product was purified by column chromatography (12 g SiO.sub.2 Cartridge, 0-20% methanol in DCM) to give the desired compound as a light yellow oil.

[0563] (0.267 g, 36%). LCMS-D: RT 4.95 min; m/z 351.2 [M+H].sup.+.

(b) 1-Amino-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol (A16)

[0564] A mixture of 2-(2-hydroxy-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)propyl)isoindoline-1,3-dione A15 (0.267 g, 0.762 mmol) and hydrazine monohydrate (0.075 mL, 1.5 mmol) in ethanol (2 mL) and DCM (1 mL) was stirred at room temperature for 20 hours under a nitrogen atmosphere. The volatiles were removed by rotary evaporation. The residue was dissolved in methanol and passed through a SCX cartridge (5 g, Agilent, Bond Elut, Mega BE-SCX) washing with 100% methanol and eluting with 100% 2 M ammonia in methanol solution to give the desired compound (0.150 g, 89%). The material was used in the next step without further purification.

[0565] A solution of 4-chlorobenzoic acid (0.117 g, 0.749 mmol) in N,N-dimethylformamide (2 mL) containing N,N-diisopropylethylamine (0.474 mL, 2.72 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.196 g, 1.02 mmol) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 0.156 g, 1.02 mmol) was stirred at room temperature for 20 minutes under a nitrogen atmosphere. A solution of 1-amino-3-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol A16 (0.150 g, 0.681 mmol) in N,N-dimethylformamide (2 mL) was added and stirred at room temperature for 20 hours under a nitrogen atmosphere. Water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with water (×3), brine, dried (sodium sulfate), filtered and concentrated in vacuo to give the product. The material was adsorbed directly onto silica gel and purified by column chromatography (12 g SiO.sub.2 Cartridge, 0-20% DCM in methanol) to give the desired compound as an amorphous white solid (0.075 g, 30%).sup.1H NMR (300 MHz, d.sub.4-methanol) δ 7.83 (d, J=8.55 Hz, 2H), 7.49 (d, J=8.55 Hz, 2H), 7.06 (br. s., 4H), 3.99-3.95 (m, 1H), 3.50-3.48 (m, 2H), 3.10-2.58 (m, 7H), 2.15-2.11 (m, 1H), 1.68-1.61 (m, 1H). LCMS-D: RT 3.63 min; m/z 359.3 [M+H].sup.+.

Example 16: 4-Chloro-N-(3-((7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-hydroxypropyl)benzamide (31)

[0566] ##STR00153##

(a) tert-Butyl (3-((7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-hydroxypropyl)carbamate (A17)

[0567] 7-Fluoro-1,2,3,4-tetrahydro-napthalene-2-ylamine hydrochloride (120 mg) was neutralised by adding 10% w/v NaOH (aq.) (5 mL) and DCM (5 mL) to the salt. The phases were separated and the aqueous phase was extracted with DCM (3×10 mL). The combined organic phases were dried with sodium sulfate and concentrated under reduced pressure to give the free amine (76 mg) as an oil. To a solution of 7-fluoro-1,2,3,4-tetrahydro-napthalene-2-ylamine (76 mg, 0.46 mmol) in dry acetonitrile (1.5 mL) was added tert-butyl N-(oxiran-2-yl methyl) carbamate (159 mg, 0.92 mmol). The flask was sealed and the reaction was allowed to stir at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol and applied to an SCX cartridge (5 g). The cartridge was washed with methanol (25 mL) and eluted with 2 M ammonia in methanol (15 mL). The volatiles were removed under vacuum to afford the desired compound (131 mg, 84%). The material was taken onto the next step without further purification.

(b) 1-Amino-3-((7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol (A18)

[0568] tert-Butyl (3-((7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-hydroxypropyl)carbamate A17 (131 mg, 0.39 mmol) was dissolved in DCM (7 mL) and to the solution was added TFA (0.531 mL, 7.74 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere overnight and the solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (7 mL) and applied to an SCX cartridge. The cartridge was washed with methanol (25 mL) and eluted with 2 M ammonia in ethanol (15 mL). The ammonia eluate was concentrated under vacuum to give the desired compound (91 mg, 99%); .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.01 (m, 1H), 6.82-6.72 (m, 2H), 3.68 (m, 1H), 3.02-2.50 (m, 11H), 2.01 (m, 1H), 1.59 (m, 1H).

[0569] To a solution of 4-chlorobenzoic acid (66 mg, 0.42 mmol) in DCM (7.0 mL) was added N,N-diisopropylethylamine (221 μL, 1.27 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.552 mmol) and 1-hydroxybenzotriazole hydrate (84.5 mg, 0.552 mmol) under a nitrogen atmosphere. The solution was stirred for 20 minutes at room temperature and 1-amino-3-((7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol A18 (91 mg, 0.38 mmol) was added. The reaction was stirred at room temperature for 24 hours. Water (25 mL) and DCM (25 mL) were added and the aqueous phase was extracted with DCM (3×20 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated. The resulting oil was dissolved in methanol and applied to an SCX cartridge (5 g), the cartridge was washed with methanol (30 mL) then eluted with 2 M ammonia in ethanol (20 mL). The ammonia eluate was concentrated and the resulting residue was purified by preparative HPLC (Waters) to give the desired compound (5 mg, 3%). LCMS-D RT 5.17 min; m/z 377.3.

Example 17: 4-Chloro-N-(3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-hydroxypropyl)benzamide (32)

[0570] ##STR00154##

(a) tert-Butyl (3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-hydroxypropyl)carbamate (A19)

[0571] 6-Fluoro-1,2,3,4-tetrahydro-napthalene-2-ylamine hydrochloride (100 mg) was neutralised by adding 10% NaOH (aq.) (5 mL) and DCM (10 mL) to the salt. The phases were separated and the aqueous phase was extracted with DCM (2×10 mL). The combined organic phases were dried with sodium sulfate and concentrated under reduced pressure to give the free amine as an oil (86 mg). To a solution of 6-fluoro-1,2,3,4-tetrahydro-napthalene-2-ylamine (86 mg, 0.52 mmol) in dry acetonitrile (1.5 mL) was added tert-butyl N-(oxiran-2-yl methyl) carbamate (180 mg, 1.04 mmol). The flask was sealed and the mixture stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL) and applied to an SCX cartridge (5 g). The cartridge was washed with methanol (25 mL) then eluted with 2 M ammonia in methanol (15 mL). The ammonia eluate was concentrated under vacuum to give the desired compound (172 mg, 98%); .sup.1H NMR (300 MHz, CDCl.sub.3) 6.99 (m, 1H), 6.82-6.74 (m, 2H), 5.24 (m, 1H), 3.73 (m, 1H), 3.32 (m, 1H), 3.12 (m, 1H), 2.95-2.75 (m, 7H), 2.64 (m, 1H), 2.54 (m, 1H), 2.04 (m, 1H), 1.57 (m, 1H), 1.43 (s, 9H).

(b) 1-Amino-3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol (A20)

[0572] tert-Butyl (3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-hydroxypropyl)carbamate A19 (172 mg, 0.51 mmol) was dissolved in DCM (7 mL) and to the solution was added trifluoroacetic acid (697 μL, 10.2 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 22 hours and the solvent was removed under reduced pressure. The resulting oil was dissolved in methanol (5 mL) and applied to an SCX cartridge. The cartridge was washed with methanol (25 mL) and eluted with 2 M ammonia in ethanol (15 mL). The ammonia eluate was concentrated under vacuum to give the desired compound (121 mg, 100%); .sup.1H NMR (300 MHz, CDCl.sub.3) 6.98 (m, 1H), 6.78 (m, 2H), 3.65 (m, 1H), 3.01-2.48 (m, 13H), 2.01 (m, 1H), 1.57 (m, 1H).

[0573] To a solution of 4-chlorobenzoic acid (88 mg, 0.56 mmol) in DCM (7.0 mL) was added N,N-diisopropylethylamine (294 μL, 1.69 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (140.6 mg, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (112 mg, 0.73 mmol) under a nitrogen atmosphere. The solution was stirred for 20 minutes at room temperature and 1-amino-3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol A20 (121 mg, 0.51 mmol) was added. The mixture was stirred at room temperature for 24 hours. Water (25 mL) and DCM (25 mL) were added and the aqueous phase was extracted with DCM (3×20 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated. The resulting oil was dissolved in methanol (5 mL) and applied to an SCX cartridge (5 g). The cartridge was washed with methanol (30 mL) then eluted with 2 M ammonia in ethanol (20 mL). The ammonia eluate was concentrated and the resulting residue was purified by preparative HPLC (Waters) to give the desired compound (2 mg, 1%); LCMS-D RT 5.07 min; m/z 377.2.

Example 18: 4-Chloro-N-(2-hydroxy-3-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino)propyl) benzamide (33)

[0574] ##STR00155##

(a) 2-(2-Hydroxy-3-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino)propyl)isoindoline-1,3-dione (A21)

[0575] A mixture of N-(2,3-epoxypropyl)phthalimide (0.463 g, 2.27 mmol) and N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine (0.368 mL, 2.17 mmol) in ethanol (3 mL) was refluxed for 4 hours under a nitrogen atmosphere. The volatiles were removed in vacuo. The material was adsorbed onto silica gel and purified by column chromatography (12 g SiO.sub.2 Cartridge, 0-15% methanol in dichloromethane) to give the desired compound as a light yellow coloured oil (0.525 g, 66%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.89-7.85 (m, 2H), 7.75-7.72 (m, 2H), 7.14-7.07 (m, 4H), 4.21-4.09 (br. s., 1H), 3.90-3.73 (m, 2H), 3.04-2.72 (m, 8H), 2.49 (br. s., 3H), 2.19-2.06 (m, 1H), 1.80-1.66 (m, 1H).

(b) 1-Amino-3-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol (A22)

[0576] A mixture of 2-(2-hydroxy-3-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino)propyl)isoindoline-1,3-dione A21 (0.525 g, 1.44 mmol) and hydrazine monohydrate (0.143 mL, 2.88 mmol) in ethanol (2 mL) and dichloromethane (2 mL) was stirred at room temperature for 20 hours under a nitrogen atmosphere. The volatiles were removed by rotary evaporation. The residue was dissolved in methanol and passed through a SCX cartridge (5 g, Agilent, Bond Elut, Mega BE-SCX) washing with 100% methanol and eluting with 100% 2 M ammonia in methanol solution to give the desired compound (0.283 g, 83%). The material was used in the next step without further purification.

[0577] A solution of 4-chlorobenzoic acid (0.208 g, 1.32 mmol) in N,N-dimethylformamide (3 mL) containing N,N-diisopropylethylamine (0.841 mL, 4.83 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.347 g, 1.81 mmol) and 1-hydroxybenzotriazole hydrate (wetted with not less than 20 wt. % water, 0.277 g, 1.81 mmol) was stirred at room temperature for 20 minutes. After this time, a solution of 1-amino-3-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino)propan-2-ol A22 (0.283 g, 1.20 mmol) in N,N-dimethylformamide (3 mL) was added and stirred at room temperature for 20 hours under a nitrogen atmosphere. Water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with water (2×20 mL), brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by column chromatography (12 g SiO.sub.2 Cartridge, 0-10% methanol in dichloromethane) to give the desired compound as a white solid (0.279 g, 61%). .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 7.81 (dd, J=8.52, 1.41 Hz, 2H), 7.48 (dd, J=8.58, 0.99 Hz, 2H), 7.05-7.04 (m, 4H), 3.99-3.93 (m, 1H), 3.54 (dd, J=13.53, 4.89 Hz, 1H), 3.44-3.35 (m, 1H), 2.92-2.80 (m, 5H), 2.68-2.63 (m, 2H), 2.43 (s, 3H), 2.10-2.02 (m, 1H), 1.70-1.59 (m, 1H). LCMS-D: RT 5.12 min; m/z 373.3 [M+H].sup.+.

Example 19: N-(3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylamino)-2-hydroxypropyl)-4-chlorobenzamide (34)

[0578] ##STR00156##

[0579] A mixture of N-(3-amino-2-hydroxypropyl)-4-chlorobenzamide hydrochloride A10 (0.080 g, 0.30 mmol), N,N-diisopropylethylamine (0.053 mL, 0.30 mmol), benzocylclobuten-1(2H)-one (0.039 mL, 0.33 mmol) and titanium(IV) isopropoxide (0.119 mL, 0.392 mmol) in absolute ethanol (2 mL) was stirred at 30° C. for 16 hours under a nitrogen atmosphere. Sodium borohydride (0.023 g, 0.60 mmol) was added and the mixture was stirred for 6 hours under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The precipitated inorganic solid was separated by filtration and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water, brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-15% methanol in DCM) to give the desired compound as a white solid (0.028 g, 28%). .sup.1H NMR (300 MHz, d.sub.4-methanol) δ 7.80 (d, J=8.61 Hz, 2H), 7.46 (d, J=8.61 Hz, 2H), 7.30 (t, J=3.85 Hz, 1H), 7.22-7.11 (m, 3H), 4.05-3.94 (m, 1H), 3.91-3.77 (m, 2H), 3.51-3.43 (m, 1H), 2.88-2.65 (m, 2H), 2.37 (s, 2H). LCMS-D: RT 4.77 min; m/z 331.2 [M+H].sup.+.

Example 20: 2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide (35)

[0580] ##STR00157##

(a) Methyl 2-((1-acetylpiperidin-4-yl)amino)isonicotinate (A23)

[0581] A mixture of 1-(4-aminopiperidin-1-yl)ethan-1-one hydrochloride (0.500 g, 2.80 mmol), methyl 2-bromoisonicotinate (0.423 g, 1.96 mmol), Cs.sub.2CO.sub.3 (2.55 g, 7.84 mmol), xantphos (0.057 g, 0.098 mmol) and Pd.sub.2(dba).sub.3 (0.090 g, 0.098 mmol) in 1,4-dioxane (15 mL) was bubbled with nitrogen for 10 minutes. The mixture was stirred under an atmosphere of nitrogen at 80° C. for 16 hours. Another portion of Cs.sub.2CO.sub.3 (2.55 g, 7.84 mmol), xantphos (0.057 g, 0.098 mmol) and Pd.sub.2(dba).sub.3 (0.090 g, 0.098 mmol) was added. The mixture was stirred under an atmosphere of nitrogen at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (˜50 mL). Solid impurities were removed by filtration and the filtrate was removed in vacuo. The resultant solid was purified by column chromatography (40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% MeOH in EtOAc) to give the desired compound as a yellow oil (0.268 g, 49%). LCMS-B: RT 3.08 min; m/z 278.2 [M+H].sup.+.

(b) 2-((1-Acetylpiperidin-4-yl)amino)isonicotinic acid (A24)

[0582] A mixture of methyl 2-((1-acetylpiperidin-4-yl)amino)isonicotinate A23 (0.268 g, 0.966 mmol), LiOH.H.sub.2O (0.811 g, 19.3 mmol), THF (7 mL), MeOH (7 mL) and H.sub.2O (1.5 mL) was stirred at 40° C. for 2 hours. The mixture was cooled to room temperature and the volatiles were removed. Water (˜20 mL) was added and the pH was adjusted to ˜6 with aqueous HCl (2 M). A yellow precipitate formed which was isolated by vacuum filtration and air dried to give the desired compound as a yellow solid (0.058 g, 23%). The aqueous filtrate was passed through an Oasis HLB 35 cc LP extraction cartridge (6 g) which was washed with 3 column volumes of water. The lipophilic component was eluted with 3 column volumes of MeOH and concentration in vacuo gave the desired compound as a yellow solid (0.122 g, 48%). Overall yield: 0.180 g, 71%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.08 (d, J=5.2 Hz, 1H), 7.01-6.95 (m, 1H), 6.85 (dd, J=5.2, 1.4 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.27-4.15 (m, 1H), 4.02-3.91 (m, 1H), 3.82-3.71 (m, 1H), 3.22-3.11 (m, 1H), 2.86-2.74 (m, 1H), 2.00 (s, 3H), 1.97-1.83 (m, 2H), 1.41-1.14 (m, 2H); LCMS-B: RT 1.26 min; m/z 264.2 [M+H].sup.+

[0583] A mixture of 2-((1-acetylpiperidin-4-yl)amino)isonicotinic acid A24 (0.122 g, 0.463 mmol), triethylamine (258 μL, 1.85 mmol), and DCM (10 mL) was cooled to 0° C. under a nitrogen atmosphere and isobutyl chloroformate (61 μL, 0.46 mmol) was added. The mixture was stirred for 30 minutes at 0° C. before being transferred via syringe to a solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.096 g, 0.46 mmol) in DCM (10 mL) at 0° C. After 2.5 hours, the mixture was diluted with DCM (10 mL), water (10 mL) and aqueous sodium hydroxide (2 M, 10 mL). The separated aqueous phase was extracted with DCM (2×15 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-35% MeOH in CHCl.sub.3) to give the desired compound as a yellow oil (0.012 g, 6%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.76 (t, J=5.9, 5.9 Hz, 1H), 8.05 (d, J=5.2 Hz, 1H), 7.26-7.22 (m, 2H), 7.20-7.16 (m, 2H), 6.94-6.87 (m, 2H), 6.76 (d, J=7.6 Hz, 1H), 5.78 (s, 1H), 4.26-4.17 (m, 1H), 4.03-3.91 (m, 3H), 3.82-3.72 (m, 1H), 3.32-3.20 (m, 4H), 3.17-3.06 (m, 5H), 2.91-2.83 (m, 1H), 2.83-2.74 (m, 1H), 2.00 (s, 3H), 1.95-1.82 (m, 2H), 1.41-1.21 (m, 2H); LCMS-A: RT 4.06 min; m/z 452.2 [M+H].sup.+.

Example 21: (S)-4-((3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid (36)

[0584] ##STR00158##

(a) Methyl (S)-4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoate (A25)

[0585] To a solution of 4-(methoxycarbonyl)benzoic acid (0.96 g, 5.3 mmol) in DCM (30 mL) at 0° C. was added HATU (2.77 g, 7.28 mmol). A solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol (1.0 g, 4.9 mmol) in DCM (20 mL) and DIPEA (1.87 mL, 14.6 mmol) were added and the mixture stirred at room temperature overnight. Water (25 mL) and DCM (25 mL) were added and the organic layer separated. The aqueous layer was further extracted with DCM (2×25 mL) and the combined organic layers dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (ethyl acetate: petroleum ether=1:50, then DCM, then DCM: methanol 10:1) to give the desired compound as a white solid (958 mg, 53%). LCMS-E: RT 1.86 min; m/z 369.2 [M+H].sup.+.

(b) (S)-4-((3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid (36)

[0586] To a solution of (S)-methyl 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl) carbamoyl) benzoate A25 (935 mg, 2.54 mmol) in a mixture of THF (15 mL), methanol (8 mL) and water (4 mL) was added LiOH.H.sub.2O (533 mg, 12.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the remaining aqueous solution acidified to pH=5-6 with 2 M HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the desired compound as a white solid (610 mg, 67%). LCMS-E: RT 0.69 min; m/z 355.2 [M+H].sup.+.

Example 22: N—((S)-3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-((R)-3-methylmorpholine-4-carbonyl)benzamide (37)

[0587] ##STR00159##

[0588] To a solution of (S)-4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl) benzoic acid 36 (50 mg, 0.14 mmol) in DMF (2 mL) were added HATU (80 mg, 0.21 mmol), triethylamine (52 mg, 0.52 mmol) and (R)-3-methylmorpholine (17 mg, 0.17 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with water (30 mL×2) and brine (30 mL×4), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue obtained was purified by Preparative TLC (DCM:MeOH=10:1) to give the desired product as a yellow solid (14 mg, 23%). LCMS-C: RT 0.78 min; m/z 438.3 [M+H].sup.+.

Example 23: N—((S)-3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-((S)-3-methylmorpholine-4-carbonyl)benzamide (38)

[0589] ##STR00160##

[0590] To a solution of (S)-4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl) benzoic acid 36 (50 mg, 0.14 mmol) in DMF (2 mL) were added HATU (80 mg, 0.21 mmol), triethylamine (52 mg, 0.52 mmol) and (S)-3-methylmorpholine (17 mg, 0.17 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (30 mL×3), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by Preparative TLC (DCM:MeOH=10:1) to give the desired compound as a white solid (6 mg, 10%); LCMS-C: RT 0.91 min; m/z 438.3 [M+H].sup.+.

Example 24: 4-(8-Oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide (39)

[0591] ##STR00161##

[0592] To a solution of 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl) benzoic acid 19 (50 mg, 0.14 mmol) in a mixture of DCM (15 mL) and DMF (5 mL) were added HATU (76 mg, 0.20 mmol) and DIPEA (82 mg, 0.63 mmol). The mixture was stirred at room temperature for 30 minutes, then 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (25.4 mg, 0.17 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×4). The combined organic layers were washed with brine (30 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by Preparative-TLC (DCM:MeOH=10:1) to give the desired product as an off-white solid (20 mg, 32%). LCMS-C: RT 0.83 min; m/z 450.2 [M+H].sup.+.

Example 25: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide (40)

[0593] ##STR00162##

[0594] To a solution of 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl) benzoic acid 19 (50 mg, 0.14 mmol) in DCM (4 mL) were added HATU (80 mg, 0.21 mmol) and DIPEA (73 mg, 0.56 mmol). The mixture was stirred at room temperature for 30 minutes. 3-Oxa-8-azabicyclo[3.2.1]octane hydrochloride (25 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with DCM (10 mL×5). The combined organic layers were washed with brine (10 mL×3), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by Preparative TLC (DCM:MeOH=15:1) to give the desired compound as an off-white solid (35 mg, 56%). LCMS-C: RT 1.03 min; m/z 450.3 [M+H].sup.+.

Example 26: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(2,2-dimethylmorpholine-4-carbonyl)benzamide (41)

[0595] ##STR00163##

[0596] To a solution of 4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl) benzoic acid 19 (50 mg, 0.14 mmol) in a mixture of DCM (15 mL) and DMF (5 mL) were added HATU (76 mg, 0.20 mmol) and DIPEA (82 mg, 0.63 mmol). The mixture was stirred at room temperature for 30 minutes, then 2,2-dimethylmorpholine (19.6 mg, 0.17 mmol) was added and the resulting mixture stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×4). The combined organic layers were washed with water (30 mL×3) and brine (30 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by Preparative TLC (DCM:MeOH=10:1) to give the desired compound as an off-white solid (15 mg, 24%). LCMS-C: RT 1.24 min; m/z 452.3 [M+H].sup.+.

Example 27: (S)-3-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide (42)

[0597] ##STR00164##

(a) tert-Butyl 4-((3-(methoxycarbonyl)phenyl)amino)piperidine-1-carboxylate A26

[0598] A mixture of 1-Boc-4-piperidone (0.725 g, 3.64 mmol), methyl 3-aminobenzoate (0.500 g, 3.31 mmol) and acetic acid (0.38 mL, 6.6 mmol) in DCE (25 mL) was stirred at room temperature for 15 minutes before sodium triacetoxyborohydride (1.05 g, 4.96 mmol) was added. The mixture was stirred for a further 16 hours at room temperature and then quenched by the addition of H.sub.2O (20 mL). The mixture was concentrated in vacuo, saturated aqueous NaHCO.sub.3 (50 mL) was added and the aqueous was extracted with EtOAc (3×75 mL). The organic layers were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo. The solid residue was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the desired compound as a colourless oil (1.35 g, ˜80% purity, >95% yield). .sup.1H NMR (400 MHz, chloroform-d) δ 7.46-7.40 (m, 1H), 7.38-7.32 (m, 1H), 7.25-7.17 (m, 1H), 6.92-6.84 (m, 1H), 4.07-3.99 (m, 1H), 3.90-3.86 (m, 3H), 3.71 (t, J=6.2 Hz, 1H), 3.47 (tt, J=10.4, 3.9 Hz, 1H), 2.90 (t, J=12.5 Hz, 2H), 2.43 (t, J=6.2 Hz, 1H), 2.10-1.97 (m, 2H), 1.46 (s, 9H), 1.41-1.31 (m, 2H). LCMS-A: RT 6.70 min; m/z 279.1 [M-t-Bu+2H].sup.+.

(b) 3-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)benzoic acid A27

[0599] A mixture of tert-butyl 4-((3-(methoxycarbonyl)phenyl)amino)piperidine-1-carboxylate A26 (1.35 g, ˜80 purity, 3.23 mmol), LiOH.H.sub.2O (1.69 g, 40.4 mmol), THF (14 mL), MeOH (14 mL) and H.sub.2O (3 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, H.sub.2O (50 mL) and aqueous NaOH (2 M, 30 mL) were added and the aqueous solution was washed with EtOAc (3×50 mL). The aqueous phase was acidified with an aqueous HCl solution (2 M) and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo to give the desired compound as a yellow oil (0.801 g, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.20-7.14 (m, 2H), 7.12-7.08 (m, 1H), 6.84-6.77 (m, 1H), 5.78 (s, 1H), 3.92-3.80 (m, 2H), 3.49-3.39 (m, 1H), 3.02-2.82 (m, 2H), 1.89-1.82 (m, 2H), 1.40 (s, 9H), 1.28-1.19 (m, 2H). LCMS-A: RT 6.04 min; m/z 265.1 [M-t-Bu+2H]+; 319.1 [M−H].sup.−.

(c) tert-Butyl (R)-4-((3-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)phenyl)amino)piperidine-1-carboxylate A28

[0600] A solution of 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)benzoic acid A27 (0.099 g, 0.31 mmol) and DIPEA (98 μL, 0.56 mmol) in DCM (5 mL) was stirred with HATU (0.117 g, 0.309 mmol) for 10 minutes at room temperature. A solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10 (0.100 g, 0.281 mmol) in DCM (5 mL) was then added dropwise and the mixture was stirred at room temperature for 24 h. Water (30 mL) and aqueous NaOH (2 M, 10 mL) were then added and the aqueous was extracted with DCM (3×30 mL). The organic layers were combined, the solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the desired compound as a colourless oil (0.105 g, 56%). .sup.1H NMR (400 MHz, chloroform-d) δ 7.18-7.08 (m, 6H), 7.01 (t, J=2.0 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.71-6.60 (m, 2H), 6.43 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.3, 2.4 Hz, 1H), 4.07-3.98 (m, 2H), 3.87-3.81 (m, 2H), 3.79-3.73 (m, 7H), 3.71-3.54 (m, 3H), 3.51-3.40 (m, 1H), 3.36-3.24 (m, 1H), 3.14-2.98 (m, 4H), 2.95-2.86 (m, 2H), 2.65-2.48 (m, 2H), 2.01-1.97 (m, 1H), 1.46 (s, 9H), 1.36-1.28 (m, 2H); N—H and O—H not observed. LCMS-A: RT 5.20 min; m/z 659.3 [M+H].sup.+.

(d) (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-3-(piperidin-4-ylamino)benzamide A29

[0601] A mixture of tert-butyl (R)-4-((3-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)phenyl)amino)piperidine-1-carboxylate A28 (0.105 g, 0.159 mmol) and TFA (122 μL, 1.59 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. Water (20 mL) was added and the aqueous was washed with DCM (3×10 mL). The aqueous was adjusted to a pH of ˜14 with an aqueous NaOH solution (2 M) and then extracted with DCM (3×15 mL). The organic layers were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo to give the desired compound as a white powder (0.024 g, 27%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (t, J=5.4 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.19-7.04 (m, 5H), 6.96 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.69 (dd, J=8.1, 2.3 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.3, 2.4 Hz, 1H), 5.59 (d, J=8.1 Hz, 1H), 4.66 (d, J=4.3 Hz, 1H), 3.83-3.75 (m, 1H), 3.73-3.68 (m, 7H), 3.57 (d, J=2.8 Hz, 2H), 3.27-3.09 (m, obscured by solvent), 3.01-2.80 (m, 7H), 2.47-2.39 (m, obscured by solvent), 1.88-1.77 (m, 2H), 1.26-1.14 (m, 3H).

(e) (R)-3-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)benzamide A30

[0602] A solution of (R)—N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-3-(piperidin-4-ylamino)benzamide A29 (0.024 g, 0.043 mmol) and triethylamine (12 μL, 0.086 mmol) in DCM (4 mL) was cooled to 0° C. before acetic anhydride (4 μL, 0.05 mmol) was added. The mixture was stirred and allowed to return to room temperature over 3 hours. Water (10 mL) and an aqueous solution of NaOH (2 M, 10 mL) were added and the mixture was stirred for 20 minutes. The aqueous was extracted with DCM (3×15 mL), the organic layers were combined and the solvent removed in vacuo to give the desired compound as a white solid (0.026 g, >95%). LCMS-B: RT 3.38 min; m/z 601.3 [M+H].sup.+.

(f) (S)-3-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide 42

[0603] A mixture of (R)-3-((1-acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)benzamide A30 (0.026 g, 0.043 mmol) and TFA (2 mL) was stirred at 70° C. for 16 hours. The mixture was returned to room temperature, water was added (20 mL) and the aqueous was washed with DCM (3×20 mL). The pH of the aqueous layer was adjusted to ˜14 with an aqueous NaOH solution (2 M) and then extracted with DCM (3×20 mL). The organic layers were combined and the solvent removed in vacuo to give the desired compound as a white solid (0.017 g, 87%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.26 (t, J=5.7 Hz, 1H), 7.21-7.03 (m, 6H), 6.94 (d, J=7.6 Hz, 1H), 6.78-6.66 (m, 1H), 5.70 (d, J=8.2 Hz, 1H), 4.97-4.76 (m, 1H), 4.29-4.14 (m, 1H), 3.83-3.73 (m, 1H), 3.72-3.65 (m, 1H), 3.54-3.45 (m, 2H), 3.30-3.21 (m, 2H), 3.21-3.13 (m, 1H), 3.09-2.99 (m, 2H), 2.86-2.75 (m, 1H), 2.70-2.50 (m, 4H), 2.00 (s, 3H), 1.96-1.82 (m, 2H), 1.36-1.12 (m, 2H); N—H not observed. LCMS-B:RT 3.20 min; m/z 451.3 [M+H].sup.+.

Example 28: Amide Couplings

[0604] ##STR00165##

[0605] Method X1—A solution of HATU (0.080 g, 0.21 mmol, 1.5 equiv) in CH.sub.3CN (1 mL) was added to the desired acid (0.14 mmol, 1 equiv.), CH.sub.3CN (1 mL) and DIPEA (73 μL, 0.42 mmol, 3 equiv.) and the mixture was stirred for 10 minutes. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I2 (0.050 g, 0.14 mmol, 1 equiv) in DMF (1 mL) was then added and the mixture was stirred at room temperature for 16 h. DCM (1 mL) and a solution of NaOH (aqueous 2 M, 2 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (2 mL) and the organic layers were combined. The organic extracts were concentrated by a stream of air and the resultant residue dissolved in MeOH and purified by solid-phase extraction (1 g SCX-2 cartridge, 4 column volumes of methanol followed by 4 column volumes of 7 N NH.sub.3 in MeOH). The basic fractions were concentrated by a stream of air, taken up in TFA (0.5 mL) and stirred at 70° C. for 5 hours. Water (2 mL) was added and the aqueous solution was washed with DCM (3×2 mL). The aqueous layer was brought to ˜pH 14 by the addition of an aqueous NaOH solution (2 M) and then extracted with DCM (2×2 mL). The organic layers were concentrated with a stream of air to give the desired compounds.

TABLE-US-00004 Compound Name and structure LCMS data Method 43 [00166] embedded image LCMS-B: RT = 3.35 min, m/z = 409 [M + H].sup.+. X1 2-(cyclopentyl(methyl)amino)-N-(3-((2,3-dihydro-1H- inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 44 [00167] LCMS-B: RT = 3.14 min, m/z = 395 [M + H].sup.+. X1 2-(cyclopentylamino)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)isonicotinamide 45 [00168] embedded image LCMS-B: RT = 3.21 min, m/z = 378 [M + H].sup.+. X1 N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)- 5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide 46 [00169] LCMS-B: RT = 3.18 min, m/z = 378 [M + H].sup.+. X1 N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)- 1-(pyridin-3-yl)-1H-pyrazole-4-carboxamide 47 [00170] embedded image LCMS-B: RT = 3.14 min, m/z = 397 [M + H].sup.+. X1 N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-2-morpholinoisonicotinamide 48 [00171] LCMS-B: RT = 3.13 min, m/z = 381 [M + H].sup.+. X1 N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-2-(pyrrolidin-1-yl)isonicotinamide 49 [00172] embedded image LCMS-B: RT = 3.35 min, m/z = 378 [M + H].sup.+. X1 N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-2-(1H-pyrazol-1-yl)isonicotinamide

Example 29: 2-((1-Acetylpiperidin-4-yl)oxy)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 50

[0606] ##STR00173##

(a) 2-((1-(tert-Butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid A31

[0607] 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, 9.94 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, H.sub.2O (20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜2 with an aqueous HCl solution (2 M). The aqueous solution was extracted with EtOAc (3×30 mL), the organic layers 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 that was an approximate 1:1 mixture of the desired product and the isonicotinic acid starting material. This material was dissolved in DMF (5 mL) and added to a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.500 g, 2.48 mmol) in anhydrous DMF (5 mL) that had been added to a stirring suspension of sodium hydride (60% dispersion in mineral oil; 0.238 g, 9.94 mmol) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred for 16 hours before H.sub.2O (20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ˜2 with an aqueous HCl solution (2 M). The aqueous solution was extracted with DCM (3×30 mL), the organic layers 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 as a white solid (0.419 g, 58%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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); COOH not observed. LCMS-B: RT 3.65 min; m/z 321.2 [M−H].sup.−.

(b) tert-Butyl 4-((4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate A32

[0608] A mixture of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid A31 (0.100 g, 0.310 mmol), DIPEA (108 μL, 0.620 mmol) and HATU (0.118 g, 0.310 mmol) in DCM (5 mL) was stirred for 15 minutes at room temperature under an atmosphere of nitrogen. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I12 (0.111 g, 0.310 mmol) in DCM (5 mL) was then added and the mixture was stirred for 16 hours at room temperature. An aqueous NaOH solution (2 M, 20 mL) was added and the aqueous was extracted with DCM (3×30 mL). The organic layers were combined, dried (MgSO.sub.4), filtered, and the volatiles removed in vacuo. The residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-10% MeOH in DCM) to give the desired compound as a brown oil (0.204 g, >95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.53 (t, J=5.6 Hz, 1H), 8.24 (d, J=5.2 Hz, 1H), 7.31-7.24 (m, 2H), 7.19-7.04 (m, 5H), 6.48 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.3, 2.4 Hz, 1H), 5.26-5.14 (m, 1H), 4.67 (d, J=4.3 Hz, 1H), 3.85-3.76 (m, 1H), 3.76-3.63 (m, 10H), 3.57 (s, 2H), 3.25-3.09 (m, 3H), 3.01-2.78 (m, 4H), 2.45 (d, J=6.0 Hz, 2H), 2.00-1.89 (m, 2H), 1.62-1.51 (m, 2H), 1.41 (s, 9H). LCMS-A: RT 2.10 min; m/z 661.3 [M+H].sup.+.

(c) N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-(piperidin-4-yloxy)isonicotinamide A33

[0609] A mixture of tert-butyl 4-((4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate A32 (0.184 g, 0.278 mmol), TFA (0.32 mL, 4.2 mmol) and DCM (10 mL) was stirred at room temperature for 1 hour. Another aliquot of TFA (0.11 mL, 1.4 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Water (10 mL) and aqueous NaOH (2 M, 10 mL) were added and the aqueous was extracted with DCM (3×15 mL). The organic layers were combined and the solvent removed in vacuo to give a yellow oil that was dissolved in a minimum amount of MeOH and loaded onto an SCX cartridge (SiliCycle SCX-2 cartridge, 5 g). The cartridge was washed with 5 column volumes of MeOH before the desired component was eluted with 5 column volumes of NH.sub.3 in MeOH (3.5 M). The fractions containing the suspected product were combined and the solvent removed in vacuo to give a colourless oil. The oil was taken up in a minimum amount of DCM and cyclohexane was added to form a white precipitate. The volatiles were removed in vacuo to give the desired compound as a white solid (0.115 g, 74%). .sup.1H NMR (400 MHz, chloroform-d) δ 8.18 (d, J=5.3 Hz, 1H), 7.19-7.06 (m, 5H), 7.04 (dd, J=5.2, 1.5 Hz, 1H), 7.01-6.95 (m, 1H), 6.70 (t, J=5.5 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.38 (dd, J=8.2, 2.4 Hz, 1H), 5.31-5.05 (m, 1H), 3.84-3.76 (m, 8H), 3.62-3.51 (m, 2H), 3.47 (s, 2H), 3.33-3.24 (m, 1H), 3.22-3.14 (m, 2H), 3.12-3.03 (m, 1H), 3.01-2.83 (m, 5H), 2.53 (dd, J=13.2, 4.1 Hz, 1H), 2.49-2.41 (m, 1H), 2.15-2.05 (m, 2H), 1.80-1.70 (m, 2H); N—H not observed. LCMS-A: RT 4.42 min; m/z 561.3 [M+H].sup.+.

(d) 2-((1-Acetylpiperidin-4-yl)oxy)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A34

[0610] A solution of N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-(piperidin-4-yloxy)isonicotinamide A33 (0.030 g, 0.054 mmol) and triethylamine (11 μL, 0.080 mmol) in DCM (2 mL) was cooled to 0° C. under an atmosphere of nitrogen. Acetic anhydride (5 μL, 0.05 mmol) was added and the mixture was returned to room temperature, with stirring, over 5 hours. Water (10 mL) and an aqueous NaOH solution (2 M, 10 mL) were added and the mixture was stirred for 20 minutes. The aqueous was extracted with DCM (3×15 mL), the organic layers were combined and the solvent removed in vacuo to give the desired compound as a yellow oil (0.032 g, >95%). LCMS-A: RT 4.79 min; m/z 603.3 [M+H].sup.+.

(e) 2-((1-Acetylpiperidin-4-yl)oxy)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 50

[0611] A solution of 2-((1-acetylpiperidin-4-yl)oxy)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A34 (0.032 g, 0.053 mmol) in TFA (2 mL) was stirred at 70° C. for 4 hours. Water (25 mL) was added and the acidic aqueous phase was washed with DCM (3×15 mL). The aqueous was adjusted to pH ˜14 with aqueous NaOH (2 M) and extracted with DCM (3×20 mL). The organic layers were combined and the solvent removed in vacuo to give the desired compound as a white solid (0.004 g, 15%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.70 (t, J=5.7 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.33-7.27 (m, 1H), 7.21-7.14 (m, 3H), 7.12-7.05 (m, 2H), 5.30-5.19 (m, 1H), 4.87 (s, 1H), 3.92-3.81 (m, 1H), 3.76-3.65 (m, 2H), 3.50 (m, 1H), 3.30-3.20 (m, peaks obscured by solvent), 3.11-2.99 (m, 2H), 2.72-2.61 (m, 3H), 2.55 (dd, J=11.8, 6.8 Hz, 1H), 2.06-1.88 (m, 5H), 1.72-1.47 (m, 2H). LCMS-B: RT 3.18 min; m/z 453.3 [M+H].sup.+.

Example 30: N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-(piperidin-4-yloxy)isonicotinamide 51

[0612] ##STR00174##

[0613] A solution of N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-(piperidin-4-yloxy)isonicotinamide A33 (0.020 g, 0.036 mmol) in TFA (2 mL) was stirred at 70° C. for 16 hours. The solution was concentrated in vacuo before H.sub.2O (15 mL) was added and the acidic aqueous phase was washed with DCM (3×15 mL). The aqueous phase was adjusted to pH ˜14 with an aqueous NaOH solution (2 M) and extracted with DCM (3×15 mL). The organic layers were combined and the solvent removed in vacuo to give the desired compound as a yellow oil (0.005 g, 34%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.69 (t, J=5.8 Hz, 1H), 8.23 (d, J=5.5 Hz, 1H), 7.31-7.24 (m, 1H), 7.20-7.13 (m, 3H), 7.12-7.06 (m, 2H), 5.15-5.04 (m, 1H), 4.90 (s, 1H), 3.76-3.66 (m, 1H), 3.54-3.46 (m, peaks obscured by solvent), 3.28-3.22 (m, peaks obscured by solvent), 3.10-2.96 (m, 4H), 2.71-2.62 (m, 5H), 2.55 (dd, J=11.8, 6.8 Hz, 1H), 2.01-1.92 (m, 2H), 1.61-1.49 (m, 2H). LCMS-A: RT 1.69 min; m/z 411.2 [M+H].sup.+.

Example 31: 6-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrazine-2-carboxamide 52

[0614] ##STR00175##

(a) tert-Butyl (1-acetylpiperidin-4-yl)carbamate A35

[0615] Acetic anhydride (4.71 mL, 49.9 mmol) was added to a solution of tert-butyl piperidin-4-ylcarbamate (10.0 g, 49.9 mmol) and triethylamine (10.4 mL, 74.9 mmol) in anhydrous DCM (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours before water (100 mL) and DCM (50 mL) were added. The organic phase was separated, washed with sat. aqueous NaHCO.sub.3 (100 mL) and dried (MgSO.sub.4). The solvent was removed in vacuo to give the desired compound as a white solid (10.72 g, 89%). .sup.1H NMR (400 MHz, chloroform-d) δ 4.54-4.42 (m, 2H), 3.80-3.70 (m, 1H), 3.70-3.58 (m, 1H), 3.12 (m, 1H), 2.78-2.65 (m, 1H), 2.07 (s, 3H), 2.05-1.97 (m, 1H), 1.96-1.87 (m, 1H), 1.43 (s, 9H), 1.36-1.20 (m, 2H).

(b) 1-Acetylpiperidin-4-aminium chloride A36

[0616] A solution of tert-butyl (1-acetylpiperidin-4-yl)carbamate A35 (10.72 g, 44.24 mmol) in dioxane (100 mL) was cooled to 0° C. and treated with 4.0 M HCl in dioxane (12.2 mL, 48.7 mmol). The white precipitate was isolated by filtration and found to contain starting material. The precipitate was dissolved in MeOH (100 mL) and treated with 4.0 M HCl in dioxane (12.2 mL, 48.7 mmol) and the mixture was stirred at room temperature for 16 hours. Another aliquot of 4.0 M HCl in dioxane (6.10 mL, 24.4 mmol) was added and the reaction mixture was stirred for 1.5 hours at 40° C. The volatiles were removed in vacuo and the white solid was dried under high vacuum to give the desired compound (8.60 g, ˜90% purity, >95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52-8.23 (m, 3H), 4.39-4.26 (m, 1H), 3.89-3.77 (m, 1H), 3.28-3.14 (m, 1H), 3.11-3.00 (m, 1H), 2.65-2.54 (m, 1H), 1.99 (s, 3H), 1.97-1.86 (m, 2H), 1.54-1.41 (m, 1H), 1.41-1.27 (m, 1H).

[0617] A mixture of 6-chloropyrazine-2-carboxylic acid (0.122 g, 0.771 mmol), DIPEA (0.24 mL, 1.4 mmol), HATU (0.293 g, 0.771 mmol) and DCM (10 mL) was stirred at room temperature under an atmosphere of nitrogen for 15 minutes. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I12 (0.250 g, 0.701 mmol) in DCM (5 mL) was then added and the mixture was stirred at room temperature overnight. The mixture was quenched by the addition of an aqueous NaOH solution (2 M, 20 mL) and H.sub.2O (10 mL). DCM (10 mL) was added and the mixture was separated. The aqueous was extracted with DCM (2×30 mL), the organic layers were combined and the solvent removed in vacuo. The resultant residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-10% MeOH (containing 1% v/v TEA) in DCM) to give the desired compound as a yellow oil (0.208 g, 60%). .sup.1H NMR (400 MHz, chloroform-d) δ 9.21 (s, 1H), 8.74 (s, 1H), 7.96 (s, 1H), 7.20-7.13 (m, 2H), 7.10-7.02 (m, 3H), 6.49-6.32 (m, 2H), 4.31-4.09 (m, 1H), 3.62-3.50 (m, 2H), 3.39-3.30 (m, 1H), 3.12-2.89 (m, 4H), 2.80 (s, 6H), 2.57-2.38 (m, 2H), 1.61 (s, 2H). LCMS-B: RT 3.66 min; m/z 497.3 [M+H].sup.+.

(d) 6-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrazine-2-carboxamide A38

[0618] A mixture of 6-chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrazine-2-carboxamide A37 (0.108 g, 0.217 mmol), 1-acetylpiperidin-4-aminium chloride A36 (0.058 g, 0.33 mmol), Cs.sub.2CO.sub.3 (0.354 g, 1.09 mmol), xantphos (0.006 g, 0.01 mmol) and Pd.sub.2(dba).sub.3 (0.010 g, 0.01 mmol) in 1,4-dioxane (5 mL) was bubbled with nitrogen for 10 min. The mixture was then stirred in the microwave at 120° C. for 20 minutes. The mixture was diluted with EtOAc and the solids removed by filtration. The filtrate solvent was removed in vacuo and the residue was taken up in toluene (5 mL). An extra portion of 1-acetylpiperidin-4-aminium chloride A36 (0.058 g, 0.33 mmol), rac-BINAP (0.014 g, 0.022 mmol), Pd.sub.2(dba).sub.3 (0.020 g, 0.022 mmol), and t-BuOK (0.196 g, 1.75 mmol) were added and the mixture was bubbled with nitrogen for 10 minutes before heating in the microwave at 120° C. for 30 minutes. The solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) to give the desired compound as a yellow oil (0.032 g, 24%). LCMS-B: RT 3.32 min; m/z 603.4 [M+H].sup.+.

(e) 6-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrazine-2-carboxamide 52

[0619] A mixture of 6-((1-acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrazine-2-carboxamide A38 (0.032 g, 0.053 mmol) and TFA (5 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature and the volatiles were removed in vacuo. Water (30 mL) and aqueous NaOH (2 M) were added to the residue and the mixture was extracted with DCM (3×30 mL), dried (MgSO.sub.4) and the solvent removed in vauco. The resultant oil was dissolved in a minimum amount of DCM and a solid was precipitated by the addition of cyclohexane. The solid was isolated by vacuum filtration and air dried to give the desired compound as a yellow solid (0.013 g, 54%, ˜90% purity as assessed by .sup.1H NMR). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.37 (t, J=5.9 Hz, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.19-7.13 (m, 2H), 7.12-7.06 (m, 2H), 5.05 (s, 1H), 4.25-4.16 (m, 1H), 4.12-4.03 (m, 1H), 3.85-3.71 (m, 4H), 3.28-3.16 (m, peaks obscured by solvent), 3.10-3.00 (m, 2H), 2.85 (t, J=12.1 Hz, 1H), 2.71-2.58 (m, 4H), 2.01-1.98 (m, 3H), 1.97-1.87 (m, 2H), 1.29-1.21 (m, peaks obscured by solvent). LCMS-B: RT 3.18 min; m/z 453.3 [M+H].sup.+.

Example 32: 5-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)nicotinamide 53

[0620] ##STR00176##

(a) Methyl 5-bromonicotinate A39

[0621] A mixture of 5-bromonicotinic acid (1.00 g, 4.95 mmol), sulfuric acid (98%, 0.5 mL) and MeOH (20 mL) was stirred at 80° C. for 16 hours. The volatiles were removed in vacuo and H.sub.2O (10 mL) and aqueous NaOH (2 M, 20 mL) were added to the residue. The aqueous was extracted with DCM (40 mL) and the mixture passed through an Isolute Phase Separator. The aqueous was extracted further with DCM (2×40 mL) with the mixture passed through an Isolute Phase Separator after each extraction. The organic layers were combined and the solvent removed in vacuo to give the desired compound as a yellow solid (0.822 g, 77%). 1H NMR (400 MHz, chloroform-d) δ 9.12 (d, J=1.8 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.45-8.42 (m, 1H), 3.97 (s, 3H). LCMS-B: RT 3.56 min; m/z 216/218 [M+H].sup.+.

(b) Methyl 5-((1-acetylpiperidin-4-yl)amino)nicotinate A40

[0622] A mixture of methyl 5-bromonicotinate A39 (0.500 g, 2.31 mmol), 1-acetylpiperidin-4-aminium chloride A36 (0.620 g, 3.47 mmol), Cs.sub.2CO.sub.3 (3.77 g, 11.6 mmol), xantphos (0.067 g, 0.12 mmol) and Pd.sub.2(dba).sub.3 (0.106 g, 0.116 mmol) in 1,4-dioxane (25 mL) was bubbled with nitrogen for 10 min. The mixture was stirred under an atmosphere of nitrogen at 80° C. for 16 hours. Starting material was still present after this time, so another portion of Cs.sub.2CO.sub.3 (3.77 g, 11.6 mmol), xantphos (0.067 g, 0.12 mmol) and Pd.sub.2(dba).sub.3 (0.106 g, 0.116 mmol) were added. The mixture was stirred under an atmosphere of nitrogen at 80° C. for 5 days. The mixture was returned to room temperature and diluted with EtOAc (50 mL), filtered and the filtrate was concentrated in vacuo. The crude solid was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% MeOH in EtOAc) to give the desired compound as a yellow solid (0.273 g, 43%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.26 (d, J=1.8 Hz, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.41-7.39 (m, 1H), 6.18 (d, J=8.1 Hz, 1H), 4.24-4.17 (m, 1H), 3.84 (s, 3H), 3.81-3.73 (m, 1H), 3.64-3.54 (m, 1H), 3.25-3.15 (m, 1H), 2.88-2.79 (m, 1H), 2.01 (s, 3H), 1.96-1.83 (m, 2H), 1.36-1.19 (m, 2H). LCMS-B: RT 3.06 min; m/z 278.2 [M+H].sup.+.

[0623] A mixture of methyl 5-((1-acetylpiperidin-4-yl)amino)nicotinate A40 (0.273 g, 0.984 mmol), LiOH.H.sub.2O (0.413 g, 9.84 mmol), THF (7 mL), MeOH (7 mL) and H.sub.2O (1.5 mL) was stirred at 40° C. for 3 hours. The mixture was returned to room temperature and the volatiles were removed in vacuo. Water (20 mL) was added and the pH was adjusted to ˜6 with aqueous HCl (2 M). A yellow precipitate was removed by filtration and the aqueous filtrate was passed through an Oasis HLB 35 cc LP extraction cartridge (6 g). The cartridge was washed with 3 column volumes of water before the lipophilic component was eluted with 3 column volumes of MeOH. Evaporation of the MeOH in vacuo gave the desired compound as a yellow oil (0.144 g, 56%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27-8.22 (m, 2H), 8.15 (d, J=2.8 Hz, 1H), 7.40-7.36 (m, 1H), 6.07 (d, J=8.0 Hz, 1H), 4.26-4.16 (m, 1H), 3.80-3.74 (m, 1H), 3.60-3.53 (m, peaks obscured by solvent), 3.24-3.16 (m, peaks obscured by solvent), 2.87-2.77 (m, 1H), 2.00 (s, 3H), 1.96-1.84 (m, 2H), 1.36-1.16 (m, 2H). LCMS-B: RT 1.80 min; m/z 264.2 [M+H].sup.+.

(d) 5-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)nicotinamide A42

[0624] A mixture of 5-((1-acetylpiperidin-4-yl)amino)nicotinic acid A41 (0.050 g, 0.19 mmol), DIPEA (60 μL, 0.35 mmol) and HATU (0.072 g, 0.19 mmol) in DCM (5 mL) was stirred for 15 minutes at room temperature under an atmosphere of nitrogen. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I12 (0.062 g, 0.17 mmol) in DCM (5 mL) was then added and the mixture was stirred for 4 hours at room temperature. Aqueous NaOH (2 M, 20 mL) was added and the aqueous was extracted with DCM (3×30 mL). The organic layers were combined, filtered through a Biotage phase separator and the volatiles removed in vacuo. The residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-20% MeOH in DCM) to give the desired compound as a colourless oil (0.066 g, 64%). LCMS-B: RT 3.51 min; m/z 602.4 [M+H].sup.+.

(e) 5-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)nicotinamide 53

[0625] A mixture of 5-((1-acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)nicotinamide A42 (0.066 g, 0.11 mmol) and TFA (5 mL) was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and the volatiles were removed in vacuo. Water (30 mL) was added to the residue and the aqueous was washed with DCM (3×20 mL). The aqueous layer was made basic by the addition of aqueous NaOH (2 M) and the mixture was extracted with DCM (3×30 mL). The organic extract was filtered through a Biotage phase separator cartridge and the solvent was removed in vacuo. The colourless oil was dissolved in a minimum amount of DCM and a solid was precipitated by the addition of cyclohexane. The solid was isolated by vacuum filtration and air dried to give the desired compound as a white solid (0.040 g, 81%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (t, J=5.7 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.32-7.26 (m, 1H), 7.19-7.14 (m, 2H), 7.12-7.07 (m, 2H), 6.02 (d, J=8.0 Hz, 1H), 4.96-4.84 (m, 1H), 4.27-4.17 (m, 1H), 3.82-3.75 (m, 1H), 3.73-3.67 (m, 1H), 3.60-3.53 (m, 1H), 3.52-3.46 (m, 1H), 3.29-3.14 (m, peaks obscured by solvent), 3.09-3.00 (m, 2H), 2.85-2.77 (m, 1H), 2.69-2.61 (m, 3H), 2.57-2.52 (m, peaks obscured by solvent), 2.00 (s, 3H), 1.93-1.84 (m, 2H), 1.37-1.15 (m, 2H). LCMS-B: RT 3.10 min; m/z 452.3 [M+H].sup.+.

Example 33: 2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide 54

[0626] ##STR00177##

(a) 2-Chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A43

[0627] A mixture of 2-chloropyrimidine-4-carboxylic acid (0.122 g, 0.771 mmol), DIPEA (0.24 mL, 1.4 mmol), HATU (0.293 g, 0.771 mmol) and DCM (10 mL) was stirred at room temperature under an atmosphere of nitrogen for 15 minutes. A solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I12 (0.250 g, 0.701 mmol) in DCM (5 mL) was then added and the mixture was stirred at room temperature overnight. The mixture was quenched by the addition of an aqueous NaOH solution (2 M, 20 mL) and H.sub.2O (10 mL). DCM (10 mL) was added and the mixture was separated. The aqueous was extracted with DCM (2×30 mL), the organic phases were combined and the solvent removed in vacuo. The resultant residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-10% MeOH (containing 1% v/v TEA) in DCM) to give the desired compound as a yellow oil (0.253 g, 73%). LCMS-B: RT 3.67 min; m/z 497.3 [M+H].sup.+.

(b) 2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A44

[0628] A mixture of 2-chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A43 (0.100 g, 0.201 mmol), 1-acetylpiperidin-4-aminium chloride A36 (0.108 g, 0.604 mmol), triethylamine (0.28 mL, 2.0 mmol) and i-PrOH (5 mL) was heated in the microwave at the following temperatures for the amount of time indicated, with a TLC of the reaction mixture conducted after each heating period: 110° C. for 10 minutes; 110° C. for 15 minutes; 120° C. for 15 minutes; 120° C. for 15 minutes; 130° C. for 10 minutes; 150° C. for 10 minutes. The solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-10% MeOH (containing 1% v/v TEA) in DCM) to give the desired compound as a yellow oil (0.022 g, 18%). LCMS-B: RT 3.33 min; m/z 603.5 [M+H].sup.+.

(c) 2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide 54

[0629] A solution of 2-((1-acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A44 (0.022 g, 0.037 mmol) in TFA (5 mL) was stirred at 70° C. for 16 hours. The volatiles were removed in vacuo before the residue was diluted with H.sub.2O (10 mL). The aqueous phase was washed with DCM (3×30 mL) and then made basic by the addition of an aqueous NaOH solution (2 M). The aqueous was extracted with DCM (3×20 mL), the organic layers were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo. The crude residue was dissolved in a minimum amount of DCM and a precipitate formed by the addition of cyclohexane. The precipitate was isolated by vacuum filtration and air dried to give the desired compound as a white solid (0.006 g, 36%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.60-8.24 (m, 2H), 7.46 (s, 1H), 7.20-7.14 (m, 2H), 7.12-7.04 (m, 3H), 5.04 (s, 1H), 4.27 (d, J=13.3 Hz, 1H), 4.04 (s, 1H), 3.86-3.63 (m, 2H), 3.57-3.41 (m, peaks obscured by solvent), 3.19-2.99 (m, 3H), 2.80-2.57 (m, 6H), 2.00 (s, 3H), 1.95-1.81 (m, 2H), 1.45-1.24 (m, peaks obscured by solvent). LCMS-A: RT 4.41 min; m/z 453.3 [M+H].sup.+.

Example 35: (R)-2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 55

[0630] ##STR00178##

(a) Methyl 2-bromoisonicotinate A45

[0631] A solution of 2-bromoisonicotinic acid (5.00 g, 24.8 mmol) in MeOH (50 mL) was treated with sulfuric acid (98%, 0.50 mL, 9.4 mmol) and the reaction mixture was stirred at 80° C. for 1 hour. The mixture was returned to room temperature and stirred for a further 96 hours before heating to 80° C. and stirring for 24 hours. The reaction mixture was cooled to room temperature, and the volatiles were removed in vacuo. Aqueous NaOH (2 M, 50 mL) was added to the residue and the aqueous was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo to give the desired compound as a yellow oil (4.14 g, 77%). .sup.1H NMR (400 MHz, chloroform-d) δ 8.52 (dd, J=5.0, 0.8 Hz, 1H), 8.04 (t, J=1.2 Hz, 1H), 7.80 (dd, J=5.0, 1.4 Hz, 1H), 3.96 (s, 3H). LCMS-B: RT 3.55 min; m/z 216/218 [M+H].sup.+.

(b) Methyl 2-((1-acetylpiperidin-4-yl)amino)isonicotinate A46

[0632] A mixture of 1-acetylpiperidin-4-aminium chloride A36 (2.25 g, 12.6 mmol), methyl 2-bromoisonicotinate A45 (1.81 g, 8.38 mmol), Cs.sub.2CO.sub.3 (10.92 g, 33.51 mmol), xantphos (0.242 g, 0.419 mmol) and Pd.sub.2(dba).sub.3 (0.384 g, 0.419 mmol) in 1,4-dioxane (40 mL) was bubbled with nitrogen for 10 min. The mixture was then stirred under an atmosphere of nitrogen at 80° C. for 24 hours. Another portion of Cs.sub.2CO.sub.3 (5.46 g, 16.8 mmol), xantphos (0.121 g, 0.209 mmol) and Pd.sub.2(dba).sub.3 (0.192 g, 0.210 mmol) were added and the mixture was stirred under an atmosphere of nitrogen at 80° C. for 5 days. The reaction mixture was returned to room temperature and diluted with EtOAc (150 mL). Solid impurities were removed by filtration and the filtrate solvent was removed in vacuo. The resultant solid was purified by column chromatography (Biotage Isolera, 40 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% MeOH (containing 1% v/v TEA) in EtOAc) to give the desired compound as a yellow solid (0.558 g, 24%). LCMS-B: RT 3.05 min; m/z 278.2 [M+H].sup.+.

[0633] A mixture of methyl 2-((1-acetylpiperidin-4-yl)amino)isonicotinate A46 (0.558 g, 2.01 mmol), LiOH.H.sub.2O (1.69 g, 40.2 mmol), THF (7 mL), MeOH (7 mL) and H.sub.2O (1.5 mL) was stirred at 40° C. for 2 hours. The mixture was returned to room temperature and the volatiles were removed in vacuo. Water (30 mL) was added and the pH was adjusted to ˜6 with aqueous HCl (2 M). The aqueous was passed through an Oasis HLB 35 cc LP extraction cartridge (6 g) which was washed with 4 column volumes of water. The lipophilic component was then eluted with 4 column volumes of MeOH. Evaporation of the MeOH in vacuo gave the desired compound as a yellow solid (0.197 g, 37%). The aqueous phase from the first iteration of cartridge purification was passed through another Oasis HLB 35 cc LP extraction cartridge (6 g). The column was washed with 4 column volumes of water and the product was eluted with 4 column volumes of MeOH. Evaporation of the MeOH in vacuo gave the desired compound as a white solid (0.128 g, 24%; overall yield: 0.325 g, 61%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (d, J=5.2 Hz, 1H), 6.98 (s, 1H), 6.86-6.79 (m, 2H), 4.26-4.16 (m, 1H), 4.03-3.90 (m, 1H), 3.81-3.72 (m, 1H), 3.21-3.12 (m, 1H), 2.85-2.74 (m, 1H), 2.00 (s, 3H), 1.97-1.83 (m, 2H), 1.41-1.16 (m, 2H); —OH not observed. LCMS-B: RT 1.17 min; m/z 262.1 [M−H].sup.−.

(d) (R)-2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 55

[0634] A mixture of 2-((1-acetylpiperidin-4-yl)amino)isonicotinic acid A47 (0.067 g, 0.26 mmol), DIPEA (63 μL, 0.36 mmol), HATU (0.097 g, 0.26 mmol) and DCM (5 mL) was stirred at room temperature for 15 minutes. A solution of (S)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I4 (0.050 g, 0.24 mmol) in DCM (5 mL) was then added and the mixture was stirred for 16 hours at room temperature. Water (20 mL) was added and the aqueous was extracted with DCM (3×30 mL). The organic layers 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, 24 g SiO.sub.2 cartridge, 0-30% MeOH (containing 1% v/v TEA) in DCM) to give a colourless oil. The oil was taken up in a minimum amount of DCM and the product was precipitated by the addition of cyclohexane. The product was isolated by vacuum filtration and air dried to give the desired compound as a white solid (0.011 g, 10%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (t, J=5.7 Hz, 1H), 8.02 (d, J=5.2 Hz, 1H), 7.21-7.14 (m, 2H), 7.12-7.06 (m, 2H), 6.84 (s, 1H), 6.77 (d, J=5.5 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 4.93 (s, 1H), 4.28-4.14 (m, 1H), 4.02-3.88 (m, 1H), 3.83-3.66 (m, 2H), 3.52 (p, J=6.6, 6.6, 6.5, 6.5 Hz, 1H), 3.29-3.12 (m, 3H), 3.11-3.00 (m, 2H), 2.82-2.74 (m, 1H), 2.72-2.62 (m, 3H), 2.59-2.53 (m, 1H), 2.00 (s, 3H), 1.96-1.81 (m, 2H), 1.38-1.14 (m, 2H); N—H not observed. LCMS-B: RT 3.11 min; m/z 452.3 [M+H].sup.+.

Example 36: (S)-2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 56

[0635] ##STR00179##

(a) (R)-2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A48

[0636] A mixture of 2-((1-acetylpiperidin-4-yl)amino)isonicotinic acid A47 (0.075 g, 0.29 mmol), DIPEA (68 μL, 0.39 mmol), HATU (0.108 g, 0.285 mmol) and DCM (10 mL) was stirred at room temperature for 15 minutes. A solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10 (0.092 g, 0.26 mmol) in DCM (5 mL) was then added and the mixture was stirred for 24 hours at room temperature. Water (30 mL) was added and the aqueous was extracted with DCM (3×30 mL). The organic layers 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, 12 g SiO.sub.2 cartridge, 0-20% MeOH (containing 1% v/v TEA) in DCM) to give the desired compound as a colourless oil (0.084 g, 54%). LCMS-B: RT 3.28 min; m/z 602.5 [M+H].sup.+.

(b) (S)-2-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide 56

[0637] A mixture of (R)-2-((1-acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A48 (0.080 g, 0.13 mmol) and TFA (5 mL) was stirred at 70° C. for 16 hours. The volatiles were removed in vacuo before the residue was diluted with H.sub.2O (20 mL). The aqueous phase was washed with DCM (3×30 mL) and then made basic by the addition of solid NaHCO.sub.3. The aqueous was extracted with DCM (3×30 mL), the organic layers 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, 24 g SiO.sub.2 cartridge, 0-40% MeOH (containing 1% v/v TEA) in DCM) to give a colourless oil. The oil was dissolved in a minimum amount of DCM and the product was precipitated by the addition of cyclohexane. The solid was isolated by vacuum filtration and air dried to give the desired compound as a white solid (0.030 g, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (t, J=5.7 Hz, 1H), 8.02 (d, J=5.3 Hz, 1H), 7.21-7.14 (m, 2H), 7.13-7.06 (m, 2H), 6.84 (s, 1H), 6.77 (d, J=5.3 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 4.92 (s, 1H), 4.27-4.15 (m, 1H), 4.04-3.89 (m, 1H), 3.83-3.66 (m, 2H), 3.58-3.47 (m, 1H), 3.30-3.22 (m, peaks obscured by solvent), 3.20-3.12 (m, 1H), 3.10-3.00 (m, 2H), 2.84-2.74 (m, 1H), 2.72-2.62 (m, 3H), 2.60-2.52 (m, 1H), 2.00 (s, 3H), 1.97-1.82 (m, 2H), 1.38-1.15 (m, 2H). LCMS-B: RT 3.09 min; m/z 452.3 [M+H].sup.+.

Example 37: 6-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)picolinamide 57

[0638] ##STR00180##

(a) Ethyl 6-((1-acetylpiperidin-4-yl)amino)picolinate A49

[0639] A mixture of 1-acetylpiperidin-4-aminium chloride A36 (0.231 g, 1.29 mmol), 6-bromopyridine-2-carboxylic acid ethyl ester (0.198 g, 0.862 mmol), Cs.sub.2CO.sub.3 (1.40 g, 4.31 mmol), xantphos (0.025 g, 0.043 mmol) and Pd.sub.2(dba).sub.3 (0.039 g, 0.043 mmol) in 1,4-dioxane (10 mL) was bubbled with nitrogen for 10 min. The mixture was then stirred under an atmosphere of nitrogen at 80° C. for 16 hours. The reaction mixture was returned to room temperature and diluted with MeOH (20 mL). Solid impurities were removed by filtration and the filtrate solvent was removed in vacuo. The resultant solid was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% MeOH in EtOAc) to give the desired compound as a yellow oil (0.121 g, 48%). LCMS-A: RT 4.65 min; m/z 292.2 [M+H].sup.+.

(b) 6-((1-Acetylpiperidin-4-yl)amino)picolinic acid A50

[0640] A mixture of ethyl 6-((1-acetylpiperidin-4-yl)amino)picolinate A49 (0.121 g, 0.415 mmol), LiOH.H.sub.2O (0.349 g, 8.31 mmol), MeOH (7 mL), THF (7 mL) and H.sub.2O (1.5 mL) was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the resultant solid was taken up in H.sub.2O (10 mL) and the aqueous adjusted to pH ˜6 with aqueous HCl (2 M). The mixture was loaded onto an Oasis HLB 35 cc LP extraction cartridge (6 g) which was washed with 3 column volumes of water. The lipophilic component was then eluted with 3 column volumes of MeOH. Evaporation of the MeOH in vacuo gave the desired compound as a yellow solid (0.097 g, 89%). .sup.1H NMR (400 MHz, chloroform-d) δ 7.91-7.82 (m, 1H), 7.46 (d, J=7.2 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.25 (s, 1H), 3.99-3.88 (m, 1H), 3.80 (s, 1H), 3.41-3.31 (m, 1H), 3.29-3.14 (m, 1H), 2.13 (s, 3H), 2.09-1.94 (m, 2H), 1.83 (s, 1H), 1.74-1.60 (m, 1H). LCMS-A: RT 1.75 min; m/z 264.2 [M+H].sup.+.

[0641] A mixture of 6-((1-acetylpiperidin-4-yl)amino)picolinic acid A50 (0.097 g, 0.37 mmol), triethylamine (0.20 mL, 1.5 mmol), and DCM (5 mL) was cooled to 0° C. under a nitrogen atmosphere before isobutyl chloroformate (48 μL, 0.37 mmol) was added. The mixture was stirred for 20 min at 0° C. before being transferred via syringe to a solution of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.076 g, 0.37 mmol) in DCM (5 mL) at 0° C. After 2 h the mixture was diluted with DCM (10 mL), water (10 mL) and aqueous sodium hydroxide (2 M, 10 mL). The separated aqueous phase was extracted with DCM (2×15 mL), the pooled DCM extracts washed with brine (25 mL), dried (MgSO.sub.4) and the solvent evaporated in vacuo. The residue was purified by column chromatography (Biotage Isolera, 12 g SiO.sub.2 cartridge, 0-20% MeOH (containing 1% v/v 2 M NH.sub.3 in MeOH) in DCM) to give the desired compound as a white solid (0.049 g, 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.66-8.55 (m, 1H), 7.57-7.47 (m, 1H), 7.28-7.21 (m, 2H), 7.20-7.14 (m, 3H), 6.82 (d, J=7.7 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.92-5.81 (m, 1H), 4.27-4.14 (m, 2H), 4.09-3.96 (m, 2H), 3.82-3.67 (m, 1H), 3.52-3.38 (m, 2H), 3.30-3.21 (m, 3H), 3.18-3.03 (m, 3H), 2.96-2.84 (m, 2H), 2.03-1.96 (m, 3H), 1.96-1.83 (m, 2H), 1.38-1.20 (m, 2H); N—H not observed. LCMS-A: RT 4.46 min; m/z 452.3 [M+H].sup.+.

Example 38: 6-((1-Acetylazetidin-3-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetic acid salt 58

[0642] ##STR00181##

(a) tert-Butyl (1-acetylazetidin-3-yl)carbamate A51

[0643] Acetic anhydride (0.81 mL, 8.6 mmol) was added to a solution of tert-butyl azetidin-3-ylcarbamate (0.990 g, 5.75 mmol) and TEA (1.20 mL, 8.62 mmol) in DCM (20 mL) at 0° C. The mixture was stirred for 2 hours at 0° C. before water (50 mL) was added. The organic phase was separated and the aqueous was extracted with DCM (2×25 mL). The organic layers were combined, washed with brine and dried (MgSO.sub.4). The solvent was removed in vacuo to give the desired compound as a colourless oil (0.915 g, 74%). .sup.1H NMR (400 MHz, chloroform-d) δ 5.13-4.92 (m, 1H), 4.55-4.34 (m, 2H), 4.28 (t, J=9.2 Hz, 1H), 3.94 (dd, J=8.7, 4.8 Hz, 1H), 3.79 (dd, J=10.4, 4.9 Hz, 1H), 1.86 (s, 3H), 1.44 (s, 9H).

(b) 1-(3-Aminoazetidin-1-yl)ethan-1-one A52

[0644] A solution of tert-butyl (1-acetylazetidin-3-yl)carbamate A51 (0.879 g, 4.10 mmol) in MeOH (20 mL) was stirred with HCl (˜1.25 M in MeOH, 3.61 mL, 4.51 mmol) at room temperature for 30 minutes. Another aliquot of HCl (˜1.25 M in MeOH, 3.61 mL, 4.51 mmol) was added and the mixture was stirred for a further 16 hours at room temperature. TLC showed the continued presence of starting material, so another aliquot of HCl (˜1.25 M in MeOH, 7.22 mL, 9.03 mmol) was added. The mixture was stirred for 2 hours at room temperature and then at 45° C. for 2 hours. The solvent was evaporated under reduced pressure and the resultant residue was taken up in DCM (10 mL) and treated with TFA (3.14 mL, 41.0 mmol). The mixture was stirred for 3 hours at room temperature before the volatiles were removed in vacuo. The residue was taken up in MeOH and loaded onto an SCX cartridge (BondElut, 10 g). The column was washed with 5 column volumes of MeOH before the desired product was eluted with 5 column volumes of 3.5 M NH.sub.3 in MeOH. The basic fractions were combined and the solvent removed in vacuo to give the desired compound as a yellow oil (0.505 g, ˜90% purity, >95% yield). .sup.1H NMR (400 MHz, chloroform-d) δ 4.39-4.29 (m, 1H), 4.27-4.19 (m, 1H), 3.90-3.72 (m, 2H), 3.70-3.59 (m, 1H), 1.86 (s, 3H); —NH.sub.2 not observed.

[0645] Oxalyl chloride (15.3 mL, 0.178 mol) was added to a mixture of 6-hydroxypyrimidine-4-carboxylic acid (5.00 g, 35.7 mmol) in EtOAc (50 mL). The mixture was stirred at room temperature for 20 min before DMF (0.1 mL) was added and stirring continued at 80° C. for 16 hours. The volatiles were removed in vacuo and the residue was azeotroped with toluene (×3) to give the desired compound as a black solid (5.87 g, 93%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.23 (d, J=1.1 Hz, 1H), 8.15 (d, J=1.1 Hz, 1H).

(d) 6-Chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A54

[0646] A solution of 6-chloropyrimidine-4-carbonyl chloride A53 (0.179 g, 1.01 mmol) in DCM (10 mL) was slowly added to a mixture of 1-amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.250 g, 1.21 mmol) and TEA (1.41 mL, 10.1 mmol) in DCM (10 mL) at 0° C. under an atmosphere of nitrogen. The mixture was slowly allowed to return to room temperature and stirred for a further 16 hours under a balloon of nitrogen. Water (20 mL) and an aqueous NaOH solution (2 M, 10 mL) were added and the mixture was extracted with DCM (3×30 mL). The organic layers were combined, washed with brine and dried (MgSO.sub.4). The solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO.sub.2 cartridge, 0-10% MeOH (containing 1% v/v 2 M NH.sub.3 in MeOH) in DCM) to give the desired compound as a white solid (0.111 g, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (d, J=0.6 Hz, 1H), 9.07 (t, J=5.8 Hz, 1H), 8.08 (d, J=1.1 Hz, 1H), 7.20-7.14 (m, 2H), 7.12-7.06 (m, 2H), 5.06-4.92 (m, 1H), 3.80-3.68 (m, 1H), 3.53-3.46 (m, 1H), 3.45-3.38 (m, peaks obscured by solvent), 3.10-3.00 (m, 2H), 2.70-2.57 (m, 4H). LCMS-A: RT 4.46 min; m/z 347.1 [M+H].sup.+.

(e) 6-((1-Acetylazetidin-3-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetic acid salt 58

[0647] A mixture of 1-(3-aminoazetidin-1-yl)ethan-1-one A52 (0.013 g, ˜90% purity, 0.10 mmol), 6-chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A54 (0.035 g, 0.10 mmol), triethylamine (0.056 mL, 0.40 mmol) and i-PrOH (5 mL) was stirred at 70° C. for 1 hour and then 75° C. for 60 hours. The mixture was returned to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage Isolera, 4 g SiO.sub.2 cartridge, 0-20% MeOH (containing 1% v/v NEt.sub.3) in DCM). The resultant white solid was purified further by RP-HPLC (5-100% CH.sub.3CN in water containing 0.1% TFA over 20 minutes) to give the TFA salt of the desired compound (0.020 g, 37% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60-8.50 (m, 1H), 7.29-7.24 (m, 2H), 7.23-7.17 (m, 3H), 4.83-4.72 (m, 1H), 4.64-4.54 (m, 1H), 4.40-4.30 (m, 1H), 4.16-4.05 (m, 3H), 3.90 (dd, J=10.4, 5.2 Hz, 1H), 3.60-3.47 (m, 2H), 3.46-3.37 (m, 2H), 3.25 (dd, J=12.6, 3.1 Hz, 1H), 3.18-3.09 (m, 2H), 3.03 (dd, J=12.8, 9.4 Hz, 1H), 1.90 (s, 3H). LCMS-A: RT 1.67 min; m/z 459.1 [M+Cl].sup.−, 423.2 [M−H].sup.−.

Example 39: 6-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetic acid salt 59

[0648] ##STR00182##

[0649] A mixture of 1-acetylpiperidin-4-aminium chloride A36 (0.026 g, 0.14 mmol), 6-chloro-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)pyrimidine-4-carboxamide A54 (0.050 g, 0.14 mmol), triethylamine (0.080 mL, 0.58 mmol) and i-PrOH (5 mL) was stirred at 60° C. for 16 hours. Another aliquot of triethylamine (0.16 mL, 1.1 mmol) was added and the mixture was stirred at 60° C. for 3 hours and then at 70° C. for 16 hours. Another aliquot of triethylamine (0.24 mL, 1.7 mmol) was added and the mixture was stirred at 70° C. for 4.5 hours. A final addition of triethylamine (1.0 mL, 7.2 mmol) was followed by stirring of the reaction mixture for 16 hours at 75° C. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (Biotage Isolera, 4 g SiO.sub.2 cartridge, 0-20% MeOH (containing 1% v/v 2 M NH.sub.3/MeOH) in DCM). The resultant white solid was purified further by RP-HPLC (5-100% CH.sub.3CN in water containing 0.1% TFA over 20 minutes) to give the TFA salt of the desired compound (0.026 g, 32% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.55 (s, 1H), 7.28-7.24 (m, 2H), 7.23-7.19 (m, 2H), 7.16 (s, 1H), 4.47 (d, J=13.4 Hz, 1H), 4.34-4.18 (m, 1H), 4.16-4.06 (m, 2H), 4.01-3.91 (m, 1H), 3.59-3.47 (m, 2H), 3.46-3.37 (m, 2H), 3.28-3.22 (m, peak obscured by solvent), 3.20-3.09 (m, 2H), 3.09-2.98 (m, 1H), 2.93-2.82 (m, 1H), 2.13 (s, 3H), 2.12-1.98 (m, 2H), 1.61-1.39 (m, 2H); pyrimidine N—H, amide N—H, —OH and amine N—H not observed. LCMS-A: RT 4.28 min; m/z 487.2 [M+Cl].sup.−, 451.2 [M−H].sup.−.

Example 40: Amide Couplings

General Method X2

[0650] ##STR00183##

[0651] To a solution of the amine (0.20 mmol, 1 equiv) in DMF (2 mL) and MeCN (5 mL) was added 114 (100 mg, 0.198 mmol, 1 equiv), DIPEA (104 μL, 0.595 mmol, 3 equiv) and HATU (113 mg, 0.297 mmol, 1.5 equiv). The reaction was stirred at room temperature for 16 h. The mixture was quenched with a 1M aqueous solution of sodium hydroxide (10 mL) and stirred for 2 h at room temperature. Dichloromethane was added and the mixture stirred and then passed through a phase separation cartridge (3 repeats). The organic filtrates were dried in vacuo. The residue was taken up in TFA (0.5 mL) and stirred at 70° C. for 5 h. Water (2 mL) was added and the aqueous was washed with DCM (3×2 mL) and the layers separated using a phase separation cartridge. The aqueous was brought to pH ˜14 by the addition of aqueous NaOH (1 M) and then extracted with DCM (2×2 mL) using a phase separation cartridge to isolate the organic fraction. The organic layers were concentrated in vacuo. The residue was taken up in MeOH 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 desired compound.

General Method X3

[0652] ##STR00184##

[0653] To a solution of the acid (53 mg, 0.22 mmol, 1 equiv), in MeCN (3 mL) and DMF (1 mL) was added DIPEA (117 μL, 0.670 mmol, 3 equiv) and HATU (128 mg, 0.337 mmol, 1.5 equiv). A solution of the amine 110 (80 mg, 0.22 mmol, 1 equiv) in DMF (1 mL) was added and the solution stirred at room temperature for 16 h. The reaction was quenched with a 1M aqueous solution of NaOH (15 mL) and then extracted with dichloromethane (3×8 mL—separation using a phase separation cartridge). The pooled organic filtrates were concentrated in vacuo then TFA (0.5 mL) was added and the solution stirred at 70° C. for 5 h. The reaction was quenched by the addition of DCM (2 mL) and water (2 mL). The phases were thoroughly mixed and the aqueous layer isolated using a phase separation cartridge. The aqueous layer was brought to pH ˜14 by the addition of aqueous NaOH (1 M) and then extracted with DCM (2×2 mL) using a phase separation cartridge to isolate the organic fraction. The organic layers were concentrated in vacuo. The residue was taken up in MeOH 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 ammonia in methanol) to give the desired compound.

TABLE-US-00005 Example Name and Structure LCMS data Method 60 [00185] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(4- hydroxypiperidine-1- carbonyl)benzamide LCMS-B: RT = 3.13 min, m/z = 438 [M + H].sup.+ X2 61 [00186] (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(4- (hydroxymethyl)piperidine-1- carbonyl)benzamide LCMS-B: RT = 3.14 min, m/z = 452 [M + H].sup.+ X2 62 [00187] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-3- (morpholine-4-carbonyl)benzamide LCMS-A: RT = 3.39 min, m/z = 424 X3

Example 41: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(2-oxopiperidin-1-yl)benzamide 63

[0654] ##STR00188##

(a) N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(2-oxopiperidin-1-yl)benzamide 63

[0655] 1-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propan-2-ol I2 (0.084 g, 0.407 mmol), 4-(2-oxopiperidin-1-yl)benzoic acid (0.074 g, 0.339 mmol), EDCl (0.098 g, 0.509 mmol), HOBt (0.069 g, 0.509 mmol) and DIPEA (0.177 mL, 1.018 mmol) in dry DMF (5 mL) were stirred at room temperature for 45 hours under an atmosphere of nitrogen. The reaction was diluted with EtOAc (50 mL) and washed with a sat. aqueous NaHCO.sub.3 (50 mL), the aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a beige solid. Purification by column chromatography (Isolera Biotage, SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-35% MeOH in EtOAc) gave a gum which was triturated with diethyl ether and further air-dried to yield the desired compound (0.010 g, 7% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.47 (t, J=5.7 Hz, 1H), 7.85-7.79 (m, 2H), 7.40-7.33 (m, 2H), 7.21-7.14 (m, 2H), 7.14-7.06 (m, 2H), 4.91-4.85 (m, 1H), 3.76-3.66 (m, 1H), 3.66-3.61 (m, 2H), 3.49 (p, J=6.6 Hz, 1H), 3.38-3.23 (m, 3H, obscured by solvent signal), 3.09-3.00 (m, 2H), 2.70-2.61 (m, 3H), 2.58-2.52 (m, 1H), 2.44-2.38 (m, 2H), 1.93-1.80 (m, 4H). LCMS-B: RT 3.227 min, m/z 408.3 [M+H].sup.+

Example 42: 4-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl) benzamide 64

[0656] ##STR00189## ##STR00190##

(a) tert-Butyl 4-((4-(methoxycarbonyl)phenyl)amino)piperidine-1-carboxylate A55

[0657] Methyl 4-aminobenzoate (0.250 g, 1.654 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.494 g, 2.481 mmol) were dissolved in dry DCE (15 mL) under an atmosphere of nitrogen and acetic acid (0.189 mL, 3.308 mmol) was added followed by sodium triacetoxyborohydride (0.701 g, 3.308 mmol). The reaction was stirred at room temperature for 45 hours, then quenched by addition of water (5 mL) and diluted with EtOAc (50 mL) and sat. aqueous NaHCO.sub.3 (50 mL). The organic phase was washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo then purified by silica gel column chromatography (Isolera Biotage: 40 g SiO.sub.2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the desired compound (0.478 g, 86% yield) as a colourless oil which partly solidified upon standing. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92-7.84 (m, 2H), 6.74-6.53 (m, 2H), 4.16-3.98 (m, 2H), 3.86 (s, 3H), 3.48 (tt, J=10.4, 3.9 Hz, 1H), 2.95-2.82 (m, 2H), 2.08-1.99 (m, 2H), 1.49-1.35 (m, 11H). NH proton not visible. LCMS-B: RT 3.826 min; m/z 279.2 [M−.sup.tBu+H].sup.+.

(b) Methyl 4-(piperidin-4-ylamino)benzoate A56

[0658] tert-Butyl 4-((4-(methoxycarbonyl)phenyl)amino)piperidine-1-carboxylate A55 (0.475 g, 1.420 mmol) was dissolved in DCM (10 mL) under an atmosphere of nitrogen and trifluoroacetic acid (3.2 mL, 42.6 mmol) was added. The reaction was then stirred at room temperature for 2 hours. The volatiles were removed in vacua and the resulting residue diluted with EtOAc (50 mL) followed by sat. aqueous Na.sub.2CO.sub.3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL), the combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the desired compound (0.178 g, 53% yield) as a white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 7.70-7.64 (m, 2H), 6.62-6.57 (m, 2H), 6.44 (d, J=7.8 Hz, 1H), 3.73 (s, 3H), 2.99 (dt, J=12.8, 3.6 Hz, 2H), 2.60 (td, J=12.1, 2.6 Hz, 2H), 1.92-1.79 (m, 2H), 1.35-1.21 (m, 2H). One of NH protons not visible, CH proton obscured by solvent peak. LCMS-B: RT 3.179 min; m/z 235.2 [M+H].sup.+.

[0659] Methyl 4-(piperidin-4-ylamino)benzoate A56 (0.175 g, 0.747 mmol) was dissolved in DCM (7 mL) under an atmosphere of nitrogen and DIPEA (0.260 mL, 1.494 mmol) was added followed by acetic anhydride (0.070 mL, 0.747 mmol). The reaction was stirred at room temperature for 6 hours, then diluted with EtOAc (50 mL) followed by sat. aqueous Na.sub.2CO.sub.3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL), the combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the desired compound (0.170 g, 82% yield) as an off-white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 7.71-7.66 (m, 2H), 6.67-6.60 (m, 2H), 6.46 (d, J=7.8 Hz, 1H), 4.28-4.20 (m, 1H), 3.82-3.71 (m, 4H), 3.63-3.51 (m, 1H), 3.22-3.12 (m, 1H), 2.83-2.74 (m, 1H), 2.00 (s, 3H), 1.97-1.84 (m, 2H), 1.37-1.15 (m, 2H). LCMS-B: RT 3.333 and 3.376 (two major peaks present) min; m/z 277.2 [M+H].sup.+.

(d) 4-((1-Acetylpiperidin-4-yl)amino)benzoic acid A58

[0660] Methyl 4-((1-acetylpiperidin-4-yl)amino)benzoate A57 (0.168 g, 0.608 mmol) was dissolved in THF (7 mL), MeOH (1 mL) and water (1 mL) and lithium hydroxide monohydrate (0.077 g, 1.823 mmol) was added. The reaction was then stirred at room temperature for 70 hours. Additional lithium hydroxide monohydrate (0.154 g) was added and the reaction was stirred for another 8 hours and then heated to 40° C. and stirred for an additional 45 hours. The volatiles were removed in vacuo and the resulting residue diluted with EtOAc (50 mL) followed by 2M aqueous NaOH (50 mL). The layers were separated and the organic layer was washed with 2M aqueous NaOH (50 mL), the aqueous layers were combined and acidified by addition of 2 M aqueous HCl (checked with pH paper), then extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the desired compound (0.060 g, 38% yield) as an off-white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 12.04 (br s, 1H), 7.69-7.62 (m, 2H), 6.65-6.57 (m, 2H), 6.36 (d, J=7.9 Hz, 1H), 4.26-4.20 (m, 1H), 3.82-3.74 (m, 1H), 3.62-3.50 (m, 1H), 3.24-3.13 (m, 1H), 2.84-2.72 (m, 1H), 2.00 (s, 3H), 1.97-1.84 (m, 2H), 1.38-1.13 (m, 2H). LCMS-B: RT 3.134 and 3.196 (two major peaks present) min; m/z 263.2 [M+H].sup.+.

(e) 4-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxy benzyl) amino)-2-hydroxypropyl)benzamide A59

[0661] 4-((1-Acetylpiperidin-4-yl)amino)benzoic acid A58 (0.056 g, 0.213 mmol) was dissolved in DCM (5 mL) and DMF (0.5 mL) and DIPEA (0.068 mL, 0.388 mmol) followed by HATU (0.081 g, 0.213 mmol) were added. The mixture was then stirred at room temperature for 10 min before 1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol 112 (0.069 g, 0.194 mmol) in DCM (2 mL) was added. The reaction was then stirred at room temperature for 45 hours. The volatiles were removed in vacuo and the resulting residue diluted with EtOAc (50 mL) followed by sat. aqueous Na.sub.2CO.sub.3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL), the combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (Isolera Biotage, 12 g SiO.sub.2 Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-50% MeOH with 1% Et.sub.3N in EtOAc) to give the desired compound (0.062 g, 53% yield) as an off-white foam. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 7.90 (t, J=5.4 Hz, 1H), 7.61-7.52 (m, 2H), 7.28 (d, J=8.3 Hz, 1H), 7.20-7.02 (m, 4H), 6.60-6.54 (m, 2H), 6.49 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.3, 2.4 Hz, 1H), 6.07 (d, J=7.9 Hz, 1H), 4.67 (d, J=4.2 Hz, 1H), 4.27-4.18 (m, 1H), 3.81-3.66 (m, 9H), 3.60-3.46 (m, 3H), 3.30-3.24 (m, 1H), 3.23-3.08 (m, 2H), 3.00-2.74 (m, 5H), 2.48-2.39 (m, 1H), 2.00 (s, 3H), 1.97-1.82 (m, 2H), 1.36-1.19 (m, 2H). Missing one proton, possibly obscured behind solvent signal.

(f) 4-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxy propyl) benzamide 64

[0662] To 4-((1-Acetylpiperidin-4-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxy benzyl) amino)-2-hydroxypropyl)benzamide A59 (0.060 g, 0.100 mmol) was added TFA (4.0 mL) and the reaction was then stirred at 50° C. for 70 hours. The volatiles were removed in vacuo and the resulting residue was diluted with EtOAc (50 mL) followed by 2 M aqueous NaOH (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL), the combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the desired compound (0.031 g, 69% yield) as an off-white solid. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 8.06 (t, J=5.6 Hz, 1H), 7.62-7.56 (m, 2H), 7.22-7.15 (m, 2H), 7.14-7.07 (m, 2H), 6.61-6.54 (m, 2H), 6.08 (d, J=8.0 Hz, 1H), 4.92 (s, 1H), 4.27-4.17 (m, 1H), 3.83-3.74 (m, 1H), 3.72-3.65 (m, 1H), 3.58-3.48 (m, 2H), 3.30-3.13 (m, 3H, obscured by solvent signal), 3.11-3.00 (m, 2H), 2.84-2.74 (m, 1H), 2.73-2.62 (m, 3H), 2.55 (dd, J=11.7, 6.8 Hz, 1H), 2.00 (s, 3H), 1.97-1.82 (m, 2H), 1.35-1.16 (m, 2H). One NH proton not visible. LCMS-A: RT 4.427 min; m/z 451.3 [M+H].sup.+.

Example 43: (S)—N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(1,1-dioxidothiomorpholine-4-carbonyl)benzamide 65

[0663] ##STR00191##

(a) (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-4-(1,1-dioxidothiomorpholine-4-carbonyl)benzamide A60

[0664] (R)-4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid I14 (50 mg, 0.10 mmol), thiomorpholine dioxide (20 mg, 0.15 mmol), MeCN (1 mL), DIPEA (0.052 mL, 0.30 mmol) and HATU (41 mg, 0.11 mmol) were stirred at room temperature. After 2.5 hours methanol (1 mL) was added and the mixture concentrated in vacuo. Chromatography (4 g silica cartridge, 20-100% ethyl acetate/hexanes then 0-10% methanol/ethyl acetate) gave the desired compound as a pale yellow syrup (26 mg, 42% yield). LCMS: RT 3.38 min; m/z (positive ion): 622.4 [M+H].sup.+.

(b) (S)—N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-4-(1,1-dioxidothiomorpholine-4-carbonyl)benzamide 65

[0665] (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-4-(1,1-dioxidothiomorpholine-4-carbonyl)benzamide A60 (24 mg, 0.042 mmol) and TFA (3 mL) were stirred at 70° C. After four hours the mixture was concentrated in vacuo and the residue dissolved in methanol (3 mL). The mixture was loaded onto a 2 g SCX cartridge, the cartridge washed with methanol (25 mL) and eluted with 7M ammonia in methanol (15 mL). The basic eluate was concentrated to give the desired compound as a pale yellow syrup (15 mg, 84% yield). LCMS-B: RT 3.17 min; m/z (positive ion) 472.3 [M+H].sup.+.

Example 44: Amide Couplings

General Method A

[0666] ##STR00192##

[0667] To a stirred solution of the acid (1 eq.) and NEt.sub.3 (3.0 eq.) in dry DCM was added HATU (1.0 eq.). A solution of the amine 16 (1.0 eq.) in DCM was then added and the reaction stirred at room temperature overnight. The crude mixture was concentrated in vacuo and the residue obtained dissolved in DCM and washed with saturated aqueous NaHCO.sub.3. The aqueous layer was further extracted with DCM (×3) and the combined organic layers were dried (Na.sub.2SO.sub.4) then concentrated in vacuo. The crude material was purified by silica gel chromatography (DCM:MeOH=50:1) to yield the desired product.

General Method B

[0668] ##STR00193##

[0669] To a solution of the acid (1.0 eq.) and amine 16 (1.0 eq.) in DCM were added DIPEA (3.0 eq.), HOBt (0.1 eq.) and EDCl (2.0 eq.). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction and the mixture extracted with DCM (×3). 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 column chromatography (DCM: MeOH=50:1) to give the desired product.

General Method C

[0670] ##STR00194##

[0671] To a solution of the acid (1.0 eq.) in DCM were added DIPEA (3.0 eq.) and HATU (1.0 eq.). The amine 110 (1.0 eq.) in DCM was then added and the solution stirred at room temperature overnight. Water was added and the reaction mixture extracted with DCM×3. 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 column chromatography (DCM:MeOH=50:1) to give the dimethoxybenzyl protected intermediate A.

[0672] A solution of the dimethoxybenzyl protected intermediate A (1.0 eq.) in trifluoroacetic acid was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product. A saturated aqueous solution of NaHCO.sub.3 was then added and the resulting mixture extracted with DCM (×3). The combined organic layers were dried and concentrated to give the crude product which was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product.

General Method D

[0673] ##STR00195##

[0674] To a solution of the acid (1.0 eq.) and the amine 110 (1.0 eq.) in DCM were added DIPEA (3.0 eq.), HOBt (0.1 eq.), and EDCl (2.0 eq.). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous extracted with DCM×3. 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 column chromatography (DCM: MeOH=50:1) to give the dimethoxybenzyl protected intermediate A. A solution of the dimethoxybenzyl protected intermediate A (1.0 eq.) in trifluoroacetic acid was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product which was suspended in a saturated aqueous solution of NaHCO.sub.3. The resulting mixture was extracted with DCM (×3). The organic layers were combined, dried (Na.sub.2SO.sub.4) and concentrated to give the crude residue which was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product.

General Method E

[0675] ##STR00196##

[0676] To a solution of the acid (1.0 eq.) and amine 118 (1.0 eq.) in DCM were added DIPEA (3.5 eq.), HOBt (1.4 eq.), and EDCl (1.4 eq.). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous extracted with DCM×3. 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 column chromatography (DCM:MeOH=20:1) to give the dimethoxybenzyl protected intermediate A. A solution of the DMB protected intermediate A (1.0 eq.) in trifluoroacetic acid was stirred at 70° C. for 2 h. The mixture was concentrated to give the crude product which was suspended in a saturated aqueous solution of NaHCO.sub.3. The resulting mixture was extracted with DCM (×3), the organic layers were combined, dried (Na.sub.2SO.sub.4) and concentrated to give the crude residue which was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product.

General Method F

[0677] ##STR00197##

[0678] To a solution of the acid I14 (1.0 eq.) in dry DCM were added DIPEA (3.0 eq.) and HATU (1.0 eq.). The amine (1.0 eq.) in DCM was then added and the solution stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous layer extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude residue obtained was purified by column chromatography (DCM:MeOH=50:1) to give the desired dimethoxybenzyl intermediate A. A solution of compound A (1.0 eq.) in trifluoroacetic acid was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product which was suspended in a solution of saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with DCM (×3) and the combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product B

General Method G

[0679] ##STR00198##

[0680] To a solution of the acid I14 (1.0 eq.) and amine (1.0 eq.) in DCM were added DIPEA (3.0 eq.), HOBt (0.1 eq.) and EDCl (2.0 eq.). The resulting mixture was stirred at room temperature overnight. Water was added and the mixture extracted with DCM (×3). 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 column chromatography (DCM:MeOH=50:1) to give the desired dimethoxybenzyl intermediate A.

[0681] A solution of the dimethoxybenzyl intermediate A in trifluoroacetic acid was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product which was suspended in a solution of saturated aqueous NaHCO.sub.3. The mixture was extracted with DCM (×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified preparative TLC (DCM:MeOH=10:1) to give the desired product B.

General Method H

[0682] ##STR00199##

[0683] To a solution of the acid 36 (1.0 eq.) in dry DCM was added Et.sub.3N (5.0 eq.) and HATU (1.2 eq.). The amine (1.2 eq.) in DCM was then added and the solution was stirred at room temperature overnight. Water was added to the reaction mixture. The mixture was extracted with DCM×3. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (DCM:MeOH=50:1) to give the desired product A.

General Method I

[0684] ##STR00200##

[0685] To a solution of the acid (1.0 eq.) and the amine (1.0 eq.) in DCM were added DIPEA (3.0 eq), HOBt (0.1 eq.), and EDCl (2.0 eq.). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous extracted with DCM (×3). 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 column chromatography (DCM: MeOH=50:1) to give the dimethoxybenzyl protected intermediate A.

[0686] A solution of the dimethoxybenzyl protected intermediate A (1.0 eq) in trifluoroacetic acid was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product which was suspended in a saturated aqueous solution of NaHCO.sub.3. The resulting mixture was extracted with DCM (×3). The organic layers were combined, dried (Na.sub.2SO.sub.4) and concentrated to give the residue which was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product.

General Method J

[0687] ##STR00201##

[0688] To a solution of the acid (1.0 eq) and the amine 1117 (1.0 eq) in DCM were added DIPEA (3.0 eq), HOBt (0.1 eq) and EDCl (2.0 eq). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous extracted with DCM (×3). 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 preparative TLC (DCM:MeOH=20:1) to give the Boc protected intermediate A.

[0689] A solution of the Boc protected intermediate A (1.0 eq) in a saturated solution of HCl in either EtOAc or Et.sub.2O was stirred at room temperature for 3 h. The mixture was concentrated to give the crude product. The solid was rinsed with diethyl ether to provide the desired product as a HCl salt. If the product was not pure, the HCl salt was partitioned between DCM and a saturated aqueous solution of NaHCO.sub.3 and the aqueous extracted with DCM. The combined organic fractions were dried (Na.sub.2SO.sub.4) and concentrated and the crude residue obtained purified by preparative TLC (DCM:MeOH˜15:1 v/v) to give the desired product.

General Method K

[0690] ##STR00202##

[0691] To a solution of the acid (1.0 eq) and the amine 1117 (1.0 eq) in DCM were added DIPEA (3.0 eq), HOBt (0.1 eq) and EDCl (2.0 eq). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous extracted with DCM (×3). 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 preparative TLC (DCM:MeOH=20:1) to give the Boc protected intermediate A.

[0692] A solution of the Boc protected intermediate A (1.0 eq) in DCM/trifluoroacetic acid (8:1 v/v) was stirred at room temperature for 1 h. Water was added and the pH of the solution adjusted to 8-9 by addition of saturated aqueous NaHCO.sub.3 solution. The resulting mixture was extracted with DCM (×3) and the combined organic fractions were dried (Na.sub.2SO.sub.4) and concentrated to give the desired product B.

[0693] All Examples in the following Table were prepared using starting materials with the absolute stereochemistry as indicated in the Schemes above, unless stated otherwise in the Method column.

TABLE-US-00006 Com- pound Name and Structure QC data Method 66 [00203] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(2-oxa- 6-azaspiro[3.3]heptane-6- carbonyl)benzamide .sup.1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.86-6.77 (m, 2H), 6.77- 6.69 (m, 2H), 4.15 (s, 2H), 3.96 (s, 2H), 3.66-3.51 (m, 1H), 3.18- 3.04 (m, 2H), 2.97-2.90 (m, 3H), 2.89-2.78 (m, 2H), 2.54-2.30 (m, 4H). 2 Protons obscured by water LCMS: RT 0.51 min, m/z 436.2 [M + H].sup.+ H 67 [00204] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-6- (piperidine-1-carbonyl)nicotinamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.00 (s, 1 H), 8.32-8.29 (m, 1 H), 7.64-7.62 (d, J = 8.0 Hz, 1 H), 7.19- 7.10 (m, 4 H), 3.99-3.94 (m, 1 H), 3.75-3.73 (m, 2 H), 3.69-3.62 (m, 1 H), 3.55-3.45 (m, 2 H), 3.36-3.33 (m, 2 H), 3.23-3.16 (m, 2 H), 2.86-2.79 (m, 3 H), 2.76-2.69 (m, 1 H), 1.72 (m, 4 H), 1.58 (m, 2 H). LCMS: RT 1.39 min, m/z 423.2 [M + H].sup.+ A (Using racemic amine) 68 [00205] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-6- (piperidine-1-carbonyl)nicotinamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.00 (d, J = 1.6 Hz, 1 H), 8.31-8.29 (m, 1 H), 7.63-7.61 (m, 1 H), 7.18- 7.16 (m, 2 H), 7.11-7.09 (m, 2 H), 3.99-3.93 (m, 1 H), 3.74-3.71 (m, 2 H), 3.65-3.58 (m, 1 H), 3.55-3.45 (m, 2 H), 3.35-3.33 (m, 2 H), 3.21-3.14 (m, 2 H), 2.83-2.76 (m, 3 H), 2.72- 2.67 (m, 1 H), 1.71 (m, 4 H), 1.57 (m, 2 H). LCMS: RT 1.40 min, m/z 423.3 [M + H].sup.+ A 69 [00206] embedded image (R)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-6- (piperidine-1-carbonyl)nicotinamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.00 (d, J = 1.6 Hz, 1 H), 8.32-8.30 (m, 1 H), 7.65-7.63 (m, 1 H), 7.19- 7.17 (m, 2H), 7.12-7.10 (m, 2H), 4.00-3.94 (m, 1H), 3.75-3.74 (m, 2H), 3.69-3.63 (m, 1H), 3.55- 3.45 (m, 2 H), 3.36-3.33 (m, 2 H), 3.24-3.17 (m, 2 H), 2.87-2.79 (m, 3 H), 2.75-2.71 (m, 1 H), 1.72 (m, 4 H), 1.58 (m, 2 H). LCMS: RT 1.52 min, m/z 423.2 [M + H].sup.+ A (Using (S)-acid) 70 [00207] embedded image N-((S)-3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-((S)-3- ethylmorpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93-7.91 (m, 2 H), 7.51-7.49 (m, 2 H), 7.18-7.12 (m, 4 H), 3.97-3.66 (m, 6 H), 3.50-3.49 (m, 4 H), 3.24- 3.17 (m, 2 H), 2.86-2.71 (m, 5 H), 1.98-1.80 (m, 2 H), 1.02-0.75 (m, 3 H). LCMS: RT 3.48 min, m/z 452.3 [M + H].sup.+ F DIPEA (3.5 eq) used 71 [00208] embedded image N-((S)-3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-((R)-3- ethylmorpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93-7.91 (m, 2 H), 7.51-7.49 (m, 2 H), 7.20-7.11 (m, 4 H), 4.49-4.28 (m, 1 H), 3.98-3.64 (m, 6 H), 3.50- 3.48 (m, 4 H), 3.26-3.19 (m, 2H), 2.90-2.82 (m, 3 H), 2.77-2.72 (m, 1 H), 2.00-1.81 (m, 2 H), 1.03-0.76 (m, 3 H). LCMS: RT 3.48 min, m/z 452.3 [M + H].sup.+ F 72 [00209] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(2,2- dimethylmorpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95-7.93 (m, 2 H), 7.53 (m, 2 H), 7.23-7.15 (m, 4 H), 4.05-4.04 (m, 1 H), 3.90-3.46 (m, 8 H), 3.39-3.24 (m, 3 H), 3.06-2.85 (m, 4 H), 1.29 (s, 3 H), 1.12 (s, 3 H). LCMS: RT 3.43 min, m/z 452.3 [M + H].sup.+ F 73 [00210] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- propoxybenzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.96-7.94 (m, 1 H), 7.52-7.49 (m, 1 H), 7.25-7.14 (m, 5 H), 7.08-7.04 (m, 1 H), 4.17-4.03 (m, 4 H), 3.64- 3.52 (m, 2 H), 3.43-3.37 (m, 2 H), 3.21-3.08 (m, 3 H), 3.05-3.00 (m, 1 H), 1.96-1.90 (m, 2 H), 1.12-1.08 (m, 3 H). LCMS: RT 3.92 min, m/z 369.2 [M + H].sup.+ D (using racemic amine) 74 [00211] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- isopropoxybenzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.00-7.98 (m, 1 H), 7.54-7.50 (m, 1 H), 7.26-7.19 (m, 5 H), 7.09-7.06 (m, 1 H), 4.15-4.05 (m, 2 H), 3.81- 3.54 (m, 3 H), 3.45-3.39 (m, 2 H), 3.22-3.01 (m, 4 H), 1.47-1.06 (m, 6 H). LCMS: RT 2.18 min, m/z 369.2 [M + H].sup.+ D (Using racemic amine) 75 [00212] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2-ethoxy- 4-(morpholine-4-carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.02-8.00 (m, 1 H), 7.23-7.08 (m, 6 H), 4.30-4.25 (m, 2H), 4.04-4.01 (m, 1 H), 3.89-3.76 (m, 5 H), 3.63-3.44 (m, 6 H), 3.33-3.26 (m, 2 H, overlap), 3.03-2.85 (m, 4 H), 1.54- 1.51 (m, 3 H). LCMS: RT 3.29 min, m/z 468.3 [M + H].sup.+ I 76 [00213] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2-ethoxy- 4-(pyrrolidine-1-carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.00-7.98 (m, 1 H), 7.25-7.19 (m, 6 H), 4.28-4.26 (m, 2 H), 4.07-3.98 (m, 2 H), 3.61-3.58 (m, 3 H), 3.55- 3.50 (m, 1 H), 3.46-3.43 (m, 2H), 3.40-3.35 (m, 2 H), 3.15-2.98 (m, 4 H), 2.02-1.91 (m, 4 H), 1.54-1.50 (m, 3 H). LCMS: RT 2.01 min, m/z 452.3 [M + H].sup.+ I 77 [00214] embedded image 4-(3-oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-N-((S)-3-((2,3-dihydro-1H- inden-2-yl)amino)-2-hydroxypropyl)-2- ethoxybenzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.03-8.01 (m, 1 H), 7.23 (s, 1 H), 7.18-7.15 (m, 3 H), 7.13-7.09 (m, 2 H), 4.64 (s, 1 H), 4.30-4.24 (m, 2 H), 3.97-3.92 (m, 2 H), 3.83-3.81 (m, 1 H), 3.73-3.57 (m, 5 H), 3.49-3.44 (m, 1 H), 3.23-3.16 (m, 2 H), 2.85- 2.71 (m, 4 H), 2.06-2.00 (m, 4 H), 1.54-1.51 (m, 3 H). LCMS: RT 1.87 min, m/z 494.3 [M + H].sup.+ D and I 78 [00215] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-6-(2-oxo- 2-(piperidin-1-yl)ethyl)nicotinamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.98-8.95 (m, 1 H), 8.25-8.20 (m, 1 H), 7.50-7.45 (m, 1 H), 7.28-7.19 (m, 4 H), 4.60 (s, 2 H), 4.15-4.11 (m, 1 H), 3.76-3.69 (m, 2 H), 3.60- 3.55 (m, 4 H), 3.48-3.40 (m, 2 H), 3.27-3.20 (m, 3 H), 3.18-3.13 (m, 1 H), 3.10-3.03 (m, 1 H), 1.70-1.63 (m, 2 H), 1.57-1.50 (m, 4 H). LCMS: RT 0.26 min, m/z 437.3 [M + H].sup.+ B EDCl (1.5 eq) HOBt (1.5 eq) DIPEA (3.5 eq) 79 [00216] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- (methoxymethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.55-7.53 (m, 1 H), 7.48-7.41 (m, 3 H), 7.28-7.20 (m, 4 H), 4.68-4.60 (m, 2 H), 4.16-4.08 (m, 2 H), 3.53- 3.41 (m, 4 H), 3.33 (s, 3 H), 3.28- 3.25 (m, 1 H), 3.19-3.09 (m, 3 H). LCMS: RT 3.26 min, m/z 355.2 [M + H].sup.+ A DIPEA (3.5 eq); using racemic amine 80 [00217] embedded image N-((S)-3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(2- (methoxymethyl)piperidine-1- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.94-7.92 (m, 2 H), 7.52-7.50 (m, 2 H), 7.27-7.19 (m, 4 H), 4.61-4.53 (m, 1 H), 4.12-4.06 (m, 2 H), 3.81- 3.76 (m, 1 H), 3.58-3.38 (m, 8 H), 3.31 (s, 3 H), 3.23-3.09 (m, 4 H), 3.05-2.99 (m, 1 H), 1.68 (m, 4 H). LCMS: RT 3.43 min, m/z 466.3 [M + H].sup.+ G 81 [00218] embedded image N-((S)-3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(3- methoxypyrrolidine-1- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.96-7.94 (m, 2 H), 7.64-7.62 (m, 2 H), 7.27-7.20 (m, 4 H), 4.14-4.06 (m, 3 H), 3.75-3.64 (m, 2 H), 3.62- 3.54 (m, 2 H), 3.52-3.38 (m, 6 H), 3.26-3.21 (m, 2 H), 3.17-3.10 (m, 2 H), 3.06-3.01 (m, 1 H), 2.18-1.95 (m, 2 H). LCMS: RT 3.05 min, m/z 438.3 [M + H].sup.+ G 82 [00219] embedded image 1-benzyl-N-(3-((2,3-dihydro-1H-inden- 2-yl)amino)-2-hydroxypropyl)-2-oxo- 1,2-dihydropyridine-4-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83-7.80 (m, 1 H), 7.35-7.20 (m, 9 H), 6.95 (d, J = 1.6 Hz, 1 H), 6.70- 6.68 (dd, J = 7.2, 2.0 Hz, 1 H), 5.22 (s, 2 H), 4.13-4.08 (m, 2 H), 3.46- 3.39 (m, 4 H), 3.18-3.10 (m, 3H), 3.04-2.99 (m, 1 H). LCMS: RT 3.28 min, m/z 418.1 [M + H].sup.+ D (Using racemic amine) 83 [00220] embedded image 4-(2-(4-acetylpiperazin-1-yl)-2- oxoethyl)-N-(3-((2,3-dihydro-1H- inden-2-yl)amino)-2- hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.85-7.83 (m, 2 H), 7.40-7.38 (m, 2 H), 7.28-7.20 (m, 4 H), 4.14-4.10 (m, 2 H), 3.90 (s, 2 H), 3.67-3.46 (m, 12 H), 3.31-3.01 (m, 4 H), 2.11- 2.09 (m, 3 H) LCMS: RT 3.20 min, m/z 479.3 [M + H].sup.+ E (Using racemic acid) 84 [00221] embedded image 4-(4-acetylpiperazine-1-carbonyl)-N- (3-((2,3-dihydro-1H-inden-2-yl)amino)- 2-hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.97-7.95 (d, J = 8.0 Hz, 2 H), 7.57- 7.55 (d, J = 8.4 Hz, 2 H), 7.25-7.17 (m, 4 H), 4.09-4.06 (m, 1 H), 3.98- 3.93 (m, 1 H), 3.85-3.46 (m, 10 H), 3.39-3.34 (m, 2 H), 3.13-3.01 (m, 3 H), 2.97-2.92 (m, 1 H), 2.16 (s, 3 H). LCMS: RT 0.26 min, m/z 465.3 [M + H].sup.+ F (Using racemic acid) 85 [00222] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-1-methyl 2-oxo-1,2-dihydropyridine-4- carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.76-7.74 (m, 1 H), 7.24-7.19 (m, 4 H), 6.92 (s, 1 H), 6.68-6.67 (m, 1 H), 4.04-3.96 (m, 2 H), 3.59 (s, 3 H), 3.52-3.39 (m, 4 H), 3.13-3.03 (m, 3 H), 2.95-2.90 (m, 1 H). LCMS: RT 0.62 min, m/z 342.2 [M + H].sup.+ C (Using racemic amine) 86 [00223] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(4- methoxypiperidine-1- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95-7.93 (d, J = 8.0 Hz, 2 H), 7.52- 7.50 (d, J = 8.0 Hz, 2 H), 7.28-7.20 (m, 4 H), 4.16-4.09 (m, 2 H), 3.59- 3.49 (m, 4 H), 3.47-3.40 (m, 3 H), 3.37 (s, 3 H), 3.27-3.12 (m, 5 H), 3.08-3.03 (m, 1 H), 2.04-1.97 (m, 2 H), 1.71-1.59 (m, 2 H). LCMS: RT 0.26 min, m/z 452.3 [M + H].sup.+ H 87 [00224] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- methoxy-4-(2-morpholino-2- oxoethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.90-7.88 (m 1 H), 7.27-7.20 (m, 4 H), 7.08 (s, 1 H), 6.98-6.96 (m, 1 H), 4.13-4.10 (m, 2 H), 3.99 (s, 3 H), 3.85 (s, 2 H), 3.63-3.54 (m, 9 H), 3.45-3.40 (m, 2 H), 3.24-2.97 (m, 5 H). LCMS: RT 1.61 min, m/z 468.3 [M + H].sup.+ C 88 [00225] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(1-oxa- 7-azaspiro[3.5]nonane-7- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.94-7.92 (m, 2 H), 7.48-7.46 (m, 2 H), 7.22-7.13 (m, 4 H), 5.57 (br s, 1 H), 5.36 (br s, 1 H), 4.49 (br s, 1 H), 4.04 (br s, 1 H), 3.89-3.70 (m, 2 H), 3.49 (m, 2 H), 3.20-3.13 (m, 3 H), 2.93-2.87 (m, 3 H), 2.78-2.72 (m, 1 H), 2.14-2.08 (m, 4 H), 1.33 (s, 1 H), 1.23-1.22 (m, 2 H). LCMS: RT 1.11 min, m/z 464.3 [M + H].sup.+ G 89 [00226] embedded image (S)-methyl 2-(4-((3-((2,3-dihydro-1H- inden-2-yl)amino)-2- hydroxypropyl)carbamoyl)phenyl)acetate .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83-7.81 (m, 2 H), 7.40-7.38 (m, 2 H), 7.27-7.19 (m, 4 H), 4.12-4.07 (m, 2 H), 3.73 (s, 2 H), 3.68 (s, 3 H), 3.53-3.49 (m, 2 H), 3.44-3.38 (m, 2 H), 3.24-3.20 (m, 1 H), 3.17- 3.13 (m, 2 H), 3.05-3.00 (m, 1 H). LCMS: RT 3.28 min, m/z 383.2 [M + H].sup.+ A With DIPEA 90 [00227] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(2- morpholino-2-oxoethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.86-7.84 (m, 2 H), 7.41-7.38 (m, 2 H), 7.28-7.20 (m, 4 H), 4.13-4.06 (m, 2 H), 3.88 (s, 2 H), 3.65-3.61 (m, 4 H), 3.59-3.55 (m, 4 H), 3.54- 3.47 (m, 2 H), 3.45-3.38 (m, 2 H), 3.23-3.19 (m, 1 H), 3.16-3.10 (m, 2 H), 3.05-3.00 (m, 1 H). LCMS: RT 0.67 min, m/z 438.3 [M + H].sup.+ A 91 [00228] embedded image (R)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(2-oxo- 2-(pyrrolidin-1-yl)ethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82-7.80 (m, 2 H), 7.39-7.37 (m, 2 H), 7.25-7.17 (m, 4 H), 4.10-4.00 (m, 2 H), 3.78 (s, 2 H), 3.56-3.34 (m, 8 H), 3.15-2.93 (m, 4 H), 1.80- 2.10 (m, 4 H). LCMS: RT 3.37 min, m/z 422.3 [M + H].sup.+ A Using (S)- amine 92 [00229] embedded image 2-(2-cyclopropylacetyl)-N-(3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)isoindoline-5- carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83-7.80 (m, 2H), 7.47-7.43 (m, 1H), 7.25-7.18 (m, 4H), 4.92 (br s, 2H), 1H), 4.80 (br s, 2H), 4.41-4.00 (m, 2H), 3.54-3.48 (m, 2H), 3.41- 3.35 (m, 2H), 3.14-3.30 (m, 5H), 2.42-40 (m, 2H), 0.59-0.57 (m, 2H), 0.24-0.23 (m, 2H). LCMS: RT 1.97 min, m/z 434.3 [M + H].sup.+ A With DIPEA; Using racemic amine 93 [00230] embedded image 2-(2-cyclopropylacetyl)-N-(3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-1,2,3,4- tetrahydroisoquinoline-7-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.67 (br s, 2H), 7.29-7.27 (m, 1 H), 7.18 (br s, 2 H) 7.13 (br s, 2 H), 4.76 (br s, 2 H), 3.97 (br s, 1 H), 3.83-3.69 (m, 3H), 3.48 (br s, 2H), 3.24-3.21 (m, 2H), 2.99- 2.96 (m, 1H), 2.89-2.88 (m, 4H), 2.79-2.74 (m, 2H), 2.44-2.42 (m, 2H), 0.60 (br s, 2 H), 0.30 (br s, 2 H). LCMS: RT 2.07 min, m/z 448.3 [M + H].sup.+ A With DIPEA; Using racemic amine 94 [00231] embedded image 2-(2-cyclopropylacetyl)-N-(3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.67 (br s, 2H), 7.34-7.33 (m, 1H), 7.24-7.13 (m, 4H), 4.76 (s, 2H), 4.00-3.97 (m, 1H), 3.84-3.75 (m, 3H), 3.49-3.46 (m, 2H), 3.26-3.22 (m, 2 H), 2.98-2.86 (m, 5H), 2.80- 2.78 (m, 2H), 244-2.42 (m, 2H), 0.56-0.53 (m, 2H), 0.22-0.18 (m, 2H). LCMS: RT 1.99 min, m/z 448.3 [M + H].sup.+ B With DIPEA; Using racemic amine 95 [00232] embedded image 2-acetyl-N-(3-((2,3-dihydro-1H-inden- 2-yl)amino)-2-hydroxypropyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69-7.66 (m, 2H), 7.30-7.26 (m, 1 H), 7.21-7.19 (m, 2H), 7.15- 7.12 (m, 2H), 4.76-4.73 (m, 2H), 4.54 (br s, 1H), 4.02-3.98 (m, 1H), 3.81-3.75 (m, 3 H), 3.51-3.44 (m, 2 H) 3.25-3.23 (m, 1 H), 3.00-2.78 (m, 5H), 2.85-2.78 (m, 1H), 2.19 (s, 3H). LCMS: RT 3.04 min, m/z 408.3 [M + H].sup.+ B Using racemic amine 96 [00233] embedded image 2-acetyl-N-(3-((2,3-dihydro-1H-inden- 2-yl)amino)-2-hydroxypropyl)-1,2,3,4- tetrahydroisoquinoline-7-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.68-7.66 (m, 2H), 7.31-7.29 (m, 1H), 7.21-7.20 (m, 2H), 7.16-7.14 (m, 2H), 4.75-4.74 (m, 2H), 4.02- 3.99 (m, 1H), 3.81-3.75 (m, 3 H), 3.49-3.46 (m, 2H), 3.27-3.24 (m, 2 H) 2.99-2.98 (m, 3H), 2.92-2.90 (m, 2 H), 2.89-2.81 (m, 1 H), 2.19 (s, 3H). LCMS: RT 3.25 min, m/z 408.3 [M + H].sup.+ B Using racemic amine 97 [00234] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2-(2,2,2- trifluoroethoxy)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83-7.81 (m, 1H), 7.55-7.50 (m, 1H), 7.21-7.13 (m, 6H), 4.76- 4.70 (m, 2H), 4.03-4.97 (m, 1H), 3.84-3.77 (m, 1H), 3.59-3.47 (m, 2H), 3.29-3.24 (m, 2H), 3.00-2.82 (m, 4H). LCMS: RT 2.01 min, m/z 409.2 [M + H].sup.+ B with Et.sub.3N (4.5 eq); Using racemic amine 98 [00235] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- methoxy-4-(morpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.99 (d, J = 8 Hz, 1 H), 7.29-7.21 (m, 5 H), 7.13 (d, J = 7.6 Hz, 1 H), 4.16-4.13 (m, 2 H), 4.03 (s, 3 H), 3.78-3.41 (m, 12 H), 3.28-3.05 (m, 4 H). LCMS: RT 3.00 min, m/z 454.2 [M + H].sup.+ B 100 [00236] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(2-oxo- 2-(pyrrolidin-1-yl)ethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.27-7.19 (m, 4 H), 4.11-4.05 (m, 2 H), 3.78 (s, 2H), 3.56-3.50 (m, 4 H), 3.48-3.37 (m, 4 H), 3.23-3.10 (m, 3 H), 3.06- 2.98 (m, 1 H), 2.02-1.96 (m, 2H), 1.94-1.87 (m, 2 H). LCMS: RT 3.43 min, m/z 422.3 [M + H].sup.+ A 101 [00237] embedded image N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4- ((3R,5R)-3,5-dimethylmorpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.92-7.90 (m, 2H), 7.59-7.57 (m, 2H), 7.17-7.11 (m, 4H), 3.96- 3.89 (m, 5H), 3.67-3.60 (m, 1H), 3.52-3.48 (m, 4H), 3.22-3.15 (m, 2H), 2.83-2.68 (m, 4H), 1.28 (s, 3H), 1.27 (s, 3H). LCMS: RT 1.81 min, m/z 452.3 [M + H].sup.+ A Using racemic amine 102 [00238] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(3,3- dimethylmorpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.92-7.89 (m, 2H), 7.52-7.50 (m, 2H), 7.22-7.13 (m, 4H), 4.04-3.98 (m, 1H), 3.82-3.77 (m, 1H), 3.74- 3.72 (m, 2H), 3.56-3.46 (m, 4H), 3.37-3.35 (m, 2H), 3.29-3.23 (m, 2H), 2.98-2.88 (m, 3H), 2.84-2.78 (m, 1H), 1.52 (s, 6H). LCMS: RT 1.87 min, m/z 452.3 [M + H].sup.+ F 103 [00239] embedded image 4-(3-oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-N-((S)-3-((2,3-dihydro-1H- inden-2-yl)amino)-2- hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93-7.91 (m, 2H), 7.60-7.58 (m, 2H), 7.19-7.10 (m, 4H), 3.98-3.93 (m, 2H), 3.84-3.57 (m, 6H), 3.50- 3.49 (m, 2H), 3.22-3.15 (m, 2H), 2.85-2.78 (m, 3H), 2.73-2.68 (m, 1H), 2.08-2.01 (m, 4H). LCMS: RT 0.77 min, m/z 450.3 [M + H].sup.+ G 104 [00240] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(8-oxa- 5-azaspiro[3.5]nonane-5- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93-7.91 (m, 2H), 7.60-7.58 (m, 2H), 7.24-7.16 (m, 4H), 4.09-4.03 (m, 1H), 3.97-3.90 (m, 1H), 3.83 (s, 2H), 3.56-3.41 (m, 6H), 3.37-3.33 (m, 2H), 3.10-2.89 (m, 4H), 2.41- 2.22 (m, 4H), 1.86-1.73 (m, 2H). LCMS: RT 1.95 min, m/z 464.3 [M + H].sup.+ F 105 [00241] embedded image 4-(8-oxa-3-azabicyclo[3.2.1]octane-3- carbonyl)-N-((S)-3-((2,3-dihydro-1H- inden-2-yl)amino)-2- hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.94-7.92 (m, 2H), 7.52-7.50 (m, 2H), 7.22-7.14 (m, 4H), 4.46-4.44 (m, 1H), 4.36-4.32 (m, 1H), 4.24- 4.23 (m, 1H), 4.06-4.00 (m, 1H), 3.87-3.80 (m, 1H), 3.55-3.46 (m, 3H), 3.29-3.25 (m, 2H), 3.16-3.12 (m, 1H), 3.02-2.92 (m, 3H), 2.88- 2.81 (m, 2H), 1.99-1.86 (m, 3H), 1.72-1.67 (m, 1H). LCMS: RT 0.75 min, m/z 450.3 [M + H].sup.+ F 113 [00242] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl) benzo[d]thiazole-7-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.33 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.22-7.13 (m, 4H), 4.10-4.04 (m, 1H), 3.90-3.81 (m, 1H), 3.62-3.49 (m, 2H), 3.28- 3.26 (m, 1H), 3.06-2.86(m, 5H) LCMS: RT 1.16 min, m/z 368.2 [M + H].sup.+ D 114 [00243] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-4-(1,1- dioxidothiomorpholine-4-carbonyl)-2- ethoxybenzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.02 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.25-7.16 (m, 5H), 4.60 (s, 2H), 4.31-4.26 (m, 2 H), 4.20-3.86 (m, 6H), 3.64-3.50 (m, 2H), 3.38- 3.34 (m, 2H), 3.18-2.93 (m, 6H), 1.53 (t, J = 6.8 Hz, 3H). LCMS: RT 3.06 min, m/z 516.3 [M + H].sup.+ I 115 [00244] embedded image 6-(3-oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-N-((S)-3-((2,3-dihydro-1H- inden-2-yl)amino)-2-hydroxypropyl)-2- ethoxynicotinamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.44 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1 H), 7.22-7.13 (m, 4H) 4.71-4.65 (m, 2H), 4.57-4.49 (m, 2 H), 4.05-3.99 (m, 1 H), 3.91-3.89 (m, 1H), 3.84-3.68 (m, 4H), 3.64- 3.59 (m, 1H), 3.53-3.47 (m, 1H), 3.28-3.24 (m, 2H), 2.99-2.83 (m, 4H), 2.10-1.98 (m, 4H), 1.50 (t, J = 6.8 Hz, 3H). LCMS: RT 4.83 min, m/z 495.0 [M + H].sup.+ J 116 [00245] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2-ethoxy- 4-(5-methyl-1,3,4-oxadiazol-2- yl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.09 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1 H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.18-7.16 (m, 2H), 7.11-7.09 (m, 2H), 4.33 (q, J = 6.8 Hz, 2H), 3.96-3.92 (m, 1H), 3.68- 3.58 (m, 2H), 3.50-3.45 (m, 1H), 3.23-3.16 (m, 2H), 2.85-2.71 (m, 4H), 2.64 (s, 3H), 1.55 (t, J = 6.8 Hz, 3H). LCMS: RT 2.00 min, m/z 437.0 [M + H].sup.+ K 117 [00246] embedded image (S)-N.sup.1-(3-((2,3-dihydro-1H-inden-2 yl)amino)-hydroxypropyl)-N.sup.3- methylisophthalamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.34 (s, 1 H), 8.01-7.96 (m, 2 H), 7.57 (t, J = 8.0 Hz, 1H), 7.25-7.17 (m, 4 H), 4.11-4.01 (m, 2 H), 3.59- 3.47 (m, 2 H), 3.42-3.35 (m, 2 H) 3.21-3.17 (m, 1 H), 3.13-3.06 (m, 2 H), 3.03-2.97 (m, 1 H), 2.93 (s, 3 H). LCMS: RT 2.80 min, m/z 368.2 [M + H].sup.+ D 118 [00247] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- (trifluoromethyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J = 7.6 Hz, 1 H), 7.73-7.60 (m, 3 H), 7.28-7.20 (m, 4 H), 4.16- 4.08 (m, 2 H), 3.51 (d, J = 6.0 Hz, 2 H), 3.47-3.41 (m, 2 H), 3.28-3.24 (m, 1 H), 3.20-3.13 (m, 2 H), 3.10- 3.04 (m, 1 H). LCMS: RT 1.90 min, m/z 379.2 [M + H].sup.+ D 119 [00248] embedded image (S)-3-(difluoromethoxy)-N-(3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.75 (d, J = 8.0 Hz, 1 H), 7.65 (s, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.36- 7.33 (m, 1 H), 7.26-7.18 (m, 4 H), 7.09-6.72 (m, 1 H), 4.15-4.04 (m, 2 H), 3.57-3.45 (m, 2 H), 3.44-3.37 m, 2 H), 3.23-3.19 (m, 1 H), 3.16- 3.09 (m, 2 H), 3.04-2.99 (m, 1 H). LCMS: RT 1.93 min, m/z 377.2 [M + H].sup.+ D 120 [00249] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-1H- benzo[d]imidazole-4-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.44 (s, 1 H), 7.98 (d, J = 7.2 Hz, 1 7.84 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.23-7.17 (m, 4 H), 4.23-4.21 (m, 1 H), 4.16-4.09 (m, 1 H), 3.74-3.64 (m, 2 H), 3.45- 3.38 (m, 2 H), 3.34-3.32 (m, 1 H), 3.19-3.09 (m, 3 H). LCMS: RT 0.38 min, m/z 351.2 [M + H].sup.+ D 121 [00250] embedded image 4-(3-oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-2-chloro-N-((S)-3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.63 (d, J = 1.2 Hz, 1 H), 7.59-7.58 (m, 1 H), 7.52 (dd, J = 8.0, 1.2 Hz, 1 H), 7.24-7.16 (m, 4 H), 4.63-4.59 (m, 2 H), 4.08-4.02 (m, 1 H), 3.98- 3.90 (m, 2 H), 3.83-3.80 (m, 1 H), 3.72-3.69 (m, 2 H), 3.60-3.58 (m, 1 H), 3.52 (d, J = 5.6 Hz, 2 H), 3.37- 3.35 (m, 1 H), 3.14-3.10 (m, 1 H), 3.05-2.92 (m, 3 H), 2.10 (m, 4H). LCMS: RT 3.29 min, m/z 484.2 [M + H].sup.+ D 122 [00251] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- ethoxy-5-methyl-4-(morpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83 (s, 1H), 7.27-7.19 (m, 4H), 7.01 (s, 1H), 4.26-4.21 (m, 2H), 4.13-4.06 (m, 2H), 3.79-3.76 (m, 4H), 3.66-3.57 (m, 4H), 3.45-3.39 (m, 2H), 3.27-3.26 (m, 2H), 3.22- 3.02 (m, 4H), 3.27 (s, 3H), . 1.50 (t, J = 7.2 Hz, 3H). LCMS: RT 1.74 min, m/z 482.3 [M + H].sup.+ D 123 [00252] embedded image N-((S)-3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- ethoxy-4-((R)-3-methylmorpholine- 4-carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.00 (d, J = 7.6 Hz, 1H), 7.27-7.07 (m, 6H), 4.31-4.26 (m, 2H), 4.15- 4.04 (m, 2H), 3.75-3.48 (m, 7H), 3.44-3.38 (m, 3H), 3.22-3.01 (m, 5H), 1.53 (t, J = 6.8 Hz, 3H), 1.38- 1.37 (m, 3H) LCMS: RT 0.93 min, m/z 482.3 [M + H].sup.+ I 124 [00253] embedded image N-((S)-3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2- ethoxy-4-((S)-3-ethylmorpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.01 (d, J = 7.6 Hz, 1H), 7.23-7.07 (m, 6H), 4.30-4.25 (m, 2H), 4.08- 4.02 (m, 1H), 3.94-3.87 (m, 2H), 3.76 (s, 1H), 3.67-3.47 (m, 5H), 3.36-3.29 (m, 4H), 3.07-2.89 (m, 4H), 1.97-1.79 (m, 2H), 1.53 (t, J = 6.8 Hz, 3H), 1.02-0.78 (m, 3H) LCMS: RT 2.06 min, m/z 496.3 [M + H].sup.+ I 125 [00254] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2- hydroxypropyl)benzo[d]thiazole-4- carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.46 (s, 1H), 8.33-8.30 (m, 2H), 7.66-7.62 (m, 1H), 7.20-7.14 (m, 4H), 4.15-4.09 (m, 1H), 3.94-3.87 (m, 1H), 3.75-3.62 (m, 2H), 3.35- 3.31 (m, 1H, overlap), 3.12-2.92 (m, 5H) LCMS: RT 1.43 min, m/z 368.2 [M + H].sup.+ D 126 [00255] embedded image 6-(3-oxa-8-azabicyclo[3.2.1]octane- 8-carbonyl)-N-((S)-3-((2,3-dihydro- 1H-inden-2-yl(amino-2- hydroxypropyl)-4- ethoxynicotinamide dihydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.96 (s, 1H), 7.71 (s, 1 H), 7.28- 7.20 (m, 4H) 4.70-4.69 (m, 1H), 4.55-4.50 (m, 2H), 4.34 (s, 1H), 4.18-4.13 (m, 2H), 3.86-3.73 (m, 3H), 3.66-3.54 (m, 3H), 3.47-3.12 (m, 2H), 3.27-3.26 (m, 1H), 3.22- 3.07 (m, 3H), 2.09-2.08 (m, 4H), 1.58 (t, J = 6.8 Hz, 3H). LCMS: RT 3.32 min, m/z 495.1 [M + H].sup.+ for the freebase J 127 [00256] embedded image 4-((1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptane-5- carbonyl)-N-((S)-3-((2,3-dihydro- 1H-inden-2-yl)amino)-2- hydroxypropyl)-2-ethoxybenzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.02-7.97 (m, 1H), 7.26-7.17 (m, 6H), 4.73-4.45 (m, 2H), 4.31-4.26 (m, 2H), 4.13-4.06 (m, 2H), 4.00- 3.96 (m, 1H), 3.88-3.77 (m, 1H), 3.63-3.39 (m, 6H), 3.24-3.21 (m, 1H), 3.14-3.03 (m, 3H), 2.03-1.92 (m, 2H), 1.53 (t, J = 6.8 Hz, 3H). LCMS: RT 0.93 min, m/z 480.2 [M + H].sup.+ I 128 [00257] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-1H- indazole-4-carboxamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.43 (s, 1H), 7.77-7.52 (m, 1H), 7.66-7.64 (m, 1H), 7.51-7.49 (m, 1H), 7.26-7.22 (m, 4H), 4.62 (br s, 1H), 4.19-4.13 (m, 2H), 3.61-3.55 (m, 2H), 3.47-3.41 (m, 2H), 3.20- 3.07 (m, 3H) LCMS: RT 0.53 min, m/z 351.2 [M + H].sup.+ D 129 [00258] embedded image 4-(2-(3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)-2-oxoethyl)-N-((S)-3-((2,3- dihydro-1H-inden-2-yl)amino)-2- hydroxypropyl)-2-ethoxybenzamide .sup.1H NMR (400 MHz, MeOH-d.sub.6) δ 7.91 (d, J = 8.0 Hz, 1H), 7.29- 7.18 (m, 4H), 7.12 (s, 1H), 7.01 (d, J = 7.9 Hz, 1H), 4.52 (d, J = 6.3 Hz, 1H), 4.34 (d, J = 4.9 Hz, 1H), 4.30- 4.24 (m, 2H), 4.18-4.09 (m, 2H), 3.88-3.76 (m, 2H), 3.68-3.54 (m, 5H), 3.49-3.40 (m, 3H), 3.26- 3.21 (m, 1H), 3.20-3.04 (m, 3H), 2.04-1.83 (m, 4H), 1.52 (t, J = 6.9 Hz, 3H). LCMS: RT 3.23 min, m/z 508.4 [M + H].sup.+ J 130 [00259] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-2-ethoxy- 3-methyl-4-(morpholine-4- carbonyl)benzamide .sup.1H NMR (400 MHz, MeOH-d.sub.6) δ 7.66 (d, J = 7.9 Hz, 1H), 7.23 (m, 4H), 7.09 (d, J = 7.9 Hz, 1H), 4.15 4.05 (m, 2H), 3.98 (m, 2H), 3.84- 3.74 (m, 4H), 3.65-3.48 (m, 4H), 3.41 (m, 2H), 3.28-3.18 (m, 3H), 3.18 - 3.00 (m, 3H), 2.26 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H). LCMS: RT 1.40 min, m/z 482.3 [M + H].sup.+ D 131 [00260] embedded image (S)-2-chloro-N-(3-((2,3-dihydro-1H- inden-2-yl)amino)-2- hydroxypropyl)benzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.47-7.40 (m, 4H), 7.21-7.15 (m, 4H), 3.99 (br s, 1H), 3.79 (m, 1H), 3.48 (m, 2H), 3.50 (m, 2H), 3.02- 2.84 (m, 4H). LCMS: RT 1.07 min, m/z 345.1; [M + H].sup.+ D 132 [00261] embedded image (S)-N-(3-((2,3-dihydro-1H-inden-2- yl)amino)-2-hydroxypropyl)-1H- indazole-7-carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.80 (br s, 1H), 8.17 (br s, 1H), 7.98-7.91 (m, 2H), 7.22-7.15 (m, 5H), 5.45 (br s, 1H), 3.94-3.37 (m, 2H), 3.22-3.17 (m, 4H), 2.99-2.78 (m, 4H). LCMS: RT 1.12 min, m/z 351.2 [M + H].sup.+ D 133 [00262] embedded image 4-(3-oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-N((S)-3-((2,3-dihydro-1H- inden-2-yl)amino)-2-hydroxypropyl)-2- fluorobenzamide .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.84 (t, J = 7.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.23-7.21 (m, 2H), 7.16- 7.14 (m, 2H), 4.64-4.59 (m, 3H), 4.04-3.96 (m, 2H), 3.86-3.81 (m, 2H), 3.75-3.70 (m, 2H), 3.61-3.52 (m, 3H), 3.03-2.92 (m, 3H), 2.29- 2.83 (m, 1H), 2.08-2.02 (m, 4H). LCMS: RT 3.27 min, m/z 468.3 [M + H].sup.+ J 134 [00263] embedded image 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8- carbonyl)-N-((S)-3-((2,3-dihydro-1H- inden-2-yl)amino)-2-hydroxypropyl)-2- methoxybenzamide hydrochloride .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.98 (d, J = 7.6 Hz, 1H), 7.27-7.17 (m, 6H), 4.66 (br s, 1H), 4.15-4.13 (m, 2H), 4.03 (s, 3H), 3.98 (br s, 1H), 3.82-3.82 (m, 1H), 3.72-3.72 (m, 2H), 3.62-3.56 (m, 3H), 3.46- 3.41 (m, 2H), 3.26-3.04 (m, 4H), 2.08-1.99 (m, 4H). LCMS: RT 1.57 min, m/z 480.3 [M + H].sup.+ J

Example 45: N-(2-Amino-3-((2,3-dihydro-1H-inden-2-yl)amino)propyl)-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide 106

[0694] ##STR00264##

(a) N-(2-Azido-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propyl)-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide A62

[0695] To a solution of 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)benzamide (Racemic analogue of Intermediate A in synthesis of 103, made in analogous way but with a racemic starting material) (100 mg, 0.17 mmol) in THF (5 mL) was added DPPA (95 mg, 0.34 mmol) and DBU (52 mg, 0.34 mmol). The resulting mixture was stirred at 60° C. overnight. LCMS showed the starting materials remained, further DPPA (46 mg, 0.17 mmol) and DBU (25 mg, 0.17 mmol) were added and the mixture was stirred at 60° C. overnight. The solvent was removed and the residue was purified by column chromatography (0-25% EtOAc/petroleum ether) to give the desired compound as an off-white solid (85 mg, 82%): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.66-7.64 (m, 2H), 7.56-7.54 (m, 2H), 7.21-7.14 (m, 6H), 6.45-6.38 (m, 2H), 4.75 (br s, 1H), 3.95-3.83 (m, 5H), 3.79-3.76 (m, 5H), 3.74-3.69 (m, 6H), 3.65-3.59 (m, 2H), 3.35-3.30 (m, 1H), 3.21-3.12 (m, 4H), 2.07-2.05 (m, 4H): LCMS: RT 2.65 min, m/z 625.3 [M+H].sup.+

(b) N-(2-Amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propyl)-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide A63

[0696] To a solution of N-(2-azido-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propyl)-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide A62 (70 mg, 0.11 mmol) in THF (2 mL) was added PPh.sub.3 (44 mg, 0.17 mmol). The resulting mixture was stirred at 50° C. for 3 h and then water (0.5 mL) was added dropwise and the mixture stirred at 30° C. overnight. The solvent was removed and the residue diluted with DCM (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the crude product as a pale yellow solid (100 mg). The product was used directly for the next step without further purification. LCMS: RT 2.60 min, m/z 599.3 [M+H].sup.+

[0697] A mixture of N-(2-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propyl)-4-(3-oxa-8 azabicyclo[3.2.1]octane-8-carbonyl)benzamide A63 (67 mg, 0.11 mmol) in TFA (1 mL) was stirred at 70° C. for 6 h. The solvent was removed and the residue was diluted with water (5 mL). The aqueous layer was washed with DCM (2×10 mL) and the pH adjusted to 9 by addition of solid Na.sub.2CO.sub.3 The aqueous layer was extracted with (10% MeOH in CH.sub.2Cl.sub.2) (6×10 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow solid (24 mg, 48%): .sup.1H NMR (400 MHz, d.sub.4-MeOD) δ 7.91-7.89 (m, 2H), 7.61-7.59 (m, 2H), 7.17-7.08 (m, 4H), 4.66 (br s, 1H), 3.95 (s, 1H), 3.83-3.69 (m, 4H), 3.61-3.56 (m, 2H), 3.49-3.45 (m, 1H), 3.24-3.15 (m, 2H), 2.98-2.93 (m, 1H), 2.83-2.62 (m, 4H), 2.07-2.01 (m, 4H): LCMS:RT 0.61 min, m/z 449.2 [M+H].sup.+

Example 46: N-(3-Amino-2-(((2,3-dihydro-1H-inden-2-yl)amino)methyl)-3-oxopropyl)-4-(morpholine-4-carbonyl)benzamide 107

[0698] ##STR00265## ##STR00266##

(a) Methyl 2-((1,3-dioxoisoindolin-2-yl)methyl)acrylate A63

[0699] To a solution of methyl 2-(bromomethyl)acrylate (2.0 g, 11.2 mmol) in toluene (50 mL) was added potassium 1,3-dioxoisoindolin-2-ide (2.0 g, 11.2 mmol) and 18-crown-6 (2.9 g, 11.2 mmol). The resulting mixture was stirred at 90° C. overnight. The reaction was partitioned with water (50 mL) and the aqueous layer further extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (4×100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a white solid (2.3 g, 85%): LCMS:RT 2.20 min, m/z 246.1 [M+H].sup.+

(b) Methyl 3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)propanoate A64

[0700] To a solution of methyl 2-((1,3-dioxoisoindolin-2-yl)methyl)acrylate A63 (2.0 g, 8.2 mmol) in CHCl.sub.3 (15 mL) was added N-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-inden-2-amine I9 (2.3 g, 8.2 mmol). The resulting mixture was heated at reflux for 3 days. The solvent was removed and the residue purified by column chromatography (0-17% Petroleum ether/EtOAc) to give the desired compound as a yellow oil (2.6 g, 60%): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84-7.82 (m, 2H), 7.72-7.70 (m, 2H), 7.29-7.27 (m, 1H), 7.16-7.15 (m, 2H), 7.11-7.08 (m, 2H), 6.47-6.44 (m, 1H), 6.42-6.40 (m, 1H), 3.93-3.92 (m, 1H), 3.84-3.81 (m, 3H), 3.78-3.77 (m, 6H), 3.76-3.73 (m, 2H), 3.62 (s, 3H), 3.16-3.13 (m, 1H), 3.00-2.93 (m, 4H), 2.69-2.64 (m, 1H): LCMS:RT 2.41 min, m/z 529.3 [M+H].sup.+

[0701] To a solution of methyl-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)propanoate A64 (2.6 g, 4.9 mmol) in MeOH (30 mL) was added DCM (5 mL) and hydrazine hydrate (85% aqueous solution, 270 mg, 5.4 mmol). The resultant mixture was stirred at room temperature overnight. The precipitate which formed was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with DCM (100 mL) and a 2 M aqueous HCl solution (50 mL) was added. The pH of the aqueous layer was adjusted to 10 by addition of 6 M aqueous NaOH solution and extracted with DCM (3×100 mL). The organic layers were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the desired compound as a yellow oil (1.0 g, 51%). The compound was used in the next step without further purification: LCMS:RT 1.38 min, m/z 399.3 [M+H].sup.+

(d) Methyl 3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-((4-(morpholine-4-carbonyl)benzamido)methyl)propanoate A66

[0702] To a solution of 4-(morpholine-4-carbonyl)benzoic acid I27 (420 mg, 1.80 mmol) in DCM (15 mL) was added HATU (685 mg, 1.80 mmol) and DIPEA (526 mg, 4.07 mmol) and the mixture was stirred at room temperature for 30 min. Methyl 3-amino-2-(((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino) methyl) propanoate A65 (650 mg, 1.63 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (70 mL) washed with water (70 mL), saturated aqueous NaHCO.sub.3 (70 mL), water (70 mL) and brine (70 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0-30% EtOAc in DCM) to give the desired compound as a light solid (450 mg, 45%): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.23 (br s, 1H), 7.68-7.66 (m, 2H), 7.34-7.33 (m, 2H), 7.19-7.17 (m, 2H), 7.12-7.10 (m, 3H), 6.43-6.41 (m, 1H), 6.34 (s, 1H), 3.99-3.84 (m, 4H), 3.82-3.70 (m, 12H), 3.56 (s, 3H), 3.52-3.38 (m, 4H), 3.04 (br s, 3H), 2.97-2.94 (m, 3H): LCMS:RT 2.21 min, m/z 616.4 [M+H].sup.+

(e) 3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-((4-(morpholine-4-carbonyl)benzamido)methyl)propanoic acid A67

[0703] To a solution of methyl 3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-((4-(morpholine-4-carbonyl)benzamido)methyl)propanoate A66 (100 mg, 0.16 mmol) in MeOH (5 mL) was added a solution of NaOH (13 mg, 0.32 mmol) in water (0.5 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue obtained dissolved in water. The pH of the aqueous solution was adjusted to 3 by addition of a 2 M aqueous HCl solution. The aqueous layer was extracted with DCM (3×20 mL) and the combined organic layers dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as a yellow solid (100 mg, 100%): LCMS: RT 2.38 min, m/z 602.4 [M+H].sup.+

(f) N-(3-Amino-2-(((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)methyl)-3-oxopropyl)-4-(morpholine-4-carbonyl)benzamide A68

[0704] To a solution of 3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-((4-(morpholine-4-carbonyl)benzamido)methyl)propanoic acid A67 (50 mg, 0.08 mmol) in DMF (0.5 mL) was added HATU (32 mg, 0.08 mmol) and DIPEA (32 mg, 0.24 mmol). The mixture was stirred at room temperature for 30 min, then poured into aqueous ammonia (26%, 2 mL) and stirred at room temperature for 1 h. The mixture was diluted with DCM (50 mL) and washed with water (2×50 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by preparative TLC (10% methanol in DCM) to give the desired compound as a yellow solid (30 mg, 40%): LCMS: RT 2.18 min, m/z 601.3 [M+H].sup.+

(g) N-(3-Amino-2-(((2,3-dihydro-1H-inden-2-yl)amino)methyl)-3-oxopropyl)-4-(morpholine-4-carbonyl)benzamide 107

[0705] A mixture of N-(3-amino-2-(((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)methyl)-3-oxopropyl)-4-(morpholine-4-carbonyl)benzamide A68 (30 mg, 0.05 mmol) in TFA (1 mL) was stirred at 70° C. for 6 h. The solvent was removed and the residue suspended in water. The pH was adjusted to 8 by addition of saturated aqueous NaHCO.sub.3 solution. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers washed with water (20 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by preparative TLC (10% methanol in DCM) to give the desired compound as a yellow solid (10 mg, 45%): .sup.1H NMR (400 MHz, d.sub.4-methanol) δ 7.94-7.92 (m, 2H), 7.56-7.52 (m 2H), 7.25-7.16 (m, 4H), 3.96-3.89 (m, 1H), 3.77-3.61 (m, 8H), 3.42 (brs, 2H), 3.37-3.31 (m, 2H), 3.27-3.22 (m, 1H), 3.13-3.01 (m, 4H): LCMS:RT 3.02 min, m/z 451.2 [M+H].sup.+

Example 47: N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-(hydroxymethyl)propyl)-4-(morpholine-4-carbonyl)benzamide 108

[0706] ##STR00267##

(a) 3-Amino-2-(((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)methyl)propan-1-ol A69

[0707] To a solution of methyl 3-amino-2-(((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino) methyl)propanoate A65 (50 mg, 0.13 mmol) in THF (4 mL) was added LiAlH.sub.4 (10 mg, 0.26 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was quenched with water (2×0.5 mL) 10% aqueous NaOH (0.5 mL) and water (0.5 mL) and stirred at room temperature for 10 min. The solvent was removed, water was added and the mixture was extracted with DCM (3×10 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated to give the desired compound as yellow oil (45 mg, 98%): LCMS: RT 0.96 min, m/z 371.2 [M+H].sup.+

(b) N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-(hydroxymethyl)propyl)-4-(morpholine-4-carbonyl)benzamide A70

[0708] To a solution of 3-amino-2-(((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl) amino)methyl) propan-1-ol A69 (180 mg, 0.48 mmol) in DCM (10 mL) was added 4-(morpholine-4-carbonyl)benzoic acid I27 (125 mg, 0.53 mmol), DIPEA (186 mg, 1.44 mmol), HOBt (7 mg, 0.05 mmol) and EDCl (110 mg, 0.58 mmol). The resulting mixture was stirred at room temperature for two days. The mixture was diluted with DCM (50 mL) and the organic layer washed with water (50 mL), saturated aqueous NaHCO.sub.3 (50 mL), water (50 mL) and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (0-2% MeOH in DCM) to give the desired compound as a yellow solid (80 mg, 28%): LCMS: RT 2.25 min, m/z 588.2 [M+H].sup.+

[0709] A mixture of N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-(hydroxyl methyl) propyl)-4-(morpholine-4-carbonyl)benzamide A70 (80 mg, 0.14 mmol) in TFA (4 mL) was stirred at 70° C. for 6 h. The solvent was removed and the residue suspended in water. The pH was adjusted to 8 by addition of saturated aqueous NaHCO.sub.3 solution. The aqueous layer was extracted with DCM (3×20 mL) and the combined organic layers washed with water (40 mL) and brine (40 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by preparative TLC (10% methanol in DCM) to give the desired compound as a yellow solid (30 mg, 51%): .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.92-7.90 (m, 2H), 7.54-7.52 (m, 2H), 7.22-7.17 (m, 4H), 3.87-3.42 (m, 14H), 3.31 (m, 1H, overlap), 3.02-2.89 (m, 4H), 2.19-2.15 (m, 1H). LCMS: RT 3.13 min, m/z 438.2 [M+H].sup.+

Example 48: (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-((1-(methylsulfonyl)azetidin-3-yl)amino)isonicotinamide bis 2,2,2-trifluoroacetic acid salt 109

[0710] ##STR00268##

(a) Methyl 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)isonicotinate A71

[0711] To a solution of methyl 2-bromoisonicotinate (3.0 g, 14.0 mmol) in dioxane (40 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (3.6 g, 21.0 mmol), cesium carbonate (9.1 g, 28.0 mmol), Xantphos (1.6 g, 2.8 mmol) and Pd.sub.2(dba).sub.3 (1.3 g, 1.4 mmol) under a nitrogen atmosphere. The reaction was heated at reflux overnight, then concentrated and the residue diluted with water (40 mL). The resulting mixture was extracted with DCM (3×40 mL) and the combined organic extracts washed with saturated aqueous NaHCO.sub.3 (3×30 mL) and brine (3×30 mL), dried (Na.sub.2SO.sub.4) and concentrated to give a crude residue which was purified by column chromatography (20% ethyl acetate/petroleum ether) to give the desired compound as a white solid (940 mg, 22%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20-8.19 (m, 1H), 7.15-7.14 (m, 1H), 6.93 (s, 1H), 5.16-5.15 (m, 1H), 4.59-4.51 (m, 1H), 4.35-4.31 (m, 2H), 3.91 (s, 3H), 3.78-3.75 (m, 2H), 1.44 (s, 9H); LCMS RT 2.45 min; m/z 308.1 [M+H].sup.+.

(b) 2-((1-(tert-Butoxycarbonyl)azetidin-3-yl)amino)isonicotinic acid A72

[0712] To a solution of methyl 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)isonicotinate A71 (930 mg, 3.1 mmol) in a mixture of THF (10 mL), MeOH (5 mL) and water (4 mL) was added lithium hydroxide hydrate (1.3 g, 30.3 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, then diluted with water. The pH of the aqueous solution was adjusted to 1-2 by addition of 4M aqueous HCl. Removal of the solvent provided the crude product containing lithium chloride (1.3 g). The material was carried forward without further purification. LCMS RT 1.26 min; m/z 294.1 [M+H].sup.+

(c) (R)-tert-Butyl-3-((4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)azetidine-1-carboxylate A73

[0713] To a suspension of 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)isonicotinic acid A72 (600 mg, 2.1 mmol) in DCM (10 mL) was added EDCl (786 mg, 4.1 mmol), HOBt (555 mg, 4.1 mmol) and DIEA (1.3 g, 10.3 mmol). A solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimeth-oxybenzyl)amino)propan-2-ol I10 (875 mg, 2.5 mmol) in DCM (10 mL) was added and the resulting mixture stirred at room temperature overnight. The mixture was diluted with water (20 mL) and DCM (20 mL) and the aqueous layer extracted with DCM (3×10 mL). The combined organic extracts were washed with saturated aqueous 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 column chromatography (ethyl acetate: petroleum ether=2:1) to give the desired compound as an off-white solid (600 mg, 46%). LCMS RT 2.42 min; m/z 632.4 [M+H].sup.+

(d) (R)-2-(Azetidin-3-ylamino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A74

[0714] A solution of (R)-tert-butyl 3-((4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl) amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)azetidine-1-carboxylate A73 (600 mg, 0.95 mmol) in a saturated solution of HCl (g) in EtOAc (30 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue obtained dissolved in DCM (30 mL) and partitioned with water. The aqueous layer neutralized by addition of saturated aqueous NaHCO.sub.3 to a pH of 7-8. The organic layer was separated and the aqueous solution further extracted with DCM (3×10 mL). The combined organic extracts were washed with saturated brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give the desired product as a yellow solid (400 mg, 79%) which was used without further purification. LCMS RT 3.13 min; m/z 532.3 [M+H].sup.+

(e) (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-((1-(methylsulfonyl)azetidin-3-yl)amino)isonicotinamide A75

[0715] To a solution of (R)-2-(azetidin-3-ylamino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A74 (150 mg, 0.28 mmol) in DCM (5 mL) was added triethylamine (85 mg, 0.84 mmol). A solution of methanesulfonyl chloride (33 mg, 0.28 mmol) in DCM (1 mL) was added dropwise into the mixture and the reaction stirred at room temperature for 2 h. Water (15 mL) and DCM (10 mL) were added to the mixture and the aqueous layer extracted with DCM (3×5 mL). The combined organic extracts were washed with brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by preparative TLC (5% methanol in dichloromethane) to give the desired compound as a yellow solid (70 mg, 41%). LCMS RT 2.01 min; m/z 610.3 [M+H].sup.+

(f) (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-((1-(methylsulfonyl)azetidin-3-yl)amino)isonicotinamide bis 2,2,2-trifluoroacetic acid salt 109

[0716] A solution of (R)—N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-((1-(methylsulfonyl)azetidin-3-yl)amino)isonicotinamide A75 (60 mg, 0.1 mmol) in trifluoroacetic acid (2 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue dissolved in DCM (10 mL) and partitioned with saturated aqueous NaHCO.sub.3 (10 mL). The aqueous layer was further extracted with DCM (3×5 mL) and the aqueous layer was concentrated under reduced pressure to give a crude residue. The residue was suspended in methanol/dichloromethane (1/20) (40 mL) and the salts removed by filtration. The organic solvent was removed to give the crude product which was purified by preparative HPLC to give the bis-TFA salt of the desired compound (23 mg, 51%) as an off-white solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.20-8.18 (m, 1H), 7.40 (m, 1H), 7.27-7.20 (m, 5H), 4.87-4.81 (m, 1H), 4.68-4.63 (m, 1H), 4.58-4.52 (m, 1H), 4.15-4.08 (m, 2H), 3.56-3.52 (m, 1H), 3.48-3.36 (m, 5H), 3.28-3.24 (m, 1H), 3.19-3.11 (m, 2H), 3.06-3.01 (m, 1H), 2.97 (s, 3H); LCMS RT 0.26 min; m/z 460.2 [M+H].sup.+. (freebase)

Example 49: (S)-2-((1-Acetylazetidin-3-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide bis 2,2,2-trifluoroacetic acid salt 110

[0717] ##STR00269##

(a) (R)-2-((1-acetylazetidin-3-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A76

[0718] To a solution of (R)-2-(azetidin-3-ylamino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A74 (220 mg, 0.41 mmol) in DCM (5 mL) was added triethylamine (212 mg, 2.10 mmol) followed by a solution of acetic anhydride (42 mg, 0.41 mmol) in DCM (1 mL) dropwise. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue dissolved in DCM (20 mL) and partitioned with water (15 mL). The aqueous layer was extracted with DCM (3×10 mL) and the combined organic extracts washed with brine (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by preparative TLC (5% methanol in dichloromethane) to give the desired compound as a white solid (150 mg, 64%). LCMS RT 2.04 min; m/z 574.3 [M+H].sup.+.

(b) (S)-2-((1-Acetylazetidin-3-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide bis 2,2,2-trifluoroacetic acid salt 110

[0719] A solution of (R)-2-((1-acetylazetidin-3-yl)amino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide A76 (130 mg, 0.23 mmol) in trifluoroacetic acid (4 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue obtained dissolved in DCM (10 mL) and partitioned with saturated aqueous NaHCO.sub.3 (10 mL). The aqueous layer was washed with DCM (3×5 mL) then concentrated to give a crude residue. The residue obtained was suspended in a mixture of methanol/dichloromethane (1/20) (40 mL) and the inorganic salts removed by filtration. The filtrate was concentrated and the residue was purified by preparative HPLC to give the bis-TFA salt of the desired compound (40 mg, 41%) as an off-white solid: .sup.1H NMR (400 MHz, MeOD) δ 8.08-8.06 (m, 1H), 7.28-7.20 (m, 5H), 7.16-7.14 (m, 1H), 4.66-4.60 (m, 2H), 4.42-4.38 (m, 1H), 4.16-4.10 (m, 3H), 3.93-3.90 (m, 1H), 3.57-3.53 (m, 1H), 3.48-3.39 (m, 3H), 3.28-3.24 (m, 1H), 3.18-3.11 (m, 2H), 3.07-3.01 (m, 1H), 1.90 (s, 3H); LCMS: RT 2.37 min; m/z 424.3 [M+H].sup.+.

Example 50: (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-N-methyl-4-(morpholine-4-carbonyl)benzamide 111

[0720] ##STR00270##

(a) (R)-Tert-butyl (3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl) carbamate A77

[0721] To a solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl) amino)propan-2-ol I10 (500 mg, 1.4 mmol) in dichloromethane (15 mL) was added triethylamine (284.0 mg, 2.8 mmol) and (Boc).sub.2O (305.0 mg, 1.4 mmol). The resulting mixture was stirred at room temperature overnight. Water was added to the solution and the mixture was extracted with dichloromethane (20 mL×3). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by column chromatography (Petroleum ether: ethyl acetate=3:1) to give the desired product (380 mg, 59%) as yellow oil. LCMS: RT 2.21 min; m/z 457.3 [M+H].sup.+

(b) (R)-1-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-3-(methylamino)propan-2-ol A78

[0722] To a solution of (R)-tert-butyl (3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamate A77 (670 mg, 1.47 mmol) in dry THF (10 mL) was added lithium aluminum hydride (334.3 mg, 8.82 mmol). The mixture was heated at reflux for 10 h. To the mixture was added a solution of NaOH (1.05 g, 26.4 mmol) in water (1 mL) and the precipitate that formed removed by filtration. The filter cake was rinsed with THF (200 mL×3) and the filtrate combined, dried (Na.sub.2SO.sub.4) and concentrated to give the crude product which was purified by column chromatography (Petroleum ether:ethyl acetate=1:1 to dichloromethane:methanol=20:1) to give the desired product (230 mg, 42%) as yellow oil. LCMS: RT 0.37 min; m/z 371.3 [M+H].sup.+

(c) (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-N-methyl-4-(morpholine-4-carbonyl)benzamide A79

[0723] To a solution of I27 (127.0 mg, 0.54 mmol) and (R)-1-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-3-(methylamino)propan-2-ol A78 (200 mg, 0.54 mmol) in DCM (910 mL) was added DIPEA (279.0 mg, 2.16 mmol), HOBt (114.8 mg, 0.75 mmol), and EDCl (143.0 mg, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture extracted with DCM. 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 column chromatography (DCM:MeOH=50:1) to give the desired product (170 mg, 53%) as yellow oil. LCMS: RT 2.10 min, m/z 588.3 [M+H].sup.+

(d) (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-N-methyl-4-(morpholine-4-carbonyl)benzamide 111

[0724] A mixture of (S)—N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-N-methyl-4-(morpholine-4-carbonyl)benzamide A79 (170 mg, 0.29 mmol) in TFA (5 mL) was stirred at 70° C. for 6 h. The solvent was removed and the residue suspended in water. The pH was adjusted to 8 by addition of saturated aqueous NaHCO.sub.3 solution. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers washed with water (20 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue obtained was purified by preparative TLC (10% methanol in DCM) to give the desired compound as a white solid (40 mg, 30%): .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.57-7.55 (m, 4H), 7.26-7.21 (m, 4H), 4.27 (m, 1H), 4.08-4.04 (m, 1H), 3.76-3.76 (m, 5H), 3.64-3.57 (m, 2H), 3.58-3.56 (m, 1H) 3.55-3.35 (m, 4H), 3.22-3.05 (m, 5H) 3.00-2.86 (m, 2H), LCMS: RT 0.49 min, m/z 438.2 [M+H].sup.+

Example 51: Alternative synthesis of 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxybenzamide 77

[0725] ##STR00271##

(a) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((R)-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-ethoxybenzamide A5

[0726] To a solution of (R)-4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)-3-ethoxybenzoic acid I25 (5.2 g, 9.48 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.42 g, 9.48 mmol) in DCM (20 mL) was added DIPEA (4.8 g, 37.9 mmol), HOBt (0.29 g, 1.9 mmol), and EDCl (3.6 g, 19.0 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 (20 mL×3). 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 column chromatography (DCM:MeOH=100:1) to give the desired product (5.8 g, 95%) as yellow oil. LCMS: RT 2.22 min, m/z 644.3 [M+H].sup.+

(b) Alternate synthesis of 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxybenzamide 77

[0727] A solution of 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((R)-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-2-ethoxybenzamide A5 (5.8 g, 90.0 mmol) in trifluoroacetic acid (30 mL) was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product which was suspended in saturated aqueous NaHCO.sub.3 (100 mL). The resulting mixture was extracted with DCM (×3) and the organic layers were combined, dried (Na.sub.2SO.sub.4) and concentrated to give a crude residue which was purified by column chromatography (DCM:MeOH=80:1.fwdarw.20:1) to give the desired product (2.13 g, 48%) as a white solid. LCMS: RT 1.87 min, m/z 494.3 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.03-8.01 (m, 1H), 7.24 (brs, 1H), 7.18-7.15 (m, 3H), 7.13-7.09 (m, 2H), 4.64 (s, 1H), 4.30-4.25 (m, 2H), 3.97-3.92 (m, 2H), 3.84-3.71 (m, 3H), 3.67-3.57 (m, 3H), 3.49-3.44 (m, 1H), 3.23-3.16 (m, 2H), 2.85-2.71 (m, 4H), 2.06-2.00 (m, 4H), 1.54-1.51 (m, 3H).

Example 52: (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(methyl)amino)-2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide 112

[0728] ##STR00272##

(a) (R)—N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide A80

[0729] To a solution of 4-(morpholine-4-carbonyl)benzoic acid I27 (659 mg, 2.8 mmol) in DCM (35 mL) at 0° C. was added DIPEA (1.09 g, 8.4 mmol) and HATU (1.17 g, 3.08 mmol). The mixture was stirred at 0° C. for 30 min. To the mixture was added a solution of (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10 (1.0 g, 2.8 mmol) in DCM (15 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. Water was added to the mixture and the solution extracted with DCM (30 mL×3). The combined organic layers were dried and concentrated to give the crude product which was purified by column chromatography (DCM:MeOH=50:1) to give the desired product (1.38 g, about 70% purity) as a yellow oil. LCMS: RT 2.00 min; m/z 574.3 [M+H].sup.+

(b) N-(2,4-dimethoxybenzyl)-N—((R)-2-hydroxy-3-(4-(morpholine-4-carbonyl)benzamido)propyl)-N-methyl-2,3-dihydro-1H-inden-2-aminium iodide A81

[0730] To a solution of (R)—N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-4-(morpholine-4-carbonyl)benzamide A80 (400 mg, 0.68 mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (282 mg, 2.04 mmol) and iodomethane (288 mg, 2.04 mmol). The resulting mixture was stirred at 55° C. in a sealed tube overnight. Water was added to the mixture and the solution extracted with DCM (20 mL×3). The organic layer was washed with brine (20 mL×4), dried and concentrated to give the crude product which was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (90 mg, 22%) as a yellow solid. LCMS: RT2.09 min; m/z 588.1 [M+H].sup.+.

[0731] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=8.80-8.71 (m, 1H), 7.96-7.85 (m, 2H), 7.54-7.45 (m, 3H), 7.31-7.12 (m, 4H), 6.66-6.61 (m, 1H), 6.56-6.47 (m, 1H). 5.93-5.92 (m, 1H), 5.81-5.75 (m, 1H), 4.84-4.80 (m, 1H), 4.67-4.45 (m, 2H), 4.30-4.26 (m, 1H), 4.25 (br s, 1H), 3.82-3.74 (m, 5H), 3.74 (s, 2H), 3.68-3.50 (m, 8H), 3.50-3.43 (m, 3H), 3.22-3.17 (m, 2H), 2.99 (s, 1H), 2.87 (s, 1H), 2.20-1.96 (m, 1H).

[0732] A solution of N-(2,4-dimethoxybenzyl)-N—((R)-2-hydroxy-3-(4-(morpholine-4-carbonyl)benzamido) propyl)-N-methyl-2,3-dihydro-1H-inden-2-aminium iodide A81 (100 mg, 0.17 mmol) in trifluoroacetic acid was stirred at 70° C. for 4 h. The mixture was concentrated to give the crude product. Saturated aqueous NaHCO.sub.3 solution was then added and the resulting mixture was extracted with DCM (×3). The organic layers were combined, dried and concentrated to give the crude product which was purified by preparative TLC (DCM:MeOH˜10:1) to give the desired product (20 mg, 27%) as a yellow solid. LCMS: RT 0.46 min; m/z 438.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=8.69 (s, 1H), 7.95-7.93 (m, 2H), 7.50-7.48 (m, 2H), 7.19-7.15 (m, 4H), 4.09-4.02 (m, 1H), 3.63-3.56 (m, 6H), 3.44-3.37 (m, 9H), 3.11-3.13 (m, 4H), 2.64-2.55 (m, 2H)

Example 53: 4-(3-Oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxybenzamide 135

[0733] ##STR00273##

(a) Ethyl (3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-2-ethoxybenzoate A82

[0734] To a solution of 3-ethoxy-4-(ethoxycarbonyl)benzoic acid I70 (73 mg, 0.31 mmol, 1 equiv) in DMF (2 mL) and acetonitrile (5 mL) was added DIPEA (160 μL, 0.917 mmol, 3 equiv), HATU (174 mg, 0.458 mmol, 1.5 equiv) and 3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (50 mg, 0.31 mmol, 1 equiv). 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 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 A83

[0735] To a solution of the ester A82 (88 mg, 0.25 mmol, 1 equiv) in THF:H.sub.2O:MeOH (3:1:0.5 v/v, 9 mL) was added LiOH.H.sub.2O (32 mg, 0.76 mmol, 3 equiv). The reaction was stirred at room temperature for 16 h before quenching by the addition of a 0.5 M aqueous solution of citric acid (10 mL) and extraction 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. The crude product mixture was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-100% EtOAc in petroleum benzine) to give the title compound (55 mg, 68% yield) as a colourless oil. .sup.1H NMR (400 MHz, 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)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxybenzamide 135

[0736] To a solution of the acid A83 (83 mg, 0.26 mmol, 1 equiv), DIPEA (136 μL, 0.780 mmol, 3 equiv) and HATU (148 mg, 0.390 mmol, 1.5 equiv) in DMF (2 mL) was added a solution of the amine 1117 (80 mg, 0.26 mmol, 1 equiv) in CH.sub.3CN (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 v/v) 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). 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 followed by 0-20% MeOH in EtOAc modified by the addition of 1% v/v of 2.0 M methanolic ammonia) to give the title compound (51 mg, 39% yield, 95% purity by .sup.1H NMR) as a colourless oil. .sup.1H NMR (400 MHz, MeOD) δ 8.02 (d, J=7.9 Hz, 1H), 7.23-7.15 (m, 3H), 7.13-7.03 (m, 3H), 4.52 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 4.06-3.76 (m, 5H), 3.68-3.55 (m, 3H), 3.53-3.43 (m, 1H), 3.24-3.12 (m, 2H), 2.87-2.51 (m, 5H), 2.00-1.95 (m, 2H), 1.92-1.79 (m, 2H), 1.76-1.63 (m, 1H), 1.53 (t, J=7.0 Hz, 3H). LCMS-B: RT=2.91 min, m/z=508.3 [M+H].sup.+.

Example 54: 4-((1R,5S)-3-Oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide 136

[0737] ##STR00274##

(a) Methyl (R)-4-((3-((tert-butoxycarbonyl)(2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoate A84

[0738] To a solution of 4-(methoxycarbonyl)benzoic acid (176 mg, 0.979 mmol, 1 equiv), DIPEA (512 μL, 2.94 mmol, 3 equiv) and HATU (558 mg, 1.47 mmol, 1.5 equiv) in CH.sub.3CN (10 mL) was added tert-butyl (R)-(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117 (300 mg, 0.979 mmol, 1 equiv). 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. The crude material was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-100% EtOAc in 40° C.-60° C. petroleum benzine) to give the title compound A84 (384 mg, 84% yield) as a pale yellow foam. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.07 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.61 (s, 1H), 7.21-7.08 (m, 4H), 4.64 (p, J=8.2 Hz, 1H), 4.00-3.82 (m, 5H), 3.78-3.71 (m, 1H), 3.53-3.26 (m, 3H), 3.24-2.99 (m, 4H), 1.39 (s, 9H). LCMS-B: RT=3.43 min, m/z=467.2 [M−H].sup.−, 369.2 [M+2H−Boc].sup.+.

(b) (R)-4-((3-((tert-butoxycarbonyl)(2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid A85

[0739] To a solution of the ester A84 (384 mg, 0.820 mmol, 1 equiv) in THF:H.sub.2O:MeOH (3:1:0.5 v/v, 9 mL) was added LiOH.H.sub.2O (59 mg, 2.5 mmol, 3 equiv). The reaction was stirred at room temperature overnight 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 concentrated in vacuo to give the title compound A85 (358 mg, 96% yield) as a white foam. LCMS-B: RT=3.27 min, m/z=355.1 [M+2H−Boc].sup.+.

(c) 4-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide 136

[0740] To a solution of (S)-4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)benzoic acid A85 (50 mg, 0.11 mmol, 1 equiv), DIPEA (57 μL, 0.33 mmol, 3 equiv) and HATU (63 mg, 0.17 mmol, 1.5 equiv) in DMF (2 mL) was added a solution of the amine 3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (18 mg, 0.11 mmol, 1 equiv) in CH.sub.3CN (10 mL). The reaction was stirred at room temperature overnight, quenched with a 1.0 M solution of aqueous NaOH (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 v/v) was added and the reaction stirred at room temperature for 60 h. 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). 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 followed by 0-30% MeOH in EtOAc modified by the addition of 1% v/v of 3.5 M methanolic ammonia) to give the title compound (34 mg, 67% yield) as a glassy solid. .sup.1H NMR (400 MHz, MeOD) δ 7.92 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.22-7.15 (m, 2H), 7.15-7.06 (m, 2H), 4.54 (s, 1H), 4.16-3.76 (m, 5H), 3.67 (p, J=7.0 Hz, 1H), 3.61-3.55 (m, 1H), 3.53-3.45 (m, 1H), 3.27-3.16 (m, 2H), 2.90-2.79 (m, 3H), 2.73 (dd, J=12.2, 8.1 Hz, 1H), 2.69-2.51 (m, 1H), 2.08-1.76 (m, 5H), 1.74-1.62 (m, 1H). LCMS-B: RT=2.83 min, m/z=464.2 [M+H].sup.+. Purity ˜95% by .sup.1H-NMR.

Example 55

[0741] ##STR00275##

[0742] To a solution of the 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 (R)-(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117 (52 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 v/v) 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 title compound.

TABLE-US-00007 Modifications to the general Compound Structure & name Analysis method 137 [00276] embedded image (S)-2-(difluoromethyl)-N-(3- ((2,3-dihydro-1H-inden-2- yl)amino)-2- hydroxypropyl)benzamide LCMS-B: RT = 2.87 min, m/z = 361.2 [M + H].sup.+. Stir in TFA overnight 138 [00277] (S)-3-(difluoromethyl)-N-(3- ((2,3-dihydro-1H-inden-2- yl)amino)-2- hydroxypropyl)benzamide LCMS-B: RT = 2.87 min, m/z = 361.1 [M + H].sup.+. Stir in TFA overnight

Example 56: 3-((3-Acetyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide 139

[0743] ##STR00278##

(a) Methyl 3-((3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)amino)benzoate A86

[0744] Methyl 3-aminobenzoate (0.100 g, 0.66 mmol) and (1R,5S)-3-benzyl-3-azabicyclo[3.2.1]octan-8-one (0.214 g, 0.99 mmol) were dissolved in dry DCE (5 mL) under an atmosphere of nitrogen and acetic acid (0.076 mL, 1.32 mmol) was added followed by sodium triacetoxyborohydride (0.280 g, 1.32 mmol). The reaction was then stirred at room temperature for 20 hours. The reaction was quenched by addition of water (5 mL) and then diluted with EtOAc (50 mL) and saturated aqueous NaHCO.sub.3 (50 mL). The organic phase was washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (Isolera Biotage: 12 g SiO.sub.2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound (0.230 g, 99% yield) as a pale yellow gum. LCMS (LCMS-B): RT 3.406 min; m/z 351.2 [M+H].sup.+.

(b) Lithium 3-((3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)amino)benzoate A87

[0745] Methyl 3-((3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)amino)benzoate A86 (0.230 g, 0.656 mmol) was dissolved in THF (7 mL), MeOH (1 mL) and water (1 mL) and lithium hydroxide monohydrate (0.275 g, 6.563 mmol) was added. The reaction was then stirred at room temperature for 48 hours. The volatiles were removed in vacuo and the resulting residue diluted with EtOAc (50 mL) followed by 1M aqueous NaOH (50 mL). The layers were separated and the organic layer was concentrated in vacuo to give the title compound (0.200 g, 89% yield) as a pale yellow gum. LC-MS (LCMS-B): RT 3.298 min; m/z 337.3 [M+H].sup.+ as the free acid.

(c) 3-((3-Benzyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-N—((R)-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)benzamide A88

[0746] Lithium 3-((3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)amino)benzoate A87 (0.200 g, 0.584 mmol) was dissolved in DCM (5 mL) and DMF (1 mL) and DIPEA (0.278 mL, 1.593 mmol) followed by HATU (0.263 g, 0.690 mmol) were added. The mixture was then stirred at room temperature for 10 min before (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10 (0.189 g, 0.531 mmol) in DCM (2 mL) 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 saturated aqueous NaHCO.sub.3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL), the combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product. Purification by column chromatography (Isolera Biotage, 24 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% MeOH in EtOAc) gave the title compound (0.194 g, 54% yield) as an off-white solid. LCMS (LCMS-B): RT 3.524 min, m/z 676.5 [M+H].sup.+

(d) 3-((3-Acetyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)benzamide 139

[0747] 3-(3-Benzyl-3-azabicyclo[3.2.1]octan-8-ylamino)-N—((R)-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)benzamide A88 (0.190 g, 0.282 mmol) was dissolved in EtOH (8 mL) under an atmosphere of nitrogen and 4 drops of concentrated HCl were added followed by 10% Pd/C (wet with water, 53%) (0.070 g) in EtOAc (4 mL). The atmosphere was changed to hydrogen and the flask was fitted with a hydrogen balloon (1 atm). The reaction was then stirred at room temperature for 24 hours then the atmosphere was changed to nitrogen and additional 10% Pd/C (wet with water, 53%) (0.070 g) in EtOAc (4 mL) was added. The atmosphere was again changed to hydrogen and the flask was fitted with a hydrogen balloon (1 atm). The reaction was then stirred at room temperature for 5 days. The reaction was filtered through Celite which was rinsed with EtOAc (˜70 mL). A white precipitate was collected by filtration. Upon air-drying, the solid turned into a gum which was rinsed off the filter paper with methanol and the solution was concentrated in vacuo to give a brown foam. This residue was dissolved in DCM (3 mL) under an atmosphere of nitrogen and DIPEA (0.043 mL, 0.246 mmol) followed by acetic anhydride (0.008 mL, 0.082 mmol) were added. The reaction was stirred at room temperature for 24 hours, then diluted with DCM (20 mL) and washed with saturated aqueous NaHCO.sub.3 (20 mL), brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. To the resulting residue was added TFA (3 mL) and the reaction mixture was then heated to 70° C. and stirred for 20 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 extracted with EtOAc (50 mL), the combined organic layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Purification by column chromatography (Isolera Biotage, 4 g SiO.sub.2 Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-66% MeOH (containing 1% 2M NH.sub.3 v/v) in EtOAc) gave the title compound (0.006 g, 21% yield) as a brown gum. LC-MS (LCMS-B): RT 3.289 min, m/z 477.3 [M+H].sup.+

Example 57: (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3-(methylsulfonamido) benzamide 140

[0748] ##STR00279##

(a) (R)—N-(3-((2,3-Dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-3-(methylsulfonamido)benzamide A89

[0749] 3-(Methylsulfonamido)benzoic acid (0.109 g, 0.505 mmol) was dissolved in DCM (5 mL) and DIPEA (0.220 mL, 1.262 mmol) followed by HATU (0.208 g, 0.547 mmol) were added. The mixture was then stirred at room temperature for 10 min before (R)-1-amino-3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)propan-2-ol I10 (0.150 g, 0.421 mmol) in DCM (2 mL) was added. The reaction was stirred at room temperature for 20 hours, then diluted with DCM (50 mL) and washed with saturated aqueous NaHCO.sub.3 solution (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the crude product. Purification by column chromatography (Isolera Biotage, 12 g SiO.sub.2 Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-35% MeOH in EtOAc) gave the title compound (0.092 g, 39% yield) as a pale yellow solid. LCMS (LCMS-A): RT 4.849 min, m/z 554.3[M+H].sup.+

(b) (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3-(methylsulfonamido) benzamide 140

[0750] To (R)—N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)-3-(methylsulfonamido)benzamide A89 (0.090 g, 0.163 mmol) was added TFA (3 mL) and the reaction mixture was heated to 70° C. and stirred at this temperature for 45 hours. The volatiles were partly removed in vacuo, methanol (10 mL) was added and the solution was loaded onto a SCX cartridge (2 g), the cartridge was washed with methanol (5 column volumes), then eluted with 2 M ammonia in methanol (3 column volumes). The eluate was then concentrated in vacuo to give the title compound (0.057 g, 88% yield) as a beige gum. LCMS (LCMS-B): RT 3.217 min, m/z 404.1 [M+H].sup.+.

Example 58: 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxy-5-fluorobenzamide 141

[0751] ##STR00280##

(a) Ethyl 4-bromo-2-ethoxy-5-fluorobenzoate A90

[0752] 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 two hours a thick precipitate had formed. The mixture was diluted with dry THF (50 mL) and the stir bar replaced with a larger 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/petroleum benzine) to give ethyl 4-bromo-2-ethoxy-5-fluorobenzoate A90 as a white solid (216 mg, 18% yield). LCMS-B: RT 3.53 min; m/z 245.0 [M-OEt].sup.+ for .sup.79Br; .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).

(b) Ethyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate A91

[0753] 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 A90 (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. 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 ethyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate A91 as a pale yellow film (41 mg, 16% yield). LCMS-B RT 3.23 min; m/z (positive ion) 352.1 [M+H]; .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).

[0754] A solution of ethyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate (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 lithium 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate. LCMS-B: RT 2.96 min; m/z (negative ion) 322.1 [M−Li].sup.−

(d) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxy-5-fluorobenzamide 141

[0755] Lithium 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-5-fluorobenzoate A92 (used directly from previous step, ˜0.059 mmol), triethylamine (0.016 mL, 0.12 mmol), tert-butyl (R)-(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117 (18 mg, 0.059 mmol) and HATU (34 mg, 0.18 mmol) in DMF (0.5 mL) were stood at room temperature. After 18 hours the mixture was diluted with water and DCM (1.5 mL each). The organic phase was separated with a phase separation cartridge and treated with Dowex 50WX8H.sup.+-form (200-400 mesh, 100 mg). The mixture was filtered and the filtrate diluted with 4.0 M HCl in dioxane (2 mL). After three hours 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 title compound. LCMS: RT 2.90 min; m/z (positive ion) 512.2 [M+H]

Example 59: (S)-Methyl 3-((4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)azetidine-1-carboxylate bis(2,2,2-trifluoroacetate) 142

[0756] ##STR00281##

(a) (R)-Methyl 3-((4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)azetidine-1-carboxylate A93

[0757] To a solution of (R)-2-(azetidin-3-ylamino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide dihydrochloride A74 (100 mg, 0.18 mmol) in DCM (4 mL) was added triethylamine (95 mg, 0.94 mmol). A solution of methyl chloroformate (22 mg, 0.22 mmol) in DCM (1 mL) was added dropwise into the mixture. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and the residue partitioned between DCM (10 mL) and water (10 mL). The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts washed with brine (3×5 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by preparative TLC (5% methanol in dichloromethane) to give the title compound as a white solid (53 mg, 48%). LCMS RT 2.07 min; m/z 590.3 [M+H].sup.+

(b) (S)-Methyl 3-((4-((3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)azetidine-1-carboxylate bis(2,2,2-trifluoroacetate) 142

[0758] A solution of (R)-methyl 3-((4-((3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)azetidine-1-carboxylate A93 (50 mg, 0.08 mmol) in trifluoroacetic acid (4 mL) was heated at reflux 6 h. The mixture was concentrated under vacuum and the residue obtained dissolved in DCM (10 mL). The reaction was quenched with saturated aqueous NaHCO.sub.3 solution (15 mL). The aqueous layer was extracted with DCM (3×10 mL) and the combined organic extracts washed with saturated aqueous NaHCO.sub.3 solution (3×5 mL), brine (3×5 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by preparative HPLC to give the title compound as a yellow solid (15 mg, 40%). .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.04 (d, J=6.4 Hz, 1H), 7.33 (s, 1H), 7.27-7.19 (m, 5H), 4.66-4.60 (m, 1H), 4.45-4.40 (m, 2H), 4.14-4.08 (m, 2H), 3.98-3.95 (m, 2H), 3.68 (s, 3H), 3.57-3.53 (m, 1H), 3.49-3.38 (m, 3H), 3.29-3.25 (m, 1H), 3.19-3.11 (m, 2H), 3.07-3.02 (m, 1H). LCMS RT 2.74 min; m/z 440.2 [M+H].sup.+ for the free base.

Example 60: (S)-2-(azetidin-3-ylamino)-N-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)isonicotinamide tris(2,2,2-trifluoroacetate) 143

[0759] ##STR00282##

[0760] A solution of (R)-2-(azetidin-3-ylamino)-N-(3-((2,3-dihydro-1H-inden-2-yl)(2,4-dimethoxybenzyl)amino)-2-hydroxypropyl)isonicotinamide dihydrochloride A74 (70 mg, 0.13 mmol) in trifluoroacetic acid (3 mL) was heated at reflux 4 h. The mixture was concentrated under vacuum and the residue obtained dissolved in DCM (10 mL). The mixture was quenched with a saturated aqueous NaHCO.sub.3 solution (10 mL). The aqueous layer was extracted with DCM (3×5 mL) and concentrated under vacuum. The residue was dissolved in a mixed solution of methanol/dichloromethane (20 mL, 1/20 v/v) and the mixture filtered. The filtrate was concentrated and the residue purified by preparative HPLC to give the title compound as an off-white solid (16 mg, 32%): .sup.1H NMR (400 MHz, MeOD) δ 8.25 (d, J=6.8 Hz, 1H), 7.49 (s, 1H), 7.33 (d, J=6.4 Hz, 1H), 7.27-7.20 (m, 4H), 5.02-4.96 (m, 1H), 4.79-4.74 (m, 1H), 4.68-4.63 (m, 1H), 4.15-4.08 (m, 2H), 3.57-3.53 (m, 1H), 3.49-3.35 (m, 5H), 3.29-3.25 (m, 1H), 3.19-3.11 (m, 2H), 3.07-3.02 (m, 1H); LCMS RT 0.27 min; m/z 382.2 [M+H].sup.+ for the free base.

Example 61: 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((R)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxybenzamide hydrochloride 144

[0761] ##STR00283##

(a) tert-Butyl((R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate A94

[0762] A mixture of (S)-tert-butyl (3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate (1.0 g, 3.26 mmol) I123, 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzoic acid I72 (1.14 g, 3.92 mmol), HOBt (0.66 g, 4.89 mmol), EDCl (0.94 g, 4.89 mmol) and triethylamine (1.32 g, 13.04 mmol) in CH.sub.2Cl.sub.2 (20 mL) under N.sub.2 was stirred at room temperature overnight. The mixture was poured into water and diluted with EtOAc, the organic layer was washed with a 0.1 M aqueous HCl solution, brine, dried (Na.sub.2SO.sub.4), filtered, concentrated and purified by silica gel chromatography (MeOH/CH.sub.2Cl.sub.2=1/1, v/v) to give the title compound (1.3 g, 67%) as a white solid. LCMS: RT 3.02 min; m/z 594.4 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.54 (br s, 1H), 8.19 (d, J=0.8 Hz, 1H), 7.16-7.07 (m, 6H), 4.72-4.68 (m, 2H), 4.23 (q, J=6.8 Hz, 2H), 3.93-3.85 (m, 3H), 3.74-3.59 (m, 4H), 3.39-3.32 (m, 3H), 3.18-3.12 (m, 2H), 3.08-2.99 (m, 2H), 2.05-1.93 (m, 4H), 1.54 (t, J=7.2 Hz, 3H), 1.41 (s, 9H).

(b) 4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-N—((R)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxybenzamide hydrochloride 144

[0763] To a solution of tert-butyl ((2S)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate (500 mg, 0.84 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added dropwise a solution of HCl (2.5 M, in dioxane, 5 mL) at 0° C. The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and Et.sub.2O was added, the precipitate was collected by filtration and washed with Et.sub.2O and dried to give the title compound (435 mg, 97%) as a white solid. LCMS:RT 1.95 min, m/z 494.1 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (br s, 2H), 8.42 (t, J=5.6 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.26-7.11 (m, 5H), 5.82 (d, J=4.2 Hz, 1H), 4.52 (br s, 1H), 4.23 (q, J=6.8 Hz, 2H), 4.05-4.02 (m, 2H), 3.86 (br s, 1H), 3.67-3.61 (m, 3H), 3.51-3.42 (m, 3H), 3.29-3.25 (m, 2H), 3.17-3.10 (m, 3H), 2.95-2.90 (m, 1H), 1.88 (br s, 4H), 1.42 (t, J=6.8 Hz, 3H).

Example 62: 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)nicotinamide 145

[0764] ##STR00284##

(a) Methyl 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate A95

[0765] To a solution of methyl 6-chloronicotinate (300 mg, 1.75 mmol) in dry DMF (15 mL) was added 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (392 mg, 2.62 mmol, 1.5 equiv) and triethylamine (0.609 mL, 4.37 mmol, 2.5 equiv). The system was flushed with N.sub.2 and heated at 80° C. for 20 h. The reaction was allowed to reach room temperature and was diluted with water/EtOAc. The aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered, and the solvent removed in vacuo. The crude residue was purified by column chromatography (24 g SiO.sub.2 cartridge, 0-35% EtOAc in petroleum benzine 40° C.-60° C.) to give the title compound (400 mg, 92 yield) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.76 (dd, J=2.3, 0.8 Hz, 1H), 8.00 (dd, J=9.0, 2.4 Hz, 1H), 6.48 (dd, J=9.1, 0.8 Hz, 1H), 4.52-4.41 (m, 2H), 3.96-3.87 (m, 2H), 3.84 (s, 3H), 3.18 (dd, J=12.6, 2.7 Hz, 2H), 1.99-1.89 (m, 2H), 1.83-1.74 (m, 2H). LCMS-B: RT 3.05 min, m/z=249.1 [M+H].sup.+.

(b) 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinic acid A96

[0766] To a solution of the desired ester methyl 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate A95 (400 mg, 1.61 mmol) in THF:H.sub.2O:MeOH (3:1:0.5 v/v, 10 mL) was added LiOH.H.sub.2O (203 mg, 4.83 mmol, 3 equiv). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. Water was added and the pH adjusted to 3 by the addition of a 0.5 M aqueous citric acid solution. The aqueous mixture was extracted with ethyl acetate (×3), washed with water, brine, dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo to give the title compound (347 mg, 92% yield) as a light brown solid. .sup.1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2.3 Hz, 1H), 7.90 (dd, J=9.0, 2.4 Hz, 1H), 6.73 (d, J=9.0 Hz, 1H), 4.41 (dd, J=4.2, 2.1 Hz, 2H), 3.94 (d, J=12.5 Hz, 2H), 3.01 (dd, J=12.7, 2.6 Hz, 2H), 1.87-1.72 (m, 2H), 1.65 (q, J=7.1, 6.5 Hz, 2H). LCMS-A: RT 1.85 min, m/z=235.2 [M+H].sup.+.

[0767] To a solution of tert-butyl (R)-(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117 (100 mg, 0.326 mmol), DIPEA (171 μL, 0.979 mmol, 3 equiv) and HATU (186 mg, 0.490 mmol, 1.5 equiv) in DMF (2 mL) was added a solution of the 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinic acid A96 (76 mg, 0.33 mmol, 1 equiv) in DMF (3 mL). The reaction was stirred at room temperature overnight, quenched with a 1 M aqueous solution of NaOH (15 mL) and stirred for 4 h. The aqueous mixture was extracted with EtOAc (3×40 mL) and 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 v/v) was added and the reaction stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and then purified by solid-phase extraction (5 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 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 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N—((S)-3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)nicotinamide (56 mg, 41% yield) as a white solid. .sup.1H NMR (400 MHz, MeOD) δ 8.60 (dd, J=2.5, 0.7 Hz, 1H), 7.95 (dd, J=9.0, 2.5 Hz, 1H), 7.25-7.16 (m, 2H), 7.16-7.06 (m, 2H), 6.74 (dd, J=9.2, 0.8 Hz, 1H), 4.51-4.42 (m, 2H), 4.01-3.90 (m, 3H), 3.73 (p, J=7.0 Hz, 1H), 3.51-3.38 (m, 2H), 3.28-3.18 (m, 2H), 3.12 (dd, J=12.7, 2.6 Hz, 2H), 2.94-2.82 (m, 3H), 2.76 (dd, J=12.3, 8.2 Hz, 1H), 2.00-1.91 (m, 2H), 1.86-1.73 (m, 2H). LCMS-B: RT 2.83 min, m/z=423.2 [M+H].sup.+.

Example 63: (S)—N-(3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxy-6-morpholinonicotinamide 146

[0768] ##STR00285##

(a) 2-Ethoxy-6-morpholinonicotinic acid A97

[0769] 6-Chloro-2-ethoxynicotinic acid (0.250 g, 1.24 mmol) was dissolved in 1,4-dioxane (2 mL) and Et.sub.3N (0.52 mL, 3.72 mmol) and morpholine (0.16 mL, 1.86 mmol) were added and the reaction was heated in a microwave at 150° C. for 45 minutes. The solvent was evaporated and the residue was purified by chromatography (Isolera Biotage, 12 g SiO.sub.2 cartridge, 0-100 EtOAc in petroleum benzine 40-60° C., then 0-5% MeOH in EtOAc) to give the title compound (0.174 g, 56% yield) as a pale pink solid. .sup.1H NMR (400 MHz, MeOD) δ 8.05 (d, J=8.7 Hz, 1H), 6.36 (d, J=8.7 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.79-3.73 (m, 4H), 3.67-3.62 (m, 4H), 1.40 (t, J=7.0 Hz, 3H). LCMS-B: RT 3.098 min, m/z 253.1 [M+H].sup.+

(b) tert-Butyl (R)-(2,3-dihydro-1H-inden-2-yl)(3-(2-ethoxy-6-morpholinonicotinamido)-2-hydroxypropyl)carbamate A98

[0770] 2-Ethoxy-6-morpholinonicotinic acid A97 (0.050 g, 0.198 mmol) was dissolved in DMF (4 mL) and Et.sub.3N (0.083 mL, 0.595 mmol) followed by HATU (0.113 g, 0.297 mmol) were added. The mixture was then stirred at room temperature for 10 minutes before tert-butyl (R)-(3-amino-2-hydroxypropyl)(2,3-dihydro-1H-inden-2-yl)carbamate I117 (0.061 g, 0.198 mmol) was added. The reaction was stirred at room temperature for 20 hours, then diluted with EtOAc (70 mL) and washed with saturated aqueous NaHCO.sub.3 solution (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, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound (0.073 g, 68% yield) as a colourless gum. LCMS-B: RT 3.552 min, m/z 541.3 [M+H].sup.+

[0771] tert-Butyl (R)-(2,3-dihydro-1H-inden-2-yl)(3-(2-ethoxy-6-morpholinonicotinamido)-2-hydroxypropyl)carbamate A98 (0.073 g, 0.135 mmol) was dissolved in DCM (4 mL), TFA (0.310 mL, 4.051 mmol) was added and the reaction was stirred at room temperature for 20 hours. Volatiles were removed in vacuo and the residue was diluted with EtOAc (70 mL) and washed with 2 M aqueous NaOH solution (70 mL), brine (70 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo, taken up in diethyl ether and evaporated in vacuo to give the title compound (0.053 g, 89% yield) as a white foam. .sup.1H NMR (400 MHz, MeOD) δ 8.14 (d, 1H), 7.20-7.08 (m, 4H), 6.41 (d, J=8.7 Hz, 1H), 4.54-4.47 (m, 2H), 3.95-3.87 (m, 1H), 3.79-3.74 (m, 4H), 3.69-3.54 (m, 6H), 3.42 (dd, J=13.8, 6.4 Hz, 1H), 3.19 (ddd, J=15.7, 7.2, 5.3 Hz, 2H), 2.85-2.76 (m, 3H), 2.71 (dd, J=12.1, 8.0 Hz, 1H), 1.46 (t, J=7.1 Hz, 3H). LCMS-B: RT 2.981 min, m/z 441.2 [M+H].sup.+

Assays

PRMT5 Biochemical Assay

[0772] 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-NH.sub.2). Full-length PRMT5 enzyme (NCBI Reference sequence NP-006100.2) was co-expressed with Hiss-MEP50 in insect cells and purified via Nickel immobilized metal affinity and gel filtration chromatography (“the enzyme”).

[0773] 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 (% I) 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])AD)))) 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-00008 Compound Number IC.sub.50 (μM) 1 0.792 2 0.31 3 0.309 4 3.79 5 9.78 6 1.55 7 2.45 8 0.263 9 3.72 10 1.44 11 0.83 12 0.695 13 0.634 14 0.445 15 0.218 16 0.301 17 0.629 18 0.238 20 0.977 21 1.111 22 0.171 24 0.425 25 2.22 26 3.87 27 0.434 28 69.4 29 4.43 30 0.905 31 22.58 32 18.8 33 24.9 34 41.1 35 0.050 37 0.095 38 0.210 39 0.120 40 0.057 41 0.157

PRMT5 Biomarker Assay

[0774] Compounds of the invention may be tested for potency to inhibit symmetrical dimethylation of arginine in the following assay:

[0775] 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 H4R3 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-00009 Compound Number IC.sub.50 (μM) 2 0.069 8 0.336 13 0.348 14 0.21 15 0.030 16 0.259 18 0.092 22 0.018 24 0.363 30 1.910 35 0.008 37 0.019 38 0.011 40 0.002 98 0.007

Revised PRMT5 Biochemical Assay

[0776] 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-NH.sub.2). Full-length PRMT5 enzyme (NCBI Reference sequence NP-006100.2) was co-expressed with Hiss-MEP50 in insect cells and purified via Nickel immobilized metal affinity and gel filtration chromatography (“the enzyme”).

[0777] 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 (% I) 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−F((B−A)/(1+((C/[I])AD)))) 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-00010 Compound Number IC.sub.50 (μM) 35 0.155 37 0.163 38 0.310 42 0.137 43 1.010 44 0.373 45 12.822 46 4.988 47 11.441 48 4.784 49 25.309 50 0.466 51 0.709 52 74.637 53 0.164 54 5.769 55 0.450 56 0.098 57 2.533 58 0.883 59 0.487 60 0.630 61 0.180 62 6.925 63 7.295 64 1.104 65 1.299 66 1.559 67 6.871 68 6.171 69 10.004 70 0.157 71 0.237 72 0.341 73 4.379 74 3.135 75 0.064 76 0.209 77 0.029 78 5.577 79 24.001 80 0.253 81 1.366 82 1.813 83 3.458 84 0.585 85 7.684 86 0.682 87 2.762 88 0.229 89 0.853 90 3.153 91 1.226 92 1.383 93 0.505 94 1.346 95 0.931 96 0.733 97 4.319 98 0.281 100 1.104 101 0.457 102 0.482 103 0.120 104 0.514 105 0.196 106 24.254 107 52.161 108 21.239 109 11.105 110 0.166 111 10.382 112 9.413 113 4.146 114 0.066 115 0.305 116 0.276 117 31.368 118 102.627 119 5.082 120 13.317 121 0.130 122 0.166 123 0.040 124 0.048 125 6.724 126 0.226 127 0.137 128 15.438 129 0.629 130 1.129 131 4.591 132 29.683 133 0.131 134 0.238 135 0.015 136 0.050 137 46.992 138 16.890 139 0.771 140 4.679 141 0.695

Revised PRMT5 Biomarker Assay

[0778] Compounds of the invention may be tested for potency to inhibit symmetrical dimethylation of arginine in the following assay:

[0779] 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-00011 IC.sub.50 (μM) - plate Compound Number reader based 15 0.025 22 0.106 35 0.040 38 0.053 40 0.021 53 0.662 55 0.122 56 0.007 70 0.015 75 0.004 76 0.008 77 0.0005 98 0.361 103 0.017 105 0.010 111 >2 114 0.024 121 0.016 123 0.012 124 0.013 127 0.002 133 0.009 135 0.0003

AMINOINDANE-, AMINOTETRAHYDRONAPHTHALENE- AND AMINOBENZOCYCLOBUTANE-DERIVED PRMT5-INHIBITORS

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