Linear glycosidase inhibitors

Abstract

Compounds of formula (I), wherein A, R, W, Q, L, n and m 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) ##STR00186## wherein R is straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH; W is CH or N; L is CONR.sup.3′, NR.sup.3′CO, SO.sub.2NR.sup.3′, NR.sup.3′SO.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′, NR.sup.3′, NR.sup.3′COCH.sub.2, CH.sub.2NR.sup.3′CO, NR.sup.3′SO.sub.2CH.sub.2, CH.sub.2NR.sup.3′SO.sub.2, O, OCH.sub.2, CH.sub.2O, S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00187## A denotes one of the following groups: ##STR00188## X is N or CR′″; 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, ##STR00189## 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: ##STR00190## or R′″, R″″ independently denote one of the following groups: ##STR00191## R.sup.3, R.sup.4 denote each independently H or a straight chain or branched alkyl group having 1 to 12 carbon atoms; Q denotes one of the following groups: ##STR00192## ##STR00193## ##STR00194## Y is N or CR′″; Y.sup.1 and Y.sup.2 is each independently CH.sub.2, NR.sup.3, O, S, SO, SO.sub.2 or S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00195## Z.sup.1 is S, O, NR.sup.3; Z.sup.2, Z.sup.3 independently denote CR.sup.5 or N; Z.sup.4 is N, CH, CON, COCH; Z.sup.5 is NR.sup.8, CHR.sup.5, S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00196## Z.sup.6 is CH.sub.2, CO, SO.sub.2, S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00197## 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, O and wherein 1 to 5 hydrogen atoms may be replaced by Hal; R.sup.5, R.sup.6, R.sup.7 independently denote H, Hal, CN, 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 ##STR00198## 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: ##STR00199## or R.sup.5, R.sup.6, R.sup.7 denote Ar, Het or Cyc or one of the following groups: ##STR00200## 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 ##STR00201## 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: ##STR00202## or R.sup.8 denote one of the following groups: ##STR00203## Hal denotes F, Cl, Br or I; Het denotes a saturated, unsaturated or aromatic ring, being monocyclic or bicyclic or fused-bicyclic 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 bicyclic 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 or Hal or OH; m and n denote independently from one another 0, 1, 2 or 3, t and q denote independently from one another 0, 1, 2 or 3, with t+q≥1; or a pharmaceutically usable derivative, solvate, salt, prodrug, tautomer, enantiomer, racemate, stereoisomer, compound of formula I wherein one or more H atoms are replaced by D (deuterium), or a mixture thereof.

2. A compound chosen from the group consisting of formula Ia and Ib: ##STR00204## wherein A, R, W, Q, L, n and m have the meaning given in claim 1.

3. A mixture comprising compounds Ia and Ib according to claim 2, having identical groups A, R, W, Q, L, n and m in equal or unequal amounts.

4. A compound of formula I according to claim 1, wherein R is methyl.

5. A compound of formula I according to claim 1, wherein the group L denotes CONH, NHCO, CONHCH.sub.2, CH.sub.2CONH, NH, NHCOCH.sub.2, CH.sub.2NHCO, O, OCH.sub.2, CH.sub.2O, S(O)(NR.sup.3′), N(SO)R.sup.3′, ##STR00205##

6. A compound of formula I according to claim 1, wherein Q denotes one of the following groups: ##STR00206## ##STR00207## ##STR00208## ##STR00209## wherein T, Y, Z.sup.5, Z.sup.6, R′″, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 have the meaning given in claim 1.

7. A compound of formula I according to claim 1, wherein R.sup.5, R.sup.6, R.sup.7 are independently selected from H, 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, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, alkoxy (Oalkyl), hydroxyalkylene, alkoxyalkylene, COOH, COOalkyl, CONHalkyl, CONH.sub.2, CON(CH.sub.3).sub.2, NHCOalkyl, 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, ##STR00210## wherein t+q is 2 or 3, Z.sup.7, R.sup.3, R.sup.4 and R.sup.3′ have the meaning given in claim 1.

8. A compound of formula I according to claim 1, wherein m and n simultaneously denote 1.

9. A compound according to claim 1, selected from the following group consisting of: TABLE-US-00005 Example No Structure Chirality 17 Racemic 18 Racemic 19 Racemic 20 Racemic 21 Racemic 22 Racemic 23 Racemic 24 Racemic 25 Racemic 26 Racemic 27 Racemic 28 Chiral SFC, method C, first eluting 29 Racemic 30 Racemic 31 Chiral SFC, method B, first eluting 32 Racemic 33 Racemic 34 Racemic 35 Racemic 36 Racemic 37 Racemic 38 Racemic 39 Chiral SFC, method C, second eluting 40 41 or a pharmaceutically usable derivative, solvate, salt, tautomer, enantiomer, racemate, stereoisomer, or mixture thereof in all ratios.

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

Description

EXPERIMENTAL PART

(1) The compounds according to Formula (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) and related formulae obtained as a racemic mixture can be separated to provide an enantiomerically enriched mixture or a pure enantiomer.

(2) 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.

(3) The HPLC, MS and NMR data provided in the examples described below are obtained as followed:

(4) .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).

(5) LCMS Analysis Condition:

(6) Instrument name: Agilent Technologies 1290 infinity 11.

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

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

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

(10) HPLC Analysis Condition:

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

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

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

(14) Chiral HPLC Analysis Condition:

(15) Instrument name: Agilent 1260 infinity II

(16) Method A: Mobile Phase: 0.1% DEA in n-Hexane: EtOH: 60:40; flow rate: 1.0 mL/min; column: Chiralcell OD-H (250×4.6 mm, 5 μm).

(17) Chiral SFC Analysis Condition:

(18) Instrument name: THAR-SFC 80 and THAR-SFC 200 (analytical)

(19) Ratio between CO.sub.2 and co-solvent is ranging between 50:50 and 90:10

(20) Method A: Mobile Phase: 20 mM ammonia in methanol, flow rate: 4 mL/min; column: YMC Cellulose C (250×4.6 mm, 5 μm).

(21) Method B: Mobile Phase: 20 mM ammonia in methanol, flow rate: 3 mL/min; column: Chiralpak IA (250×4.6 mm, 5 μm).

(22) Method C: Mobile Phase: 20 mM ammonia in IPA, flow rate: 3 mL/min; column: Lux A1 (250×4.6 mm, 5 μm).

(23) Prep-HPLC Analysis Condition:

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

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

(26) Chiral Preparative SFC analysis condition:

(27) Instrument name: THAR-SFC 80, THAR-SFC 200 and Pic SFC 10-150

(28) Ratio between CO.sub.2 and co-solvent is ranging between 50:50 and 90:10

(29) Method A: Mobile Phase: 20 mM ammonia in methanol, flow rate: 5 mL/min; column: YMC Cellulose C (250×30 mm, 5 μm).

(30) Method B: Mobile Phase: 20 mM ammonia in methanol, flow rate: 5 mL/min; column: Chiralpak IA (250×30 mm, 5 μm).

(31) Method C: Mobile Phase: 20 mM ammonia in IPA; flow rate: 5 mL/min; column: Lux A1 (250×30 mm, 5 μm).

(32) The microwave chemistry was performed on a single mode microwave reactor Initiator™ Sixty from Biotage.

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

Intermediate 1: (1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine)

(34) ##STR00087##

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

(35) ##STR00088##

(36) 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), pet 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

(37) ##STR00089##

(38) 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 1N NaOH solution (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

(39) ##STR00090##

(40) To a stirred solution of 1, 4-dibromo-2-(2-bromoethoxy)benzene (946 g, 2.64 mol) in dry THE (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 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

(41) ##STR00091##

(42) To a stirred solution of 2, 3-dihydrobenzofuran-6-carbaldehyde (404 g, 2.73 mol) in dry THE (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.4C 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 pet 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) (alkene), 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

(43) ##STR00092##

(44) 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 it 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-Chloro), Rt. 4.2 min, 77.2% (Max).

Step 6: tert-butyl 4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate

(45) ##STR00093##

(46) To a stirred solution of tert-butyl piperazine-1-carboxylate (562 g, 3.02 mol) in DMF (2000 mL), 6-(1-chloroethyl)-2, 3-dihydrobenzofuran (220 g, 1.21 mol) in DMF (400 mL) was added and the resulting mixture was stirred at 50° C. for 20 h. After completion of the reaction (monitored by TLC), the mixture was diluted with water (500 mL) and extracted with EtOAc (2×1000 mL). The combined organic layer was washed with brine (500 mL), dried over Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash chromatography (silica gel: 60-120 mesh, eluent: 22% EtOAc in pet ether) to afford the title compound. Yield: 35% (210 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.13 (d, J=7.2 Hz, 1H), 6.73-6.68 (m, 2H), 4.49 (q, J=8.8 Hz, 2H), 3.33-3.26 (m, 3H), 3.12 (t, J=8.4 Hz, 2H), 2.33-2.22 (m, 4H), 1.45 (s, 9H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 333.0 (M+H), Rt. 3.2 min, 71.8% (Max).

Step 7: 1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine

(47) ##STR00094##

(48) To a stirred solution of tert-butyl 4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl) piperazine-1-carboxylate (202 g, 608.4 mmol) in 1, 4 dioxane (300 mL), HCl solution in dioxane (1000 mL, 4M) was added dropwise at 0° C. and stirred overnight. After completion of the reaction was monitored by HPLC (Method A). The reaction mixture was then filtered and washed with 1, 4 dioxane (200 ml), EtOAc (200 mL), acetonitrile (200 mL) and diethyl ether (200 mL). The obtained solid was dissolved in water (350 mL) and washed with EtOAc (3×300 mL). The aqueous layer was basified with 5N NaOH solution (300 mL) until pH=13 and extracted with EtOAc (2×300 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (silica gel: 60-120 mesh, eluent: 10% methanol in DCM) to afford the title compound. Yield: 73% (103 g, pale brown gummy solid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.12 (d, J=9.6 Hz, 1H), 6.73-6.67 (m, 2H), 4.48 (t, J=8.7 Hz, 2H), 3.26 (q, J=6.6 Hz, 1H), 3.12-3.09 (m, 2H), 2.64-2.61 (m, 4H), 2.26-2.20 (m, 4H), 1.21 (d, J=6.6 Hz, 3H). LCMS: (Method A) 233.0 (M+H), Rt. 1.7 min. 92.1% (Max).

Intermediate 2: (S)-1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine or (R)-1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine

(49) ##STR00095##

(50) To a stirred solution of intermediate 1 (102 g, 439.7 mmol) in 5% water in methanol (1236 mL, 12V), D-di-p-anisoyltartaric acid (92.86 g, 219.8 mmol) was added at RT and refluxed for 30 min. In first instance all the material was dissolved and then salt was precipitated as a white solid. The mixture was stirred at RT overnight before the solid was collected by filtration and washed twice with 5% of water in methanol (2×1.0 L). The optical purities of the solid was 87% ee. The solid was refluxed in methanol containing 5% of water 12 V (1.2 L). The mixture was allowed to cool to RT and stirred overnight before the solid was collected by filtration and washed twice with 5% of water in methanol (2×1.0 L). The optical purity of the solid was 94% ee. The solid was again dissolved in refluxing methanol containing 5% of water (1.2 L). The mixture was allowed to cool to RT and stirred overnight before the solid was collected by filtration and washed with 5% of water in methanol (1.2 L). The optical purity of the solid was 97.94% ee (enantiomeric purity: 98.9%). The latter was dried in vacuum to furnish the title compound as D-di-p-anisoyltartaric acid salt (1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine hemi((2R,3R)-2,3-bis((4-methoxybenzoyl)oxy)succinate)). Yield: 33% (65 g, off-white solid). The above solid was dissolved in water (100 mL) and the resulting solution was basified (pH=14) using 5 N NaOH solution (200 mL). The compound was extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine solution (500 mL), dried over anhydrous Na.sub.2SO.sub.4. It was evaporated under vacuum to give the title compound. Yield: 59% (30.5 g, pale brown gummy solid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.12 (d, J=7.2 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.66 (s, 1H), 4.49 (t, J=8.7 Hz, 2H), 3.30 (q, J=6.6 Hz, 1H), 3.12 (t, J=8.6 Hz, 2H), 2.65-2.62 (m, 4H), 2.20-2.17 (m, 4H), 1.20 (d, J=6.6 Hz, 3H). LCMS: (Method A) 233.0 (M+H), Rt. 1.6 min, 84.2% (Max). HPLC: (Method A) Rt. 1.6 min, 85.8% (Max). Chiral HPLC: (Method A) Rt. 3.0 min, 97.8% (Max).

Intermediate 3: 5-(1-(piperazin-1-yl)ethyl)benzo[d]thiazole

(51) ##STR00096##

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

(52) ##STR00097##

(53) To a degassed solution of 5-bromo benzothiazole (Combi-Blocks, 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 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 (12 L) solution 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 and the solids were washed with MTBE (4 L). The combined filtrate was concentrated under vacuum and the residue was dissolved in EtOAc (2.5 L) followed by charcoal (35 g) was added to the resulting mixture. 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

(54) ##STR00098##

(55) 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 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

(56) ##STR00099##

(57) 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 and the 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).

Step 4: tert-butyl 4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazine-1-carboxylate

(58) ##STR00100##

(59) To a stirred solution of tert-butyl piperazine-1-carboxylate (522 g, 2.97 mol) and TEA (2.5 L, 17.34 mol) in DMF (2 L), (5-(1-chloroethyl)benzo[d]thiazole) (488 g, 2.48 mol) in DMF (3 L) was added dropwise at RT under N.sub.2 atm and the reaction mixture was heated to 60° C. for 24 h. Completion of the reaction was monitored by TLC and the mixture was then cooled to RT. To the resulting mixture, water (10 L) was added and the aqueous layer was extracted with EtOAc (6×2 L). The combined organic layer was washed with brine (2.5 L), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (silica gel: 60-120 mesh, eluent: 40% EtOAc in pet-ether) to afford the title compound. Yield: 81% (700 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 3.45 (q, J=6.8 Hz, 1H), 3.34-3.29 (m, 4H), 2.37-2.27 (m, 4H), 1.41-1.18 (m, 12H). LCMS: (Method A) 348.1 (M+H), Rt. 1.6 min, 85.6% (Max). HPLC: (Method A) Rt. 2.89 min, 81.5% (Max).

Step 5: 5-(1-(piperazin-1-yl)ethyl)benzo[d]thiazole

(60) ##STR00101##

(61) To a stirred solution of tert-butyl 4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazine-1-carboxylate (700 g, 2.02 mol) in 1, 4-dioxane (3 L), HCl solution in dioxane (3.50 L, 4M) was added dropwise at 0° C. and the resulting solution was stirred at RT for 6 h. After completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum and the resulting crude material was triturated with EtOAc (1 L) and filtrated. This procedure was repeated a second time (1 L). The hydrochloride salt was dissolved in water (2.5 L) and aqueous layer was washed with EtOAc (3×2 L) and DCM (3×2 L). The resulting aqueous layer was basified with 6N NaOH (pH ˜12) and extracted with EtOAc (3×2 L). The combined organic layer was washed with brine (500 mL), water (500 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound. Yield: 70% (350 g, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.46 (dd, J=8.4, 1.2 Hz, 1H), 3.33 (m, 1H), 3.58 (q, J=6.8 Hz, 1H), 2.71-2.68 (m, 4H), 2.37-2.27 (m, 4H), 1.19 (d, J=6.8 Hz, 3H). LCMS: (Method A) 248.1 (M+H), Rt. 0.88 min, 97.3% (Max). HPLC: (Method A) Rt. 1.6 min, 99.1% (Max).

Intermediate 4: 6-(1-(piperazin-1-yl)ethyl)quinoxaline

(62) ##STR00102##

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

(63) ##STR00103##

(64) To a degassed stirred solution of 6-bromo quinoxaline (2.0 g, 9.50 mmol) in toluene (20 mL), 1-ethoxy vinyl 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 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 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 (Biotage Isolera, 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

(65) ##STR00104##

(66) 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 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

(67) ##STR00105##

(68) 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).

Step 4: tert-butyl 4-(1-(quinoxalin-6-yl) ethyl) piperazine-1-carboxylate

(69) ##STR00106##

(70) To a stirred solution of 1-Boc piperazine (3.8 g, 20.83 mmol) in dry DMF (40 mL), TEA (8.7 mL, 62.4 mmol) and 6-(1-chloroethyl) quinoxaline (4 g, 20.83 mmol) were added at RT and stirred overnight at 90° C. Completion of the reaction was monitored by TLC. The reaction mixture was cooled to RT and concentrated under vacuum. To the resulting crude mixture, water (50 mL) was added and the aqueous layer was extracted with DCM (150 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 45-50% EtOAc in hexane) to afford the title compound. Yield: 46% (3.5 g, brown solid). LCMS: (Method A) 343.2 (M+H), Rt. 2.5 min, 75.3% (Max).

Step 5: 6-(1-(piperazin-1-yl) ethyl) quinoxaline Hydrochloride

(71) ##STR00107##

(72) To a stirred solution of tert-butyl 4-(1-(quinoxalin-6-yl) ethyl) piperazine-1-carboxylate (3.5 g, 10.23 mmol) in methanol (5 mL), HCl in dioxane (35 mL, 10 V, 4M) was added at 0° C. and stirred at RT for 2 h. Completion of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The resulting crude material was triturated with diethyl ether (15 mL) to afford the title compound. Yield: 87% (2.1 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.94 (d, J=6.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 3.85 (d, J=6.8 Hz, 1H), 3.54 (t, J=5.2 Hz, 2H), 3.16 (d, J=3.6 Hz, 2H), 3.06-2.96 (m, 1H), 2.92-3.02 (m, 1H), 2.67 (s, 2H), 2.55-2.58 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 243.3 (M+H), Rt. 1.3 min, 95.0% (Max).

Intermediate 5: 2-methyl-5-(1-(piperazin-1-yl) ethyl)benzo[d]thiazole

(73) ##STR00108##

Step 1: 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-one

(74) ##STR00109##

(75) To a degassed solution of 5-bromo-2-methylbenzo[d]thiazole (10 g, 43.85 mmol, Combi block) in dry toluene (40 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (3.07 g, 4.3 mmol) followed by 1-ethoxyvinyl tributyltin (16.2 mL, 48.2 mmol) were added and the reaction mixture was heated at 90° C. for 16 h. Completion of the reaction was monitored by TLC. The mixture was then cooled to 0° C. and filtered through celite. The resulting filtrate was evaporated under vacuum, and then 6N HCl solution (80 mL) was added to the crude material. The reaction mixture was stirred at RT for 1 h, then neutralized by using NaHCO.sub.3 and the aqueous layer was extracted with EtOAc (2×80 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash column chromatography (Biotage Isolera, eluent: 60-80% EtOAc in hexane). Yield: 72% (6 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.48 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 2.85 (s, 3H), 2.67 (s, 3H). LCMS: (Method A) 192.3 (M+H), Rt. 2.9 min, 96.8% (Max).

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

(76) ##STR00110##

(77) To a stirred solution of 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-one (6 g, 31.31 mmol) in methanol (30 mL), NaBH.sub.4 (2.37 g, 62.74 mmol) 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 and evaporated under vacuum. To the resulting mixture, water (10 mL) was added and was extracted with EtOAc (2×60 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 70-90% EtOAc in hexane). Yield: 87% (5.3 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.94 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.38 (dd, J=8.2, 1.2 Hz, 1H), 5.28 (d, J=4.4 Hz, 1H), 4.90-4.80 (m, 1H), 2.79 (s, 3H), 1.38 (d, J=6.4 Hz, 3H). LCMS: (Method A) 194.2 (M+H), Rt. 2.5 min, 98.9% (Max).

Step 3: 5-(1-chloroethyl)-2-methylbenzo[d]thiazole

(78) ##STR00111##

(79) To a stirred solution of 1-(2-methylbenzo[d]thiazol-5-yl) ethan-1-ol (5.3 g, 27.4 mmol) in dry DCM (50 mL), thionyl chloride (4 mL, 54.8 mmol) was added drop wise at 0° C. and stirred at 25° C. for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was then concentrated under vacuum and co-distilled with toluene (10 mL). The resulting crude material was dried under high vacuum to afford the title compound which was used in the next step without further purification. Yield: 5.5 g (crude), brown oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.05-8.01 (m, 2H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 5.51 (q, J=6.8 Hz, 1H), 2.81 (s, 3H), 1.86 (d, J=6.8 Hz, 3H). LCMS: (Method A) 212.2 (M+H), Rt. 4.26 min. 36.1% (Max).

Step 4:2-methyl-5-(1-(piperazin-1-yl)ethyl)benzo[d]thiazole

(80) ##STR00112##

(81) To a stirred solution of piperazine (13.6 g, 15.9 mmol) in dry DCM (80 mL), 5-(1-chloroethyl)-2-methylbenzo[d]thiazole (4.2 g, 19.8 mmol) was added dropwise over a period of 20 min and the reaction mixture was stirred at RT overnight. After completion of the reaction (monitored by TLC), water (50 mL) was added to the resulting mixture and stirred for 10 min. The organic layer was separated, washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 18-20% methanol in DCM) to afford the title compound. Yield: 16% (870 mg, pale brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.32 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.80 (s, 1H), 7.34 (d, J=8.8 Hz, 1H), 3.52-3.48 (m, 1H), 2.78 (s, 3H), 2.70 (t, J=6.0 Hz, 4H), 2.44-2.24 (m, 4H), 1.33 (d, J=8.8 Hz, 3H). LCMS: (Method A) 262.2 (M+H), Rt. 1.8 min, 97.3% (Max).

Intermediate 6: 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine

(82) ##STR00113##

Step 1:1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-ol

(83) ##STR00114##

(84) To a stirred solution of 3, 4-methylenedioxy acetophenone (50.0 g, 0.31 mol, Alfa aesar) in dry methanol (1000 mL), NaBH.sub.4 (13.83 g, 0.37 mol, Loba chemie) was added slowly at 0° C. and the reaction mixture was stirred at RT for 1 h. Completion of the reaction was monitored by TLC and the mixture was concentrated under vacuum. The resulting material was dissolved in EtOAc, the organic layer was washed with water, brine and dried over anhydrous Na.sub.2SO.sub.4. The organic layer was evaporated under vacuum and the resulting crude material was forwarded to the next step without any further purification. Yield: 98% (50.0 g, colorless liquid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 6.89 (s, 1H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J=8.0 Hz, 1H), 1.46 (d, J=8.0 Hz, 3H). LCMS: (Method B) 149.0 (M−H.sub.2O+H); Rt. 2.5 min, 98.6% (Max). HPLC: (Method A) RT 2.4 min, 99.5% (Max).

Step 2: 5-(1-Chloroethyl)benzo[d][1,3]dioxole

(85) ##STR00115##

(86) To a stirred solution of 1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-ol (50.0 g, 0.3 mol) in DCM (400 mL), thionyl chloride was added slowly at 0° C. and continued at RT for 2 h. After completion of the reaction, the mixture was concentrated under vacuum and co-distilled with DCM (100 mL). The resulting crude material was forwarded to the next step as such without further purification. Yield: 64% (35.0 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.06 (d, J=4.0 Hz, 1H), 6.93 (d, J=8.0 Hz. 1H), 6.86 (d, J=8.0 Hz, 1H), 6.01 (s, 2H), 2.49 (q, J=8.9 Hz, 1H), 1.74 (d, J=8.9 Hz, 3H). LCMS: (Method B) 149.0 (M−Cl+H); Rt. 3.7 min, 80.2% (Max).

Step 3: t-Butyl 4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate

(87) ##STR00116##

(88) To a stirred solution of 5-(1-Chloroethyl)benzo[d][1,3]dioxole (35.0 g, 0.19 mol) and Boc-piperizine (35.26 g, 0.19 mol) in MeCN (350 mL), DIPEA (98.23 g, 0.76 mol) was added slowly at 0° C. and stirred for 48 h at RT. After completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum and EtOAc was added to the resulting mixture. The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 30-50% EtOAc in hexane) to afford the title compound. Yield: 44% (28 g, colorless gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.85-6.82 (m, 2H), 6.74-6.71 (m, 1H), 5.98 (d, J=1.6 Hz, 2H), 3.37-3.36 (m, 1H), 3.27 (m, 4H), 2.28-2.21 (m, 4H), 1.37 (s, 9H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 335.2 (M+H); Rt. 3.1 min, 93.2% (Max). HPLC: (Method A) Rt. 3.1 min, 95.0% (Max).

Step 4: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine Hydrochloride

(89) ##STR00117##

(90) To a stirred solution of t-Butyl 4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate (48 g, 0.143 mol) in dry methanol (250 mL), HCl solution in dioxane (480 mL, 4M) was added at 0° C. and the reaction mixture was stirred at RT for 2 h. After completion the mixture was concentrated under vacuum and the resulting crude material was purified by recrystallization with diethyl ether to afford the title compound. Yield: 90% (38 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.09 (m, 1H), 9.43 (m, 1H), 9.20 (m, 1H), 7.30 (s, 1H), 7.07-7.02 (m, 2H), 6.08 (s, 2H), 4.55 (m, 1H), 3.82 (m, 1H), 3.50-3.39 (m, 3H), 3.17-2.96 (m, 2H), 1.68 (s, 3H). LCMS: (Method B) 235.0 (M+H); Rt. 4.2 min, 98.6% (Max).

Intermediate 7: methyl 1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidine-4-carboxylate

(91) ##STR00118##

(92) To a stirred solution of methyl piperidine-4-carboxylate (2.35 g, 16.40 mmol), TEA (4.6 mL, 32.70 mmol) in DMF (40 mL), 6-(1-chloroethyl)-2,3-dihydrobenzofuran (2.0 g, 10.90 mmol, synthesis described in intermediate 1, steps 1 to 5) was added at RT and stirred overnight at 70° C. Completion of the reaction was monitored by TLC and then the reaction mixture was evaporated at 50° C. under vacuum. To the resulting mixture, water (100 mL) was added and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 50% EtOAc in pet ether) to afford the title compound. Yield: 31% (1.0 g, brown gummy solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.12 (d, J=7.2 Hz, 1H), 6.78 (d, J=7.2 Hz, 2H), 4.58 (t, J=8.8 Hz, 2H), 3.67 (s, 3H), 3.38-3.36 (m, 1H), 3.20 (t, J=8.8 Hz, 2H), 3.02-2.97 (m, 1H), 2.84-2.81 (m, 1H), 2.27-2.22 (m, 1H), 2.02-1.89 (m, 3H), 1.82-1.68 (m, 3H), 1.35 (d, J=6.8 Hz, 3H). LCMS: (Method A) 290.0 (M+H), Rt. 2.0 min, 81.6% (Max).

Intermediate 8: 1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-ol

(93) ##STR00119##

(94) To a stirred solution of piperidin-4-ol (3 g, 29.6 mmol) in DMF (20 mL), 6-(1-chloroethyl)-2, 3-dihydrobenzofuran (5.9 g, 32.6 mmol, synthesis described in intermediate 1, steps 1 to 5) followed by TEA (12.5 mL, 88.9 mmol) were added and the reaction mixture was stirred overnight at RT. Completion of the reaction was monitored by TLC and the mixture was then evaporated under vacuum. To the resulting mixture, water (10 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 100% EtOAc) to afford the title compound. Yield: 25% (1.8 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.13 (d, J=7.2 Hz, 1H), 6.72 (d, J=4.8 Hz, 1H), 6.67 (s, 1H), 4.79 (d, J=4.0 Hz, 1H), 4.50-4.48 (m, 2H), 3.80-3.74 (m, 2H), 3.59-3.52 (m, 1H), 3.33-3.10 (m, 4H), 3.01-2.97 (m, 2H), 2.71-2.68 (m, 1H), 2.00-1.89 (m, 2H), 1.32-1.21 (m, 3H). LCMS: (Method A) 248.2 (M+H), Rt. 1.9 min, 84.9% (Max).

Intermediate 9: 1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-amine

(95) ##STR00120##

Step 1: tert-butyl(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)carbamate

(96) ##STR00121##

(97) To a stirred solution of tert-butyl piperidin-4-ylcarbamate (1 g, 4.9 mmol) in MeCN (50 mL), 6-(1-chloroethyl)-2,3-dihydrobenzofuran (1.09 g, 5.9 mmol, synthesis described in intermediate 1, steps 1 to 5) followed by TEA (2.10 mL, 14.9 mmol) were added at RT and heated overnight at 50° C. Completion of the reaction was monitored by TLC, then the reaction mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 5% methanol in EtOAc) to afford the title compound. Yield: 68% (1.5 g, yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.13 (d, J=7.2 Hz, 1H), 6.72-6.67 (m, 2H), 6.67 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.29-3.17 (m, 1H), 3.15-3.11 (m, 1H), 3.14 (t, J=8.4 Hz, 2H), 2.90-2.87 (m, 1H), 2.67-2.51 (m, 1H), 2.00-1.86 (m, 2H), 1.80-1.58 (m, 2H), 1.40 (s, 9H), 1.23-1.20 (m, 1H), 1.17 (d, J=7.2 Hz, 3H). LCMS: (Method A) 347.3 (M+H), Rt. 3.0 min, 95.4% (Max).

Step 2: 1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-amine

(98) ##STR00122##

(99) To a stirred solution of tert-butyl (1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)carbamate (1.2 g, 3.4 mmol) in 1, 4-dioxane (20 mL), HCl solution in dioxane (3.4 mL, 13.8 mmol, 4M) was added at 0° C. and stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the mixture was evaporated under vacuum and the resulting solid was triturated with EtOAC, hexane and diethyl ether. Yield: 70% (600 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.33 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.61 (t, J=8.8 Hz, 2H), 4.43-4.41 (m, 1H), 3.88 (s, 1H), 3.43-3.41 (m, 2H), 3.25 (t, J=8.4 Hz, 2H), 3.09-3.08 (m, 1H), 2.97-2.96 (m, 1H), 2.35-2.29 (m, 1H), 2.22-2.18 (m, 2H), 2.02-1.97 (m, 1H), 1.79 (d, J=6.8 Hz, 3H). LCMS: (Method A) 247.2 (M+H), Rt. 1.6 min, 95.3% (Max). HPLC: (Method A), Rt. 1.6 min, 96.6% (Max).

Intermediate 10: 3-(piperidin-4-yloxy)pyridine Hydrochloride

(100) ##STR00123##

Step-1: tert-butyl 4-(pyridin-3-yloxy)piperidine-1-carboxylate

(101) ##STR00124##

(102) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.23 g, 21.0 mmol) in THE (30 mL), 3-hydroxypyridine (2.0 g, 21.0 mmol), TPP (6.61 g, 25.2 mmol) followed by DTAD (6.0 g, 25.2 mmol) were added and the reaction mixture was stirred overnight at 55° C. After completion of the reaction (monitored by TLC), water was added to the resulting mixture and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 53% EtOAc in hexane); Yield: 35% (2.0 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.29 (d, J=7.6 Hz, 1H), 7.29-7.24 (m, 2H), 4.53 (t, J=4.8 Hz, 1H), 4.50-3.69 (m, 2H), 3.41-3.32 (m, 2H), 1.96-1.77 (m, 4H), 1.49 (d, J=3.2 Hz, 9H). LCMS: (Method A) 279.3 (M+H), Rt. 2.0 min, 74.9% (Max).

Step 2: 3-(piperidin-4-yloxy)pyridine Hydrochloride

(103) ##STR00125##

(104) To a stirred solution of tert-butyl 4-(pyridin-3-yloxy) piperidine-1-carboxylate (1.9 g, 6.8 mmol) in 1, 4-dioxane (19 mL, 10 V) at 0° C., HCl solution in dioxane (10.0 ml, 4M) was added dropwise and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the mixture was concentrated completely and the resulting mixture was triturated with EtOAc to afford the title compound. Yield: 89% (1.5 g, pale yellow solid). LCMS: (Method A) 179.2 (M+H), Rt. 2.6 min. 89.2 (Max).

Examples 1 and 16: (S)-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1-(2-methoxyethyl)-1H-pyrazol-4-yl)methanone and (S)-(4-(1-(2,3-dihydrobenzofuran-6-VI)ethyl)piperazin-1-yl)(1-(2-methoxyethyl)-1H-pyrazol-4-yl)methanone

(105) ##STR00126##

(106) To a stirred solution of example 2 (500 mg, 1.53 mmol) in MeCN (15 mL), 1-bromo-2-methoxyethane (253 mg, 1.84 mmol) followed by K.sub.2CO.sub.3 (634 mg, 4.60 mmol) were added and refluxed overnight at 70° C. Completion of the reaction was monitored by TLC and the reaction mixture was then evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 100% EtOAc) to afford the title compound as racemic form. The mixture of enantiomers was separated by SFC Mobile Phase: 20 mM ammonia in methanol, column: YMC Cellulose C (Method A). The first and second eluting fractions were concentrated to afford the title compounds.

(107) Analysis of second eluting fraction (example 1): Yield: 23% (42.26 mg, yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (s, 1H), 7.64 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.25 (t, J=5.2 Hz, 2H), 3.68 (t, J=5.2 Hz, 2H), 3.61-3.56 (m, 4H), 3.41-3.38 (m, 1H), 3.22 (s, 3H), 3.14 (t, J=8.8 Hz, 2H), 2.41-2.30 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 385.2 (M+H), Rt. 2.2 min, 98.7% (Max). HPLC: (Method A), Rt. 2.2 min, 98.7% (Max). Chiral SFC: (Method A) Rt. 4.1 min, 99.2% (Max).

(108) Analysis of first eluting fraction (example 16): Yield: 25% (46.82 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (s, 1H), 7.64 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.25 (t, J=5.2 Hz, 2H), 3.68 (t, J=5.2 Hz, 2H), 3.61-3.56 (m, 4H), 3.36 (q, J=6.8 Hz, 1H), 3.22 (s, 3H), 3.13 (t, J=8.8 Hz, 2H), 2.38-2.33 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 385.2 (M+H), Rt. 2.2 min, 98.3% (Max). HPLC: (Method A), Rt. 2.2 min, 97.9% (Max). Chiral SFC: (Method A) Rt. 2.7 min, 99.3% (Max).

Example 2: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1H-pyrazol-4-yl)methanone

(109) ##STR00127##

(110) To a stirred solution of 1H-pyrazole-4-carboxylic acid (58 mg, 0.51 mmol) in DMF (1 mL, 20 V), TEA (0.18 mL, 1.29 mmol), T.sub.3P (0.4 mL, 0.65 mmol, 50% in EtOAc) and intermediate 1 (100 mg, 0.43 mmol) were added and the reaction mixture was stirred overnight at RT. After completion of the reaction (monitored by TLC), the mixture was quenched with ice cold water and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 1-2% methanol in EtOAc) to afford the title compound. Yield: 21% (30 mg, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.17 (s, 1H), 8.04 (s, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.76-6.71 (m, 2H), 4.50 (t, J=8.4 Hz, 2H), 3.59 (bs, 4H), 3.18-3.13 (m, 2H), 2.40-2.29 (m, 4H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 327.2 (M+H), Rt. 1.9 min, 96.9% (Max). HPLC: (Method A) Rt. 2.0 min, 97.3% (Max).

Example 3: (S)-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone or (R)-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone

(111) ##STR00128##

(112) To a stirred solution of intermediate 2 (200 mg, 0.86 mmol) in DMF (10 mL), 1-methyl-1H-pyrazole-4-carboxylic acid (130 mg, 1.03 mmol), TEA (0.4 mL, 2.58 mmol) followed by T.sub.3P (0.5 mL, 1.72 mmol) were added and stirred overnight at RT. Completion of the reaction was monitored by TLC and the reaction mixture was then evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 4% methanol in EtOAc) to afford the title compound. Yield: 10% (28.20 mg, brown gummy oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.00 (s, 1H), 7.60 (s, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 4.50 (t, J=8.4 Hz, 2H), 3.82 (s, 3H), 3.61-3.52 (m, 5H), 3.13 (t, J=8.4 Hz, 2H), 2.41-2.36 (m, 4H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method B) 341.2 (M+H), Rt. 4.9 min, 94.2% (Max). HPLC: (Method B), Rt. 4.2 min, 94.0% (Max).

Example 4: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1H-indazol-5-yl)methanone

(113) ##STR00129##

(114) To the stirred solution of intermediate 1 (0.2 g, 0.86 mmol) and 1H-indazole-5-carboxylic acid (0.16 g, 1.03 mmol) in DCM (5 mL), TEA (0.18 mL, 1.29 mmol) followed by T.sub.3P (0.26 mL, 0.86 mmol, 50 wt. % in EtOAc) were added and stirred overnight at RT. Completion of the reaction was monitored by TLC. Then the reaction mixture was diluted with DCM (20 mL). The organic layer was washed with water (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash column chromatography (Biotage Isolera, eluent: 10% methanol in DCM) to afford the title compound. Yield: 21% (0.09 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.23 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.39-3.33 (m, 5H), 3.13 (t, J=8.4 Hz, 2H), 2.40-2.33 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.3 min, 96.2% (Max). HPLC: (Method A) Rt. 2.3 min, 98.1% (Max).

Example 5: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone

(115) ##STR00130##

(116) To the stirred solution of example 2 (0.35 g, 1.07 mmol) in DMF (5 mL), NaH (60%) (0.08 g, 2.14 mmol) was added at 0° C. and stirred for 15 min. Then methyl iodide (0.13 mL, 2.14 mmol) was added and the reaction mixture was stirred overnight at RT. After completion of the reaction (monitored by TLC), the mixture was quenched with ice cold water (5 mL) and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash column chromatography (Biotage Isolera, gradient: 2-5% methanol in DCM) to afford the tittle compound. Yield: 4% (0.01 g, yellow gummy oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (s, 1H), 7.61 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.4 Hz, 2H), 3.83 (s, 3H), 3.55-3.44 (m, 4H), 3.38-3.34 (m, 1H), 3.14 (t, J=8.8 Hz, 2H), 2.41-2.39 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 341.2 (M+H), Rt. 2.1 min, 96.9% (Max). HPLC: (Method A) Rt. 2.1 min, 96.6% (Max).

Example 6: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1-(2-methoxyethyl)-1H-pyrazol-4-yl)methanone

(117) ##STR00131##

(118) To a stirred solution of example 2 (500 mg, 1.53 mmol) in MeCN (15 mL), 1-bromo-2-methoxyethane (253 mg, 1.84 mmol) followed by K.sub.2CO.sub.3 (634 mg, 4.60 mmol) were added and refluxed overnight at 70° C. Completion of the reaction was monitored by TLC. Then the reaction mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 2-5% methanol in DCM) to afford the title compound. Yield: 29% (168.91 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (s, 1H), 7.64 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.26 (t, J=5.6 Hz, 2H), 3.68 (t, J=5.2 Hz, 2H), 3.60-3.56 (m, 4H), 3.38-3.35 (m, 1H), 3.22 (s, 3H), 3.14 (t, J=8.4 Hz, 2H), 2.41-2.38 (m, 2H), 2.34-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 385.2 (M+H), Rt. 2.2 min, 96.2% (Max). HPLC: (Method A), Rt. 2.3 min, 97.2% (Max).

Example 7: (4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1H-indazol-6-yl)methanone

(119) ##STR00132##

(120) To the stirred solution of intermediate 1 (0.2 g, 0.86 mmol) and 1H-indazole-6-carboxylic acid (0.16 g, 1.03 mmol, Combi-blocks) in DCM (5 mL), TEA (0.18 mL, 1.29 mmol) followed by T.sub.3P (0.8 mL, 1.29 mmol, 50% wt. solution in EtOAc) were added at 0° C. and stirred overnight at RT. Completion of the reaction was monitored by TLC and the reaction mixture was then diluted with DCM (20 mL). The organic layer was washed with water (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude material was purified by flash column chromatography (Biotage Isolera, gradient: 5% methanol in DCM) to afford the tittle compound. Yield: 9% (0.04 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.19 (s, 1H), 8.11 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.49 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.07-7.05 (m, 1H), 6.74 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.39-3.37 (m, 5H), 3.15-3.13 (m, 2H), 2.40-2.33 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.5 min, 95.5% (Max). HPLC: (Method A) Rt. 2.5 min, 93.9% (Max).

Example 8: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(quinolin-6-yl)methanone

(121) ##STR00133##

Step 1: Quinoline-6-carboxylic Acid

(122) ##STR00134##

(123) To a stirred solution of methyl quinoline-6-carboxylate (1 g, 5.3 mmol) in 1, 4-dioxane (9 mL), water (1 mL) and methanol (0.5 mL) were added and cooled to 0° C., then NaOH (0.43 g, 10.6 mmol) was added and the reaction mixture was stirred at RT overnight. After completion of the reaction (monitored by TLC), the mixture was concentrated and the resulting mixture was neutralised with 1.5 N HCl. The obtained solid was filtered, washed with pet ether (10 mL) and dried under vacuum to afford the title compound. Yield: 87% (0.8 g, white solid).

(124) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.28 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.69 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 8.22 (t, J=7.2 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.65-7.64 (m, 1H). LCMS: (Method B) 174.0 (M+H), Rt. 1.4 min, 99.4% (Max).

Step 2: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(quinolin-6-yl)methanone

(125) ##STR00135##

(126) To a mixture of Intermediate 1 (0.2 g, 0.86 mmol) and quinoline-6-carboxylic acid (0.22 g, 1.30 mmol) in DCM (2 mL) at 0° C., TEA (0.36 mL, 2.6 mmol) and T.sub.3P (0.4 g, 1.30 mmol, 50% wt. solution in EtOAc) were added and the reaction mixture was stirred at RT overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO.sub.3 (5 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 2-4% methanol in DCM) to afford the title compound. Yield: 15% (50 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.96 (d, J=2.8 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 8.04 (d, J=3.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.61-7.60 (m, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.69-3.63 (m, 2H), 3.41-3.39 (m, 3H), 3.14 (t, J=8.4 Hz, 2H), 2.44-2.34 (m, 4H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 388.3 (M+H), Rt. 2.0 min, 96.9% (Max). HPLC: (Method A) Rt. 2.0 min, 97.4% (Max).

Example 9: (4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone

(127) ##STR00136##

(128) To a stirred solution of intermediate 3 (300 mg, 1.21 mmol) in DMF (6.0 mL, 20 V), TEA (0.5 mL, 3.63 mmol), T.sub.3P (1.15 mL, 1.81 mmol, 50% in EtOAc) and 1-methyl-1H-pyrazole-4-carboxylic acid (230 mg, 1.81 mmol) were added and stirred at RT overnight. 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 (2×100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 1-2% methanol in EtOAc) to afford the title compound. Yield: 21% (30 mg, pale yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 8.01 (d, J=3.6 Hz, 2H), 7.61 (s, 1H), 7.49 (d, J=9.2 Hz, 1H), 3.82 (s, 3H), 3.67 (d, J=6.8 Hz, 1H), 3.58-3.55 (m s, 4H), 2.51-2.34 (m, 4H), 1.40 (d, J=6.8 Hz, 3H). LCMS: (Method A) 356.1 (M+H), Rt. 2.0 min, 98.3% (Max). HPLC: (Method A) Rt. 1.9 min, 98.7% (Max).

Example 10: (1-methyl-1H-pyrazol-4-yl)(4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)methanone

(129) ##STR00137##

(130) To a stirred solution of intermediate 5 (0.3 g, 1.15 mmol) in DCM (3 mL), 1-methyl-1H-pyrazole-4-carboxylic acid (0.22 g, 1.72 mmol), TEA (0.64 mL, 4.60 mmol) and T.sub.3P (0.73 g, 2.30 mmol, 50% in EtOAc) were added at 0° C. and stirred overnight at RT. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO.sub.3 (5 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 3-4% methanol in DCM) to afford the title compound. Yield: 33% (145 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.00 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 3.82 (s, 3H), 3.62-3.60 (m, 1H), 3.60-3.55 (m, 4H), 2.78 (s, 3H), 2.44-2.43 (m, 4H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.1 min, 97.4% (Max). HPLC: (Method A) Rt. 2.2 min, 98.7% (Max).

Example 11: (4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(1H-pyrazol-3-yl)methanone

(131) ##STR00138##

(132) To a stirred solution of intermediate 1 (250 mg, 1.08 mmol) in DMF (3 mL), 1H-pyrazole-3-carboxylic acid (115 mg, 1.03 mmol) followed by HATU (0.65 g, 0.86 mmol) and TEA (0.2 mL, 4.1 mmol) were added and stirred overnight at RT. After completion of the reaction (monitored by TLC), the mixture was evaporated under vacuum and the resulting crude was dissolved in EtOAc (25 mL). The organic layer was washed with brine solution (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 2-5% methanol in DCM) to afford the title compound. Yield: 20% (120 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.12 (s, 1H), 7.77 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 6.51 (s, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.84 (s, 2H), 3.42 (s, 2H), 3.38 (s, 1H), 3.15 (s, 2H), 2.67 (s, 2H), 2.50 (s, 2H), 1.27 (s, 3H). LCMS: (Method A) 327.2 (M+H), Rt. 2.1 min, 94.4% (Max). HPLC: (Method A) Rt. 2.0, 95.3% (Max).

Example 12: (4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(pyridin-3-yl)methanone

(133) ##STR00139##

(134) To a stirred solution of intermediate 1 (350 mg, 1.50 mmol) in DMF (5 mL), nicotinic acid (222 mg, 1.81 mmol) followed by HATU (859 mg, 2.26 mmol) and TEA (0.87 mL, 6.03 mmol) were added at 0° C. and stirred overnight at RT. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (25 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by prep. HPLC (Method A) to afford the title compound. Yield: 27% (133.41 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.63-8.56 (m, 2H), 7.80-7.77 (m, 1H), 7.47-7.43 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.75-6.70 (m, 2H), 4.49 (t, J=8.8 Hz, 2H), 3.40-3.35 (m, 5H), 3.12 (t, J=8.8 Hz, 2H), 2.40-2.28 (m, 4H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 338.3 (M+H), Rt. 1.8 min, 99.3% (Max). HPLC: (Method A) Rt. 1.8 min. 99.5% (Max).

Example 13: (4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)(6-methylpyridin-3-yl)methanone

(135) ##STR00140##

(136) To a stirred solution of intermediate 3 (300 mg, 1.21 mmol) in DMF (6.0 mL, 20 V), TEA (0.5 mL, 3.63 mmol), T.sub.3P (1.15 mL, 1.81 mmol, 50% in EtOAc) and 6-methylnicotinic acid (250 mg, 1.81 mmol) were added and stirred overnight at RT. 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 (2×100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 1-2% methanol in EtOAc) to afford the title compound. Yield: 21% (30 mg, pale yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (d, J=2.8 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.12 (dd, J=8.2, 2.8 Hz, 1H), 8.01 (s, 1H), 7.69-7.67 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 3.69-3.68 (m, 3H), 3.36-3.34 (m, 5H), 2.52-2.50 (m, 4H), 1.39 (d, J=4.0 Hz, 3H). LCMS: (Method A) 367.1 (M+H), Rt. 1.8 min, 98.8% (Max). HPLC: (Method A) Rt. 1.7 min, 98.8% (Max).

Example 14: (4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)(pyridin-2-yl)methanone

(137) ##STR00141##

(138) To a stirred solution of intermediate 1 (350 mg, 1.50 mmol) in DMF (5 mL), picolinic acid (220 mg, 1.81 mmol) followed by HATU (900 mg, 2.37 mmol) and TEA (0.87 mL, 6.03 mmol) were added at 0° C. and stirred overnight at RT. Completion of the reaction was monitored by TLC and then the reaction mixture was evaporated under vacuum. To the resulting mixture, water (25 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 10% methanol in DCM) to afford the title compound. Yield: 9% (43.69 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.56-8.54 (m, 1H), 7.92-7.87 (m, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.47-7.43 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.74-6.69 (m, 2H), 4.50 (t, J=8.8 Hz, 2H), 3.64-3.56 (m, 2H), 3.41-3.35 (m, 3H), 3.13 (t, J=8.8 Hz, 2H), 2.41-2.32 (m, 3H), 2.29-2.24 (m, 1H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 338.3 (M+H), Rt. 2.2 min, 96.8% (Max). HPLC: (Method A) Rt. 2.2 min, 97.4% (Max).

Example 15: pyridin-2-yl(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)methanone

(139) ##STR00142##

(140) To a stirred solution of intermediate 4 (0.3 g, 1.07 mmol) in DMF (3 mL), TEA (0.45 mL, 3.23 mmol), picolinic acid (0.198 g, 1.62 mmol) and T.sub.3P (0.96 mL, 3.23 mmol, 50% in EtOAc) were added at 0° C. and stirred overnight at RT. Completion of the reaction was monitored by TLC, and then the reaction mixture was evaporated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 8% methanol in DCM) to afford the title compound. Yield: 32% (0.12 g, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=5.6 Hz, 2H), 8.55 (d, J=4.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (q, J=4.4 Hz, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.45 (q, J=4.8 Hz, 1H), 3.81 (d, J=6.8 Hz, 1H), 3.65-3.64 (m, 4H), 2.51-2.54 (m, 2H), 2.35 (t, J=5.2 Hz, 2H), 1.43 (d, J=6.4 Hz, 3H). LCMS: (Method A) 348.3 (M+H), Rt. 1.6 min, 99.5% (Max). HPLC: (Method A) Rt 1.7 min, 99.4% (Max).

Example 17: 4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)-N-(3-(trifluoromethyl)-1H-pyrazol-5-yl)piperazine-1-carboxamide

(141) ##STR00143##

(142) To a stirred solution of intermediate 1 (0.3 g, 1.3 mmol) in DCM (2.5 mL), pyridine (0.26 mL, 3.23 mmol) and triphosgene (0.15 g, 0.52 mmol) in DCM (1 mL) were added at 0° C. and stirred at RT for 2 h. Meanwhile a stirred solution of 3-(trifluoromethyl)-1H-pyrazol-5-amine (0.2 g, 1.3 mmol) in DCM and DIPEA (0.56 mL, 3.23 mmol) was prepared at 0° C. and was added to the above reaction mixture and stirred at RT overnight. After completion of the reaction (monitored by TLC), the mixture was then diluted with DCM (5 mL), poured into sat. NaHCO.sub.3 (5 mL) and stirred for 10 min. The organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 35-40% EtOAc in pet ether) and the obtained material was further purified by prep-HPLC (Method B) to afford the title compound. Yield: 8% (43 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.16 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.71 (s, 1H), 6.25 (s, 2H), 5.64 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.59-3.54 (m, 4H), 3.42-3.40 (m, 1H), 3.14 (t, J=8.8 Hz, 2H), 2.47-2.45 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 410.2 (M+H), Rt. 3.4 min, 99.5% (Max). HPLC: (Method A) Rt. 3.4 min, 99.7% (Max).

Example 18: 4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-N-(tetrahydrofuran-3-yl)piperazine-1-carboxamide

(143) ##STR00144##

(144) To a stirred solution of intermediate 1 (0.21 g, 0.9 mmol) and TEA (0.37 mL, 2.7 mmol) in dry DCM (5 mL) at 0° C., triphosgene (0.268 g, 0.90 mmol) was added and stirred for 2 h at RT. Completion of the reaction was monitored by TLC. The reaction mixture was then poured into water (10 mL) and stirred for 10 min. The organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude mixture was dissolved in dry DCM (10 mL), then TEA (0.37 mL, 2.7 mmol) followed by tetrahydrofuran-3-amine (0.12 g, 1.35 mmol) were added at 0° C. under nitrogen atm and stirred for 4 h at RT. Completion of the reaction was monitored by TLC. The mixture was poured into sat. NaHCO.sub.3 (10 mL) and the resulting mixture was stirred for 10 min. The organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 7% methanol in DCM) to afford the title compound. Yield: 10% (31.34 mg, white solid). H NMR (400 MHz, DMSO-d.sub.6): δ 7.13 (d, J=7.6 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.68 (s, 1H), 6.38 (d, J=5.6 Hz, 1H), 4.49 (t, J=8.4 Hz, 2H), 4.12-4.05 (m, 1H), 3.79-3.70 (m, 2H), 3.63-3.57 (m, 1H), 3.40-3.30 (m, 1H), 3.27-3.20 (m, 4H), 3.12 (t, J=8.4 Hz, 2H), 2.33-2.25 (m, 3H), 2.21-2.17 (m, 2H), 2.05-1.95 (m, 1H), 1.79-1.68 (m, 1H), 1.2 (d, J=6.4 Hz, 3H). LCMS: (Method A) 346.3 (M+H), Rt. 2.0 min, 96.3% (Max). HPLC: (Method A) Rt. 2.1 min, 96.3% (Max).

Example 19: 4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-N-phenylpiperazine-1-carboxamide

(145) ##STR00145##

(146) To a stirred solution of intermediate 6 (0.3 g, 1.11 mmol) in chloroform (1.5 mL), DIPEA (0.28 mL, 1.67 mmol) and phenyl isocyanate (0.17 g, 1.11 mmol) were added slowly at 0° C. and the mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the mixture was quenched with water and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 2-4% methanol in DCM) to afford the title compound. Yield: 58% (152.12 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.44 (s, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.22-7.18 (m, 2H), 6.93-6.89 (m, 2H), 6.88-6.86 (m, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (s, 2H), 3.40-3.36 (m, 5H), 2.39-2.29 (m, 4H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A) 354.2 (M+H), Rt. 2.8 min, 97.9% (Max). HPLC: (Method A) Rt. 2.8 min, 98.7% (Max).

Example 20: 4-(1-(benzo[d][1, 3]dioxol-5-yl)ethyl)-N-(4-chlorophenyl)piperazine-1-carboxamide

(147) ##STR00146##

(148) To a stirred solution of intermediate 6 (0.3 g, 1.11 mmol) in chloroform (1.5 mL), DIPEA (0.28 mL, 1.67 mmol) and 4-chloro phenyl isocyanate (0.17 g, 1.11 mmol) were added slowly at 0° C. and stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 2-4% methanol in DCM) to afford the title compound. Yield: 16% (60.14 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.59 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 6.88 (s, 1H), 6.85 (d, J=8.8 Hz, 1H) 6.75 (d, J=8.8 Hz, 1H) 5.98 (s, 2H), 3.40-3.41 (m, 5H), 2.37-2.30 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 3.4 min, 94.9% (Max), 92.1% (254 nm). HPLC: (Method A) Rt. 3.3 min, 94.7% (Max), 91.0% (254 nm).

Example 21: N-(4-cyanobenzyl)-1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidine-4-carboxamide

(149) ##STR00147##

(150) To the stirred solution of intermediate 7 (0.3 g, 1.04 mmol) and 4-(aminomethyl)benzonitrile (0.26 g, 1.24 mmol) in toluene (10 mL), DABAL (0.53 g, 2.07 mmol) was added portion wise at 0° C. for 10 min and the reaction mixture was heated at 90° C. overnight. After completion of the reaction (monitored by TLC), the mixture was quenched with ice water (25 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine solution (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated at 40° C. under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 4-5% methanol in DCM), then the obtained material was further purified by Prep-HPLC (Method B) to afford the title compound. Yield: 44% (180 mg, off-white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.37 (s, 1H), 7.79 (t, J=2.0 Hz, 2H), 7.40 (t, J=1.2 Hz, 2H), 7.14 (s, 1H), 6.75-6.69 (m, 2H), 4.52-4.49 (m, 2H), 4.32 (s, 2H), 3.15-3.14 (m, 2H), 2.98-2.96 (m, 1H), 2.78-2.75 (m, 1H), 2.15-1.04 (m, 1H), 1.92-1.50 (m, 7H), 1.24 (d, J=4.8 Hz, 3H). LCMS: (Method A) 390.2 (M+H), Rt. 2.8 min, 98.8% (Max). HPLC: (Method A) Rt. 2.9 min, 99.2% (Max).

Example 22: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-N-(4-(methylsulfonyl)benzyl)piperidine-4-carboxamide

(151) ##STR00148##

(152) To the stirred solution of intermediate 7 (0.35 g, 1.21 mmol) and (4-(methylsulfonyl)phenyl)methanamine (0.26 g, 1.45 mmol) in toluene (10 mL), DABAL (0.62 mg, 2.42 mmol) was added portion wise at 0° C. and heated at 90° C. overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (25 mL) and the aqueous part was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine solution (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated at 40° C. under reduced pressure. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 4-5% methanol in DCM), then the obtained material was further purified by Prep-HPLC (Method B) to afford the title compound. Yield: 27% (320 mg, off-white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.39 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.15 (d, J=5.2 Hz, 1H), 6.72 (d, J=18.0 Hz, 2H), 4.53-4.49 (m, 2H), 4.34 (d, J=5.6 Hz, 2H), 3.35-3.35 (m, 1H), 3.19-3.12 (m, 5H), 3.15-2.91 (m, 1H), 2.85-2.72 (m, 1H), 2.22-2.13 (m, 1H), 1.91-1.55 (m, 6H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 443.2 (M+H), Rt. 2.5 min, 94.8% (Max). HPLC: (Method A) Rt. 2.5 min, 94.8% (Max).

Example 23: 1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)-N-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide

(153) ##STR00149##

(154) To the stirred solution of intermediate 7 (0.35 g, 1.21 mmol) and (4-(trifluoromethyl)phenyl)methanamine (0.26 g, 1.45 mmol) in toluene (10 mL), DABAL (0.62 mg, 2.42 mmol) was added portion wise at 0° C. for 10 min and the reaction mixture was stirred overnight at 90° C. After completion of the reaction (monitored by TLC), the mixture was quenched with ice water (25 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine solution (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated at 40° C. under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 4-5% methanol in DCM), then the obtained material was further purified by Prep-HPLC (Method B) to afford the title compound. Yield: 26% (310 mg, off-white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.34 (t, J=5.6 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=7.6 Hz, 2H), 7.13 (d, J=7.2 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 4.52-4.48 (m, 2H), 4.32 (d, J=6.0 Hz, 2H), 3.34-3.31 (m, 1H), 3.13 (t, J=17.6 Hz, 2H), 2.98-2.95 (m, 1H), 2.77-2.75 (m, 1H), 2.12-2.06 (m, 1H), 1.92-1.86 (m, 1H), 1.82-1.76 (m, 1H), 1.72-1.69 (m, 1H), 1.64-1.62 (m, 2H), 1.56-1.50 (m, 1H), 1.20 (d, J=6.4 Hz, 3H). LCMS: (Method A) 433.2 (M+H), Rt. 3.7 min, 97.5% (Max). HPLC: (Method A) Rt. 3.7 min, 97.3% (Max).

Example 24: N-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)pyridin-3-amine

(155) ##STR00150##

Step 1: tert-butyl 4-(pyridin-3-ylamino)piperidine-1-carboxylate

(156) ##STR00151##

(157) To a stirred solution of 3-aminopyridine (2.0 g, 21.2 mmol) in dry DCM (50 mL), N-Boc-pyridone (5.08 mL, 25.4 mmol) and sodium triacetoxy borohydride (STAB) (9.0 g, 44.2 mmol) were added at RT and the reaction mixture was refluxed overnight at 50° C. Completion of reaction was monitored by TLC and the mixture was then concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 50% EtOAc in pet ether) to afford the title compound. Yield: 80% (4.7 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98 (s, 1H), 7.74 (s, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 5.74 (d, J=8.4 Hz, 1H), 4.70 (d, J=4.0 Hz, 1H), 3.89-3.33 (m, 8H), 1.39 (d, J=6.8 Hz, 9H). LCMS: (Method A) 278.0 (M+H), Rt. 2.1 min, 95.9% (Max).

Step 2: N-(piperidin-4-yl)pyridin-3-amine Dihydrochloride

(158) ##STR00152##

(159) To a stirred solution of tert-butyl 4-(pyridin-3-ylamino) piperidine-1-carboxylate (2.3 g, 8.29 mmol) in 1, 4-dioxane (23 mL, 10 V), HCl solution in dioxane (10.0 mL, 4M) was added at 0° C. dropwise over 10 min and the reaction mixture was continued at RT for 6 h. Completion of the reaction was confirmed by TLC and then the mixture was concentrated under vacuum. The resulting crude material was triturated with EtOAc to afford the title compound. Yield: 94% (1.7 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (s, 1H), 8.01 (d, J=4.4 Hz, 1H), 7.76-7.69 (m, 2H), 7.50 (s, 1H), 3.29 (bs, 1H), 3.13-2.94 (m, 5H), 2.06-1.08 (m, 4H). LCMS: (Method A) 178.0 (M+H), Rt. 2.6 min, 89.2% (Max).

Step 3: N-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)pyridin-3-amine

(160) ##STR00153##

(161) To a stirred solution of 6-(1-chloroethyl)-2, 3-dihydrobenzofuran (synthesis described in intermediate 1, steps 1 to 5) (0.75 g, 4.1 mmol) in DMF (2.5 mL), TEA (2.3 mL, 16.4 mmol) and N-(piperidin-4-yl)pyridin-3-amine dihydrochloride (1.13 g, 4.5 mmol) were added at RT and heated overnight at 70° C. After completion of reaction (monitored by TLC), the mixture was concentrated under vacuum and resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 4-8% methanol in DCM). The obtained material was further purified by prep-HPLC (Method B) to afford the title compound. Yield: 5% (20.0 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.93 (d, J=2.8 Hz, 1H), 7.14 (d, J=6.8 Hz, 1H), 7.02 (d, J=4.4 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 5.66 (d, J=6.8 Hz, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.35 (d, J=6.8 Hz, 1H), 3.14 (t, J=8.8 Hz, 4H), 2.90-2.88 (m, 1H), 2.72-2.67 (m, 1H), 2.04-1.82 (m, 4H), 1.38-1.25 (m, 5H). LCMS: (Method A) 324.0 (M+H), Rt. 1.9 min, 97.8% (Max). HPLC: (Method A) Rt. 1.9 min, 98.2% (Max).

Example 25: N-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

(162) ##STR00154##

(163) To a stirred solution of intermediate 9 (150 mg, 0.60 mmol) in MeCN (15 mL), 2-(4-(methylsulfonyl)phenyl)acetic acid (156 mg, 0.73 mmol) and TEA (0.25 mL, 1.82 mmol) followed by T.sub.3P (0.29 mL, 0.91 mmol) were added and stirred overnight at RT. Completion of the reaction was monitored by TLC and then the mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×20 mL).

(164) The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 3% methanol in DCM) then the obtained material was further purified by prep.HPLC (Method A) to afford the title compound. Yield: 7% (17 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.08 (s, 1H), 7.81 (d, J=6.8 Hz, 2H), 7.48 (d, J=6.8 Hz, 2H), 7.13 (d, J=6.0, 1H), 6.72-6.68 (m, 2H), 4.49 (t, J=8.4 Hz, 2H), 3.50 (s, 3H), 3.42-3.41 (m, 1H), 3.18-3.10 (m, 7H), 2.32-1.67 (m, 3H), 1.33-1.23 (m, 5H). LCMS: (Method A) 443.2 (M+H), Rt. 3.6 min, 95.9% (Max). HPLC: (Method A), Rt. 3.6 min, 97.4% (Max).

Example 26: 2-(4-cyanophenyl)-N-(1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)acetamide

(165) ##STR00155##

(166) To a stirred solution of intermediate 9 (200 mg, 0.81 mmol) in THE (20 mL), 2-(4-cyanophenyl) acetic acid (157 mg, 0.97 mmol), TEA (0.35 mL, 2.43 mmol) followed by T.sub.3P (0.38 mL, 1.21 mmol) were added and stirred overnight at RT. Completion of the reaction was monitored by TLC and then the mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 4% methanol in DCM), then the obtained material was further purified by prep-HPLC (Method A) to afford the title compound. Yield: 3% (9.48 mg, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.06 (d, J=6.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.48 (s, 2H), 3.48-3.47 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.99-2.85 (m, 1H), 2.35-2.33 (m, 2H), 1.97-1.91 (m, 2H), 1.71-1.64 (m, 2H), 1.40-1.30 (m, 2H), 1.2 (d, J=6.4 Hz, 3H). LCMS: (Method A) 390.2 (M+H), Rt. 2.8 min, 98.5% (Max). HPLC: (Method A), Rt. 2.8 min, 98.5% (Max).

Example 27: N-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

(167) ##STR00156##

(168) To a stirred solution of intermediate 9 (200 mg, 0.81 mmol) in THE (20 mL), 2-(4-(trifluoromethyl)phenyl)acetic acid (199 mg, 0.97 mmol), TEA (0.35 mL, 2.43 mmol) followed by T.sub.3P (0.38 mL, 1.21 mmol) were added and stirred overnight at RT. Completion of the reaction was monitored by TLC, then the reaction mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 4% methanol in DCM) to afford the title compound. Yield: 15% (50 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.06 (d, J=7.6 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.13 (d, J=7.2 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.49 (s, 2H), 3.44-3.42 (m, 1H), 3.34-3.32 (m, 1H), 3.13 (t, J=8.40 Hz, 2H), 2.88-2.86 (m, 1H), 2.68-2.66 (m, 1H), 1.98-1.85 (m, 2H), 1.74-1.64 (m, 2H), 1.43-1.38 (m, 2H), 1.3 (d, J=6.4 Hz, 3H). LCMS: (Method A) 433.2 (M+H), Rt. 3.6 min, 95.9% (Max). HPLC: (Method A), Rt. 3.6 min, 97.4% (Max).

Examples 28 and 39: (S)-3-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyridine and (R)-3-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyridine

(169) ##STR00157##

(170) To a stirred solution of intermediate 10 (200 mg, 1.12 mmol) in MeCN (15 mL), 6-(1-chloroethyl)-2,3-dihydrobenzofuran (245 mg, 1.34 mmol, synthesis described in intermediate 1, steps 1 to 5) and TEA (0.34 mL, 3.36 mmol) were added and the reaction mixture was heated overnight at 60° C. Completion of the reaction was monitored by TLC and then the mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 3% methanol in DCM), then the obtained material was further purified by prep-HPLC (Method A) to afford the title compound. The enantiomers of this racemic compound was separated by SFC, mobile phase: 20 mM ammonia in IPA, column: Lux A1 (Method C), the first and second eluting fractions were concentrated to afford the title compound.

(171) Analysis of first eluting fraction (example 28): Yield: 3% (7.94 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.24 (d, J=2.4 Hz, 1H), 8.12 (d, J=4.4 Hz, 1H), 7.40-7.37 (m, 1H), 7.30-7.26 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 4.40-4.36 (m, 1H), 3.44-3.39 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.77-2.74 (m, 1H), 2.67-2.65 (m, 1H), 2.19-2.13 (m, 2H), 1.93-1.76 (m, 2H), 1.64-1.55 (m, 2H), 1.30 (d, J=6.4 Hz, 3H). LCMS: (Method A) 325.2 (M+H), Rt. 1.8 min, 93.8% (Max). HPLC: (Method A), Rt. 1.9 min, 94.2% (Max). Chiral SFC: (Method C) Rt. 6.7 min, 98.8% (Max).

(172) Analysis of second eluting fraction (example 39): Yield: 2% (6.76 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.24 (d, J=2.4 Hz, 1H), 8.12 (d, J=3.6 Hz, 1H), 7.40-7.37 (m, 1H), 7.30-7.26 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 4.40-4.36 (m, 1H), 3.44-3.33 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.77-2.68 (m, 1H), 2.67-2.65 (m, 1H), 2.19-2.13 (m, 2H), 1.92-1.90 (m, 2H), 1.62-1.55 (m, 2H), 1.30 (d, J=6.4 Hz, 3H). LCMS: (Method A) 325.3 (M+H), Rt. 1.8 min, 97.4% (Max). HPLC: (Method A), Rt. 1.9 min, 98.3% (Max). Chiral SFC: (Method C) Rt. 7.5 min, 100% (Max).

Example 29: 4-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)-2-methoxypyridine

(173) ##STR00158##

Step 1: tert-butyl 4-((2-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate

(174) ##STR00159##

(175) A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.967 mmol), TPP (1.62 g, 5.934 mmol), 2-methoxypyridin-4-ol (0.74 g, 5.915 mmol) and DTAD (1.67 g, 5.943 mmol) in THE (10 mL) were stirred overnight at RT. Completion of the reaction was monitored by TLC. Then, the reaction mixture was diluted with water (20 mL) and stirred for 15 min at RT. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was washed with water (20 mL), brine (20 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound. Yield: 73% (1.1 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.96 (d, J=5.6 Hz, 1H), 6.62-6.60 (m, 1H), 6.39 (d, J=2.0 Hz, 1H), 4.69-4.66 (m, 1H), 3.81 (s, 3H), 3.69-3.63 (m, 2H), 3.19-3.14 (m, 2H), 1.99-1.95 (m, 2H), 1.93-1.91 (m, 2H), 1.56-1.39 (m, 9H). LCMS: (Method A) 309.0 (M+H), Rt 2.2 min, 99.8% (Max).

Step 2: 2-methoxy-3-(piperidin-4-yloxy)pyridine Hydrochloride

(176) ##STR00160##

(177) To a stirred solution of tert-butyl 4-((2-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate (1 g, 3.25 mmol) in 1, 4 dioxane (10 mL), HCl solution in dioxane (5 mL, 4M) was added dropwise at 0° C. and stirred for 2 h at RT. Completion of the reaction was monitored by TLC. The reaction mixture was then evaporated under vacuum to afford the title compound. Yield: 89% (0.7 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.12 (d, J=6.4 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.71 (d, J=Hz, 1H), 4.94-4.92 (m, 1H), 4.93 (t, J=7.2 Hz, 2H), 3.94 (s, 3H), 3.21 (m, 2H), 3.09-3.06 (m, 2H), 2.18-2.13 (m, 2H), 1.94-1.87 (m, 2H).

Step 3: 3-((1-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperidin-4-yl)oxy)-2-methoxypyridine

(178) ##STR00161##

(179) To a stirred solution of 2-methoxy-3-(piperidin-4-yloxy)pyridine hydrochloride (0.7 g, 3.35 mmol), TEA (1.4 mL, 10 mmol) in MeCN (7 mL), 6-(1-chloroethyl)-2,3-dihydrobenzofuran (0.73 g, 4.02 mmol, synthesis described in intermediate 1, steps 1 to 5) was added slowly under nitrogen atmosphere at RT and heated overnight at 60° C. After completion of the reaction (monitored by LCMS), the reaction mixture was cooled to RT, diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (10 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated at 45° C. under vacuum. The resulting crude material was purified by flash chromatography (Biotage Islera, eluent: 1-2% methanol in DCM) to afford the title compound. Yield: 7% (75 mg, gummy oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (d, J=6.0 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 6.57 (d, J=8.0 Hz, 1H), 6.30 (d, J=2.0 Hz, 1H), 4.52-4.48 (m, 2H), 4.44-4.40 (m, 1H), 3.79 (s, 3H), 3.41-3.39 (m, 1H), 3.15-3.11 (m, 2H), 2.75-2.73 (m, 1H), 2.63-2.61 (m, 1H), 2.20-2.16 (m, 2H), 1.91-1.87 (m, 2H), 1.62-1.53 (m, 2H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A) 355.2 (M+H), Rt. 1.8 min, 97.7% (Max). HPLC: (Method A) Rt. 2.0 min, 99.3% (Max).

Example 30: 2-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)-5-(methylsulfonyl)pyridine

(180) ##STR00162##

Step 1: 2-choro-5-(methylthio) pyridine

(181) ##STR00163##

(182) To a stirred solution of tert-butyl nitrite (2.78 g, 23.62 mmol) and 1, 2-dimethyldisulfane (2.78 g, 31.24 mmol) in dry DCM (40 mL), 2-chloro-5-(amino)pyridine (2 g, 15.62 mmol) was added portion wise at 0° C. for 40 min and the reaction mixture was stirred at RT overnight. Completion of the reaction was monitored by TLC. The mixture was then concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 20-30% EtOAc in hexane) to afford the title compound. Yield: 76% (1.8 g, yellow liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.25 (d, J=4.0 Hz, 1H), 7.25-7.26 (m, 1H), 7.39-7.37 (m, 1H), 2.54 (s, 3H).

Step 2: 2-choro-5-(methylsulfonyl) pyridine

(183) ##STR00164##

(184) To a stirred solution of 2-chloro-5-(methylthio) pyridine (800 mg, 5.01 mmol) in dry DCM (20 mL), m-CPBA (2.5 g, 15.03 mmol) was added portion wise at −20° C. and the reaction mixture was stirred at same temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH.sub.4Cl solution and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isoera, eluent: 6-7% EtOAc in hexane) to afford the title compound. Yield: 70% (600 mg, off White solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.90 (d, J=4.0 Hz, 1H), 8.32-8.29 (m, 1H), 7.71-7.69 (m, 1H), 3.21 (s, 3H). LCMS: (Method A) 191.9 (M+H), Rt. 1.6 min, 96.2% (Max).

Step 3:2-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)-5-(methylsulfonyl)pyridine

(185) ##STR00165##

(186) To a stirred solution of intermediate 8 (120 mg, 0.48 m mol) in dry DMF (10 mL), NaH (60%) (29 mg, 4.86 mmol) was added at 0° C., then 2-chloro-5-(methylsulfonyl) pyridine was added and stirred for 1 h at RT. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 80-90% EtOAc in hexane) to afford the title compound. Yield: 30% (30 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.63 (d, J=4.0 Hz, 1H), 8.14-8.12 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.76 (d, J=4.0 Hz, 1H), 6.71 (s, 1H), 5.07-5.03 (m, 1H), 4.52-4.48 (m, 2H), 3.40 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.15-3.11 (m, 2H), 2.77 (s, 1H), 2.68-2.67 (m, 1H), 2.21-2.16 (m, 2H), 1.97 (s, 2H), 1.7 (d, J=8.0 Hz, 2H), 1.3 (s, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.8 min, 98.6%. HPLC: (Method A) Rt. 2.8 min, 98.9% (Max).

Example 31: (S)-5-(1-(4-(pyridin-3-yloxy)piperidin-1-yl)ethyl)benzo[d]thiazole or (R)-5-(1-(4-(pyridin-3-yloxy)piperidin-1-yl)ethyl)benzo[d]thiazole

(187) ##STR00166##

(188) To a stirred solution of intermediate 10 (277 mg, 1.68 mmol) in DMF (5 mL, 20 V), TEA (0.62 mL, 4.59 mmol) and 5-(1-chloroethyl) benzo[d]thiazole (300 mg, 1.53 mmol, synthesis described in intermediate 3, steps 1 to 3) were added and the reaction mixture was stirred overnight at 80° C. Completion of the reaction was monitored by TLC. The reaction mixture was cooled to RT and concentrated under vacuum. To the resulting mixture, water (30 mL) was added and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 7-8% methanol in DCM) then the obtained material was further purified by prep-HPLC (Method A) to afford the racemic compound. The two enantiomers were separated by SFC (Method B: mobile phase: 20 mM ammonia in methanol; column: Chiralpak IA). The first eluting fraction was concentrated to afford example 31. Yield: 18% (26 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.24 (d, J=2.8 Hz, 1H), 8.13-8.11 (m, 2H), 8.01 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.39-7.36 (m, 1H), 7.27 (dd, J=8.4, 4.8 Hz, 1H), 4.42-4.37 (m, 1H), 3.72 (q, J=6.8 Hz, 1H), 2.84-2.81 (m, 1H), 2.73-2.67 (m, 1H), 2.2 (t, J=9.2 Hz, 2H), 1.9 (s, 2H), 1.67-1.60 (m, 2H), 1.5 (d, J=6.4 Hz, 3H). LCMS: (Method A) 340.3 (M+H), Rt. 1.6 min, 99.1% (Max). HPLC: (Method A) Rt. 1.7 min, 98.9% (Max). Chiral SFC: (Method B) Rt. 5.8 min, 100% (Max).

(189) The second eluting fraction. Yield: 9% (13 mg, light brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.23 (s, 1H), 8.12-8.10 (m, 2H), 8.01 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.39-7.36 (m, 1H), 7.27 (dd, J=8.4, 4.8 Hz, 1H), 4.39-4.40 (m, 1H), 3.72 (q, J=6.8 Hz, 1H), 2.84-2.81 (m, 1H), 2.72-2.70 (m, 1H), 2.25 (t, J=9.2 Hz, 2H), 1.94 (br. s, 2H), 1.64-1.59 (m, 2H), 1.5 (d, J=6.4 Hz, 3H). LCMS: (Method A) 340.0 (M+H), Rt. 0.9 min, 99.6% (Max). HPLC: (Method A) Rt. 1.7 min, 98.5% (Max). Chiral SFC: (Method B) Rt. 6.9 min, 99.1% (Max).

Example 32: 3-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyridine

(190) ##STR00167##

(191) To a stirred solution of 6-(1-chloroethyl)-2,3-dihydrobenzofuran (0.75 g, 4.10 mmol, synthesis described in intermediate 1, steps 1 to 5) in DMF (2.5 mL), TEA (2.3 mL, 16.40 mmol) and intermediate 10 (1.1 g, 4.20 mmol) were added at RT and heated overnight at 70° C. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 4-8% methanol in DCM). The obtained material was further purified by prep-HPLC (Method B) and dried over anhydrous Na.sub.2SO.sub.4 to afford the title compound. Yield: 8% (55 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.25 (s, 1H), 8.12 (d, J=4.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.28 (q, J=4.4 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 4.50 (t, J=8.4 Hz, 2H), 4.38 (s, 1H), 3.40 (t, J=6.0 Hz, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.76 (s, 1H), 2.67-2.64 (m, 1H), 2.16 (d, J=7.60 Hz, 2H), 1.92 (s. 2H), 1.61-1.58 (m 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 325.2 (M+H), Rt. 1.9 min, 98.3% (Max). HPLC: (Method A) Rt. 1.7 min, 98.9% (Max).

Example 33: 6-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)nicotinonitrile

(192) ##STR00168##

(193) To a stirred solution of intermediate 8 (0.10 g, 0.41 mmol) in DMF (1 mL, 10 V), NaH (60%) (0.03 mg, 1.22 mmol) was added at 0° C. and stirred at RT for 30 min. Then 6-chloronicotinonitrile (0.14 g, 0.81 mmol) was added and the reaction mixture was stirred overnight at RT. Completion of the reaction was confirmed by TLC and the reaction mixture was concentrated under vacuum. To the resulting mixture, water (10 mL) was added and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 40-50% in EtOAc in hexane) to afford the title compound. Yield: 13% (18.4 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.66 (s, 1H), 8.12 (dd, J=8.8, 2.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.71 (s, 1H), 5.04-4.99 (m, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.42-3.38 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.80-2.70 (m, 1H) 2.68-2.64 (m, 1H), 2.20-2.10 (m, 2H), 2.00-1.90 (m, 2H), 1.70-1.60 (m, 2H), 1.29 (d, J=4.0 Hz, 3H). LCMS: (Method A) 350.2 (M+H), Rt. 3.1 min, 99.3% (Max). HPLC: (Method A) Rt. 3.1 min, 99.4% (Max).

Example 34: 5-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyrimidine

(194) ##STR00169##

Step 1: tert-butyl 4-((2-chloropyrimidin-5-yl)oxy)piperidine-1-carboxylate

(195) ##STR00170##

(196) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.5 g, 12.60 mmol) in THE (30 mL), 2-chloropyrimidin-5-ol (1.5 g, 11.4 mmol), TPP (7.4 g, 22.9 mmol) followed by di-tert-butyl azocarboxylate (DTAD, 5.2 g, 22.9 mmol) were added and the reaction mixture was stirred at RT overnight. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layer was washed with water (5 mL), brine solution (5 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 50% EtOAc in hexane) to afford the title compound. Yield: 48% (1.8 g, yellow solid). LCMS: (Method A) 258.2 (M-t-butyl), Rt. 4.5 min, 96.8% (Max).

Step 2: tert-butyl 4-(pyrimidin-5-yloxy)piperidine-1-carboxylate

(197) ##STR00171##

(198) To a stirred solution of tert-butyl 4-((2-chloropyrimidin-5-yl)oxy)piperidine-1-carboxylate (1 g, 3.19 mmol) in ethanol (30 mL), Zn dust (0.83 g, 12.7 mmol) followed by aqueous ammonia (5 mL) were added in a sealed tube and the reaction mixture was heated for 4 h at 80° C. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite bed and the filtrate was evaporated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 40-60% EtOAc in hexane) to afford the title compound. Yield: 79% (700 mg, yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.80 (s, 1H), 8.60 (s, 2H), 4.77-4.75 (m, 1H), 4.06-4.01 (m, 2H), 3.20-3.15 (m, 2H), 1.98-1.96 (m, 2H), 1.79-1.75 (m, 2H), 1.85 (s, 9H). LCMS: (Method A) 224.1 (M-t-butyl), Rt. 3.5 min, 87.1% (Max). HPLC: (Method A), Rt. 3.5 min, 80.3% (Max).

Step 3: 5-(piperidin-4-yloxy)pyrimidine

(199) ##STR00172##

(200) To a stirred solution of tert-butyl 4-(pyrimidin-5-yloxy)piperidine-1-carboxylate (700 mg, 2.5 mmol) in 1, 4-dioxane (20 mL) at 0° C., HCl solution in dioxane (0.6 mL, 2.54 mmol, 4M) was added and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under vacuum and the resulting crude material was triturated with EtOAc, hexane and diethyl ether to afford the title compound. Yield: 89% (400 mg, yellow solid). .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 9.15 (s, 1H), 9.04 (s, 2H), 5.06-5.02 (m, 1H), 3.68-3.67 (m, 1H), 3.49-3.44 (m, 2H), 3.32-3.27 (m, 2H), 2.31-2.29 (m, 2H), 2.19-2.15 (m 2H). LCMS: (Method A) 180.1 (M+H), Rt. 0.6 min. 81.9% (Max).

Step 4:5-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyrimidine

(201) ##STR00173##

(202) To a stirred solution of 5-(piperidin-4-yloxy)pyrimidine (400 mg, 2.2 mmol) in MeCN (5 mL), TEA (0.94 mL, 6.69 mmol) and 6-(1-chloroethyl)-2,3-dihydrobenzofuran (447 mg, 2.45 mmol, synthesis described in intermediate 1, steps 1 to 5) were added and the reaction mixture was heated overnight at 60° C. Completion of the reaction was monitored by TLC and the reaction mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, gradient: 3% methanol in DCM). The resulting material was further purified by prep-HPLC (Method A) to afford the title compound. Yield: 2% (15 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.77 (s, 1H), 8.54 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 1.00 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.53-4.48 (m, 3H), 3.45-3.33 (m, 1H), 3.13 (t, J=8.4 Hz, 2H), 2.78-2.75 (m, 1H), 2.68-2.66 (m, 1H), 2.20-2.16 (m, 2H), 1.96-1.95 (m, 2H), 1.64-1.57 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 326.3 (M+H), Rt. 2.2 min, 96.3% (Max). HPLC: (Method A), Rt. 2.3 min, 98.2% (Max).

Example 35: 3-(((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)methyl)pyridine

(203) ##STR00174##

(204) To a stirred solution of intermediate 8 (100 mg, 0.04 mmol) in dry DMF (10 mL) at 0° C., NaH (60%) (18 mg, 0.81 mmol) was added and stirred for 15 min. Then 3-(chloromethyl) pyridine (0.24 g, 0.02 mmol) was added and the reaction mixture was stirred overnight at RT. After completion the reaction (monitored by TLC), the mixture was quenched with ice cold water and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 40% EtOAc in pet ether) to afford the title compound. Yield: 19% (25 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.52-8.48 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.14 (s, 1H), 6.72 (m, 2H), 4.53-4.49 (m, 4H), 3.16-3.12 (m, 2H), 2.74-2.67 (m, 1H), 2.10-1.92 (m, 2H), 1.91-1.71 (m, 2H), 1.48-1.43 (m, 2H), 1.28-1.15 (m, 4H). LCMS: (Method A) 339.2 (M+H), Rt. 1.9 min, 93.1% (Max). HPLC: (Method A) Rt. 1.9 min, 93.4% (Max).

Example 36: 2-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)-5-(methylsulfonyl)pyrimidine

(205) ##STR00175##

Step 1: 2-choro-5-(methylthio)pyrimidine

(206) ##STR00176##

(207) To a stirred solution of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol) and 1, 2-dimethyldisulfane (2.92 g, 31.02 mmol) in THE (15 mL), n-BuLi (16.0 mL, 25.8 mmol, 1.6 M in hexane) was added at −78° C. and stirred for 1 h under the same temperature. After completion of the reaction (monitored by TLC), the mixture was quenched with the addition of sat.NH.sub.4Cl (15 mL) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with water (10 mL), brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. The resulting crude material was purified by flash chromatography (silica gel: 60-120 mesh, eluent: 15% EtOAc in pet ether) to afford the title compound. Yield: 13% (0.6 g, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.50 (s, 2H), 2.56 (s, 3H). LCMS: (Method A) 161.1 (M+H), Rt. 2.1 min, 95.2% (Max). HPLC: (Method A) Rt. 2.4 min, 98.5% (Max).

Step 2: 2-choro-5-(methylsulfonyl)pyrimidine

(208) ##STR00177##

(209) To a stirred solution of 2-chloro-5-(methylthio)pyrimidine (600 mg, 3.75 mmol) in DCM (30 mL) at 0° C., m-CPBA (1.94 g, 11.3 mmol) was added and the reaction mixture was stirred at RT for 3 h. Completion of the reaction was monitored by TLC and the reaction mixture was then evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 25% EtOAc in hexane). Yield: 85% (612 mg, yellow gummy oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.25 (s, 2H), 3.43 (s, 3H). HPLC: (Method A), Rt. 1.4 min, 93.3% (Max).

Step 3: 2-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)-5-(methylsulfonyl)pyrimidine

(210) ##STR00178##

(211) To a stirred solution of intermediate 8 (300 mg, 1.21 mmol) in DMF (10 mL) at 0° C., NaH (60%) (38 mg, 2.42 mmol) was added and stirred for 20 min, then 2-chloro-5-(methylsulfonyl)pyrimidine (257 mg, 1.33 mmol) was added to the reaction mixture and stirred at 70° C. overnight. Completion of the reaction was monitored by TLC and the mixture was then evaporated under vacuum. To the resulting mixture, water (5 mL) was added and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 100% EtOAc) to afford the title compound. Yield: 3% (8.74 mg, brown gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.01 (s, 2H), 7.14 (d, J=6.8 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 5.05 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.43-3.41 (m, 1H), 3.20 (s, 3H), 3.17-3.11 (m, 2H), 2.70-2.63 (m, 2H), 2.33-2.23 (m, 2H), 1.99-1.97 (m, 2H), 1.71-1.65 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 404.2 (M+H), Rt. 2.5 min, 97.2% (Max). HPLC: (Method A), Rt. 2.6 min, 97.1% (Max).

Example 37: 2-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyrimidine

(212) ##STR00179##

(213) To a stirred solution of intermediate 8 (0.25 g, 1.01 mmol) in DMF (10 mL), NaH (60%) (0.08 g, 2.02 mmol) was added at 0° C. and stirred at RT for 1 h, then 2-chloro pyrimidine (0.23 g, 2.02 mmol) was added and the reaction mixture was heated overnight at 60° C. 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 (2×15 mL). The combined organic layer was washed with water (5 mL), brine solution (5 mL), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 85% EtOAc in pet ether) to afford the title compound. Yield: 14% (46 mg, pale yellow gummy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (d, J=4.7 Hz, 2H), 7.15 (d, J=7.0 Hz, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.85-4.80 (m, 1H), 4.51 (t, J=8.7 Hz, 2H), 3.50-3.40 (m, 1H), 3.14 (t, J=8.7 Hz, 2H), 2.80-2.60 (m, 2H), 2.30-2.20 (m, 2H), 2.00-1.90 (m, 2H), 1.80-1.60 (m, 2H), 1.27 (d, J=6.12 Hz, 3H). LCMS: (Method A) 326.2 (M+H), Rt. 2.4 min, 98.4% (Max). HPLC: (Method A) Rt. 2.4 min, 99.1% (Max).

Example 38: 3-((1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyridazine

(214) ##STR00180##

Step 1: tert-butyl 4-(pyridazin-3-yloxy)piperidine-1-carboxylate

(215) ##STR00181##

(216) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 0.05 mmol) and pyridazin-3(2H)-one (0.62 g, 0.01 mmol) in dry THE (20 mL), triphenylphosphine (TPP, 1.6 g, 0.01 mmol) followed by di-tert-butyl azocarboxylate (DTAD, 1.7 g, 0.01 mmol) were added at 0° C. and stirred at RT overnight. After completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum and the resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 20-30% EtOAc in pet ether) to afford the title compound. Yield: 39% (0.5 g, white solid). LCMS: (Method A) 180.0 (M-Boc), Rt. 2.3 min, 4.4% (Max).

Step 2: 3-(piperidin-4-yloxy)pyridazine

(217) ##STR00182##

(218) To a stirred solution of tert-butyl 4-(pyridazin-3-yloxy)piperidine-1-carboxylate (0.5 g, 0.002 mmol) in dry DCM (5 mL) at 0° C., HCl solution in dioxane (5 mL, 4M) was added and the reaction mixture was stirred at RT overnight. After completion of the reaction (monitored by TLC), the mixture was concentrated. The resulting crude material was triturated with diethyl ether (10 mL) and dried under vacuum to afford the title compound. Yield: 94% (0.3 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.00-7.99 (m, 2H), 7.44-7.40 (m, 1H), 6.96 (dd, J=9.4, 2.0 Hz, 1H), 5.10-5.05 (m, 1H), 3.37-3.32 (m, 2H), 3.15-3.06 (m, 2H), 2.15-2.05 (m, 2H), 1.92-1.90 (m, 2H). LCMS: (Method A) 180.0 (M+H), Rt. 0.6 min, 82.2% (Max).

Step 3: 3-((1-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl)oxy)pyridazine

(219) ##STR00183##

(220) To a stirred solution of 3-(piperidin-4-yloxy)pyridazine (0.2 g, 0.001 mol) in dry DMF (10 mL) at 0° C., TEA (0.7 mL, 0.006 mol) and 6-(1-chloroethyl)-2,3-dihydrobenzofuran (0.24 g, 0.0013 mol, synthesis described in intermediate 1, steps 1 to 5) were added and stirred at RT overnight. Completion of the reaction was monitored by TLC, then the reaction mixture was concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 40% EtOAc in pet ether) to afford the title compound. Yield: 9% (30 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.96-7.95 (m, 1H), 7.38 (dd, J=9.4, 4.0 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.91 (dd, J=9.2, 1.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.71-4.66 (m, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.43-3.35 (m, 1H), 3.16-3.06 (m, 3H), 2.87 (d, J=11.2 Hz, 1H), 2.09-2.03 (m, 1H), 1.99-1.80 (m, 3H), 1.79-1.74 (m, 1H), 1.72-1.67 (m, 1H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 326.2 (M+H), Rt. 2.2 min, 99.3% (Max).

Example B01: Human O-GlcNAcase Enzyme Inhibition Assay

(221) 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 (λ.sub.exc 485 nm; (λ.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)

(222) 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. 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.

(223) Total Protein O-GlcNAcylation Immunoassay:

(224) 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

(225) (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.

(226) (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.

(227) (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.Math.2 H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.Math.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.

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

(229) (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.

(230) (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.

(231) (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.

(232) (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.

(233) (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

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

(235) Methods

Preparation of DMSO Stock Solution

(236) 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.

(237) Sample Preparation Procedure:

(238) 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.

(239) Chromatographic Conditions:

(240) LC-MS/MS: API 4000 LC-MS/MS

(241) Software: Analyst Version 1.6.1

(242) Column Phenomenex Synergy 30*4.6*5μ

(243) Column Oven: 40° C.

(244) Mode: ESI Positive

(245) Injection volume: 5 μl

(246) Flow Rate: 1000 μL/mL

(247) Buffer: 0.1% Formic acid in Water

(248) Method: Isocratic Method/Gradient

(249) Composition: A) 0.1% Formic acid in Water B) 0.1% Formic acid in Methanol

(250) TABLE-US-00002 Mobile Mobile Time (Sec) Flow (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

(251) Results Calculation

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

(253) $\%\mathrm{fraction}\mathrm{unbound}=\frac{\mathrm{Drug}\mathrm{concentration}\mathrm{in}\mathrm{buffer}\mathrm{after}5\mathrm{hours}}{\mathrm{Drug}\mathrm{concentration}\mathrm{in}\mathrm{plasma}\mathrm{after}5\mathrm{hours}}\times 100$

(254) 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

(255) 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:

(256) Materials CD-1 Mice liver microsomes, pooled male (Life Technologies, Cat No. MSMC-PL) (20 mg/ml) SD Rat liver microsomes, pooled male (Life Technologies, Cat No. RTMCL-PL) (20 mg/ml) Human liver microsomes, pooled mixed gender (Life Technologies, Cat No. HMMC-PL) (20 mg/ml) NADPH (SRL Mumbai, Cat No. 99197) Verapamil (Sigma, Cat No. V4629) Atenolol (Sigma, Cat No. A7655) Tolbutamide (Sigma Cat. No. T0891) Assay buffer: 50 mM potassium phosphate buffer, pH 7.4 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.

(257) Methods

(258) Preparation of Working Solutions of Test and Reference Compounds:

(259) 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%.

(260) Metabolic Stability Assay

(261) 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.

(262) 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.

(263) 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).

(264) 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.

(265) LC-MS/MS Conditions (Generic Method)

(266) TABLE-US-00003 LC-MS/MS: API Sciex 4000 with Nexera  ™ UHPLC Software: Analyst Version 1.6.1 Column: Phenomenex kinetex C18 50 × 3.0 mm, 2.6 μ Column Oven : 40° C. Mode : ESI Positive Injection volume: 5 μl Flow Rate: 1000 μL/mL Buffer: 0.1% Formic acid in Water

(267) Method: Isocratic Method/Gradient

(268) Composition: A) 0.1% Formic acid in Water B) 0.1% Formic acid in Methanol

(269) TABLE-US-00004 Mobile Mobile Time (Sec) Flow (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

(270) Results Calculation

(271) 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:

(272) $C{L}_{\mathrm{int}}=\frac{0.693}{\mathrm{In}\mathrm{vitro}{t}_{1/2}}X\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}}}$

(273) Where K.sub.el is Elimination Constant (slope)

(274) 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.

(275) If chemical bonds in the structures above are drawn as follows: or

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

(277) This is exemplified below, wherein the structure

(278) ##STR00184##

(279) is representing only one of the two possible enantiomers,

(280) ##STR00185##

(281) i.e. a single individual chemical structure as opposed to a mixture of enantiomers.