TETRAHYDRO-BENZOAZEPINE GLYCOSIDASE INHIBITORS

Abstract

Compounds of formula (I′), wherein A, R.sup.1, R.sup.2, T.sup.1, T.sup.2, T.sup.3, T.sup.4, L, W, Z, R′″, m and n have the meaning according to the claims, can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.

##STR00001##

Claims

1. A compound of formula (I′) ##STR00628## Wherein R.sup.1, R.sup.2 denote each independently a straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH or one of R.sup.1, R.sup.2 denotes H, while the other denotes a straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH or R.sup.1 and R.sup.2 may both denote H, if A denotes the following group: ##STR00629## Z denotes H, OR.sup.3, OCF.sub.3, Hal, a straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OR.sup.3 T.sup.1, T.sup.2, T.sup.3, T.sup.4 denote each independently CR′″ or N; L is a single bond or one of the following groups: O, NR.sup.3′, CH.sub.2, OCH.sub.2, CH.sub.2CH.sub.2, CONR.sup.3′, CONR.sup.3′CH.sub.2, NR.sup.3CO, NR.sup.3COCH.sub.2, SO.sub.2NR.sup.3′, NR.sup.3SO.sub.2, CONR.sup.3′CH.sub.2, CH.sub.2CONR.sup.3′ SO.sub.2NR.sup.3′CH.sub.2, CH.sub.2SO.sub.2NR.sup.3′, CH.sub.2NR.sup.3′CO, NR.sup.3′SO.sub.2CH.sub.2, CH.sub.2NR.sup.3′SO.sub.2, CH.sub.2O, S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00630## m, n denote 0, 1 or 2, wherein m+n is 2; A denotes one of the following groups: ##STR00631## ##STR00632## X is N or CR′″; X.sup.a is N, NR.sup.3, C or CR′″; X.sup.b is N or C; Y is O, S, SO or SO.sub.2; R′, R″ denote each independently H, Hal or straight chain or branched alkyl having 1 to 12 carbon atoms; R′″, R′″ independently denote H, Hal, NR.sup.3R.sup.4, CHR.sup.3R.sup.4, OR.sup.3, CN or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from O, NR.sup.3, S, SO, SO.sub.2, S(O)(NR.sup.3′), N(SO)R.sup.3′, CO, COO, OCO, CONR.sup.3, NR.sup.3CO, ##STR00633## and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR.sup.3R.sup.4 or NO.sub.2 or by one of the following groups: ##STR00634## or R′″, R″″ independently denote one of the following groups: ##STR00635## R.sup.3, R.sup.4 denote each independently H or a straight chain or branched alkyl group having 1 to 12 carbon atoms; R.sup.3a denote a straight chain or branched alkyl group having 1 to 12 carbon atoms; W denotes Q or R Q denotes one of the following groups: ##STR00636## ##STR00637## Z.sup.1 is S, O, NR.sup.3; Z.sup.2, Z.sup.3 independently denote CR.sup.5, CR.sup.6 or N; Z.sup.4 is N, CH, CON, COCH; Z.sup.5 is O, NR.sup.8, CHR.sup.5, SO.sub.2, S(O)(NR.sup.3), N(SO)R.sup.3′, ##STR00638## Z.sup.6 is CH.sub.2, CO, S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00639## Z.sup.7 is C(R.sup.3′).sub.2, S, O, NR.sup.3′; s denotes 0 or 1; T is N, CH or CR.sup.7; R.sup.3′ denotes H or a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from SO.sub.2, CO, 0 and wherein 1 to 5 hydrogen atoms may be replaced by Hal; R, R.sup.5, R.sup.6, R.sup.7 independently denote H, Hal, CN, OH, NR.sup.3R.sup.4, NO.sub.2 or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from O, NR.sup.3, S, SO, SO.sub.2, S(O)(NR.sup.3′), N(SO)R.sup.3′, CO, COO, OCO, CONR.sup.3, NR.sup.3CO ##STR00640## and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR.sup.3R.sup.4, NO.sub.2, OR.sup.3, Het, Ar, Cyc or by one of the following groups: ##STR00641## or R, R.sup.5, R.sup.6, R.sup.7 denote Ar, Het or Cyc or one of the following groups: ##STR00642## R.sup.8 denotes H or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from SO, SO.sub.2, S(O)(NR.sup.3′), N(SO)R.sup.3′, CO, COO, OCO, CONR.sup.3, NR.sup.3CO, and ##STR00643## and further wherein 1 to 5 hydrogen atoms may be replaced by CN, OR.sup.3, SR.sup.3, Hal, NR.sup.3R.sup.4, NO.sub.2 or by one of the following groups: ##STR00644## or R.sup.8 denote one of the following groups: ##STR00645## Hal denotes F, Cl, Br or I; Het denotes a saturated, unsaturated or aromatic ring, being monocyclic or bicyclic or fusedbicyclic and having 3 to 8 members and containing 1 to 4 heteroatoms selected from N, O and S, which may be substituted by 1 to 3 substituents selected from R.sup.5, Hal and OR.sup.3; Ar denotes a 6-membered carbocyclic aromatic ring or a fused or non-fused bicylic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R.sup.5, OR.sup.3 and Hal; Cyc denotes a saturated or an unsaturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R.sup.5, Hal and OH; t and q denote independently from one another 0, 1, 2 or 3, with t+q≥1, and pharmaceutically usable derivatives, solvates, salts, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms may be replaced by D (deuterium).

2. A compound chosen from the group of formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih: ##STR00646## ##STR00647## wherein A, W, L, T.sup.1, T.sup.2, T.sup.3, T.sup.4, R′″, m and n have the meaning given in claim 1 and wherein R.sup.1 and R.sup.2 denote each independently a straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH.

3. A mixture comprising compounds of formulae Ia and Ic or a mixture comprising compounds of formulae Ib and Id or a mixture comprising compounds of formulae Ie and If or a mixture comprising compounds of formulae Ig and Ih according to claim 2, having identical groups A, W, L, R.sup.1, R.sup.2, T.sup.1, T.sup.2, T.sup.3, T.sup.4, R′″, m and n, in equal or unequal amounts.

4. A compound of formula I according to any one of claims 1 to 3, wherein R.sup.1 is methyl and R.sup.2 denotes H or wherein R.sup.1 and R.sup.2 are both methyl.

5. A compound of formula I according to any one of claims 1 to 4, wherein A denotes one of the following groups: ##STR00648## ##STR00649## wherein R.sup.3, X, R′, R″ and R′″ have the meaning given in claim 1.

6. A compound of formula I according to any one of claims 1 to 5, wherein the group Q denotes H or one of the following groups: ##STR00650## ##STR00651## ##STR00652## wherein X, R′″, R.sup.3, T, Z.sup.5, Z.sup.6, R.sup.6 and R.sup.7 have the meaning given in claim 1.

7. A compound of formula I according to any one of claims 1 to 6, wherein R, R.sup.5, R.sup.6, R.sup.7 are independently selected from H, ON, SO.sub.2CH.sub.3, SO.sub.2CH.sub.2CH.sub.3, SO.sub.2CH.sub.2CH.sub.2OH, SO.sub.2CH.sub.2CH.sub.2OCH.sub.3, S(O)(NR.sup.3′)CH.sub.3, S(O)(NR.sup.3′)CH.sub.2CH.sub.3, S(O)(NR.sup.3′)CH.sub.2CH.sub.2OH, S(O)(NR.sup.3′)CH.sub.2CH.sub.2OCH.sub.3, N(SO)R.sup.3′CH.sub.3, N(SO)R.sup.3′CH.sub.2CH.sub.3, N(SO)R.sup.3′CH.sub.2CH.sub.2OH, N(SO)R.sup.3′CH.sub.2CH.sub.2OCH.sub.3, Hal, NR.sup.3R.sup.4, NO.sub.2, phenyl, benzyl, CH.sub.2-pyridyl, O-phenyl, O-pyridyl, O-pyrimidinyl, O-benzyl, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, alkoxy (Oalkyl), hydroxyalkylen, alkoxyalkylen, COOH, COOalkyl, CONHalkyl, CONH.sub.2, CON(CH.sub.3).sub.2, NHCOalkyl, NHCOCH.sub.3, NHCOphenyl, NHCOpyridyl, NHCH.sub.2CH.sub.3, NHCH.sub.2CH.sub.2CH.sub.3, NHCOCH.sub.2CH.sub.2OH, CO—N-morpholinyl, CON(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, CO-1-piperidinyl, CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl, CH.sub.2—N-morpholinyl, CH.sub.2N(H)COCH.sub.3, CH.sub.2N(CH.sub.3)COCH.sub.3, CH.sub.2NH.sub.2, NH.sub.2, CH(OH)CH.sub.3, CH(OR.sup.3)CH.sub.3 and a group ##STR00653## wherein t+q is 2 or 3, and Z.sup.7, R.sup.3′, R.sup.3 and R.sup.4 have the meaning given in claim 1.

8. A compound of formula I according to any one of claims 1 to 7, wherein L is a single bond or —O—.

9. A compound of formula I according to any one of claims 1 to 8, wherein m and n simultaneously denote 1.

10. A compound according to claim 1, selected from the following group: TABLE-US-00006 No Structure 1 4 7 10 11 12 13 14 15 16 17 18 19 20 23 24 25 26 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 116 117 120 121 122 123 124 125 126 127 128 129 130 131 132 133 and/or and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios.

11. A compound of formula (I′) according to any one of claims 1 to 10 for use as a medicament.

12. A compound of formula (I′) according to any one of claims 1 to 10 and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios, for use in a method of treating a condition selected from the group consisting of neurodegenerative diseases, diabetes, cancer, cardiovascular diseases and stroke.

13. A compound for use in a treatment of a condition according to claim 12, wherein the condition is selected from the group of one or more tauopathies and Alzheimer's disease, Dementia, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain disease, Behavioural variant frontotemporal dementia (BvFTD), Bluit disease, Chronic traumatic encephalopathy, Corticobasal degeneration (CBP), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobar degeneration (FTLD), Ganglioglioma, Gangliocytoma, Gerstmann-Straussler-Scheinker disease, Globular glia tauopathy, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), Lead encephalopathy, Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease (PiD), Parkinson's disease dementia, Postencephalitic parkinsonism (PEP), Primary progressive aphasia, Prion diseases (including Creutzfeldt-Jakob Disease (CJD), Progressive nonfluent aphasia, Variant Creutzfeldt-Jakob Disease (vCJD)), Fatal Familial Insomnia, Kuru, Progressive supercortical gliosis, Progressive supranuclear palsy (PSP), Semantic dementia, Steele-Richardson-Olszewski syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, Tuberous sclerosis, Huntington's disease and Parkinson's disease, preferably one or more tauopathies and Alzheimer's disease.

14. A method for treating a tauopathy, wherein a compound defined in any one of claims 1 to 10 is administered to a mammal in need of such treatment.

15. A method for inhibiting a glycosidase, wherein a system expressing the glycosidase is contacted with a compound as defined in any one of claims 1 to 10 under in-vitro conditions such that the glycosidase is inhibited.

16. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 10 together with pharmaceutically tolerable adjuvants and/or excipients, optionally in combination with one or more further active ingredients.

Description

EXPERIMENTAL PART

[0279] The compounds according to Formula (I′) or (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways are described below in the examples. All reported yields are non optimized yields. Unless otherwise stated, compounds of Formula (I′) or (I) and related formulae obtained as a racemic mixture can be separated to provide an enantiomerically enriched mixture or a pure enantiomer.

[0280] The commercially available starting materials used in the following experimental description were purchased from Aldrich, Sigma, ACROS, ABCR, Combi-Blocks, Matrix, Apollo scientific, Alfa Aesar, etc. unless otherwise reported.

[0281] The HPLC, MS and NMR data provided in the examples described below are obtained as followed: .sup.1H NMR analyses were carried out using BRUKER NMR, model AV-II and AV-III 400 MHz FT-NMR. Residual signal of deuterated solvent was used as internal reference. Chemical shifts (δ) are reported in ppm in relative to the residual solvent signal (δ=2.50 for .sup.1H NMR in DMSO-d.sub.6, and 7.26 in CDCl.sub.3). s (singlet), d (doublet), t (triplet), q (quadruplet), br (broad), quint (quintuplet).

LCMS Analysis Condition:

[0282] Instrument name: Agilent Technologies 1290 infinity 11.

[0283] Method A: Method: A-0.1% TFA in H.sub.2O, B-0.1% TFA in ACN; flow rate: 2.0 mL/min; column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

[0284] Method B: Method: A-10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B-ACN; flow rate: 1.0 mL/min; column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

[0285] Method C: Method: A-0.1% HCOOH in H.sub.2O, B-ACN; flow rate: 1.5 ml/min; column: ZORBAX Eclipse XDB-C18 (50×4.6 mm, 3.5 μm), +ve mode

HPLC Analysis Condition:

[0286] Instrument name: Agilent 1200 Series instruments as followed using % with UV detection (maxplot).

[0287] Method A: Method: A-0.1% TFA in H.sub.2O, B-0.1% TFA in ACN; flow rate: 2.0 mL/min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0288] Method B: Method: A-10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B-ACN; flow rate: 1.0 mL/min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

Chiral SFC Analysis Condition:

[0289] Instrument name: PIC-P20 (analytical)

[0290] Ratio between CO.sub.2 and co-solvent is ranging between 50:50 and 90:10

[0291] Method A: Mobile Phase: 0.5% isopropylamine in IPA, flow rate: 3 mL/min; column: Chiralcel OJ-H (250×4.6 mm, 5 μm).

[0292] Method B: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 3 mL/min; column: YMC Cellulose C (250×4.6 mm, 5 μm).

[0293] Method C: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 4 mL/min; column: Lux A1 (250×4.6 mm, 5 μm).

[0294] Method D: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 3 mL/min; column: Chiralcel OJ-H (250×4.6 mm, 5 μm).

[0295] Method G: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 3 mL/min; column: Chiralcel OD-H (250×4.6 mm, 5 μm).

Prep-HPLC Condition:

[0296] Method A: A-0.1% TFA in H.sub.2O, B-MeOH or CAN; column: Sunfire C8 (19×250 mm, 5 μm) or Sunfire C18 (30×250 mm, 10 μm).

[0297] Method B: A-10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B-MeOH or ACN, Column: Sunfire C8 (19×250 mm, 5 μm) or Sunfire C18 (30×250 mm, 10 μm).

Chiral Preparative SFC Condition:

[0298] Instrument name: PIC SFC 100

[0299] Ratio between CO.sub.2 and co-solvent is ranging between 50:50 and 90:10

[0300] Method A: Mobile Phase: 0.5% isopropylamine in IPA, flow rate: 100 mL/min; column: Chiralcel OJ-H (250×30 mm, 5 μm).

[0301] Method B: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 100 mL/min; column: YMC Cellulose C (250×30 mm, 5 μm).

[0302] Method C: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 100 mL/min; column: Lux A1 (250×30 mm, 5 μm).

[0303] Method D: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 100 mL/min; column: Chiralcel OJ-H (250×30 mm, 5 μm).

[0304] Method E: Mobile Phase: 0.5% isopropylamine in IPA, flow rate: 100 mL/min; column: YMC Amylose SA (250×30 mm, 5 μm).

[0305] Method F: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 100 mL/min; column: YMC Amylose SA (250×30 mm, 5 μm).

[0306] Method G: Mobile Phase: 0.5% isopropylamine in methanol, flow rate: 100 mL/min; column: Chiralcel OD-H (250×30 mm, 5 μm).

[0307] General flash chromatography conditions used for the purification of intermediates or compounds of Formula I: silica gel 230-400 mesh; gradients used as elutent: 10 to 80% EtOAc in petroleum ether or 1 to 15% MeOH in DCM.

[0308] The microwave chemistry was performed on a single mode microwave reactor Initiator™ Sixty from Biotage.

Specific Optical Rotation

[0309] Instrument name: Autopol VI, by Rudolph Research Analytical, Hackettstown, N.J., USA.

Intermediate 1: 5-(1-chloroethyl)benzo[c][1,2,5]thiadiazole

[0310] ##STR00481##

Step 1: 1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-ol

[0311] ##STR00482##

[0312] A stirred solution of benzo[c][1,2,5]thiadiazole-5-carbaldehyde (1.0 g, 6.10 mmol) in dry THF (10 mL) under nitrogen atmosphere was cooled in an ice bath, followed by the slow addition of methylmagnesium chloride (3.0 mL, 9.13 mmol, 3 M in THF) and the reaction mixture was stirred for 2 h at the same temperature. Upon completion (TLC), the reaction mixture was quenched with aq. sat. NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layer was washed with water, brine solution, dried over sodium sulphate (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The resulting crude was purified by flash chromatography (Silica gel: 230-400 mesh, Eluent: 25% ethyl acetate in petroleum ether) to give the title compound. Yield: 55% (600 mg, pale orange solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.12-7.92 (m, 2H), 7.66 (dd, J=2.0, 9.0 Hz, 1H), 5.11 (q, J=6.8 Hz, 1H), 1.61 (dd, J=6.4 Hz, 3H). LCMS: (Method A) 181.0 (M+H), Rt. 2.0 min, 97.1% (Max).

Step 2: 5-(1-chloroethyl)benzo[c][1,2,5]thiadiazole

[0313] ##STR00483##

[0314] To a stirred solution of Step 1: Intermediate 1, (0.5 g, 2.77 mmol) in dry DCM (4 mL) was added thionyl chloride (0.3 mL, 4.13 mmol) slowly at 0° C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under vacuum and co-distilled with DCM (3×5 mL). Then completely dried under vacuum to give the title compound which was used in the next step without further purification. Yield: 90% (500 mg, pale orange gum). LCMS: (Method A) 163.1 (M−HCl), Rt. 2.9 min, 76.0% (Max).

Intermediate 2: 5-(1-chloroethyl)benzo[d]thiazole

[0315] ##STR00484##

Step 1: 1-(benzo[d]thiazol-5-yl)ethan-1-one

[0316] ##STR00485##

[0317] To a degassed solution of 5-bromo benzothiazole (750 g, 3.51 mol) in dry toluene (6 L), 1-ethoxyvinyl tributyltin (1.42 L, 4.21 mol) followed by Pd(PPh.sub.3).sub.2Cl.sub.2 (105.6 g, 150.7 mmol) were added at RT and the resulting mixture was heated at 90° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, filtered through celite and washed with EtOAc (1 L). The filtrate was evaporated under vacuum and 5N HCl solution (2.5 L) was added to the crude mixture. The resulting light brown coloured solution was stirred at RT for 1.5 h, neutralized with the slow addition of a saturated NaHCO.sub.3 solution (12 L) over 1 h at 0° C. and was extracted with EtOAc (2×5 L). The combined organic layer was washed with brine solution (2.5 L), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was dissolved in DCM (750 mL), hexane (3 L) was added to it and the resulting solid was filtered. The solids were washed with MTBE (4 L). The combined filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (2.5 L) and charcoal (35 g) was added. The organic layer was stirred for 6 h at RT and filtered and solids were washed with excess of EtOAc (1 L). The organic layer was concentrated to afford the title compound. Yield: 79% (475 g, light brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.53 (s, 1H), 8.69 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.04 (dd, J=8.4, 1.3 Hz, 1H), 2.71 (s, 3H). LCMS: (Method C) 178.0 (M+H), Rt. 1.4 min, 98.5% (Max). HPLC: (Method A) Rt 2.6 min, 97.2% (Max).

Step 2: 1-(benzo[d]thiazol-5-yl)ethan-1-ol

[0318] ##STR00486##

[0319] To a stirred solution of 1-(benzo[d]thiazol-5-yl)ethan-1-one (475 g, 2.68 mol)) in methanol (4.75 L), NaBH.sub.4 (152.28 g, 4.03 mol) was added portion wise at 0° C. and the reaction mixture was stirred at RT for 1 h. Completion of the reaction was monitored by TLC, the reaction mixture was then quenched with ice water (400 mL) at 0° C. and concentrated under vacuum. To the resulting crude mixture, water (2.5 L) was added and the aqueous layer was extracted with EtOAc (2×2.5 L). The combined organic layer was washed with brine (2 L), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude solid was triturated with hexane:diethyl ether (8:2) and decanted to afford the title compound. Yield: 93% crude (440 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.50 (d, J=1.2 Hz, 1H), 5.32 (d, J=4.0 Hz, 1H), 4.93-4.89 (m, 1H), 1.40 (d, J=6.4 Hz, 3H). LCMS: (Method C) 180.1 (M+H), Rt. 1.2 min, 98.7% (Max). HPLC: (Method A) Rt. 2.2 min, 99.5% (Max).

Step 3: 5-(1-chloroethyl)benzo[d]thiazole

[0320] ##STR00487##

[0321] To a stirred solution of 1-(benzo[d]thiazol-5-yl)ethan-1-ol (440 g, 2.46 mol)) in DCM (4.4 L), thionyl chloride (534 mL, 7.37 mol) was added drop wise over 30 min at 0° C. and the reaction mixture was stirred for 1 h at 0-10° C. Completion of the reaction was monitored by TLC, the reaction mixture was then evaporated under vacuum. The resulting crude material was co-distilled with dry DCM (3×400 mL), dried under vacuum to afford title compound which was used in the next step without further purification. Yield: 100% crude (488 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.79 (s, 1H), 8.52 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 5.30-5.24 (m, 1H), 1.91 (d, J=6.8 Hz, 3H). LCMS: (Method C) 198.1 (M+H), Rt. 2.0 min, 50.1% (Max). HPLC: (Method A) Rt. 3.9 min, 66.8% (Max).

Intermediate 3: 6-(1-chloroethyl)-2, 3-dihydrobenzofuran

[0322] ##STR00488##

Step 1: 2-(2, 5-dibromophenoxy)ethan-1-ol

[0323] ##STR00489##

[0324] To a stirred solution of 1, 4-dibromo-2-fluorobenzene (Combi-Blocks, 1000 g, 3.94 mol) in ethylene glycol (5100 mL), NMP (500 mL) was added at RT under nitrogen atmosphere. Then KO.sup.tBu (1547 g, 1.38 mol) was added in portions over 45 min at 5° C. and the resulting mixture was heated at 90° C. for 16 h. Completion of the reaction was monitored by HPLC (Method A), the reaction mixture was then cooled to RT. diluted with water (2000 mL) and stirred for 15 min. The resulting solid was filtered and washed with ethylene glycol (2×300 mL). Water (16000 mL) was added to the filtrate, cooled to 10° C. and stirred for 1 h at the same temperature to precipitate out the whole solid. The obtained solid was filtered and washed with water (2×1000 mL), petroleum ether (3×1000 mL) and dried under vacuum. This solid was co-distilled with toluene (3×500 mL) to afford the title compound. Yield: 78% (910 g, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.41 (d, J=8.0 Hz, 1H), 7.06-7.00 (m, 2H), 4.14 (t, J=4.0 Hz, 2H), 4.01 (q, J=3.6 Hz, 2H). LCMS: (Method A) 296.0 (M+H), Rt. 3.9 min, 98.2% (Max). HPLC: (Method A) Rt. 3.7 min, 99.5% (Max).

Step 2: 1, 4-dibromo-2-(2-bromoethoxy)benzene

[0325] ##STR00490##

[0326] To a stirred solution of 2-(2, 5-dibromophenoxy) ethan-1-ol (910.0 g, 3.07 mol) in toluene (6370 mL), PBr.sub.3 (Aldrich, 145 mL, 1.54 mol) was added under nitrogen atmosphere at 0° C. over 15 min. The resulting mixture was heated at 90° C. for 4 h and then cooled to 0° C. PBr.sub.3 (13.57 mL, 142.92 mmol) was added followed by the slow addition of water (20 mL) and heating was continued at 90° C. for 3 h. Completion of the reaction was monitored by TLC, the reaction mixture was then cooled to 10° C. and quenched with NaOH solution (1 N, 2200 mL). The milky solid layer, formed immediately after quenching, was filtered through celite pad. The organic layer was separated, washed with water (1820 mL), brine solution (1820 mL) and dried over anhydrous Na.sub.2SO.sub.4. It was then evaporated at 45° C. under vacuum. The resulting crude material was dissolved in EtOAc (3185 mL), the organic layer was washed with water (1820 mL), brine solution (1820 mL) and dried over anhydrous Na.sub.2SO.sub.4. The organic layer was evaporated at 40° C. under reduced pressure to afford the title compound. Yield: 86% (946 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.54 (d, J=8.4 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.13-7.10 (m, 1H), 4.45 (t, J=1.2 Hz, 2H), 3.82 (t, J=1.6 Hz, 2H). HPLC: (Method A) Rt. 4.7 min, 93.0% (Max).

Step 3: 2, 3-dihydrobenzofuran-6-carbaldehyde

[0327] ##STR00491##

[0328] To a stirred solution of 1, 4-dibromo-2-(2-bromoethoxy)benzene (946 g, 2.64 mol) in dry THF (9.5 L) under nitrogen atmosphere, n-butyl lithium (1812 mL, 2.89 mol, 1.6 M in hexane) was added slowly over 30 min at −78° C. and stirring was continued for 1 h at the same temperature. A second batch of n-butyl lithium (1812 mL, 2.89 mol, 1.6 M in hexane) was added slowly over 30 min at −78° C. and stirring was continued for another 1 h. Then DMF (408 mL, 5.27 mol) was added slowly at same temperature and the mixture was stirred for 45 min. After completion of the reaction (monitored by TLC), the reaction mixture was warmed to 10° C., quenched with the addition of sat. NH.sub.4Cl solution (3784 mL) and the aqueous layer was extracted with EtOAc (2×2800 mL). The combined organic layer was washed with water (2838 mL), brine solution (2838 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated at 40° C. under reduced pressure to afford the title compound. Yield: 96% crude (404 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.90 (s, 1H), 7.45 (dd, J=5.2, 1.2 Hz, 2H), 7.19 (s, 1H), 4.60 (t, J=8.7 Hz, 2H), 3.27 (t, J=8.7 Hz, 2H). HPLC: (Method A) Rt. 2.9 min, 84.3% (Max).

Step 4: 1-(2, 3-dihydrobenzofuran-6-yl)ethan-1-ol

[0329] ##STR00492##

[0330] To a stirred solution of 2, 3-dihydrobenzofuran-6-carbaldehyde (404 g, 2.73 mol) in dry THF (4040 mL) under nitrogen atmosphere, methyl magnesium chloride solution (1820 mL, 5.45 mol, 3 M in THF) was added slowly over 30 min at 0° C. and stirred for 2 h at RT. Completion of the reaction was monitored by TLC, the reaction mixture was then quenched by using sat. NH.sub.4Cl solution (1616 mL) and extracted with EtOAc (2×2828 mL). The combined organic layer was washed with water (1616 mL), brine solution (1616 mL), dried over Na.sub.2SO.sub.4 and evaporated at 45° C. under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel: 60-120 mesh, eluent: 18% EtOAc in petroleum ether) to afford the title compound. Yield: 46% (210 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.12 (d, J=7.2 Hz, 1H), 6.77 (dd, J=7.6, 0.8 Hz, 1H), 6.72 (s, 1H), 5.05 (d, J=4.4 Hz, 1H), 4.66-4.60 (m, 1H), 4.48 (t, J=8.4 Hz, 2H), 3.12 (t, J=8.4 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H). LCMS: (Method A) 147.0 (M−H.sub.2O+H), Rt. 2.7 min, 90.7% (Max). HPLC: (Method A) Rt. 2.6 min, 91.7% (Max).

Step 5: 6-(1-chloroethyl)-2, 3-dihydrobenzofuran

[0331] ##STR00493##

[0332] To a stirred solution of 1-(2, 3-dihydrobenzofuran-6-yl)ethan-1-ol (200 g, 1.22 mmol) in DCM (1600 mL) at 0° C., oxalyl chloride (155 mL, 3.66 mmol) and catalytic amount of DMF (2 mL) were added and the reaction mixture was stirred at RT for 16 h. Then the reaction mixture was concentrated under vacuum and co-distilled with dry DCM (3×500 mL) to afford the title compound. Yield: 97% (crude) (220 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.32 (d, J=7.6 Hz, 1H), 6.92 (d, J=9.6 Hz, 2H), 5.28 (q, J=13.2 Hz, 1H), 4.52 (t, J=8.4 Hz, 2H), 3.15 (t, J=8.8 Hz, 2H), 1.75 (d, J=8.4 Hz, 3H). LCMS: (Method A) 147.2 (M+H-HCl), Rt. 4.2 min, 77.2% (Max).

Intermediate 4: 6-(1-chloroethyl)quinoxaline

[0333] ##STR00494##

Step 1: 1-(quinoxalin-6-yl)ethan-1-one

[0334] ##STR00495##

[0335] To a degassed stirred solution of 6-bromo quinoxaline (2.0 g, 9.50 mmol) in toluene (20 mL), 1-ethoxyvinyl tributyltin (3.8 g, 10.5 mmol) followed by Pd(PPh.sub.3).sub.2Cl.sub.2 (0.67 g, 0.95 mmol) were added at RT and the reaction mixture was stirred at 90° C. overnight. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT. filtered through celite and the obtained filtrate was evaporated under vacuum. To the resulting crude mixture, 6 N HCl solution (20 mL) was added and the reaction mixture was stirred at RT for 1 h. The solution was neutralized with sat. NaHCO.sub.3 and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (eluent: 30% EtOAc in hexane) to afford the title compound. Yield: 45% (800 mg, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.06-9.04 (m, 2H), 8.70 (d, J=2.4 Hz, 1H), 8.28 (dd, J=8.8, 2.8 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 2.97 (s, 3H). LCMS: (Method A) 173 (M+H), Rt. 2.2 min, 99.1% (Max).

Step 2: 1-(quinoxalin-6-yl)ethan-1-ol

[0336] ##STR00496##

[0337] To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-one (0.8 g, 4.65 mmol) in dry methanol (20 mL) at 0° C., NaBH.sub.4 (0.36 g, 9.30 mmol) was added portion wise and the resulting mixture was stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and the aqueous layer was extracted with DCM (2×40 mL). The combined organic layer was washed with water (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was forwarded to the next step without any further purification. Yield: 75% (600 mg, dark brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.91-8.89 (m, 2H), 8.03 (t, J=11.6 Hz, 2H), 7.87-7.86 (m, 1H), 5.49 (d, J=5.9 Hz, 1H), 4.98-4.97 (m, 1H), 1.42 (d, J=8.6 Hz, 3H). LCMS: (Method A) 175.0 (M+H), Rt. 1.89 min, 95.0% (Max).

Step 3: 6-(1-chloroethyl)quinoxaline

[0338] ##STR00497##

[0339] To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-ol (0.6 g, 3.46 mmol) in dry DCM (10 mL), thionyl chloride (0.5 mL, 6.93 mmol) was added dropwise at 0° C. and stirred at RT for 1 h. The reaction mixture was evaporated to dryness under vacuum and the resulting crude material was forwarded to the next step as such without any further purification. Yield: 97% (650 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.74 (s, 2H), 7.93 (s, 1H), 7.70-7.68 (m, 2H), 4.46-4.23 (m, 1H), 1.87 (s, 3H). LCMS: (Method A) 193.0 (M+H), Rt. 3.4 min, 71.4% (Max).

Intermediate 5: tert-butyl 7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate and tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0340] ##STR00498##

Step 1: 7-bromo-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one and 7-bromo-1,2,4,5-tetrahydro3H-benzo[c]azepin-3-one

[0341] ##STR00499##

[0342] To a stirred solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (1.0 g, 11.1 mmol) in MeSO.sub.3H (10 mL), was added NaN.sub.3 (1.58 g, 12.3 mmol) slowly, in portions at 0° C. The reaction mixture was stirred at RT for 2 h. After completion (by TLC), all the batches were combined and slowly added to ice cooled KOH (1 M) solution. The resulting mixture was extracted with EtOAc (2×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Five batches of this reaction were performed and the combined crude material was purified by flash chromatography using 1-2% MeOH in DCM to afford mixture of tittle compound as a mixture of regioisomers. Yield: 62% (3.25 g, dark brown solid). LCMS: (Method A) 241.9 (M+H), Rt. 2.2 min, 74.6% (Max).

Step 2: 7-bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine

[0343] ##STR00500##

[0344] To a stirred solution of Step 1: Intermediate 5 (3.25 g, 13.43 mmol) in THF (30 mL) was added a solution of BH.sub.3-THF (1.0 M, 21 mL, 21 mmol) at 0° C. and the mixture was stirred at 65° C. for overnight. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was slowly quenched with methanol (21 mL) at 0° C. and then heated to 50° C. for 1 h. Then reaction mixture was concentrated under reduced pressure. The residue was as such taken for next step without any purification. Yield: 42% (2.2 g, pale brown gummy solid). LCMS: (Method A) 227.9 (M+H), Rt. 1.9 min, 48.6% (Max).

Step 3: tert-butyl 7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate and tert-butyl7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0345] ##STR00501##

[0346] To a stirred solution of Step 2: Intermediate 5 (2.2 g, 9.69 mmol) and TEA (3.4 mL, 24.44 mmol) in DCM (3 mL), was added (Boc).sub.2O (3.1 g, 14.6 mmol) at 0° C. and the mixture was stirred at RT for overnight. Completion of the reaction was monitored by TLC and the reaction mixture was evaporated at 50° C. under reduced pressure. The resulting crude was purified by flash chromatography using 1-2% MeOH in DCM to afford the tittle compound. Yield: 76% (2.4 g, pale brown gummy solid). LCMS: (Method A) 227.9 (M-Boc), Rt. 3.3 min, 78.1% (Max).

Intermediate 6: 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0347] ##STR00502##

Step 1: N-(2,2-dimethoxyethyl)-2-(4-methoxyphenyl)acetamide

[0348] ##STR00503##

[0349] To a stirred solution of 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.08 mmol) in DCM (50 mL), were added aminoacetaldehyde (3.79 g, 36.10 mmol), TEA (12.5 mL, 90.25 mmol), T3P (28.7 mL, 45.12 mmol) and the reaction mixture was stirred at RT for overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched with water (100 mL), extracted with DCM (2×150 mL), washed with aq. NaHCO.sub.3 solution (10%, 100 mL) and brine (50 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude material was purified by flash chromatography using 50-60% EtOAc in petroleum ether to afford the title compound. Yield: 70% (5.3 g, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.18-8.10 (m, 1H), 7.22-7.19 (m, 1H), 6.83-6.77 (m, 3H), 4.33 (t, J=8.4 Hz, 1H), 3.73 (s, 3H), 3.33 (s, 2H), 3.25 (s, 6H), 3.17-3.12 (m, 2H). LCMS: (Method D) 254.1 (M+H), Rt. 2.0 min, 98.8 (Max).

Step 2: 8-methoxy-1,3-dihydro-2H-benzo[d]azepin-2-one

[0350] ##STR00504##

[0351] A solution of N-(2,2-dimethoxyethyl)-2-(4-methoxyphenyl)acetamide (5.3 g, 20.91 mmol, Step 1: Intermediate 6) in concentrated HCl (50 mL, 10 V) and glacial acetic acid (53 mL) was stirred at RT overnight. The completion of the reaction was confirmed by TLC, the reaction mixture was quenched with water (100 mL) and the resulting solid was filtered. It was washed with petroleum ether and dried under vacuum to afford the title compound. Yield: 53% (2.1 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.50 (s, 1H), 7.20 (d, J=7.6 Hz, 1H), 6.95-6.78 (m, 2H), 6.28-6.14 (m, 2H), 3.77 (s, 3H), 3.35 (s, 2H). LCMS: (Method A) 190.0 (M+H), Rt. 2.1 min, 98.9% (Max).

Step 3: 8-methoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0352] ##STR00505##

[0353] 8-methoxy-1,3-dihydro-2H-benzo[d]azepin-2-one (2.1 g, 30.08 mmol, Step 2: Intermediate 6) was dissolved in methanol and acetic acid (1:1, mL). Palladium on carbon (10 wt %, 0.2 g) was added to the reaction mixture and the suspension was put under hydrogen pressure (3 kg/cm.sup.2) for at RT 8 h. After completion, the catalyst was filtered off through a pad of celite, and the filtrate was concentrated to afford the title compound which was used without further purification. Yield: 90% (1.9 g, Brown solid). LCMS: (Method A) 192.0 (M+H), Rt. 1.6 min, 99.3% (Max).

Step 4: 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0354] ##STR00506##

[0355] To a stirred solution of 8-methoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (1.9 g, 9.93 mmol, Step 3: Intermediate 6) in THF (6 mL) at 0° C. was added a solution of BH.sub.3-THF (14.9 mL, 1.0 M, 14.9 mmol) and the mixture was stirred at 65° C. for overnight. After completion, the reaction mixture was slowly quenched with methanol (6 mL) at 0° C. followed by HCl (1.5 N, 6 mL) and the mixture was heated to 50° C. for 1 h. Then reaction mixture was concentrated under reduced pressure and washed with EtOAc (2×50 mL). The aqueous layer was basified with 10% aq. NaOH to neutral pH and extracted with EtOAc (2×150 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the tittle compound. Yield: 69% (1.2 g, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.11 (d, J=11.0 Hz, 1H), 6.80-6.71 (m, 2H), 3.74 (s, 3H), 3.61 (t, J=9.0 Hz, 2H), 3.44 (t, J=18.2 Hz, 2H), 1.80-1.70 (m, 2H), 1.57-1.45 (m, 2H). LCMS: (Method A) 178.1 (M+H), Rt. 1.3 min, 86.1% (Max).

Intermediate 7: tert-butyl 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[0356] ##STR00507##

Step 1: 2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol

[0357] ##STR00508##

[0358] To a stirred solution of 7-methoxy-2,3,4,5-tetrahydro-1 H-benzo[d]azepine (0.9 g, 5.07 mmol, Intermediate 6) in DCM (9.0 mL), was added BBr.sub.3 (7.6 mL, 1.0 M solution in DCM) at 0□ and the reaction mixture was stirred at RT for overnight. After completion of reaction (TLC), the reaction mixture was quenched by methanol at 0□ and concentrated under reduced pressure. The resulting solid was triturated with hexane-diethyl ether (8:2) to give the title compound. Yield: 75% (0.9 g, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.98 (d, J=8.0 Hz, 1H), 6.62-6.54 (m, 2H), 3.17-3.12 (m, 4H), 2.98-2.95 (m, 4H). LCMS: (Method A) 164.2 (M+H), Rt. 0.7 min, 69.4% (Max).

Intermediate 7: tert-butyl 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[0359] ##STR00509##

[0360] To a stirred solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (0.9 g, 5.52 mmol, Step 1: Intermediate 7) in DCM (9.0 mL), were added TEA (2.30 mL, 16.56 mmol) and Boc-anhydride (1.8 mL, 8.27 mmol) at 0□ and the reaction mixture was stirred at room temperature for overnight. Completion of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched by water and extracted with EtOAc (2×150 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the tittle compound. Yield: 76% (1.1 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.98 (d, J=8.0 Hz, 1H), 6.62-6.54 (m, 2H), 3.17-3.12 (m, 4H), 2.98-2.95 (m, 4H), 1.41 (s, 9H). LCMS: (Method A) 164.2 (M+H), Rt. 0.73 min, 69.38% (Max).

Intermediate 8: 7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0361] ##STR00510##

Step 1: methyl (2-(3-methoxyphenyl)acetyl)alaninate

[0362] ##STR00511##

[0363] To a stirred solution of 2-(3-methoxyphenyl)acetic acid (5.0 g, 30.30 mmol), methyl alaninate hydrochloride (4.63 g, 33.15 mmol) and TEA (10.5 mL, 75.38 mmol) added T.sub.3P (50% in EtOAc, 28.7 mL, 45.21 mmol) at 0° C. and stirred at RT for 4 h. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (3×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give the tittle compound. Yield: 63% (4.7 g, pale brown gummy solid). LCMS: (Method A) 252.0 (M+H), Rt. 2.2 min, 90.7% (Max).

Step 2: N-(1-hydroxypropan-2-yl)-2-(3-methoxyphenyl)acetamide

[0364] ##STR00512##

[0365] To a stirred solution of Step 1: Intermediate 8, (4.7 g, 18.65 mmol) in MeOH (50 mL), was added NaBH.sub.4 (2.8 g, 74.9 mmol) slowly at 0° C. Then reaction mixture stirred at RT for overnight. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (2×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue obtained was purified by flash chromatography using 1-2% MeOH in DCM to afford the tittle compound. Yield: 76% (3.2 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.83-7.81 (m, 1H), 7.22-7.17 (m, 1H), 6.82-6.77 (m, 3H), 4.70-4.66 (m, 1H), 3.73-3.71 (m, 4H), 3.32 (s, 3H), 3.25-3.19 (m, 1H), 1.01 (d, J=8.8 Hz, 3H). LCMS: (Method A) 224.1 (M+H), Rt. 2.0 min, 87.4% (Max).

Step 3: N-(1,1-dimethoxypropan-2-yl)-2-(3-methoxyphenyl)acetamide

[0366] ##STR00513##

[0367] To a stirred solution of Step 2: Intermediate 8, (3.2 g, 14.35 mmol) in dry DCM (32 mL), was added Dess-Martin periodinane (7.3 g, 17.21 mmol) slowly at 0° C. and the reaction mixture was stirred at 0° C. for 3 h. After completion, the reaction mixture was filtered through a cellite pad and the filtrate was washed with aq. NaHCO.sub.3 solution (50 mL). The organic layer was concentrated at 40° C. The resulting residue was diluted with MeOH (30 mL). Then trimethyl orthoformate (3 mL, 28.1 mmol), and PTSA (0.27 g, 1.4 mmol) were added and the mixture was heated to 50° C. for 3 h. After completion, the reaction mixture was concentrated, the residue was diluted with aq. NaHCO.sub.3 solution (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by flash chromatography using 1-2% MeOH in DCM to afford the tittle compound. Yield: 56% (2.1 g, off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.29-7.27 (m, 1H), 6.86-6.83 (m, 3H), 5.65-5.60 (m, 1H), 4.21-4.17 (m, 1H), 4.13 (d, J=3.6 Hz, 1H), 3.83 (s, 3H), 3.55 (s, 2H), 3.40 (s, 3H), 3.36 (s, 3H), 1.08 (d, J=6.8 Hz, 3H). LCMS: (Method A) 236.1 (M−32), Rt. 2.3 min, 83.7% (Max).

Step 4: 8-methoxy-4-methyl-1,3-dihydro-2H-benzo[d]azepin-2-one

[0368] ##STR00514##

[0369] To a stirred solution of Step 3: Intermediate 8, (2.1 g, 7.83 mmol) in AcOH (10 mL), was added aq. HCl (36%, 10 mL) slowly at 0° C. and the reaction mixture was stirred at RT for overnight. After completion, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the tittle compound. Yield: 51% (0.8 g, off white solid). LCMS: (Method A) 204.3 (M+H), Rt. 2.3 min, 56.6% (Max).

Step 5: 8-methoxy-4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0370] ##STR00515##

[0371] To a stirred solution of Step 4: Intermediate 8 (0.8 g, 3.94 mmol) in (1:1) MeOH—AcOH (20 mL), was added 10% Pd—C (160 mg) at RT and the reaction mixture was stirred at RT for 3 days at 1 kg/cm.sup.3 pressure. After completion, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated to get the tittle compound. Yield: 76% (0.6 g, off white solid). LCMS: (Method A) 206.1 (M+H), Rt. 1.8 min, 80.6% (Max).

Step 6: 7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0372] ##STR00516##

[0373] To a stirred solution of Step 5: Intermediate 8 (0.6 g, 2.91 mmol) in THF (6 mL) was added a solution of BH.sub.3-THF (1.0 M, 6 mL, 5.8 mmol) at 0° C. and the mixture was stirred at 65° C. for overnight. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was slowly diluted with methanol (6 mL) at 0° C. followed by 1.5 N HCl (6 mL) and then the mixture was heated to 50° C. for 1 h. The reaction mixture was concentrated under reduced pressure and washed with EtOAc (2×20 mL). The aqueous layer was collected and basified with 10% NaOH solution to neutral pH and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the tittle compound. Yield: 48% (0.27 g, off white gummy solid). LCMS: (Method A) 192.2 (M+H), Rt. 2.0 min, 63.2% (Max).

Intermediate 9: 6-(1-chloroethyl)-2,3-dihydrofuro[3,2-b]pyridine

[0374] ##STR00517##

Step 1: methyl 5-hydroxy-6-iodonicotinate

[0375] ##STR00518##

[0376] To a stirred solution of methyl 5-hydroxynicotinate (10 g, 65.29 mmol) in a mixture of THF (200 mL) and water (200 mL) were added I.sub.2 (41.4 g, 163.2 mmol) and Na.sub.2CO.sub.3 (20.7 g, 195.8 mmol) and the stirring was continued at RT for 4 h. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 and then neutralized with aq. HCl (6 N). The resulting mixture was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound. Yield: 67% (1.5 g, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.42 (s, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 3.86 (s, 3H). LCMS: (Method A) 280.0 (M+H), Rt. 2.7 min, 92.5% (Max).

Step 2: methyl 5-acetoxy-6-iodonicotinate

[0377] ##STR00519##

[0378] To a stirred solution of methyl 5-hydroxy-6-iodonicotinate (12.5 g, 65.29 mmol, Step 1: Example 34) in DCM (250 mL) at 0° C. were added acetyl chloride (41.4 g, 163.2 mmol) and TEA (20.7 g, 195.8 mmol) and the stirring was continued at RT for 1 h. Upon completion (TLC), the reaction mixture was quenched with aq. sodium bicarbonate solution and the mixture was extracted with DCM (2×250 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound. Yield: 97% (14.0 g, brown gum). LCMS: (Method A) 322.0 (M+H), Rt. 3.6 min, 79.8% (Max).

Step 3: methyl 5-acetoxy-6-((trimethylsilyl)ethynyl)nicotinate

[0379] ##STR00520##

[0380] A stirred solution of methyl 5-acetoxy-6-iodonicotinate (14.0 g, 43.60 mmol, Step 2: Example 34) in THF (140 mL) was degassed with N.sub.2 for 10 min at RT. TMS-acetylene (7.2 mL, 5.1 g, 52.32 mmol), TEA (18.2 mL, 130.84 mmol), CuI (0.83 g, 4.36 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (1.53 g, 2.18 mmol) were added to the reaction mixture and the stirring was continued overnight at RT. Completion of the reaction was monitored by TLC. The reaction mixture was filtered through a celite pad and the filtrate was diluted with ethyl acetate. The mixture was washed with water (280 mL), brine (120 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound. Yield: 87% (11.1 g, brown gum). LCMS: (Method A) 292.1 (M+H), Rt. 3.6 min, 60.4% (Max).

Step 4: methyl furo[3,2-b]pyridine-6-carboxylate

[0381] ##STR00521##

[0382] Potassium fluoride (2.21 g, 38.09 mmol) was added to a solution of methyl 5-acetoxy-6-((trimethylsilyl)ethynyl)nicotinate (11.1 g, 38.09 mmol, Step 3: Example 34) in MeOH at 0° C. and the reaction mixture was stirred at RT for 2 h. The completion of the reaction was confirmed by TLC. The reaction mixture was concentrated, water was added, and the resulting mixture was extracted with DCM (2×300 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by flash column chromatography using 30-35% EtOAc in petroleum ether to afford the title compound. Yield: 52% (4.5 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.09 (d, J=2.0 Hz, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.53 (d, J=1.2 Hz, 1H), 7.32-7.26 (m, 1H), 3.93 (s, 3H). LCMS: (Method A) 178.2 (M+H), Rt. 1.8 min, 88.2% (Max).

Step 5: methyl 2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate

[0383] ##STR00522##

[0384] Methyl furo[3,2-b]pyridine-6-carboxylate (3.0 g, 16.93 mmol, Step 4: Example 34) was dissolved in MeOH (60 mL). Palladium on carbon (600 mg, 10 wt %) was added and the reaction mixture was stirred under an atmosphere of hydrogen at 5 kg/cm.sup.2 pressure, at 60° C. for 48 h. After completion (TLC), the catalyst was filtered off through a celite-pad, and the filtrate was concentrated to afford the title compound. Yield: 60% (1.8 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.54 (d, J=2.0 Hz, 1H), 7.49 (d, J=1.2 Hz, 1H), 4.71 (t, J=12.0 Hz, 2H), 3.86 (s, 3H), 3.34 (t, J=12.0 Hz, 2H). LCMS: (Method A) 180.2 (M+H), Rt. 1.7 min, 97.7% (Max).

Step 6: (2,3-dihydrofuro[3,2-b]pyridin-6-yl)methanol

[0385] ##STR00523##

[0386] To a stirred solution of methyl 2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate (1.8 g, 10.04 mmol, Step 5: Example 34) in dry THF (18.0 mL) at −78° C. was added LAH (6.5 mL, 13.06 mmol, 2.0 M in THF). The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was quenched by addition of sat. aq. NH.sub.4Cl, and the mixture was extracted by EtOAc (2×50 mL). The combined organic layer was washed with water (30 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash column chromatography using 60-70% ethyl acetate in petroleum ether as eluent to afford the title compound. Yield: 80% (1.3 g, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (s, 1H), 7.04 (s, 1H), 5.27-5.23 (m, 1H), 4.62 (t, J=9.2 Hz, 2H), 4.45 (d, J=5.6 Hz, 2H), 3.22 (t, J=8.8 Hz, 2H). LCMS: (Method A) 152.2 (M+H), Rt. 0.5 min, 88.0% (Max).

Step 7: 2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde

[0387] ##STR00524##

[0388] To a stirred solution of (2,3-dihydrofuro[3,2-b]pyridin-6-yl)methanol (1.3 g, 8.60 mmol, Step 6: Example 34) in DCM (26 mL, 20 V) at 0° C. was added Dess-Martin periodinane (4.74 g, 11.18 mmol) and the stirring was continued at RT for 2 h. After completion (TLC), the reaction mixture was filtered, and the filtrate was washed with sat. aq. sodium bicarbonate (50 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound. Yield: 79% (1.1 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.02 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 4.72 (t, J=12.0 Hz, 2H), 3.41-3.30 (m, 2H).

Step 8: 1-(2,3-dihydrofuro[3,2-b]pyridin-6-yl)ethan-1-ol

[0389] ##STR00525##

[0390] To a stirred solution of 2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde (1.0 g, 6.75 mmol, Step 7: Example 34) in dry THF (10 mL) at −20° C. was added MeMgBr (3.35 mL, 10.05 mmol, 3.0 M in THF). The reaction mixture was stirred at RT for 2 h. After completion (TLC), the reaction mixture was quenched by addition of saturated, aqueous NH4Cl solution, then the reaction mixture was extracted with EtOAc (2×60 mL). The combined organic layer was washed with water (50 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude material was purified by flash column chromatography using 80-90% ethyl acetate in pet-ether as eluent affording the title compound. Yield: 63% (700 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.94 (d, J=2.0 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 5.23 (d, J=6.0 Hz, 1H), 4.71 (q, J=6.0 Hz, 1H), 4.61 (t, J=11.6 Hz, 2H), 3.20 (t, J=11.6 Hz, 2H), 1.31 (d, J=8.4 Hz, 3H). LCMS: (Method A) 166.3 (M+H), Rt. 0.55 min, 95.4% (Max).

Step 9: 6-(1-chloroethyl)-2,3-dihydrofuro[3,2-b]pyridine

[0391] ##STR00526##

[0392] To a stirred solution of 1-(2,3-dihydrofuro[3,2-b]pyridin-6-yl)ethan-1-ol (100 mg, 0.60 mmol, Step 8: Example 34) in DCM (2.0 mL) at 0° C., was added thionyl chloride (0.15 mL, 1.81 mmol) drop wise and the reaction mixture was stirred for 2 h at RT. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum, co-distilled with dry DCM (3×10 mL) and dried under vacuum to afford the title compound. Yield: 100% (120 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.18 (s, 1H), 7.49 (s, 1H), 5.41 (q, J=6.4 Hz, 1H), 4.72 (t, J=8.8 Hz, 1H), 3.35 (dd, J=15.0, 4.0 Hz, 2H), 1.80 (d, J=6.8 Hz, 3H). LCMS: (Method A) 184.2 (M+H), Rt. 1.8 min, 89.1% (Max).

Example 1: 5-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[c][1,2,5]thiadiazole

[0393] ##STR00527##

[0394] To a stirred solution of Intermediate 1 (0.5 g, 2.52 mmol) in dry DMF (3.0 mL) under nitrogen atmosphere, were added triethylamine (1.0 mL 7.19 mmol) and Intermediate 6 (0.44 g, 2.48 mmol) sequentially at RT. The reaction mixture was stirred overnight at 70° C. The completion of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude was purified by Prep-HPLC (Method B) to give the title compound. Yield: 26% (220 mg, Pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.04 (d, J=9.2 Hz, 1H), 7.94 (s, 1H), 7.88 (dd, J=1.6, 9.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.61 (dd, J=2.4, 8.2 Hz, 1H), 4.11-4.09 (m, 1H), 3.68 (s, 3H), 2.81-2.76 (m, 4H), 2.63-2.51 (m, 4H), 1.41 (d, J=6.80 Hz, 3H). LCMS: (Method A) 340.1 (M+H), Rt. 2.2 min, 98.7% (Max). HPLC: (Method A) Rt. 3.16 min, 98.1% (Max).

Example 2 and 3: (S)-5-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[c][1,2,5]thiadiazole and (R)-5-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[c][1.2.5]thiadiazole

[0395] ##STR00528##

[0396] The enantiomers of Example 1 were separated by Chiral preparative SFC (Method A). The first peak was concentrated to give Example 2 and the second peak was concentrated to give Example 3.

[0397] Example 2: Yield: 38% (72 mg, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.03 (d, J=9.2 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.61 (dd, J=2.4, 8.2 Hz, 1H), 4.10 (d, J=6.8 Hz, 1H), 3.68 (s, 3H), 2.81-2.76 (m, 4H), 2.63-2.55 (m, 4H), 1.41 (d, J=6.80 Hz, 3H). LCMS: (Method A) 340.2 (M+H), Rt. 2.2 min, 99.1% (Max). HPLC: (Method A) Rt. 3.1 min, 97.8% (Max). CHIRAL SFC: (Method A), Rt. 3.0 min, 99.1%. [α].sup.24D −11.00±0.00, c 0.10 (MeOH).

[0398] Example 3: Yield: 34% (65 mg, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.03 (d, J=9.2 Hz, 1H), 7.93 (s, 1H), 7.87 (dd, J=1.2, 9.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.66 (d, J=2.8 Hz, 1H), 6.60 (q, J=2.4 Hz, 1H), 4.09 (q, J=6.4 Hz, 1H), 3.67 (s, 3H), 2.81-2.75 (m, 4H), 2.67-2.52 (m, 4H), 1.40 (d, J=6.80 Hz, 3H). LCMS: (Method A) 340.2 (M+H), Rt. 2.2 min, 98.8% (Max). HPLC: (Method A), Rt. 3.1 min, 98.3% (Max). CHIRAL SFC: (Method A), Rt. 3.4 min, 99.1%.

Example 4: 5-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0399] ##STR00529##

[0400] To a stirred solution of Intermediate 2 (0.2 g, 1.01 mmol) in ACN (8 mL), Intermediate 6 (0.215 g, 1.21 mmol) was added, followed by TEA (0.42 mL, 3.04 mmol) and the mixture was heated under reflux at 70° C. for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under vacuum. Water (20 mL) was added and was extracted with EtOAc (2×25 mL). Combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by Prep-HPLC (Method B) to get the title compound. Yield: 40% (140 mg, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.96 (q, J=8.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.59 (dd, J=2.8, 8.0 Hz, 1H), 4.05 (q, J=6.8 Hz, 1H), 3.67 (s, 3H), 2.80-2.78 (m, 4H), 2.60-2.58 (m, 4H), 1.42 (d, J=6.80 Hz, 3H). LCMS: (Method A) 351.1 (M+H), Rt. 2.2 min, 99.7% (Max). HPLC: (Method A) Rt. 3.0 min, 99.8% (Max).

Example 5 and 6: (S)-5-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole and (R)-5-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0401] ##STR00530##

[0402] The enantiomers of Example 4 were separated by chiral preparative SFC (Method B). The first peak was concentrated and lyophilized to give Example 5 and the second peak was concentrated and lyophilized to give Example 6.

[0403] Example 5: Yield: 29% (36 mg, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J=8.4 Hz, 1H), 4.05 (q, J=6.8 Hz, 1H), 3.67 (s, 3H), 2.78 (t, J=5.6 Hz, 4H), 2.58 (t, J=8.0 Hz, 4H), 1.42 (d, J=6.4 Hz, 3H). LCMS: (Method A) 339.1 (M+H), Rt. 2.1 min, 99.9% (Max). HPLC: (Method A) Rt. 3.0 min, 99.5% (Max). Chiral SFC: (Method B) Rt. 4.6 min, 100% (Max). [α].sup.26D −0.35±0.00, c 0.56 (MeOH).

[0404] Example 6: Yield: 32% (39 mg, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.59 (dd, J=2.4, 8.2 Hz, 1H), 4.05 (q, J=7.2 Hz, 1H), 3.67 (s, 3H), 2.80-2.79 (m, 4H), 2.60-2.58 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 339.1 (M+H), Rt. 2.1 min, 99.8% (Max). HPLC: (Method A) Rt. 3.0 min, 98.0% (Max). Chiral SFC: (Method B) Rt. 5.6 min, 98.1% (Max).

Example 7: 3-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0405] ##STR00531##

[0406] To a stirred solution of Intermediate 3 (0.4 g, 2.18 mmol) in ACN (10 mL), Intermediate 6 (0.323 g, 1.82 mmol) was added, followed by TEA (0.92 mL, 6.57 mmol) and the reaction mixture was heated to reflux at 70° C. 16 h. After completion (monitored by TLC), the reaction mixture was evaporated under vacuum and water (20 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by Prep-HPLC (Method B) to get the title compound. Yield: 28% (198 mg, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.12 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.79-6.72 (m, 2H), 6.68-6.57 (m, 2H), 4.49 (t, J=8.4 Hz, 2H), 3.76 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 3.12 (t, J=8.4 Hz, 2H), 2.79-2.68 (m, 4H), 2.57-2.38 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 324.2 (M+H), Rt. 2.3 min, 96.2% (Max). HPLC: (Method A) Rt. 3.4 min, 97.4% (Max).

Example 8 and Example 9: (S)-3-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (R)-3-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0407] ##STR00532##

[0408] The enantiomers of Example 7 were purified by chiral preparative SFC (Method C). The first peak was concentrated and lyophilised to give Example 8 and the second peak was concentrated and lyophilised to give Example 9.

[0409] Example 8: Yield: 40% (50 mg, Pale brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.12 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.79-6.72 (m, 2H), 6.68-6.57 (m, 2H), 4.49 (t, J=8.4 Hz, 2H), 3.76 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 3.12 (t, J=8.4 Hz, 2H), 2.79-2.68 (m, 4H), 2.57-2.38 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 324.2 (M+H), Rt. 2.3 min, 99.3% (Max). HPLC: (Method A) Rt. 3.3 min, 97.7% (Max). Chiral SFC (Method C) Rt. 3.0 min, 100.0% (Max). [α].sup.26D −6.92±0.54, c 0.13 (MeOH).

[0410] Example 9: Yield: 20% (19 mg, Pale brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.12 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.79-6.72 (m, 2H), 6.68-6.57 (m, 2H), 4.49 (t, J=8.4 Hz, 2H), 3.76 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 3.12 (t, J=8.4 Hz, 2H), 2.79-2.68 (m, 4H), 2.57-2.38 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 324.2 (M+H), Rt. 2.3 min, 99.3% (Max). HPLC: (Method A) Rt. 3.3 min, 98.2% (Max). Chiral SFC (Method C) Rt. 4.1 min, 96.9% (Max).

Example 10 and Example 11: 5-(1-(6-chloro-7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole and 5-(1-(7-chloro-8-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0411] ##STR00533##

Step 1: 7-chloro-8-methoxy-2,3,4,5-tetrahydro-H-benzo[d]azepine hydrochloride 6-chloro-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride

[0412] ##STR00534##

[0413] To a stirred suspension of Intermediate 6 (0.2 g, 1.19 mmol) in glacial acetic acid (2 mL) was added SO.sub.2Cl.sub.2 (0.1 mL, 1.23 mmol) dropwise at RT. After stirring for 2.5 hours at RT. the reaction mixture was concentrated. The residue was co-distilled with toluene, dried under vacuum and was re-suspended in THF. Di-tert-butyl dicarbonate (0.37 mL, 1.69 mmol) and triethylamine (0.32 mL, 2.30 mmol) were added and the mixture was stirred at RT for 3 h and then concentrated. The residue was dissolved in EtOAc and washed with sat. aq. Na.sub.2CO.sub.3 solution. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude material was purified by flash chromatography (Silica gel: 230-400 mesh, Eluent: 15% ethyl acetate in petroleum ether) to give the titled compounds as a mixture of regioisomers. To a stirred solution of this mixture of regioisomers (230 mg, 0.74 mmol) in dry 1,4 dioxane (1.0 mL) at 0□ was added HCl in dioxane (4 M, 17 mL) and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and it was triturated with ethyl acetate to get the title compounds as a mixture of regioisomers (about 1:1 mixture calculated by .sup.1H NMR). Yield: 82% (230 mg, pale brown solid). Regioisomer 1: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.21-9.12 (m, 2H), 7.28 (s, 1H), 7.04 (s, 1H), 3.82 (s, 3H), 3.13-3.03 (m, 8H). Regioisomer 2: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.21-9.12 (m, 2H), 7.16 (d, J=11.2 Hz, 1H), 6.96 (d, J=11.2 Hz, 1H), 3.82 (s, 3H), 3.13-3.03 (m, 8H). LCMS: (Method A) 212.1 (M+H), 1.sup.st Rt. 1.4 min, 42.0% (Max) and 2.sup.nd Rt. 1.5 min, 47.7% (Max).

Step 2: 5-(1-(6-chloro-7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole and 5-(1-(7-chloro-8-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0414] ##STR00535##

[0415] To a stirred solution of Step 1: Example 10 (0.23 g, 1.08 mmol) in dry ACN (3.0 mL) under nitrogen atmosphere, triethyl amine (TEA) (0.3 mL 2.17 mmol), and Intermediate 2 (0.236 g, 1.19 mmol) were added sequentially at RT. The reaction mixture was stirred overnight at 70° C. The completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude residue was purified by flash chromatography (Silica gel: 230-400 mesh, Eluent: 45% ethyl acetate in petroleum ether) to give the title compound as a mixture of two regioisomers (Example 10:Example 11 ratio of 45:50). The regioisomers were separated by Prep-HPLC (Method A), and the first peak was concentrated to give title compound Example 10. The second peak was concentrated to give the title compound Example 11.

[0416] Example 10: Yield: 10% (22.0 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.51 (dd, J=1.2, 8.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.03 (q, J=6.8 Hz, 1H), 3.77 (s, 3H), 3.09-2.83 (m, 4H), 2.68-2.51 (m, 4H), 1.42 (d, J=6.8 Hz, 3H); LCMS: (Method A) 373.0 (M+H), Rt. 2.2 min, 99.6% (Max). HPLC: (Method A) Rt. 3.2 min, 99.3% (Max).

[0417] Example 11: Yield: 20% (45 mg, off white solid); .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.53 (dd, J=1.2, 8.4 Hz, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 4.06 (q, J=6.8 Hz, 1H), 3.78 (s, 3H), 2.85-2.76 (m, 4H), 2.61-2.51 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 373.0 (M+H), Rt. 2.3 min, 98.2% (Max). HPLC: (Method A) Rt. 3.3 min 97.9% (Max).

Example 12: 7-methoxy-3-(1-(quinoxalin-6-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0418] ##STR00536##

[0419] To a stirred solution of Intermediate 6 (0.14 g, 0.78 mmol), and TEA (0.54 mL, 3.39 mmol) in DMF (1.4 mL), was added Intermediate 4 (0.226 g, 1.79 mmol) at RT and the mixture was stirred at 80° C. overnight. After completion (by TLC), the reaction mixture was concentrated at 50° C. under reduced pressure. The crude residue was suspended in water (10 mL), extracted with EtOAc (2×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude material was purified by flash chromatography using 50-60% EtOAc in petroleum ether followed by further purification by Pep-HPLC (Method A) to get the tittle compound. Yield: 21% (56 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (d, J=6.8 Hz, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 4.16 (d, J=6.8 Hz, 1H), 3.67 (s, 1H), 2.90-2.69 (m, 4H), 2.57-2.42 (m, 4H), 1.45 (d, J=6.4 Hz, 3H). LCMS: (Method A) 334.1 (M+H), Rt. 2.0 min, 97.6% (Max). HPLC: (Method A) Rt. 2.6 min, 98.0% (Max).

Example 13 and Example 14: 5-(1-(7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl)benzo[d]thiazole and 5-(1-(7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0420] ##STR00537##

Step 1: 7-bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride and 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride

[0421] ##STR00538##

[0422] To a stirred solution of Intermediate 5 (0.4 g, 1.22 mmol) in 1,4 dioxane (4 mL) was added HCl in dioxane (4 M, 4 mL) at 0° C. The reaction mixture was stirred for 4 h at RT, while being monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to get the tittle compound. Yield: 95% (0.3 g, off white solid). LCMS: (Method A) 227.9 (M+H), Rt. 1.9 min, 83.2% (Max) (single peak observed under these LC conditions).

Step 2: 5-(1-(7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl)benzo[d]thiazole and 5-(1-(7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0423] ##STR00539##

[0424] To a stirred solution of Step 1: Example 13 (0.27 g, 1.0 mmol), TEA (0.4 mL, 2.6 mmol) in DMF (3 mL), Intermediate 2 (0.25 g, 1.3 mmol) was added at RT and the mixture was stirred at 70° C. for overnight. Completion of the reaction was monitored by TLC and the reaction mixture was concentrated at 50° C. under reduced pressure. The residue was suspended with water (10 mL), extracted with EtOAc (2×25 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by flash chromatography using 1-2% MeOH in DCM to get the mixture of regioisomers. Yield: 22% (87 mg, pale brown gummy solid). The regioisomers were separated by Prep-HPLC (Method B) and the first fraction was collected to get Example 13, and the second fraction was collected to get tittle compound Example 14.

[0425] Example 13: Yield: 4% (13 mg, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.27-7.24 (m, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.92 (d, J=14.8 Hz, 1H), 3.77-3.75 (m, 1H), 3.65 (d, J=14.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.99-2.94 (m, 1H), 2.88-2.85 (m, 2H), 1.67-1.66 (m, 1H), 1.62-1.58 (m, 1H), 1.3 (d, J=6.8 Hz, 3H). LCMS: (Method A) 388.9 (M+H), Rt. 2.3 min, 99.6% (Max). HPLC: (Method A) Rt. 3.4 min, 99.9% (Max).

[0426] Example 14: Yield: 4% (16 mg, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.25-7.22 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.09-4.04 (m, 1H), 2.83-2.83 (m, 4H), 2.60-2.50 (m, 4H), 1.41 (d, J=6.8 Hz, 3H). LCMS: (Method A) 388.9 (M+H), Rt. 2.3 min, 98.9% (Max). HPLC: (Method A) Rt. 3.5 min, 98.5% (Max).

Example 15 and Example 16: 2-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-7-carbonitrile and 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-carbonitrile

[0427] ##STR00540##

Step 1: tert-butyl 7-cyano-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate and tert-butyl 7-cyano-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[0428] ##STR00541##

[0429] To a stirred solution of Intermediate 5 (1.0 g, 3.07 mmol) in DMF (3 mL), was added Zn(CN).sub.2 (0.72 g, 6.15 mmol) at RT and the solution was purged with nitrogen for 10 min. Then PdCl.sub.2(dppf).DCM-complex (0.25 g, 0.31 mmol) was added and the reaction mixture was stirred at 120° C. for overnight. After completion, (by TLC) and the reaction mixture was suspended with water (10 mL), and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by flash chromatography using 50-60% EtOAc in Pet-Ether to afford the tittle compound as a mixture of regioisomers. Yield: 61% (0.51 g, pale brown gummy solid). LCMS: (Method A) 173.1 (M-Boc), Rt. 3.0 min, 93.1% (Max).

Step 2: 2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-carbonitrile hydrochloride and 2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-carbonitrile hydrochloride

[0430] ##STR00542##

[0431] To a stirred solution of Step 1: Example 15 (0.5 g, 1.83 mmol) in 1,4 dioxane (5 mL) was added HCl in dioxane (4 M, 5 mL) at 0□. The reaction mixture was stirred for 4 h at RT while being monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to get the tittle compound as a mixture of regioisomers. Yield: 78% (0.3 g, off white solid). LCMS: (Method A) 173.1 (M+H), Rt. 1.5 min, 92.1% (Max).

Step 3: 2-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-7-carbonitrile and 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-carbonitrile

[0432] ##STR00543##

[0433] To a stirred solution of Step 2: Example 15 (0.3 g, 1.73 mmol), TEA (0.5 mL, 3.6 mmol) in DMF (3 mL), Intermediate 2 (0.34 g, 1.72 mmol) was added at RT and the reaction mixture was stirred at 70° C. for overnight. The reaction was monitored by TLC, upon completion, the reaction mixture was evaporated at 50° C. under reduced pressure. The residue was suspended with water (10 mL), extracted with EtOAc (2×25 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude residue was purified by flash chromatography using 1-2% MeOH in DCM to get the title compound as a mixture of regioisomers. Yield: 25% (120 mg, pale brown gummy solid). The regioisomers were separated by SFC (Method E). The first fraction was collected to get Example 15 and the second fraction was collected to get Example 16.

[0434] Example 15: Yield: 13% (14 mg, Off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.10-8.07 (m, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.05 (d, J=6.0 Hz, 1H), 4.00 (d, J=14.4 Hz, 1H), 3.78-3.70 (m, 2H), 3.15-3.05 (m, 1H), 2.98-2.92 (m, 3H), 1.67-1.62 (m, 2H), 1.36-1.34 (m, 3H). LCMS: (Method A) 334.1 (M+H), Rt. 1.77 min, 98.8% (Max). HPLC: (Method A) Rt. 2.71 min, 97.6% (Max).

[0435] Example 16: Yield: 13% (21 mg, Off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.36 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.54-7.51 (m, 3H), 7.28 (d, J=7.6 Hz, 1H), 4.08-4.07 (m, 1H), 2.92-2.85 (m, 4H), 2.67-2.66 (m, 2H), 2.54-2.52 (m, 2H), 1.41 (d, J=6.8 Hz, 3H). LCMS: (Method A) 334.2 (M+H), Rt. 1.9 min, 98.3% (Max). HPLC: (Method A) Rt. 2.7 min, 98.2% (Max).

Example 17 and Example 18: 5-(1-(7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl)benzo[d]thiazole and 5-(1-(7-(methylsulfonyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0436] ##STR00544##

Step 1: tert-butyl 7-(methylthio)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate and tert-butyl 7-(methylthio)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0437] ##STR00545##

[0438] To a stirred solution of Intermediate 5 (0.6 g, 1.84 mmol) in THF (6 mL), n-BuLi (1.22 mL, 3.05 mmol) was added at −78° C. and the reaction mixture was stirred at −78° C. for 30 min. Then Me.sub.2S.sub.2 was added slowly at −78° C. and the mixture was stirred for another 30 min. After completion (TLC), the reaction mixture was quenched with aq. NH.sub.4Cl solution (10 mL), extracted with EtOAc (2×50 mL), and the combined organic layer was dried over sodium sulphate and concentrated. The resulting crude material was purified by flash chromatography using 50-60% EtOAc in pet-ether to afford the tittle compound as a mixture of regioisomers. Yield: 75% (0.41 g, pale brown gummy solid). LCMS: (Method A) 194.1 (M+H), Rt. 3.2 min, 96.7% (Max).

Step 2: tert-butyl 7-(methylsulfonyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate and tert-butyl 7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0439] ##STR00546##

[0440] To a stirred solution of Step 1: Example 17 (0.4 g, 2.06 mmol) in DCM (4 mL), mCPBA (0.73 g, 4.22 mmol) was added at 0° C. and the reaction mixture was stirred at RT for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 solution (10 mL), extracted with DCM (2×25 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the tittle compound as a mixture of regioisomers. Yield: 45% (0.42 g, colorless liquid). LCMS: (Method A) 226.0 (M-Boc), Rt. 2.7 min, 96.0% (Max).

Step 3: 7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride and 7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride

[0441] ##STR00547##

[0442] To a stirred solution of Step 2: Example 17 (0.4 g, 1.23 mmol) in 1,4-dioxane (4 mL) was added HCl in dioxane (4 M, 4 mL) at 0□. The reaction mixture was stirred for 4 h at RT while being monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to get the tittle compounds as a mixture of regioisomers. Yield: 91% (0.3 g, off white solid). LCMS: (Method A) 226.0 (M+H), Rt. 1.0 min, 88.5% (Max).

Step 4: 5-(1-(7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl)benzo[d]thiazole and 5-(1-(7-(methylsulfonyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0443] ##STR00548##

[0444] To a stirred solution of Step 3: Example 17 (0.3 g, 1.15 mmol), TEA (0.4 mL, 2.87 mmol) in DMF (3 mL), 5-(1-chloroethyl)benzo[d]thiazole (Intermediate 2) (0.27 g, 1.37 mmol) was added at RT and the reaction mixture was stirred at 70° C. for overnight. After completion, the reaction mixture was evaporated at 50° C. under reduced pressure. The residue was suspended with water (10 mL), extracted with EtOAc (2×25 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by flash chromatography using 1-2% MeOH in DCM to get the title compounds as a mixture of regioisomers. Yield: 45% (200 mg, pale brown gummy solid). The regioisomers were separated by SFC (Method F). The first fraction was collected to get Example 17 and the second fraction was collected to get Example 18.

[0445] Example 17: Yield: 14% (63 mg, Off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.64-7.62 (m, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 4.02 (d, J=14.4 Hz, 1H), 3.84-3.73 (m, 2H), 3.21 (s, 3H), 3.09-2.97 (m, 4H), 1.71-1.65 (m, 2H), 1.38 (d, J=6.4 Hz, 3H). LCMS: (Method B) 387.1 (M+H), Rt. 2.9 min, 98.2% (Max). HPLC: (Method B) Rt. 5.6 min, 98.9% (Max).

[0446] Example 18: Yield: 10% (46 mg, Off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.63 (s, 1H), 7.62-7.60 (m, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 4.09-4.08 (m, 1H), 3.14 (s, 3H), 2.96-2.93 (m, 4H), 2.66-2.49 (m, 4H), 1.42 (d, J=6.80 Hz, 3H). LCMS: (Method B) 387.1 (M+H), Rt. 2.6 min, 96.9% (Max). HPLC: (Method B) Rt. 5.6 min, 95.1% (Max).

Example 19: 5-(1-(7-methoxy-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0447] ##STR00549##

[0448] To a stirred solution of Intermediate 8 (0.27 g, 1.37 mmol), TEA (0.5 mL, 3.5 mmol) in DMF (3 mL), Intermediate 2 (0.33 g, 1.67 mmol) was added at RT and stirred at 70° C. for overnight. Completion of the reaction was monitored by TLC and the reaction mixture was concentrated at 50° C. under reduced pressure. The residue was suspended in water (10 mL), extracted with EtOAc (2×50 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude was purified by Pep-HPLC (Method B) to get the tittle compound as mixture of diastereomers in 1:1.2 ratio. Yield: 8% (40 mg, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.13-8.05 (m, 2H), 7.55 (d, J=8.0 Hz, 1H), 6.96-6.91 (m, 1H), 6.64-6.63 (m, 2H), 4.16-4.09 (m, 1H), 3.70 (s, 3H), 3.29-1.17 (m, 2H), 2.98-2.84 (m, 2H), 2.68-2.65 (m, 1H), 2.50-2.40 (m, 2H), 1.38-1.33 (m, 3H), 0.76-0.74 (m, 3H). LCMS: (Method A) 353.1 (M+H), Rt. 3.0 min, 94.6% (Max). HPLC: (Method A) Rt. 3.2 min, 99.6% (Max) (single peak observed under these LC conditions).

Example 20: 5-(1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0449] ##STR00550##

[0450] To a stirred solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 1.36 mmol), and TEA (0.5 mL, 3.4 mmol) in DMF (2 mL), were added Intermediate 2 (0.32 g, 1.6 mmol) at RT and the mixture was stirred at 70 □ for overnight. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated at 50° C. under reduced pressure. The residue was suspended in water (10 mL), extracted with EtOAc (2×25 mL), and the combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude was purified by flash chromatography using 1-2% MeOH in DCM to get the tittle compound. Yield: 48% (0.2 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.04 (s, 4H), 4.06-4.05 (m, 1H), 2.84-2.82 (m, 4H), 2.63-2.59 (m, 2H), 2.59-2.50 (m, 2H), 1.41 (d, J=6.8 Hz, 3H). LCMS: (Method A) 309.2 (M+H), Rt. 2.2 min, 96.7% (Max). HPLC: (Method A) Rt. 2.9 min, 97.4% (Max).

Example 21 and Example 22: (S)-5-(1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole and (R)-5-(1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0451] ##STR00551##

[0452] Enantiomers of Example 20 were separated by chiral preparative SFC (Method D). The first fraction was collected to get Example 21 and the second fraction was collected to get Example 22.

[0453] Example 21: Yield: 48% (0.05 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.55-7.53 (m, 1H), 7.05 (s, 4H), 4.09-4.04 (m, 1H), 2.85-2.83 (m, 4H), 2.64-2.63 (m, 2H), 2.59-2.50 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 309.2 (M+H), Rt. 1.6 min, 99.4% (Max). HPLC: (Method A) Rt. 3.0 min, 99.3% (Max). Chiral SFC: (Method D) Rt. 4.2 min, 100% (Max). [α].sup.26D −3.77±0.17, c 0.52 (MeOH).

[0454] Example 22: Yield: 48% (0.05 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.55-7.53 (m, 1H), 7.05 (s, 4H), 4.09-4.04 (m, 1H), 2.85-2.83 (m, 4H), 2.60-2.58 (m, 2H), 2.58-2.50 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 309.2 (M+H), Rt. 1.6 min, 99.5% (Max). HPLC: (Method A) Rt. 2.9 min, 98.8% (Max). Chiral SFC: (Method D) Rt. 4.6 min, 97.3% (Max).

Example 23: 5-(1-(7-((6-fluoropyridin-2-yl)oxy)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0455] ##STR00552##

[0456] To a stirred solution of 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (100 mg, 0.30 mmol, Example 33) in dry THF (1 mL) at 0° C. was added NaH (22 mg, 0.46 mmol) and the reaction mixture was stirred for 1 h at RT. 2,6-Difluoropyridine (35 mg, 0.30 mmol) was added into the reaction mixture and the stirring was continued for another 2 h. After completion (TLC), the reaction mixture was quenched by ice and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by Biotage isolera using 50-60% EtOAc in petroleum ether to afford the title compound. Yield: 10% (9 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.98-7.96 (m, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.85-6.83 (m, 3H), 4.07 (q, J=6.8 Hz, 1H), 2.91-2.81 (m, 4H), 2.67-2.55 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 420.0 (M+H), Rt. 2.5 min, 99.5% (Max). HPLC: (Method A) Rt. 3.6 min, 99.9% (Max), 99.8% (220 nm).

Example 24: 5-(1-(7-(difluoromethoxy)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0457] ##STR00553##

Step 1: 7-hydroxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0458] ##STR00554##

[0459] To a stirred solution of 8-methoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (1.0 g, 5.23 mmol, Step 3: Intermediate 6) in DCM (10 mL), was added BBr.sub.3 (7.84 mL, 1.0 M solution in DCM, 7.84 mmol) at 0□ and the mixture was stirred at RT for overnight. After completion (TLC), the reaction mixture was quenched by methanol at 0□ and then concentrated under reduced pressure. The resulting solid was triturated with hexane-diethyl ether (8:2) to give the title compound. Yield: 77% (720 mg, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.54 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 6.49 (s, 1H), 3.60 (s, 2H), 3.38-3.37 (m, 2H), 2.88-2.86 (m, 2H). LCMS: (Method A) 178.2 (M+H), Rt. 1.5 min, 63.9% (Max).

Step 2: 7-(difluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0460] ##STR00555##

[0461] To a stirred solution of 7-hydroxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (0.2 g, 1.04 mmol, Step 1: Example 24) in ACN (2.0 mL) and H.sub.2O (0.4 mL) at 0° C., were added KOH (171 mg, 3.05 mmol) and diethyl (bromodifluoromethyl)phosphonate (419 mg, 1.57 mmol). The reaction mixture was stirred at RT for overnight while being monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by Biotage isolera using 50-60% EtOAc in petroleum ether as eluent to get the tittle compound. Yield: 87% (180 mg, brown gum). LCMS: (Method A) 228.2 (M+H), Rt. 2.2 min, 71.6% (Max).

Step 3: 7-(difluoromethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0462] ##STR00556##

[0463] To a stirred solution of 7-(difluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (180 mg, 0.79 mmol, Step 2: Example 24) in THF (6 mL) was added a solution of BH.sub.3-THF (1.0 M, 1.18 mL, 1.18 mmol) at 0□ and the reaction mixture was stirred at 65□ for overnight. After completion (TLC), the reaction mixture was slowly quenched with methanol (6 mL) at 0□ followed by 1.5 N HCl (6 mL) at RT and then the mixture was heated to 50° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to afford the crude tittle compound which was directly used in the next step. Yield: 77% (130 mg, pale brown gum).

Example 24: 5-(1-(7-(difluoromethoxy)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0464] ##STR00557##

[0465] To a stirred solution of 7-(difluoromethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (130 mg, 0.61 mmol, Step 3: Example 24) and TEA (0.25 mL, 1.83 mmol) in DMF (1.3 mL), was added 5-(1-chloroethyl)benzo[d]thiazole, Intermediate 2, (145 mg, 0.73 mmol) at RT and the reaction mixture was stirred at 80 □ for overnight. After completion (TLC), the reaction mixture was concentrated under reduced pressure. The residue was suspended with water (10 mL), extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by Biotage isolera using 50-60% EtOAc in petroleum ether as the eluent to get the tittle compound. Yield: 13% (19 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.53 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.30-6.93 (m, 2H), 6.92-6.82 (m, 2H), 4.07 (q, J=6.8 Hz, 1H), 2.90-2.69 (m, 4H), 2.68-2.51 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375.1 (M+H), Rt. 1.7 min, 94.6% (Max). HPLC: (Method A) Rt. 3.4 min, 96.6% (Max), 96.6% (220 nm).

Example 25: 5-(1-(7-isopropoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0466] ##STR00558##

Step 1: tert-butyl 7-isopropoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[0467] ##STR00559##

[0468] To a stirred solution of tert-butyl 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate, Intermediate 7, (300 mg, 1.14 mmol) in DMF (3.0 mL), were added K.sub.2CO.sub.3 (472 mg, 3.42 mmol) and 2-bromopropane (210 mg, 1.70 mmol) at RT and the reaction mixture was stirred at 80° C. for overnight. After completion (TLC), the reaction mixture was concentrated under reduced pressure at 50° C. The residue was suspended with water (10 mL) and extracted with EtOAc (2×60 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to get tittle compound. Yield: 43% (300 mg, pale yellow gum). LCMS: (Method A) 206.4 (M-Boc+H), Rt. 3.3 min, 27% (Max).

Step 2: 7-isopropoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride

[0469] ##STR00560##

[0470] To a stirred solution of tert-butyl 7-isopropoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate, Step 1: Example 25, (300 mg, 0.98 mmol) in 1,4 dioxane (1.0 mL) was added HCl in 1,4-dioxane (4 M, 1.0 mL) at 0° C. The reaction mixture was stirred for 4 h at RT. After completion (TLC), the reaction mixture was concentrated under reduced pressure and was triturated with EtOAc to get the tittle compound. Yield: 93% (110 mg, off white solid). LCMS: (Method A) 206.4 (M+H), Rt. 1.9 min, 36% (Max).

Example 25: 5-(1-(7-isopropoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0471] ##STR00561##

[0472] To a stirred solution of 7-isopropoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride, Step 2: Example 25, (180 mg, 0.87 mmol) in dry DMF (2 mL), were added 5-(1-chloroethyl)benzo[d]thiazole (250 mg, 0.96 mmol) and TEA (0.25 mL, 1.74 mmol) and the mixture was heated at 70° C. for overnight. After completion (TLC), the reaction mixture was concentrated under vacuum. To the resulting residue, water was added, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by prep. HPLC (Method A) to afford the title compound. Yield: 11% (13 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.65-6.60 (m, 1H), 6.56 (dd, J=8.0 Hz, 2.4 Hz, 1H), 4.49 (h, J=6.4 Hz, 1H), 4.09-4.00 (m, 1H), 2.82-2.70 (m, 4H), 2.66-2.48 (m, 4H), 1.41 (d, J=6.8 Hz, 3H), 1.22-1.13 (m, 6H). LCMS: (Method A) 367.2 (M+H), Rt. 2.3 min, 99.5% (Max). HPLC: (Method A) Rt. 3.7 min, 99.1% (Max), 99.0% (220 nm).

Example 26: 5-(1-(7-isobutoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0473] ##STR00562##

Step 1: tert-butyl 7-isobutoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[0474] ##STR00563##

[0475] To a stirred solution of tert-butyl 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (300 mg, 1.14 mmol, Intermediate 7) in DMF (3.0 mL), were added K.sub.2CO.sub.3 (472 mg, 3.42 mmol) and 1-bromo-2-methylpropane (230 mg, 1.70 mmol) at RT and the mixture was stirred at 80° C. for overnight. After (TLC) the reaction mixture was concentrated under reduced pressure. The residue was suspended with water (10 mL), extracted with EtOAc (2×60 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to get the tittle compound. Yield: 49% (360 mg, pale yellow gum). LCMS: (Method A) 220.4 (M-Boc+H), Rt. 3.56 min, 35% (Max).

Step 2: 7-isobutoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride

[0476] ##STR00564##

[0477] To a stirred solution of tert-butyl 7-isobutoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (360 mg, 0.98 mmol, Step 1—Example 26) in 1,4 dioxane (1.2 mL) was added HCl in 1,4 dioxane (4 M, 1.2 mL) at 0° C. The reaction mixture was stirred for at RT 4 h. After completion (TLC), the reaction mixture was concentrated under reduced pressure and the residue was triturated with EtOAc to get the tittle compound. Yield: 93% (110 mg, off white solid). LCMS: (Method A) 220.3 (M+H), Rt. 2.17 min, 47% (Max).

Example 26: 5-(1-(7-isobutoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0478] ##STR00565##

[0479] To a stirred solution of 7-isobutoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (360 mg, 1.42 mmol, Step 2: Example 26) in dry DMF (3.6 mL), were added 5-(1-chloroethyl)benzo[d]thiazole (309 mg, 1.56 mmol) and TEA (0.59 mL, 4.26 mmol) and the reaction mixture was heated at 70° C. for overnight. After completion (TLC), the reaction mixture was concentrated under vacuum. The crude residue was diluted with water and was extracted with EtOAc (2×20 mL). The combined organic layer was washed with water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by prep. HPLC (Method A) to afford title compound. Yield: 38% (75 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.53 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.0 Hz, 2.8 Hz, 1H), 4.06 (q, J=6.8 Hz, 1H), 3.65 (d, J=6.4 Hz, 2H), 2.87-2.72 (m, 4H), 2.66-2.53 (m, 4H), 1.95 (h, J=6.8 Hz, 1H), 1.41 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H). LCMS: (Method A) 381.1 (M+H), Rt. 3.5 min, 97.4% (Max).

[0480] HPLC: (Method A) Rt. 4.1 min, 96.5% (Max), 97.3% (220 nm).

Example 27: (R)-5-(1-(7-isobutoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole or (S)-5-(1-(7-isobutoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0481] ##STR00566##

[0482] Enantiomers of Example 26 were separated by chiral preparative SFC (Method G). The second fraction was collected to get Example 27.

[0483] Example 27: Yield: 19% (16 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.42 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.59 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.64 (dd, J=8.4 Hz, 2.4 Hz, 1H), 4.11 (q, J=6.8 Hz, 1H), 3.70 (d, J=6.4 Hz, 2H), 2.90-2.75 (m, 4H), 2.72-2.57 (m, 4H), 2.01 (h, J=6.4 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 6H). LCMS: (Method A) 381.2 (M+H), Rt. 2.6 min, 99.1% (Max). HPLC: (Method A) Rt. 4.1 min, 97.5% (Max), 98.4% (220 nm). Chiral SFC: (Method G) Rt. 4.1 min, 99.6% (Max).

Example 28: 5-((7-methoxy-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)benzo[c][1,2,5]thiadiazole

[0484] ##STR00567##

Step 1: benzo[c][1,2,5]thiadiazol-5-ylmethanol

[0485] ##STR00568##

[0486] To a stirred solution of benzo[c][1,2,5]thiadiazole-5-carbaldehyde (1.0 g, 6.09 mmol) in MeOH (8 mL) was added NaBH.sub.4 (0.25 g, 6.71 mmol) at 0□ and the reaction mixture was stirred for 1 h at RT. After completion (TLC), and the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford tittle compound. Yield: 71% (0.72 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.06-8.03 (m, 1H), 7.96-7.87 (m, 1H), 7.68-7.65 (m, 1H), 5.55 (t, J=7.6 Hz, 1H), 4.71 (d, J=9.2 Hz, 2H). LCMS: (Method A) No ionisation (M+H), Rt. 1.3 min, 95.4% (Max).

Step 2: 5-(chloromethyl)benzo[c][1,2,5]thiadiazole

[0487] ##STR00569##

[0488] To a stirred solution of Step 1: Example 29 (benzo[c][1,2,5]thiadiazol-5-ylmethanol) (0.40 g, 2.42 mmol) in dry DCM (4 mL), was added thionyl chloride (0.6 mL, 7.22 mmol) slowly at 0° C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under vacuum and the resulting residue was diluted with DCM (50 mL). The DCM layer was washed with water (2×10 mL), brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give tittle compound. Yield: 94% (0.42 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.18-8.13 (m, 1H), 8.10-8.04 (m, 1H), 7.78-7.75 (m, 1H), 4.99 (s, 2H). LCMS: (Method A) No ionisation (M+H), Rt. 2.1 min, 85.9% (Max).

Step 3: 5-((7-methoxy-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)benzo[c][1,2,5]thiadiazole

[0489] ##STR00570##

[0490] To a stirred solution of Intermediate 8 (0.27 g, 1.41 mmol), TEA (0.6 mL, 4.24 mmol) in ACN (3 mL), was added Step 2: Example 29, 5-(chloromethyl)benzo[c][1,2,5]thiadiazole, (0.28 g, 1.55 mmol) at room temperature and stirred at RT for 48 h. The reaction was monitored by TLC, after completion, the reaction mixture was concentrated at 50° C. under reduced pressure. The residue was suspended with water (10 mL), and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by flash chromatography using 1-2% MeOH in DCM to get the tittle compound. Yield: 30% (0.14 g, pale brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.06 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.68-6.64 (m, 2H), 4.00-3.87 (m, 2H), 3.61 (s, 3H), 3.28-3.24 (m, 1H), 3.16-3.13 (m, 1H), 3.02-2.99 (m, 1H), 2.72-2.62 (m, 2H), 2.60-2.51 (m, 2H), 0.79 (d, J=6.80 Hz, 3H). LCMS: (Method A) 340.2 (M+H), Rt. 1.6 min, 97.1% (Max). HPLC: (Method A) Rt. 3.1 min, 97.1% (Max).

Example 29: 5-((7-methoxy-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)benzo[d]thiazole

[0491] ##STR00571##

Step 1: benzo[d]thiazol-5-ylmethanol

[0492] ##STR00572##

[0493] To a stirred solution of methyl benzo[d]thiazole-5-carboxylate (1.0 g, 5.18 mmol) in THF (10 mL) was added a solution of LAH in THF (1.0 M, 6.22 mL, 6.22 mmol) at −78□ and the reaction mixture was stirred for 1 h at −78□. Upon completion (TLC), the reaction mixture was quenched with sat. aq. NH.sub.4Cl (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by Biotage Isolera flash column chromatography using 50% petroleum ether in EtOAc to get the tittle compound. Yield: 38% (0.32 g, pale yellow solid). LCMS: (Method A) 166.1 (M+H), Rt. 1.2 min, 58.7% (Max).

Step 2: 5-(chloromethyl)benzo[d]thiazole

[0494] ##STR00573##

[0495] To a stirred solution of benzo[d]thiazol-5-ylmethanol, Step 1: Example 29, (0.3 g, 1.82 mmol) in dry DCM (3 mL), was added thionyl chloride (0.4 mL, 5.46 mmol) slowly at 0° C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was then concentrated and the resulting crude residue was co-distilled with DCM (3×10 mL) and dried under vacuum to give the tittle compound. Yield: 85% (0.28 g, pale yellow solid). LCMS: (Method A) 184.0 (M+H), Rt. 1.9 min, 94.1% (Max).

Example 29: 5-((7-methoxy-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)benzo[d]thiazole

[0496] ##STR00574##

[0497] To a stirred solution of Intermediate 8 (0.12 g, 0.63 mmol) and TEA (0.22 mL, 1.57 mmol) in DMF (2 mL), was added 5-(chloromethyl)benzo[d]thiazole, Step 2: Example 29, (0.13 g, 0.69 mmol) at RT and the reaction mixture was stirred at RT for 48 h while being monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, the residue was suspended with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude residue was purified first by Biotage Isolera using 1-2% MeOH in DCM as eluent, followed by prep-HPLC using method B to get the tittle compound. Yield: 48% (102 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.52 (dd, J=8.0 Hz, 1.2 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.67-6.61 (m, 2H), 3.92 (d, J=18.0 Hz, 1H), 3.84 (d, J=14.0 Hz, 1H), 3.70 (s, 3H), 3.24 (d, J=14.0 Hz, 1H), 3.17-3.06 (m, 1H), 3.03-2.95 (m, 1H), 2.72-2.45 (m, 4H), 0.76 (d, J=6.4 Hz, 3H). LCMS: (Method A) 339.2 (M+H), Rt. 1.6 min, 99.3% (Max). HPLC: (Method A) Rt. 3.3 min, 99.4% (Max), 98.7% (220 nm).

Example 30: 7-methoxy-2-methyl-3-((2,3,4a,8a-tetrahydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0498] ##STR00575##

Step 1: (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol

[0499] ##STR00576##

[0500] To a stirred solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (1.0 g, 6.09 mmol) in MeOH (10 mL) was added NaBH.sub.4 (0.28 g, 6.69 mmol) at 0□ and the reaction mixture was stirred for 1 h at RT. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with water (20 mL), and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the tittle compound. Yield: 70% (0.71 g, colourless gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.79-6.73 (m, 3H), 5.04 (t, J=5.6 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.23 (s, 4H). LCMS: (Method A) No ionisation (M+H), Rt. 1.3 min, 95.7% (Max).

Step 2: 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine

[0501] ##STR00577##

[0502] To a stirred solution of (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol, Step 1: Example 30, (0.3 g, 1.81 mmol) in dry DCM (3 mL), was added thionyl chloride (0.4 mL, 5.42 mmol) slowly at 0° C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, and the resulting residue was co-distilled with DCM (3×10 mL) and dried under vacuum to give the tittle compound. Yield: 95% (0.31 g, colourless gummy solid). LCMS: (Method A) No ionisation (M+H), Rt. 1.8 min, 82.3% (Max).

Example 30: 3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0503] ##STR00578##

[0504] To a stirred solution of Intermediate 8 (0.12 g, 0.63 mmol) and TEA (0.22 mL, 1.57 mmol) in DMF (2 mL), was added 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine, Step 2: Example 30 (0.13 g, 0.69 mmol) at RT and the reaction mixture was stirred at RT for 48 h. After completion (TLC), the reaction mixture was concentrated under reduced pressure. The residue was suspended in water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by Isolera using 1-2% MeOH in DCM followed by Prep-HPLC using Method B to get tittle compound. Yield: 32% (71 mg, pale brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.94 (d, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.78 (br s, 2H), 6.67-6.60 (m, 2H), 4.21 (s, 4H), 3.70 (s, 3H), 3.64-3.50 (m, 2H), 3.17 (d, J=14.0 Hz, 1H), 3.09-3.00 (m, 1H), 2.98-2.89 (m, 1H), 2.62-2.45 (m, 4H), 0.69 (d, J=6.4 Hz, 3H). LCMS: (Method A) 340.3 (M+H), Rt. 1.7 min, 99.5% (Max). HPLC: (Method A) Rt. 3.0 min, 98.6% (Max), 98.8% (220 nm).

Example 31: 5-((7-methoxy-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)benzo[d]thiazole

[0505] ##STR00579##

Step 1: 2,3-dibromo-6-methoxypyridine

[0506] ##STR00580##

[0507] To a stirred solution of 2-bromo-6-methoxypyridine (10 g, 0.053 mol) in dry ACN (100 mL), was added N-bromosuccinimide (18.82 g, 0.106 mol) at RT. The reaction mixture was stirred at 90□ for 16 h. The completion of reaction was monitored by TLC. After completion, the reaction was filtered through a celite bed, diluted with water (30 mL) and exacted with 10% EtOAc in petroleum ether (2×100 mL). The combined organic layer washed with water (10 mL), brine (10 mL) dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude material was purified by crystallization (5 mL DCM in 50 mL n-pentane). The solid was filtered, washed with n-pentane and then dried unber vacuum to get afford the tittle compound. Yield: 35% (4.92 g, off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.70 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), LCMS: (Method A) 367.9 (M+H), Rt. 2.4 min, 96.7% (Max).

Step 2: 4,4,5,5-tetramethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,3,2-dioxaborolane

[0508] ##STR00581##

[0509] To a stirred solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (10 g, 0.048 mol) in dry DMF (240 mL), were added bis(pinacolato)diboron (18.31 g, 0.071 mol), polymer-bound PPh.sub.3 (1.2 g, 0.004 mol), LiOMe (3.63 g, 0.096 mol), CuI (0.91 g, 0.004 mol) at RT. The reaction mixture was stirred at RT for overnight. Completion of the reaction was monitored by TLC. After completion, the mixture was filtered through a celite-bed and washed with DCM (2×10 mL). The filtrate was poured into sat. NH.sub.4Cl solution (50 mL) and exacted with EtOAc (3×100 mL). The combined organic layer was washed with ice-cold water (2×50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the title compound. Yield: 70% (8.5 g, colorless liquid). .sup.1H NMR: 1H-NMR (400 MHz, CDCl.sub.3): δ 4.64 (t, J=4.0 Hz, 1H), 3.94-3.88 (m, 2H), 3.56-3.52 (m, 2H), 1.90-1.75 (m, 1H), 1.73-1.65 (m, 1H), 1.61-1.52 (m, 4H), 1.28 (s, 12H), 1.21 (t, J=8.0 Hz, 2H),

Step 3: Potassium trifluoro(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)borate

[0510] ##STR00582##

[0511] To a stirred solution of 4,4,5,5-tetramethyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,3,2-dioxaborolane, Step 2: Example 31, (6 g, 23.44 mmol) in dry THF (90 mL), was added sat. aq. KHF.sub.2 solution (5.72 g, 73.33 mmol) at RT, and the mixture was stirred at RT for 2 h. Then the reaction mixture was concentrated. The resulting gum was washed with dry acetone (4×60 mL), filtered and concentrated under reduced pressure. The residue was dissolved in dry acetone (20 mL), cooled to 0° C., and diethyl ether was added until a small amount of precipitate formed. The suspension was stirred at 0□ for 30 min and filtered. The solid was washed with diethyl ether (20 mL) to afford the tittle compound. Yield: 74% (4.1 g, white solid). .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 4.43 (t, J=4.0 Hz, 1H), 3.74-3.71 (m, 1H), 3.61-3.54 (m, 1H), 3.36-3.26 (m, 1H), 3.25-3.21 (m, 1H), 1.71-1.66 (m, 1H), 1.58-1.51 (m, 1H), 1.45-1.36 (m, 4H), 0.38-0.24 (m, 2H),

Step 4: 6-methoxy-2,3-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine

[0512] ##STR00583##

[0513] To a stirred solution of 2,3-dibromo-6-methoxypyridine, Step 1: Example 31, (1.4 g, 5.30 mmol), potassium trifluoro(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)borate, Step 3: Example 31, (3.7 g, 15.90 mmol) and cataCXium®A (0.35 g, 1.06 mmol) in dry 1,4 dioxane (12 mL), was added a solution of cesium carbonate (1.62 g, 31.80 mmol) in water (4 mL) at RT. The reaction mixture was degassed for 10 min using N.sub.2 gas. Then Pd(OAc).sub.2 (0.33 g, 1.59 mmol) was added at RT and the reaction mixture was heated to 100□ for 20 h. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with EtOAc (10 mL) and brine (10 mL) and the aqueous layer was extracted with EtOAc (2×20 mL), washed with water (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography using 12-15% EtOAc in petroleum ether to afford the tittle compound. Yield: 57% (1.1 g, brown gummy solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.40 (d, J=8.4 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 4.62 (d, J=20.8 Hz, 2H), 4.20-4.11 (m, 1H), 3.95-3.89 (m, 2H), 3.88 (s, 3H), 3.81-3.70 (m, 2H), 3.61-3.51 (m, 1H), 3.50-3.46 (m, 2H), 3.07 (t, J=7.2 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 1.81 (t, J=8.4 Hz, 2H), 1.71 (t, J=10.0 Hz, 2H), 1.62-1.59 (m, 8H). LCMS: (Method A) 366.2 (M+H), 1.7 min, 90.1% (Max).

Step 5: 2,2′-(6-methoxypyridine-2,3-diyl)bis(ethan-1-ol)

[0514] ##STR00584##

[0515] To a stirred solution of 6-methoxy-2,3-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine, Step 4: Example 31, (1.1 g, 3.01 mmol) in dry MeOH (12 mL) was added p-TsOH.H.sub.2O (1.31 g, 6.93 mmol) at 0° C. and the reaction mixture was stirred at RT for overnight. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated, diluted with sat. aq. NaHCO.sub.3 solution (10 mL) and extracted with DCM (2×20 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude residue was taken for next step without further purification. Yield: 55% (325 mg, yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.47 (d, J=2.4 Hz, 1H), 6.65 (d, J=3.2 Hz, 1H), 4.09 (t, J=4.8 Hz, 2H), 3.93 (s, 3H), 3.84 (t, J=3.6 Hz, 2H), 3.00 (t, J=5.6 Hz, 2H), 2.85 (t, J=3.6 Hz, 2H). LCMS: (Method A) 198.1 (M+H), 0.5 min, 82.6% (Max).

Step 6: (6-methoxypyridine-2,3-diyl)bis(ethane-2,1-diyl) dimethanesulfonate

[0516] ##STR00585##

[0517] To a stirred solution of 2,2′-(6-methoxypyridine-2,3-diyl)bis(ethan-1-ol), Step 5: Example 31, (320 mg, 1.63 mmol) in dry DCM (4 mL), were added TEA (0.68 mL, 4.89 mmol) and mesyl chloride (0.29 mL, 4.08 mmol) at 0□ and the reaction mixture was stirred at RT for 30 min. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated, diluted with sat. aq. NaHCO.sub.3 solution (3 mL) and extracted with DCM (2×20 mL). The combined organic layer was washed with water (3 mL), brine (3 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude residue was taken for next step without any purification. Yield: 87% (500 mg, yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.42 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.75 (t, J=3.6 Hz, 2H), 4.36 (t, J=7.2 Hz, 2H), 3.91 (s, 3H), 3.18 (t, J=6.8 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.95 (s, 3H), 2.94 (s, 3H). LCMS: (Method A) 354.0 (M+H), 1.6 min, 85.4% (Max).

Step 7: 7-benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine

[0518] ##STR00586##

[0519] To a stirred solution of (6-methoxypyridine-2,3-diyl)bis(ethane-2,1-diyl) dimethanesulfonate, Step 6: Example 31, (500 mg, 1.14 mmol) in dry dichloroethane (2.5 mL) was added benzyl amine (1.5 mL, 14.16 mmol) at RT. The reaction mixture was stirred for 16 h at 50□. The completion of reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM (10 mL), washed with sat. aq. NaHCO.sub.3 solution (3×3 mL), brine (2 mL), dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude residue was purified by flash chromatography using 70-90% EtOAc in petroleum ether to get the tittle compound. Yield: 78%, (300 mg, yellow liquid). LCMS: (Method A) 269.2 (M+H), Rt.1.2 min, 48.1% (Max).

Step 8: 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine

[0520] ##STR00587##

[0521] To a stirred solution of 7-benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine, Step 7: Example 31, (300 mg, 1.19 mmol) in dry MeOH (2.5 mL), was added Pd—C (30 mg, 10 wt %) at RT and the reaction mixture was degassed with H.sub.2 gas. The reaction mixture was stirred under H.sub.2 pressure (4 kg/cm.sup.2) for 16 h at 50□. The completion of reaction was monitored by LCMS. After completion, the reaction mixture was filtered through a celite-bed and concentrated to obtain the crude title compound which was used in the next step directly. Yield: 69% (140 mg, colorless liquid). LCMS: (Method A) 179.1 (M+H), Rt.0.4 min, 70.2% (Max).

Step 9: 5-(1-(2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)ethyl)benzo[d]thiazole

[0522] ##STR00588##

[0523] To a stirred solution of 5 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine, Step 8: Example 31, (130 mg, 0.73 mmol) in dry DMF (2 mL), was added TEA (0.15 mL, 1.09 mmol) and the reaction mixture was stirred for 10 min at RT. 5-(1-chloroethyl)benzo[d]thiazole, Intermediate 2, (172 mg, 0.87 mmol), was added and the reaction mixture was stirred for 16 h at 80□. Completion of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated, diluted with water (2 mL) and extracted with DCM (3×10 mL). The combined organic layer washed with water (5 mL), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude residue was purified by Prep-HPLC (method B) to afford the tittle compound. Yield: 5% (13 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.48 (d, J=8.0 Hz, 1H), 4.07 (q, J=6.4 Hz, 1H), 3.76 (s, 3H), 2.93 (t, J=4.0 Hz, 2H), 2.76 (t, J=3.6 Hz, 2H), 2.69-2.55 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 340.1 (M+H), Rt.1.3 min, 98.1% (Max). HPLC: (Method B) Rt. 5.6 min, 98.4% (Max), 97.3% (220 nm).

Example 32: 5-(1-(7-(pyridin-2-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0524] ##STR00589##

Step 1: 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl trifluoromethanesulfonate

[0525] ##STR00590##

[0526] To a stirred solution of 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol, Example 33, (200 mg, 0.61 mmol) in DCM at 0° C. were added trifluoromethanesulfonic anhydride (0.35 mL, 0.92 mmol) and TEA (0.26 mL, 1.85 mmol) and the reaction mixture was stirred at RT for 1 h. After completion (TLC), the reaction mixture was quenched with aq. NaHCO.sub.3 (10%, 50 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude residue was purified by Biotage Isolera column chromatography using 50% EtOAc in petroleum ether to afford the tittle compound. Yield: 29% (82 mg, brown gum). LCMS: (Method A) 457.0 (M+H), Rt. 1.8 min, 69.4% (Max).

Step 2: 5-(1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0527] ##STR00591##

[0528] A solution of 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl trifluoromethanesulfonate, Step 1: Example 32, (80 mg, 0.17 mmol) in 1,4-dioxane (0.8 mL) was degassed with nitrogen for 10 min. KOAc (52 mg, 0.52 mmol), bis(pinacolato)diboron (67 mg, 0.26 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (8 mg, 0.01 mmol) were added and the reaction mixture was stirred for overnight at 100° C. After completion (TLC), the reaction mixture was filtered through a celite pad and the filtrate was concentrated. This residue was diluted with water and extracted with DCM (2×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford the tittle compound. Yield: 76% (120 mg, brown gum). LCMS: (Method A) 435.2 (M+H), Rt. 1.9 min, 53.5% (Max).

Example 32: 5-(1-(7-(pyridin-2-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole

[0529] ##STR00592##

[0530] A stirred solution of 5-(1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)benzo[d]thiazole, Step 2: Example 32, (120 mg, 0.27 mmol) in 1,4-dioxane (0.96 mL) and water (0.24 mL) was degassed with nitrogen for 10 min. Cs.sub.2CO.sub.3 (270 mg, 0.82 mmol), 2-chloropyridine (34 mg, 0.30 mmol) and Pd(PPh.sub.3).sub.4 (32 mg, 0.02 mmol) were added and the reaction mixture was stirred for overnight at 90° C. After completion (TLC), the reaction mixture was filtered through a celite-pad and the filtrate was concentrated. The residue was diluted water and extracted with DCM (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude residue was purified by prep-HPLC (method A) to afford the title compound. Yield: 10% (6 mg, pale yellow gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.61 (d, J=4.4 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.90-7.76 (m, 4H), 7.56 (d, J=9.6 Hz, 1H), 7.32-7.28 (m, 1H), 7.18 (d, J=8.4 Hz, 1H), 4.10 (q, J=6.8 Hz, 1H), 2.97-2.88 (m, 4H), 2.68-2.52 (m, 4H), 1.44 (d, J=6.8 Hz, 3H), LCMS: (Method A) 386.1 (M+H), Rt. 1.1 min, 99.1% (Max). HPLC: (Method A) Rt. 2.1 min, 99.0% (Max), 99.1% (220 nm).

Example 33: 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol

[0531] ##STR00593##

Step 1: 2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol hydrobromide

[0532] ##STR00594##

[0533] A solution of 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine, Intermediate 6, (1.1 g, 9.93 mmol) in aq. HBr (48%, 3.3 mL) was stirred at 65° C. for overnight. After completion (TLC), the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with hexane-diethyl ether (8:2) to give the title compound. Yield: 75% (0.6 g, brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.98 (d, J=8.0 Hz, 1H), 6.62-6.54 (m, 2H), 3.17-3.12 (m, 4H), 2.98-2.95 (m, 4H). LCMS: (Method A) 164.2 (M+H), Rt. 0.7 min, 69.4% (Max).

Example 33: 3-(1-(benzo[d]thiazol-5-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol

[0534] ##STR00595##

[0535] To a stirred solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (300 mg, 1.83 mmol, Step 1: Example 33) in dry DMF (3 mL), were added TEA (0.76 mL, 5.45 mmol) and 5-(1-chloroethyl)benzo[d]thiazole, Intermediate 2, (430 mg, 2.17 mmol) at RT and the reaction mixture was stirred at 70° C. for overnight. After completion (TLC), and the reaction mixture was concentrated at 50° C. under reduced pressure. The residue was suspended with water (10 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by Biotage Isolera using 2-3% MeOH in DCM to afford the title compound. Yield: 29% (170 mg, pale brown gum). LCMS: (Method A) 325.0 (M+H), Rt. 1.9 min, 59.5% (Max).

[0536] Portion of this material (70 mg) was further purified by Prep-HPLC (Method B) to obtain the title compound. Yield: 32 mg, pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H), 9.01 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.46 (s, 1H), 6.41 (d, J=8.0 Hz, 1H), 4.03 (q, J=6.8 Hz, 1H), 2.71-2.67 (m, 4H), 2.56-2.50 (m, 4H), 1.40 (d, J=6.40 Hz, 3H). LCMS: (Method A) 325.1 (M+H), Rt. 1.3 min, 98.7% (Max). HPLC: (Method A) Rt. 2.41 min, 98.7% (Max), 98.6% (220 nm).

Example 34: 6-(1-(7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)-2,3-dihydrofuro[3,2-b]pyridine

[0537] ##STR00596##

[0538] To a stirred solution of 6-(1-chloroethyl)-2,3-dihydrofuro[3,2-b]pyridine, Intermediate 9, (120 mg, 0.65 mmol) in dry DMF (1.2 mL) were added 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine, Intermediate 6, (127 mg, 0.59 mmol) and TEA (0.25 mL, 3.26 mmol) and the reaction mixture was heated to 80° C. overnight. After completion, the reaction mixture was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc (2×40 mL). The combined organic layer was washed with water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by flash column chromatography using 50-60% EtOAc in petroleum ether as eluent to get the title compound. Yield: 29% (0.048 g, pale brown gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.93 (s, 1H), 7.09 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.66 (dd, J=8.0 Hz, 2.4 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 3.87 (q, J=7.2 Hz, 1H), 3.68 (s, 3H), 3.20 (t, J=8.8 Hz, 2H), 2.82-2.72 (m, 4H), 2.62-2.35 (m, 4H), 1.32 (d, J=6.8 Hz, 3H). LCMS: (Method A) 325.2 (M+H), Rt. 1.3 min, 96.7% (Max). HPLC: (Method A) Rt. 2.4 min, 96.6% (Max), 96.6% (220 nm).

[0539] The examples below were synthesized according to procedures described in the previous examples. These compounds and their tautomers, enantiomers, and salts are further preferred embodiments of the present invention.

TABLE-US-00003 Con- figura- Opti- tion cal speci- rota- fica- No Structure tion tion 1H NMR 28 [00597] Racemic 1H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.68-6.64 (m, 2H), 4.00-3.87 (m, 2H), 3.61 (s, 3H), 3.28-3.24 (m, 1H), 3.16-3.13 (m, 1H), 3.02-2.99 (m, 1H), 2.72-2.62 (m, 2H), 2.60-2.51 (m, 2H), 0.79 (d, J = 6.8 Hz, 3H). 29 [00598] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.52 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.67-6.61 (m, 2H), 3.92 (d, J = 18.0 Hz, 1H), 3.84 (d, J = 14.0 Hz, 1H), 3.70 (s, 3H), 3.24 (d, J = 14.0 Hz, 1H), 3.17-3.06 (m, 1H), 3.03-2.95 (m, 1H), 2.72-2.45 (m, 4H), 0.76 (d, J = 6.4 Hz, 3H). 30 [00599] Racemic 1H NMR (400 MHz, DMSO-d6): δ 6.94 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.78 (br s, 2H), 6.67-6.60 (m, 2H), 4.21 (s, 4H), 3.70 (s, 3H), 3.64-3.50 (m, 2H), 3.17 (d, J = 14.0 Hz, 1H), 3.09-3.00 (m, 1H), 2.98-2.89 (m, 1H), 2.62-2.45 (m, 4H), 0.69 (d, J = 6.4 Hz, 3H). 37 [00600] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 7.62 (t, J = 3.4 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 4.10-4.05 (m, 2H), 3.00 (s, 3H), 2.95-2.86 (m, 4H), 2.68-2.63 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). 43 [00601] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.37 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.27-7.24 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 4.06 (q, J = 6.0 Hz, 1H), 2.78 (br s, 4H), 2.65-2.48 (m, 4H), 1.99 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H). 51 [00602] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.05-8.03 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 4.12 (q, J = 6.4 Hz, 1H), 3.26 (s, 3H), 3.19-3.16 (m, 2H), 3.01-2.95 (m, 2H), 2.75-2.58 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H). 52 [00603] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.68 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 4.35 (s, 1H), 4.10 (q, J = 6.4 Hz, 1H), 3.19-3.11 (m, 2H), 3.08 (s, 3H), 2.99-2.94 (m, 2H), 2.75-2.54 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). 60 [00604] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.28 (d, J = 5.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4, 8.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.65 (dd, J = 2.4, 5.6 Hz, 1H), 4.09 (q, J = 6.8 Hz, 1H), 2.92-2.81 (m, 4H), 2.67-2.55 (m, 4H), 2.38 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H). 62 [00605] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.56-7.53 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.90-6.84 (m, 2H), 6.62 (s, 1H), 4.10-4.06 (m, 1H), 2.88-2.82 (m, 4H), 2.68-2.52 (m, 4H), 2.38 (s, 3H), 2.35 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H). 92 [00606] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.38 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 4.12-4.05 (m, 1H), 3.00-2.96 (m, 2H), 2.86-2.77 (m, 2H), 2.68-2.65 (m, 2H), 2.59-2.54 (m, 2H), 2.03 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). 98 [00607] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 4.12 (q, J = 6.8 Hz, 1H), 3.25-3.16 (m, 2H), 3.06-2.98 (m, 2H), 2.76-2.54 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 99 [00608] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.74 (br s, 1H), 9.36 (s, 1H), 8.10-8.03 (m, 3H), 7.54 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 4.10-4.05 (m, 1H), 3.02-2.95 (m, 2H), 2.97 (s, 3H), 2.84-2.76 (m, 2H), 2.65-2.56 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). 106 [00609] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.39 (d, J = 1.6 Hz, 1H), 9.12 (s, 1H), 8.15-8.10 (m, 2H), 8.00 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 3.88 (q, J = 6.0 Hz, 1H), 3.79 (d, J = 15.2 Hz, 1H), 3.25-3.10 (m, 3H), 3.09-2.98 (m, 1H), 1.74-1.72 (m, 2H), 3.00 (d, J = 6.0 Hz, 3H). 107 [00610] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 9.37 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.46-7.42 (m, 1H), 7.36 (d,J = 2.0 Hz, 1H, 7.27 (dd, J = 2.0, 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 14.4 Hz, 1H), 3.73 (q, J = 6.8 Hz, 1H), 3.64 (d, J = 14.4 Hz, 1H), 3.13- 3.03 (m, 1H), 2.98-2.92 (m, 1H), 2.84-2.77 (m, 2H), 2.03 (s, 3H), 1.70-1.52 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H). 108 [00611] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.48 (dd, J = 1.6, 8.2 Hz, 1H), 6.19 (s, 2H), 4.03 (q, J = 6.4 Hz, 1H), 2.72-1.67 (m, 2H), 2.62-2.45 (m, 6H), 1.34 (d, J = 6.8 Hz, 3H). 109 [00612] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04-8.03 (m, 2H), 7.76 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.27-7.22 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 4.09-4.07 (m, 1H), 3.83 (s, 3H), 2.87-2.80 (m, 4H), 2.68-2.52 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). 110 [00613] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.11-8.08 (m, 2H), 7.95 (s, 1H), 7.83 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 6.8 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 3.86 (s, 3H), 3.78 (q, J = 6.4 Hz, 1H), 3.67 (d, J = 14.8 Hz, 1H), 3.18-3.09 (m, 1H), 3.01-2.96 (m, 1H), 2.88 (t, J = 4.8 Hz, 2H), 1.73-1.58 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H). 111 [00614] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.02-6.94 (m, 3H), 4.06 (t, J = 6.4 Hz, 1H), 2.81-2.80 (m, 4H), 2.68-2.60 (m, 4H), 2.41 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). 112 [00615] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 6.96 (t, J = 2.0 Hz, 1H), 6.79 (d, J = 6.8 Hz, 1H), 3.91 (d, J = 14.8 Hz, 1H), 3.78-3.72 (m, 1H), 3.64 (d, J = 14.4 Hz, 1H), 3.09 (br s, 1H), 3.00-2.92 (m, 1H), 2.84 (br s, 2H), 2.46 (s, 3H), 1.72-1.53 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H). 113 [00616] 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.63-7.60 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.12-4.05 (m, 2H), 3.00 (s, 3H), 2.95-2.86 (m, 4H), 2.68-2.53 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). 114 [00617] 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.63-7.60 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.12-4.05 (m, 2H), 3.00 (s, 3H), 2.95-2.86 (m, 4H), 2.68-2.53 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). 115 [00618] 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.63-7.60 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.12-4.05 (m, 2H), 3.00 (s, 3H), 2.95-2.86 (m, 4H), 2.68-2.53 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). 116 [00619] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.11-8.01 (m, 2H), 7.55-7.50 (m, 1H), 7.30-7.26 (m, 1H), 6.70-6.63 (m, 2H), 5.26-5.18 (m, 1H), 4.72-4.66 (m, 1H), 4.12-4.05 (m, 1H), 3.73-3.67 (m, 3H), 3.05-2.72 (m, 4H), 2.21-2.13 (m, 2H), 1.45-1.40 (m, 3H). 117 [00620] Racemic 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.56-7.53 (m, 2H), 6.63 (d, J = 2.4 Hz, 1H), 4.97 (br s, 2H), 4.05 (q, J = 6.8 Hz, 1H), 2.89-2.85 (m, 2H), 2.79-2.65 (m, 2H), 2.59-2.52 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). 118 [00621] 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.02-6.94 (m, 3H), 4.06 (q, J = 6.8 Hz, 1H), 2.83-2.73 (m, 4H), 2.62-2.45 (m, 4H), 2.40 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). 119 [00622] 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.02-6.94 (m, 3H), 4.06 (q, J = 6.8 Hz, 1H), 2.83-2.73 (m, 4H), 2.62-2.45 (m, 4H), 2.40 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). 120 [00623] Racemic 1H NMR (400 MHz, CD3OD): δ 9.25 (s, 1H), 8.13-8.03 (m, 3H), 7.62 (dd, J = 1.6, 8.4 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 4.11 (q, J = 6.8 Hz, 1H), 3.17-3.12 (m, 2H), 2.95-2.91 (m, 2H), 2.82-2.71 (m, 4H), 2.58-2.53 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.04-0.95 (m, 4H). 121 [00624] Racemic 1H NMR (400 MHz, CD3OD): δ 9.26 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.07-8.01 (m, 2H), 7.54-7.51 (m, 1H), 7.16-7.15 (s, 1H), 4.01 (d, J = 14.8 Hz, 1H), 3.86 (q, J = 6.4 Hz, 1H), 3.77 (d, J = 14.8 Hz, 1H), 3.31-3.13 (m, 4H), 2.56-2.52 (m, 1H), 1.87-1.82 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H), 1.02-0.96 (m, 4H). 122 [00625] Racemic 1H NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 7.16-7.12 (m, 5H), 4.26-4.15 (m, 1H), 3.59-3.51 (m, 1H), 3.18-3.08 (m, 1H), 3.01-2.88 (m, 4H), 2.11 (s, 3H), 1.65-1.50 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H).

Example B01: Human O-GlcNAcase Enzyme Inhibition Assay

[0540] 5 μl of the appropriate concentration of a solution of inhibitor in McIlvaine's Buffer (pH 6.5) in 2% DMSO (for a dose response curve calculation) is added into each well of a 384-well plate (Greiner, 781900). Then, 20 nM of His-Tagged hOGA and 10 μM of FL-GlcNAc (Fluorescein mono-beta-D-(2-deoxy-2-N-acetyl) glucopyranoside; Marker Gene Technologies Inc, M1485) were added to the 384-well plate for a final volume of 20 μl. After incubation for 60 min at room temperature, the reaction was terminated by the addition of 10 μL of stop buffer (200 mM glycine, pH 10.75). The level of fluorescence (Δ.sub.exc 485 nm; (Δ.sub.emm 520 nm) was read on a PHERAstar machine. The amount of fluorescence measured was plotted against the concentration of inhibitor to produce a sigmoidal dose response curve to calculate an IC.sub.50. All individual data was corrected by subtraction of the background (Thiamet 3 uM=100% inhibition) whilst 0.5% DMSO was considered as the control value (no inhibition).

Example B02: Pharmacodynamic Model: Total Protein O-GlcNAcylation Immunoassay (RL2 mAb, Meso Scale Electrochemiluminescence (ECL) Assay)

[0541] The test compound was administered orally to C57BL/6J mice. At defined time intervals after compound administration, typically a time ranging between 2 and 48 hours, preferably between 4 and 24 hours, mice were sacrificed by decapitation for blood collection and forebrain dissection. Right brain hemispheres were placed in 2 ml Precellys tubes, snap frozen in dry ice and stored at −80° C. Left hemispheres were placed in 2 ml Eppendorf tubes, snap frozen in dry ice and stored at −80° C. until further processing. Blood samples were collected in Sarstedt tubes containing 35 IU of Heparin and kept at 4° C. After centrifugation for 10 min at 3800×g, 4° C., 50 μL of plasma from each sample was transferred to a 1.5 ml Eppendorf tube and stored at −80° C.

[0542] For the preparation of soluble brain protein for the immunoassay the hemispheres were homogenized in ice-cold Cytobuster reagent (71009-Merck Millipore) buffer with protease inhibitor cocktail. After centrifugation for 15 min at 17000×g at 4° C. the supernatants were transferred into polycarbonate tubes (1 ml). The supernatants were cleared by centrifugation for 1 h. at 100000×g, 4° C., and the protein concentrations were determined by using the BCA kit (23227—Pierce, Rockford, Ill.) according to the manufacturer's instructions.

Total Protein O-GlcNAcylation Immunoassay:

[0543] Samples were randomised and 120 μg/ml (25 μl/well) of soluble brain protein was directly coated on a Multi-array 96-well high bind plate (L15XB-3 High bind—Meso Scale Discovery) overnight at 4° C. After washing (3× with PBS-T buffer), the plate was blocked with MSD blocker A solution for 1 h. at room temperature (RT) under agitation. After washing (3× with PBS-T buffer), the plate was incubated with 0.1 μg/ml of a mouse monoclonal antibody directed against O-GlcNAc moieties (RL2; MA1-072—Thermo Scientific) for 1 h. at RT under agitation. For the ECL assay, after washing (3× with PBS-T buffer), 1 μg/ml of a SULFO-TAG™ labeled anti-mouse secondary antibody (Meso Scale Discovery) was added and the plate was incubated for 1 h. at RT under agitation and protected from light. After washing (3× with PBS-T buffer), 150 μl/well of 1× Read Buffer T was added to the plates before reading on a Sector Imager 6000 (Meso Scale Discovery).

Example B03: Pharmaceutical Preparations

[0544] (A) Injection vials: A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate in 3 l of bi-distilled water was adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilized under sterile conditions and sealed under sterile conditions. Each injection vial contained 5 mg of active ingredient.

[0545] (B) Suppositories: A mixture of 20 g of an active ingredient according to the invention was melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contained 20 mg of active ingredient.

[0546] (C) Solution: A solution was prepared from 1 g of an active ingredient according to the invention, 9.38 g of NaH.sub.2PO.sub.4.2 H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12 H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bi-distilled water. The pH was adjusted to 6.8, and the solution was made up to 1 l and sterilized by irradiation. This solution could be used in the form of eye drops.

[0547] (D) Ointment: 500 mg of an active ingredient according to the invention were mixed with 99.5 g of Vaseline under aseptic conditions.

[0548] (E) Tablets: A mixture of 1 kg of an active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was pressed to give tablets in a conventional manner in such a way that each tablet contained 10 mg of active ingredient.

[0549] (F) Coated tablets: Tablets were pressed analogously to EXAMPLE E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

[0550] (G) Capsules: 2 kg of an active ingredient according to the invention were introduced into hard gelatin capsules in a conventional manner in such a way that each capsule contained 20 mg of the active ingredient.

[0551] (H) Ampoules: A solution of 1 kg of an active ingredient according to the invention in 60 l of bi-distilled water was sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contained 10 mg of active ingredient.

[0552] (I′) or (I) Inhalation spray: 14 g of an active ingredient according to the invention were dissolved in 10 l of isotonic NaCl solution, and the solution was transferred into commercially available spray containers with a pump mechanism. The solution could be sprayed into the mouth or nose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14 mg.

Example B04: Protein Binding in Mice Plasma Using Rapid Equilibrium Dialysis

Materials

[0553] CD1 Mice Plasma: pooled male, K2-EDTA (MSEPLEDTA2, Bioreclammation, USA [0554] Phosphate Buffered Saline (1×PBS), pH 7.4, 100 mM (Sigma, Cat No. P4417) [0555] RED inserts (Pierce, Cat No. 9006, 8 kDa MWCO) [0556] Sample Analysis: LC-MS/MS

Methods

[0557] Preparation of DMSO Stock Solution

[0558] From 20 mM DMSO stock solutions of reference and test compounds, 1 mM DMSO intermediate working solutions are prepared. From 1 mM intermediate working solutions, 100 μM DMSO working solutions are prepared.

[0559] Sample Preparation Procedure:

[0560] Selected plasma is brought from −20° C. to 37° C. using water bath before its use. Test solution is prepared by adding the DMSO working solution of the reference or test compound (2 μL; 100 μM) to the selected plasma (198 μL). Spiked plasma (200 μl) is transferred to sample compartment of RED insert placed in the teflon plate. 350 μl of 1×PBS is added in the buffer compartment of RED insert. The teflon plate is covered with sealing mat and agitated at 37° C. for 5 hours at 500 RPM in a Thermomixer. After incubation time, an aliquot of plasma (50 μl) from sample compartment is mixed with blank 1×PBS (50 μl). Similarly, an aliquot of buffer (50 μl) from buffer compartment is mixed with blank plasma (50 μl). Quenching solution (200 μL, acetonitrile containing internal standard tolbutamide (0.5 μg/mL)) is added and the resulting solutions are mixed using a vortex mixer and centrifuged (Eppendorf 5415, 13792 g). Supernatants are analyzed using a Mass Spectrometer. The sample (supernatant fraction, 5 μL) is injected into the LC-MS/MS instrument.

[0561] Chromatographic Conditions: [0562] LC-MS/MS: API 4000 LC-MS/MS [0563] Software: Analyst Version 1.6.1 [0564] Column Phenomenex Synergy 30*4.6*5μ [0565] Column Oven: 40° C. [0566] Mode: ESI Positive [0567] Injection volume: 5 μl [0568] Flow Rate: 1000 μL/mL [0569] Buffer: 0.1% Formic acid in Water [0570] Method: Isocratic Method/Gradient [0571] Composition: A) 0.1% Formic acid in Water [0572] B) 0.1% Formic acid in Methanol

TABLE-US-00004 Time Flow Mobile Mobile (Sec) (μL) Phase A Phase B 0.01 1000 10 90 0.4 1000 10 90 0.8 1000 90 10 1.5 1000 90 10 1.8 1000 10 90 2.5 1000 10 90

Results Calculation

[0573] After the concentration of free drug and total drug has been determined by LCMS/MS, percent plasma protein binding can be calculated as follows:

[00001]$\%\mathrm{fraction}\mathrm{unbound}=\frac{\mathrm{Drug}\mathrm{concentration}\mathrm{in}\mathrm{buffer}\mathrm{after}5\mathrm{hours}}{\mathrm{Drug}\mathrm{concentration}\mathrm{in}\mathrm{plasma}\mathrm{after}5\mathrm{hours}}\times 100$

[0574] Following this protocol, % fraction unbound in plasma from different species can be also measured.

Example B05: Determination of In Vitro Intrinsic Clearance (Cl.SUB.int.-In Vitro) with Mouse, Rat and Human Liver Microsomes

[0575] In this assay, test compounds are incubated with liver microsomes from mouse, rat and human, and rate of disappearance of drug is determined using LC-MS/MS. Conditions used in the assay are summarized below:

Materials

[0576] CD-1 Mice liver microsomes, pooled male (Life Technologies, Cat No. MSMC-PL) (20 mg/ml) [0577] SD Rat liver microsomes, pooled male (Life Technologies, Cat No. RTMCL-PL) (20 mg/ml) [0578] Human liver microsomes, pooled mixed gender (Life Technologies, Cat No. HMMC-PL) (20 mg/ml) [0579] NADPH (SRL Mumbai, Cat No. 99197) [0580] Verapamil (Sigma, Cat No. V4629) [0581] Atenolol (Sigma, Cat No. A7655) [0582] Tolbutamide (Sigma Cat. No. T0891) [0583] Assay buffer: 50 mM potassium phosphate buffer, pH 7.4 [0584] Test & reference compounds: DMSO stock solutions (10 mM concentration) are prepared and stored at room temperature. An intermediate 1 mM solution of test or reference compounds is prepared by mixing 10 μL of 10 mM DMSO stock with 90 μL of DMSO. The contents are mixed vigorously in a vortex mixer.

Methods

[0585] Preparation of Working Solutions of Test and Reference Compounds:

[0586] Working solution (100 μM concentration) is prepared by mixing 10 μL of 1 mM DMSO solution of test or reference compounds with 90 μL of assay buffer. The mixture is mixed vigorously in a vortex mixer. This resulting solution is containing 10% of DMSO. For the metabolic stability assay, 10 μL of this 100 μM working solution is added to a final assay volume of 1 mL, yielding final test concentration of 1 μM and DMSO concentration of 0.1%.

[0587] Metabolic Stability Assay

[0588] Metabolic stability assay is done in a final volume of 1 ml in 50 mM assay buffer, potassium phosphate buffer, pH 7.4. Assay is carried out in duplicates (n=2). A mixture containing 955 μL of assay buffer, 25 μL of liver microsomes and 10 μL of 100 μM test compound solution is pre-incubated for 10 minutes in a water-bath maintained at 37° C. After pre-incubation, reaction is started by adding 10 μL of 100 mM NADPH solution. The solution is mixed and incubated at 37° C. in a water-bath. The final concentration of the different components in the assay is: DMSO 0.1%, test compound 1 μM, liver microsome protein 0.5 mg/ml and NADPH 1 mM.

[0589] Aliquots (100 μL) are taken at various time-points (0, 5, 15, 30 and 45 minutes) and quenched with 100 μL of acetonitrile containing tolbutamide (500 ng/mL) as internal standard. Samples are mixed using a vortex mixer and centrifuged at 4000 rpm for 10 minutes (Eppendorf 5810R, 3000 g). The supernatants (5 μL) are transferred to 96 well plates and submitted for LC-MS/MS analysis.

[0590] Separate incubations in the same assay mixture, but in the absence of NADPH, are run in parallel as control for compound stability. This control assay is carried out in duplicates (n=2). After pre-incubation, addition of NADPH is omitted and replaced with 10 μL of assay buffer. The final assay volume is 1 mL and aliquots (100 μL) are withdrawn and processed for analysis as described for metabolic stability assay.

[0591] LC-MS/MS Conditions (Generic Method) [0592] LC-MS/MS: API Sciex 4000 with Nexera™ UHPLC [0593] Software: Analyst Version 1.6.1 [0594] Column: Phenomenex kinetex C18 50×3.0 mm, 2.6μ [0595] Column Oven: 40° C. [0596] Mode: ESI Positive [0597] Injection volume: 5 μl [0598] Flow Rate: 1000 μL/mL [0599] Buffer: 0.1% Formic acid in Water [0600] Method: Isocratic Method/Gradient [0601] Composition: A) 0.1% Formic acid in Water [0602] B) 0.1% Formic acid in Methanol

TABLE-US-00005 Time Flow Mobile Mobile (Sec) (μL) Phase A Phase B 0.01 1000 10 90 0.4 1000 10 90 1 1000 90 10 1.5 1000 90 10 1.8 1000 10 90 3 1000 10 90

Results Calculation

[0603] From LC-MS/MS data, amount of drug remaining at different time points was determined (% PCR). The logarithm of % PCR was plotted against time to get the slope value. From the slope value, in vitro T.sub.1/2 was determined. In vitro intrinsic clearance (Cl.sub.int) was calculated using the following formulae:

[00002]${\mathrm{CL}}_{\mathrm{int}}=\frac{0.693}{\mathrm{In}\mathrm{vitro}{t}_{1/2}}\times \frac{\mathrm{Volume}\mathrm{of}\mathrm{incubation}}{\mathrm{mg}\mathrm{of}\mathrm{microsomal}\mathrm{protein}}$$\mathrm{In}\mathrm{vitro}{t}_{1/2}=\frac{0.693}{K_{\mathrm{el}}}$

[0604] Where K.sub.el is Elimination Constant (slope)

[0605] Methods for treating the diseases mentioned in this specification, such as tauopathy, by administering one or more of the compounds of the present invention to a patient in need thereof are also object of this invention.

[0606] If chemical bonds in the structures above are drawn as follows: or .

they indicate a defined preferred, i.e. R or S, stereochemistry at at least one of the atoms to which they are attached to.

[0607] This is exemplified below, wherein the structure

##STR00626##

is representing preferably one of the two possible enantiomers,

##STR00627##